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2022 Volume 16 • 2021

www.USCjournal.com www.VERjournal.com www.ICRjournal.com Editor-in-Chief Bill Gogas, MD, PhD, FACC Nanjing University, Jiangsu, China

Section Editors Interventional Cardiology Research M Chadi Alraies, MD, FACC

Preventive Cardiology Aditya Khetan, MD

Heart Failure Andrew J Sauer, MD

Detroit Medical Center, Detroit, MI

Case Western Reserve University, Cleveland, OH

University of Kansas Medical Center, Kansas City, KS

Electrophysiology Sourbha S Dani, MD, FACC

Cardiovascular Disease in Women Anastasia S Mihailidou, FAHA, FCSANZ

Heart Failure Amin Yehya, MD, MS, FACC, FHFSA

Eastern Maine Medical Center, Bangor, ME

Royal North Shore Hospital, Sydney, Australia

Sentara Heart, Norfolk, VA

Acute Coronary Syndromes Farshad Forouzandeh, MD, PhD, FACC, FSCAI Case Western Reserve University, Cleveland, OH

Imaging Akhil Narang, MD, FACC Northwestern University, Chicago, IL

Structural Heart Interventions Prasad Gunasekaran, MD, FACC, FSCAI

Interventional/Structural Rishi Puri, MD, PhD, FRACP

Mercy Heart Hospital, Springfield, MO

Cleveland Clinic, Cleveland, OH

Associate Editors Misbahul Ferdous, MBBS, FMD, MMed, PhD

Chad A Kliger, MD

Rajalakshmi Santhanakrishnan, MD, MBBS

Fuwai Hospital, Beijing, China

Lenox Hill Heart and Vascular Institute, New York, NY

Sahil Khera, MD, MPH, FACC

Yogesh Reddy, MD, MSc

Bruce Stambler, MD

Mayo Clinic, Rochester, MN

Piedmont Healthcare, Atlanta, GA

Columbia University, New York, NY

Wright State University, Dayton, OH

Statistical Editor Juan Luis Gutiérrez-Chico, MD, PhD, FESC, FACC Cardio Care Cardiovascular Heart Centre Marbella, Marbella, Spain

Editorial Board Mirvat Alasnag, MD, FSCAI

Michael R Gold, MD, PhD, FHRS

Danielle Belardo, MD

Martha Gulati, MD, MSM FACC, FAHA, FASPC, FESC

King Fahd Armed Forces Hospital, Jeddah, Saudi Arabia Institute of Plant Based Medicine, Los Angeles, CA

Ralph G Brindis, MD, MPH, MACC, FSCAI, FAHA

University of California, San Francisco, CA

Robert Chait, MD, FACC, FACP JFK Medical Center, Atlantis, FL

Nita Ray Chaudhuri, MD, FACC

JW Ruby Memorial Hospital, Morgantown, WV

NA Mark Estes III, MD

Medical University of South Carolina, Charleston, SC

University of Arizona College of Medicine, Tucson, AZ

Thomas A Haffey, DO, FACCM FACOI, FNLA

Western University of Health Sciences, Pomona, CA

Ankur Kalra, MD, FACP, FACC, FSCAI Case Western Reserve University School of Medicine, Cleveland, OH

Dinesh K Kalra, MD, FACC, FSCCT, FSCMR

Tufts University School of Medicine, Boston, MA

Rush University Medical Center, Chicago, IL

Alexandra Frogoudaki, MD, PhD, FHFA, FESC

University of California at Irvine, Orange, CA

Attikon University Hospital, Athens University, Athens, Greece

Bernard J Gersh, MB, ChB, DPhil, FACC, FRCP Mayo Clinic, Minnesota, US

Morton J Kern, MD

Jackson J Liang, MD, DO

Erin D Michos, MD, MHS

Johns Hopkins University School of Medicine, Baltimore, MD

Ki Park, MD, MS, FSCAI

University of Florida and Malcom Randall VA Medical Center, Gainsville, FL

Duane Pinto, MD, MPH Harvard Medical School, Boston, MA

Krishna Pothineni, MD

University of Arkansas for Medical Sciences, Little Rock, AR

Rahul Sharma, MD, MBBS, FACP, FACC, FSCAI

Virginia Tech Carilion School of Medicine, Roanoke, VA

Isabella Tan, MD, MBBS, MBA, AM, FRACP, FACP, FACC, FCSANZ Macquarie University, Sydney, Australia

Poonam Velagapudi, MD, MS, FACC, FSCAI

University of Michigan, Ann Arbor, MI

University of Nebraska, Omaha, NE

Sara C Martinez, MD, PhD

W Douglas Weaver, MD, FACC, FESC

Mayo Clinic, Rochester, MN

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Contents Vulnerable Plaque in Patients with Acute Coronary Syndrome: Identification, Importance, and Management

Atsushi Sakamoto, MD, Anne Cornelissen, MD, Yu Sato, MD, Masayuki Mori, MD, Rika Kawakami, MD, Kenji Kawai, MD, Saikat Kumar B Ghosh, PhD, Weili Xu, MD, Biniyam G Abebe, MD, Armelle Dikongue, MS, Frank D Kolodgie, PhD, Renu Virmani, MD, and Aloke V Finn, MD https://doi.org/10.15420/usc.2021.22

Robotic Percutaneous Coronary Intervention: The Good, the Bad, and What is to Come Laura Young and Jaikirshan Khatri https://doi.org/10.15420/usc.2020.28R1

Cardiogenic Shock Management and Research: Past, Present, and Future Outlook

Sascha Ott, MD, Laura Leser, MD, Pia Lanmüller, MD, Isabell A Just, MD, David Leistner, MD, Evgenij Potapov, MD, Benjamin O’Brien, MD, and Jan Klages, MD https://doi.org/10.15420/usc.2021.25

Dual Antiplatelet Regimens for Transcatheter Aortic Valve Replacement and Corresponding Cardiac CT Evaluation of the Leaflets: Single-center Experience

Mirvat Alasnag, MD, FACC, FACP, FSCAI, FSCCT, Waqar Ahmed, MD, FACC, FACP, FSCAI, Ibrahim Al-Nasser, and Khaled Al-Shaibi, MD, FACC, FACP, FSCAI https://doi.org/10.15420/usc.2021.07

Hemodynamic-based Assessment and Management of Cardiogenic Shock

Jaime Hernandez-Montfort, MD, MPH, MSc, Diana Miranda, MD, Varinder Kaur Randhawa, MD, PhD, Jose Sleiman, MD, Yelenis Seijo de Armas, MD, Antonio Lewis, MD, Ziad Taimeh, MD, Paulino Alvarez, MD, Paul Cremer, MD, MPH, Bernardo Perez-Villa, MD, MSc, Viviana Navas, MD, Emad Hakemi, MD, MSc, Mauricio Velez, MD, Luis Hernandez-Mejia, MD, Cedric Sheffield, MD, Nicolas Brozzi, MD, Robert Cubeddu, MD, Jose Navia, MD, and Jerry D Estep, MD https://doi.org/10.15420/usc.2021.12

Advocacy and Legislation for Regionalization Practices in the Treatment of Cardiogenic Shock: The Time Is Now Kari Gorder, MD, Steve Rudick, MD, and Timothy D Smith, MD https://doi.org/10.15420/usc.2021.14

Redo-Transcatheter Aortic Valve Replacement: Strategies When the First Transcatheter Aortic Valve Replacement Fails Nils Perrin, MD, MSc, and Anita W Asgar, MD, MSc https://doi.org/10.15420/usc.2021.18

Echocardiography in the Evaluation of the Right Heart Angelos Tsipis, MD, and Evdokia Petropoulou, MD https://doi.org/10.15420/usc.2021.03

Valve-in-valve Transcatheter Aortic Valve Replacement for Failed Surgical Valves and Adjunctive Therapies Emily Perdoncin, MD, Gaetano Paone, MD, and Isida Byku, MD https://doi.org/10.15420/usc.2021.20

Transcatheter Aortic Valve Replacement Optimization Strategies: Cusp Overlap, Commissural Alignment, Sizing, and Positioning Saima Siddique, MD, Resha Khanal, MD, Amit N Vora, MD, MPH, and Hemal Gada, MD, MBA https://doi.org/10.15420/usc.2021.24

Role of Coronary CT Angiography in the Evaluation of Acute Chest Pain and Suspected or Confirmed Acute Coronary Syndrome Tasveer Khawaja, MD, Scott Janus, MD, and Sadeer G Al-Kindi, MD https://doi.org/10.15420/usc.2021.30

Contemporary Review of Hemodynamic Monitoring in the Critical Care Setting

Aniket S Rali, MD, Amy Butcher, PA-C, Ryan J Tedford, MD, Shashank S Sinha, MD, MSc, Pakinam Mekki, MD, Harriette GC Van Spall, MD, and Andrew J Sauer, MD https://doi.org/10.15420/usc.2021.34

The Final Word: Current Strategies for the Lifetime Management of Patients with Aortic Valve Stenosis Anne H Tavenier, MD, Johny Nicolas, MD, MSc, and Roxana Mehran, MD https://doi.org/10.15420/usc.2022.07

Age Considerations in the Invasive Management of Acute Coronary Syndromes

Mansi Oberoi, MD, Nitesh Ainani, MD, J Dawn Abbott, MD, Mamas A Mamas, MBBCh, and Poonam Velagapudi, MD https://doi.org/10.15420/usc.2021.29

© RADCLIFFE CARDIOLOGY 2022 Access at: www.USCjournal.com

REVIEW

Acute Coronary Syndrome

Vulnerable Plaque in Patients with Acute Coronary Syndrome: Identification, Importance, and Management Atsushi Sakamoto, MD, ,1 Anne Cornelissen, MD, ,1 Yu Sato, MD, ,1 Masayuki Mori, MD, ,1 Rika Kawakami, MD, ,1 Kenji Kawai, MD, ,1 Saikat Kumar B Ghosh, PhD,1 Weili Xu, MD,1 Biniyam G Abebe, MD, ,1 Armelle Dikongue, MS,1 Frank D Kolodgie, PhD, ,1 Renu Virmani, MD, ,1 and Aloke V Finn, MD, 1,2 1. CVPath Institute, Gaithersburg, MD; 2. University of Maryland, School of Medicine, Baltimore, MD

Abstract

MI is a leading cause of morbidity and mortality worldwide. Coronary artery thrombosis is the final pathologic feature of the most cases of acute MI primarily caused by atherosclerotic coronary artery disease. The concept of vulnerable plaque has evolved over the years but originated from early pioneering work unveiling the crucial role of plaque rupture and subsequent coronary thrombosis as the dominant cause of MI. Along with systemic cardiovascular risk factors, developments of intravascular and non-invasive imaging modalities have allowed us to identify coronary plaques thought to be at high risk for rupture. However, morphological features alone may only be one of many factors which promote plaque progression. The current vulnerable-plaque-oriented approaches to accomplish personalized risk assessment and treatment have significant room for improvement. In this review, the authors discuss recent advances in the understanding of vulnerable plaque and its management strategy from pathology and clinical perspectives.

Keywords

Vulnerable plaque, acute coronary syndrome, plaque rupture, thin-cap fibroatheroma Disclosure: AC receives research grants from University Hospital RWTH Aachen. RV has received honoraria from Abbott Vascular, Biosensors, Boston Scientific, Celonova, Cook Medical, Cordis, CSI, Lutonix Bard, Medtronic, OrbusNeich Medical, CeloNova, SINOMED, ReCore, Terumo, WL Gore, and Spectranetics, and is a consultant for Abbott Vascular, Boston Scientific, Celonova, Cook Medical, Cordis, CSI, Edwards Lifesciences, Lutonix Bard, Medtronic, OrbusNeich Medical, ReCore, Sinomededical Technology, Spectranetics, Surmodics, Terumo Corporation, WL Gore, and Xeltis. AVF has received honoraria from Abbott Vascular, Biosensors, Boston Scientific, Celonova, Cook Medical, CSI, Lutonix Bard, Sinomed, and Terumo, and is a consultant for Amgen, Abbott Vascular, Boston Scientific, Celonova, Cook Medical, Lutonix Bard, and Sinomed. CVPath Institute has received institutional research support from R01 HL141425 Leducq Foundation Grant, 480 Biomedical, 4C Medical, 4Tech, Abbott, Accumedical, Amgen, Biosensors, Boston Scientific, Cardiac Implants, Celonova, Claret Medical, Concept Medical, Cook, CSI, DuNing, Inc, Edwards LifeSciences, Emboline, Endotronix, Envision Scientific, Lutonix/Bard, Gateway, Lifetech, Limflo, MedAlliance, Medtronic, Mercator, Merill, Microport Medical, Microvention, Mitraalign, Mitra assist, NAMSA, Nanova, Neovasc, NIPRO, Novogate, Occulotech, OrbusNeich Medical, Phenox, Profusa, Protembis, Qool, Recor, Senseonics, Shockwave, SINOMED, Spectranetics, Surmodics, Symic, Vesper, WL Gore, and Xeltis. All other authors have no conflicts of interest to declare.

Funding: This study was sponsored by CVPath Institute.

Received: July 7, 2021 Accepted: October 7, 2021 Citation: US Cardiology Review 2022;16:e01. DOI: https://doi.org/10.15420/usc.2021.22 Correspondence: Aloke V Finn, CVPath Institute, 19 Firstfield Rd, Gaithersburg, MD 20878. E: afinn@cvpath.org Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

MI was once considered a major health concern in industrialized nations, but is now seen routinely worldwide including in developing countries, which bear the greatest burden of cardiovascular disease.1 Coronary artery thrombosis is the final pathologic finding in most cases of MI and is mainly caused by atherosclerotic coronary artery disease (CAD).2 Our understanding of ‘vulnerable plaques’, defined as rupture-prone (or event-prone) plaques, has advanced dramatically in the last two decades, along with its recognition and subsequent treatment. This has been the result of advancements in basic and clinical investigations along with the development of imaging techniques and treatment technologies.

However, at the same time, the results of vulnerable-plaque-oriented approaches to accomplish personalized risk assessment, stratification and treatment have room for significant improvement. In this review, we discuss the recent advancements in our understanding of vulnerable plaque and its management strategies from pathology to clinical management.

Plaque Phenotype as a Cause of Coronary Thrombosis

Prior autopsy studies have recognized three distinct morphologic entities leading to coronary thrombosis: plaque rupture (PR), plaque erosion (PE), and calcified nodules (CN; Figures 1A–1C).3 Our autopsy series of more than 800 people who died suddenly because of coronary artery thrombosis revealed that 55–60% of cases had underlying PR, 30–35% of the etiology was PE, and in 2–7% it was because of CN.2 A worldwide review of 22 autopsy studies, including 1,847 cases of hospital-based acute MI and sudden coronary death, also showed that 73% of fatal coronary thrombi originated from PR and 27% from PE.4

Plaque Rupture

PR refers to an advanced atheromatous lesion consisting of necrotic core with an overlying ruptured thin fibrous cap. ‘Rupture’ represents a structural defect in the fibrous cap that separates the highly thrombotic

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Vulnerable Plaque and Acute Coronary Syndrome Figure 1: Pathology and Intra-coronary Imaging (OCT) of Human Coronary Artery Morphologies Associated With ACS Plaque rupture

Plaque erosion

A

paradigm is largely based on the mechanisms and morphologic characteristics thought to promote PR.

Plaque Erosion

Calcified nodule

B

C Ca

Ca

Th

Th

Th

NC

LP 1mm

Ca 1mm

Thin-cap fibroatheroma

Intra-plaque hemorrhage

D

E

1mm Nodular calcification F Ca

Ca NC

NC+IPH Ca 1mm

1mm

OCT-Erosion

Plaque rupture G

1mm

H

OCT-Calcified nodule I

Thin-cap fibroatheroma K

J

The second common cause of intracoronary thrombosis is PE, which is defined as intracoronary thrombosis without evidence of fibrous cap rupture but that may include a necrotic core.3 As pathologic studies have revealed, the denudated endothelial layer is usually observed in the culprit site of PE.3 Exposure of underlying proteoglycans and collagen could be the nidus for thrombus formation. Generally, the underlying plaque phenotype is fibroatheroma with a thick fibrous cap or pathologic intimal thickening. Recent innovation of in vivo intra-coronary imaging modalities, such as optical coherence tomography (OCT), has allowed us to understand the underlying etiology of acute coronary syndromes (ACS) in the clinical setting.12 OCT studies of clinically determined ACS cases suggested the prevalence of PE is 27–31%.13,14 According to pathology and OCT studies, individuals of younger age (i.e. <50 years), female sex, and smokers are more likely to develop PE compared to PR.13,15,16 Moreover, traditional risk factors (e.g. diabetes, hypertension, hyperlipidemia, and chronic kidney disease) are less common in PE than PR.17,18 Local disturbed blood flow, toll-like receptor-2 activation in endothelial cells, endothelial apoptosis, concentrated extracellular matrix (e.g. hyaluronan and versican) in the subendothelial intimal layer, granulocyte rich inflammatory response, and neutrophil extracellular trap formation are considered to be underlying mechanisms of PE.19 However, the precursor lesion to thrombotic PE is still unclear, and the exact series of events that predispose to PE are unknown. Therefore, at present, the concept of vulnerable plaque pertaining to PE has not been developed and requires further investigation.

Calcified Nodule

K

Pathologic (A–F) and OCT-based classification (G–K) of human coronary artery associated with ACS. A: plaque rupture; B: plaque erosion with underlying pathologic intimal thickening; C: calcified nodule; D: thin-cap fibroatheroma (black arrowhead shows thin fibrous cap); E: intra-plaque hemorrhage; F: nodular calcification; G: OCT-plaque rupture (white arrow shows disrupted thin fibrous cap); H; OCT-erosion (white arrow shows white thrombus); I: OCT-calcified nodule (white arrow shows overlying superficial calcification with red thrombus); J–K: thin-cap fibroatheroma. J shows low-power image. K is high-power magnification of the rectangular area in J. The white arrow head in J shows low backscattering, signal-poor region with diffuse border, suggesting large necrotic core. The double-head white arrow in K shows thin fibrous cap.

ACS = acute coronary syndrome; Ca = calcification; IPH = intra-plaque hemorrhage; LP = lipid pool; NC = necrotic core; OCT = optical coherence tomography; Th = thrombus. Source: Panels G, H, J and K: Otsuka et al. 2014.12 Adapted with permission from Springer Nature. Panel I: Jia et al.

2013.13 Adapted with permission from Elsevier.

necrotic core contents from the bloodstream.5 It has been considered that the site of rupture is usually located at its mechanically weakest point, often near the shoulder regions.6 However, this is not always the case, as we have observed a comparable number of ruptures at the mid portion of the fibrous cap, especially in individuals who are dying during exertion.7 Therefore, it is reasonable that multiple processes can be involved in the mechanisms of fibrous cap rupture, e.g. fibrous cap degradation by matrix metalloproteinases released from inflammatory cells, great wall shear stress, and macrophage and smooth-muscle-cell apoptosis in the cap, as previously reported.8–10 The exposure to the blood of the lipid-rich necrotic core containing a large amount of prothrombotic tissue factor activates the coagulation cascade, resulting in the occlusion of the coronary artery by thrombus formation and subsequent MI.11 As will be discussed below, the vulnerable plaque

CN is a third common mechanism of intracoronary thrombosis, with a prevalence of 3.3% in our autopsy case series who died suddenly due to acute coronary thrombosis.3 OCT-based clinical studies suggest the prevalence of CN in ACS is 2–8%.13,20 Pathologically, CN is defined as a disrupted luminal surface by nodules of dense calcium with overlying thrombus and little or no underlying necrotic core in arteries that are highly calcified, tortuous, and often have large sheets of calcification.

Pathologic definitions of ‘eruptive calcified nodule’ (Figure 1C) and ‘nodular calcification’ (Figure 1F) need to be differentiated; the latter occurs within the plaque and does not involve disruption of the fibrous cap or contact with the lumen, but it is often associated with medial wall disruption with or without extension into the adventitia. The mechanism of fibrous cap disruption in CN causing overlying thrombosis is thought to be the fragmentation of necrotic core calcification by mechanical means.

Areas of CN are often sandwiched between proximal and distal hard sheet calcification (most frequent in the mid-right coronary artery or left anterior descending artery-sites of maximal torsion).3,21 These sites of nodular calcification serve as sites of hinge motion and repeated trauma is thought to encourage the creation of nodules of calcium that can protrude into the lumen causing thrombosis. However, in order to define the precursor lesion to CN, further clinical investigations with better resolution imaging modalities need to be conducted.

What is the Concept of Vulnerable Plaque?

Thin-cap Fibroatheroma as a Precursor Lesion of Plaque Rupture

In the 1980s, James Muller coined the term ‘vulnerable plaques’ as precursor lesions from which MIs frequently developed.22 The morphological criteria for the definition of thin-cap fibroatheroma (TCFA)

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Vulnerable Plaque and Acute Coronary Syndrome or vulnerable plaque originated from the concept that lesions that precede PR should have similar features (Figure 1D). Generally, ruptured plaques have large necrotic cores with ruptured thin fibrous caps accompanied by inflammatory cell infiltration including macrophages and – to a lesser extent – T lymphocytes, along with scant or a complete lack of smooth muscle cells. Our pathologic observation in cases of coronary PR revealed the thickness of the fibrous cap close to the rupture site was 23 ± 19 μm, with 95% of caps measuring <65 μm.23 Lesions with intact (non-ruptured) fibrous caps of <65 μm are also detected in non-culprit sites/vessels in patients dying of acute PR and are designated vulnerable plaques or TCFAs. In the year 2000, TCFA as the vulnerable plaque phenotype was first highlighted in a modified American Heart Association consensus described by Virmani et al.3 Subsequently, TCFA as the precursor lesion of PR became widely recognized; therefore, the original definition of vulnerable plaque is exclusively applicable to the PR paradigm.

Similar to PR, most TCFAs locate in the proximal segment of major coronary arteries.24 The pathologic features of TCFA are different from ruptured plaques in terms of smaller necrotic cores, less macrophage infiltration in the fibrous cap, and less calcification.25,26 Additionally, 70% of cases of sudden coronary death by acute PR commonly show evidence of TCFAs in non-culprit lesion or vessels.27 The frequency of TCFA was much smaller (around 30%) in people who died with flow-limiting severe coronary stenosis with stable fibrocalcific plaques. These findings imply that the presence of TCFA and rupture are not directly correlated (i.e. some TCFA may proceed to rupture while others do not).26 In addition, previous basic studies have revealed that inflammation, matrix metalloproteinases activity, and necrotic core expansion are all enhanced when TCFA is transforming into unstable plaques.8,28–32 However, precise triggers critical to the phenotypic transformation of TCFA plaques are still unclear.

Intra-Plaque Hemorrhage: Another Vulnerable Plaque Phenotype

Intra-plaque hemorrhage (IPH; Figure 1E) is considered one of the factors contributing to plaque destabilization and sudden increase in plaque volume.32,33 In 1987, Glagov reported that atherosclerotic coronary arteries undergo a progressive enlargement (i.e. positive remodeling) that allows preservation of the lumen area up to a point.34 Stenosis of the lumen only occurs once a plaque develops beyond 40% cross-sectional area (CSA) narrowing.34 Repeated subclinical PR and healing with luminal thrombus, as well as IPH (without luminal thrombus), are two major critical contributors for progressive plaque expansion until vessel occlusion and symptom onset.35 According to a large series of human plaques from cases of sudden coronary death, signs of previous IPH were frequently found in high-risk plaques prone to rupture compared to early lesion and stable plaques. Previously, our group showed the accumulation of erythrocyte membranes that contain a large amount of free cholesterol at the site of IPH contributes to the necrotic core expansion and further plaque vulnerability.36 Moreover, IPH is the essential trigger for macrophage phenotypic conversion into alternative subtypes distinct from lipid-laden foamy macrophages.37 IPH results in erythrocyte lysis through oxidative stress with release of free hemoglobin.38 Free hemoglobin immediately forms complexes with plasma haptoglobin, and macrophages internalize hemoglobin–haptoglobin complexes via the CD163 scavenger receptor for effective clearance.39,40 Recently, we reported that the mechanisms of CD163-positive alternative macrophages provoke micro angiogenesis and microvascular permeability by releasing vascular endothelial growth factor responding to hemoglobin–

haptoglobin stimuli.41 Thereby, small amounts of intimal angiogenesis and bleeding could be exacerbated by the inflammatory response, initiating a vicious cycle whereby bleeding begets more bleeding. Collectively, both components, including cholesterol-rich erythrocyte membrane and released hemoglobin at the site of IPH, may synergistically accelerate plaque vulnerability leading to further adverse cardiovascular complications.

Calcification in the Plaque: The Contradictory Role on Plaque Vulnerability

Calcification is one of the common features of advanced atherosclerotic lesions, which develops and progresses with plaque type and luminal narrowing.42 A robust amount of clinical data has confirmed that the degree of coronary artery calcification is directly related to adverse cardiovascular outcomes in all populations, and it is a more reliable marker for future events than using risk equations based upon traditional risk factors (e.g. Framingham risk index).43 However, whether the coronary calcified plaques directly cause cardiac events or are just a reliable surrogate marker for the presence of CAD burden on a population-based level remains uncertain. Indeed, whether the presence of coronary calcification predicts plaque instability or stability is a crucial question for daily practice. One cannot treat coronary artery calcification as an all-ornone variable.

The type of calcification, location, volume, as well as density may all affect clinical risk and outcomes in distinctive ways.44 A study conducted detailed pathologic analysis of calcification, which included 510 coronary segments (17 cases) from acute MI cases, as well as 450 segments (15 cases) from age-matched controls who died of non-cardiac causes.45 In patient-based analysis, calcification was more abundant in cases of acute MI versus controls. However, in lesion-based analysis, an inverse correlation was observed between the extension of calcification and cap inflammation.

Multivariate regression analysis confirmed that the calcification was not correlated with the presence of unstable plaques.45 Recent imagingbased human studies suggested that spotty calcification predicts plaque vulnerability in patients presenting with ACS, while large and heavy calcification correlates with overall plaque burden in the coronary tree.46 Spotty calcification with positive vessel remodeling and low attenuation, detected by coronary CT angiography (CCTA), was more frequent in patients with ACS or likely to develop ACS in the short term.47 This imagingbased spotty calcification (<3 mm diameter) is comparable with pathological fragmented calcification, which is frequently found in the outer rim of necrotic core (this should not be confused with microcalcification mentioned below).48 According to these pathologic observations, progressive calcification of human plaque occurs from the outer rim of the necrotic core into the surrounding collagenous matrix while the central core is preserved at this stage.48 When the calcification progresses into the central necrotic core, the calcification turns into sheets, a typical feature of stable calcified plaque. Therefore, in pathology, coronary calcium burden is greater in stable fibrocalcific plaques than unstable plaques including PR and TCFA and exhibit an opposite correlation with necrotic core area. Coronary calcium scoring might be helpful to detect the general risk of adverse coronary events in a population, i.e. suggesting the presence of coronary atherosclerotic plaque. However, it is not useful specifically to prospectively identify a culprit lesion of a future ACS. Regarding direct correlation between calcification and plaque vulnerability, Vengrenyuk et al. proposed the role of microcalcification in the cap as one of the contributors of fibrous cap rupture behaving as local

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Vulnerable Plaque and Acute Coronary Syndrome Figure 2: Characteristics of Invasive and Non-invasive Coronary Imaging Modalities to Detect High-risk Vulnerable Plaques Modality

CCTA

IVUS

IVUS-RF Analysis

OCT/OFDI

NIRS

Energy source

X-ray

Ultrasound (20–60 MHz)

Ultrasound (20–40 MHz)

Near-infrared light

Near-infrared light

Resolution

0.5–1 mm

100–200 µm

100–200 µm

10–15 µm

NA

Penetration

NA

8–10 mm

8–10 mm

2–3 mm

1–2 mm

Features of high-risk plaque

Eccentric pattern, outward remodeling, low attenuation plaque

by HU, spotty calcification, napkin ring sign

Eccentric pattern, outward remodeling, large plaque burden, large lipid core (echolucent core), spotty calcification

Plaque composition (fibrous, fibro -fatty, necrotic core, And calcification), large necrotic core (RF-IVUSderived TCFA)

Thin fibrous cap, macrophage infiltration, neovascularization, large lipid core, spotty calcification

High lipid contents (high LCBI)

Limitation

Radiation, contrast agent, limited spatial resolution

Invasiveness, limited spatial resolution

Invasiveness, limited spatial resolution,

Invasiveness, limited tissue penetration, need for flushing

Invasiveness, limited tissue penetration

CCTA = coronary CT angiography; HU = Hounsfield unit; IVUS = intravascular ultrasound; RF = radiofrequency; OCT = optical coherence tomography; OFDI = optical frequency domain imaging; NIRS = near-infrared spectroscopy; NA = not applicable; TCFA = thin-cap fibroatheroma; LCBI = lipid-core burden index. Source: Madder et al.83 Adapted with permission from Elsevier.

tissues stress concentrators.49,50 However, pathologically defined microcalcification (i.e. 0.5–15 µm diameter) requires extremely high spatial resolution to visualize and cannot be evaluated by current in-vivo clinical imaging.49–52 The detection of microcalcification in the fibrous cap could potentially be one of the predictors for vulnerable plaque. However, innovations in coronary imaging modalities are necessary to make them useful for this purpose.

Identification of Vulnerable Plaque

by Imaging Modalities

A comprehensive risk stratification with high accuracy for determining an individual’s cardiovascular risk is desired. The scoring tools based on traditional risk factors such as age, sex, smoking, blood pressure, diabetes, and cholesterol levels (e.g. Framingham risk score, the Systematic Coronary Risk Evaluation, and Atherosclerotic Cardiovascular Disease risk estimator) could successfully stratify cardiovascular risk in whole populations.43,53,54 However, their effectiveness is limited by variations in lifetime risk level of patients and/or discrepancies between different algorithms arising from varying risk factors evaluated. Thus, in general practice, the use of currently developed risk stratification algorithms is low because of their oversimplification and concerns with over prescribing of medications.55 Moreover, most cardiovascular events occur in patients classified as low or intermediate risk by traditional risk factors.56 Therefore, more reliable atherosclerotic lesion-based stratifications by coronary imaging modalities are still considered worthy of study by cardiovascular clinicians and researchers. The characteristics of imaging

modalities for high-risk coronary plaque detection and the summary of large clinical trials examining the effectiveness for these modalities are shown in Figure 2 and Table 1.57–69

Coronary CT Angiography

Substantial evidence suggests that coronary plaque burden is associated with the likelihood of future cardiovascular events. Coronary artery calcium score as assessed by CCTA has been shown to be predictive of coronary events in different ethnic populations independently of standard risk factors or scores.70 Further, an assessment of plaque vulnerability by CCTA is also thought to improve the diagnostic accuracy for patients with CAD. CCTA can provide reliable assessment in terms of the presence, size, and thickness of necrotic core, by grading tissue in Hounsfield units (HU).71 Currently accepted high-risk plaque characteristics by CCTA include positive remodeling (remodeling index ≥1.1), low-attenuation (a focal central area of plaque with an attenuation density of <30 HU), spotty calcification (<3 mm in maximum diameter), and napkin-ring sign (i.e. a central area of low-attenuation plaque with a peripheral rim of high attenuation). These high-risk features are robust markers of ruptureprone lesions supported by evidence gained from multiple clinical studies.

For instance, the recently reported SCOT-HEART trial, which included 1,769 cases with 5 years of follow-up, demonstrated that patients with adverse plaque characteristics (i.e. positive remodeling or low attenuation plaque) have a greater risk of coronary death or non-fatal MI.58 Moreover, a large-scale clinical CCTA study (3,158 patients) also indicated that the combination of high-risk plaque characteristics, significant stenosis, and plaque progression by serial examination allows for better prognostic values for future ACS events.59

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Pt who suspected or known CAD Japan underwent coronary CTA

Motoyama et al.59

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Pt with ACS underwent 3-vessel IVUS/RF-IVUS after culprit PCI

Pt with SAP or ACS underwent 3-vessel IVUS/RF-IVUS after culprit PCI

Pt with STEMI underwent IVUS/ RF-IVUS to non-culprit vessel after culprit PCI (with highintensity statin intervention)

Pt with STEMI underwent OCT to Europe non-culprit vessel after culprit PCI (with high-intensity statin intervention)

PROSPECT62

VIVA63

IBIS-4: IVUS64

IBIS-4: OCT65

Europe

UK

USA and Europe

Pt undergoing diagnostic CAG or the NL PCI for ACS or stable AP

Japan

Scotland

ATHEROREMOIVUS61

ODYSSEY J-IVUS60 Pt with ACS underwent IVUS/ RF-IVUS to non-culprit vessel after culprit PCI (RCT: with or without alicromab intervention)

Pt with stable chest pain underwent coronary CTA

SCOT-HEART58

USA

Pt with acute chest pain but without objective evidence of myocardial ischemia or MI

ROMICAT-II57

Country

Study Population

Trial

OCT

IVUS/ RF-IVUS

IVUS/ RF-IVUS

IVUS/ RF-IVUS

IVUS/ RF-IVUS

IVUS

CTA

CTA

CTA

Thin fibrous cap, macrophage infiltration

RF-IVUS derived TCFA

Non-calcified RF-IVUS derived TCFA

Large PB, small MLA, RF-IVUS derived TCFA

Large PB, small MLA, RF-IVUS derived TCFA

NA

HRP, positive remodeling and/ or low HU

Positive remodeling, low HU, napkin ring sign, spotty calcium

Positive remodeling, low HU, napkin ring sign, spotty calcium

Coronary Features of Imaging High-risk Modality Plaque by Imaging

100%

0.0%

0.0%

7.8%

41.2%

Pt = 82/NCV = 100% 153

Pt = 82/NCV = 100% 146

Pt = 170/NCL = 931

Pt = 623/NCL 100% = 2,709 (RF-IVUS analysis)

Pt = 581/NCV 54.7% = 581

Pt = 206

Pt = 449

Pt = 1,768

Pt = 472

ACS occurred in 48/294 (16.3%) of HRP (+) and 40/2,864 (1.4%) of HRP (−) patients.

MACE

MACE

13 months Change of plaque characteristics by statin therapy

Small MLA and large PB in NCV predict long term adverse CV outcome. RF-IVUS derived single isolated parameter could not be a better prognostic value.

Relatively greater percent reduction in normalized TAV was observed with alirocumab treatment

CTA-verified HRP was an independent predictor of ACS.

Adverse plaque characteristics confer an increased risk of coronary death or nonfatal MI.

Presence of high-risk plaques on CTA increased the likelihood of ACS independent of significant CAD and clinical risk assessment

Interpretation

Minimum fibrous cap thickness (baseline: 64.9 μm, 13 months: 87.9 μm), macrophage line arc (baseline 9.6°; 13 months 6.4°)

High-intensity statin over 13 months is associated with increased fibrous cap and reduced macrophage accumulation in NCV among STEMI Pt

High-intensity statin over 13 months is associated with regression of atheroma in NCV without changes in RF-IVUS defined NC or plaque phenotype among STEMI Pt

Non-restenotic MACE rate: non-calcified RF-IVUS (VH-IVUS) can identify plaques RF-IVUS derived TCFA (5/175; 2.9%), PB at increased risk of subsequent events >70% (9/178; 5.1%)

MACE rate: all RF-IVUS derived TCFA Overall PB coupled with high-risk feature (26/595, 4.9%), RF-IVUS derived TCFA + (RF-IVUS derived TCFA) offer better PB >70% + MLA <4 mm2 (18.2%) predictive strength for MACE compared to individual parameters

RF-IVUS derived TCFA by itself was not predictive of MACE but MLA <4 mm2 was. A combination of MLA <4 mm2 + PB >70% + TCFA offered the best predictive accuracy

Change of TAV Percent change in normalized TAV was assessed by −3.1% with standard care versus −4.8% IVUS with alirocumab (p=0.23).

ACS

13 months Change of Frequency of RF-IVUS derived TCFA: plaque (baseline: 124/165; 75.2%, 13 months: characteristics 116/165; 70.3%) by statin therapy

3 years

median 3.4 years

High-risk plaques were more frequent in pts with ACS and remained a significant predictor of ACS after adjusting % stenosis

Results

Coronary death Coronary death or nonfatal MI was or nonfatal MI three times more frequent in patients with adverse plaque (25/608 [4.1%] versus 16/1,161 [1.4%]).

Diagnostic ability for ACS

median 4.7 MACE years

3 years

mean 3.9 years

5 years

NA

Number of Patients Follow- Endpoint Pt/lesions with ACS up or Vessels at Baseline duration (%)

Table 1: Summary of Coronary Imaging-based High-risk Plaque Detection and Outcomes

Vulnerable Plaque and Acute Coronary Syndrome

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Pt with suspected CAD US and underwent NIRS-IVUS to Europe non-culprit lesion after culprit PCI

LPR69

High maxLCBI4mm, Pt = 275/NCV 42.5% maxLCBI10mm = 275

LRP (max lipid arc Pt = 1378/NCL 72.9% >180°), TCFA = 3533 (fibrous cap <65 μm)

NIRS + IVUS High maxLCBI4mm

Pt = 1271/WS = 5755

53.7%

ACS

2 years

non culprit MACE

median 3.7 non culprit years MACE

median 4.1 MACE years

median 6 years

Number of Patients Follow- Endpoint Pt/lesions with ACS up or Vessels at Baseline duration (%)

NIRS + IVUS High maxLCBI4mm, Pt = 898/NCL 100% (recent large PB, small = 3629 MI) MLA

NIRS

OCT

Coronary Features of Imaging High-risk Modality Plaque by Imaging

NIRS-derived LCBI is associated with adverse cardiac outcome in CAD patients independent of clinical risk factors and PB.

Non-culprit plaques with LRP and TCFA in non-culprit plaques may predict an increased risk of ACS

Interpretation

maxLCBI4mm >400; pt-level adjusted HR 1.89 (95% CI [1.26–2.83]; p=0.0021), plaque-level adjusted HR 3.39 (95% CI [1.85–6.20]; p<0.0001)

NIRS can identify patients and segments higher risk for non-culprit MACE.

maxLCBI4mm >324.7; pt-level adjusted OR Combined NIRS + IVUS detect lesion 2.27 (95% CI [1.25–4.13]), lesion-level with high lipid content and large PB that adjusted OR 7·83 (95% CI [4.12–14.89]) are at high risk for future event

Independent relationship between higher risk of MACE and maxLCBI4mm, maxLCBI10mm was confirmed. Each 100 units increase of MaxLCBI4mm was associated with a 19% increase in MACE.

OCT derived LRP, TCFA, and smaller MLA were independently associated with ACS

Results

ACS = acute coronary syndrome; CAD = coronary artery disease; CAG = coronary angiography; CTA = CT angiography; CV = cardiovascular; HRP = high-risk plaque; HU = Hounsfield unit; IVUS = intravascular ultrasound; LCBI = lipid core burden index; LRP = lipid-rich plaque; MACE = major adverse cardiovascular event; MLA = minimal lumen area; NA = not applicable; NCL = non culprit lesion; NCV = non culprit vessel; NIRS = near-infrared spectroscopy; OCT = optical coherence tomography; PB = plaque burden; PCI = percutaneous coronary intervention; Pt = patients; RF-IVUS = radiofrequency IVUS; SAP = stable angina pectoris; STEMI = ST-segment elevation MI; TCFA = thin-cap fibroatheroma; VH = virtual histology; WS = ware segment.

Europe

Pt with recent MI underwent 3-vessel NIRS-IVUS

PROSPECT II68

Japan

the NL

Pt with SAP or ACS underwent OCT to non-culprit artery after CAG or PCI

Kubo et al.66

Country

ATHEROREMOPt with SAP or ACS underwent NIRS/IBIS-3 NIRS67 NIRS to non-culprit artery after CAG or PCI

Study Population

Trial

Table 1: Cont.

Vulnerable Plaque and Acute Coronary Syndrome

Vulnerable Plaque and Acute Coronary Syndrome Intravascular Ultrasound

A number of pathologic studies and clinical papers have proposed the idea of precursor lesion to PR that could be located and treated before it causes coronary events. Catheter-based invasive imaging techniques, including intravascular ultrasound (IVUS), can identify some features of ‘vulnerable plaques’ in atherosclerotic lesions in daily practice, although it cannot visualize exact thinness of the fibrous cap and other more specific details (resolution of IVUS >100 µm). In grayscale IVUS images, coronary plaques can be classified as soft, intermediate, calcified, or mixed according to their echo signals. Additionally, assessment of plaque burden (formula: plaque plus media CSA/external elastic membrane CSA), vessel remodeling index (formula: lesion external elastic membrane CSA/ reference external elastic membrane CSA), atheroma eccentricity (formula: [maximum plaque + media thickness − minimum plaque + media thickness]/maximum plaque + media thickness), as well as plaque characterization by reflecting echo signal amplitude, frequency, and power (e.g. integrated backscatter IVUS and virtual histology IVUS.) can provide additional information about potential vulnerable plaque, with the idea that once identified we would be able to treat them before an event can occur.62,72,73 Accordingly, larger plaque burden, eccentric pattern, outward remodeling (remodeling index >1.0), spotty calcification, signal attenuation without dense calcium, presence of an echolucent zone, and plaque composition of necrotic core determined by radiofrequency analysis have been reported to be vulnerable plaque characteristics.74 However, in general, the results of clinical studies have not clearly supported the theory of IVUS-defined TCFAs as the lesion causing clinical events. The PROSPECT trial was a prospective study of 697 ACS patients who underwent three-vessel coronary angiography and gray-scale and radiofrequency IVUS.62 From 595 identified IVUS-defined TCFAs, only 26 sites had a coronary event at a median follow-up of 3.4 years. When combined with other criteria, such as a plaque burden of >70% and a minimum lumen area of <4 mm2, the HR increased to 11.05 for any lesion having these criteria, yet 88.2% of patients harboring these plaques did not go on to have an event during the study. Another clinical study using virtual histology IVUS also revealed similar results, although the number of patients and follow-up duration were lower.63

Optical Coherence Tomography

Optical coherence tomography (OCT) is another major coronary artery invasive imaging modality using near-infrared light and has 10 times greater resolution compared with IVUS (resolution >10 µm). Therefore, fibrous cap thickness can be measured by OCT, and this technology has emerged as the best discriminator of plaque type in autopsy studies.75,76,77 To verify the findings of pathologic autopsy study regarding fibrous cap thickness and other features in coronary plaques, an OCT- and IVUSbased in-vivo clinical study was conducted.23,78 The specific morphological characteristics of ruptured culprit plaque responsible for acute events, ruptured non-culprit plaques (without lumen occlusion), and non-ruptured TCFA were compared in patients with ACS.78 In total 126 plaques from 82 cases were analyzed, and fibrous cap thickness was thinner in ruptured plaques (both culprit [43 ± 11 μm] and non-culprit [41 ± 10 μm] lesions) than in TCFA (56 ± 9 μm, p<0.001 and p<0.001, respectively).

Another OCT-based clinical study involving 643 plaques from 255 patients showed that TCFA were highly prevalent in various stages of coronary atherosclerotic disease suggesting their dynamic nature.79 Compared to mildly stenotic TCFAs, severely stenotic TCFAs showed greater plaque burden as well as more vulnerable plaque features. This suggests severely stenotic TCFAs may be more likely to lead to rupture and thrombosis in the near future. Recently, Kubo et al. demonstrated a

prospective OCT study, including 3,533 non-culprit plaques from 1,378 patients.66 Seventy-two ACS arose from initial non-culprit plaques within 6 years of follow-up. A larger maximum lipid arc, thinner minimum fibrous cap thickness, and smaller minimum lumen area were independent risks for subsequent ACS at the lesion level.66 On the other hand, regarding other vulnerable plaque characteristics, such as IPH and microcalcification in the fibrous cap, the performance of OCT remains uncertain (i.e. the former is because of the complex findings during healing of hemorrhage in the necrotic core, and the latter is because of the lower end of the spectrum [microcalcification <5 µm diameter]). In addition, discriminating calcified areas from lipid core in OCT is difficult as both appear as signalpoor regions.80

Near-infrared Spectroscopy

Near-infrared spectroscopy (NIRS) is another clinically available intracoronary imaging modality using characteristic emission spectra produced by plaque contents following interaction with photons. NIRS can be used to identify lipid core plaque (LCP) as validated in several pre-clinical and clinical studies.81–83 The calculated data by intra-coronary NIRS system provides a two-dimensional map of the vessel (chemogram), i.e. the x- and y-axis represent pullback position and circumferential position in degrees (0–360°), respectively, with a color scale from red to yellow indicating probability for the LCP presence. From the chemogram, a summary metric of the probability of LCP presence in at a 2-mm interval during pullback can be computed and displayed in a color map (block chemogram).84 Lipid core burden index (LCBI) is a quantitative summary metric of the LCP presence in the entire scanned segment, which is the fraction of valid pixel in the chemogram that exceeds an LCP probability of 0.6, multiplied by 1,000. For instance, maxLCBI4mm indicates the maximum value of the LCBI for any of the 4 mm segments in the interrogated region.84 This method is able to quantify the lipid content of plaque, especially in cases of positive remodeling with large lipid-rich necrotic core.85 A recent large-scale clinical trial using NIRS, the LPR study, revealed the usefulness of NIRS-based vulnerable plaque and patient risk stratification.69 A total of 1,563 patients with CAD underwent NIRS-IVUS assessment in two or more non-culprit arteries, and patient- and plaque-level events were enrolled. To examine the association between maximum 4 mm LCBI (maxLCBI4mm) and non-culprit major adverse cardiovascular events, patients with large versus small lipid-rich plaque (maxLCBI4mm ≥250 versus maxLCBI4mm <250, respectively) were followed for up for 2 years. The adjusted patient-level analysis found an 18% higher risk of experiencing a non-culprit event within 2 years for each 100 unit increase in LCBI 4 mm segment. More recently the prospective multicenter trial PROSPECT II also examined the usefulness of combined coronary plaque assessment with NIRS + IVUS in 3,629 non-culprit lesions of 898 patients with recent MI.68 Adverse events within 4 years occurred in 112 patients (13.2%), with 66 events (8.0%) that originated from non-culprit lesions. Highly lipid-rich lesions assessed by maxLCBI4mm, large plaque burden, as well as minimum lumen area were independent predictors of non-culprit lesion related MACEs. Although these data suggest plaque assessment by NIRS + IVUS can predict overall risk of events, analysis on an individual plaque basis was not presented. Therefore, on a patient- and plaque-specific basis, the technology could not discriminate the future risk of events in the near term for a specific plaque.

What is the Significance of Vulnerable Plaque Detection by Imaging Modalities?

The fact that even PR events do not always cause acute MI or sudden coronary death and can happen without clinical symptoms complicates the

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Vulnerable Plaque and Acute Coronary Syndrome Table 2. Factors and Conditions Associated with Increased Risk for Acute Coronary Events Coronary Plaque Characteristics

Coronary Blood Flow Dynamics

Intrinsic Hemostasis Factors

Metabolic and Neurohormonal Inflammatory Conditions Imbalance

Environmental Factors and Drugs

Plaque burden

Blood viscosity

Platelet function/volume

Diabetes

Stress

Smoking

Lumen encroachment

Shear stress

Circadian variation

Obesity

Catecholamine surges

Pollution

Lesion location

Reduced blood flow/low cardiac output

Factor V Leiden deficiency

Dyslipidemia

Depression

Climate

Plaque composition

Vascular tone and reactivity Von Willebrand factor deficiency Connective tissue diseases

Exertion

Legal drugs

Plaque biology

Arterial hypertension

Infections

Autonomic dysfunction Illegal drugs

Renal disease

Endocrine imbalance

Anti-phospholipid syndrome

Plaque configuration and remodeling Endothelial dysfunction

Diet Sedentary lifestyle

Source: Arbab-Zadeh et al. Reproduced with permission from Wolters Kluwer Health.

94

quest to identify vulnerable plaque by imaging modalities in order to prevent clinical events.86,87 Arbab-Zadeh et al. reviewed 11 clinical and pathological studies involving 1,371 patients and identified subclinical PR was detected in the non-culprit lesion in 11.5% of patients with stable CAD or healthy controls, as well as 21.5% of patients who presented with ACS.87 Prior pathological evidence by Mann et al. advanced the theory that repeated silent PRs are one of the critical triggers of phasic rather than linear progression of luminal narrowing in diseased coronary arteries which may involve subclinical thrombus formation and healing.88 Also, a histopathology study from our group involving 142 cases who died of sudden coronary death revealed frequent observation of multiple healed PR sites with layering in the lesion with acute and healed PR.35 Moreover, in patients dying without acute thrombus, healed PR sites were identified in 80% of cases, and cumulative healed PRs at the same location clearly related to increased percentage stenosis. Combined with the evidence from IVUS-based studies that 75% of TCFAs convert into thick-capped fibroatheromas within a 12 month follow-up period, silent PR and healing are not uncommon in vivo.89 Together, this evidence suggests that even if the location of vulnerable plaque was detected precisely, many of them would not cause clinically important symptomatic events. Furthermore, multiple sub-clinical ruptured plaques as well as non-ruptured TCFA have been detected in addition to culprit lesions in patients with ACS, suggesting a systemic condition leading plaque vulnerability throughout the coronary tree.90 The concept of the ‘vulnerable patient’ as a contributor to near-term events in subjects harboring multiple vulnerable plaques needs more attention.91,92

Factors Associated With Acute Coronary Event: Plaque Development and Coagulation Status

The vast majority of sites identified by imaging as vulnerable plaque (TCFA) do not cause symptomatic arterial thrombotic occlusion. The above-mentioned PROSPECT trial showed that only 4.4% (26/595) of nonculprit TCFA lesions detected by Virtual Histology-IVUS (VH-IVUS) in 313 patients turned in clinically detectable thrombotic events during 3 years follow up.62 Indeed, large number of plaque rupture or erosion event can happen silently (without leading symptomatic coronary events) as shown in pathology and clinical studies.2,93 These silent thrombotic events mainly result in plaque volume progression by intramural thrombus organization rather than life threatening acute coronary occlusion and MI. Therefore, although the release of pro-thrombotic necrotic core components (e.g. tissue factor) to blood stream after fibrous cap disruption in PR or the exposure of pro-thrombotic subendothelial tissue matrix caused by endothelial disruption in PE can be an initial trigger of thrombotic

formation. Multiple other factors may also contribute to subsequent thrombus enlargement and final luminal occlusion. Factors and conditions associated with increased acute coronary event risk may be further categorized into being related to plaque characteristics, coronary flow dynamics, intrinsic hemostatic/fibrinolytic dysfunction, neurohormonal dysregulation, and environmental factors and triggers as shown by ArbabZadeh et al. (Table 2).94 Therefore, even though the detection of vulnerable plaque is a quite important, for comprehensive understanding of acute coronary event (to recognize ‘vulnerable patient’), identification of factors associated with plaque development/progression, with local/systemic blood procoagulant status, or with combination of them need to be considered. In this regard, cardiovascular physicians need to appreciate these nuances – many of which remain incompletely understood.

Management and Treatment of Coronary Vulnerable Plaque Lipid-lowering Treatment

A number of clinical trials revealed that the reduction of LDL cholesterol with statins is associated with improvements in fatal cardiovascular events.95 According to the recently available clinical guidelines, lipidlowering using statins is a standard treatment for the primary and secondary prevention of cardiovascular disease caused by atherosclerosis.96,97 Furthermore, statin therapy is recommended in both ACS and prior to percutaneous coronary intervention (PCI), and this has originated from its pleiotropic effect on several cellular pathways regarding anti-inflammation and subsequent anti-thrombosis.98 A regression of coronary plaque burden by statin therapy was confirmed by observation with IVUS in a pooled analysis of eight clinical trials including 4,477 patients with high-risk plaques.99 The long-term effect of statin on coronary plaque was also confirmed in recent PARADIGM study.100 In this prospective, multinational trial over 2 years of follow-up, statin treatment was associated with slower progression of overall coronary atherosclerosis, a reduction of high-risk plaque characteristics, and increased plaque calcification.100 A reduction of plaque burden and an increase in fibrous cap thickness of coronary fibroatheroma was also confirmed by several OCT-based clinical studies.101 When comparing lowand high-dose statin treatment, high-dose treatment was associated with fewer vulnerable plaque features including lipid volume and fibrous cap thickness confirmed by serial OCT observation.102 In addition to statins, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have recently emerged as another intensive lipid-lowering agent.103 Large scale randomized controlled trials confirmed the significant effect of PCSK9 inhibitors on LDL-cholesterol levels as well as

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Vulnerable Plaque and Acute Coronary Syndrome cardiovascular event reductions in patients with a background of statin therapy.104,105 The updated European lipid-lowering guideline recommends adding a PCSK9 inhibitor early after the ACS event in patients whose LDLcholesterol levels have not reached goal despite maximum tolerated statin and ezetimibe treatment.97 The US guidelines consider patients with ACS within 12 months as a very high-risk population. In patients in this category whose LDL-C level is >1.8 mmol/l on maximally tolerated statin and ezetimibe, adding a PCSK9 inhibitor in this setting is reasonable.106 A study of the GLAGOV trial, which investigated 968 statin-treated CAD patients who underwent serial IVUS imaging before and after (i.e. 76 weeks) adding placebo or evolocumab treatment, revealed greater reduction of atheroma volume in evolocumab group.107 However, serial plaque compositions assessed by virtual histology IVUS were similar between evolocumab and placebo groups.107 An ongoing multicenter, double-blind, placebo-controlled trial, PACMAN-AMI, will determine the effect of alirocumab on top of high-intensity statin therapy on high-risk coronary plaque characteristics by serial assessment with intra-coronary multimodalities including IVUS, NIRS, and OCT.108

Anti-inflammatory Treatment

More than two decades ago, the role of inflammation in atherosclerosis was raised as a potentially important target.109 Ridker et al. demonstrated apparently healthy individuals with elevated levels of high-sensitive C-reactive protein (hsCRP) to be at high vascular risk (MI and stroke) irrespective of lipid levels.109 Recently, the inflammatory character of atherosclerosis has come into the forefront with the results of several clinical trials.

The effect of canakinumab, a therapeutic monoclonal antibody targeting interleukin (IL)-1β was tested in a large scale randomized, double-blind trial, CANTOS.110 A total of 10,061 patients with previous MI history with elevated hsCRP were randomly allocated to canakinumab and placebo and followed-up for 3.7 years. The anti-inflammatory therapy achieved a 15% relative reduction in risk for recurrent MI, stroke, or cardiac death.

Individuals who responded to canakinumab therapy by accomplishing a greater than median reduction in hsCRP had a 26% reduction in the primary end point and a decrease in all-cause mortality. Because IL-1β participates in host defenses, canakinumab treatment was also associated with a higher incidence of fatal infection than placebo. Thus, the data did not completely support the use of anti-inflammatory medicines as a method to decrease plaque vulnerability, and the Food and Drug Administration did not support labeling for canakinumab as a targeted therapy for reduction of cardiovascular events.

Another anti-inflammatory agent, methotrexate, has also been tested for efficacy in cardiovascular risk prevention in a large scale, randomized, double-blind trial, and the result was recently reported.111 However, lowdose methotrexate did not reduce levels of IL-1β, IL-6, or CRP and did not result in fewer cardiovascular events than the placebo.

Colchicine is an alkaloid derivative that has been traditionally used for treating gout as well as several other rheumatic diseases.112 Growing evidence suggests that colchicine’s anti-inflammatory mechanisms, such as NLRP2 inflammasome inhibition, can be a treatment option for atherosclerotic disease. The effect of colchicine treatment in patients with stable CAD on top of statin and antiplatelet therapy was tested in two randomized clinical trials: LoDoCo and LoDoCo-2.113,114 The latter trial had a much larger population of 5,522 patients with stable CAD on statin and antiplatelet therapy who were allocated to colchicine versus placebo.

Those who received colchicine had a 31% risk reduction in primary

outcomes, including cardiovascular mortality, myocardial ischemia, ischemia-driven revascularization, and stroke compared with the placebo (p<0.05).114 As opposed to canakinumab in the CANTOS trial, colchicine used in this study was not associated with an increased rate of hospitalization for infection. Moreover, colchicine’s effect on secondary cardiovascular prevention was evaluated in the large scale COLCOT trial.115 In this study, 4,745 patients who had suffered a recent MI were randomly assigned to two groups: low dose colchicine or placebo. The colchicine group had a significant risk reduction (23%) in the primary composite end point, i.e. cardiovascular death, cardiac arrest, MI, stroke, or urgent coronary revascularization. Considering the inflammatory characteristics of ruptureprone vulnerable plaques, anti-inflammatory treatment might decrease the risk of rupture, but their routine use in this setting likely requires more data.

Invasive Treatment

As shown in the ISCHEMIA trial, our current understanding of the effectiveness of a PCI strategy added to guideline-directed medical therapy in patients with stable CAD is questionable, with likely no beneficial effect on cardiovascular outcomes compared to medical therapy alone.116 On the other hand, a recently reported meta-analysis analyzed 46 trials, including 37,757 patients, and revealed a beneficial effect of PCI in unstable patient scenarios including: post-MI patients who did not receive immediate revascularization; patients who underwent primary PCI for ST-elevation MI but with residual coronary lesions; and patients with non-ST-elevation MI.117 Overall, in these unstable scenarios, PCI reduced all cause of death (RR 0.84; 95% CI [0.75–0.93]; p=0.02), cardiac death (RR 0.69; 95% CI [0.53–0.90]; p=0.007) and MI (RR 0.74; 95% CI [0.62–0.90]; p=0.002). Patients undergoing coronary angiography often present with multi-vessel disease, and the finding of vulnerable plaques is common under observation with in-vivo imaging modalities, especially in unstable scenarios. However, to date, there is no evidence that prophylactic revascularization of vulnerable plaques is beneficial, and the significance of imaging techniques in the assessment of vulnerable plaques still needs more evidence to be routinely considered as necessary. The CANARY trial tested the correlation between lipid rich plaque as detected by NIRS and periprocedural MI presumably because of distal embolization.118 Eighty-five patients were enrolled at nine US sites. NIRS-IVUS were performed at baseline, and lesions with a maxLCBI4mm >600 were randomly allocated to PCI with or without distal protection filter. Periprocedural MI developed in 21 patients (24.7%) and the maxLCBI4mm was significantly higher in patients with versus without MI (p<0.05). Although the beneficial effect of distal protection was not confirmed in 31 randomized lesions with maxLCBI4mm >600 probably because of the lack of study power, the attempt to perform tailor-made PCI treatment with plaque characterization by contemporary coronary imaging needs further evaluation.

As mentioned above, current OCT imaging allows us to identify underlying plaque morphology in ACS. Compared with PR, the culprit lesion of PE typically has larger lumen, preserved vascular structure, and platelet-rich thrombus.13,15,119 Because drug-eluting stent implantation has the intrinsic disadvantages (e.g. the development of neoatherosclerosis, limiting normal vasomotion, and preclusion of bypass surgery due to metallic caging120,121) conservative management with antithrombotic therapy (particularly antiplatelet therapy) without stenting can be a management option for ACS caused by PE. Several small clinical trials have shown the feasibility of this treatment strategy in short- and long-term outcomes.122,123 Large-scale randomized trials are needed to replicate these pilot study results and to further confirm long-term outcomes of this new treatment option in patients with ACS caused by PE.

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Vulnerable Plaque and Acute Coronary Syndrome Figure 3: Concept of the ‘Vulnerable Patient’

Elevated total atheroma burden

Prothrombotic state Total risk of ACS

Atherosclerotic disease activity

The illustration demonstrates the concept of vulnerable patients. A conglomerate of findings such as a prothrombotic state, elevated total atheroma burden and an overall systemic measure of atherosclerotic disease activity (for example inflammatory biomarkers) would constitute the vulnerable patient. ACS = acute coronary syndrome.

Conclusion

The vulnerable plaque concept originating from human pathology studies has led to a remarkable advancement in our understanding of pathogenesis and treatment for atherosclerosis. We know, to date, that comprehensive risk assessment needs to be performed to identify patients at risk for adverse cardiovascular events (Figure 3). Developments of invasive and non-invasive coronary imaging techniques are allowing for the detailed detection of rupture-prone vulnerable plaque 1.

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characteristics. In combination with cardiovascular risk factors, plaque imaging might provide a more accurate picture of an individual’s risk.

The diagnostic value of currently available intra-coronary imaging (e.g.

IVUS, OCT, and NIRS) is extraordinary as many interventional cardiologists have already recognized. However, the use of intra-coronary imaging in daily practice is still low, especially in western countries.124 Its high cost, the prolongation of procedure time, and risk of complications are all potential reasons for the low adoption.124 As mentioned, a number of clinical studies have demonstrated the usefulness of current intracoronary imaging modalities not only to define plaque characterization but also to facilitate the optimal stenting process. Also, regarding economic impact, the favorable incremental cost-effectiveness of IVUSguided PCI versus angiography-guided PCI has been reported in several studies.125,126 Therefore, more use of intra-coronary imaging in daily clinical PCI procedures should be encouraged to achieve better clinical outcomes.

Reimbursement issues as well as complexity in its interpretation (sometime requiring significant expertise) remain as additional barrier to its widespread adoption.

According to the results of large-scale clinical trials, the effectiveness of invasive PCI strategies in stable CAD patients is quite limited. Unstable patient populations who might harbor more vulnerable plaques need to be stratified, and more intensive medical therapeutic approaches need to be considered. As of now, imaging is not able to determine with high accuracy on a patient- or lesion-basis who is at high-risk in the near term for PR. More work needs to be done to understand other features that determine plaque vulnerability beyond those determined by morphology.

In addition, the current approach of imaging-based vulnerable plaque detection is mainly focused on rupture prone lesions, which are represented as TCFA in pathology. Since the precursor lesion of PE and CN (more than 30% of the population in the case of ACS) has not been determined yet, further basic and clinical studies, including coronary imaging, need to be advanced for better risk stratification in patients with CAD.

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REVIEW

Interventional Cardiology

Robotic Percutaneous Coronary Intervention: The Good, the Bad, and What is to Come Laura Young

and Jaikirshan Khatri

Heart, Vascular & Thoracic Institute, Cleveland Clinic, Cleveland, OH

Abstract

The introduction of robots into healthcare has brought a wealth of opportunity for technical advancements, ranging from cleaning robots to disinfect hospital rooms to the high-tech surgical robots used in the operating room. Robotic-assisted percutaneous coronary intervention (R-PCI) has been a more recent development in the field, and is particularly revolutionary in that it serves to benefit the interventional cardiologist as well as the patient. Published data on R-PCI have shown its feasibility, safety, and more recently, its potential benefits. This review examines the current role of the robot in the catheterization laboratory, the authors’ experience with the most current generation of the robot, and what is yet to come.

Keywords

Robotics, percutaneous coronary intervention, complex percutaneous coronary intervention, interventional devices, innovation Disclosure: The authors have no conflicts of interest to declare.

Received: November 22, 2020 Accepted: September 6, 2021 Citation: US Cardiology Review 2022;16:e02. DOI: https://doi.org/10.15420/usc.2020.28R1 Correspondence: Laura Young, 9500 Euclid Ave, J2-3, Cleveland, OH 44195. E: youngL8@ccf.org Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

The field of percutaneous coronary intervention (PCI) has rapidly evolved since its inauguration in 1977. Its constant adaptation and advancement have allowed it to remain a mainstay in the treatment of patients with coronary artery disease and acute coronary syndromes. Logically, the majority of technological advancements within the field have focused on ensuring patient safety and expanding the scope of which transcatheter interventions can be used. While there have been significant innovations in what we can do, adaptations in how we perform PCI have lagged behind. As a result, operator fatigue and occupational hazards related to both radiation exposure and orthopedic injury from prolonged standing remain top concerns of interventional cardiologists. Robotic-assisted PCI (R-PCI) is one of the novel innovations within interventional cardiology, aiming to address both occupational hazards for the operator alongside procedural quality and safety improvement for the patient. We review the current role of the robot in the catheterization laboratory, the current systems available for use, and our experience with R-PCI.

The Potential of Robotics in the Catheterization Laboratory

When initially conceptualized, the appeal of a robotic system in the catheterization laboratory reflected that seen in the operating room, where the robot could provide a means of standardizing procedural precision and reproducibility while also addressing occupational hazards of the primary operator. The concept was to create a remote system that would allow for the primary operator to sit behind a shielded console, colloquially termed the ‘cockpit’, thereby reducing radiation exposure and orthopedic injury from prolonged standing at the bedside in a full lead apron. There has been widespread recognition of the risks of long-term radiation exposure, with a definitively increased risk of cataracts and

numerous malignancies involving the thyroid, brain, and bone marrow.1–3 Lead shielding has remained the mainstay of radiation protection for staff throughout the decades. While its armamentarium has expanded from lead aprons to include more novel ideas, such as lead-lined gloves and hats, and ‘zero-gravity’ lead (ceiling-suspended lead aprons), the overall paradigm remains unchanged, focusing on personal protective equipment. The incidence of orthopedic injury amongst interventional cardiologists remains alarmingly high, with 49% of interventionalists reporting at least one orthopedic injury in a 2014 nationwide survey.4,5 Robotic-assisted PCI offers a novel modality that can combat both radiation exposure and orthopedic injury for the interventionalist.

The robotic system also provides a potential for precision of device delivery that could supersede what can be achieved by the human eye, particularly when standing a foot away from the screen. The ability to control the robotic arm to move equipment sub-millimeter amounts with such accuracy would certainly be beneficial in the interventional cardiology realm, where accurate stent and balloon placement is critical.

Furthermore, the algorithmic capability of a robotic system could create the potential for standardization of the procedure by equalizing the skill set of operators in guidewire navigation and device delivery.

Removing the primary operator from the bedside opens the possibility of remote procedures, a concept that has colloquially been termed ‘telestenting’. The idea of remote operator PCI seemed futuristic a decade ago, but Patel et al. proved its feasibility in early 2019.6 They had a primary operator perform robotic PCI for five patients with type A coronary lesions while situated 20 miles away from the catheterization laboratory. The operator was able to perform the robotic PCI successfully

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Robotic PCI: The Good, the Bad, and What is to Come Figure 1: Robotic Percutaneous Coronary Intervention in the Cleveland Clinic Catheterization Laboratory

Corindus Vascular System, the CorPath 200. While it currently lags in technical advancements, the inherent rivalry between systems is encouraging to promote innovation within the field.

The systems are made up of two subunits – the robotic arm that is stationed bedside and the interventional cockpit, where the primary operator will sit to perform the PCI (Figures 1 and 2). The robotic arm is stationed at the caudal end of the table and can be retracted to the side when not in use. A single use cassette is attached to the arm in a sterile fashion and contains three equipment tracks: one designated for the guidewire, an active track for device advancement using the robot, and a passive track for devices that are left in place (such as a guide catheter extension) or that are used in a hybrid approach with manual advancement of the device by the bedside operator.

The general setup of our robotic percutaneous coronary intervention cases at the Cleveland Clinic.

One of the interventional cardiology operators sits in the cockpit to control the robotic arm, while the other is at bedside to assist with device exchanges and manipulation of the image intensifier.

Figure 2: Anatomy of the Robotic Single-use Cassette

The interventional cockpit can be placed in the catheterization laboratory behind a radiation shield or alternatively can be placed in the control room. Either way, the primary operator is able to perform the PCI without the orthopedic burden of a lead apron. The setup of the cockpit varies amongst the different systems, but the general concept is similar. There is a high-resolution screen that allows the operator to monitor the fluoroscopy screen, hemodynamics, and the bedside operations simultaneously (the latter from a camera that is setup above the table).

The gears of the robot are then controlled by individual joysticks, which manipulate the equipment in an assigned track. Both systems have a joystick for the guidewire and one for the device, while the CorPath GRX has a third joystick for control of the guide catheter.

Data

Close up view of the CorPath GRX robotic arm, mounted with the single use cassette

without conversion to a manual approach in all of the patients. In early 2020, Madder et al. demonstrated the feasibility of transcontinental telestenting in preclinical models, where the operator was located over 3,000 miles away from the ex vivo model.7 They found that there was no difference in performance and safety when telestenting was performed regionally versus transcontinental. As would be expected, they found that there was greater latency of media transmission in the transcontinental cases, although this was qualified as imperceptible by the operators. Telestenting is still in its infancy but ultimately could serve a multitude of purposes. Its biggest appeal has been to improve PCI access in remote and underserved regions. It could at the very least allow experts to aid in complex procedures from afar, widening the reach of these highly skilled operators. Furthermore, in the era of the COVID-19 pandemic, we must consider its utility in treating highly infectious patients while keeping our staff safe.

Systems

There are currently two commercially available robotic systems for PCI: the CorPath (Corindus) and the R-One (Robocath). The CorPath 200 was the first PCI robotic system to receive Food and Drug Administration clearance in 2005 and Corindus has since introduced their secondgeneration system, CorPath GRX. The R-One system by Robocath received a CE marking in February 2019 and is currently available throughout Europe and Africa. It has similar features to the first iteration of the

A number of observational studies have been published evaluating the feasibility, safety, and potential benefits of R-PCI for both patients and operators. Given the relatively recent approval of the Robocath R-One for commercial use, the majority of data have come from use of the Corindus CorPath robot models. The preclinical randomized trial for the R-One device was conducted by three operators in 2017, with a 100% technical success rate and no major adverse cardiac events.8 The data overall have been positive in terms of safety, feasibility, and short-term outcomes. A recent meta-analysis reflects this, including 148 R-PCI patients from five studies in comparison to 493 patients who underwent manual PCI. They found that operators had lower radiation exposure in the R-PCI group without compromise in total stents per case, fluoroscopy time, or procedural success rates.9 The PRECISE study was the inaugural study to evaluate safety and feasibility of robotic PCI, published by Weisz et al. in 2013.10 This nonrandomized, multicenter study enrolled patients with at least 50% coronary stenosis that could be treated with a single stent, with the majority of lesions being classified as type A (28.7%) or B1 (39.6%). These stringent inclusion criteria essentially allowed this study to serve as a proof of concept for R-PCI. The results were favorable, with technical success achieved in 162 of 164 patients (98.8%) without conversion to manual operation. At 30-day follow-up, there were no deaths, strokes, non-fatal MI, or target lesion revascularization. Perhaps the most exciting result though was the significant reduction in median radiation exposure of the primary operator, which was found to be 95.2% less during time spent in the interventional cockpit compared to time spent at the traditional table position.

CORA-PCI was designed to assess the feasibility of R-PCI for more complex patient lesions, whereby the inherently longer procedural

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Robotic PCI: The Good, the Bad, and What is to Come duration would make the robot an appealing tool.11 This was a nonrandomized single center comparison of patients undergoing R-PCI – notably performed by a single operator – versus those undergoing manual PCI in the CathPCI registry. Type C lesions made up the majority of those compared in both groups of the study. The authors found that the total procedure time was slightly longer in the R-PCI group (43 minutes versus 34 minutes; p=0.007), but there were no differences in contrast volume or dose area product of the patient between the two groups.

Within the R-PCI group, 81.5% of cases were completed entirely robotically while 7.4% required conversion to manual approach due to technical limitations of the robotic platform or limited guidewire or guide catheter support (this was notably using the CorPath 200, which does not have robotic guide catheter manipulation). There were three patients in the robotic cohort who required at least partial manual assistance due to an adverse event. Two of these were due to coronary dissection following balloon predilation and one was due to acute vessel closure during advancement of a guidewire. All three cases were successfully treated with manual stent placement and without further issue. These findings overall supported the feasibility of R-PCI for more complex lesions. This was further supported by a recent publication by Hirai et al., who published data from two centers that retrospectively compared 49 patients who underwent chronic total occlusion (CTO) PCI via R-PCI versus 46 patients who were treated with traditional PCI.12 R-PCI for CTOs was not associated with excess adverse events with significant reduction in radiation exposure for the primary operator, with on average ~48% of time spent in the cockpit.

While data from these early studies were favorable in terms of benefit for the operator without harm to the patients, there was no clear evidence of a benefit to the patients until recently. Patel et al. published data from a single center observational study comparing outcomes of traditional PCI versus robotic PCI.13 A total of 310 patients (31.1%) were included in the R-PCI group and 686 patients (68.9%) in the traditional PCI group. Twentytwo patients in the R-PCI group required conversion to a manual approach, but were included in the R-PCI group for an intention-to-treat analysis.

After propensity score matching, they found that R-PCI was actually associated with a significant reduction in radiation exposure to the patient (mean dose area product 4,734 cGycm2 [range: 2,695–7,746] versus 5,746 cGycm2 [3,751–7,833]; p=0.003). With the interventionalist in the cockpit, table height was not limited by the operator’s ergonomic comfort and so it could be raised to minimize radiation exposure to the patient. There was no significant difference in fluoroscopy time or contrast volume between the two groups, though total procedural time was notably higher within the R-PCI group, presumably related to time required to set up the robot (mean: 27 minutes [range: 21–40] versus mean: 37 minutes [range: 27– 50]; p<0.0005).

Robotic-assisted Percutaneous Coronary Intervention in the Real World: Our Experience

Our institution performed our first robotic-assisted PCI in August 2019 using the CorPath GRX Vascular Robotic System by Corindus. Since then, we have performed just over 100 R-PCI cases, comprising everything from left main trunk stenting to CTO lesions and single-access Impella cases (Table 1).14 As an academic institute, our interventional cardiology fellows are involved in all PCI cases, including robotic ones. For R-PCI, the interventional cardiology fellow will spend their first few cases at the bedside learning how to operate the robotic arm and then will have the opportunity to reside in the cockpit during interventions, while the attending physician acts as the bedside operator. Our cockpit is lead-lined itself and situated within the lab, allowing for direct communication

Table 1: Our Experience with Robotic Percutaneous Coronary Intervention at the Cleveland Clinic Lesion Characteristics

n (%)/mean ± SD

ACC/AHA lesion classification A B1 B2 C

2 (3.4%) 14 (23.7%) 11 (18.6%) 32 (54.2%)

Chronic total occlusions

19 (32.2%)

Lesion location LMT LAD LCx RCA Grafts

4 (6.8%) 21 (35.6%) 13 (22.0%) 24 (40.7%) 3 (5.1%)

Aorto-ostial lesions

11 (18.6%)

Bifurcations

15 (25.4%)

Procedural Details Lesion wired robotically

18 (30.5%)

Conversion to manual approach Inadequate guide catheter control Inability to deliver equipment

5 (8.4%) 2 (40%) 3 (60%)

Atherectomy

8 (13.6%)

Total contrast volume (ml)

133 ± 60.5

Fluoroscopy time (min)

34.9 ± 19.9

Total procedural time (min)

101.9 ± 48.6

ACC = American College of Cardiology; AHA = American Heart Association; LAD = left anterior descending; LCx = left circumflex; LMT = left main trunk; PCI = percutaneous coronary intervention; RCA = right coronary artery.

Table 2: Limitations of the Current Generation of Robotic Percutaneous Coronary Intervention Systems • • • •

Inadequate guide catheter and guidewire control.

Inability to accommodate over-the-wire-equipment.

Inability to accommodate coronary pressure wires for invasive hemodynamics.

Inability to reliably accommodate intravascular imaging devices without interruption in workflow.

between both operators. We have found that there is a relatively small learning curve for use of the robot, with the biggest challenge being converting from tactile and visual feedback to only visual cues.

The robotic arm is attached to the end of the bed and is then brought into position and draped in a sterile fashion when needed. It takes less than 5 minutes to drape and position the robot at the beginning of the procedure.

Each device exchange is then performed by the bedside operator and will usually take less than a minute to perform, whereby the previous device is removed and the next one loaded and advanced to the 90/100 cm mark, depending on guide catheter length. In our experience, there is a marginal increase in procedural time with a robotic approach, although not necessarily fluoroscopic time.

Understanding the current limitations of the robot in addition to its potential has allowed us to select appropriate cases for a robotic approach (Table 2). One of the major limitations of the available iterations is a lack of adequate guide catheter control. All of the current robotic systems require the operator to manually obtain vascular access and engage the coronary artery with the guide catheter. Only after the guide

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Robotic PCI: The Good, the Bad, and What is to Come catheter has been engaged should it be connected to the robotic arm.

The guide catheter is locked into place within the cassette, which inhibits further manual adjustments unless the robotic arm is disconnected. The CorPath GRX system has an upgraded feature in attempt to allow for robotic guide catheter control through joystick manipulation. This is certainly a vast improvement from the prior iteration, there was no alternative to disconnecting the system and reengaging the coronary manually. While ideal for subtle adjustments of the guide catheter during the case, we have found it very difficult to reengage the guide catheter entirely using the robot alone despite anecdotal reports of this being possible. Instead, we find it much more efficient to briefly disconnect the guide catheter for manual manipulation. The joystick allows for advancement and retraction as well as torquing of the guide catheter. It should be noted that advancement and retraction will result in movement of all connected devices, and so guidewires and catheters should be watched closely to prevent inadvertent complications. We have also learned that 90 cm guide catheters, often used in CTO cases for retrograde access, are often too short to complete PCI robotically. When connected to the robotic arm, these shorter guide catheters create too much tension to maintain stable coronary engagement. In taller patients, 90 cm guide catheters lack the necessary length to connect to the robotic cassette.

With the first generation of the CorPath robotic system, aorto-ostial lesions were difficult due to the inability to control the guide catheter.

Now with the upgraded system, ostial lesions are feasible as long as the operator has adequate ability to actively control the guide catheter. If the patient has tortuous anatomy or radial spasm, an alternative approach should be considered.

Similar to guide catheter manipulation with the robot, robotic guidewire navigation requires the operator to rely only on visual feedback. The robot can accommodate any 0.014 inch guidewire within its track. It should be noted that the current robotic iterations do not support the use of pressure guidewires for invasive hemodynamics, though the guidewire can be used once disconnected from the modular connector. One of the major appeals of R-PCI is the computational capability of the robot, which could allow for the creation of algorithms based on techniques of advanced operators – essentially leveling the playing field for all interventionalists. Corindus recently released its upgraded software for the CorPath GRX, including a proprietary program called ‘Rotate on Retract’, which is the first installation of its proprietary technIQ Smart Procedural Automation. The automation was designed to improve procedural reproducibility independent of an operator’s individual skills by creating algorithms based on the experience of highly skilled interventional cardiologists. When the ‘Rotate on Retract’ feature is activated, the robot will automatically rotate the guidewire 270o with each retraction input, so as to set the operator up for an alternative approach as one would at the bedside. Objective, preclinical data were favorable when the feature was used for wiring coronaries in a porcine model.15 It is also possible to torque the guidewire manually using the joystick, although there is a significant delay between input and wire response. We look forward to the implementation of future automated movements including spin, wiggle, Dotter, and constant speed, all of which could greatly improve robotic navigation and lesion crossing.

When considering device delivery, the robot is impartial in terms of device companies and can accommodate rapid exchange catheters up to 7 Fr (although off label, we have been able to use 8 Fr guide catheters without issue). Over-the-wire equipment, such as rotational or orbital atherectomy systems, cannot yet be accommodated for R-PCI. While it is possible to perform atherectomy and then transition to a robotic approach, this

cannot be done with a hybrid approach. Microcatheters, a fundamental tool for PCI of chronic total occlusions, cannot be accommodated either, which makes attempts at robotic wiring of these lesions implausible with the current systems. The gears within the system also prohibit the use of fragile catheters that lack a rigid hypotube, such as the Beta-Cath for brachytherapy (Novoste) or the Dragonfly Optis catheter for optical coherence tomography imaging (Abbott).

Intravascular imaging is a crucial step in our daily PCI practice so it is imperative that we can incorporate it into the workflow of R-PCI. The robotic systems cannot accommodate automatic pullback runs of rotational devices, although this is not an issue in our laboratory as we predominantly use solid-state intravascular ultrasound (IVUS) imaging.

While it is possible to perform a pullback robotically using the device joystick, we have found that the robotic gears can occasionally damage the IVUS catheter and render it defective. This often occurs in calcified or tortuous lesions, where the robotic gears slip as the IVUS catheter is gripped within the vessel. As a large majority of our patients have at least one of these two vessel characteristics, we prefer to use IVUS in a hybrid approach by placing the catheter in the passive device track, which allows the catheter to be advanced and retracted manually by the bedside operator.

One of the major benefits that we have found in using the R-PCI relates to its ability to assist in precision with measurements. The CorPath GRX has patented software that allows for lesion length measurement during pullback of any intracoronary device. The distal marker or end of the device is placed at the distal target lesion border and the device position counter is then reset to zero. The operator can then retract the device until the distal marker is at the proximal target lesion border, where the total length traveled will be displayed on screen in mm. Appropriate stent length, even when multiple stents are needed, can then be chosen without any guesswork. It should be noted that accuracy of the software depends on 1:1 joystick input to movement responsiveness of the device, which is not always the case. If the device is stuck, the program will still count and render an inaccurate measurement. We find that this often happens with the IVUS catheter but is less of an issue with balloons or stents. Prior data have also suggested that R-PCI lowers the incidence of longitudinal geographic miss compared to manual PCI.16 This is likely related to a combination of improved measurement accuracy with the robotic software, improved visualization given closer screen proximity for the operator, and finally the controlled pinning of the device during inflation and deployment by the robot gears.

While we have found it to be relatively uncommon to need to abort a robotic approach, conversion to manual PCI is quite straightforward. The guide catheter must be unlocked from the robotic arm, which thereby frees up the catheter and equipment for manual use and the robot can then be positioned at the end of the bed. This step is not particularly cumbersome but does add about a minute of procedural time. On our experience, we have not found this to be detrimental to our workflow.

Overall, we have found that R-PCI can be easily incorporated into daily use for non-complex coronary lesions and is certainly feasible for complex coronary lesions. Catheterization laboratories do have to be thoughtful about resource utilization and financial burden of novel equipment.

Encouragingly, data are starting to emerge suggesting that the cost of R-PCI is comparable to manual cases overall, with the expected increase in direct supplies cost related to the single-use robotic equipment.16,17 At our institution, we see this cost can be seen as a long-term investment for our operators’ radiation safety and long-term health with reduced

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Robotic PCI: The Good, the Bad, and What is to Come orthopedic burden from standing in lead. Economically, R-PCI has the potential to improve our accuracy leading to cost savings in terms of percase stent use; preliminary data have suggested that this holds true, though dedicated studies are needed to validate this potential.17

Conclusion

There is no doubt that R-PCI has significant potential for expanding our capabilities in the catheterization laboratory, whether regarding standardization of the procedure, improved operator endurance, or the prospect of telestenting. While we have made significant strides in the 1.

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Roguin A, Goldstein J, Bar O, Goldstein JA. Brain and neck tumors among physicians performing interventional procedures. Am J Cardiol 2013;111:1368–72. https://doi. org/10.1016/j.amjcard.2012.12.060; PMID: 23419190.

Zielinski JM, Garner MJ, Band PR, et al. Health outcomes of low-dose ionizing radiation exposure among medical workers: a cohort study of the Canadian national dose registry of radiation workers. Int J Occup Med Environ Health 2009;22:149–56. https://doi.org/10.2478/v10001-0090010-y; PMID: 19546093.

Karatasakis A, Brilakis HS, Danek BA, et al. Radiationassociated lens changes in the cardiac catheterization laboratory: Results from the IC-CATARACT (CATaracts Attributed to RAdiation in the CaTh lab) study. Catheter Cardiovasc Interv 2018;91:647–54. https://doi.org/10.1002/ ccd.27173; PMID: 28707381.

Andreassi MG, Piccaluga E, Guagliumi G, et al. Occupational health risks in cardiac catheterization laboratory workers.

Circ Cardiovasc Interv 2016;9:e003273. https://doi.org/10.1161/ CIRCINTERVENTIONS.115.003273; PMID: 27072525.

Klein LW, Tra Y, Garratt KN, et al. Occupational health hazards of interventional cardiologists in the current decade: results of the 2014 SCAI membership survey.

Catheter Cardiovasc Interv 2015;86:913-24. https://doi. org/10.1002/ccd.25927; PMID: 25810341.

Patel TM, Shah SC, Pancholy SB. Long distance tele-roboticassisted percutaneous coronary intervention: a report of first-in-human experience. EClinicalMedicine 2019;14:53–8.

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technical capabilities of R-PCI over the past decade, robotic systems will need to continue to evolve to adapt for the needs of the procedure. With the influx of data supporting intravascular imaging for optimization of PCI, it is imperative that upgrades be made so that these devices can seamlessly and reliably be used within the robotic system. Likewise, the routine need for over-the-wire equipment in complex PCI cases must be addressed. While there is still a way to go, it is important to recognize how far we have come. We must continue to purposefully practice the workflow of R-PCI to improve our efficiency and unleash the potential of this technology.

https://doi.org/10.1016/j.eclinm.2019.07.017; PMID: 31709402.

Madder RD, VanOosterhout S, Parker J, et al. Robotic telestenting performance in transcontinental and regional pre-clinical models. Catheter Cardiovasc Interv 2021;97:E327– 32. https://doi.org/10.1002/ccd.29115; PMID: 32583944.

Robocath Demonstrates Safety and Efficacy OF R-One. Robocath Robocath Demonstrates Safety and Efficacy of ROne Comments. https://www.robocath.com/robocathdemonstrates-safety-and-efficacy-of-r-one/ (accessed 14 December 2021).

Allencherril J, Hyman D, Loya A, et al. Outcomes of robotically assisted versus manual percutaneous coronary intervention: a systematic review and meta-analysis. J Invasive Cardiol 2019;31:199–203; PMID: 31088991.

Weisz G, Metzger DC, Caputo RP, et al. Safety and feasibility of robotic percutaneous coronary intervention: PRECISE (Percutaneous Robotically-Enhanced Coronary Intervention) study. J Am Coll Cardiol 2013;61:1596–600. https://doi. org/10.1016/j.jacc.2012.12.045; PMID: 23500318.

Mahmud E, Naghi J, Ang L, et al. Demonstration of the safety and feasibility of robotically assisted percutaneous coronary intervention in complex coronary lesions: Results of the CORA-PCI study (Complex Robotically Assisted Percutaneous Coronary Intervention). JACC Cardiovasc Interv 2017;10:1320–7. https://doi.org/10.1016/j.jcin.2017.03.050; PMID: 28683937.

Hirai T, Kearney K, Kataruka A, et al. Initial report of safety and procedure duration of robotic-assisted chronic total

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occlusion coronary intervention. Catheter Cardiovasc Interv 2020;95:165–9. https://doi.org/10.1002/ccd.28477; PMID: 31483078.

Patel TM, Shah SC, Soni YY, et al. Comparison of robotic percutaneous coronary intervention with traditional percutaneous coronary intervention: A propensity scorematched analysis of a large cohort. Circ Cardiovasc Interv 2020;13:e008888. https://doi.org/10.1161/ CIRCINTERVENTIONS.119.008888; PMID: 32406263.

Nagaraja V, Khatri JJ. Hybrid robotic impella assisted single arterial access complex high risk percutaneous coronary intervention. Cardiovasc Revasc Med 2020;21:105–7. https:// doi.org/10.1016/j.carrev.2019.12.007; PMID: 31948848.

Madder R LW, Parikh M, Kandzari D, et al. TCT-539. Impact of a novel advanced robotic wiring algorithm on time to wire a coronary artery bifurcation in a porcine model. J Am Coll Cardiol 2017;70(18 Suppl):B223. https://doi.org/10.1016/j. jacc.2017.09.712.

Bezerra HG, Mehanna E, Vetrovec GW, et al. Longitudinal geographic miss (lGM) in robotic assisted versus manual percutaneous coronary interventions. J Interv Cardiol 2015;28:449–55. https://doi.org/10.1111/joic.12231; PMID: 26489972.

Hamandi M, Cobb R, Foster L, et al. Cost and efficacy analysis of robotically assisted percutaneous coronary interventions. J Am Coll Cardiol 2019;73(9 Suppl 1):1114. https://doi.org/10.1016/S0735-1097(19)31721-8.

REVIEW

Cardiogenic Shock

Cardiogenic Shock Management and Research: Past, Present, and Future Outlook Sascha Ott, MD, ,1,2,3 Laura Leser, MD,1 Pia Lanmüller, MD, ,2,4 Isabell A Just, MD, ,2,4 David Manuel Leistner, MD, ,2,5,6 Evgenij Potapov, MD, ,2,4 Benjamin O’Brien, MD, ,1,2,3,7 and Jan Klages, MD1 1. Department of Cardiac Anesthesiology and Intensive Care Medicine, German Heart Center Berlin, Berlin, Germany; 2. German Center for Cardiovascular Research (DZHK), Partner Site Berlin, Berlin, Germany; 3. Department of Cardiac Anesthesiology and Intensive Care Medicine, Charité-Universitätsmedizin Berlin, Berlin, Germany; 4. Department of Cardiothoracic and Vascular Surgery, German Heart Center Berlin, Berlin, Germany; 5. Department of Cardiology, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany; 6. Berlin Institute of Health, Berlin, Germany; 7. William Harvey Research Institute, London, UK

Abstract

Although great strides have been made in the pathophysiological understanding, diagnosis and management of cardiogenic shock (CS), morbidity and mortality in patients presenting with the condition remain high. Acute MI is the commonest cause of CS; consequently, most existing literature concerns MI-associated CS. However, there are many more phenotypes of patients with acute heart failure. Medical treatment and mechanical circulatory support are well-established therapeutic options, but evidence for many current treatment regimens is limited. The issue is further complicated by the fact that implementing adequately powered, randomized controlled trials are challenging for many reasons.

In this review, the authors discuss the history, landmark trials, current topics of medical therapy and mechanical circulatory support regimens, and future perspectives of CS management.

Keywords

Cardiogenic shock, mechanical circulatory support, intra-aortic balloon pump, extracorporeal life support, extracorporeal membrane oxygenation, Impella, Ecmella Disclosure: SO has received research and study grants from Novartis; EP is proctor and consultant for and has received institutional grants from Abbott, Medtronic, and Abiomed; BO is a consultant for Teleflex and has received research funding from the British Heart Foundation and the National Institute for Health Science Research. All other authors have no conflict of interest to declare.

Received: August 5, 2021 Accepted: October 21, 2021 Citation: US Cardiology Review 2022;16:e03. DOI: https://doi.org/10.15420/usc.2021.25 Correspondence: Sascha Ott, Deutsches Herzzentrum Berlin, Augustenburger Platz 1, 13353 Berlin, Germany. E: sott@dhzb.de Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

In 1939, Harrison introduced cardiogenic shock (CS) as a specific entity and differentiated it from other forms of shock.1 Acute MI (AMI) is the most common cause of CS and has a mortality rate of up to 50%, which has changed little in the past two decades.2 In the early years of interventional AMI therapy, intracoronary thrombolytic agents were used to dissolve thrombi.3,4 Later, in 1977, Gruentzig performed the first percutaneous coronary artery balloon angioplasty.

Nearly one decade later in 1986, the first bare metal stent was implanted.

Since then, coronary artery stents have undergone significant development, spawning generations of drug-eluting stents.5 In 1999, Hochman et al. published one of the first major randomized controlled trials (RCTs) in the field, the SHOCK trial, proving early revascularization in AMI-associated CS (AMICS) to be the cornerstone of successful treatment and reduction in mortality for these patients.6 Another fundamental pillar for supporting AMICS patients is to bridge hemodynamic instability with mechanical circulatory support (MCS) devices. More than 50 years after the intra-aortic balloon pump (IABP) was developed in 1968 as the first MCS technology, the arsenal has increased considerably. Currently, IABP, the Impella (a miniaturized ventricular assist device; Abiomed) and extracorporeal life support

(ECLS) circuits are the most common devices for acute and short-term MCS in CS. Technical advances in the performance and manageability of MCS devices have led to their widespread availability and more frequent use. However, despite the remarkable increase in short-term MCS use, there is still little evidence from RCTs showing any significant improvement in strong outcome parameters.

Landmark Trials and a Slow Evolution

Table 1 provides an overview of the key trials in medical and mechanical therapy of CS in the past 20 years. The initial trials of MCS were predominantly retrospective cohort analyses with all their known limitations. Since the first use of a heart-lung machine by Gibbon in 1965, meaningful scientific interrogation of MCS modalities has evolved slowly.

First, a major issue in performing and comparing trials in the field of CS and MCS related to CS is the absence of a standard definition. Table 2 summarizes different definitions of CS by the US and European societies as well as those of some landmark trials. In addition, differing primary endpoints among study groups further complicate the situation.

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Cardiogenic Shock: Past, Present, and Future Outlook Table 1: Key Trials in Cardiogenic Shock Trial

n

Study Type

Objective

Primary Outcome Measures

Results

Medical Treatment and Interventional Trials in CS SHOCK 19996

302

RCT MC

Emergency revascularization versus initial medical stabilization in AMICS

30-day all-cause mortality Secondary endpoint: 6-month survival

No difference in 30-day mortality Significant survival benefit after 6 months

SHOCK White et al. 200580

302

RCT MC

Subgroup analysis of SHOCK trial: comparison of PCI versus CABG for early revascularization

30-day and 1-year survival

No difference in 30-day or 1-year survival

TRIUMPH 200781

398

RCT MC

Effect of tilarginine acetate in AMICS

30-day all-cause mortality

No mortality reduction Study terminated after 398 patients

SHOCK-2 200782

79

RCT MC

l-n-monomethyl-arginine (l-NMMA), a non-selective nitric oxide synthase inhibitor, versus placebo in AMICS

Absolute change in mean arterial pressure (MAP) at 2 h

l-NMMA resulted in modest increases in MAP at 15 min compared with placebo, but there were no differences at 2 h

Fuhrmann et al.

200883

32

RCT SC

Levosimendan versus enoximone on top of PCI, IABP and inotropes in refractory CS due to acute MI

30-day all-cause mortality

Improved survival in levosimendan group

SOAP-2 201077

1,679

RCT MC

Dopamine versus norepinephrine in the treatment of shock

28-day all-cause mortality

No mortality difference Dopamine: greater number of adverse events Subgroup of CS: Increased mortality when treated with dopamine

PRAGUE-784

80

RCT MC

Abciximab pre/post PCI versus control

Combined: death, reinfarction, stroke, or new renal failure at 30 days

No benefit of abciximab

CULPRIT SHOCK 201736

706

RCT MC

PCI of culprit lesion alone versus immediate multivessel PCI

Composite of death or severe renal failure leading to renal replacement therapy within 30 days

PCI of culprit lesion is superior to multivessel PCI regarding the composite endpoint

OptimaCC 201878

57

RCT MC

Epinephrine versus norepinephrine for AMICS

Cardiac index evolution Primary safety outcome was the occurrence of refractory CS

Epinephrine compared with norepinephrine was associated with similar effects on arterial pressure and cardiac index and a higher incidence of refractory shock

SHOCK COOL75

40

RCT SC

Mild hypothermia (33°C) in AMICS versus control

Cardiac power index at 24 hours Secondary endpoint: 30-day mortality

No difference in cardiac power index No difference in 30-day mortality

Mechanical Circulatory Support Trials in CS Thiele et al. 200585

41

RCT SC

IABP versus TandemHeart (TH) in AMICS

Cardiac power index

TH: improved cardiac power index TH: more bleeding and limb ischemia – no difference in 30-day mortality

Burkhoff et al. 200686

33

RCT MC

IABP versus TandemHeart in AMICS

30-day all-cause mortality

No difference in 30-day mortality

ISAR-SHOCK 200844

26

RCT MC

IABP versus Impella 2.5

Cardiac index 1 h after device implantation

Impella: improved cardiac index No difference in 30-day mortality

IABP-SHOCK II 201287

600

RCT MC

IABP versus standard care

30-day all-cause mortality

No mortality reduction due to IABP

IMPRESS 201647

48

RCT MC

IABP versus Impella CP

30-day all-cause mortality

No difference in 30-day mortality or after 6 months Impella: more major bleeding

Basir et al. 201930

171

p-Coh

Hemodynamic monitoring and early MCS with Impella in AMICS

Survival to discharge

Standardized shock protocol and early MCS with Impella is associated with improved survival

Pozzi et al. 202062

56

r-Coh SC

VA-ECMO in AMICS

Survival to discharge

Survival-to-discharge rate 41%

Lemor et al. 202055

6,290 r-Coh MC PSM

Impella (n=5,730) versus V‑A ECMO (n=569) in AMICS

In-hospital mortality

Lower mortality with Impella than with VA-ECMO

Dhruva et al. 202053

3536

r-Coh MC PSM

Impella versus IABP in AMICS

In-hospital mortality Major bleeding

Increased risk of in-hospital death and major bleeding with Impella compared with IABP

ARREST 202073

30

RCT SC

Early ECMO-facilitated resuscitation versus standard ACLS treatment

Survival to discharge

ECMO group: significantly improved survival

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Cardiogenic Shock: Past, Present, and Future Outlook Table 1: Cont.

Trial

n

Study Type

Objective

Primary Outcome Measures

Results

Varshney et al. 202088

55

Case series

Impella 5.5 in AMICS

Survival to explant Recovery of native heart function

Survival to explant: 83.6% Recovery of native heart function: 76.1%

ECLS-SHOCK 202064

41

RCT SC

VA-ECMO versus standard care in AMICS

Left ventricular ejection fraction after 30 days Secondary: 1-year mortality

No decrease in 1-year mortality with V‑A ECMO Study was not powered to assess mortality

Schrage et al. 2020 72

510

r-Coh MC PSM

LV unloading with Impella versus no unloading in patients treated with VA-ECMO for CS

30-day all-cause mortality

LV venting: lower all-cause mortality but more severe bleeding

AMICS = acute MI-associated cardiogenic shock; CABG = coronary artery bypass surgery; CS = cardiogenic shock; IABP = intra-aortic balloon pump; LV = left ventricular; RCT = randomized controlled trial; MAP = mean arterial pressure; MC = multicenter; SC = single center; PCI = percutaneous coronary intervention; p-Coh = prospective cohort analysis; r-Coh – retrospective cohort analysis; PSM = propensity-score matched; VA-ECMO = veno-arterial extracorporeal membrane oxygenation.

Table 2: Different Definitions of Cardiogenic Shock Clinical Definitions

European Society of Cardiology89

SHOCK Trial6

IABP-SHOCK II87

CULPRIT SHOCK36

Ineffective cardiac output due to primary cardiac dysfunction resulting in inadequate end-organ perfusion

Clinical criteria: SBP <90 mmHg with adequate volume and clinical or laboratory signs of hypoperfusion

Clinical criteria: acute MI complicated by left ventricular dysfunction SBP <90 mmHg for >30 min or support to maintain SBP >90 mmHg and end-organ hypoperfusion (urine output <30 ml/h or cool extremities)

Clinical criteria: acute MI SBP <90 mmHg or >30 min or catecholamines to maintain SBP >90 mmHg and clinical pulmonary congestion and impaired end-organ perfusion (altered mental status, cold/ clammy skin and extremities, urine output <30 ml/hour, or lactate >2.0 mmol/l)

Clinical criteria: SBP<90mmHg for longer than 30 min or Catecholamine therapy to maintain a SBP >90 mmHg, clinical signs of pulmonary congestion, and signs of impaired organ perfusion with at least one of the following manifestations: altered mental status; cold and clammy skin and limbs; oliguria with urine output <30ml/h; or arterial lactate level >2.0 mmol/l

Cardiac disorder that results in both clinical and biochemical evidence of tissue hypoperfusion A clinical condition of inadequate tissue (end-organ) perfusion due to cardiac dysfunction

Clinical hypoperfusion: cold extremities, oliguria, mental confusion, dizziness, narrow pulse pressure Laboratory hypoperfusion: metabolic acidosis, elevated serum lactate, elevated serum creatinine

Hemodynamic criteria: cardiac index <2.2 l/min/m2 and PCWP >15 mmHg

PCWP = pulmonary capillary wedge pressure; SBP = systolic blood pressure.

Second, although AMI is the most common cause of CS, there are many more phenotypes of patients with acute heart failure, which adds complexity to screening and randomizing patients for a trial in timepressured circumstances.2 Defining a specific study population can be problematic and obtaining patients’ informed consent difficult.

Furthermore, blinding is normally not possible.

Consequently, the first randomized controlled trials (RCTs) in the field of MCS were small trials enrolling fewer than 50 patients. Table 1 provides an overview of the RCTs in MCS. Most of the trials were aborted because of low recruitment rates, highlighting one of the major problems in prospective RCTs in MCS.7 Other than increasing the number of recruiting centers in multicenter trials, the hub and spoke model proposed by van Diepen et al. could improve recruitment yield.8 Furthermore, there are ethical issues around randomizing critically ill patients to be supported with MCS, which is often thought to be a lastchance treatment option, and such issues will require careful consideration when designing a trial. In this context, the study protocol of the DAWN trial, explained by Samsky et al., could be helpful.9,10 Moreover, the necessary infrastructure participating sites need to establish to successfully undertake trials in MCS is complex, costly, and can be delivered by only a limited number of select centers.11

Finally, volume/outcome relationships for MCS programs are increasingly well documented, and the need for dedicated cardiogenic shock centers has become apparent.12,13

Current Topics and Updates from Recent Studies Definition and Diagnosis of Cardiogenic Shock

Therapeutic intervention is often time critical, not least to minimize secondary end-organ damage, so early diagnosis is key.

Recently, Chioncel et al. again highlighted the significance of early detection of tissue hypoperfusion in patients with evolving or established CS.14 Shortly afterwards, Chioncel et al. published a position statement on behalf of the European Society of Cardiology Heart Failure Association, presenting a new definition of CS that focuses on the importance of hypoperfusion and organ dysfunction.15 In this context, hypotension is no longer a required criterion, and the definition now includes normotensive CS. Baran et al. presented the Society for Cardiovascular Angiography and Interventions (SCAI) clinical expert consensus statement on the classification of cardiogenic shock, defining a grading system of CS ranging from stage A with patients At risk, through to B and C (Beginning and Classic CS) – then to D and E (Deteriorating patients and those in Extremis).16 This classification was shown to correlate with both in-hospital mortality and mortality after hospital discharge.17–20

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Cardiogenic Shock: Past, Present, and Future Outlook Ceglarek et al. published the results of a CULPRIT-SHOCK biomarker substudy and presented a novel, fast, and objective, biomarker-based mortality risk score for patients with AMICS.21 Based on an evaluation of cystatin c, lactate, interleukin-6 and N-terminal pro-B-type natriuretic peptide, they established and validated the CLIP score as a mortality risk predictor.

0.96]) and a lower rate of renal replacement therapy requirement (5.9% versus 15.9%; adjusted OR 0.40; 95% CI [0.16-0.97]).37 However, this benefit could not be confirmed at the 1-year follow up. The causes for the improved short-term endpoints warrant further research.

Hemodynamic Monitoring

In 2013, Thiele et al. published the IABP-SHOCK II trial, the first adequately powered prospective, randomized multicenter trial comparing IABP against controls in a CS population, which showed no improvement in 30-day, 12-month, or 6-year mortality rates.38,39 Consequently, European guidelines do not recommend routine IABP implantation in CS (class 3b).40 The last US guideline for managing AMICS from 2013 did not yet include the IABP-SHOCK II data and issued a class 2a recommendation.35 Later updates, however, downgraded the recommendation for the routine use of IABP.28, 41

Cardiac output (CO) or cardiac index (CI) are key parameters in evaluating patients with CS. There is an ongoing debate over the role of the pulmonary catheter (PAC). Although the PAC was first introduced and studied in the mid-1970s, 50 years later there is still no clear evidence concerning its significance.22 The use of PACs has decreased over the years, probably influenced by the ESCAPE trial and other studies which showed there was no benefit from PAC monitoring.23,24 However, this study did not enroll CS patients. To date, PACs have never been studied specifically in a CS population.

Existing data were obtained from different study populations and reveal contradictory results.25 In a propensity score-matched retrospective cohort study with the remarkable number of 9,431,944 patients, Hernandez et al. showed that the use of PACs in patients with heart failure was, indeed, associated with increased mortality (9.9% versus 3.3%; OR 3.96; p<0.001); however, in patients with CS, PACs were associated with lower mortality (35.1% versus 39.2%; OR 0.91; p< 0.001).26 Another recently published study and two expert consensus articles support the use of PACs in CS.27–29 Consequently, CS treatment algorithms in current studies include PAC monitoring.12,30 However, because of concerns about the safety of PACs, alternatives, such as transpulmonary thermodilution (TPTD), are being investigated.

Only a few studies have addressed the accuracy and utility of TPTD methods in patients with CS. Schmid et al. compared values derived from TPTD and PAC in a population of 11 patients with CS and found they gave identical results.31 Zhang et al. prospectively randomized 60 patients with AMICS to a pulse contour (invasive) continuous cardiac output (PiCCO)guided therapy group versus standard care and demonstrated a mortality benefit in patients treated with PiCCO, a TPTD method.32 Technical advances in the past decade have opened up new avenues of noninvasive cardiac output monitoring (NICOM). While setting out to assess these innovations, the recently published NICOM study reported disappointing results, showing one NICOM modality to be unreliable in measuring cardiac output in patients with decompensated heart failure and CS.33

Reperfusion strategies

Early revascularization has been accepted for many years as the key intervention to treat patients with AMI to prevent deterioration to CS and is firmly established in current guidelines and recommendations.6,34,35 A significant number of patients with acute MI, however, present with more than one coronary lesion. The CULPRIT-SHOCK trial prospectively showed a culprit-lesion-only percutaneous coronary intervention (PCI) strategy to be superior to an immediate multivessel PCI in patients presenting with AMICS.36 Another aspect was identified in a sub-study of the CULPRIT-SHOCK trial.

Guedeney et al. were able to show that transradial artery access compared with transfemoral artery access was associated with a lower 30-day death rate (34.7% versus 49.7%; adjusted OR 0.56; 95% CI [0.33–

Mechanical Circulatory Support Intra-aortic Balloon Pump

In a subgroup analysis of the IABP-SHOCK II trial, Fuernau et al. investigated the impact of timing of IABP on mortality in CS and found no difference whether IABP was implanted before or after PCI.42

Impella

Although the Impella has been shown to provide superior hemodynamic support to IABP, there are conflicting results with respect to hard outcome parameters.43–45 However, these conflicting results originate mostly from studies comparing Impella to other MCS strategies.44,46-48 To date there is only one study, a retrospective, single-center cohort analysis, comparing Impella to medical treatment in patients after out-ofhospital cardiac arrest due to AMI who subsequently present with CS.49 This analysis suggests an Impella-associated survival benefit at hospital discharge and after 6 months.

Scherer et al. recently presented propensity-score matched data from a retrospective analysis comparing Impella CP (n=70) with non-MCS-treated CS patients (n=70).50 While, naturally, there were more bleeding complications in the Impella groups, mortality rates did not differ.

The ISAR-SHOCK trial compared Impella 2.5 (n=12) with IABP (n=13) in patients presenting with AMICS, and revealed a higher CI in the Impella group.44 Mortality, however, was not influenced.

Manzo-Silberman et al. retrospectively compared Impella 2.5 with IABP in 78 patients and found no difference in mortality, but a higher rate of bleeding complications in the Impella group.46 Patients in the Impella group were on higher catecholamine doses (epinephrine 2.3 mg/h versus 1.0 mg/h; p=0.04) and their left ventricular (LV) ejection fraction was lower (25% versus 35%; p=0.01), indicating the groups were not balanced with respect to illness severity.

In 2017, Ouweneel et al. presented the IMPRESS study, the first prospective multicenter trial comparing Impella CP (n=24) with IABP (n=24).47 This study, again, showed no significant difference in mortality rate (50% versus 46%; p=0.92); differences in bleeding complications also failed to reach statistical significance. Notably, all patients in the Impella group and 83% of the IABP group underwent cardiopulmonary resuscitation before device implantation.

A study by Pieri et al., though retrospective, single-centered and nonrandomized, also identified aspects warranting further evaluation.48 As in

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Cardiogenic Shock: Past, Present, and Future Outlook the study by Manzo-Silberman et al., patients in the Impella group (2.5 and CP models) were more critically ill, as indicated by more frequent catecholamine support (93% versus 57%; p=0.002), and were on higher doses of inotropes (indicated by an inotropic score of 8 versus 5; p=0.02).

Nevertheless, the 30-day mortality rate tended to be lower in the Impella group (79% versus 94%; p=0.11). In any case, mortality rates of 79% or 94% appear conspicuously high. At 6-month follow-up, LV ejection fraction and cardiac recovery rate were higher in the Impella group. A retrospective comparison of historical cohorts on Impella versus IABP support by Alushi et al. yielded similar results.51

ECLS and Impella.58 In this context, the results from the currently recruiting DanGer Shock trial are eagerly awaited.59 In this multicenter RCT, Udesen et al. are prospectively comparing Impella CP versus conventional therapy in patients with AMICS.

Another remarkable study, by Schrage et al., compared Impella 2.5 and CP with a historical control group from the IABP-SHOCK II trial treated with IABP or medical treatment; it showed no survival benefit for the Impella group, but more bleeding and peripheral vascular complications.52 Adjusting the control group to IABP patients alone did not change the results; however, a comparative analysis after adjusting for medical treatment alone was not performed.

Veno-arterial Extracorporeal Life Support

The recently published propensity-matched, registry-based, retrospective cohort study by Dhruva et al. attracted attention after reporting a higher adjusted risk of in-hospital death or major bleeding complications under Impella support compared to IABP.53 This study, however, has been heavily criticized for statistical limitations and incomplete conditions for comparison.54 In contrast, Lemor et al. retrospectively analyzed data of 6,290 patients from the US National Inpatient Sample register to compare Impella with veno-arterial extracorporeal membrane oxygenation (VA-ECMO) in patients with AMICS.55 In this propensity score-matched study, patients treated with Impella had a significantly lower in-hospital mortality rates than those receiving V‑A ECMO (26.7% versus 43.3%; OR: 2.10; p=0.021).

However, these data are based on the International Classification of Diseases (ICD) and CS was thus identified on the basis of the ICD code, not on hemodynamic parameters. Furthermore, there was no discrimination as to the specific devices or cannulation strategies. Despite these substantial limitations, the impressive number of patients must be acknowledged, and the results are consistent with current findings that VA-ECMO is not, at least not in isolation, the panacea for CS. On the basis of available data, there are growing calls for limiting the unrestricted use of Impella in AMICS.56 The limitations of these data, however, bring us back to the root of the problem. While propensity-score matched analyses mitigate numerous limiting factors of retrospective studies, they are still not RCTs and significant limitations remain. Wellpowered, prospective, multicenter RCTs producing high-quality data to delineate the significance of Impella are still lacking, and numerous other questions, such as those concerning timing of implantation, choice of Impella device, combination with other devices or just suitable patient selection, have not yet been sufficiently addressed.

For example, Nersesian et al. identified a lactate level >8 mmol/l or having received cardiopulmonary resuscitation before implantation as predictors for increased 30-day mortality in a mixed etiology cohort of patients with CS treated with Impella 5 or 5.5.57 Indeed, the use of Impella 5 or 5.5 in CS after cardiopulmonary resuscitation was associated with an increase in 30-day mortality (92% versus 41%, p=0.001).

Another approach, intended to reduce bleeding and other complications, is the ECMELLA 2.0 concept, where single arterial access is used for VA-

The recently published consensus statement by the European Association of Percutaneous Cardiovascular Interventions and the Association for Acute Cardiovascular Care recommends Impella CP to be considered for short-term MCS in CS stage C and D with a potentially reversible underlying cause, as a bridge to transplant, or in ventricular assist device candidates.60 The Extracorporeal Life Support Organization published a position paper in 2019 addressing the nomenclature of ECLS.61 According to this, ECLS is defined as a set of therapies that focus on oxygenation, carbon dioxide removal, cardiac support, or a combination thereof. ECMO is one ECLS entity used for temporary support of patients with respiratory and/or cardiac failure. Therefore, in general, the term ECLS is used in this article; when reviewing former studies that used the term ECMO, this terminology was maintained.

Even though VA-ECLS is significantly older than Impella, high-quality data are even more scarce. The first RCTs that systematically addressed the role of VA-ECLS in CS have only been published in the past 2 years.

The retrospective cohort analyses by Lemor et al. discussed above, which has significant limitations, showed VA-ECLS to be inferior to Impella in treating CS.55 Pozzi et al. recently published a retrospective observational analysis from their institutional database of patients treated with VA-ECMO in AMICS.62 Between 2007 and 2017, they treated 56 patients with VA-ECMO and demonstrated a survival-to-discharge rate of 41.1% (n=23). Notably, the results of a subgroup analysis showed that patients aged ≤60 years had a better chance of survival. This matches the findings of Muller et al., who identified an age of ≥60 years as an independent risk factor for death during an ICU stay.63 However, in Pozzi et al.’s study, the survival rate with VA-ECMO did not substantially exceed common survival rates of CS treated conventionally. Relatively little is known about their local MCS protocols, and it is questionable whether a median of less than six patients per year can support a complex intervention like ECLS to become standard care.

The only published randomized trial comparing VA-ECMO treatment of CS with standard care is the ECLS-SHOCK trial.64,65 Forty-one patients with AMICS were randomized to receive VA-ECMO or not. There was no difference in the primary endpoint of LV recovery. All-cause mortality after 1 year showed no difference either but a trend of lower mortality in the VA-ECLS group was observed (19% versus 38%; p=0.31). Mortality was a secondary endpoint though, and the study was underpowered to detect a difference.

Left Ventricular Unloading and ECMELLA

Despite the ability of VA-ECLS to support cardiac and pulmonary function, there are considerable limitations and disadvantages to this approach.

The increase in LV afterload and consecutive rise in LV wall stress impeding recovery has been known about for many years.66–68 The mortality-reducing effect of LV unloading regardless of the method applied (IABP, Impella, right upper pulmonary vein drainage, or transseptal left atrial cannula) has been underlined by recent meta-analyses.69-71

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Cardiogenic Shock: Past, Present, and Future Outlook Table 3: Ongoing Trials in Cardiogenic Shock Name

n

Status

Study Type

Intervention

Medical Treatment Trials in CS COCCA (NCT03773822)

380

Recruiting

RCT MC

Combination of hydrocortisone + fludrocortisone versus placebo

DAPT-SHOCK-AMI (NCT03551964)

304

Recruiting

RCT MC

Comparison of intravenous cangrelor and oral ticagrelor in patients with acute MI complicated by initial cardiogenic shock and treated with primary angioplasty

ACCOST-HH (NCT03989531)

150

Recruiting

RCT MC

Adrecizumab versus placebo

Mechanical Circulatory Support Trials in CS EURO SHOCK (NCT03813134)

428

Recruiting

RCT MC

Early intervention with ECMO therapy or standard treatment with no ECMO

REVERSE (NCT03431467)

96

Recruiting

RCT MC

Patients randomized to the experimental arm will have an Impella-CP implanted in addition to VA-ECMO within a maximum of 10 hours of institution of VA-ECMO

ECMO-CS (NCT02301819)

120

Recruiting

RCT MC

Immediate VA-ECMO versus early conservative therapy according to standard practice

DanShock (NCT01633502)

360

Recruiting

RCT MC

Impella CP versus conventional circulatory support

ECLS-SHOCK (NCT03637205)

420

Recruiting

RCT MC

PCI (or CABG) plus medical treatment + extracorporeal life support in CS versus PCI (or CABG) plus medical treatment

UNLOAD-AMI (NCT04562272)

80

Recruiting

RCT SC

Mechanical unloading by Impella-CP for 36-48 hours, as add-on to the standard treatment versus standard treatment

SMART-RESCUE II (NCT04143893)

1,000

Recruiting

RCT SC

MCS + medical treatment versus medical treatment alone

CABG = coronary artery bypass graft; Coh = prospective cohort analysis; ECMO = extracorporeal membrane oxygenation; MC = multicenter; nyR = not yet recruiting; PCI = percutaneous coronary intervention; R = recruiting; RCT = randomized controlled trial; SBP = systolic blood pressure; SC = single center; VA-ECMO veno-arterial extracorporeal membrane oxygenation.

The latest study addressing the combination of VA-ECLS with an Impella for LV-unloading, called ECMELLA, was recently published by Schrage et al.72 This retrospective, international, multicenter, 1:1 propensity-score matched cohort analysis compared 510 patients with CS treated with VAECMO with or without LV unloading by Impella. LV unloading was associated with a lower 30-day mortality (HR 0.79; 95% CI [0.63–0.98]; p=0.03). This reduction in mortality was seen even though patients with LV unloading were more likely to experience complications such as severe bleeding (38.4% versus 17.9%; p<0.01), access site-related ischemia (21.6% versus 12.3%; p<0.01), abdominal compartment syndrome (9.4% versus 3.7%; p=0.02), and a requirement for renal replacement therapy (58.5% versus 39.1%; p<0.01). Even though the data give a signal for the beneficial effect of LV unloading, this concept, again, is based on retrospective analysis of observational studies and adequate RCTs are missing.

Extracorporeal Life Support in Cardiopulmonary Resuscitation

Since VA-ECLS is quite easily and rapidly implanted at the bedside, provides biventricular and pulmonary support, and is furthermore of comparatively low cost, it distinguishes itself as a firstline MCS for patients in cardiac arrest.

In 2020, Yannopoulos et al. presented the ARREST trial, comparing ECMOfacilitated resuscitation with standard advanced cardiac life support treatment in patients with out-of-hospital cardiac arrest and refractory VF.73 For just short of a year, they randomly assigned 15 patients to each group, and there was a 36 percentage point better survival rate in the ECMO-facilitated resuscitation group (43% versus 7% survival; HR 0.16; 95% CI [0.06 – 0.41]; p<0.0001). Notably, all survivors in the ECMO group had good cerebral performance scores at 6 months. Although the trial

was planned to enroll 77 patients, it was discontinued after the first interim analysis because of the superiority of VA-ECMO.

Hypothermia

The discussion whether mild hypothermia in patients with AMICS but not specifically after cardiac arrest improves morbidity and mortality has been ongoing for several years.74 The SHOCK-COOL trial investigated the impact of therapeutic hypothermia (33°C) for 24 hours in AMICS patients without a history of cardiac arrest.75 The primary endpoint was the cardiac power index after 24 hours; secondary endpoints were several hemodynamic parameters and lactate levels. There was no difference in the cardiac power index or hemodynamic parameters. Lactate levels were higher in the hypothermia group; there were no significant differences in 30-day mortality (60% versus 50%; HR 1.27; 95% CI [0.55–2.94]; p=0.55).

The HYPO-ECMO trial, a prospective, multicenter RCT examining the impact of moderate hypothermia (33–34°C) during VA-ECLS in CS patients, was recently completed and is expected to be published in 2022.76

Current Clinical Trials

Table 3 and Supplementary Material Table 1 provide an overview of ongoing clinical trials in the field of CS. Besides some trials investigating medical therapies, a considerable number of MCS studies have been initiated.

Interestingly, despite the conflicting evidence regarding the significance of Impella in CS, only the DanGer trial and the UNLOAD-AMI trial (NCT04562272) are focusing on this question.59 The ECMO-CS trial

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Cardiogenic Shock: Past, Present, and Future Outlook Table 4: Unresolved Issues in Cardiogenic Shock Care Basic Treatment

Medical Treatment

Method of invasive hemodynamic Catecholamine regimens measurement Antiplatelet drugs Target mean arterial pressure Anticoagulation Transfusion strategies

Target blood glucose level

Anti-inflammatory and immunomodulatory approaches

Interventional Treatment

Mechanical Circulatory Support

Others

Revascularization strategy (PCI versus bypass)

Timing of implantation

Genetic factors predisposing or contributing to CS

Timing of completion of revascularization after initial treatment of the culprit lesion

Patient selection

Duration of MCS Device selection

Role of endothelial dysfunction in CS

Anticoagulation regime Avoidance and monitoring of limb ischemia

CS = cardiogenic shock; MCS = mechanical circulatory support; PCI = percutaneous coronary intervention.

(NCT02301819) and the EURO-SHOCK trial (NCT03813134) will examine the impact of early ECLS intervention in patients with CS. Eagerly anticipated are the results of the REVERSE trial (NCT03431467) by Schrage et al., who are prospectively investigating the potential superiority of the ECMELLA concept compared with VA-ECLS alone.72

Conclusion

CS remains a leading cause of death in patients with acute cardiac diseases. Despite a considerable number of studies in the field of CS, major areas of care are poorly understood. Table 4 provides an overview of unresolved issues in CS care.

The key question in management of CS is how to interrupt the vicious cycle of CS progression. With AMICS, revascularization is crucial; nonetheless, evolving CS has to be treated symptomatically. Inotropic and vasopressor support has shown to have limited benefit or even cause harm in CS.77,78 The effect MCS can have on stabilizing hemodynamics has led to its widespread use, but is yet to be shown to improve clinical outcomes that matter to patients and caregivers.

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79. Schrage B, Beer BN, Savarese G, et al. Eligibility for mechanical circulatory support devices based on current and past randomised cardiogenic shock trials. Eur J Heart Fail 2021; 23:1942–51. https://doi.org/10.1002/ejhf.2274; PMID: 34145680.

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ORIGINAL RESEARCH

Interventional Cardiology

Dual Antiplatelet Regimens for Transcatheter Aortic Valve Replacement and Corresponding Cardiac CT Evaluation of the Leaflets: Single-center Experience Mirvat Alasnag, MD, FACC, FACP, FSCAI, FSCCT, ,1 Waqar Ahmed, MD, FACC, FACP, FSCAI,1 Ibrahim Al-Nasser,2 and Khaled Al-Shaibi, MD, FACC, FACP, FSCAI1 1. Cardiac Center, King Fahd Armed Forces Hospital, Jeddah, Saudi Arabia; 2. Radiodiagnostics Department, King Fahd Armed Forces Hospital, Jeddah, Saudi Arabia

Abstract

Background: Transcatheter aortic valve replacement (TAVR) is a globally established therapy. However, there is significant variability in the antithrombotic management post-procedure. The data on antiplatetet and direct antithrombin agents suggest antiplatelet agents suffice. The degree of leaflet thickening on cardiac CT and the clinical implications of this finding remain poorly understood. Here, the authors aim to examine a low-risk cohort treated with dual antiplatelet therapy and the corresponding cardiac CT and clinical findings. Methods: This is a descriptive single center study examining patients who received dual antiplatelet therapy post-TAVR from 2017 to 2019. Patients underwent clinical, echocardiographic and cardiac CT follow up. Signs and symptoms of ischemic stroke, valve function, gradient, and cardiac CT findings of hypo-attenuated leaflet thickening and reduced leaflet mobility were recorded for all those who completed 6 months of follow-up. The study was registered and approved by the Ethics Committee. Results: A total of 116 patients were included. Hypo-attenuated leaflet thickening was detected in 11 patients. Only one had accompanying reduced leaflet mobility and an increase in gradient. This patient did not have any evidence of stroke or valve dysfunction.

After switching to rivaroxaban, the gradient improved and a repeat cardiac CT demonstrated resolution of the leaflet thickening. Conclusion: This study illustrates the utility of cardiac CT in detecting leaflet thickening and restricted mobility post-TAVR in low-risk individuals treated with dual antiplatelet therapy. However, its role in guiding antithrombotic regimens cannot be ascertained from this study and additional larger scale studies comparing different regimens in both symptomatic and asymptomatic patients are necessary. Trial Registration: N/A.

Keywords

Transcatheter aortic valve implantation, dual antiplatelet therapy, cardiac computed tomography, leaflet thickening Disclosure: MA is on the US Cardiology Review editorial board; this did not affect peer review. All other authors have no conflicts of interest to declare.

Ethics: The Declaration of Helsinki is noted by all authors and its principles understood and adopted in this study.

Informed Consent: Informed consent to participate was obtained from all individuals involved in the study.

Data Availability: The authors elect that research data are not shared.

Received: April 7, 2021 Accepted: September 23, 2021 Citation: US Cardiology Review 2022;16:e04. DOI: https://doi.org/10.15420/usc.2021.07 Correspondence: Mirvat Alasnag, King Fahd Armed Forces Hospital, PO Box 9862, Jeddah 21159, Saudi Arabia. E: mirvat@jeddacath.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Transcatheter aortic valve replacement (TAVR) is an established method for the treatment of severe aortic stenosis in inoperable, high-risk and intermediate-risk individuals. Recently, the indication for TAVR was expanded to include low-risk individuals based on the PARTNER 3 and Evolut Low Risk Trials.1,2 These trials demonstrated equivalent outcomes in terms of mortality and stroke between transcatheter and surgical valve replacements.

To date, there remains no consensus on the optimal antiplatelet or antithrombotic regimen to reduce stroke and ensure valve durability (Figure 1). The American College of Cardiology (ACC) valve guidelines currently recommend aspirin or clopidogrel monotherapy in the periprocedural period in patients without an indication for anticoagulation therapy. Then, for the first 3–6 months after TAVR, either single or dual antiplatelet therapy (DAPT) is recommended, based on the individual bleeding risk. After the initial 3–6 months, single antiplatelet therapy is recommended long-term. For those with an indication for anticoagulation,

the guidelines recommend aspirin or clopidogrel monotherapy only (no anticoagulation) in the periprocedural period. In the first 3–6 months post-procedure, anticoagulation with or without single antiplatelet therapy is recommended, depending on the risk of bleeding. After the initial 3–6-month post-procedure period, oral anticoagulation monotherapy is recommended.3 Cardiac CT (CCT) evaluation of the prosthetic valves is often employed to detect thickening, hypo-attenuated leaflet thickening (HALT) and reduced leaflet mobility (RELM). These findings have been described in the literature and assist in grading the degree of bioprosthetic leaflet thickening and dysfunction following TAVR. Figure 2 provides an illustration of the grading described by Jilaihawi et al.4 The PORTICO IDE study, RESOLVE registry, the SAVORY registry and the PARTNER 3 CT sub-study were all trials that assessed leaflet motion and HALT using CCT in those who were asymptomatic, as well as those who suffered a stroke after TAVR. In these trials, there was poor correlation of the CCT findings with clinical outcomes

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Dual Antiplatelet Regimens for TAVR and Cardiac CT Evaluation of Leaflets Figure 1: Integrated Approach to Patient Management Plans After a Transcatheter Aortic Valve Replacement Procedure

CCT expertise and volume Randomized data Validated CCT Systemic protocols embolization or other symptoms

RELM and HALT Patient factors: AF, antiplatelet resistance, atheromatous aorta

Cerebral embolic protection Valve-invalve

THV preparation

Operator expertise and volume

Worsening transvalvular gradients

Antithrombotic regimen CCT = cardiac CT; HALT = hypo-attenuated leaflet thickening; RELM = reduced leaflet mobility TAVR = transcatheter aortic valve replacement; THV = transcatheter heart valve.

Figure 2: Grades of Reduced Leaflet Mobility

Grade 0

Grade 1

Grade 2

Grade 0

Normal

Grade 1

<25%

Grade 2

25–50% restriction

Grade 3

50–75% restriction

Grade 4

>75% restriction

Grade 3

Grade 4

Systematic CT methodology for the evaluation of subclinical leaflet thrombosis was described by Jilaihawi et al. in 2017 in JACC: Cardiovascular Imaging.4

in particular stroke and valve function.5–8 The GALILEO 4D sub-study included patients without an indication for long-term anticoagulation who had undergone successful TAVR.9 A rivaroxaban-based antithrombotic strategy was adopted and found to be more effective than an antiplateletbased strategy in preventing subclinical leaflet-motion abnormalities.

However, in the main GALILEO trial, the rivaroxaban-based strategy was associated with a higher risk of death and thromboembolic complications as well as a higher risk of bleeding than the antiplatelet-based strategy.10 Accordingly, it was terminated early and direct oral anticoagulants are currently not routinely recommended after TAVR. The objective of this single center observational study is to examine the clinical, echocardiographic and CCT findings of all patients receiving DAPT after their TAVR procedure. The aim is to identify any clinical correlation of this regimen with the incidence of HALT or RELM and define the role of CCT in the evaluation of patients with worsening gradients or symptoms.

Methods

This is a single center retrospective descriptive study of all patients who underwent TAVR using the Sapien XT, Sapien 3, CoreValve, Evolut R or Acurate Neo valve between 2017 and 2019. Patients above the age of 18

undergoing transfemoral TAVR were enrolled. For those who successfully completed the TAVR procedure and were discharged from the hospital, a follow-up CCT was arranged at 6 months and they were included in the final analysis. As part of the center’s protocol, all patients received a DAPT regimen consisting of a loading dose of aspirin 300 mg and clopidogrel 600 mg the day before the planned procedure and aspirin 81 mg daily and clopidogrel 75 mg daily for 1 year followed by a single antiplatelet therapy consisting of aspirin 81 mg daily. Those with AF as an indication for anticoagulation were placed on a direct oral anticoagulant (apixaban 5 mg twice daily or rivaroxaban 20 mg daily) alone on the first day postprocedure (if no bleeding complication occurred) and continued indefinitely. Patients on anticoagulation for reasons other than AF, specifically the presence of a mitral mechanical valve prosthesis, were excluded. Other exclusion criteria were valve-in-valve TAVR, aspirin allergy, bleeding or thrombotic disorders, or those requiring alternate access.

Baseline demographics, characteristics, Society of Thoracic Surgeons (STS) score for mortality and echocardiographic findings and clinical outcomes were compiled through a chart review. Patients were followed up clinically and echocardiographically at 1 month, 3–6 months and 1 year as part of the routine protocol. The echocardiographic findings at baseline and 6-month follow-up consisted of left ventricular function, hypertrophy, valve gradient, valve regurgitation and other valve disease. Patients were also assessed clinically for symptoms as part of their routine evaluation on the day of the follow-up echocardiogram. Those who completed 6 months of follow up underwent CCT examination of the aortic valve prosthesis.

Cardiac CT Protocol

The CCT findings at follow up primarily focused on the bioprosthetic valve leaflet thickness, attenuation and mobility, and paravalvular leak.

Examinations were acquired in the caudocranial direction using a dualsource CT system (Siemens Somatom Definition Flash, Siemens Healthcare). Retrospective ECG-gating with high-pitch helical (3.4) acquisition was employed. Contrast media (Ultravist 350 mg/ml) was administered as a 10 ml test bolus followed by 50 ml for all scans. Saline flush (50 ml) was the employed chaser. Heart rate reduction with β-blockade (metoprolol) was prescribed for the majority of patients to achieve a rate <65 BPM. Standard collimation of 128 by 0.750 mm, a gantry rotation time of 280 ms, and a tube current ranging from 450 to 750 mA with a fixed tube potential of 100 kV (BMI <30 kg/m2) or 120 kV (BMI >30 kg/m2) was selected for the acquisition protocol. Current modulation to 20% of maximum was used when possible for dose reduction. Images were evaluated on the Syngo Via workstation using multiplanar reformatting (slice thickness 0.75 mm), maximal intensity projections (slab thickness of 3–5 mm) in short axis, two chamber long axis and four chamber long axis as well as 3D volume rendered reconstruction of the aortic valve using automated aortic valve and prosthetic valve views, as well as 4D volume rendering. The maximal leaflet excursion was assessed using at least 10–15 phases. The distance between the frame margin and the maximally open leaflet tip of the thickened leaflet and the center of the frame was measured to determine the excursion.

HALT was classified in accordance with previously published definitions as follows: present requiring further assessment of impaired leaflet mobility; absent; or indeterminate (uninterpretable scan).4 Similarly, RELM was classified as follows (Figure 2): Grade 0, normal; Grade 1, <25%; Grade 2, 25–50% restriction; Grade 3, 50–75% restriction; Grade 4, >75% restriction.4

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Dual Antiplatelet Regimens for TAVR and Cardiac CT Evaluation of Leaflets Statistical Analysis

Continuous variables are presented as mean ± SD. Categorical variables are presented a percentage.

Table 1: Baseline Characteristics Characteristic

n=116, n (%)

Mean age (years)

76

Women

46 (39.7)

Diabetes

55 (47.4)

Hypertension

96 (82.8)

Hyperlipidemia

90 (77.6)

A total of 116 patients were included in this study. The mean age was 76 years and 39.7% were women. The baseline characteristics are summarized in Table 1. Of note, three patients had a prior history of a cerebrovascular accident and three had peripheral vascular disease that required revascularization in the past. At baseline, five patients had AF and were receiving oral anticoagulation (all were direct antithrombin inhibitors). The mean STS score was 2.85 ± 1.35. The baseline mean ejection fraction was 54.3% (range 30–75% ), mean gradient 50 mmHg and mean peak gradient 80 mmHg. DAPT was assigned to 111 of the total group, with five requiring anticoagulation for AF (four rivaroxaban and one apixaban).

Renal insufficiency

12 (10.3)

Pulmonary disease

10 (8.6)

Coronary artery disease

40 (34.5)

Peripheral vascular disease

3 (2.6)

LV systolic dysfunction

29 (25)

Cerebrovascular disease

3 (2.6)

Coagulopathy

1 (0.86)

Porcelain aorta

3 (2.6)

Prior PCI

21 (18.1)

Prior CABG

10 (8.6)

The valves implanted are shown in Table 2. The aortic valve annulus ranged from 18 mm to 34 mm (mean 24.55 mm). There were two cerebrovascular events recorded in this low-risk cohort. The two strokes occurred during the index hospitalization; both were ischemic events and both patients were receiving DAPT. One was a watershed infarction due to profound hypotension during the procedure. The second occurred within the first 24 hours of the procedure and was deemed embolic. There were no mortalities recorded in this cohort during the initial follow up before a CCT was performed or during the subsequent 6 months (Table 3).

STS score (%); mean ± SD

2.85 ± 1.35

Patient and Public Involvement

The involvement of patients was only through their chart review with no direct impact on their institutionally determined management plan.

Results

Echocardiographic findings at 6-month follow-up are summarized in Table 4. Mean gradient was 12 mmHg. One patient had an increased mean gradient of 40 mmHg at 6 months. This patient was receiving DAPT that was subsequently changed to rivaroxaban. Incidentally, his CCT showed mild HALT and 25–50% restricted excursion. He was asymptomatic and had no clinical evidence of stroke.

The CCT images obtained for all 116 patients were interpretable with very little artifact registered. HALT was detected in 11 of the total patients enrolled (Table 5, Figures 3 and 4, and Supplementary Figures 1 and 2).

Ten of the 11 patients did not have accompanying RELM or increase in valve gradient on echocardiography. None of the 11 patients had any symptoms or clinical parameters of concern. The one patient with thickening and limited mobility with an elevated mean gradient across the aortic valve was converted to rivaroxaban therapy. A follow-up echocardiogram and CCT 3 months later demonstrated improved gradient (14 mmHg) and a significant reduction in HALT.

Discussion

The cohort reported in this study is a low-risk cohort with a mean STS score of 2.85. Nevertheless, 47.4% had diabetes and 82.8% had hypertension, which places them at risk for stroke. The population in this study is representative of the general population treated in the region at a high volume TAVR center with a 10-year-old TAVR program. The protocols adopted are also representative of most practices in the region with DAPT being the standard of care. DAPT was assigned to 111 of the total, with only five requiring anticoagulation (four rivaroxaban and one apixaban) for underlying AF. None of the five receiving anticoagulation had leaflet abnormalities on CCT. This number is too small to draw any meaningful

CABG = coronary artery bypass grafting; LV = left ventricle; PCI = percutaneous coronary intervention; STS = Society of Thoracic Surgeons.

Table 2: Type and Number of Valves Implanted Valve

n=116

Sapien 3

68

Sapien XT

25

Evolut R

1

CoreValve

19

Acurate Neo

3

Table 3: Clinical Follow-up at 6 Months Event

n=116, n (%)

Permanent pacemaker

11 (9.5)

Stroke

2 (1.7)

Death

0 (0)

Table 4: Echocardiographic Follow-up at 6 Months Parameter

n=116

Aortic valve mean gradient (mmHg); mean ± SD

12.84 ± 4.51

Paravalvular regurgitation, n (%):

• • • •

None

87 (75)

Trace

27 (23.2)

Mild

1 (0.86)

Moderate

1 (0.86)

Mean left ventricular ejection fraction (%)

54.3

conclusions on the role of oral anticoagulation for the treatment of newly implanted TAVR valves, particularly direct oral anticoagulants. The only available data for direct thrombin inhibition is that provided by the GALILEO 4D trial, which was terminated early because of excessive mortality.9 Other ongoing studies include the ENVISAGE and ATLANTIS

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Dual Antiplatelet Regimens for TAVR and Cardiac CT Evaluation of Leaflets Table 5: Cardiac CT Follow-up at 6 Months Parameter

trials examining oral anticoagulation post TAVR in individuals with underlying AF.11,12 The POPular TAVI study concluded that among patients who underwent TAVR and had an indication for long-term anticoagulation, oral anticoagulation alone was associated with a reduction in all bleeding and procedural bleeding compared with oral anticoagulation plus clopidogrel. Oral anticoagulation alone compared with oral anticoagulation plus clopidogrel was noninferior with respect to major adverse ischemic events. However, only 24% were treated with a direct oral anticoagulant.13

n=116, n (%)

Hypo-attenuated leaflet thickening grade 0

105 (90.5)

1

11 (9.5)

2

1 (0.86)

3

0 (0)

As for antiplatelet regimens, the ARTE trial randomized 222 patients to aspirin (80–100 mg/day) plus clopidogrel (75 mg/day) or aspirin alone.

The rate of major or life- threatening bleeding events at 3 months was higher in the DAPT arm and there was no difference between the two arms in the rate of ischemic stroke, MI or death.14 The SAT-TAVI study evaluated 120 patients undergoing TAVR. Subjects were randomly assigned to aspirin or DAPT (aspirin plus clopidogrel 75 mg or plus ticlopidine 500 mg). There was no difference between the two arms in the rate of ischemic stroke (DAPT 1.7%; SAPT 1.7%; p=not significant).15 Based on such studies, DAPT is currently the regimen employed by the majority of TAVR centers worldwide and is the currently adopted recommendation of the ACC valve guidelines.3 Our cohort did not display any increase in bleeding or ischemic events with a DAPT regimen.

Reduced leaflet mobility grade 0–1

105 (90.5)

2

11 (9.5)

3

1 (0.86)

4

0 (0)

Figure 3: Cardiac CT at 3 Months Demonstrating Early Grades of Hypo-attenuated Leaflet Thickening and Reduced Leaflet Mobility A

B

A: Minimal intensity projections of an Edward Sapien 3 valve in multiple projections; B: 3D volume rendered images of a deployed Edward Sapien 3 valve.

Figure 4: Cardiac CT at 3 Months Demonstrating the Absence of Hypo-attenuated Leaflet Thickening and Reduced Leaflet Mobility A

B

C

D

The role of CCT in the evaluation of TAVR prosthesis is still not well understood. CCT is a powerful tool to detect leaflet dysfunction and thickening with a high positive predictive value and sensitivity.

Nevertheless, there is poor correlation with clinical events. In our cohort, there were only two cerebrovascular events, of which only one was ischemic and occurred eight months after the TAVR procedure. This patient did not have any HALT or RELM detected on CCT. To date, all studies evaluating leaflet thickening and anticoagulation found poor correlation between anticoagulation regimens, HALT symptoms and valve function (the PORTICO IDE study, RESOLVE registry, SAVORY registry and the PARTNER 3 C Trial).5–8 In our study, all patients underwent a CCT to evaluate the leaflets. The CCT was interpretable and provided accurate information. In the majority of patients, >90%, DAPT was sufficient with no evidence of leaflet dysfunction by CCT. In those with leaflet thickening and limited leaflet mobility, the majority had no symptoms and only one had a high mean gradient. This patient had grade 3 HALT and a high mean gradient, but did not develop any symptoms or any clinical ischemic events. The patient was receiving DAPT that was switched to rivaroxaban.

Although the gradient decreased by echocardiography and the grade of HALT decreased, he did not express any change in symptoms or overall activity. In the GALILEO 4D trial patients underwent a CCT at 3 months in both the rivaroxaban (n=115) and DAPT (n=116) arms. Similar to our study, there were too few events to permit any conclusion on the impact of HALT and RELM on clinical outcomes. However, what was notable in that study was that there were fewer thickened leaflets with restricted mobility in the rivaroxaban arm compared with the DAPT arm.9 The incidence of HALT by valve type cannot be analyzed based on this small cohort. Finally, cerebral embolic protection devices were not used in any of the patients enrolled in this study. Hence, the incidence of stroke was not impacted by use of such devices. Of note, any potential benefit of embolic protection would be in the immediate post-procedure period and not the intermediate term follow-up captured in this study, which was 6 months.

A and B: Minimal intensity projections of an Evolut CoreValve in multiple projections; C and D: 3D volume rendered images of a deployed Evolut CoreValve.

CCT is an accurate tool to detect and grade leaflet thickening and restricted mobility in TAVR prosthesis.6 At this time, the detailed

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Dual Antiplatelet Regimens for TAVR and Cardiac CT Evaluation of Leaflets information provided by CCT is required only if patients are symptomatic (especially ischemic stroke) or the gradients on echocardiography have increased. Implications on the management once HALT and RELM are detected on CCT remain uncertain. Nevertheless, the majority of clinicians would opt to switch antiplatelet regimens to anticoagulation if a significant increase in gradient is associated with HALT/RELM. Based on the current body of CCT evidence generated by studies including this one, DAPT appears to be a reasonable initial regimen post TAVR in those without an indication for anticoagulation. For those undergoing valve-in-valve procedures, suffer systemic embolizations or have sustained elevation of gradients, CCT cannot define the antithrombotic regimen based on the currently available evidence nor is it supported by the guidelines.

Limitations

This is a relatively small single-center study that may not be representative of other center practices. Additionally, this is a low-risk population and the 1.

2.

3.

4.

5.

6.

Leon MB, Mack MJ, Hahn RT, et al. Outcomes 2 years after transcatheter aortic valve replacement in patients at low surgical risk. J Am Coll Cardiol 2021;77:1149–61. https://doi. org/10.1016/j.jacc.2020.12.052; PMID: 33663731.

Popma JJ, Deeb GM, Yakubov SJ, et al. Transcatheter aorticvalve replacement with a self-expanding valve in low-risk patients. N Engl J Med 2019;380:1706–15. https://doi. org/10.1056/NEJMoa1816885; PMID: 30883053.

Otto CM, Nishimura RA, Bonow RO, et al. 2020 ACC/AHA guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol 2021;77:e25– 197. https://doi.org/10.1016/j.jacc.2020.11.018; PMID: 33342586.

Jilaihawi H, Asch FM, Manasse E, et al. Systematic CT methodology for the evaluation of subclinical leaflet thrombosis. JACC Cardiovasc Imaging 2017;10:461–70. https:// doi.org/10.1016/j.jcmg.2017.02.005; PMID: 28385256.

Fontana GP, Bedogni F, Groh M, et al. Safety profile of an intra-annular self-expanding transcatheter aortic valve and next-generation low-profile delivery system. JACC Cardiovasc Interv 2020;13:2467–78. https://doi.org/10.1016/j. jcin.2020.06.041; PMID: 33153563.

Kazuno Y, Maeno Y, Kawamori H, et al. Comparison of SAPIEN 3 and SAPIEN XT transcatheter heart valve stent-

7.

8.

9.

10.

11.

role of both DAPT and CCT at 6 months may not be applicable for a higher-risk population requiring closer and longer follow-up and more intensive therapy. Finally, CCT protocols and expertise may not be widely available to permit wide scale use of CCT for routine follow up. However, these are real-world data representative of the type of patients undergoing TAVR, the standard regimen of DAPT and the utility of CCT in most tertiary care centers in this region.

Conclusion

Our study demonstrates the ability of CCT to detect and grade leaflet thickening and restriction post-TAVR in low-risk individuals treated with DAPT. However, the role of CCT in guiding antithrombotic regimens cannot be ascertained from this study. Additional larger scale randomized studies determining the ability of CCT to impact prognosis and to compare the efficacy of different regimens in both symptomatic and asymptomatic patients are necessary, particularly in high-risk populations.

frame expansion: evaluation using multi-slice computed tomography. Eur Heart J Cardiovasc Imaging 2016;17:1054–62. https://doi.org/10.1093/ehjci/jew032; PMID: 27002141.

Sondergaard L, De Backer O, Kofoed KF, et al. Natural history of subclinical leaflet thrombosis affecting motion in bioprosthetic aortic valves. Eur Heart J 2017;38:2201–7. https://doi.org/10.1093/eurheartj/ehx369; PMID: 28838044.

Makkar RR, Blanke P, Leipsic J, et al. Subclinical leaflet thrombosis in transcatheter and surgical bioprosthetic valves: PARTNER 3 cardiac computed tomography substudy.

J Am Coll Cardiol 2020;75:3003–15. https://doi.org/10.1016/j. jacc.2020.04.043; PMID: 32553252.

De Backer O, Dangas GD, Jilaihawi H, et al. Reduced leaflet motion after transcatheter aortic-valve replacement. N Engl J Med 2020;382:130–9. https://doi.org/10.1056/NEJMoa191142; PMID: 31733182.

Dangas GD, Tijssen JGP, Wöhrle J, et al. A controlled trial of rivaroxaban after transcatheter aortic-valve replacement. N Engl J Med 2020;382:120–9. https://doi.org/10.1056/ NEJMoa1911425; PMID: 31733180.

Van Mieghem NM, Unverdorben M, Valgimigli M, et al.

Edoxaban versus standard of care and their effects on clinical outcomes in patients having undergone transcatheter aortic valve implantation in atrial fibrillationrationale and design of the ENVISAGE-TAVI AF trial. Am Heart J 2018;205:63–9. https://doi.org/10.1016/j.ahj.2018.07.006;

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PMID: 30172099.

12. Collet JP, Berti S, Cequier A, et al. Oral anti-Xa anticoagulation after trans-aortic valve implantation for aortic stenosis: The randomized ATLANTIS trial. Am Heart J 2018;200:44–50. https://doi.org/10.1016/j.ahj.2018.03.008; PMID: 29898848.

13. Nijenhuis VJ, Brouwer J, Delewi R, et al. Anticoagulation with or without clopidogrel after transcatheter aortic-valve implantation. N Engl J Med 2020;382:1696–707. https://doi. org/10.1056/NEJMoa1915152; PMID: 32223116.

14. Rodés-Cabau J, Masson JB, Welsh RC, et al. Aspirin versus aspirin plus clopidogrel as antithrombotic treatment following transcatheter aortic valve replacement with a balloon-expandable valve: the ARTE (aspirin versus aspirin + clopidogrel following transcatheter aortic valve implantation) randomized clinical trial. JACC Cardiovasc Interv 2017;10:1357–65. https://doi.org/10.1016/j.jcin.2017.04.014; PMID: 28527771.

15. Stabile E, Pucciarelli A, Cota L, et al. SAT-TAVI (single antiplatelet therapy for TAVI) study: a pilot randomized study comparing double to single antiplatelet therapy for transcatheter aortic valve implantation. Int J Cardiol 2014;174:624–7. https://doi.org/10.1016/j.ijcard.2014.04.170; PMID: 24809922.

REVIEW

Cardiogenic Shock

Hemodynamic-based Assessment and Management of Cardiogenic Shock Jaime Hernandez-Montfort, MD, MPH, MSc, ,1 Diana Miranda, MD,2 Varinder Kaur Randhawa, MD, PhD, ,3 Jose Sleiman, MD, ,2 Yelenis Seijo de Armas, MD, ,2 Antonio Lewis, MD, ,2 Ziad Taimeh, MD, ,3 Paulino Alvarez, MD, ,3 Paul Cremer, MD, MPH,3 Bernardo Perez-Villa, MD, MSc, ,2 Viviana Navas, MD,2 Emad Hakemi, MD, MSc,2 Mauricio Velez, MD,2 Luis Hernandez-Mejia, MD,2 Cedric Sheffield, MD,2 Nicolas Brozzi, MD, ,2 Robert Cubeddu, MD,2 Jose Navia, MD,2 and Jerry D Estep, MD3 1. Department of Medicine, Division of Cardiology, Baylor Scott and White Health, Temple, TX; 2. Department of Cardiovascular Medicine, Cleveland Clinic Florida, Weston Hospital, Weston, FL; 3. Department of Cardiovascular Medicine, Kaufman Center for Heart Failure and Recovery, Heart, Vascular and Thoracic Institute, Cleveland Clinic, Cleveland, OH

Abstract

Cardiogenic shock (CS) remains a deadly disease entity challenging patients, caregivers, and communities across the globe. CS can rapidly lead to the development of hypoperfusion and end-organ dysfunction, transforming a predictable hemodynamic event into a potential highresource, intense, hemometabolic clinical catastrophe. Based on the scalable heterogeneity from a cellular level to healthcare systems in the hemodynamic-based management of patients experiencing CS, the authors present considerations towards systematic hemodynamic-based transitions in which distinct clinical entities share the common path of early identification and rapid transitions through an adaptive longitudinal situational awareness model of care that influences specific management considerations. Future studies are needed to best understand optimal management of drugs and devices along with engagement of health systems of care for patients with CS.

Keywords

Cardiogenic shock, acute myocardial infarction, acute decompensated heart failure, post-cardiotomy shock, pulmonary embolism, valvular heart disease Disclosures: JHM has acted as a consultant for Abiomed. JE has acted as a consultant for Abbott and Getinge. All other authors have no conflicts of interest to declare.

Received: March 24, 2021 Accepted: August 13, 2021 Citation: US Cardiology Review 2022;16:e05. DOI: https://doi.org/10.15420/usc.2021.12 Correspondence: Jaime Hernandez-Montfort, Department of Medicine, Division of Cardiology, Baylor Scott and White Health 20401 South 31st St, Temple, TX 76508.

E: jaime.hernandezmontfort@bswhealth.org Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Cardiogenic shock (CS) remains a deadly disease entity, challenging patients, caregivers, and communities across the globe.1 The spectral and time-sensitive nature of CS is compromised by clinical heterogeneity and access to an interdisciplinary health system structure capable of delivering disease-specific diagnostic and therapeutic services.2 Clinical trials and registry-based studies have historically enrolled patients with CS that is refractory to fluid resuscitation and/or requires vasoactive agents to improve systolic blood pressure ≥90 mmHg. CS was defined by the presence of systemic hypoperfusion and tissue hypoxia from systolic blood pressure <90 mmHg for ≥30 minutes in the setting of severe myocardial dysfunction. However, the heterogeneity of CS populations has led to varying clinical outcomes due, in part, to different responses to standard treatment modalities.3,4 Current algorithmic initiatives endorsing management based on hemodynamic profiling among patients with CS have predominantly focused on acute MI (AMI)-related CS.5 Recently, contemporary registry data have identified CS related to heart failure (HF), post-cardiotomy, pulmonary embolism (PE), or valvular heart disease as distinct clinical phenotypes to AMI-CS, with specific risk-related classifications and invasive hemodynamic profiles beyond the previously mentioned standard clinical definition.6 Within the AMI-, HF-, PE-, and VHD-related

phenotypes, there are additional specific considerations, such as right ventricular infarction and fulminant viral myocarditis, refractory cardiac arrest (CA), PE burden, or stenotic or regurgitant valvular lesions, which have distinct invasive hemodynamic and imaging characteristics and unique modes of treatment with acute mechanical circulatory support (AMCS).7–9 CS can rapidly lead to the development of hypoperfusion (lactate elevation) and end-organ dysfunction (lung, renal, and/or hepatic injury), transforming a predictable hemodynamic event into a potential highresource, intense, hemometabolic clinical catastrophe, which may be further challenged by its heterogeneous and time-sensitive nature.10–12 Although the use of AMCS continues to increase, there is a paucity of data on the management trends and strategies derived from the utilization of invasive hemodynamic monitoring.13 Importantly, distinct interpretations as to the value of a pulmonary artery catheter (PAC) arise from the extrapolation of studies among patients with acute decompensated HF without CS.14 Recently, the use of complete hemodynamics among patients with PAC for AMI- and HF-related CS was associated with increased survival.15 However, granular details on the information derived from the PAC and echocardiography as a tool to guide management remain limited among patient cohorts of AMI- and non-AMI-CS.16

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Hemodynamics in Cardiogenic Shock Defining hemodynamic time zero in non-AMI-CS (compared to AMI-CSderived metrics such as door-to-balloon time) and how early intervention and transitions affect the longitudinal outcomes of patients remain major global challenges.17,18 The administrative mechanisms and networks required to allow patients to transition to a center capable of providing timely clinical, hemodynamic, and imaging profiling in CS are limited; however, despite heterogeneous practices among healthcare systems, a well-outlined spectral severity of illness has been identified with novel severity-based classifications.19,20 Furthermore, the effect of delaying access to dedicated cardiac intensive care units with a hemodynamicbased approach in CS remains a frontier that affects our interpretation of transitions, disease trajectory, and severity staging while impacting our connection with frontline caregivers.21,22 Based on the scalable heterogeneity from a cellular level to healthcare systems in hemodynamicbased management of patients experiencing CS, we present considerations towards systematic hemodynamic-based transitions in which distinct clinical entities (AMI-CS, HF-CS, CA-CS, post-cardiotomy shock [PCS], PE-CS, and VHD-CS; Supplementary Material Table 1) share the common path of early identification and rapid transitions through an adaptive longitudinal situational awareness model of care that influences specific management considerations.23

Early Hemodynamic-based Recognition of Cardiogenic Shock

The proposal for the standardized care of patients with CS has been predominantly derived from an AMI-oriented perspective, driven by the need for time-sensitive therapeutic interventions such as revascularization therapy or AMCS to optimize door-to-balloon or door-to-unloading time, respectively.24,25 Despite the prior and ongoing randomization of patients on AMI-CS in focused randomized control trials (RCTs), there is a paucity of data leading to the identification of CS beyond clinical signs of hypotension and hypoperfusion.26 Furthermore, the inclusion of additional factors, such as heart and vascular mechanical complications, CA, extracardiac end-organ support (mechanical ventilation and renal replacement therapy), and underlying systemic or cardiac illness, has been poorly characterized.26 Severity-of-illness characterization remains limited by the early integration of dynamic clinical, hemodynamic, and imaging data in a systematic approach across the CS care spectrum.27,28 Data regarding comprehensive non-invasive (e.g. point-of-care ultrasound [POCUS], pulse oximetry index derived), minimally invasive (e.g. arterial pressure waveform derived), and invasive (e.g. PAC) hemodynamic monitoring for the diagnosis of CS are limited.29–31 Clinical information can be derived from a first responder evaluation of vital signs (e.g. tachycardia, pulse pressure), an electrocardiogram (e.g. injury, atrial or ventricular arrhythmias, conduction disease, and/or dyssynchrony), a chest X-ray (e.g. congestion, consolidation, mediastinal widening, cardiomegaly), and laboratory evaluation of end-organ function parameters (e.g. cardiac injury/congestion biomarkers, renal and hepatic function surrogates, and systemic inflammatory response syndrome responsiveness).32 POCUS imaging can estimate right and left heart function and rule out pericardial effusion and other AMI-related complications, such as acute mitral regurgitation (MR), ventricular septal defect (VSD), and free wall rupture.33 Among HF-CS and mixed phenotypes associated with myocardial injury, particularly in cases presenting de novo, myocardial function and structure can, for example, help identify fulminant myocarditis or amyloid heart disease diagnoses.34,35 Echocardiography can also provide comprehensive hemodynamics with quantitative measures of the derived cardiac index using the left ventricular outflow tract (LVOT) velocity time integral (VTI),

and surrogates of estimated left and right heart loading conditions, including estimated right atrial pressure (RAP), pulmonary artery systolic pressure, and elevated pulmonary artery capillary wedge pressure (PCWP).36,37 Among those with a clinical and/or echocardiographic suspicion of CS, invasive hemodynamic evaluation can help with further CS profiling.38

Early Hemodynamic-based Transitions in Heart Failure-related Cardiogenic Shock

Once clinical and non-invasive hemodynamic and imaging evaluation has been established by first responders, patients with suspected CS should have immediate access to invasive hemodynamic, as well as valvular and coronary, profiling in the hybrid cardiac catheterization laboratory with percutaneous and surgical capacities.5 This facilitates a better understanding of cardiopulmonary interactions, particularly if patients have a high inotrope/vasoactive index and a need for additional respiratory and metabolic support with mechanical ventilation and/or renal replacement therapy.39 Furthermore, this allows for best practices of ultrasound- or fluoroscopic-guided access techniques and supra- or subdiaphragmatic insertion of AMCS with subsequent distal limb protection.40,41 Patients with AMI-CS or PE-CS are distinct from other CS entities because, for example, coronary or pulmonary artery revascularization is a timesensitive intervention that can affect left and/or right myocardial performance and subsequent disease trajectory.42,43 Patients in whom hemodynamic CS profiles indicate right heart-predominant congestion in the form of impaired RAP and pulmonary artery pulsatility index, even in the absence of hemometabolic CS and advanced Society for Coronary Angiography and Intervention stages, remain a high-risk cohort.44,45 Establishing invasive hemodynamic monitoring for both decision making and subsequent critical care surveillance (Figure 1) enables an ongoing conversation with the interdisciplinary team focused on:

• • • •

active management with hemocompatibility assessment; the choice and titration of inotrope/vasoactive agents; the choice of AMCS and evaluation of device dependency; consideration for revascularization, thrombectomy, or valvular interventions; • cardiovascular-focused optimization of mechanical ventilation parameters; • the addition of pulmonary vasodilators; and • decongestion with diuretics and/or renal replacement therapy.46–49 Triggers for early hemodynamic re-profiling include: refractory hypotension and/or hypoxemia, intractable or worsening arrhythmias, major bleeding, right heart failure, structural or mechanical heart lesions, and performance limitations of AMCS.50 Index and follow-up invasive hemodynamic profiling is of critical importance among patients with an inability to recover and requiring evaluation for replacement therapies, such as durable ventricular assist device and heart transplantation.51

Multimodality Hemodynamic Management in Heart Failure-related Cardiogenic Shock

The clinical adaptation of hemodynamics in CS to evaluate responsiveness to cardiovascular therapeutics, including AMCS, remains a concept with limited data and multiple practice patterns across the globe.52 There is also limited information on the longitudinal impact of serial invasive PAC hemodynamic monitoring among patients with AMI-CS and HF-CS, and of routine pressure–volume loops to best understand dynamic ventricular– arterial coupling.53 The value of increased team-based awareness of

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Hemodynamics in Cardiogenic Shock Figure 1: Clinical, Hemodynamic, and Imaging Longitudinal Profiling

Fulminant Myocarditis BiV Profile Hemometabolic SCAI E to D

Clinical, hemodynamic, and imaging longitudinal (re)profiling in biventricular, hemometabolic, Society for Coronary Angiography and Intervention Stage E heart failure-related cardiogenic shock associated with enterovirus-related lymphocytic fulminant myocarditis (Day 0) transitioned to myocardial recovery (Day 9).

impaired loading conditions, right and left heart unit axis coupling, and myocardial performance in CS incorporating imaging and hemodynamics remains elusive, with studies restricted to single-center cohorts with distinct approaches.54–56 However, the recently endorsed use of the PAC along with other device-associated parameters can help understand performance and trends in heart function and structure, as well as AMCS, including counterpulsation, transvalvular pumps, and/or extracorporeal membrane oxygenation (ECMO).57,58 Patients supported with counterpulsation with significant coronary disease, left heart congestion, and/or conditions associated with poor atrial compliance or severe MR can benefit from hemodynamic and imaging surveillance with dynamic sequential weaning and hemodynamic monitoring.59,60 Patients with transvalvular pumps also have central aortic pressure recording and pump positioning, and new-generation Smart Assist is able to provide additional information, such as surrogates of left or right heart loading conditions, including left or right ventricular enddiastolic pressure and cardiac output.61,62 Device-related surrogates can be then incorporated to available clinical, hemodynamic, and imaging information to best understand transitions to weaning and recovery.63 The role of invasive hemodynamics on veno-arterial ECMO (VA-ECMO) with or without transvalvular pumps or counterpulsation remains elusive.64,65 Importantly, invasive hemodynamics on all patients under AMCS can help with the early detection of complications related to hypovolemia associated with bleeding (low RAP), acute right heart failure (high RAP, elevated RAP/PCWP ratio and low right ventricular stroke work index), and cardiac tamponade related or not to specific AMI-related mechanical complications (elevated RAP and pulmonary artery diastolic pressure with associated hypotension).66 Furthermore, AMCS

management (Figure 2) can be established by hybrid methodologies in which surrogates or right heart loading conditions can be identified noninvasively by echocardiography and left heart loading conditions can be identified among those patients with pre-existing invasive hemodynamic surveillance strategies (e.g. implantable pulmonary artery monitor) coupled with the above-mentioned clinical and routine echocardiography and device-related surveillance mechanisms.67,68 Although invasive hemodynamic monitoring and AMCS offer targeted guidance for the management of patients with CS resulting from different etiologies and provide information on the concomitant presence of other shock states (e.g. septic, hemorrhagic, distributive, or neurogenic), it is still critical to weigh the risk–benefit ratio of these diagnostic and therapeutic interventions in these critically ill patients. Whether percutaneous or surgical interventions, all require vascular access and put the patient at higher risk of complications, including vascular injury leading to excessive bleeding, thrombosis, or distal limb ischemia; myocardial injury leading to tamponade or valvular regurgitation; neurologic injury; and infection.69 In general, vascular sheaths range in size from 7 to 29 Fr, with larger sheaths facilitating access for the AMCS and providing more support.69 Furthermore, although hemostasis can be achieved by manual compression for those AMCS using smaller-sized vascular sheaths, closure systems such as the Angioseal, Perclose, or large bore closure devices can facilitate hemostasis after removal of AMCS using largersized vascular sheaths.69 Surgical closure may be required in the event of vascular injury. When using closure systems, it is important to understand whether the clinical trajectory of a patient may require vascular access at that site in the near term (i.e. within 3 months).

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Hemodynamics in Cardiogenic Shock Figure 2: Hemodynamic, Device-related, and Imaging Hemodynamic Contextualization in the Weaning of Transvalvular Microaxial Flow Pumps

Imaging

Device hemodynamics

How often to wean? At least daily Decongestion achieved Adequate hemocompatibility Low ventilation settings Low inotropes/vasoactive index Low pump dependency Absent infection

What to look for? Combination of variables Unchanged heart rate Increased pulse pressure Improved LV/RV contractility Increased LVOT VTI >12 cm Increased CI by Fick Unchanged LVEDP, RAP, mPAP, and PCWP

CI = cardiac index; LV = left ventricle; LVEDP = LV end-diastolic pressure; LVOT = LV outflow tract; mPAP = mean pulmonary arterial pressure; PCWP = pulmonary capillary wedge pressure; RAP = right atrial pressure; RV = right ventricle; VTI = velocity time integral.

Hemodynamic Considerations in Mechanical Complications Related to AMI-CS

Although rare due to contemporary early reperfusion strategies, patients with AMI-CS can still present with mechanical complications (e.g. left ventricle [LV] free-wall rupture, VSD, papillary muscle rupture with severe MR, dynamic LVOT obstruction, pseudoaneurysm, and true aneurysm) leading to acute pulmonary edema or refractory CS.70,71 Hemodynamic monitoring can elucidate the consequences of such complications, whereas bedside echocardiography or POCUS can further identify their type, size, and location, along with the presence and direction of shunts.

Initial resuscitation efforts may require vasoactive drugs and mechanical ventilatory support.70,71 Positive-pressure ventilation can improve gas exchange and hemodynamics by augmenting cardiac output by reducing MR and LV afterload.70,71 AMCS is often required for additional myocardial unloading and hemodynamic stabilization, particularly as a temporary bridge to definitive revascularization and delayed myocardial rupture or aneurysm repair to facilitate reduced patch dehiscence and postoperative bleeding from antiplatelet therapy.70,71 In the perioperative setting, AMCS can help attenuate respiratory and hemodynamic deterioration during anesthetic induction for intubation.70,71 Although surgery has long been the mainstay, percutaneous options in patients with prohibitive surgical risk are emerging.71,72 Notably, most studies evaluating AMCS in CS largely excluded patients with mechanical complications (e.g. the IABP-Shock II trial and SHOCK Trial registry).4,42,71 Patients with multiorgan failure may benefit from biventricular mechanical circulatory support or VA-ECMO with LV venting. In these instances, the LV vent reduces LV afterload, the pulmonary shunt

fraction, and pulmonary edema; this facilitates improved gas exchange, reduces acute lung injury and Harlequin or North–South syndrome, and minimizes the risk of LV or aortic thromboses.70,71 In VSD, certain venting strategies, such as the Impella, may exacerbate right-to-left aspiration of deoxygenated blood and peripheral systemic embolization of necrotic LV debris.70,71

Hemodynamic Considerations in Cardiogenic Shock After Cardiac Arrest

The ARREST trial recently showed that ECMO-facilitated resuscitation increases survival compared with standard advanced cardiac life support protocols in patients presenting with out-of-hospital CA and refractory ventricular fibrillation or tachycardia.73 The trial was stopped early given the significant survival benefit achieved with early ECMO. The criteria used in the trial included shockable rhythm, no return of spontaneous circulation after three defibrillation shocks and an estimated transfer time of <30 minutes.73 Patients presenting with two or more of these criteria have an extremely poor prognosis. Time from the 911 call to ECMO initiation has been shown to be the most important independent predictor of survival in these patients.73 The use of PAC for hemodynamic profiling is recommended in all patients undergoing AMCS, including ECMO therapy, to monitor effectiveness, determine the need for escalation, optimize device settings, and guide the timing and rate of weaning.15 Furthermore, hemodynamic practices used by VA-ECMO centers around the world highlight some areas that need continuing evaluation, including choosing the ideal cannulation strategy for each patient, setting the flows and monitoring the interaction of the circuit and the patient’s circulation, dealing with LV pressure and volume overload, and removing support either after recovery or for palliation purposes.

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Hemodynamics in Cardiogenic Shock Figure 3: Adoption of Real-world Data and Contemporary Classification in the Management of Heart Failure-related Cardiogenic Shock

HF-CS NIDCM

One drug

HF-CS NIDCM

BiV profile Hemometabolic IABP responder SCAI D to C

One drug

One device

BiV profile Hemometabolic IABP non-responder SCAI D to C

One device

Transition to heart replacement

Transition to heart replacement

Clinical adaptation of clinical (HF-CS) hemodynamic and metabolic responsiveness to acute mechanical circulatory support using modified Cardiogenic Shock Working Group SCAI stages.

BiV= biventricular; HF-CS = heart failure-related cardiogenic shock; IABP = intra-arterial balloon pump; NIDCM = non-ischemic dilated cardiomyopathy; SCAI = Society of Coronary Angiography and Interventions.

Echocardiography provides many advantages in these scenarios: it may help direct therapy by defining the exact pathologic process leading to CS; it allows real-time guidance of wires and cannulas and reassessment of cardiac performance during cannulation; and it is crucial when weaning VAECMO because parameters such as LV ejection fraction (LVEF) >20–25%, LVOT VTI >12, the absence of LV dilatation, and no cardiac tamponade have been suggested to indicate successful weaning.74 Numerous adjunctive LV unloading strategies have been implemented to decompress the LV mechanical load. LV afterload is increased after initiation of VA-ECMO, which can lead to progressive LV distention and stasis in the setting of extremely poor cardiac function. This can exacerbate arrhythmias, myocardial ischemia, pulmonary edema, thrombus formation, and myocardial recovery. A systematic review and meta-analysis explored the efficacy, safety, and optimal timing of LV venting in patients with CS requiring VA-ECMO.75 Most patients in the study had LV venting with an intra-aortic balloon pump and more than 50% of patients underwent early venting (within 12 hours). The study concluded that LV venting significantly improved weaning from VA-ECMO and decreased short-term mortality, especially if implemented early.75 There are currently two ongoing randomized trials, namely Early LA venting during venoarterial ECMO support (EVOLVE-ECMO; NCT03740711) and the Impella CP with VA ECMO for Cardiogenic Shock (REVERSE; NCT03431467), which may provide alternative options for LV venting.

Various studies have described predictors of successful weaning from VAECMO. In 2010, Aissaoui et al. described a weaning strategy that tested daily hemodynamic tolerance of ECMO flow reduction trials using clinical, hemodynamic, and Doppler echocardiography parameters associated with successful ECMO removal.76 All weaned patients had partially or fully recovered severe cardiac dysfunction, had tolerated a full ECMO weaning trial, and exhibited certain echocardiography parameters (VTI ≥10 cm, LVEF >20–25%, and spectral tissue Doppler imaging mitral annulus peak systolic velocity ≥6 cm/s at minimal ECMO flow support).76 Currently, weaning strategies are mostly based on echocardiography parameters, as highlighted above. However, these parameters fail to provide

information about right heart function, systemic hemodynamics, and tissue perfusion. Success of resuscitation from circulatory shock involves normalization of microcirculatory and tissue perfusion. Impairment of sublingual microcirculation has been associated with CS, and inability of VA-ECMO to recruit this microcirculatory alteration predicts adverse outcomes following its implementation.

The results of a prospective observational study by Akin et al. showed that functional parameters of microcirculation, including total vessel density and perfused vessel density, reflect recovery from CS and predict successful weaning from VA-ECMO.77 Many areas of uncertainty remain, and the role and application of extracorporeal cardiopulmonary resuscitation (ECPR) remain controversial. For example, the definition of ECPR lacks granularity, and there are no clear inclusion or exclusion criteria to determine which patients would benefit from the procedure.

Finally, the most commonly considered outcomes of ECPR are death, neurological damage, and multiorgan failure. However, other possible outcomes should be considered. For example, in patients evolving to brain death, ECPR ensures end-organ perfusion, making them suitable for organ donation. In addition, patients who do not recover appropriate cardiac function but remain neurologically intact can be further bridged to heart transplant or durable mechanical circulatory support.

Conclusion

CS remains a challenging entity affecting patients and health systems across the globe, requiring an interdisciplinary system-wide approach to avoid hemometabolic presentation and to foster an environment of early transition to remission, replacement, and/or palliation. Hemodynamicbased management of CS within a platform of situational awareness can help advance the care pathways among prehospital and front line caregivers. Further research is needed in order to best acquire, scale, and transparently present and understand longitudinal transitions using hemodynamic surrogates at different levels of care and across distinct clinical phenotypes within a wide spectrum of illness and therapeutic options. Creating longitudinal registries with granular systematic data adjudication can help deconstruct this major global public health problem

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Hemodynamics in Cardiogenic Shock by triggering quality and patient-reported benchmarks in addition to adequate design of RCTs across a network of CS centers. Finally, future studies also need to explore timing around initiation and weaning, the optimal management of drugs and devices, and the engagement of 1.

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REVIEW

Cardiogenic Shock

Advocacy and Legislation for Regionalization Practices in the Treatment of Cardiogenic Shock: The Time Is Now Kari Gorder, MD, , Steve Rudick, MD, , and Timothy D Smith, MD The Christ Hospital and Lindner Center for Research and Education, Cincinnati, OH

Abstract

Cardiogenic shock is a complex hemodynamic state that, despite improvements in care, often remains challenging to treat and confers a high mortality rate. Timely application of advanced strategies, including advanced hemodynamic management and mechanical circulatory support, is of the utmost importance for this critically ill patient population. Based on data and historic experiences with similar life-threatening conditions, a national system in the US of regionalized, structured care for patients with cardiogenic shock has the potential to improve outcomes and save lives. To enact this, national and state leaders, as well as federal regulatory bodies, physician thought leaders, industry representatives, and national organizations, must collaborate and advocate for a clear, structured cardiac shock center network with a tiered model for delivery of care for the sickest population of cardiac patients.

Keywords

Cardiogenic shock, legislation, ischemic cardiomyopathy, shock center network, advocacy Disclosure: The authors have no conflicts of interest to declare.

Received: March 25, 2021 Accepted: October 4, 2021 Citation: US Cardiology Review 2022;16:e06. DOI: https://doi.org/10.15420/usc.2021.14 Correspondence: Kari Gorder, The Christ Hospital, 2139 Auburn Ave, Cincinnati, OH 45219. E: kari.gorder@thechristhospital.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Central Illustration: Advocacy and Legislation for Cardiogenic Shock Local Hospital

Prehospital Care Regional legislation

Diagnostic evaluation ± intervention, therapeutics

National mandates Protocols for stabilization and early transfer

Local triage protocols

Minutes

Early identification of CS

Hours to days

Minutes to hours

Legislative and Advocacy Efforts

Regional referral partnerships

Local and national legislation Societal guidelines and best practice recommendations

Cardiogenic Shock Referral Center

Thought leader expert opinion Industry support

Level 1 CICU 24/7 shock team Advanced MCS options

© RADCLIFFE CARDIOLOGY 2022 www.USCjournal.com

Durable VAD and/or transplant ability Multidisciplinary care

Current model Regionalized model

Advocacy and Legislation for Cardiogenic Shock Cardiogenic shock (CS), defined as a low-output cardiac state resulting in severe end-organ hypoperfusion, is a life-threatening condition requiring prompt recognition and intervention. Despite improvements in the diagnosis and management of conditions leading to CS, including early revascularization of patients with acute coronary syndrome and increased options for the application of mechanical circulatory support (MCS), the incidence of CS has increased over the past decade and in-hospital mortality remains high.1 The timely recognition, treatment, and referral of patients with CS remains paramount. However, unlike with other timesensitive disease states, there is no coordinated management and referral network in the US for these complex cardiac patients. In this article, we summarize the evidence for timely access to cardiac shock centers, review best-practice recommendations for regionalization of care for CS patients, and summarize the advocacy and legislation work to date in the field.

Timely Access to Care for Cardiogenic Shock Patients Improves Outcomes

Significant advances over the past several decades in the care of patients with cardiovascular disease have led to overall improvements in care delivery and outcomes. For example, for patients with ST-elevation MI (STEMI), timely identification and early revascularization efforts have led to a reduction in mortality of over 20%.2 However, patients presenting with CS have not shared the same fate, and unfortunately remain at high risk of further decompensation and death. Although there is some evidence that outcomes have improved slightly in certain populations of CS patients, other studies still demonstrate mortality rates approaching 50%.3,4 Although expedient first medical contact to intervention for STEMI patients is a guideline-driven recommendation, time to intervention or initiation of treatment or support for patients with CS remains unstandardized. Once CS is suspected as the etiology for a patient’s decompensated state, timely diagnosis, treatment, and escalation of care as needed are paramount to improving survival. After the landmark SHOCK trial, early revascularization with percutaneous coronary intervention (PCI) became the standard of care initial management strategy for shock secondary to acute coronary syndrome (ACS).5 Notably, some patients with ACS are at higher risk than others for presenting with or developing CS: recent data suggest that among ACS patients, those with STEMI experience a greater in-hospital risk of CS (4.4%) than those who present with a non-STEMI (1.6%), together representing over 60,000 patients each year.6,7 For non-ACS patients with CS, there is very little randomized trial data regarding management and, as such, recommendations for this population have been extrapolated from the ACS data. Interestingly, although early revascularization efforts have decreased overall mortality in ACS patients with shock, the mortality rate for patients with ACS-derived CS remains higher than for those with a non-ACS etiology.8 Regardless, for the vast majority of patients with CS, initial management will invariably involve coronary angiography, invasive hemodynamic monitoring, initiation of vasopressor or inotropic support, and, for some, initiation of MCS. Time to intervention matters for CS: the recent FITT-STEMI trial showed that for patients with both STEMI and CS, every 10-min delay in care resulted in a 3.31% additional mortality rate.9 Some patients with CS will require MCS, although there is a notable lack of guiding data regarding who should receive support, when that support should be applied, and what type of support is best.

Percutaneous options for MCS are varied. Left ventricular support devices include: the intra-aortic balloon pump, which has fallen

somewhat out of favor due to lack of improved survival for CS patients in clinical trials; the Impella 2.5 and CP (Abiomed), microaxial pumps requiring intraventricular insertion across the aortic valve; and the Tandem Heart (LivaNova), which is limited by the need for transseptal puncture.10 Right ventricular support options include the Impella RP (Abiomed) and the Protek Duo (LivaNova). Finally, extracorporeal membrane oxygenation with a left ventricular vent can support the right and left ventricles and also manage hypoxia resulting from pulmonary compromise. Of these, only the Impella family of devices is approved to treat CS by the Food and Drug Administration. Whether MCS should be initiated prior to coronary intervention is also a matter of debate, with a paucity of randomized clinical trial data in this area. Data from the National Cardiovascular Data Registry show that the majority of MCS is initiated during or after PCI for patients who present with ACS.6 STEMIDTU is an ongoing clinical trial evaluating the impact that implementation of upfront MCS (i.e. early door-to-unloading) may have on patients presenting with STEMI.11 Evidence to guide appropriate MCS application in non-ACS CS patients is even more sparse.

Limitations in evidence notwithstanding, the time-sensitive nature of CS has led to a call for a similar concept of early initiation of MCS, with a doorto-support time of ≤90 min, paralleling the STEMI literature.12 Although the field of CS as a whole is plagued by a lack of randomized controlled trials due to the complex nature of enrolling such critically ill patients, increasing retrospective evidence supports this statement. The Detroit Cardiogenic Shock Initiative evaluated the feasibility of upfront invasive hemodynamic monitoring and a protocol-driven application of early MCS with Impella for patients presenting with acute MI complicated by CS (AMICS). They found that with an average door-to-support time of 83 minutes, patients demonstrated a significantly higher survival to explant rate of 85% (versus 51% for historic institutional controls), with a survival to discharge of 76%, far above the national average.13 However, many PCI-capable centers are not able to provide access to advanced MCS options in a timely manner.

In addition, for CS patients who may not require MCS but need the resources of a larger multidisciplinary team, appropriate triage of CS patients is an area of great concern. As such, how patients in CS should achieve access to appropriate care is a salient area of discussion, and an opportunity to improve the delivery of care for these critically ill patients.

Regionalization is Standard of Care for Cardiogenic Shock Patients

While access to cardiac care has increased over the past several decades, there is mounting evidence that higher-volume centers and operators are directly linked to improved outcomes. Although this has been seen across many other areas of medicine, within the realm of cardiac emergencies the evidence suggests a direct correlation between both operator and institutional volume with outcomes for PCI and coronary artery bypass grafting.14,15 This also remains true for the most high-risk subgroups: for patients presenting with acute MI (AMI), there is a significant decline in mortality if PCI is performed by experienced operators at high-volume institutions. This has also been borne out in other high-risk subgroups, such as patients with heart failure, multivessel disease, or other comorbid conditions.16 Based on these data, it is a logical conclusion that for patients with CS of all etiologies, mortality and outcomes could be improved at high-volume centers.

A recent large trial reviewing more than 500,000 admissions for CS demonstrated that large-volume centers are more likely to appropriately treat this complex patient population.17 Compared with lower-volume centers, high-volume centers were more likely to offer standard of care

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Advocacy and Legislation for Cardiogenic Shock revascularization strategies, as well as apply more advanced MCS options. The authors also noted an increase in the application of complementary therapeutic options for patients with end-organ dysfunction, such as dialysis, at higher-volume facilities.17 Most importantly, a lower annual hospital case volume for patients with CS was associated with a significantly increased odds of in-hospital mortality. The authors’ conclusion raised the question as to whether lower-volume centers should consider early stabilization and transfer to higher-volume centers for patients with CS.17 This conclusion was supported by data from the Inova Heart and Vascular Institute’s INOVA-SHOCK Registry, which showed that timely and protocolized application of MCS for CS patients at a highvolume center significantly improved survival.18 This concept, known as regionalization of care, involves establishing systems of care whereby higher-volume, specialized facilities receive patients from outlying regional hospitals using clearly defined criteria and established transfer protocols to facilitate the timely triage of a special population of patients. This schematic has historically been successfully implemented for other emergency medical conditions, such as trauma, STEMI, and stroke, and has been associated with improved outcomes. For example, a large meta-analysis found that the establishment of a national trauma center system resulted in a 15% improvement in mortality for this high-risk patient population.19 Similarly, for cardiac emergencies, many studies have shown the feasibility and benefit of the regionalization of care for patients suffering from STEMIs, out-of-hospital cardiac arrest (OHCA), and aortic dissection.20–22 At the same time as these regionalization efforts have improved delivery of care in other realms, the standard of care for the definitive management of patients with CS has evolved. Recognizing the increasing complexity of patients with acute cardiac pathologies, various international organizations have recommended certain resource, organizational, and staffing requirements for the best delivery of cardiac critical care.23,24 This often involves a multidisciplinary shock team, staffed by interventional cardiologists, advanced heart failure cardiologists, cardiothoracic surgeons, and cardiovascular intensivists, as well as advanced support staff and ancillary services, to include emergency care and transport services. Many CS patients, especially those who require MCS, experience complications, setbacks, and the prospect of long-term care, and the spiritual or emotional needs of this patient population may differ from that of other patients with chronic medical conditions.25 Access to a palliative care team that specializes in the treatment of patients living with advanced heart failure or other end-stage cardiac conditions may only be accessible at a high-volume cardiac center. Establishing palliative care referral criteria for these patients as part of a standardized treatment algorithm may also be useful.26 Research, quality improvement processes, and education are also integral parts of improving the delivery of care to this patient population.24 This has implications for the education and training of the next generation of physicians and providers working in the cardiac space. Education regarding the management of CS, resource utilization, systems of care, and participation in the multidisciplinary heart team approach should be implemented into training pathways.

In summary, to improve the delivery of care to these complex patients, individual hospitals must come together to form partnerships within a regional referral network. Although the acuity and therapeutic capabilities of the ‘spoke’ hospitals may vary, establishing agreed-upon management strategies, delineating clear criteria for the application of advanced MCS, and acknowledging predefined triggers for consideration of transfer are the cornerstones of regionalization efforts.

Advocacy Matters: National Leaders and Associations Call for Regionalized Cardiac Shock Centers

Understanding the time-sensitive nature of access to advanced cardiac care, there is a clear need for organization of the access process: a higher level of care cannot save lives if it cannot be accessed in a timely manner.

Based on the most recent US census data, >60 million Americans live in a rural setting, and it is likely that even more potential patients live a significant distance from a center capable of providing advanced cardiac care.27 A large systematic review from 2016 addressed the degree to which healthcare outcomes are tied to where patients live, finding that lengthy travel times or long distances to appropriate healthcare facilities is strongly associated with worse outcomes.28 In short, we must get the right patients to the right place in the right time.

Drawing on experience from the stroke and trauma populations, it stands to reason that CS patients represent a key patient population that would benefit from regionalization of care with a hub-and-spoke schematic.

Although discussed previously, this concept was formally realized in 2017, when the American Heart Association (AHA) advocated for regionalization of CS patients in a similar manner to that of STEMI and OHCA patients in a landmark scientific statement.29 This proposed system of care contained detailed requirements of the receiving ‘hub’ hospital, to include a Level 1 cardiac intensive care unit (CICU) with 24/7 access for consultations, referrals, and the application of MCS technologies. Similarly, it recognized the varying capabilities of the outlying ‘spoke’ hospitals, highlighting the importance of creating CS treatment algorithms to “standardize regional management practices, provide futility parameters, and determine the timing of transfer once the diagnosis of refractory CS is established.”29 Similar statements have echoed the staffing and capability requirements to merit a Level 1 CICU designation.20 Tchantchaleishvili et al. took this a step further, advocating for organized, statewide networks of tiered centers to care for patients with AMICS.30 In their position piece, Tchantchaleishvili et al. argue that the pillars of acute trauma management in the ‘golden hour’ should be applied to the CS patient: timely recognition of CS, stabilization, and ultimately transfer to another facility with the appropriate resources. Tchantchaleishvili et al. stress that when a patient’s needs exceed a local or initial receiving center’s resources, only essential procedures should be performed, followed by expedient transfer.30 For CS patients, this may mean PCI of a culprit lesion and initiation of inotropic or vasopressor support prior to transfer to a regional facility capable of quickly upgrading the patient to MCS if needed, with the ability to manage the entirety of that patient’s needs for the duration of their illness. Tchantchaleishvili et al. echo the AHA’s spoke-and-hub model, drawing again on the trauma verbiage to describe a level 1 center that is capable of temporary and long-term advanced cardiac care, to possibly include advanced MCS capabilities, a left ventricular assist device (LVAD) program, or a cardiac transplant program.30 Level 2 centers would be capable of temporary MCS support, and level 3 centers would have no ability to provide MCS; both of these types of center would focus on expedient stabilization and transport to level 1 centers by ground or by air.30 For their part, Rab et al. mirrored these recommendations, arguing for a similar ‘systems of care’ treatment pathway for patients with AMICS, referencing again the hub-and-spoke model.12 Rab et al. advocated for designations of cardiac shock care centers, with similar tiers based on available resources to include MCS and the presence of an organized shock team. They also highlighted the importance of the chain of survival

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Advocacy and Legislation for Cardiogenic Shock for CS patients, addressing the need for close collaboration with emergency medical services (EMS) and local emergency departments, as well as the delivery of coordinated, best-practice care between the cardiac catheterization laboratory and the intensive care unit.12

place.34 However, the work for improving trauma care continues; similar to the field of cardiac emergencies, to date there is still no formal national trauma system in the US, and one-third of Americans live in an area without a complete trauma system.32

Altogether, it is evident that thought leaders and national associations alike have achieved a consensus: regionalization of cardiac care for patients with CS represents best-practice care and has the potential to improve outcomes for a patient population that has historically seen unacceptably high mortality rates despite innovation in practice. The framework for CS patients is also clear, focusing on timely recognition, appropriate triage, and expeditious transfer to an appropriate level 1 receiving cardiac care center. How, then, can we achieve a national model for delivery of care?

Looking at cardiac emergencies, the AHA has continued to advocate for coordinated systems of care and has achieved some degree of success with programs, such as Mission: Lifeline, which seeks to support local and regional healthcare systems to improve the care they give to STEMI patients. However, the implementation of STEMI systems of care in the US is limited by regional and local barriers and varies from state to state.35 To improve networked care for trauma patients, national legislation was needed; however, most legislative efforts in the US for patients with cardiac emergencies, especially for the population of patients with CS, have remained at the state level and are regionally quite variable. For example, beginning in 2006, Washington state established a formal cardiac triage process for cardiac patients in the field in addition to stroke patients, known as the Washington State Emergency Cardiac and Stroke (ECS) System. Although almost all prehospital systems have established criteria regarding hospital triage for STEMI patients, Washington state’s protocol includes cardiac arrest patients with return of spontaneous circulation, patients with cardiac conditions leading to pulmonary edema, and those who are hypotensive.36 The Washington State ECS System protocol also prioritizes transfer to a level 1 cardiac hospital over a closer level 2 facility should time allow; these named designations are specific to Washington state, but include criteria such as 24/7 availability of the cardiac catheterization laboratory, cardiac surgery coverage, and appropriate intensive care unit services. Although that protocol does not address patients with CS specifically, this network of care represents progression from historic management of patients with cardiovascular conditions, and acknowledges the concepts of facility triage for patients in CS based on field criteria. Success in implementing this novel structure was achieved through state-level legislation, which required the Washington Department of Health to support an emergency cardiac system, establish protocols and procedures with EMS leaders, and encourage the voluntary participation of local hospitals.37

Legislative and Regulatory Paths Forward for Improving Care for Cardiogenic Shock Patients

Cardiovascular disease remains the leading cause of death in the US, killing almost four times as many Americans each year than trauma.7,31 However, coordinated legislative efforts for a national cardiac care system remain limited, and are essentially absent with regard to CS patients.

Historically, meaningful, systematic change in the healthcare delivery system in the US has required national and state legislative efforts.

Looking at how other similar networks of care have been designed and the legislative support behind them can offer insights into how regionalized cardiac care centers can work to better serve patients with CS. Reference is frequently made to the trauma center designations and networks of regionalized care as a potential model for the treatment of cardiac patients. Although efforts to improve the timely care given to trauma patents in the US dates back to the Civil War, dedicated efforts for a regional trauma network began in earnest in the 1960s with the publication of a seminal report by the National Academy of Sciences entitled Accidental Death and Disability: The Neglected Disease of Modern Society, which labeled trauma care a national epidemic.32,33 After the publication of that report, national surgical and trauma organizations in the US, such as the American College of Surgeons, worked to develop national standards for trauma centers, similar to how the AHA has advocated for standards as to what designates a level 1 CICU. However, for trauma patients, legislation was necessary to formalize these recommendations. Examples of such legislation include the 1966 Highway Safety Act and the 1973 Emergency Medical Services Systems Act, both of which were key in establishing pre-hospital EMS systems and transportation services to get patients to trauma centers in a timely manner. State-level regulation also played a key role: legislation regarding seat belt laws and air bags in cars, for example, was integrated into the national and state law books throughout the 1970s and 1980s, addressing the integral role that injury prevention has in the realm of trauma.32 During this time, the American College of Surgeons established the process for categorizing hospitals into different levels, reflecting the type of trauma care the hospital was able to provide. To date, although the American College of Surgeons does not officially designate a hospital as a trauma center per se, it serves an integral role in surveying hospitals and providing national-level guidance with regard to best practices.

All this advocacy and legislative effort has worked: a landmark study published in 2006 showed that the risk of death for trauma patients was significantly lower if they were treated at a level 1 trauma center, concluding that national-level regionalization efforts should remain in

A similar system has been instituted in the state of Arizona. Led by the Arizona Department of Health Services, the Save Hearts in Arizona Registry and Education (AZ SHARE) system sought to establish formal ‘cardiac receiving centers’ with enhanced capabilities to care for patients after cardiac arrest and other cardiovascular emergencies.38 The success of this program was highlighted in a 2014 paper published in the Annals of Emergency Medicine, reporting a significant improvement in both survival and favorable neurologic outcomes for patients experiencing out of hospital cardiac arrest after the implementation of this regionalization program.39 Extrapolating this success, it stands to reason that expanding regionalized systems of care to CS patients has the potential to save additional lives.

Other states continue to advocate for this principle via legislature: in the state of Georgia, legislation passed in 2017 established the Office of Cardiac Care within the Georgia Department of Public Health, which delineates EMS triage protocols and designates levels of ‘emergency cardiac care centers’ for patients suffering from cardiac emergencies.40 However, it remains clear that there is no unified, collaborative national legislative initiative to coordinate, regionalize, and improve the systems of care for patients with cardiac emergencies, especially for those with CS. Whether the nuances of such a program should be allocated to the individual states or involve a more national legislative presence is a

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Advocacy and Legislation for Cardiogenic Shock matter for debate. Regardless, the achievement of meaningful, longitudinal improved care for this patient population will require close collaboration with national societies, state and national legislative bodies, and thought leaders in the field of cardiovascular emergencies. Finally, financial remuneration can be used, at times, to encourage the implementation of best practices. Outcome-based metrics are increasingly common methods of indexing care and reimbursement, including via government organizations. For example, the Centers for Medicare and Medicaid requires a multidisciplinary heart team approach for patients undergoing transcatheter aortic valve replacement, with requirements as to hospital- and provider-specific volumes and experience.41 Although complex to enact, a similar approach could be implemented for certain CS patients to encourage best-practice care with ultimate referral to a tertiary or quaternary center with the appropriate immediate and long-term resources.

In a similar vein, legislative and regulatory efforts that support increased research for CS patients are needed. As mentioned above, strong evidence for best practices is limited by the inherent challenges that come with studying such a critically ill yet multidimensional population as patients with CS. This has led to the development of variable practice patterns and the use of novel MCS devices without clear guidelines as to their application. Greater leadership and coordination of regulatory efforts in this realm are needed.

The Cardiac Safety Research Consortium ThinkTank is an example of an organization that was created in an attempt to address these challenges.42 This group of leaders in the field, including those from clinical practice and industry from the US and Canada, highlighted several barriers to the generation of high-quality evidence for this patient population, including: the lack of a standardized definition of CS; the use of MCS devices for off-label populations, such as patients with CS without AMI, or the use of these devices for an unspecified duration; challenges regarding enrolling CS patients in clinical trials, including lack of consent and the heterogeneity of these patients; and the operational and logistic challenges of designing a randomized controlled trial for CS patients. They drew parallels to successful research in the stroke population, wherein heterogeneous patients with time-sensitive conditions presented for care and were enrolled with clinical and ethical success. Finally, they called for an international standard for emergency research to aid in the enrollment of CS patients in further studies. The Cardiac Safety Research Consortium 1.

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Kolte D, Khera S, Aronow WS, et al. Trends in incidence, management, and outcomes of cardiogenic shock complicating ST-elevation myocardial infarction in the united states. J Am Heart Assoc 2014;3:e000590. https://doi. org/10.1161/JAHA.113.000590; PMID: 24419737.

Shah RU, Henry TD, Rutten-Ramos S, et al. Increasing percutaneous coronary interventions for ST-segment elevation myocardial infarction in the United States: progress and opportunity. JACC Cardiovasc Interv 2015;8:139– 46. https://doi.org/10.1016/j.jcin.2014.07.017; PMID: 25616918.

Goldberg RJ, Makam RC, Yarzebski J, et al. Decade-long trends (2001–11) in the incidence and hospital death rates associated with the in-hospital development of cardiogenic shock after acute myocardial infarction. Circ Cardiovasc Qual Outcomes 2016;9:117–25. https://doi.org/10.1161/ CIRCOUTCOMES.115.002359; PMID: 26884615.

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ThinkTank also agreed with the establishment of regional centers for the care of the CS patient.

If parallels are drawn to the trauma systems of care as a benchmark, we are on the right track with regard to our efforts to standardize and regionalize the care we provide for patients with CS. Leading national organizations have published clear position pieces and white papers calling for greater coordination and collaboration of care. Efforts are underway to capture high-quality data in this challenging field, and we are moving towards uniform definitions of the disease process with consensus on best practices and standards of care. State legislative bodies have acknowledged gaps in systems of care for cardiac patients and are using their regulatory powers to encourage regional- and state-level collaboration. Regulatory bodies are beginning to recognize expanded indications for MCS devices, although this remains an area in need of further work. The next step involves a clear, unified vision of care across the entire US, and even internationally, with consistent verbiage, clear evidence-based guidelines for best-practice management, and definitive legislative support at the state and national levels, including funding for registry data and quality initiatives.

Conclusion

CS is a complex state of hemodynamic embarrassment that, despite improvements in treatment modalities and delivery of care, often remains challenging to diagnose, frequently fails medical management alone, and confers a high mortality rate. Timely application of advanced strategies, including MCS for some patients, is of the utmost importance for this complex and critically ill patient population. Based on data and experiences with other life-threatening conditions, a nation-wide, wellcoordinated system of regionalized care for patients with CS will facilitate earlier recognition, stabilization, and transfer, with the potential to improve outcomes due to the more rapid application of appropriate escalation of support and care. The importance of establishing improved processes to obtain clinically rigorous evidence with the goal of establishing clearly defined best practices for this patient population cannot be understated. National and state leaders in the US, as well as federal regulatory bodies, physician thought leaders, industry representatives, and national organizations, must collaborate and advocate for a clear, structured cardiac shock center network with a tiered model for to deliver care to the sickest population of cardiac patients.

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35. American Heart Association. Opportunities to improve STEMI systems of care. 2018. https://www.heart.org/en/ professional/quality-improvement/mission-lifeline/ opportunities-to-improve-stemi-systems-of-care (accessed January 22, 2022).

36. Washington State Department of Health. State of Washington prehospital cardiac triage destination procedure. 2011. https:// www.doh.wa.gov/Portals/1/Documents/Pubs/346050.pdf (accessed January 22, 2022).

37. Washington Department of Health. Emergency cardiac and stroke (ECS) system. https://www.doh.wa.gov/ ForPublicHealthandHealthcareProviders/ EmergencyMedicalServicesEMSSystems/ EmergencyCardiacandStrokeSystem/ CategorizationApplications (accessed January 22, 2022).

38. Humble W. Dramatic results from AZ’s cardiac arrest receiving center initiative. 30 July 2014. https://blog. devazdhs.gov/dramatic-results-from-azs-cardiac-arrestreceiving-center-initiative (accessed January 22, 2022).

39. Spaite DW, Bobrow BJ, Stolz U, et al. Statewide regionalization of postarrest care for out-of-hospital cardiac arrest: association with survival and neurologic outcome.

Ann Emerg Med 2014;64:496–506.e1. https://doi.org/10.1016/j. annemergmed.2014.05.028; PMID: 25064741.

40. Georgia Department of Health. Office of Cardiac Care. 2021. https://dph.georgia.gov/cardiac (accessed January 22, 2022).

41. Centers for Medicare and Medicaid National Coverage Analysis. Transcatheter aortic valve replacement (TAVR).

CAG-00430R. 2019. https://www.cms.gov/medicarecoverage-database/view/ncacal-decision-memo. aspx?proposed=N&NCAId=293 (accessed September 8, 2021).

42. Samsky M, Krucoff M, Althouse AD, et al. Clinical and regulatory landscape for cardiogenic shock: a report from the Cardiac Safety Research Consortium ThinkTank on cardiogenic shock. Am Heart J 2020;219:1–8. https://doi. org/10.1016/j.ahj.2019.10.006; PMID: 31707323.

REVIEW

Lifetime Management of Patients with Aortic Valve Disease

Redo-Transcatheter Aortic Valve Replacement: Strategies When the First Transcatheter Aortic Valve Replacement Fails Nils Perrin, MD, MSc,1,2 and Anita W Asgar, MD, MSc

1

1. Department of Cardiology, Montreal Heart Institute, Montreal, Canada; 2. Geneva University Hospitals, Geneva, Switzerland

Abstract

Transcatheter aortic valve replacement (TAVR) is the standard of care for patients with symptomatic severe aortic stenosis at high or prohibitive surgical risk. The 2020 valvular heart disease guidelines from the American College of Cardiology and American Heart Association now include TAVR as a class I indication for patients aged 65–80 years and not at high or prohibitive risk. The longer life expectancy of this patient population raises the issue of TAVR valve durability and the management of bioprosthetic valve failure of TAVR valves. In this review, the authors discuss bioprosthetic valve dysfunction and summarize existing data regarding redo-TAVR and surgery for failed TAVR. Finally, they propose an approach to evaluate patients with failed TAVR and plan for a second TAVR procedure as indicated.

Keywords

Redo-transcatheter aortic valve replacement, transcatheter heart valve failure, valve durability, coronary obstruction Disclosure: The authors have no conflicts of interest to declare.

Received: May 17, 2021 Accepted: October 7, 2021 Citation: US Cardiology Review 2022;16:e07. DOI: https://doi.org/10.15420/usc.2021.18 Correspondence: Anita W Asgar, Montreal Heart Institute, Université de Montreal, 5000 Rue Belanger, Montreal H1T 1C8, Canada. E: anita.asgar@umontreal.ca Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Transcatheter aortic valve replacement (TAVR) is the standard of care for patients with symptomatic severe aortic stenosis at high or prohibitive surgical risk.1–4 The 2020 valvular heart disease guidelines from the American College of Cardiology and American Heart Association now include TAVR as a class I indication for patients aged 65–80 years and not high or prohibitive risk.5 The longer life expectancy of this patient population raises the issue of TAVR valve durability and the management of bioprosthetic valve failure of TAVR valves. In this review, we discuss bioprosthetic valve dysfunction and summarize existing data regarding redo-TAVR and surgery for failed TAVR. Finally, we propose an approach to evaluate patients with failed TAVR and plan for a second TAVR procedure as indicated.

Bioprosthetic Valve Dysfunction

Dysfunction of a biological valve replacement is a well-known entity in the surgical literature that also occurs with TAVR valves. There have been multiple definitions of bioprosthetic valve dysfunction (BVD), the most recent being the Valve Academic Research Consortium (VARC-3) definition.6–8 The VARC-3 definition of bioprosthetic aortic valve dysfunction is comprised of categories including structural valve deterioration, non-structural valve deterioration, thrombosis, and endocarditis (Table 1).

BVD is also divided into three stages of deterioration on the basis of hemodynamic findings as follows:

• Stage 1, morphological valve deterioration.

• Stage 2, moderate hemodynamic deterioration, defined as an

increase in mean transvalvular gradient ≥10 mmHg resulting in a

mean gradient ≥20 mmHg, or new occurrence, or an increase of ≥1 grades of intraprosthetic aortic insufficiency (AI) resulting in greater than moderate AI. • Stage 3, severe hemodynamic deterioration, defined as an increase in mean transvalvular gradient ≥20 mmHg resulting in a mean gradient ≥30 mmHg, or new occurrence, or an increase of ≥2 grades of AI resulting in severe AI. These hemodynamic changes may be caused by structural valve deterioration, valve thrombosis or endocarditis. In addition to these definitions, VARC-3 also stresses the importance of clinical presentation and defines a subclinical presentation as BVD without symptoms or hemodynamic changes, with bioprosthetic valve failure categorized into three stages, ranging from the presence of clinical symptoms to reintervention to valve-related death.8

Management of Failed TAVR Valves Redo-TAVR

Clinical data regarding redo-TAVR due to valve degeneration are scarce and reported outcomes are from case series or small multicenter studies.

Table 2 provides an overview of study size, mechanism of TAVR failure, and clinical outcomes.

The first multicenter international collaborative work was reported by Barbanti et al. pooling data from 50 redo-TAVR procedures out of more than 13,000 procedures.9 Redo-TAVR was performed mostly for aortic regurgitation, including transvalvular or paravalvular regurgitation (78% of cases). The mean time from index to redo-TAVR was 812 days. Interestingly, this delay was significantly shorter among patients undergoing redo-TAVR

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Managing Failed Transcatheter Aortic Valve Replacement Table 1: Classification of Bioprosthetic Valve Dysfunction Type of BVD

Definition

Hemodynamic Changes

Bioprosthetic Valve Failure

Structural valve deterioration

Intrinsic permanent changes to the prosthetic valve

Stage 1: Morphological valve deterioration

Stage 1: BVD with clinically expressive criteria or Stage 3 hemodynamic changes

Non-structural valve deterioration

Not intrinsic to the prosthetic valve (paravalvular regurgitation, PPM)

Stage 2: Re-intervention

Thrombosis

Subclinical Clinically significant

Stage 2: Moderate hemodynamic valve deterioration

Endocarditis

Stage 3: Severe hemodynamic valve deterioration

Duke endocarditis criteria Evidence of abscesses, pus or vegetation by reoperation or autopsy

Stage 3: Valve-related death

BVD = bioprosthetic valve dysfunction; PPM = prosthesis–patient mismatch. Source: VARC-3 Writing Committee et al.8 Adapted with permission from Oxford University Press.

Table 2: Summary of the Major Studies Reporting Redo-Transcatheter Aortic Valve Replacement Outcomes Study

No. Time from Mechanism of Patients TAVR to Device Failure Redo-TAVR*

Type of Valve Implanted

Size of THV for Redo-TAVR (mm)

Mean (± SD) Residual Mean Gradient (mmHg)

Coronary New Mortality (%) Obstruction Pacemaker (%) Rate (%)

Landes et al.10 <1 year

74

68 days [38–154 days]

AS: 16.2%; AR: 73%; combined: 10.8%

Edwards: 41%; Medtronic: 23%

NA

12.6 ± 7.5 (30 days) 1.3 12.9 ± 9.0 (1 year)

Landes et al.10 >1 year

138

5 years [3–6 years]

AS: 37%; AR: 29.7%; combined: 32.6%

Schmidt et al.30

19

644 days AS: 16%; AR: 84% [191–1,831 days]

Barbanti et al.9

50

Salaun et al.31

5

9.6

0.7

11

11 (30 days), 33 (1 year)

812 ± 750 days AS: 21.7%; AR: 78.3% Edwards: 40%; 23 (16%), 26 (30%), 12.5 ± 6.1 Medtronic: 58%; 27 (2%), 29 (42%), (in-hospital) Lotus: 2% 31 (10%)

2

8.6

N/A (30 days and 1 year); 14.9 (at a median follow-up of 586 days)

5 years

N/A

N/A

N/A

Edwards: 80%; Medtronic: 20%

23 (5%), 26 (16%), 29 (63%), 31 (16%)

9.1 ± 1.2 (1 year)

1.4 (30 days), 11.7 (1 year)

0

AS: 20%; AR: 60%; combined: 20%

Edwards: 63%; Medtronic: 37%

5.4 (30 days), 16.4 (1 year)

23 (60%), 26 (20%), 15.6 (N/A) 29 (20%)

*Data are given as mean ± SD or as the median [interquartile range]. AR = aortic regurgitation; AS = aortic stenosis; N/A = not available; TAVR = transcatheter aortic valve replacement .

for paravalvular leak (PVL) compared with valve stenosis or regurgitation.

Redo-TAVR in these 50 cases was performed with no in-hospital death or disabling stroke. The mean aortic gradient and standard deviation improved after redo-TAVR, with values remaining slightly higher compared with those after the index TAVR (15.1 ± 6.7 versus 11.9 ± 7.7 mmHg, respectively). Follow-up mortality was 14.9% at a median time of 586 days.9 The largest cohort of redo-TAVR is a multicenter international registry comprising 37 centers through Europe, North America, and the Middle East.8 This registry identified 212 consecutive redo-TAVR procedures from a total of 63,872 index TAVR cases. The repeat procedures were divided into those within (n=74) and beyond (n=138) 1 year of the index TAVR. The indication for redo-TAVR was predominantly aortic regurgitation or combined stenosis and regurgitation. There was an interesting variation in pathology according to the timing of reintervention. Patients with early reintervention were more likely to have had procedural failure, whereas those with repeat intervention after 1 year were more likely to have transcatheter heart valve (THV) failure. The mean time between the index TAVR and redo-TAVR was 68 days and 5 years for procedural and THV failure, respectively. Procedural success of redo-TAVR was achieved in 85.1% of cases, with failures occurring in patients with high residual gradients after the intervention (14.1%) or residual regurgitation (8.9%).8 An important limitation of that study was the absence of differentiation

between valvular regurgitation and paravalvular regurgitation or PVL among those with predominant aortic regurgitation as the etiology for failed TAVR. Interestingly, in another study, there was a numerical trend towards a higher 30-day mortality among patients who underwent redo-TAVR for procedural versus THV failure, but this was not statistically significant (5.4% versus 1.4%, respectively; p=0.427).8 Periprocedural complications were low, and the 30-day survival was 94.6% in those undergoing redoTAVR for procedural failure and 98.5% in those with THV failure (p=0.101).

At 1 year, survival was 83.6% and 88.3% for patients with early and late valve dysfunction, respectively.8 The interpretation and generalizability of these outcomes may be limited given the highly selected population and unadjudicated outcomes.

Surgical Aortic Valve Replacement After TAVR

Surgical intervention for failed TAVR has been performed, but the results of larger registries are sobering. Data from the Society of Thoracic Surgeons database from 2011 to 2015 was used to evaluate the results of surgical intervention after TAVR for valve failure.10 In all, 123 patients were identified, with a median age of 77 years. Indications for reoperation included early TAVR device failures, such as PVL (15%), structural prosthetic deterioration (11%), failed repair (11%), sizing or position issues (11%), and prosthetic valve endocarditis (10%). The overall operative mortality in this

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Managing Failed Transcatheter Aortic Valve Replacement group was 17.1% and the observed versus expected mortality ratios were higher for each group of preoperative risk category.11 This was a small, select cohort of initially high-risk patients who initially underwent TAVR, so these results may not be generalizable to a larger population, but they are concerning.

Considerations for Redo-TAVR

Given the risks of reoperation for these patients, evaluation for redo-TAVR and the associated risks is important to choose the appropriate therapy.

When making a decision for a second TAVR intervention, it is important to understand some key details of the index procedure, namely postprocedure gradients and the presence of patient–prosthesis mismatch (PPM), PVL, and the mechanism of valve failure (see Figure 1).

Post-procedural Valve Gradient After the Index TAVR

Normal gradients following TAVR in native aortic valve stenosis average 5–15 mmHg. According to the revised VARC-3 criteria, device success is defined as a post-procedural mean gradient of <20 mmHg.8 In the presence of immediate or acute post-procedural mean gradient elevation, distinction between normal and abnormally low effective orifice area, or PPM, will direct further management. PPM may be a challenging echocardiographic diagnosis.

In a study by Flameng et al., PPM was found to be a predictor of structural valve degeneration (SVD) following surgical aortic valve replacement at a median time of 6 years, with patients mostly presenting with valve stenosis.11 PPM is defined as hemodynamically moderately and severely significant if the indexed effective orifice areas are 0.65–0.85 and <0.65 cm2/m2, respectively.12 Moderate and severe PPM following TAVR were reported in 25% and 12% of cases, respectively, in the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy (TVT) registry of over 62,000 patients.13 The impact of PPM on mortality remains a matter of debate and needs further investigation. Although mortality was higher among patients with severe PPM compared with non-severe PPM in the TVT registry at 1 year (17.2% versus 15.8%, respectively; p=0.011),13 Liao et al. described similar mortality at 2 years in their meta-analysis of 4,691 TAVR procedures.14 The size of the initial valve implanted is key information in the management of a failed TAVR with PPM. Indeed, as expected, in the TVT registry, the size of the prosthesis was inversely correlated with the severity of PPM (40%, 32%, and 24% of patients with severe, moderate, or no PPM, respectively had a 23 mm prosthesis implanted; p<0.0001).13 Therefore, in patients with confirmed PPM and valve failure, redo-TAVR is unlikely to be the best option and surgical intervention should be considered.

Presence of Paravalvular Leak

PVL is an important challenge in the current TAVR era and is associated with increased mortality.15 This has been decreasing with improved TAVR technology, but the high rates of aortic regurgitation in failed TAVR cases remain an important concern. Technical advancements (i.e. the use of device-sealing skirts, better preprocedural anatomical assessment, optimal oversizing) along with increased operator experience have permitted progressive reductions in PVL rates with time. However, in contrast with surgical aortic valve replacement, abolition of PVL following TAVR may be limited by the persistence of the diseased native valve apparatus and calcifications interfering with valve deployment.

Echocardiography, specifically transesophageal echocardiography, is the imaging modality of choice to identify and differentiate intravalvular leak from PVL.

Figure 1: Critical Components of Patient Evaluation for Redo-Transcatheter Aortic Valve Replacement • Patient–prosthesis mismatch • Paravalvular leak • Valvular regurgitation or stenosis Knowledge • Valve gaps durability • Thrombosis • Coronary reaccess

Mechanism of TAVR failure

Evaluation for redo-TAVR

Procedural risks

• Valve sizing • Leaflet modification (BASILICA) • Commissural alignment Technical details

• Mortality • Valve embolization • Coronary obstruction • Residual gradients

The mechanism of TAVR failure must be understood and there must be an acknowledgment of gaps in existing knowledge, a consideration of procedural risks, and an assessment of important technical details. BASILICA = Bioprosthetic Aortic Scallop Intentional Laceration to prevent Iatrogenic Coronary Artery obstruction; TAVR = transcatheter aortic valve replacement.

The persistence of significant PVL is to be expected following redo-TAVR because a second TAVR is unlikely to remedy the previous problem of stent frame malapposition against a calcified annulus. PVL closure may be effective, although no device is currently approved by the Food and Drug Administration. The most commonly used devices include the Amplatzer Vascular Plug (AVP) family (Abbott Structural). Overall, for both prosthesis undersizing and underexpansion resistant to balloon post-dilation, redoTAVR will mostly fail to reduce pre-existing PVL.16 PVL due to an inadequate initial position of the TAVR valve, such as implantation too high or too low, may be addressed by a second procedure with an appropriately positioned valve.

Mechanism of Prosthesis Deterioration and Impact on Future Treatment

Characterization of the mechanism of TAVR failure plays a major role when considering redo-TAVR. Although redo-TAVR may be of interest for intravalvular regurgitation either due to SVD or non-SVD, its success for PVL seems less obvious, as discussed previously. In the largest case series to date, Landes et al. did not differentiate between intravalvular or paravalvular regurgitation among patients with aortic regurgitation, but did note that early valve failure was more frequently due to regurgitation.17 The overall modes of TAVR valve failure were stenosis (29.7%), stenosis–regurgitation (25.4%), and regurgitation (44.8%).

These values are similar to previously published data on the mode of surgical valve failure in the TAVR VIVID (Valve-in-Valve International Data) registry.18 In those patients with TAVR valve stenosis as the primary mechanism of failure, it is possible for the stent frame to expand further to permit redoTAVR. However, there is often a residual gradient, as is seen in the literature with valve-in-valve procedures for failed surgical valves.19 Registry data indicate that in those redo-TAVR patients with primarily stenosis, there was a significantly higher gradient at follow-up than in patients with failed TAVR due to combined stenosis–regurgitation or pure regurgitation (16.9 versus 10.4 mmHg, respectively, at 1 year). In addition, smaller prostheses (≤23 mm) had a significantly higher mean gradient than larger prostheses (>23 mm).13 Therefore, initial TAVR size is an important characteristic to include in the decision algorithm for redoTAVR, particularly for stenotic failed TAVR.

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Managing Failed Transcatheter Aortic Valve Replacement Among reversible factors leading to TAVR failure, valve thrombosis remains an important issue for valve durability. The true incidence of TAVR valve thrombosis is unknown because, in most cases, it remains subclinical. In the OCEAN-TAVI registry including 485 patients, late leaflet thrombosis occurred in 16.9% of patients who had a follow-up CT up to 3 years.20 Although a direct causative link between leaflet thrombosis and valve durability has yet to be established, anticoagulation therapy has been shown to both reverse thrombotic leaflet reduced motion and decrease the transvalvular gradient.21

Patient Evaluation Prior to Redo-TAVR

The mainstays of patient evaluation prior to redo-TAVR include echocardiography, coronary angiography, and cardiac CT for procedural risk assessment and planning.

Coronary Angiography

Atherosclerotic coronary artery disease (CAD) and aortic stenosis share several risk factors, and up to 70% of patients have concomitant CAD at the time of index TAVR.22 Due to the heterogeneity of inclusion criteria and patient risk profile in studies, the impact of CAD revascularization before index TAVR on clinical outcomes remains unclear, with contradictory results in the literature.23,24 In the setting of redo-TAVR, coronary angiography is important to evaluate disease progression and to assess for risks of coronary occlusion. This can also be evaluated using CT.

Cardiac CT

Preprocedural cardiac CT is crucial prior to the index TAVR procedure. It allows precise characterization of aortic root anatomy, evaluation of coronary height, and annular sizing, as well as peripheral vascular assessment. For redo-TAVR planning, cardiac CT plays an important role for the evaluation of possible coronary obstruction and valve sizing.

Assessment of the risk of coronary obstruction following redo-TAVR requires analysis of the valve sinuses (height and width), valve to coronary distance (VTC), and the position of the commissures in relation to the coronary ostia. Coronary occlusion after redo-TAVR is rare and is mostly the consequence of a further shift of the native calcified leaflets against the coronary ostium. This risk of coronary occlusion is increased by a significant valve oversizing and small sinuses of Valsalva. As opposed to TAVR in failed surgical bioprosthesis, the initial TAVR prosthesis leaflets are less likely to directly occlude coronary ostia because the stent frame acts as a barrier.

Obstruction to coronary blood flow may occur due to sinus of Valsalva sequestration. Evaluation of this requires an understanding of the height of the sinotubular junction and its relationship to the commissural level of the first TAVR valve and the width of the sinuses of Valsalva. There may be a significant risk of sinus of Valsalva sequestration in the setting of a high commissural level of the TAVR valve (at the sinotubular junction or above) along with a low sinotubular junction. In such case, deployment of the new prosthesis may tilt the leaflets of the first prosthesis up against the stent frame, forming a hermetic cylinder at the sinotubular junction. When the first THV commissural level remains below the sinotubular junction, the risk is minimal. A smaller sinus of Valsalva diameter also increases the risk of sinus of Valsalva sequestration. In the study of Ochiai et al., the risk of sinus of Valsalva sequestration in case of redo-TAVR was assessed using post-index TAVR cardiac CT. Redo-TAVR was considered at increased risk for coronary obstruction in the presence of a first THV commissure level above the sinotubular junction and a distance between the THV and sinotubular junction <2 mm. Not surprisingly, patients with supravalvular

valve design (Evolut R/Pro) had considerably higher CT-identified risks of sinus of Valsalva sequestration that those with an intra-annular valve design (SAPIEN 3; 45.5% versus 2%, respectively; p<0.001).25 VTC is a measure routinely used to plan valve-in-valve procedures in degenerated surgical bioprostheses. Patients with a virtual valve to coronary ostial distance (i.e. VTC) <4 mm had a higher risk of coronary obstruction.26 In the case of increased risk of sinus of Valsalva sequestration due to the first THV commissural level being located at the sinotubular junction level or above, or an increased risk of coronary obstruction with small VTC, additional strategies may have to be considered to modify the leaflets of the TAVR prosthesis (index valve). Bioprosthetic Aortic Scallop Intentional Laceration to prevent Iatrogenic Coronary Artery obstruction (BASILICA) is a leaflet modification technique developed to lacerate one or several leaflets of the first THV using an electrified guidewire that is punctured and snared through the leaflet before redo-TAVR.27 Although promising, all patients at risk of sinus of Valsalva sequestration or coronary occlusions are not candidates for BASILICA. Indeed, in the case of valve commissure and coronary ostia superposition, commissural posts will remain in front of the coronary ostia despite leaflet laceration. Commissural alignment at the first TAVR is of particular interest when treating younger patients who may become future candidates for redo-TAVR with potential BASILICA. As yet, with respect to the limited data, only the Evolut R/Pro platform seems to allow consistent commissural alignment with coronary ostia.28 Finally, when there is a risk of coronary obstruction after redo-TAVR and BASILICA is not an option, pre-emptive insertion of a guidewire and an undeployed stent in the left main coronary artery before THV deployment may be considered. If coronary obstruction occurs after prosthesis deployment, the stent is pulled back and implanted with protrusion in the aorta (chimney technique), although recannulation of these stents can be near impossible at a later date.29

Unanswered Questions

The prevalence of TAVR for the treatment of native aortic stenosis is rapidly increasing and permeating lower-risk populations. In the absence of long-term durability data, current experience suggests that TAVR valve failure will occur and a treatment strategy will be required. At present, redo-TAVR is emerging as a treatment option for failed TAVR valves, but concerns remain. Early experience suggests that cannulation of the coronary arteries following redo-TAVR can be unfeasible in up to 30% of patients depending on the type of index TAVR valve. The risks appear higher in those with a supra-annular THV compared with annular valves.30 Valve leaflet thrombosis is also a recognized entity despite being mainly subclinical. The impact of a second TAVR valve on future thrombosis is unclear, and whether antiplatelet, anticoagulation, or a combined therapy is the most effective regimen remains unknown. Finally, the development of new-generation THV with improved capabilities of commissural alignment and successive coronary reaccess will definitely facilitate redoTAVR planning. When treating younger patients with a long life expectancy, the lifetime management of these patients must be considered and anticipated by the heart team while planning the index TAVR procedure.

Conclusion

Redo-TAVR is an emerging procedure for failed TAVR, with an encouraging safety profile and short-term clinical outcomes. The key to success will be an understanding of the index TAVR procedure and results, the mechanism of valve failure, and meticulous planning to minimize patient risk. The optimal treatment strategy for failed TAVR valves is still unknown, and longer-term data will be needed to best understand in whom redo-TAVR will be indicated.

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Landes U, Webb JG, De Backer O, et al. Repeat transcatheter aortic valve replacement for transcatheter prosthesis dysfunction. J Am Coll Cardiol 2020;75:1882–93. https://doi.org/10.1016/j.jacc.2020.02.051; PMID: 32327098.

Dvir D, Webb J, Brecker S, et al. Transcatheter aortic valve replacement for degenerative bioprosthetic surgical valves: results from the global valve-in-valve registry. Circulation 2012;126:2335–44. https://doi.org/10.1161/ CIRCULATIONAHA.112.104505; PMID: 23052028.

Dvir D, Webb JG, Bleiziffer S, et al. Transcatheter aortic valve implantation in failed bioprosthetic surgical valves.

JAMA 2014;312:162–70. https://doi.org/10.1001/ jama.2014.7246; PMID: 25005653.

Yanagisawa R, Tanaka M, Yashima F, et al. Early and late leaflet thrombosis after transcatheter aortic valve replacement. Circ Cardiovasc Interv 2019;12:e007349. https:// doi.org/10.1161/CIRCINTERVENTIONS.118.007349; PMID: 30732472.

Dangas GD, Weitz JI, Giustino G, et al. Prosthetic heart valve thrombosis. J Am Coll Cardiol 2016;68:2670–89. https://doi. org/10.1016/j.jacc.2016.09.958; PMID: 27978952.

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22. Kotronias RA, Kwok CS, George S, et al. Transcatheter aortic valve implantation with or without percutaneous coronary artery revascularization strategy: a systematic review and meta-analysis. J Am Heart Assoc 2017;6:e005960. https://doi. org/10.1161/JAHA.117.005960; PMID: 28655733.

23. Sankaramangalam K, Banerjee K, Kandregula K, et al.

Impact of coronary artery disease on 30-day and 1-year mortality in patients undergoing transcatheter aortic valve replacement: a meta-analysis. J Am Heart Assoc 2017;6:e006092. https://doi.org/10.1161/JAHA.117.006092; PMID: 29021275.

24. D’Ascenzo F, Verardi R, Visconti M, et al. Independent impact of extent of coronary artery disease and percutaneous revascularisation on 30-day and one-year mortality after TAVI: a meta-analysis of adjusted observational results. EuroIntervention 2018;14:e1169–77. https://doi.org/10.4244/eij-d-18-00098; PMID: 30082258.

25. Ochiai T, Oakley L, Sekhon N, et al. Risk of coronary obstruction due to sinus sequestration in redo transcatheter aortic valve replacement. JACC Cardiovasc Interv 2020;13:2617–27. https://doi.org/10.1016/j.jcin.2020.09.022; PMID: 33213747.

26. Blanke P, Soon J, Dvir D, et al. Computed tomography assessment for transcatheter aortic valve in valve implantation: the Vancouver approach to predict anatomical risk for coronary obstruction and other considerations. J Cardiovasc Comput Tomogr 2016;10:491–9. https://doi. org/10.1016/j.jcct.2016.09.004; PMID: 27697505.

27. Khan JM, Dvir D, Greenbaum AB, et al. Transcatheter laceration of aortic leaflets to prevent coronary obstruction during transcatheter aortic valve replacement: concept to first-in-human. JACC Cardiovasc Interv 2018;11:677–89. https:// doi.org/10.1016/j.jcin.2018.01.247; PMID: 29622147.

28. Tang GHL, Zaid S, Fuchs A, et al. Alignment of Transcatheter Aortic-Valve Neo-Commissures (ALIGN TAVR): impact on final valve orientation and coronary artery overlap. JACC Cardiovasc Interv 2020;13:1030–42. https://doi.org/10.1016/j. jcin.2020.02.005; PMID: 32192985.

29. Chakravarty T, Jilaihawi H, Nakamura M, et al. Pre-emptive positioning of a coronary stent in the left anterior descending artery for left main protection: a prerequisite for transcatheter aortic valve-in-valve implantation for failing stentless bioprostheses? Catheter Cardiovasc Interv 2013;82:E630–6. https://doi.org/10.1002/ccd.25037; PMID: 23729203.

30. Nai Fovino L, Scotti A, Massussi M, et al. Coronary angiography after transcatheter aortic valve replacement (TAVR) to evaluate the risk of coronary access impairment after TAVR-in-TAVR. J Am Heart Assoc 2020;9:e016446. https://doi.org/10.1161/JAHA.120.016446; PMID: 32578484.

REVIEW ARTICLE

Echocardiography

Echocardiography in the Evaluation of the Right Heart Angelos Tsipis, MD, , and Evdokia Petropoulou, MD, Department of Cardiology, Metropolitan General Hospital, Athens, Greece

Abstract

The significance of the right ventricle (RV) as a predictor of outcomes in a series of cardiac conditions has recently been recognized. Consequently, more studies are now focusing on improving the assessment of the RV. Its primary function is to support adequate pulmonary perfusion pressure in different circulatory and loading situations and to ensure that there is a low systemic venous pressure. Echocardiography is the first-line method of choice due to its accuracy when assessing RV structure and function, as well as its wide availability. The geometry of the RV is complex and its evaluation can be difficult. Integrating and combining multiple parameters may be a more reliable way to determine normal or abnormal function. Novel techniques are increasingly being performed more routinely in clinical practice and are facilitating diagnosis and treatment choices.

Keywords

Echocardiography, right heart, ventricular function, pulmonary hypertension Disclosure: The authors have no conflicts of interest to declare.

Received: February 16, 2021 Accepted: September 25, 2021 Citation: US Cardiology Review 2022;16:e08. DOI: https://doi.org/10.15420/usc.2021.03 Correspondence: Angelos Tsipis, Paparseni 70 115.24, Athens, Greece E: angelostsipis@gmail.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Our knowledge of the significance of the right heart has considerably improved in the past few decades as new imaging techniques have enabled more detailed study of the right heart anatomy, physiology and pathophysiology. Many studies have emphasized the role of right heart structure and function as an important predictor in the case of heart failure, pulmonary hypertension (PH), and congenital heart disease.1,2 Right-sided heart dysfunction occurs in several conditions, such as right ventricular MI, left-sided heart failure, congenital heart disease, PH, chronic lung disease, sleep-related breathing disorders, acute pulmonary embolism, and pulmonary/tricuspid valve disease. The main function of the right ventricle (RV) is to ensure adequate pulmonary perfusion pressure in different circulatory and loading situations, and to preserve a low systemic venous pressure. The interaction between preload, contractility, afterload, ventricular interdependence and heart rhythm determines the regular RV function. Echocardiography is a non-invasive diagnostic tool that can be used to assess the function of the right heart.

The measurements to be performed and reported should involve qualitative and quantitative parameters of the right heart (Table 1). This review describes the most commonly used echocardiography methods and measurements for the analysis of right heart anatomy, function and hemodynamics.

across the short axis. The RV contains inflow and outflow compartments and is made up of the free anterior wall, posterior wall and interventricular septum.3 The complicated geometric form of the ellipsoidal shell model that covers the conical shape of the LV and the trabeculated myocardium at the apex prevents simple evaluation of RV size and function by transthoracic echocardiogram. The RV has the same stroke volume as the LV, but needs only 25% of the stroke because pulmonary resistance is low.

The muscle fibers of the RV have a longitudinal orientation from the valve annulus to the apex, and in this way obtain longitudinal contraction.4 The RV wall is thin (3–5 mm, excluding trabeculations) compared with the LV myocardium and in the case of increased pulmonary pressures or volume overload, it can respond with hypertrophy, dilatation and increased contractility.5 The tricuspid valve has a crucial role in the normal function of the RV. Evaluation of the morphological features of the RV requires the following projections:3

Right Ventricular Anatomy, Location and Physiology

•

The RV is located immediately behind the sternum and anterior to the left ventricle (LV). It extends from the right atrium (RA) to the apex of the heart, forming the majority of the anterior surface of the heart, and marks the inferior border of the cardiac silhouette. While the LV has a conical shape, the RV is shaped like a pyramid and appears as an additional slice of tissue wrapped around the circular LV, particularly when viewed in a section

• Parasternal long axis plane (to demonstrate the RV outflow tract and

•

• •

the moderator band that connects the ventricular septum to the parietal wall, and to exclude it when evaluating the diameter of the ventricular septum).

RV inflow tract views (to display the Eustachian valve behind the mural leaflet, and evaluate the anterior and inferior RV wall).

RV outflow tract views (to display the RV outflow curving over the LV, the pulmonary valve, and the bifurcation of the pulmonary trunk in the left and right arteries).

Short axis planes (to display the crescentic shape of the RV).

Apical four-chamber plane (this is optimal for morphological assessment, measurement of the tricuspid valve, RV dimension, display of the septomarginal trabeculation, the moderator band and the pulmonary veins at the back of the left atrium).

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Right Heart Evaluation Table 1: Echocardiographic Qualitative and Quantitative Parameters of the Right Heart

•

Right Heart

Echocardiographic Parameters

RV and RA size

RV basal diameter, RV wall thickness RVOT PSAX distal diameter RV PLAX proximal diameter RA major dimension, RA minor dimension, RA end-systolic area

RV systolic function

At least one of the following parameters: • TAPSE • Tissue Doppler of the free lateral wall (S΄) • Fractional area change • Pulsed Doppler MPI • Tissue Doppler MPI 3D RVEF Longitudinal strain and strain rate

Systolic pulmonary artery pressure

•

•

TR velocity RA pressure estimated from IVC IVC (size and collapse)

•

Additional measures PA diastolic pressure

PR end diastolic pressure gradient + RA pressure

RV diastolic function

E/A ratio E/e’ ratio Deceleration time RA size

IVC = inferior vena cava; MPI = myocardial performance index; PA = pulmonary artery; PLAX = parasternal long axis; PR = pulmonary regurgitant; PSAX = parasternal short axis; RA = right atrium; RV = right ventricle; RVEF = right ventricular ejection fraction; RVOT = RV outflow tract; TAPSE = tricuspid annular plane systolic excursion; TR = tricuspid regurgitation.

Figure 1: Increased Dimensions of the Right Ventricle V

10

20

reference limit of 35 mm, and in the longitudinal dimension with an upper reference limit of 86 mm.

RV wall thickness (subcostal long axis view at end-diastole, it is important to exclude trabeculations and papillary muscle, with measurements >5 mm considered abnormal).

RV outflow tract (RVOT): the anatomy of the RVOT is important and it is located between the supraventricular crest and pulmonary valve; it consists of the conus arteriosus (infundibulum), ventricular septum and RV free wall. Measurement is done of the proximal diameter of the RVOT or the subvalvular level (parasternal long axis, upper reference limit 33 mm), and the distal diameter of the RVOT or pulmonary valve level (parasternal short axis, upper reference limit 27 mm).

RV area (four-chamber view at end-diastole by planimetry of the RV cavity, excluding trabeculations and excluding the moderator band, with an upper reference limit at end-diastole of 24 cm2 in men and 20 cm2 in women).

Inferior vena cava (IVC) dimension: the dilatation of the IVC with diameter >21 mm in the case of chronic heart failure suggests hemodynamic congestion. The RA pressure algorithm is used to evaluate the diameter of the IVC and also the degree of inspiratory collapse of the IVC (IVC diameter ≤2.1 cm collapse with sniff >50% indicates normal RA pressure; IVC diameter ≥2.1 cm collapse with sniff <50% indicates high RA pressure). When the parameters of IVC diameter and collapse do not fall within these limits, an intermediate value of RA pressure may be used, or other secondary markers of elevated RA pressure could be involved.5–8

Assessment of Right Ventricular Function

The function and consistency of the RV is a strong predictor of many cardiovascular diseases. The assessment of RV function by transthoracic echocardiogram is limited due to the complex anatomy and particular shape of the RV. The biggest contraction of the RV takes place longitudinally from base to apex, providing most of the stroke volume. A significant number of echocardiographic parameters have been accepted and validated and each of them has its drawbacks and limitations.

Integrating and combining these parameters may more reliably determine normal or abnormal RV function. Among them are the following parameters: visual examination; RV index of myocardial performance (RIMP); tricuspid annular plane systolic excursion (TAPSE); 2D RV fractional area change (FAC); 2D RV ejection fraction (RVEF); 3D RVEF; tissue Doppler-derived tricuspid lateral annular systolic velocity (S΄); and longitudinal strain and strain rate.7,8

Visual Examination • Apical long and three-chamber view (to display the RV outflow in a similar way to the parasternal long axis view).

• Subcostal projection (to display the diaphragmatic wall of the RV).

Many studies have been performed to identify and establish the normal reference ranges for the echocardiographic measurements of the right heart.6–8 The measurement of the following dimensions is recommended for right heart assessment:

• RV basal–apical: transverse measurements of the RV in four-chamber imaging vary significantly because the normal RV has a complex geometric triangular form. In the four-chamber view, the RV is measured at the base with an upper reference limit of 41 mm, at mid-diameter at the level of the papillary muscles with an upper

The dimension of the RV should be compared with the size of the LV. The normal size of the RV is approximately two-thirds the size of the LV apical four-chamber and parasternal long axis views. RV size can be evaluated by tracing the endocardial border or measuring the dimensions. If the RV has a larger length or diameter, it is probably due to the dilatation of the RV (Figure 1). Endocardial tracing of the area of the RV has a higher correlation with echocardiographic estimations of RV size and function than with MRI estimations.9 Abnormal septal motion with septal flattening and an abnormal LV D-shape on short axis view may indicate RV volume or pressure overload (Figure 2). However, visual examination is often dependent on the observer and their experience.

Tricuspid Annular Plane Systolic Excursion

TAPSE is the most commonly used and simple method for the evaluation of RV function. This parameter, derived from apical four-chamber view

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Right Heart Evaluation with M-mode, measures the distance of systolic excursion of the RV segment (lateral tricuspid valve annulus) along the longitudinal plane. The disadvantage of TAPSE is that it evaluates a single segment that only partially characterizes the function of the entire RV. TAPSE is easily measured, and values lower than 16 mm indicate RV dysfunction. The width of excursion correlates with RVEF (5 mm = 20% RVEF, 10 mm = 30% RVEF, 15 mm = 40% RVEF, 20 mm = 50% RVEF).

Figure 2: D-shape on Short Axis View V

5

RV systolic function as evaluated with TAPSE can be used to assess the risk of cardiovascular death in many cardiovascular diseases.7,9–11 The ratio of TAPSE to systolic pulmonary artery pressure (i.e. TAPSE/SPAP) enhances the prognostic risk stratification in patients with heart failure and a ratio <0.36 mm/mmHg indicates a higher probability of mortality in patients with heart failure.12

10

15

Tissue Doppler of the Free Lateral Wall

This parameter of apical four-chamber tissue Doppler evaluates the longitudinal velocity of excursion of the basal free wall segment and tricuspid annulus to assess basal RV free wall function. The disadvantage of this technique is that the evaluation of the function of a single segment is used to characterize the function of the global ventricle. It is easily measured and reproducible, and values of <10 cm/s indicate RV dysfunction.

Right Ventricular Index of Myocardial Performance

This parameter is a global estimate of both systolic and diastolic function of the RV and is not dependent on ventricle geometry. It is defined as the ratio of the isovolumetric time interval to the ventricular ejection time and it is obtained using the pulsed Doppler method and the tissue Doppler method, with the following formula: RIMP = (tricuspid valve closure time − ejection time)/ejection time. This formula can also be given as RIMP = (TCO − ET)/ET or IVRT + IVCT/ET, where TCO is the tricuspid valve closure–opening time, IVCT is the isovolumetric contraction time, IVRT is the isovolumetric relaxation time, and ET is the ejection time. The disadvantage is that the method is not valid with the irregular rates that are found with AF and elevated RA pressure. Values of RIMP >0.4 using pulsed Doppler and >0.55 using tissue Doppler indicate RV dysfunction and lower values indicate normal function of the RV, given that less time is taken in the isovolumetric state and more time is taken in ejecting blood.6

Fractional Area Change

RV FAC is given by the following equation: 100 × [(end-diastolic area − endsystolic area)/end-diastolic area]. This method from four-chamber view involves tracing the endocardial borders of RV during systole and diastole, including trabeculations and tricuspid valve leaflets. The parameter has prognostic value and is an independent predictor of mortality in cases of acute MI, heart failure, pulmonary embolism and PH. Values <35% indicate RV dysfunction.8

3D Volume Estimation

This technique evaluates RV volume without relying on the geometric particularities of the complex shape of the ventricle.11 This method is more complex and is dependent on image quality, and it tends to underestimate the RV volumes measured by MRI. The lower reference limit of 3D RVEF is 45%.

Strain Imaging: Regional RV Strain and Strain Rate

This method uses dimensionless parameters tο measure myocardial deformation, and represents regional and global myocardial systolic

function. Strain is determined as the percentage change in the length of the myocardial segment, and strain rate represents the rate of deformation of the myocardium over time.7,8,13 One-dimensional strain evaluated on Doppler tissue imaging is angle dependent while 2D speckle-tracking echocardiography is an angle-independent measurement. The 2D strain is a precise method to assess RV global and regional function. Global strain of the free lateral wall of the RV is measured by the average peak systolic strain of the three segments of the free lateral wall in fourchamber view. High negative strain values indicate better systolic function and values less than −20% indicate reduced RV function. The mean RV strain in normal conditions is −29 ± 4.5%.5,8,14 The technique is not recommended for routine clinical evaluation and is best reserved for specific clinical conditions.

Right Atrium Volume

Increased RA dimensions can be an indication of volume and pressure overload, and increased RA pressure is an indication of RV dysfunction.

This method involves the measurement of RA volume from the fourchamber view. Normal values are 21 ± 6 ml/m2 for men and 25 ± 7 ml/m2 for women.9,15

Right Ventricular Diastolic Function

RV diastolic dysfunction increases atrial pressures and decreases collapsibility of the IVC. Pressure and volume overload mechanisms, such as lung disease, cardiomyopathies, ischemic heart disease and LV dysfunction, mediate ventricular interdependence and can lead to RV diastolic dysfunction. The evaluation of the following parameters are recommended for the assessment of RV diastolic function:

• 2D morphological assessment of the RV, size of the IVC, inspiratory collapse.

• Doppler velocities of the trans-tricuspid flow (E, A, E/A). Transtricuspid flow is susceptible to preload and afterload.

• Tissue Doppler velocities of the tricuspid annulus (E΄, Α΄, Ε/Α΄),

deceleration time, isovolumetric relaxation time.7,16 • Pulsed-wave Doppler for hepatic vein flow assessment. The main components of hepatic vein flow are the systolic wave (S), systolic reversal wave (SR), diastolic wave (D), and the atrial reversal wave (AR).

S/D < 1 indicates increased RA pressure. Hepatic vein systolic filling fraction <55% denotes increased RA pressure. Prominent systolic and atrial reversal waves may also indicate raised RA pressure.

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Right Heart Evaluation Semi-quantitative Methods

Figure 3: Tricuspid Leaflets with Complete Absence of Coaptation

• Vena contracta width: this is optimal for distinguishing mild from

severe TR; it can be used for eccentric jets, but not for multiple jets; a width >7 mm indicates TR. • Hepatic vein flow: systolic flow reversal indicates severe TR. • Peak E velocity: this is increased in severe TR (E-wave dominant ≥1 m/s).

• Proximal isovolumetric surface area, proximal isovelocity surface area (PISA) (radius >9 mm indicates severe TR).21–23

V

5

Quantitative Methods

10

• PISA can also be used to measure the effective regurgitant orifice

Various studies demonstrate the use of RV diastolic function assessment in the diagnostic and therapeutic management of patients.17 Fenster et al. evaluated the extent to which RV diastolic function is associated with exercise capacity in chronic obstructive pulmonary disease. RV diastolic function was assessed using the ratio of early to late tricuspid valve velocities, and an increased tricuspid valve E/A ratio was associated with an increased 6-minute walk test distance.18 Kosmala et al. assessed RV systolic and diastolic function in people with diabetes. In patients with diabetes without clinically evident heart disease, the RV function is impaired, and is indicative of diastolic abnormalities such as increased IVRT and decreased RV E’/Α’.19 Various echocardiographic markers are used in the evaluation of patients with hypertrophic cardiomyopathy (HCM). Pagourelias et al. evaluated the significance of transthoracic indices of RV diastolic function in HCM patients. RV E/E’ >6.9 was an independent predictor of heart failure mortality and of a 1.6-fold increased risk of death from heart failure.20

Tricuspid Valve

The free margins of the tricuspid valve are linked to the ventricular wall by tendinous cords attached to papillary muscles that are contiguous with the subjacent ventricular walls. The structure of the tricuspid valve consists of the annulus, three leaflets (anterior, posterior, septal), the chordae tendineae and the papillary muscles (usually three papillary muscles). The tricuspid valve is located apical-most and the occupied annulus area is 8–12 cm2. The most frequent condition of the tricuspid valve is regurgitation, which is differentiated into primary valve lesion and functional regurgitation. Functional regurgitation will usually lead to annular dilatation and increased tricuspid leaflet tethering due to pressure and volume overload of the RV. These conditions include PH, left heart disease and situations resulting in dilatation of the RV (RV infarction and pulmonary embolism). The echocardiographic approach for the evaluation of tricuspid regurgitation (TR) involves the following parameters.

Qualitative Methods

• Morphology of the tricuspid valve: flail valve and a large coaptation defect indicate severe TR (Figure 3).

• Annular diameter: annular dilatation indicates severe TR. • Color-flow TR jet: a very large central jet indicates severe TR, while

an eccentric jet that hugs the RA wall will underestimate TR severity.

• Continuous wave TR jet: velocity and shape are indicative of TR

severity; a dense envelope indicates severe TR, while poor alignment with an eccentric jet will lead to underestimation of severity.21–23

area (EROA) and regurgitant volume; EROA >40 mm2 and regurgitant volume >45 ml indicate severe TR. Although it can be used in eccentric jets, the method has numerous limitations such as that the regurgitant orifice is rarely round and the movement of the annulus during systole influences the measurement.

• RA and RV size: enlargement of the RA and RV indicates severe chronic TR.21–23

Clinical Implications

Echocardiography is a non-invasive diagnostic procedure most commonly used in the evaluation of patients with PH and pulmonary embolism. It is an important imaging procedure for determining structural and functional cardiac status and has prognostic and research value. Dysfunction of the LV secondary to MI and heart failure can influence the function of the RV. Echocardiographic assessment of the RV is useful for the evaluation of patients with left-sided heart disease. Diseases involving the tricuspid valve, such as carcinoid disease, rheumatic tricuspid disease, and myxomatous degeneration of the tricuspid valve, can also affect the function of the RV. Common congenital deformities include atrial septal defect, and patients with postoperative tetralogy of Fallot and Ebstein disorder can end up with RV dysfunction. Many studies have described the role of right heart structure and function as important predictors in patients with chronic lung disease and sleep-related breathing disorders.24–30 Echocardiography plays an important role in the detection of RV dysfunction in various clinical scenarios, and a crucial role in patient follow-up.

Pulmonary Hypertension

PH includes various clinical conditions and can complicate many cardiovascular and respiratory diseases. PH is defined as an increase in mean pulmonary artery pressure ≥25 mmHg at rest as confirmed on right heart catheterization. The classification of PH is based on the five groups of clinical conditions that cause it:

• Pre-capillary PH with normal pulmonary artery wedge pressure (PAWP) ≤15 mmHg.

• Post-capillary PH due to left heart disease with increased PAWP >15 mmHg.

• PH due to chronic lung disease and hypoxia.

• Chronic thromboembolic PH. • PH due to unclear and various mechanisms.17,24 The following echocardiographic parameters are crucial for the assessment of patients with suspected PH: TR velocity (TRV), dilated RV, flattening of the interventricular septum, short pulmonary valve acceleration time, pulmonary artery diameter >25 mm, dilated RA, and decreased inspiratory collapse of the IVC. Echocardiographic signs in addition to TRV are used to evaluate the probability of PH (Table 2). The standard echocardiographic method uses the evaluation of RV pressure

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Right Heart Evaluation Table 2: Echocardiographic Signs in Addition to Tricuspid Regurgitation Velocity to Evaluate the Probability of Pulmonary Hypertension Ventricles

Pulmonary Artery

Inferior Vena Cava

Right Atrium

RV/LV basal diameter ratio >1 Flattening of the interventricular septum

RV outflow Doppler acceleration time <105 ms Early diastolic pulmonary regurgitation velocity >2.2 m/s PA diameter >25 mm

IVC diameter >21 mm with decreased inspiratory collapse

Right atrial area (end-systole) >18 cm2

IVC = inferior vena cava; LV = left ventricle; PA = pulmonary artery; RV = right ventricle.

from the TRV and the qualitative assessment of RA pressure. Applying the simplified Bernoulli equation, p = 4(TRVmax)2, the peak TRV is squared and multiplied by 4.25 Even small errors in the absolute measurement of TRV can result in significant differences in the measurement of RV systolic pressure (RVSP). The evaluation of RVSP from TRV requires precise alignment with the TR jet, otherwise it may be under- or overestimated.

This can be prevented by using agitated saline or contrast agents.26,27 Furthermore, to estimate SPAP, the RVSP is added to the RA pressure derived from the measurement of the IVC diameter after inspiration. In many cases, the diameter of the IVC cannot be measured or the concordance between the echocardiographic evaluation of RA pressure and the invasive method is as low as 34%.26 In the assessment of the probability of PH, the measurement of TRV should be used in coordination with other echocardiographic markers of PH. The guidelines for PH recommend examining an RA area >18 cm2 for echocardiographic signs of elevated RA pressure.27,28 In the case of TRV ≤2.8 m/s and without other echocardiographic signs of PH, the probability of PH is low. If TRV is ≤2.8 m/s but there are echocardiographic signs of PH, or TRV is 2.9–3.4 m/s and there are no echocardiographic signs of PH, then there is a medium probability of PH. In the case of TRV 2.9–3.4 m/s and the presence of other echocardiographic signs of PH or TRV ≥3.4 m/s without the presence of other echocardiographic signs, there is a high probability of PH.5,27,28 PH causes increased pulmonary vascular resistance and elevated pulmonary artery pressures resulting in maladaptive RV dilatation and, 1.

2.

3.

4.

5.

6.

7.

8.

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Kovalova S, Necas J, Cerbak R, et al. Echocardiographic volumetry of the right ventricle. Eur J Echocardiogr 2005;6:15–23. https://doi.org/10.1016/j.euje.2004.04.009; PMID: 15664549.

Schneider M, Binder T. Echocardiographic evaluation of the right heart. Wien Klin Wochenschr 2018;130:413–20. https:// doi.org/10.1007/s00508-018-1330-3; PMID: 29556779.

Choudhary G, Malik AA, Stapleton D, Reddy PC. Assessment of right ventricle by echocardiogram. In: Lakshmanadoss U, ed. Echocardiography in Heart Failure and Cardiac Electrophysiology. IntechOpen, 2016. https://doi. org/10.5772/64781.

Rudski LG, Lai WW, Afilalo J, et al. Guidelines for the echocardiographic assessment of the right heart in adults: a report from the American Society of Echocardiography. J Am Soc Echocardiogr 2010;23:685–713. https://doi.org/10.1016/j. echo.2010.05.010; PMID: 20620859.

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eventually, RV failure. Many studies have proposed the concept of RV– pulmonary artery coupling to define the cardiac function in PH and predict survival time.26–29 TAPSE is an afterload-dependent parameter and patients with a TAPSE/SPAP ratio <0.25 mm/mmHg have a worse prognosis.29

Pulmonary Embolism

The known echocardiographic signs associated with pulmonary embolism have been shown to have low specificity and sensitivity and to be present in only 20% of patients.30 These parameters include pulmonary ejection acceleration time <60 ms and peak systolic tricuspid pressure gradient <60 mmHg (the 60/60 sign), and depressed contractility of the RV free wall compared with the echocardiographic RV apex (McConnell’s sign). RV dilation occurs in up to 25% of patients with pulmonary embolism.8,30 The PEITHO trial used at least one of the echocardiographic markers for RV dysfunction to identify the group with an intermediate risk of pulmonary embolism: RV end-diastolic diameter >30 mm, RV/LV end-diastolic diameter ratio >0.9, RV free wall hypokinesis, or peak TRV >2.6 m/s.8,30

Conclusion

Routine clinical 2D echocardiography has largely been used to evaluate the structure and function of the RV. Current echocardiography techniques, including 3D and strain rate imaging, may be used to further contribute to diagnosis and facilitate the choice of treatment. Assessment of RV function and dimensions should be obtained using multiple parameters and performed using multiple acoustic windows according to the published limits in guidelines.

PMID: 31175016.

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10. Bleeker GB, Steendijk P, Holman ER, et al. Assessing right ventricular function: the role of echocardiography and complementary technologies. Heart 2006;92(Suppl 1):i19– 26. https://doi.org/10.1136/hrt.2005.082503; PMID: 16543597.

11. Modin D, Møgelvang R, Andersen DM, Biering-Sørensen T. Right ventricular function evaluated by tricuspid annular plane systolic excursion predicts cardiovascular death in the general population. J Am Heart Assoc 2019;8:e012197. https:// doi.org/10.1161/JAHA.119.012197; PMID: 31088196.

12. Guazzi M, Bandera F, Pelissero G. Tricuspid annular plane systolic excursion and pulmonary arterial systolic pressure relationship in heart failure: an index of right ventricular contractile function and prognosis. Am J Physiol Heart Circ Physiol 2013;305:h1373–81. https://doi.org/10.1152/ ajpheart.00157.2013; PMID: 23997100.

13. Medvedofsky D, Mor-Avi V, Kruse E, et al. Quantification of right ventricular size and function from contrast-enhanced three-dimensional echocardiographic images. J Am Soc Echocardiogr 2017;30:1193–202. https://doi.org/10.1016/j. echo.2017.08.003; PMID: 29050828.

14. Lee JH, Park JH. Strain analysis of the right ventricle using two-dimensional echocardiography. J Cardiovasc Imaging 2018;26:111–24. https://doi.org/10.4250/jcvi.2018.26.e11; PMID: 30310878.

15. Lang RM, Badano LP, Mor-Avi V, et al. Recommendations for cardiac chamber quantification by echocardiography in

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adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Eur Heart J Cardiovasc Imaging 2015;16:233–70. https://doi.org/10.1093/ehjci/jev014; PMID: 25712077.

DiLorenzo MP, Bhatt SM, Mercer-Rosa L. How best to assess right ventricular function by echocardiography. Cardiol Young 2015;25:1473–81. https://doi.org/10.1017/S1047951115002255; PMID: 26675593.

Zaidi A, Knight DS, Augustine DX, et al. Echocardiographic assessment of the right heart in adults: a practical guideline from the British Society of Echocardiography. Echo Res Pract 2020;7:g19–41. https://doi.org/10.1530/ERP-19-0051; PMID: 32105053.

Fenster BE, Holm KE, Weinberger HD, et al. Right ventricular diastolic function and exercise capacity in COPD. Respir Med 2015;109:1287–92. https://doi.org/10.1016/j. rmed.2015.09.003; PMID: 26371994.

Kosmala W, Colonna P, Przewlocka-Kosmala M, Mazurek W. Right ventricular dysfunction in asymptomatic diabetic patients. Diabetes Care 2004;27:2736–8. https://doi. org/10.2337/diacare.27.11.2736; PMID: 15505015.

Pagourelias ED, Efthimiadis GK, Parcharidou DG, et al.

Prognostic value of right ventricular diastolic function indices in hypertrophic cardiomyopathy. Eur J Echocardiogr 2011;12:809–17. https://doi.org/10.1093/ejechocard/jer126; PMID: 21846651.

Jutant EM, Humbert M. Pulmonary hypertension: definition, classification and treatments. Biol Aujourdhui 2016;210:53–64 [in French]. https://doi.org/10.1051/jbio/2016014; PMID: 27687597.

Luxford J, Bassin L, D’Ambra M. Echocardiography of the

Right Heart Evaluation tricuspid valve. Annals of Cardiothoracic Surgery 2017;6:223– 39. https://doi.org/10.21037/acs.2017.05.15.

23. Lancellotti P, Moura L, Pierard LA, et al. European Association of Echocardiography recommendations for the assessment of valvular regurgitation. Part 2: mitral and tricuspid regurgitation (native valve disease). Eur J Echocardiogr 2010;11:307–32. https://doi.org/10.1093/ ejechocard/jeq031; PMID: 20435783.

24. Vahanian A, Alfieri O, Andreotti F, et al. The Joint Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS). Guidelines on the management of valvular heart disease (version 2012). Eur Heart J 2012;33:2451–96. https://doi.org/10.1093/ eurheartj/ehs109; PMID: 22922415.

25. Parasuramana S, Walker S, Loudon BL, et al. Assessment of pulmonary artery pressure by echocardiography: a comprehensive review. Int J Cardiol Heart Vasc 2016;12:45–

51. https://doi.org/10.1016/j.ijcha.2016.05.011; PMID: 28616542.

26. Augustine DX, Coates-Bradshaw LD, Willis J, et al.

Echocardiographic assessment of pulmonary hypertension: a guideline protocol from the British Society of Echocardiography. Echo Res Pract 2018;5:g11–24. https://doi. org/10.1530/ERP-17-0071; PMID: 30012832.

27. Galiè N, Humbert M, Vachiery JL, et al. 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension: the joint task force for the diagnosis and treatment of pulmonary hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J 2016;37:67–119. https://doi.org/10.1093/eurheartj/ehv317; PMID: 26320113.

28. Konstantinides SV, Meyer G, Becattini C, et al. 2019 ESC

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guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS): the Task Force for the diagnosis and management of acute pulmonary embolism of the European Society of Cardiology (ESC). Eur Heart J 2020;41:543–603. https://doi.org/10.1093/eurheartj/ehz405; PMID: 31504429.

29. Kazimierczyk R, Kazimierczyk E, Knapp M, et al.

Echocardiographic assessment of right ventricular–arterial coupling in predicting prognosis of pulmonary arterial hypertension patients. J Clin Med 2021;10:2995. https://doi. org/10.3390/jcm10132995; PMID: 34279478.

30. Meyer G, Vicaut E, Danays T, et al. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med 2014;370:1402–11. https://doi.org/10.1056/NEJMoa1302097; PMID: 24716681.

REVIEW

Lifetime Management of Patients with Aortic Valve Disease

Valve-in-valve Transcatheter Aortic Valve Replacement for Failed Surgical Valves and Adjunctive Therapies Emily Perdoncin, MD, ,1 Gaetano Paone, MD, ,2 and Isida Byku, MD,

1

1. Structural Heart and Valve Center, Division of Cardiology, Emory University, Atlanta, GA; 2. Structural Heart and Valve Center, Division of Cardiothoracic Surgery, Emory University, Atlanta, GA

Abstract

While redo surgical aortic valve replacement has traditionally been the gold standard for the treatment of failed surgical valves, valve-invalve (ViV) transcatheter aortic valve replacement (TAVR) has arisen as a viable, less invasive option with the potential for improved short-term morbidity and mortality. Retrospective registry data regarding ViV TAVR outcomes have been encouraging, with excellent 1-year mortality, and sustained valve performance and quality of life improvement out to 3 years. Operators must be comfortable with CT analysis for procedural planning, and be able to identify and troubleshoot patients who are at risk for coronary obstruction and patient prosthesis mismatch. The authors provide a review of clinical outcomes associated with ViV TAVR, procedural planning recommendations, and strategies to overcome technical challenges that can occur during ViV TAVR.

Keywords

Bioprosthetic heart valve failure, transcatheter aortic valve replacement, structural heart disease, coronary artery obstruction Disclosure: GP is a consultant and proctor for Edwards Lifesciences. All other authors have no conflicts of interest to declare.

Received: June 17, 2021 Accepted: October 12, 2021 Citation: US Cardiology Review 2022;16:e09. DOI: https://doi.org/10.15420/usc.2021.20 Correspondence: Isida Byku, Structural Heart and Valve Center, Interventional Cardiology, Emory University Hospitals, 550 Peachtree St NE, Davis-Fischer Building, 4th Floor S 4315, Atlanta, GA 30308. E: isida.byku@emory.edu Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

The use of bioprosthetic surgical aortic valve replacements (SAVR) has been steadily increasing in people aged 50–70 years over the past decade.1 This trend has been driven by the desire to avoid long-term anticoagulation and the development of novel percutaneous treatment options for valvular heart disease. Current-generation bioprosthetic valves remain prone to structural valve deterioration and have finite durability. This has significant implications for the younger, low-risk populations whose life-expectancy may exceed that of the initial surgical valve.2 While redo SAVR has traditionally been the gold standard for the treatment of failed surgical valves, valve-in-valve (ViV) transcatheter aortic valve replacement (TAVR) has arisen as a viable, less invasive option with the potential for improved short-term morbidity and mortality, but is only approved by the Food and Drug Administration for patients at high surgical risk for reoperation.3 The term ViV TAVR describes several clinical scenarios, including TAVR inside of a degenerated surgical valve (TAVR-in-SAVR), TAVR inside of a degenerated TAVR valve (TAVR-in-TAVR), and even TAVR inside of a TAVR valve, which was previously placed in degenerated SAVR valves (TAVR-in-TAVR-inSAVR).4 We provide a review of clinical outcomes associated with ViV TAVR, procedural planning recommendations, and strategies to overcome technical challenges that can occur during ViV TAVR.

ViV TAVR Outcomes

The available retrospective registry data regarding ViV TAVR outcomes have been encouraging. Initial data from the 2014 Valve-in-Valve International Data (VIVID) registry, which pooled patients with both stenotic and regurgitant lesions, and those treated with balloon-

expandable (BEV) and self-expanding valves (SEV), showed promising 30day and 1-year survival rates of 92% and 83%, respectively.5 The PARTNER-2 multicenter registry, which included patients at high risk for mortality with re-operative surgery (average Society of Thoracic Surgeons score 9.1 ± 4.7%) treated with ViV TAVR using the SAPIEN XT BEV (Edwards Lifesciences), demonstrated sustained performance with no change in gradients, effective orifice area, or aortic regurgitation, and improvement in quality of life and functional status at 3 years.6 Of note, the PARTNER-2 registry excluded patients with SAVR valves <21 mm, limiting the applicability of this data to patients with small annuli.5,6 A recent propensity-matched registry analysis comparing early and late outcomes between SAVR and ViV TAVR showed lower 30-day mortality with ViV TAVR compared with SAVR, as well as improved survival at 5 years (76.8% versus 66.8%; HR 0.55; 95% CI [0.30–0.99]; p=0.04).7 While ViV TAVR is currently approved only for high surgical risk patients, a recent registry study examining lower-risk ViV patients treated with Sapien 3 BEVs showed comparable 30-day and 1-year outcomes to patients undergoing native TAVR. Based on a propensity-matched analysis, 30-day all-cause mortality in the low-risk (Society of Thoracic Surgeons <4%) ViV group was comparable to native TAVR (1.0% in the low-risk group versus 1.3% in native TAVR, p=0.44). Furthermore, 1-year all-cause mortality was actually lower in the ViV group compared with native TAVR (6.1% versus 8.5%, p=0.05).8 While further study is required, the data may open the door to an expansion of the indication for ViV TAVR to lower-risk patients.

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Valve-in-valve TAVR Figure 1: CT Predictors for Coronary Obstruction with Valve-in-valve Transcatheter Aortic Valve Replacement Risk factors

High obstruction risk

Coronary height

<10 mm

Sinus width

<30 mm Above coronary ostia

Bioprosthetic leaflet length STJ height

Below coronary leaflets

Prosthetic leaflet orientation

Externally mounted

Valve-to-coronary distance

<4 mm

Valve-to-STJ distance

<2 mm

Table describing CT findings predictive of high coronary obstructive risk. Figure showing a degenerated transcatheter aortic valve replacement valve at high risk for coronary obstruction with valve-in-valve transcatheter aortic valve replacement due to bilateral valve-to-coronary distances <4 mm and valve to sinotubular junction distances <2 mm. LM = left main coronary artery; LVTC = left valve-to-coronary; LVTSTJ = left valve-to-STJ; os = ostia; RCA = right coronary artery; RVTSTJ = right valve-to-STJ; RVTC =right valve-to-coronary; STJ = sinotubular junction.

Preprocedural Planning for ViV TAVR

Initial assessment of the indwelling bioprosthetic valve via cardiac multidetector CT may be the most important part of the procedure. The size, valve type (stented, sutureless, stentless), and leaflet orientation (externally or internally mounted leaflets) of the surgical valve need to be carefully assessed and factored into the choice of transcatheter valve.

The ViV app (UBQO) is an essential source for ViV planning, providing information regarding the fluoroscopic appearance of various valves, true inner diameter measurements, and suggestions for transcatheter valve sizing.

Careful measurements of the annular plane, coronary artery heights, sinotubular junction (STJ) height, and sinus of Valsalva sizes must be made, followed by implantation of a ‘virtual valve’ to estimate valve-tocoronary (VTC) and valve-to-STJ (VTSTJ) distances (Figure 1).9 The VTC, VTSTJ, leaflet lengths, and relationship of the leaflet tips of the existing surgical valve to the coronary ostia and STJ will help determine the risk for coronary obstruction.9,10 A VTC <3–4 mm and VTSTJ <2 mm is considered high risk for coronary obstruction in the setting of ViV TAVR and warrants further, more complex procedural planning.11,12

Choice of Transcatheter Heart Valve for ViV TAVR

Selecting the appropriate transcatheter heart valve (THV) for ViV TAVR requires close attention to the individual patient’s anatomy, as well as a plan for lifetime valve management, with careful attention to the risk of coronary obstruction, feasibility of future coronary re-access, and hemodynamic results.

Coronary access after TAVR is a concern that applies to both BEV and SEV designs, and occurs more commonly with ViV TAVR than de novo TAVR.13 The height and intra-annular position of a BEV may be advantageous over the design of SEVs in regard to coronary re-access and risk for coronary obstruction during ViV TAVR or future redo TAVR procedures. In contrast, a SEV may allow for retrieval or repositioning if there is evidence of impending coronary obstruction, with the trade-off of the risk of leaflets of the supra-annular SEV reaching the STJ, thus making coronary re-access challenging and potentially prohibiting a future redo TAVR.14

Consideration for the feasibility of a future TAVR-in-TAVR or TAVR-in-TAVRin-SAVR should also be considered for the younger and lower-risk populations, who may potentially require three valves in their lifetime.

In a CT analysis study, the coronary artery ostia originated below the top of the neo-skirt in 90% of SEV first cases, compared with 67% of BEV first cases. Additionally, the risk for technically impossible coronary re-access was estimated at 27% for SEV, compared with 10% for BEV.15 This issue may be further compounded if the transcatheter heart valve is within an existing SAVR frame.

While the BEV’s low frame height may be favorable for coronary access, its intra-annular design within an existing SAVR may result in poorer hemodynamics and long-term durability. The VIVID registry found elevated postprocedural gradients, defined as mean gradients >20 mmHg, more common after BEV ViV than SEV ViV (40% versus 21.3%;, p<0.0001).

Furthermore, BEV appeared to perform even worse in small surgical valves (inner diameter <21 mm) with higher rates of elevated postprocedural gradients when compared with SEV (58.8% versus 20%; p=0.005) at 1 year.5 While these findings have not necessarily translated into obvious mortality differences, the long-term clinical implications need to be further elucidated.16,17

Pitfalls of ViV TAVR Coronary Obstruction Risk and Mitigation Strategies

Coronary artery obstruction is a rare (<1%), but life-threatening, complication of TAVR, with mortality rates as high as 41%.11,13 Coronary artery obstruction occurs more frequently among patients undergoing ViV procedures than first-time TAVR, with rates in registries ranging from 2.4% to 3.5%.11,18 Obstruction can occur when the leaflets of the existing SAVR are displaced toward the coronary ostia or STJ during TAVR valve deployment. Risk factors include female sex, low coronary ostia (<10 mm), effaced sinuses (<30 mm), narrow valve to coronary distances (<4 mm), and VTSTJ junction distances (<2 mm).11,13 Stentless bioprostheses and stented bioprostheses with externally mounted valve leaflets have been shown to be independent risk factors for coronary obstruction.19 Careful attention with preprocedural CT analysis measuring the coronary heights, STJ height and diameter, and modeling with a virtual valve will determine

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Valve-in-valve TAVR Figure 2: Rescue Snorkel Stenting for Acute Coronary Obstruction of the Left Main Coronary Artery

Figure showing acute coronary obstruction of the left main coronary artery following deployment of a transcatheter aortic valve replacement valve, salvaged with the snorkel stenting technique.

LM = left main coronary artery; TAVR = transcatheter aortic valve replacement; THV = transcatheter heart valve.

ViV risk and feasibility, and may help determine the more favorable transcatheter heart valve for a patient’s unique anatomy.9,10

Figure 3: Left BASILICA

Techniques have been developed to mitigate the risk for coronary obstruction in high-risk patients without options for redo surgical aortic valve replacements. These include coronary protection with a guidewire and/or stent and bioprosthetic or native aortic scallop intentional laceration to prevent iatrogenic coronary artery obstruction during TAVR (BASILICA).

Snorkel Stenting

Snorkel or chimney stenting involves prepositioning a coronary wire and stent in a threatened coronary artery, and then deploying the stent in the ostium and ‘snorkeling’ it alongside the TAVR valve into the aorta if there is evidence of coronary compromise (Figure 2). These stents are exposed to continuous external compression from the TAVR valve, which places them at risk for delayed coronary obstruction with extremely challenging percutaneous bailout options.12 Data from the Chimney registry reported a 5% procedural death rate and 21.6% MI rate with this technique.20 Furthermore, techniques involving coronary protection by inserting a guidewire followed by removal once the TAVR valve is deployed and there is no immediate evidence of obstruction have also been associated with increased mortality and coronary obstruction.21

BASILICA

BASILICA, which uses radiofrequency energy to create longitudinal baseto-tip lacerations of bioprosthetic or native aortic valve leaflets, is a welldescribed alternative technique with more predictable and reliable outcomes.22 Briefly, BASILICA is typically performed under general anesthesia with transesophageal guidance, and standard transfemoral or transcaval access. Cerebral embolic protection is recommended in all cases with suitable anatomy. The target leaflet of the threatened coronary is traversed with a stiff, electrified guidewire (AstatoXS 20 or AstatoXS 40; Asahi) insulated with a hubless locking microcatheter (Piggyback Wire Converter; Teleflex) through a Pachyderm-shaped (PAL1/2/3 for left coronaries and PJR4 for right coronaries, Launcher; Medtronic) guiding catheter (Figure 3A).23 Of note, the dedicated Pachyderm catheters are no longer being manufactured. We recommend an AL2 or AL3 guide catheter for left BASILICA, and a JR4 guide catheter with a manually shaped tip for the right coronary artery. The guidewire is then snared in the left

Figure showing the steps of a left BASILICA in a patient at high risk for coronary obstruction with valve-in-valve transcatheter aortic valve replacement. A,B: Traversal of the left coronary leaflet with an electrified guidewire. C: Creation of the Flying V. D: Completion of coronary angiography following laceration of the leaflet showing patent left coronary system. LCC = left coronary cusp; LVOT = left ventricular outflow tract.

ventricular outflow tract, with careful attention to avoid trapping of the mitral chordal elements, and externalized to form a loop across the base of the leaflet (Figure 3B). This ‘Flying V’ lacerating surface is then positioned across the leaflet. The leaflet is lacerated in the standard fashion using a 5% dextrose solution during a 70 W continuous duty-cycle radiofrequency ablation (Figure 3C). Following successful laceration, a THV is deployed in the standard fashion and angiography is performed to confirm patency of the coronary artery (Figure 3D).

Data from the 2019 BASILICA trial demonstrated procedural success with this technique in 93% of patients, with 100% of patients free of coronary obstruction after TAVR at 30 days. There was a higher stroke rate (10%) than seen in original PARTNER-2 (6.4%) and SurTAVI (4.5%) trials, but in an extreme-risk group of non-operative patients.24 More recent data from the 214-patient multicenter International BASILICA registry has remained encouraging. Procedural success, defined as successful traversal and laceration without mortality, coronary obstruction, or emergency

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Valve-in-valve TAVR intervention, was achieved in 86.9% of patients, with a stroke rate of only 2.8% with judicious use of cerebral embolic protection.25

centers demonstrated stable and excellent valve hemodynamics and survival at 30 days and 1 year.33

BASILICA does not address commissural malalignment or obstruction related to the skirt of the THV. BASILICA may also fail to prevent coronary obstruction in patients with challenging anatomy, such as very narrow VTCs (<2mm), diffusely calcified leaflets, and TAVR-in-TAVR procedures, due to inadequate leaflet splay despite otherwise successful leaflet laceration. An advanced BASILICA modification, balloon-assisted BASILICA, which involves inflating a coronary balloon in the target leaflet to widen the achieved splay, has been proposed to overcome these anatomical limitations.26

The ideal timing of when to perform BVF remains unclear. Fracture of the existing bioprosthetic valve first before implanting the THV may facilitate placement of a larger TAVR valve, although at the expense of potentially damaging the surgical leaflets and causing unstable aortic insufficiency.

Attempting fracture following implantation of the THV may allow for a more controlled procedure due to less concern for hemodynamic instability, but may risk structural damage to the new THV leaflets and, therefore, risk early degeneration.29,31 The timing of BVF ultimately depends on operator comfort, aggressiveness of balloon sizing and dilatation, and requires further study regarding long-term clinical outcomes associated with this technique.

Additionally, there is a risk for leaflet prolapse into the coronary arteries potentially related to incomplete displacement or expansion of lacerated leaflets, or mechanical avulsion from excessive pull, rather than controlled laceration. A small case report suggests that leaflet prolapse may be more common in patients with stentless bioprostheses with mobile, degenerated leaflets.27 While BASILICA is an excellent tool to facilitate TAVR in patients otherwise considered poor candidates for ViV TAVR due to the risk for coronary obstruction, the technique must be adopted with caution and reserved for high-volume centers with experience using this technique. Currently the Food and Drug Administration does not support proctoring for BASILICA.

Patient–Prosthesis Mismatch

Patients undergoing ViV TAVR may be at risk for patient–prosthesis mismatch (PPM) due to constraints from the existing surgical valve, which can prevent full expansion of the new TAVR valve. PPM is defined as an effective orifice area of a prosthetic valve that is smaller than the orifice of the patients’ native aortic valve, with severe PPM defined as an indexed effective orifice area ≤0.65 cm2/m2.28 In the VIVID registry, the incidence of severe PPM following ViV TAVR was 31.8%, with reduced survival seen at 1 year (74.8%) in patients with a small surgical valve size (≤21 mm) compared with patients with an intermediatesized valve (21–25 mm, 81.8%) or a large valve (≥25 mm, 93.3%). More recent data from a Sapien 3 ViV retrospective analysis did not show a difference in survival between those in a high postprocedure gradient group (≥ 20 mmHg) and those in a low postprocedure gradient group (<20 mmHg).

Proposed strategies to avoid severe PPM include the use of a supraannular SEV, aiming for higher implant depths, and performing bioprosthetic valve fracture (BVF) in patients with small surgical valves and residual gradients >20 mmHg. The BVF technique involves positioning a non-compliant valvuloplasty balloon inside the frame of the existing surgical valve and then performing high-pressure inflation to fracture the sewing ring of the surgical valve, allowing further expansion of both the surgical valve and the implanted THV. Bench-testing performed by Saxon et al. and Allen et al. demonstrated the ability to reliably fracture Magna, Magna Ease, Mitroflow, Mosaic, and Biocor Epic bioprosthetic valves.29,30 A series of 20 patients undergoing BVF either before or after ViV TAVR showed a successful and significant reduction in mean gradient (20.5 ± 7.4 mmHg to 6.7 ± 3.7 mmHg; p<0.001), and increase in effective orifice area (1.0 ± 0.4 cm2 to 1.8 ± 0.6 cm2; p<0.001) with no procedural complications.31 This was again demonstrated in a larger 75-patient, multicenter study that demonstrated significantly lower gradients when BVF was performed, without complications.32 Recent data from 139 BVF cases performed at 11

Valve Thrombosis and Anticoagulation Strategies

Clinical valve thrombosis after ViV TAVR is common, with rates as high as 7.6% in an analysis of 300 patients from the VIVID registry. This appears to be markedly reduced in patients taking oral anticoagulants (OAC) for other reasons (1.0% versus 11.3% in patients not taking OAC).34 Current guidelines recommend single antiplatelet therapy after TAVR with aspirin 75–100 mg daily for patients without co-existing indications for long-term anticoagulation.35 The POPular TAVI trial, which compared single antiplatelet therapy with dual-antiplatelet therapy after TAVR, did not show a reduction in thrombotic events with the more potent dualantiplatelet therapy regimen, but did see more bleeding.36 Unfortunately, this study did not specifically evaluate the ViV TAVR population.

The recent ATLANTIS trial compared apixiban with standard of care postTAVR, which was defined as either a vitamin K antagonist in patients with an indication for OAC or single antiplatelet therapy if there was no indication for OAC. Those treated with apixaban had a reduction in reduced leaflet motion and hypoattenuated leaflet thrombosis with the apixaban regimen, although this did not translate into an improvement in clinical outcomes at 30 days.37 Specific data for the ViV TAVR subgroup, comprising approximately 5% of each treatment arm, are not yet available.

Interestingly, some preliminary data have suggested that BASILICA may offer an additional benefit of reducing subclinical leaflet thrombosis by improving sinus washout and stasis.38 No hypoattenuated leaflet thrombosis was seen on TAVR leaflets adjacent to the lacerated aortic leaflets in the BASILICA trial.24 Until more data become available, the choice of antiplatelet or anticoagulation after ViV TAVR remains up to the discretion of the operator. Potential strategies to mitigate the risk of clinical and subclinical valve thrombosis included a cautious course of OAC in patients with low baseline bleeding risk, and/or leaflet modification strategies, such as BASILICA, to improve sinus washout. Further study is required before recommending a standardized therapy for all-comers following ViV TAVR.

Conclusion

ViV TAVR is associated with less morbidity and mortality than redo SAVR for patients with degenerated bioprosthetic surgical valves, but requires close attention to individual patient anatomy, as well as a plan for lifetime valve management with careful attention to risk for coronary obstruction, feasibility of future coronary re-access, and hemodynamic results.

Procedural modifications, such as BASILICA and BVF, may be necessary to facilitate successful ViV TAVR procedures in high-risk patients.

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Valve-in-valve TAVR

Clinical Perspective

• Valve-in-valve transcatheter aortic valve replacement (ViV TAVR) is a viable, less invasive option for patients with degenerated aortic

bioprostheses, with the potential for improved short-term morbidity and mortality when compared with redo surgical aortic valve replacement.

• ViV TAVR requires close attention to individual patient anatomy, as well as a plan for lifetime valve management with careful attention to the risk of acute coronary obstruction, feasibility of future coronary re-access, and hemodynamic results.

• The risk for coronary obstruction can be mitigated with careful preprocedural CT planning and the use of techniques, such as snorkel stenting or BASILICA.

• Bioprosthetic valve fracture may help address patient–prosthesis mismatch following ViV TAVR. • Optimal anticoagulation strategies following ViV TAVR have not yet been elucidated.

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Blanke P, Soon J, Dvir D, et al. Computed tomography assessment for transcatheter aortic valve in valve implantation: the Vancouver approach to predict anatomical risk for coronary obstruction and other considerations. J Cardiovasc Comput Tomogr 2016;10:491–9. https://doi. org/10.1016/j.jcct.2016.09.004; PMID: 27697505.

Lederman RJ, Babaliaros VC, Rogers T, et al. Preventing coronary obstruction during transcatheter aortic valve replacement: from computed tomography to BASILICA. JACC Cardiovasc Interv 2019;12:1197–216. https://doi.org/10.1016/j. jcin.2019.04.052; PMID: 31272666.

Ribeiro HB, Rodes-Cabau J, Blanke P, et al. Incidence, predictors, and clinical outcomes of coronary obstruction following transcatheter aortic valve replacement for degenerative bioprosthetic surgical valves: insights from the VIVID registry. Eur Heart J 2018;39:687–95. https://doi. org/10.1093/eurheartj/ehx455; PMID: 29020413.

Jabbour RJ, Tanaka A, Finkelstein A, et al. Delayed coronary obstruction after transcatheter aortic valve replacement. J Am Coll Cardiol 2018;71:1513–24. https://doi.org/10.1016/j. jacc.2018.01.066; PMID: 29622157.

Ribeiro HB, Webb JG, Makkar RR, et al. Predictive factors, management, and clinical outcomes of coronary obstruction

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following transcatheter aortic valve implantation: insights from a large multicenter registry. J Am Coll Cardiol 2013;62:1552–62. https://doi.org/10.1016/j.jacc.2013.07.040; PMID: 23954337.

Dvir D, Leipsic J, Blanke P, et al. Coronary obstruction in transcatheter aortic valve-in-valve implantation: preprocedural evaluation, device selection, protection, and treatment. Circ Cardiovasc Interv 2015;8:e002079. https://doi. org/10.1161/CIRCINTERVENTIONS.114.002079; PMID: 25593122.

De Backer O, Landes U, Fuchs A, et al. Coronary access after TAVR-in-TAVR as evaluated by multidetector computed tomography. JACC Cardiovasc Interv 2020;13:2528–38. https://doi.org/10.1016/j.jcin.2020.06.016; PMID: 33153567.

Lee HA, Chou AH, Wu VC, et al. Balloon-expandable versus self-expanding transcatheter aortic valve replacement for bioprosthetic dysfunction: a systematic review and metaanalysis. PLoS One 2020;15:e0233894. https://doi. org/10.1371/journal.pone.0233894; PMID: 32479546.

Ochiai T, Yoon SH, Sharma R, et al. Outcomes of selfexpanding vs. balloon-expandable transcatheter heart valves for the treatment of degenerated aortic surgical bioprostheses – a propensity score-matched comparison.

Circ J 2018;82:2655–62. https://doi.org/10.1253/circj.CJ-180157; PMID: 30068793.

Dvir D, Webb J, Brecker S, et al. Transcatheter aortic valve replacement for degenerative bioprosthetic surgical valves: results from the Global Valve-in-Valve Registry. Circulation 2012;126:2335–44. https://doi.org/10.1161/ CIRCULATIONAHA.112.104505; PMID: 23052028.

Duncan A, Moat N, Simonato M, et al. Outcomes following transcatheter aortic valve replacement for degenerative stentless versus stented bioprostheses. JACC Cardiovasc Interv 2019;12:1256–63. https://doi.org/10.1016/j. jcin.2019.02.036; PMID: 31202944.

Mercanti F, Rosseel L, Neylon A, et al. Chimney stenting for coronary occlusion during TAVR: insights from the Chimney Registry. JACC Cardiovasc Interv 2020;13:751–61. https://doi. org/10.1016/j.jcin.2020.01.227; PMID: 32192695.

Palmerini T, Chakravarty T, Saia F, et al. Coronary protection to prevent coronary obstruction during TAVR: a multicenter international registry. JACC Cardiovasc Interv 2020;13:739–47. https://doi.org/10.1016/j.jcin.2019.11.024; PMID: 32061608.

Khan JM, Dvir D, Greenbaum AB, et al. Transcatheter laceration of aortic leaflets to prevent coronary obstruction during transcatheter aortic valve replacement: concept to first-in-human. JACC Cardiovasc Interv 2018;11:677–89. https:// doi.org/10.1016/j.jcin.2018.01.247; PMID: 29622147.

Lisko JC, Babaliaros VC, Lederman RJ, et al. Pachydermshape guiding catheters to simplify BASILICA leaflet traversal. Cardiovasc Revasc Med 2019;20:782–5. https://doi. org/10.1016/j.carrev.2019.05.033; PMID: 31257172.

Khan JM, Greenbaum AB, Babaliaros VC, et al. The BASILICA trial: prospective multicenter investigation of intentional leaflet laceration to prevent TAVR coronary obstruction.

JACC Cardiovasc Interv 2019;12:1240–52. https://doi. org/10.1016/j.jcin.2019.03.035; PMID: 31202947.

Khan JM, Babaliaros VC, Greenbaum AB, et al. Preventing coronary obstruction during transcatheter aortic valve replacement: results from the multicenter international BASILICA registry. JACC Cardiovasc Interv 2021;14:941–8. https://doi.org/10.1016/j.jcin.2021.02.035; PMID: 33958168.

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26. Greenbaum AB, Kamioka N, Vavalle JP, et al. Balloonassisted BASILICA to facilitate redo TAVR. JACC Cardiovasc Interv 2021;14:578–80. https://doi.org/10.1016/j. jcin.2020.10.056; PMID: 33358650.

27. Kitamura M, Pighi M, Ribichini F, Abdel-Wahab M. Leaflet prolapse after BASILICA and transcatheter aortic valve replacement. JACC Cardiovasc Interv 2020;13:e143–5. https:// doi.org/10.1016/j.jcin.2020.04.016; PMID: 32473886.

28. Pibarot P, Dumesnil JG. Hemodynamic and clinical impact of prosthesis-patient mismatch in the aortic valve position and its prevention. J Am Coll Cardiol 2000;36:1131–41. https://doi. org/10.1016/S0735-1097(00)00859-7; PMID: 11028462.

29. Saxon JT, Allen KB, Cohen DJ, Chhatriwalla AK. bioprosthetic valve fracture during valve-in-valve TAVR: bench to bedside. Interv Cardiol 2018;13:20–6. https://doi. org/10.15420/icr.2017:29:1; PMID: 29593832.

30. Allen KB, Chhatriwalla AK, Cohen DJ, et al. Bioprosthetic valve fracture to facilitate transcatheter valve-in-valve implantation. Ann Thorac Surg 2017;104:1501–8. https://doi. org/10.1016/j.athoracsur.2017.04.007; PMID: 28669505.

31. Chhatriwalla AK, Allen KB, Saxon JT, et al. Bioprosthetic valve fracture improves the hemodynamic results of valvein-valve transcatheter aortic valve replacement. Circ Cardiovasc Interv 2017;10:e005216. https://doi.org/10.1161/ CIRCINTERVENTIONS.117.005216; PMID: 28698291.

32. Allen KB, Chhatriwalla AK, Saxon JT, et al. Bioprosthetic valve fracture: technical insights from a multicenter study. J Thorac Cardiovasc Surg 2019;158:1317–28.e1. https://doi. org/10.1016/j.jctvs.2019.01.073; PMID: 30857820.

33. Chhatriwalla AK, Allen KB, Saxon JT, et al. 1-year outcomes following bioprosthetic valve fracture to facilitate valve-in-valve transcatheter aortic valve replacement.

Structural Heart 2021;5:312–8. https://doi.org/10.1080/247487 06.2021.1895456.

34. Abdel-Wahab M, Simonato M, Latib A, et al. Clinical valve thrombosis after transcatheter aortic valve-in-valve implantation. Circ Cardiovasc Interv 2018;11:e006730. https:// doi.org/10.1161/CIRCINTERVENTIONS.118.006730; PMID: 30571208.

35. Otto CM, Nishimura RA, Bonow RO, et al. 2020 ACC/AHA guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation 2021;143:e72–227. https://doi.org/10.1161/CIR.0000000000000955; PMID: 33332150.

36. Brouwer J, Nijenhuis VJ, Delewi R, et al. Aspirin with or without clopidogrel after transcatheter aortic-valve implantation. N Engl J Med 2020;383:1447–57. https://doi. org/10.1056/NEJMoa2017815; PMID: 32865376.

37. Collet JP. Anti-Thrombotic strategy to Lower All cardiovascular and Neurologic ischemic and hemorrhagic evens after Trans-aortic valve Implantation for aortic Stenosis – ATLANTIS. Presented at: American College of Cardiology Virtual Annual Scientific Session (ACC 2021), 15 May 2021.

38. Hatoum H, Maureira P, Lilly S, Dasi LP. Impact of leaflet laceration on transcatheter aortic valve-in-valve washout: BASILICA to solve neosinus and sinus stasis. JACC Cardiovasc Interv 2019;12:1229–37. https://doi.org/10.1016/j. jcin.2019.04.013; PMID: 31272669.

REVIEW

Lifetime Management of Aortic Valve Disease

Transcatheter Aortic Valve Replacement Optimization Strategies: Cusp Overlap, Commissural Alignment, Sizing, and Positioning Saima Siddique, MD,1 Resha Khanal, MD, ,1 Amit N Vora, MD, MPH, ,1,2 and Hemal Gada, MD, MBA1 1. University of Pittsburgh Medical Center Heart and Vascular Institute, Harrisburg, PA; 2. Duke University Medical Center, Durham, NC

Abstract

As transcatheter aortic valve replacement (TAVR) rapidly expands to younger patients and those at low surgical risk, there is a compelling need to identify patients at increased risk of post-procedural complications, such as paravalvular leak, prosthesis–patient mismatch, and conduction abnormalities. This review highlights the incidence and risk factors of these procedural complications, and focuses on novel methods to reduce them by using newer generation transcatheter heart valves and the innovative cusp-overlap technique, which provides optimal fluoroscopic imaging projection to allow for precise implantation depth which minimizes interaction with the conduction system. Preserving coronary access after TAVR is another important consideration in younger patients. This paper reviews the significance of commissural alignment to allow coronary cannulation after TAVR and discusses recently published data on modified delivery techniques to improve commissural alignment.

Keywords

Transcatheter aortic valve replacement, cusp-overlap, pacemaker, commissural alignment, embolic protection Disclosure: ANV is a consultant for Medtronic. HG is a consultant for Medtronic, Bard, and Boston Scientific. All other authors have no conflicts of interest to declare.

Received: July 16, 2021 Accepted: November 15, 2021 Citation: US Cardiology Review 2022;16:e10. DOI: https://doi.org/10.15420/usc.2021.24 Correspondence: Hemal Gada, 111 S Front St, Harrisburg, PA 17101. E: hemalgada@gmail.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Transcatheter aortic valve replacement (TAVR) is an established therapeutic option for patients with symptomatic, severe aortic stenosis (AS) across the spectrum of surgical risk. With an increasing desire to expand TAVR to younger patients with low surgical risk, there have been continued technological advancements to optimize TAVR results to minimize postprocedural complications and address challenges when considering using TAVR in a younger population with a longer life expectancy. This paper will review the role of multimodality imaging to determine precise sizing and positioning of transcatheter heart valves (THVs) to avoid post-procedural complications such as paravalvular leak, prosthesis–patient mismatch, and conduction abnormalities. We will discuss innovative fluoroscopic cuspoverlap and shallow deployment techniques to minimize interaction of THVs with the conduction system and highlight recent data on the significance of commissural alignment to facilitate coronary reaccess and valve-in-valve (ViV) procedures following TAVR.

Modalities of Imaging for Pre‑procedural Size Assessment

Meticulous pre-procedure planning is an important step to clearly understand each patient’s unique anatomy and to facilitate optimal procedural workflow. A multimodality imaging approach, combining transthoracic echocardiography and multi-slice CT (MSCT), with occasional use of transesophageal echocardiography in select situations, is a better approach to predict pre- and post-procedural complications.1,2 MSCT identifies precise anatomical details including distribution and localization of calcification and allows for a more accurate delineation of the access route (transfemoral versus other). It also allows for detailed

visualization of the left ventricular outflow tract (LVOT) and coronary ostia.

MSCT is the standard imaging modality for aortic annulus measurement to determine valve size and positioning. One potential limitation of MSCT is the risk of contrast-induced kidney injury, although low-contrast protocols have been used to minimize this risk, and with accurate pre-procedure planning, TAVR can be performed using limited or no contrast dye.3 Although 3D transesophageal echocardiography (3D-TEE) had previously been used for valve size assessment, the estimation of annulus size and area by 3D-TEE is reported to be significantly smaller when compared to MSCT and can be considered only when MSCT is contraindicated.3,4 Nevertheless, it remains an important adjunct to peri-procedural imaging in select cases.

Paravalvular Leak: Role of Multi-slice CT and Accurate Device Selection

Historically there has been a higher incidence of paravalvular leak (PVL) with TAVR compared with surgical aortic valve replacement (SAVR), and this has been associated with worse outcomes.5,6 Mismatch of the valve annulus and prosthesis diameter sizes, device landing zone calcification, and suboptimal device implantation have been identified as the major predictors of PVL.7.8 With implementation of pre-procedural MSCT instead of TEE and more accurate sizing of THVs, the incidence of PVL has been significantly reduced.9 Current algorithms continue to use oversizing to ensure complete coverage of the aortic annulus. A −5% to +20% oversizing may be used with the balloon-expandable valve (BEV) and a perimeter oversizing of 7–30% for the self-expanding valve (SEV).10 While the incidence of PVL was observed to be higher in early generation valves, the rate has improved with the availability of a wider range of

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TAVR Optimization valve sizes and with the development of newer generation valves that have been engineered to provide better sealing mechanisms.11 The PARTNER 3 trial reported similar rates of moderate to severe PVL with the BEVs compared to SAVR (0.6% versus 0.5%).12 However, the incidence of moderate to severe PVL was reported to be higher with SEVs as seen in the Medtronic low-risk study (3.5% versus 0.55%).13 Medtronic CoreValve Evolut PRO is the latest generation of self-expanding valves (SEVs) that has been redesigned with a pericardial wrap on the distal outer stent to improve annular sealing and has been shown to result in none or trace/ mild PVL in >95% of patients at discharge and at 30 days.14 With continued use of current generation THV platforms with improved sealing mechanisms and increasing operator experience, the incidence of anything more than mild PVL is relatively low.

Prosthesis–Patient Mismatch

Hemodynamics of most prosthetic valves are often sub-optimal to those of the normal native valve, and a significant proportion of patients undergoing aortic valve replacement have high residual transprosthetic pressure gradients due to prosthesis–patient mismatch. Prosthesis– patient mismatch occurs when the effective orifice area (EOA) of the prosthesis is too small relative to the patient’s body surface area. It is considered absent or not clinically significant when the indexed EOA is >0.85 cm2/m2, moderate when it is between 0.65 and 0.85 cm2/m2, and severe when it is <0.65 cm2/m2.15 Although there is conflicting evidence regarding the impact of prosthesis– patient mismatch on clinical outcomes, likely because of methodological differences across studies and the patient population being studied, a large meta-analysis of 34 observational studies comprising 27,186 patients demonstrated an increased mortality in patients with prosthesis–patient mismatch following SAVR.16 Some studies of SAVR have suggested that the impact of prosthesis–patient mismatch on mortality was only observed in younger patients (aged <60–70 years) with a more active lifestyle.17,18 More recently, in an analysis of 62,125 patients from the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy (TVT) Registry who received TAVR, Herrmann et al. found that severe prosthesis–patient mismatch was associated with increased mortality and heart failure rehospitalizations at 1 year after TAVR.19 The analysis also identified important predictors of prosthesis–patient mismatch with the highest odds ratios in those receiving smaller prostheses (≤23 mm diameter), larger patients and those undergoing a ViV procedure. Although the incidence of prosthesis–patient mismatch in TAVR is generally lower than in SAVR, the study by Herrmann et al. emphasizes the importance of preventing prosthesis–patient mismatch at the time of TAVR, considering the expansion of TAVR to younger and low surgical risk patients.20 Tang et al. evaluated the incidence, predictors, and outcomes of prosthesis–patient mismatch in patients implanted with supra-annular valves in both de novo TAVR and transcatheter aortic valve (TAV) insurgical aortic valve (SAV) in the TVT Registry.21 Severe prosthesis–patient mismatch was found in 5.3% of patients undergoing de novo TAVR and 27% of patients undergoing TAV-in-SAV. The study demonstrated that an aortic annular diameter of <20 mm in de novo TAVR and TAV-in-SAV patients was a significant predictor of severe prosthesis–patient mismatch (p<0.001 for both). Although the 23 mm valve was also associated with severe prosthesis–patient mismatch, it was generally reserved for patients with annular diameters <20 mm.

Considering increasing awareness regarding implications of prosthesis– patient mismatch, it becomes important to identify patients at increased risk and adopt techniques to minimize risk. SEVs have shown a consistent reduction in prosthesis–patient mismatch incidence in both large and small annuli compared with SAVR.22 SEVs are supra-annular in position allowing for a larger EOA which can prevent prosthesis–patient mismatch when compared with BEVs, which have an intra-annular position.

In a propensity score-matched analysis comparing SEV and BEV, Okuno et al. found that the rate of prosthesis–patient mismatch was significantly lower in SEV compared with BEV (33.5% versus 46.9%; p=0.004; severe prosthesis–patient mismatch, 6.7% versus 15.6%; p=0.003).23 The effect was consistent across annulus sizes and the difference was driven by larger patients with body surface area >1.83 m2.

Jilaihawi et al. demonstrated that optimal positioning with a reduced LV depth of a self-expanding prosthesis was associated with a reduction in moderate and severe prosthesis–patient mismatch from 48% to 16%.24 Data from the TAVI-SMALL registry suggest that post-dilatation and perimeter ratio >15% protects against prosthesis–patient mismatch when patients with small annuli are treated.25 SAVR with aortic root enlargement to accommodate a larger surgical bioprosthesis may be preferred to TAVR with a 23 mm supra-annular TAV.21 Similarly, patients with pre-existing severe prosthesis–patient mismatch post-SAVR who are being considered for TAV-in-SAV will likely continue to have severe prosthesis–patient mismatch following TAVR.21 Bioprosthetic valve fracture using a highpressure balloon has also been shown to result in reduced residual transvalvular gradients and increased valve EOA.26

Conduction Abnormalities and the Significance of Implantation Depth

Conduction system abnormalities are the most common complication following TAVR and are associated with increased morbidity and mortality, length of hospital stay, and cost of care. When devising strategies to minimize injury to the conduction system, it is important to have a basic understanding of the conduction system in relation to aortic valve anatomy. The aortic annulus is an oval shaped, crown-like leaflet structure which, when seen in 3D, takes the form of a three-pronged coronet with three anchor points from the supporting ventricular structure.1,2 During annular sizing, the aortic annulus is measured at the level of the lowest hinge point of aortic leaflets at the virtual/inferior basal ring during systole.2 The atrioventricular (AV) node is located at the triangle of Koch in the right atrium. The AV node extends as the AV bundle/the His bundle, which runs on the left side of the central fibrous body prior to entering the ventricular septum. It is then divided into left and right bundle branches. The left bundle branch (LBB) and His bundle pass closely between the noncoronary cusp (NCC) and the right coronary cusp (RCC) at the base of the aortic commissure. Due to the concurrent anatomical relationship between the aortic annulus and LBB, surgical or mechanical handling of the aortic root may cause conduction abnormalities secondary to direct injury, inflammation, edema, or ischemia.27 Strategies to minimize conduction system injury focus on minimizing interaction of the valve and delivery system with the membranous and muscular septum where the conduction fibers are most superficial.

Both the balloon-expandable SAPIEN (Edwards) and the self-expanding CoreValve (Medtronic) have evolved to reduce the risk of peri-procedural complications including conduction abnormalities. Historically, data

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TAVR Optimization reveals higher incidence of permanent pacemaker implantation (PPMI) in early generation Medtronic self-expanding CoreValve compared to the balloon-expandable SAPIEN valve. A considerable difference in PPMI rate has been noticed in the current generations of both SAPIEN and CoreValve.

The rate ranged from 2.3% and 28.2% in early generation SAPIEN valves while in the newer generation SAPIEN 3 the PPMI rate has been between 4.0% and 24.0%.28 The PPMI rate with early generation CoreValve was significantly higher at 16.3–37.7%. With enhanced features of next generation Evolut R, allowing repositioning and recapturing during valve deployment, the PPMI rate has gone down to 14.7–26.7%, albeit remaining higher than the SAPIEN 3 THV.28 Despite the iterative technological advancements in THV platforms, the rate of conduction abnormalities and the need for PPMI has remained higher in TAVR compared to SAVR; the Medtronic low risk study reported the PPMI rate as 17.4% in TAVR patients compared to 6.1% among SAVR patients while in the Partner 3 trial, the PPMI rate was 6.6% in the TAVR group compared to 6.1% in the SAVR group.12,13 PPMs have been associated with significantly longer postprocedure hospitalization and higher rates of repeat hospitalizations.29 More recent data also suggests higher all-cause mortality and reduced left ventricular ejection fraction in patients who received PPM post-TAVR.30 Among other risk factors, such as pre-existing right bundle branch block and asymmetric calcification patterns, low implantation depth of the THV has been identified as an important predictor of conduction abnormalities leading to PPMI following both BEVs and SEVs.31 In an analysis of 229 patients who underwent TAVR with SAPIEN 3, Mauri et al. demonstrated that implantation depth was significantly greater in patients requiring PPMI than in those without the need for PPMI (ventricular part of the stent frame, 29 ± 11% versus 21 ± 5%; p<0.001) and described that the ventricular part of the stent frame of 25.5% as the best threshold to discriminate between patients with high and low risk for PPMI.32 In a multicenter trial of 60 patients who underwent TAVR with Evolut R, Manoharan et al. found that 11.7% of the patients required PPM.33 When the depth of implant was reviewed, the average depth for those who received a PPM (left coronary cusp [LCC] 9.4 ± 3.1 mm; non-coronary cusp [NCC] 8.1 ± 3.5 mm) was significantly deeper than that of patients who did not receive a new pacemaker (LCS 4.3 ± 2.5 mm; NCS 3.3 ± 2.5 mm; p<0.0001 for both comparisons).

Jilaihawi et al. described the variation in PPM rates depending on the length of the membranous septum and the depth of the THV.34 Their series suggested that when a THV is deployed below the membranous septum, the risk of PPMI increased. The OR of PPMI increased significantly with the difference between membranous septal length and implantation depth (p<0.001).

ViV TAVR has become a popular alternative to reoperative surgery in degenerative surgical aortic bioprostheses. In a contemporary large series of ViV TAVR patients, the rate of post-procedural PPMI was found to be relatively low (6.4%) compared to a PPMI rate of nearly 15% associated with TAVR in native aortic valves. A significant decrease in the incidence of PPMI with the use of new-generation THVs (4.7% versus 7.4%; p=0.017), mainly related to a reduced PPMI rate with the Evolut R/Pro versus CoreValve (3.7% versus 9.0%; p=0.002) was noted.35 The mechanical protection of the degenerated surgical bioprosthesis structure against a potential compression of the conduction system by the THV has been suggested as the main factor preventing conduction abnormalities after ViV TAVR.35 Also, recent studies have shown a lower risk of elevated gradients and improved valve hemodynamics with high implantation of THV in ViV TAVR.36,37

Figure 1: Location of the Atrioventricular Node and Basal Annular Plane Cusp-overlap view

Three-cusp co-planar view

Left anterior oblique view

The blue atrioventricular (AV) node is shown in the cusp-overlap view (left panel) with an increased distance from the AV node to the basal annular plane. In the three-cusp co-planar view (middle panel), the AV node appears closer to the basal annular plane due to foreshortening of the left ventricular outflow tract. The left anterior oblique view (right panel) overlaps the right coronary cusp and non-coronary cusp and isolates the left coronary cusp. The left ventricular outflow tract is also foreshortened in this view. This view had previously been advocated as the appropriate deployment but this technique has now fallen out of favor with the introduction of the cusp-overlap technique.

The instructions for CoreValve THV recommend an implantation depth of 3–5 mm below the annular plane. However, the assessment of true implantation depth remains challenging. In our recent analysis of 130 patients from the Medtronic low risk study who underwent both aortography and MSCT post-TAVR, we found a limited correlation (r=0.69) between implant depths by aortography versus MSCT, with aortography underestimating the depth of the implant. The risk of PPMI was significantly higher with deeper valve implantation assessed by MSCT (p=0.04), but not by aortography (p=0.12).38 The study highlights the need to develop techniques for precise measurement of implantation depth. The double S-curve and the cusp-overlap are innovative techniques that have allowed us to achieve a more accurate measurement of implantation depth, thereby allowing shallower valve deployment with high rates of success and minimal procedural complications.

Double S-curve

An important step in the deployment of SEVs is identifying the optimal fluoroscopic projection where the aortic annulus plane is orthogonal to the delivery catheter to remove parallax. MSCT images can be used to define the direction of structures and produce an optimal projection curve. The intersection point of the S-curve of the aortic annulus and that of the delivery catheter on the double S-curve gives the angiographic projection where the aortic annulus and the delivery catheter appear perpendicular. This is defined as the optimal projection for implantation as it eliminates foreshortening of the delivery catheter and the aortic annulus. Therefore, in this view, the position of the THV relative to the delivery catheter in NCC can be precisely measured as no foreshortening occurs. The optimal projection curve of the aortic valve annulus can be determined by pre-procedural MSCT; however, the optimal projection curve of the delivery catheter needs to be generated during the procedure.39,40

Cusp-overlap Technique

The cusp-overlap technique on fluoroscopy is a novel method that our center has used to achieve an optimal projection for deployment. This technique involves positioning the C-arm to superimpose the LCC over the RCC, and isolate the NCC, which is the most inferiorly oriented cusp in the LVOT. The fluoroscopic angulation for cusp-overlap is determined on pre-procedural MSCT. As compared with the double S-curve, the cuspoverlap technique has the advantage of not requiring any additional intraprocedural imaging. The right coronary/non-coronary commissure is displayed in the center of the fluoroscopic image and allows the operator to deploy the valve in an attempt to avoid the muscular septum and the

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TAVR Optimization Figure 2: Transcatheter Aortic Valve Replacement According to the Double S-curve and Cusp-overlap Techniques Double S-curve Technique

Cusp-overlap Technique

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Validation (LAO)

CAU = caudal; CRA = cranial; LAO = left anterior oblique; RAO = right anterior oblique; TAVR = transcatheter aortic valve replacement. Source: Ben-Shoshan et al. 2021.41 Reproduced with permission from Elsevier.

superficial conduction fibers. Below the right/non-coronary commissure, the membranous septum houses the conduction system. If the THV is deployed below the membranous septum, there is a greater chance of interaction with the conduction system.

In a non-cusp-overlap view, the LVOT is foreshortened, leading to the false perception that THV is in a shallower position relative to insertion of the NCC. The cusp overlap view minimizes foreshortening and elongates

the LVOT and highlights the NCC/RCC commissure in the center of the fluoroscopic view. Given this projection of the LVOT, there is also a greater distance between NCC insertion and the compact AV node (Figure 1). This fluoroscopic view leads to a more precise 3 mm implantation depth and minimizes the risk of interaction with the conduction system.

In a recent single-center, non-randomized retrospective study, BenShoshan et al. assessed the concordance between transcatheter aortic

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TAVR Optimization valve angles generated by the double S-curve and cusp-overlap techniques.41 The study included 100 consecutive patients undergoing TAVR with a self-expanding device planned by MSCT. TAVR was performed using the double S-curve model. Optimal projection according to the cusp-overlap technique was retrospectively generated by overlapping the right and left cups on the MSCT annular plane. The study demonstrated no significant differences in average coordinates between the double S-curve and cusp-overlap methods. The angular coordinates were noted to be in the same imaging quadrant 92% of the time with the vast majority (>80%) being in the right anterior oblique (RAO)/caudal (CAU) quadrant (Figure 2). The RAO and CAU projection of the left heart mostly represents a three-chamber view, which provides maximal elongation of the aortic root and LVOT and of the delivery catheter. Avoidance of foreshortening of the LVOT and delivery catheter provides a realistic perception of THV implant depth. The study demonstrates that the cusp-overlap method can be used as a reliable surrogate for the double S-curve model to define optimal projections for TAVR, obviating the need for intra-procedural image processing.

We have incorporated several procedural steps in addition to the cuspoverlap technique to further minimize the interaction with the conduction system during TAVR:

• We emphasize a top-down approach for deployment of the THV, •

•

•

•

•

starting with the catheter marker band positioned at the mid portion of the pigtail in the NCC. Once the capsule is retracted, the inflow of a nitinol prosthesis advances across the annulus and is positioned at 3 mm below. This maneuver avoids traumatic advancement of the bioprosthesis into the ventricle with inflow flaring deeper within the left ventricle, which results in subsequent maneuvers to retract the catheter, thus moving the transcatheter valve shallower to a more aortic position, and increasing interaction of the nose cone of the delivery system with the membranous septum.

We use a stiffer, double-curved, Lunderquist wire (Cook Medical) in most cases to hold the wire in position in the non-coronary right commissure and begin the prosthesis deployment along the posterior aspect of the annular plane. Although any wire can be used to support the delivery system, the stiffer wire may achieve more symmetrical deployment and is especially valuable when deploying larger sized THVs. Additional care should be taken when using this wire because of its stiffness to reduce the risk of ventricular injury.

The use of this wire is being tested prospectively in the OPTIMIZE PRO post-market analysis (NCT04091048).

Using the cusp-overlap view to maintain reference to the native annular plane, the marker band on the THV delivery catheter tends to lose parallax when approaching the valve plane. The loss of parallax of the marker band is the result of the delivery catheter following the stiff left ventricular wire that is generally positioned in the NCC/RCC commissure and confirms alignment of the prosthesis with the annular plane. This approach may lead to more confidence in the initial positioning of the THV in relation to the insertion of the NCC and a better assessment at the point of no recapture.

We favor sufficient pacing (140–180 BPM) during the deployment to minimize cardiac output and occurrence of premature ventricular contraction burden, allowing for stable deployment of the bioprosthesis.

Finally, once we are at 80% deployment, we rotate the gantry to a LAO projection to visualize the LCC and ensure that the inflow is not supra-annular. We aim for an implantation depth of 3 mm and no

deeper than 5 mm below the NCC to reduce the risk of conduction disturbance. We occasionally aim for a shallower deployment in patients at high risk for conduction system abnormality but recommend recapture for bioprothesis positions less than 1 mm or more than 5 mm within the ventricle.

• Once final positioning is confirmed, we retract the left ventricular wire, centralize the nose cone, and slowly release the delivery catheter from the bioprothesis by releasing the frame paddles. We are careful to avoid interaction of the delivery catheter and the bioprosthesis as the delivery catheter is retracted into the aorta.

Our institution adopted the cusp-overlap technique in October 2015 and since then witnessed a significant decline in the post-TAVR PPMI rates with the Medtronic CoreValve and Evolut platforms. In the Medtronic low risk trial, the rate of PPMI 30-days post-TAVR was 17.4%, with wide site-specific variability.13 Our single-center experience of using the cuspoverlap technique found that only 1 in 65 patients (1.5%) required a PPM. As the highest enrolling center in the study, we attribute this difference to the comprehensive use of the cusp-overlap technique at our institution.

The use of 34 mm Evolut R THV has been identified as a risk factor for PPMI with the associated rate of 16.7% in the TVT registry. From June 2016 to July 2019, we implanted the 34 mm Evolut R THV in 134 consecutive patients without a previous pacemaker, using the fluoroscopic cuspoverlap technique. It was successfully performed in 88% of the patients, with the remainder having near overlap or not having it done due to steep gantry angles. The in-hospital rate of new-onset LBB block was 10.9% and the 30-day PPMI rate was noted to be 5.2%, lower than the previously published rates.42 The study demonstrates that the risk of conduction abnormalities and PPMI with the 34 mm Evolut R can be significantly reduced using the cusp-overlap technique.

We also began formal training of the technique for physicians in Latin America in July 2018 and evaluated the clinical outcomes of Evolut THV implantation until October 2019. Fourteen implanting physicians from seven countries performed consecutive procedures on 114 patients. Of these, 105 patients did not have a prior PPM. The in-hospital rate of new PPMI was 5.7%. At 30-day follow-up that included 85 patients, no additional patients required a new PPM.43 The study demonstrates consistent results of lower rates of PPMI after Evolut THV implantation with the adoption of cusp-overlap technique across different centers.

Our experience with using cusp-overlap technique to implant Medtronic CoreValve and Evolut platforms has revealed a consistently reduced risk of conduction abnormalities and lower incidence of PPMI after TAVR compared to prior studies. The lower rates of PPMI using the cusp-overlap technique have also been reproducible by physicians from seven different Latin American countries. The OPTMIZE PRO study (NCT04091048) will expand on this with further data regarding the safety and efficacy of the technique across multiple centers.

High Implantation of SAPIEN 3

As discussed before, a low implantation depth is associated with an increased incidence of conduction abnormalities with BEVs. Traditionally, BEVs are deployed using a three cusp co-planar view in an LAO projection.

In a recent paper, Sammour et al. demonstrated a novel technique to deploy SAPIEN 3 in RAO/CAU projection instead of the conventional coplanar view with LAO projection to achieve a higher implantation depth, thereby minimizing the risk of conduction abnormalities.44

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TAVR Optimization The authors described three procedural modifications: • Deploying the valve in the RAO/CAU view to remove the parallax.

• Positioning the valve by aligning the radiolucent line that is located at the superior aspect of the lowest set of stent struts of the crimped valve at the base of the NCC. • Using a straight flush catheter instead of a pigtail to mark the native annulus, reducing the risk of trapping the pigtail catheter between the sinus and the valve.

Commissural Alignment

With the use of this novel high deployment technique (HDT), the authors demonstrated significantly smaller implantation depths (1.5 ± 1.6 mm versus 3.2 ± 1.9 mm; p<0.001) and lower rates of PPMI (5.5% versus 13.1%; p<0.001) compared to the conventional technique without a statistically significant increase in adverse clinical outcomes, aortic regurgitation, or valve embolization between the two groups.

The coronary arteries are easily accessible when coronary ostia are situated distal to the THV stent frame. This may be challenging with supraannular THVs with tall stent frames because of the need to cross the stent frame to access the coronary ostia but may be less of a problem when using THVs with short stent frame heights. Coronary reaccess can also be hindered by the random location of THV commissural posts relative to the coronary ostia as well as the native leaflets.48 Percutaneous coronary intervention after TAVR has been reported in 1.9–5.7% cases.49,50 As TAVR continues to expand to younger people and those with a lower surgical risk, achieving commissural alignment in THV becomes imperative to facilitate future coronary access.

This study signifies the understanding of optimal angiographic projections necessary to achieve a reduction in parallax and valve deployment aligned with the radiolucent line in the RAO/CAU projection to allow greater precision and consistency in a shallower deployment.

Limitations of Shallow Implantation Depth

While shallow implantation depth is associated with lower rates of PPMI, there are potential drawbacks of shallow deployment of THV, with a risk of valve embolization being the most serious. With the HDT described above, one of 406 patients (0.2%) had valve embolization. Although the risk remains low (<1%), operators who use this method must be adept with techniques to manage valve embolization, either by migrating the THV to a safe location in the aorta using a balloon (with SAPIEN) or via snare (with CoreValve) while working quickly to deploy a second prosthesis.

Shallow implantation may risk or exclude future ViV options for certain low-risk patients, as a ViV approach would push up the leaflets of the first THV to create a neoskirt that can potentially occlude native coronaries.

Coronary reaccess is another major concern, given that about two-thirds of TAVR patients have pre-existing coronary artery disease. In patients with lower surgical risk, it is essential to consider future coronary access.

In the RE-ACCESS study of 300 enrolled patients, Barbanti et al. showed that a total of 23 patients (7.7%) had an impediment to coronary ostia postTAVR (4.7% in the left coronary artery, 4.0% in the right coronary artery), compared with no cases of unsuccessful cannulation before TAVR.45 Unsuccessful cannulation occurred in 22 of 23 cases with the use of Evolut R/PRO THVs (17.9% versus 0.4%; p<0.01). The use of Evolut R/PRO THVs, sinus of Valsalva oversizing and high implantation depth (with a cutoff value <6 mm) were found to be independent predictors of unsuccessful coronary cannulation after TAVR. When an Evolut THV is implanted high, the narrow portion of the frame could potentially end up above the origin of the coronary arteries, resulting in ostia facing the inflow part of the frame, which is covered by the pericardial skirt. Hence, Evolut THV bioprosthesis needs careful selection for each patient to balance the risk for unsuccessful coronary cannulation and the risk for conduction disturbances.

Commissural alignment avoids covering the coronary ostia with the THV struts. However, a shallow deployment – particularly in patients with narrow sinus or low coronaries – may still complicate future coronary access.46

In SAVR, native calcified aortic valve leaflets are excised and the bioprosthetic valve is implanted in an anatomic orientation where the commissures of the bioprosthetic valve are aligned with the commissures of the native valve. In TAVR, the native valves remain in situ and the THV neo-commissures are oriented randomly. The commissural misalignment leads to a varying degree of overlap between the neo-commissural posts and the coronary ostia.47

Commissural alignment is also significant when ViV is considered. In patients with an increased risk of coronary artery obstruction with ViV, bioprosthetic or native aortic scallop intentional laceration to prevent iatrogenic coronary artery obstruction (BASILICA) can be performed to reduce coronary flow. However, if the initial THV commissure is not aligned and apposes the lacerated leaflet, the BASILICA technique may fail to prevent coronary obstruction.51 In the ALIGN-TAVR study, Tang et al. evaluated the impact of initial deployment orientation of THVs on their final orientation and neocommissural overlap with coronary arteries in 828 patients who underwent TAVR (483 SAPIEN 3, 245 Evolut, and 100 ACURATE-neo valves) from March 2016 to September 2019 at five centers.51 Co-planar fluoroscopic views were co-registered to pre-TAVR CT to determine commissural alignment. Severe overlap between neocommissural posts and coronary arteries was defined as 0–20° apart. More than 30–50% of cases had overlap with one or both coronary arteries. The investigators noted that with SAPIEN 3, despite crimping the valve at the 3, 6, 9, or 12 o’clock orientations relative to the delivery catheter, there was no impact on commissural alignment. Fortunately, the low stent frame profile of SAPIEN 3 renders commissural alignment less pertinent for coronary reaccess as wires and catheters can engage the coronary ostia above and through the top row of the stent frame. Nevertheless, coronary reaccess can be challenging in certain cases where the SAPIEN 3 stent frame extends beyond a narrow sinotubular junction.

Commissural alignment is particularly important for facilitating coronary reaccess following Evolut THV, given the long frame, relatively small stent diamonds and the supra-annular design that extends above the sinotubular junction and coronary ostia.

In the ALIGN-TAVR study, Tang et al. demonstrated that orienting the Evolut ‘hat’ at outer curve (OC) or center front (CF) during valve deployment resulted in improved commissural alignment and significantly less severe coronary overlap than inner curve (IC)/center back (CB) positioning with the left main artery (15.7% versus 66.0%), the right coronary artery (7.1% versus 51.1%), both coronary arteries (2.5% versus 40.4%), and one or both coronary arteries (20.2% versus 76.6%) (p<0.001 for all).51 The investigators found that having the flush port starting at 3 o’clock significantly improved

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TAVR Optimization the ‘hat’ position at outer curve or center front during initial deployment from 70.2% to 91.6% and reduced coronary artery overlap by 36–60% (p<0.05) (Figure 3).

The impact of the Evolut ‘hat’ marker deployment orientation on commissural alignment to determine the incidence of severe coronary artery overlap was also assessed in the Evolut Low Risk TAVR CT substudy, where 154 of 249 patients who underwent TAVR with the conventional delivery insertion technique using the flush port at 12 o’clock were compared to 240 patients who underwent deployment using the modified technique with the flush port at 3 o’clock. The modified technique significantly improved the ‘hat’ marker orientation at OC/CF during initial deployment (93.1% versus 69.6%; p<0.001), improved commissural alignment, and reduced severe coronary overlap (left main artery: 15.2% versus 27.7%; p=0.004; right coronary artery: 11.8% versus 27.7%; p<0.001).52 CoreValve with its supra-annular design has substantial advantages in valve hemodynamic parameters, which are superior to those with SAVR, and its hemodynamic edge may also contribute to a decreased incidence of leaflet valve thrombosis compared to SAPIEN 3, although coronary access remains challenging with CoreValve compared to SAPIEN 3.6,13,53 The modified delivery system insertion technique described in the ALIGN TAVR study resulting in better commissural alignment and less coronary overlap following Evolut THV is promising and mandates further studies to validate its reproducibility.

Conclusion

Multimodality imaging plays a vital role in the accurate assessment of THV sizing and positioning, and to balance the risk of PVL against annular rupture. Prosthesis–patient mismatch post-TAVR is increasingly being recognized as being associated with higher mortality rates. SEVs have shown reduced incidence of prosthesis–patient mismatch due to their supra-annular deployment compared to BEVs. Conduction abnormalities remain a major concern following TAVR. The incidence of PPMI remains higher in TAVR compared to SAVR. An increasing volume of data suggests that low implantation depth contributes to the need for a PPM and there is now advocacy for shallow implantation of THV. Fluoroscopic cusp 1.

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Figure 3: Flush Port Orientation and Impact of Initial ‘Hat’ Marker Orientation in Evolut Deployment A

B

Track ‘hat’ marker at OC

C

D

E

Three-cusp coplanar view

Pointing the flush port (orange circle) at 3 o’clock (A) when inserting the Evolut delivery catheter into the patient improved the ‘hat’ marker orientation to the outer curve in the descending aorta (B) and during initial valve deployment (C), resulting in C-tab at the inner curve of the aortic root (D) and better commissural alignment (E). LM = left main coronary artery; L-R = left coronary cusp-right coronary cusp; N-L = non-coronary cusp-left coronary cusp; N-R = non-coronary cusp-right coronary cusp; OC = outer curve; RCA = right coronary artery. Source: Tang et al. 2020.51 Reproduced with permission from Elsevier.

overlap technique in RAO/CAU projection has been demonstrated to be a reliable surrogate of the double S-curve and effectively allows an unforeshortened view of the LVOT and the delivery catheter, thereby eliminating parallax. This view offers true perception of THV depth and allows for a precise 3 mm implantation depth of Evolut bioprosthesis.

Recent data suggests that SAPIEN 3 deployment in RAO/CAU projection allows higher implantation, resulting in reduced rates of PPMI. Commissural misalignment during THV deployment, particularly for the Evolut platform, is now recognized to have important implications on future coronary reaccess and aortic valve reintervention. The recently introduced technique to aim the ‘hat’ position at OC or CF of the descending aorta during initial deployment showed encouraging results to achieve better commissural alignment and reduce the incidence of coronary overlap.

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Sammour Y, Banerjee K, Kumar A, et al. Systematic approach to high implantation of SAPIEN-3 valve achieves a lower rate of conduction abnormalities including pacemaker implantation. Circ Cardiovasc Interv 2021;14:e009407. https:// doi.org/10.1161/CIRCINTERVENTIONS.120.009407; PMID: 33430603.

Barbanti M, Costa G, Picci A, et al. Coronary cannulation after transcatheter aortic valve replacement. JACC Cardiovasc Interv 2020;13:2542–55. https://doi.org/10.1016/j. jcin.2020.07.006; PMID: 33069648.

Vora AN, Gada H. Staying in the shallow end: minimizing permanent pacemaker implantation with a novel implantation method. Circ Cardiovasc Interv 2021;14:e010330. https://doi.org/10.1161/CIRCINTERVENTIONS.120.010330.

Fuchs A, Kofoed KF, Yoon SH, et al. Commissural alignment of bioprosthetic aortic valve and native aortic valve following surgical and transcatheter aortic valve replacement and its impact on valvular function and coronary filling. JACC Cardiovasc Interv 2018;11:1733–43. https://doi.org/10.1016/j.jcin.2018.05.043; PMID: 30121280.

Tang GHL, Kaneko T, Cavalcante JL. Predicting the feasibility of post-TAVR coronary access and redo TAVR: more unknowns than knowns. JACC Cardiovasc Interv 2020;13:736– 8. https://doi.org/10.1016/j.jcin.2020.01.222; PMID: 32192694.

Tanaka A, Jabbour RJ, Testa L, et al. Incidence, technical safety, and feasibility of coronary angiography and intervention following self-expanding transcatheter aortic valve replacement. Cardiovasc Revasc Med 2019;20:371–5. https://doi.org/10.1016/j.carrev.2019.01.026; PMID: 30857975.

Allali A, El-Mawardy M, Schwarz B, et al. Incidence, feasibility and outcome of percutaneous coronary intervention after transcatheter aortic valve implantation with a self-expanding prosthesis. Results from a single center experience. Cardiovasc Revasc Med 2016;17:391–8. https://doi.org/10.1016/j.carrev.2016.05.010; PMID: 27396607.

Tang GHL, Zaid S, Fuchs A, et al. Alignment of transcatheter aortic-valve neo-commissures (ALIGN TAVR): impact on final valve orientation and coronary artery overlap. JACC Cardiovasc Interv 2020;13:1030–42. https://doi.org/10.1016/j. jcin.2020.02.005; PMID: 32192985.

Tang G, Alexis S, Sengupta A, et al. TCT CONNECT – 93.

Commissural alignment in Evolut TAVR: results from the low risk LTI substudy. J Am Coll Cardiol 2020;76(17 Suppl):B41. https://doi.org/10.1016/j.jacc.2020.09.107.

Chakravarty T, Søndergaard L, Friedman J, et al. Subclinical leaflet thrombosis in surgical and transcatheter bioprosthetic aortic valves: an observational study. Lancet 2017;389:2383–92. https://doi.org/10.1016/S01406736(17)30757-2; PMID: 28330690.

REVIEW

Acute Coronary Syndromes

Role of Coronary CT Angiography in the Evaluation of Acute Chest Pain and Suspected or Confirmed Acute Coronary Syndrome Tasveer Khawaja, MD, , Scott Janus, MD, , and Sadeer G Al-Kindi, MD Department of Medicine, Harrington Heart & Vascular Institute, University Hospitals, Cleveland, OH

Abstract

Advances in CT technology have resulted in improved imaging of the coronary anatomy in patients with stable coronary artery disease, using coronary CT angiography (CCTA). Recent data suggest that CCTA may play a role in higher risk patients, such as those evaluated in the emergency room with acute chest pain. Data thus far support the use of CCTA in low-risk patients with acute chest pain. Recent literature suggests that CCTA may play a role in the risk stratification of selected intermediate-risk patients. In this review, the authors discuss the emerging role of CCTA in higher risk patients, such as those with suspected or confirmed acute coronary syndrome (ACS). The excellent accuracy of CCTA in detecting obstructive coronary artery disease in patients with ACS is detailed, along with a highlighting of the safety of using CCTA in this setting. The authors also discuss the role for CCTA atheromatous plaque characterization, which is being increasingly recognized as an important predictor of clinical outcomes.

Keywords

Coronary CT, MI, chest pain, coronary artery disease, coronary computed tomography angiography Disclosure: The authors have no conflicts of interest to declare.

Received: October 4, 2021 Accepted: December 21, 2021 Citation: US Cardiology Review 2022;16:e11. DOI: https://doi.org/10.15420/usc.2021.30 Correspondence: Sadeer Al-Kindi, Division of Cardiovascular Medicine, Office 4525, Harrington Heart and Vascular Institute, University Hospitals, Case Western Reserve University School of Medicine, 2103 Cornell Rd, Cleveland, OH 44106. E: sadeer.alkindi@uhhospitals.org Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Heart disease remains the leading cause of mortality in the US, with acute MI from acute coronary syndrome (ACS) being a major contributor.1 Chest pain is one of the most common complaints in patients presenting to the emergency room (ER) in the US, with approximately 8–10 million annual visits.2 Multimodality cardiac imaging (e.g. cardiac CT, cardiac MRI) is playing an increasingly recognized role in the identification of at-risk patients, the planning of interventions, and in the understanding of the non-coronary causes of chest pain.

Advances in CT technology have improved spatial and temporal resolution, resulting in improved diagnostic capabilities. In the UK, coronary CT angiography (CCTA) has been recommended as a first-line imaging modality for patients with suspected coronary artery disease (CAD) since 2016.1 Similarly, the European Society of Cardiology (ESC) guidelines have endorsed the use of CCTA as a first-line imaging modality in the evaluation of chest pain since 2019.3 In the US, CCTA had not seen the same rate of adoption in the guidelines until the recently published 2021 multi-society guidelines for the evaluation and diagnosis of chest pain.4 CCTA now has a class I indication for the evaluation of chest pain in various scenarios, including intermediate-risk patients with acute chest pain without known CAD and intermediate or high-risk patients with stable chest pain and no known CAD.4 The 2014 American Heart Association/American College of Cardiology (AHA/ACC) guidelines for non-ST-elevation MI (NSTEMI) have assigned a class IIa recommendation for the use of CCTA in evaluating patients with possible ACS, with the caveats that a normal ECG, normal cardiac troponin, and no history of CAD be present.5

The challenge of imaging coronary arteries non-invasively is related to coronary anatomy and motion. Typically, being only millimeters in diameter and subject to motion artifact during the cardiac cycle, the achievement of the appropriate spatial and temporal resolution in the imaging of coronary arteries can be challenging. With the advent and more widespread availability of multi-slice multi-detector CT systems and other technological advancements, these hurdles have largely been overcome. Issues with image quality, however, can still exist. Specifically, noise, vascular enhancement, and coronary motion must all be optimized to achieve the best quality images.6 In this review, we highlight the role of CCTA in the evaluation of patients with acute chest pain and possible or confirmed ACS.

Role of CCTA in the Evaluation of Stable Chest Pain

Early studies focusing on the diagnostic performance of CCTA sought to evaluate the ability of this modality to detect significant coronary stenosis, usually defined as stenosis >50% on invasive coronary angiography (ICA).

A 2018 meta-analysis compared the performance of several non-invasive diagnostic modalities to rule out significant CAD in patients with angina with either ICA or invasive fractional flow reserve (FFR) as the gold standards.3 When considering CCTA, a total of nine studies with ICA as the gold standard for comparison and seven studies with invasive FFR as the gold standard for comparison were included. When the ability of these non-invasive modalities to rule out anatomically or functionally significant CAD is compared, CCTA emerged as the best modality with a pooled sensitivity of 97% (95% CI [93–99%]) in detecting anatomically significant

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Coronary CT Angiography in Acute Coronary Syndrome Figure 1: Forest Plot from a Meta-analysis of MI Following Coronary CT Angiography Versus Standard Care in Stable and Acute Chest Pain CCTA Events Total

Usual care Events Total

Weight

OR M-H Fixed 95% CI

297 200 291 444 205 1437

5.0% 8.1% 6.5% 6.2% 0.9% 26.7%

0.18 [0.02, 1.53] 1.00 [0.39, 2.57] 0.29 [0.06, 1.39] 1.12 [0.39, 3.26] 2.00 [0.18, 22.23] 0.74 [0.42, 1.29]

2014 2015 2015 2016 2016

5007 245 207 108 7433

37.5% 1.9% 32.7% 1.3% 73.3%

0.75 [0.47, 1.21] 0.5 [0.05, 5.57] 0.62 [0.37, 1.07] 0.45 [0.03, 7.26] 0.68 [0.48, 0.97]

2015 2015 2015 2016

Total (95% CI) 9442 8870 79 105 Total events Heterogeneity: χ2=5.26, d.f.=8 (p=0.73); I2=0% Test for overall effect: Z=2.39 (p=0.02) Test for subgroup differences: χ2=0.05, d.f.=1 (p=0.82); I2=0%

100.0%

0.70 [0.52, 0.94]

Study or subgroup

2.5.1 Acute chest pain CT-STAT (2011)10 1 330 PROSPECT (2015)15 9 209 CATCH (2015)14 2 285 ACRIN-PA (2016)49 11 870 PERFECT (2016)50 2 206 Subtotal (95% CI) 1891 Total events 25 Heterogeneity: χ2=4.72, d.f.=4 (p=0.32); I2=15% Test for overall effect: Z=1.06 (p=0.29) 2.5.2 Stable chest pain 30 PROMISE (2015)51 4996 CAPP (2015)52 1 243 SCOT-HEART (2015)53 22 2073 CRESCENT (2016)54 1 239 Subtotal (95% CI) 27551 Total events 54 Heterogeneity: χ2=0.41, d.f.=3 (p=0.94); I2=0% Test for overall effect: Z=2.15 (p=0.03)

5 9 7 5 1

OR M-H Fixed 95% CI

Year

27

40 2 35 1 78

0.01

0.1 Favors CCTA

1

10 Favors usual care

100

CCTA =coronary CT angiography. Source: Hwang et al. 2017.7 Reproduced with permission from Wiley.

CAD and a pooled sensitivity of 93% (95% CI [89–96%]) in detecting functionally significant CAD, albeit at the expense of poor specificity of 78% (95% CI [67–86%]) and 53% (95% CI [37–68%]), respectively.

In a meta-analysis of 13 randomized controlled trials involving 20,092 patients (10,315 were assigned to CCTA, 9,777 assigned to functional testing), CCTA was associated with higher rates of CAD diagnosis (RR 2.80; 95% CI [2.03–3.87]), an increase in the prescription of both aspirin (RR 2.21; 95% CI [1.20–4.04]) and statins (RR 2.03; 95% CI [1.09–3.76]), and a reduction in MIs (RR 0.71; 95% CI [0.53–0.96]), but at the expense of increases in both ICA (RR 1.33; 95% CI [1.12–1.59]) and revascularization (RR 1.86; 95% CI [1.43–2.43]). This was also replicated in another metaanalysis of randomized trials comparing CCTA with usual care in stable CAD and acute chest pain (Figure 1).7 Taken together, CCTA is a powerful modality for ruling out significant CAD as the etiology of chest pain; it has superior sensitivity, albeit with worse specificity. The identification of early-stage plaques and higher rates of CAD diagnosis enables higher rates of initiation and intensification of preventive therapies, lowering the risk of MI. CCTA can act as a gatekeeper for unnecessary invasive catheterizations, where traditionally one-third of patients undergoing ICA have non-obstructive disease.8

CCTA in the Evaluation of Acute Chest Pain in the Emergency Room

Chest pain is among the most common causes of ER visits, with approximately 8–10 million patients evaluated for chest pain annually in the US alone.2 Compared with stable chest pain, patients with acute chest pain in the ER are at higher risk for adverse outcomes. A sensitive test for the evaluation of these patients is thus required to avoid unnecessary hospitalizations, reduce the length of stay (LOS) and cost, and provide a

safe mechanism for ruling out significant CAD that may benefit from invasive therapies. Several trials have evaluated CCTA in the evaluation of chest pain in the ER in comparison with functional tests (Supplementary Material Table 1).9–18 The ROMICAT-II trial in 2012 randomized 1,000 patients presenting with acute chest pain (without ECG changes or troponin elevation) to early CCTA or standard evaluation in the ER.12 There was no difference between the study arms with respect to clinical outcomes, but CCTA resulted in more patients discharged from the ER (47% versus 12%, p<0.001), LOS reduced by 7.6 hours, and similar cost of care, albeit at the expense of increased downstream testing and higher radiation dose.12 The ACRIN-PA study randomized 1,370 patients with chest pain in the ER with TIMI scores 0–2 and no ischemic changes on ECG to CCTA or functional stress testing prior to evaluation of serum troponin. Only 84% of those randomized to CCTA underwent the scan and of those, 83% had no obstructive CAD. As has been demonstrated in stable chest pain populations, patients undergoing CCTA were more likely to be diagnosed with CAD (9.0% versus 3.5%), and less likely to have ICA without significant CAD. The 1-year event rate was very small and not different between the arms. That study provides practical evidence of the short-term safety of CCTA in lowrisk patients and highlights its benefits.

The 2015 CATCH trial investigated the long-term clinical safety of CCTA in patients with recent-onset acute chest pain in the low- to intermediaterisk groups.14 High-risk patients were excluded based on either abnormal ECG, elevation in troponin, or recurrence of chest pain during a 24-hour hospitalization.14 A total of 600 patients were randomized to either CCTA or standard care (exercise ECG or single-photon emission CT) following discharge. The safety of CCTA in comparison with the standard care was established by assessing the composite of cardiac death, MI,

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Coronary CT Angiography in Acute Coronary Syndrome Table 1: Recommendations for Coronary CT Angiography Use in Clinical Scenarios by Different Clinical Practice Guidelines Clinical Scenarios

US AUC55 European Guidelines28

Asian AUC/ UK Guidelines56 Guidelines1

SCCT Guidelines57

Low-risk acute chest pain with normal ECG and negative troponins

Appropriate

Recommended

Appropriate

Recommended

Appropriate

Intermediate-risk acute chest pain with normal ECG and negative troponins

Appropriate

Recommended

Appropriate

Recommended

Appropriate

High-risk acute chest pain with normal ECG and negative troponins

Uncertain

Not defined

Appropriate

Recommended

Uncertain

Low-risk acute chest pain with normal ECG and equivocal troponins

Appropriate

Recommended

Appropriate

Not defined

Appropriate

Intermediate-risk acute chest pain with normal ECG and equivocal troponins

Appropriate

Recommended

Appropriate

Not defined

Appropriate

High-risk acute chest pain with normal ECG and equivocal troponins

Uncertain

Not defined

Appropriate

Not defined

Uncertain

A selective invasive strategy after appropriate ischemia testing or detection of obstructive CAD by CCTA in low-risk patients

Not defined

Recommended

Not defined

Not defined

Not defined

Acute chest pain of uncertain cause with additional concern for pulmonary embolism and/or aortic dissection (“triple rule out”)

Uncertain

Recommended

Appropriate

Not defined

Uncertain

AUC = appropriate use criteria. Source: Kumar et al. 2021.26 Reproduced with permission from Elsevier.

hospitalization for unstable angina, late symptom-driven revascularization, and readmission for chest pain. The primary endpoint occurred significantly less frequently in the CCTA group than in the standard care group (HR 0.62; 95% CI [0.40–0.98]). The CCTA group was more likely to undergo revascularization compared with standard care, suggesting that the improved safety seen with the CCTA strategy may be related to timely revascularization.

In a systematic review of randomized controlled trials of CCTA (n=1,869 patients) versus usual care (n=1,397 patients) in the ER, there were no differences in outcomes (MI, death, ER visits, rehospitalizations). CCTA was associated with reduced LOS and ER costs, but it also led to an increase in ICA (OR 1.36; 95% CI [1.03–1.80]; p=0.030) and in revascularization with percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG; OR 1.81; 95% CI [1.20–2.72]; p=0.004).19 In a meta-analysis of studies up to 2016 evaluating diagnostic accuracy in the ER without troponin elevation, coronary CT had the highest accuracy (sensitivity 93%; specificity 90%), which was comparable to myocardial perfusion scintigraphy but more accurate than stress ECG and echocardiography.20 A Markov microsimulation model comparing cost-effectiveness strategies in acute chest pain showed that although CCTA seems to increase short-term cost, CCTA was better than standard care and that recommended by the AHA/ACC guidelines. It also expedited ER discharge and the outpatient evaluation protocol mainly due to lower cardiovascular mortality.21 Supplementary Material Table 1 lists the major trials comparing CCTA with standard care in patients presenting to the ER with chest pain.

CT-derived FFR enables the evaluation of the hemodynamic significance of coronary stenoses, especially those in the intermediate range (50– 70%) and renders many lesions non-hemodynamically significant, thus enabling timely safe discharge from the ER. The use of CT-derived FFR (FFRCT) in patients with acute chest pain was evaluated in two studies. In a substudy of the ROMICAT II trial, those with ≥50% stenosis in at least one coronary artery or those who underwent another non-invasive test were included, for a total of 116 patients.22 Due to technical limitations, such as motion and blooming artifacts, 68 patients successfully underwent FFRCT. An abnormal FFRCT (≤0.80) was significantly associated with the diagnosis of ACS compared with a normal FFRCT (57.5% versus 14.3%, p<0.001) and more often required revascularization (37.5% versus 10.7%, respectively).

Furthermore, abnormal FFRCT was associated with high-risk plaque features as assessed on CCTA. In a real-world study of 555 low-risk

patients (negative ECG and biomarkers) with chest pain presenting to the ER who underwent FFRCT (297CTA+ FFRCT and 258 CCTA only), the rejection rate for FFRCT was low (<2%), and there were no between-group differences with respect to clinical outcomes, diagnostic discordance with ICA, or cost. Negative FFR was more likely to be associated with nonobstructive disease (57% versus 8%).23 Future prospective studies comparing the diagnostic accuracy of FFRCT with CCTA involving confirmed NSTEMI patients at higher risk are under way, with the hopes of demonstrating a reduction in the need for ICA, procedure-related risks, and medical costs.24 The accuracy of CCTA in the evaluation of CAD in the ER has led to the development of protocols to simultaneously evaluate major causes of chest pain in patients presenting to the ER (CAD, pulmonary embolism, aortic dissection) through a ‘triple rule-out’ strategy. In a larger retrospective review of 12,834 patients who underwent CCTA of the chest (triple rule out, n=1,555; CCTA, n=11,279), the diagnostic yield for CAD was similar between the triple rule-out protocol and CCTA, with higher diagnostic yield for pulmonary embolism (1.1% versus 0.4%, p=0.004) and aortic dissections (1.7% versus 1.1%, p=0.046), at the expense of higher radiation (median 9.1 versus 6.2 mSv; p<0.0001), contrast load (mean 113 ± 6 ml versus 89 ± 17 ml; p<0.0001), and higher rates of non-diagnostic imaging (9.4% versus 6.5%, p<0.0001).25 Taken together, these data suggest that CCTA is an excellent tool for ruling out significant CAD in patients presenting to the ER with chest pain, with equivalent outcomes, possibly reduced cost and length of stay, at the expense of a small increase in ICA and revascularization. Table 1 lists the appropriateness of CCTA according to various guidelines and clinical scenarios.26

CCTA in NSTEMI

Clinical practice guidelines favor early invasive angiography for high-risk patients with elevated troponins/NSTEMI and selective ICA in patients based on clinical risk scores. However, up to 25% of patients with presumed NSTEMI do not have obstructive disease on ICA (this is known as MI with non-obstructive coronary arteries).27 This percentage may become even higher in the era of high-sensitivity troponin, with an estimated 50% of patients with a mild increase in high-sensitivity troponins having a normal ICA. Given the evolving role of CCTA in the evaluation of coronary atherosclerosis, it is important to discuss its emerging role in presumed NSTEMI. This role is highlighted by the 2020 ESC guidelines for

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Coronary CT Angiography in Acute Coronary Syndrome Figure 2: Performance of Coronary CT Angiography in Patients with Acute Coronary Syndrome in the VERDICT Trial Patients with ACS (n=1,023)

ICA negative n=241 (24%)

CCTA non-diagnostic n=53 (5%)

ICA positive n=24 (2%)

CCTA positive n=705 (69%)

ICA negative n=92 (9%)

ICA positive n=666 (65%)

Negative predictive value (95% CI)

90.9% [86.8–94.1]

Positive predictive value (95% CI)

87.9% [85.3–90.9]

Sensitivity (95% CI)

96.5% [94.9–97.8]

Specificity (95% CI)

72.4% [67.2–77.1]

Significant coronary artery disease ruled in

Significant coronary artery disease ruled out

CCTA negative n=265 (26%)

ACS = acute coronary syndrome; CCTA = coronary CT angiography; ICA = invasive coronary angiography. Source: Linde et al. 2020.29 Reproduced with permission from Elsevier.

the management of ACS without persistent ST-segment elevation.28 Specifically, the high negative predictive value (NPV) of CCTA for CAD allows for the exclusion of ACS.28 This has been demonstrated by several trials evaluating the diagnostic utility of CCTA in confirmed or presumed NSTEMI. The accuracy of CCTA in the diagnosis of coronary stenosis in patients with non-ST-elevation acute coronary syndrome (NSTEACS) was recently evaluated in 1,023 patients with NSTEACS who underwent CCTA as well as ICA in the VERDICT trial (Figure 2).29 Significant (≥50%) coronary stenosis was diagnosed in 69% by CCTA and 67% by ICA. The per patient NPV of CCTA was 90.9% (95% CI [86.8–94.1%]) and the positive predictive value (PPV), sensitivity and specificity were 87.9% (95% CI [85.3–90.1%]), 96.5% (95% CI [94.9–97.8%]) and 72.4% (95% CI [67.2–77.1%]), respectively.29 This performance is similar to that of CCTA in stable disease (reported sensitivity of 97% and specificity 78%).3 The higher-risk population studied in the VERDICT trial in comparison with past studies of the diagnostic performance of CCTA did not affect the NPV. In fact, when only patients with a Global Registry of Acute Coronary Events (GRACE) score >140 are considered, the NPV of CCTA remained >95%, despite the high prevalence of 74% for significant CAD in this subgroup. An important caveat not captured by the numerical value of the PPV alone is that a threshold of ≥50% stenosis was used by the authors to define a positive test. Degree of stenosis alone does not completely predict the hemodynamic significance of a coronary lesion; and other factors, largely obtained via invasive procedures, must be considered before a decision about revascularization is made. In a high-risk population with a high incidence of coronary stenosis ≥50%, by using CCTA prior to ICA we may be subjecting most patients to unnecessary radiation and contrast. The population of the VERDICT trial is a good illustration of this given that 67% of them had at least one stenosis that occupied ≥50% of the vessel lms.

The RAPID-CTCA (NCT02284191) study randomized 1,748 patients in the UK with suspected ACS and ≥1 high-risk feature (prior CAD, elevated troponin >99th percentile, or ischemic changes on ECG) to early CCTA versus standard care and followed them for a 1-year rate of all-cause death or MI. There was no difference in clinical outcomes, but CCTA led to less ICA (adjusted HR 0.81; 95% CI [0.72–0.92]; p=0.001) without a change

in coronary revascularization (HR 1.03; 95% CI [0.87–1.21]) or prescription of preventive therapy. This was at the expense of longer hospitalizations (median increase 0.21 days) and higher cost.30,31 These results are in contrast to prior trials that have demonstrated a reduction in both the cost of hospitalization and length of stay with CCTA versus usual care in lowerrisk patients.19 A follow-up analysis of the VERDICT trial evaluated the prognostic role of stenosis by CCTA.32 That study included 978 patients who underwent ICA and CCTA and followed them for a median of 4.2 years for a composite of all-cause death, non-fatal recurrent MI, hospital admission for refractory myocardial ischemia, or heart failure. All CCTAs were blinded to clinical care, and ≥50% stenosis was defined as obstructive. Overall, the association between ≥50% stenosis and outcomes was similar between CCTA (HR 1.74; 95% CI [1.22–2.49]; p=0.002) and ICA (HR 1.54; 95% CI [1.13–2.11]; p=0.007). High-risk features, defined as obstructive left main or proximal left anterior descending artery stenosis and/or multivessel disease, were similarly associated with worse outcomes on both CCTA (HR 1.56; 95% CI [1.18–2.07]; p=0.002) and ICA (HR 1.28; 95% CI [0.98– 1.69]; p=0.07). These data suggest that luminal stenosis by CCTA is an important prognostic sign for poor outcomes in those presenting with NSTEMI. The ability of CCTA to visualize plaque and identify high-risk plaque features may aid in the classification of MI (e.g. type I versus II) and the identification of culprit lesions in patients with multivessel disease. Small studies of CCTA in patients with ACS have shown that different plaque characteristics can identify culprit plaque. For example, remodeling index (RI) has been shown to be associated with culprit lesions in patients with ACS, with an RI ≥1.23 associated with a 12-fold increased odds of culprit lesion (OR 12.3; 95% CI [2.9–68.7]; p<0.01).33 Similarly, Hoffman, et al. showed that beyond luminal stenosis, remodeling index and plaque area were higher in culprit versus non-culprit lesions in patients with ACS.34 Taken together, these studies demonstrate the excellent accuracy of CCTA in detecting obstructive CAD in patients with NSTEMI and illustrate the safety of this diagnostic modality in this patient population. In the era of the COVID-19 pandemic, the diagnostic accuracy of CCTA has been

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Coronary CT Angiography in Acute Coronary Syndrome leveraged to safely evaluate patients with COVID-19 and elevated cardiac biomarkers.35 To accomplish this, many sites have increased the availability of CCTA to off-hours (5 pm–11 pm).35 CCTA also has the benefit of reducing staff contact time with patients to reduce the risk of COVID-19 transmission, leading to increases in use during the pandemic.35 In general, although CCTA has demonstrated reductions in LOS and healthcare costs in comparison with standard care in lower-risk patient populations, the evidence for similar reductions in high-risk patients is not currently present. Further studies are needed to clarify the role of CCTA in patients with NSTEMI. Limited data exist on the role of FFRCT in patients with established ACS. In a study of 48 patients with ACS and deferred intervention on non-culprit lesions, non-culprit lesion FFRCT ≤ 0.8 was associated with increased major adverse cardiac events over 19.5 months (adjusted HR 1.56; 95% CI [1.01–2.83]; p=0.048).36 An ongoing trial is evaluating the ability of FFRCT to triage patients with high-risk ACS in the ER in comparison with invasive FFR.24 The role of FFRCT in the evaluation of non-culprit lesions after STEMI was investigated in a single-center prospective study that evaluated 60 patients with recent STEMI who underwent CCTA and invasive FFR 1 month after STEMI. Compared with >50% luminal stenosis by CCTA, FFRCT improved the accuracy (72% versus 64%, p=0.033) and specificity (66% versus 49%, p < 0.001) but not sensitivity (83% versus 93%, p=0.15) to predict invasive FFR ≤ 0.8. The performance in that study population was generally lower than what was observed in stable disease in the NXT trial (sensitivity 86% and specificity of 79%), which may be related to smaller vessel volume. These findings suggest a limited application of FFRCT after STEMI, and further refinement of the computational model may be needed in this population.

Although acute plaque rupture and resulting type I MI is often the immediate concern in NSTEMI, alternative pathologies (e.g. spontaneous coronary artery dissection [SCAD], coronary embolism and vasospastic disease) are becoming increasingly recognized as of importance. SCAD often occurs in relatively young women and disproportionately in the peripartum period (up to 18% of women with SCAD). The vast majority of patients with SCAD are managed conservatively owing to the risk of propagating the dissections with coronary intervention. Therefore, noninvasive imaging is often required to identify the location and extent of SCAD to guide therapy (Figure 3).37

Atheroma Phenotyping with CCTA

Coronary atherosclerosis is often graded based on luminal stenosis. CCTA enables plaque characterization, which is being increasingly recognized as an important predictor of clinical outcome.15 Compared with invasive modalities (e.g. intracoronary imaging), CCTA allows a full coverage of the coronary tree and is not limited by the depth of imaging, although it has lower spatial resolution (~5 mm with CCTA compared with 10 μm for optical coherence tomography [OCT] and 100 μm for intravascular ultrasound [IVUS]). Plaques can be characterized by the presence or absence of calcification, overall plaque volume, and high-risk plaque features (low attenuation, napkin ring sign, macrocalcification, and positive remodeling).

In an analysis of 472 patients who underwent CCTA in the ROMICAT II trial (32 with ACS), CTA-specific thresholds for plaque burden and degree of stenosis performed significantly better than IVUS-derived thresholds (p < 0.05), with minimal luminal area also having a modestly superior performance (p=0.066).38 In the SCOT-HEART trial, patients with both obstructive disease and adverse plaque features (low attenuation or

Figure 3: Coronary CT Angiography Showing SCAD in a 48-year-old Woman with Fibromuscular Dysplasia and Recurrent Coronary Artery Dissection

SCAD = spontaneous coronary artery dissection.

positive remodeling) had a 10-fold increase in coronary heart disease death or non-fatal MI compared with patients with normal coronary arteries (HR 11.50; 95% CI [3.39–39.04]; p<0.001).39 CCTA can also provide insights regarding pericoronary adipose tissue (PCAT), which also seems to have prognostic information, which may be due to local inflammation.40 Fat attenuation index (FAI) ≥−70.1 HU has been linked to a significant increase in cardiac mortality (adjusted HR 9.04; 95% CI [3.35–24.4]; p<0.0001) in a large analysis of 1,872 patients who underwent CCTA.41 Quantitative analysis of peri-coronary fat may also facilitate the identification of vulnerable plaques and vulnerable patients during ACS presentation.42,43

Role of CCTA for Evaluation of Coronary Stents, Bypass Grafts and for PCI Planning

Advances in CT technology have improved spatial resolution and now enable evaluation of the patency of some coronary stents. A meta-analysis of 35 studies reporting on 4,131 stents showed that the pooled positive likelihood ratio was 14.0 and the pooled negative likelihood ratio was 0.10 for diagnosis of in-stent restenosis of ≥50%.44 The 2021 SCCT expert consensus document on CCTA concluded that it is appropriate to use CCTA to evaluate stents (≥3.0 mm in diameter) using special imaging protocols for image optimization, and it may be appropriate to image smaller stents (<3.0 mm in diameter) with known thin struts (<100 µm) in proximal vessels.45 The data surrounding the use of CCTA for the identification of in-stent thrombosis are limited. In-stent thrombosis is more conventionally diagnosed via ICA, IVUS and OCT. A 2011 study compared the performance of 64-slice CCTA and OCT for diagnosis of stent thrombosis in 79 patients who presented at a mean interval of 24 hours after the onset of acute chest pain within a month of the initial coronary event.46 CCTA was found to have a sensitivity of 95%, specificity of 93%, PPV of 83% and NPV of 98%. Although these data are limited to a small population of patients, the study serves as a promising proof of concept for the use of CCTA in this population. CCTA also enables evaluation of stent morphology and identification of the stent fracture non-invasively (Figure 4).

CCTA allows fairly accurate evaluation of CABG. Because grafts are typically larger than and subject to less motion artifact than native coronary arteries, CCTA is particularly useful in this population.45 A 2016 meta-analysis of 12 studies using a 64-detector CCTA protocol involving 959 patients demonstrated the high sensitivity (98%), specificity (98%) and discrimination (area under the receiver operating characteristic curve 0.99) of stenosis >50%, compared with ICA, regardless of conduit type

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Coronary CT Angiography in Acute Coronary Syndrome Figure 4: Coronary CT Angiography Showing a Stent Fracture in a Patient Presenting with Chest Pain and Abnormal Stress Test

demonstrate the course of the distal segment of occluded and large collateral vessels, which can offer a roadmap for interventions and may reduce procedure time. CCTA can additionally identify various coronary features that may be predictive of revascularization success and longterm outcomes, and identify myocardial coronary territory.48

Conclusion

(venous versus arterial).47 Evaluation of native coronary stenosis remains challenging in patients with prior CABG due to advanced atherosclerosis, often with diffuse calcification limiting luminal stenosis. Thus, CCTA for the evaluation of CABG patency may be most helpful in patients with known occluded native coronaries.

CCTA may also be helpful in procedure planning in patients with chronic total occlusions (CTOs) undergoing PCI. CCTA has the ability to 1.

2.

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CCTA is a versatile imaging modality that can play an appropriate role for coronary artery evaluation in several clinical settings. In the stable chest pain patient, it offers superior sensitivity to other non-invasive functional imaging modalities, leading to higher rates of statin and aspirin prescription rates. In low- to intermediate-risk patients with acute chest pain, it is not only safe, but potentially allows for reduced costs and LOS, and the diagnosis of non-coronary causes of acute, life-threatening chest pain that may otherwise be missed. The role of CCTA in higher-risk patients (such as those with confirmed NSTEMI) is evolving and it may provide a safe means of identifying patients without obstructive disease, for whom medical therapy may be sufficient. CCTA can also aid in plaque characterization, which can facilitate personalized therapeutic interventions and distinguish culprit from non-culprit lesions, or even non-atheromatous causes of ACS. CCTA also provides novel prognostic information with its ability to noninvasively derive information regarding plaque morphology and PCAT. Finally, it can also play an important role in evaluating prior coronary stents and CABG, and in the planning for PCI. The world of CCTA continues to expand with the development of new technologies (such as FFRCT), which will enhance the diagnostic abilities of CCTA and improve its specificity to identify hemodynamically significant stenoses.

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REVIEW

Heart Failure

Contemporary Review of Hemodynamic Monitoring in the Critical Care Setting Aniket S Rali, MD, ,1 Amy Butcher, PA-C, ,2 Ryan J Tedford, MD, ,3 Shashank S Sinha, MD, MSc,4 Pakinam Mekki, MD,5 Harriette GC Van Spall, MD, ,6 and Andrew J Sauer, MD7 1. Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN; 2. Department of Cardiovascular Anesthesia and Critical Care, Baylor College of Medicine, Houston, TX; 3. Division of Cardiology, Department of Medicine, Medical University of South Carolina, Charleston, SC; 4. Division of Cardiology, Inova Heart and Vascular Institute, Inova Fairfax Medical Campus, Falls Church, VA; 5. Department of Internal Medicine, Vanderbilt University Medical Center, Nashville, TN; 6. Department of Medicine, Department of Health Research Methods, Evidence, and Impact, Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada; 7. Department of Cardiovascular Medicine, University of Kansas Medical Center, Kansas City, KS

Abstract

Hemodynamic assessment remains the most valuable adjunct to physical examination and laboratory assessment in the diagnosis and management of shock. Through the years, multiple modalities to measure and trend hemodynamic indices have evolved with varying degrees of invasiveness. Pulmonary artery catheter (PAC) has long been considered the gold standard of hemodynamic assessment in critically ill patients and in recent years has been shown to improve clinical outcomes among patients in cardiogenic shock. The invasive nature of PAC is often cited as its major limitation and has encouraged development of less invasive technologies. In this review, the authors summarize the literature on the mechanism and validation of several minimally invasive and noninvasive modalities available in the contemporary intensive care unit. They also provide an update on the use of focused bedside echocardiography.

Keywords

Hemodynamics, hemodynamic monitoring, shock, cardiogenic shock, intensive care unit, pulmonary artery catheter, Swan-Ganz catheter Disclosure: RJT has consulting relationships with Medtronic, Abbott, Aria CV, Acceleron, CareDx, Itamar, Edwards Lifesciences, Eidos Therapeutics, Lexicon Pharmaceuticals, Gradient, and United Therapeutics, is on a steering committee for Acceleron and Abbott, a research advisory board for Abiomed, and does hemodynamic core lab work for Actelion and Merck. AJS has consulting relationships with Medtronic, Abbott, Boston Scientific, Edwards Lifesciences, and General Prognostics; serves on the steering committees for Boston Scientific, Impulse Dynamics, Medtronic, and Biotronik; and is a section editor on the US Cardiology Review editorial board; this did not influence peer review. All other authors have no conflicts of interest to declare.

Received: November 9, 2021 Accepted: March 7, 2022 Citation: US Cardiology Review 2022;16:e12. DOI: https://doi.org/10.15420/usc.2021.34 Correspondence: Aniket S Rali, Division of Cardiovascular Medicine, Vanderbilt University Medical Center, 1215 21st Avenue South, Suite 5209, Nashville, TN 37232.

E: aniket.rali@vumc.org Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Hemodynamic assessment remains the cornerstone of accurate diagnosis of shock and the assessment of the response to therapy in critically ill patients. Contemporary cardiac intensive care units (CICU) manage patients with multiple co-morbidities along with an ailing heart.1–3 An increasing number of patients with septic shock and undifferentiated shock are treated in the CICU in conjunction with patients with cardiogenic shock (CS).4,5 For this reason, rapid and accurate hemodynamic assessment is essential for the differentiation of shock and subsequent guidance for treatment including escalation to pharmacological therapies or temporary mechanical circulatory support (MCS).6 A myriad of invasive, minimally invasive, and noninvasive hemodynamic assessment modalities exists that supplement physical examination (Figure 1 and Table 1). These techniques rely on various physiological principles and assumptions to measure hemodynamic parameters. The aims of this review are to summarize the available literature on the mechanisms and clinical validity of various hemodynamic monitoring modalities as well as providing a contemporary update on pulmonary artery catheter usage. We have characterized each modality based on its level of invasiveness.

Physical Examination in Shock

The bedside physical examination is the oldest method of patient evaluation and can detect the presence of shock. Skin mottling, cool extremities, and delayed capillary refill have been correlated with mortality in patients with septic shock.7,8 Similarly, physical examination findings help grade severity of CS. Created in 1967, the Killip Classification grades heart failure (HF) severity post-MI based on progression from the presence of an S3 gallop or isolated rales, to pulmonary edema, to overt CS.9 The 2019 Society for Cardiovascular Angiography and Interventions (SCAI) Clinical Expert Consensus Statement on Classification of Cardiogenic Shock was developed based on physical examination in conjunction with biochemical and hemodynamic profiles. The SCAI physical exam can detect the worsening of CS on a continuum from isolated tachycardia and elevated jugular venous pressure; to cool extremities, pulmonary rales, oliguria, altered mentation, and narrow pulse pressure; to peri-arrest and arrest.6,8 While physical examination certainly has a part to play in the initial diagnosis of shock and the degree of shock severity, it may not be reliable

© RADCLIFFE CARDIOLOGY 2022 www.USCjournal.com

Hemodynamic Monitoring in the Critical Care Setting An Update on Pulmonary Artery Catheters

Figure 1: Hemodynamic Monitoring Devices and Associated Measured Indices

PAC has been used for the direct measurement of hemodynamic profiles for several decades. It provides direct measurement of intracardiac pressures as well as estimates of cardiac output (CO) and cardiac index.

PAC allows for the estimation of CO by two techniques – indirect Fick and bolus thermodilution (Td). Each has its pitfalls but Td is preferred over indirect Fick even in low output and severe tricuspid regurgitation.15–18 While measuring Td, it is critical that injections should be made in triplicate and all values within 10% of each other to account for beat-to-beat and manual injection variabilities. Furthermore, injection should occur at the same point of the respiratory cycle for consistent measurements.19

Pulmonary artery catheter PAP CVP RVEDP PAWP SVO2 CO/CI

PiCCO MAP CVP CO/CI

*Femoral arterial line preferred NICOM CO/CI

The original 1976 Forrester hemodynamic classification categorizes shock and CS treatment based on PAWP (‘wet’ versus ‘dry’) and cardiac index (‘warm’ versus ‘cold’) alone, thereby installing the PAC as a cornerstone of early CS management.20 Once enshrined as a permanent fixture in the management of intensive care patients, the PAC then became a focus of intense debate in the early 2000s after studies noted an increased rate of complication without a clear reduction in mortality.21–23 The 2005 ESCAPE trial then sought to determine the safety and efficacy of routine consecutive day use of PACs in patients hospitalized for chronic decompensated HF, and ultimately found no mortality benefit.24 It is worth noting that although the ESCAPE trial was a negative study, it was not focused on patients with general decompensated HF rather than the management of a CS population. The average systolic blood pressure in the study cohort was 106 mmHg and a very small percentage (<5%) would have met the clinical definition of CS. Although it did not meet its primary endpoint, ESCAPE’s secondary functional endpoints consistently favored PAC-directed therapy, especially in exercise capability and quality of life.24 However, subsequent meta-analyses of the use of PAC concluded a lack of mortality benefit with PAC placement and even a trend towards harm.25,26 In addition to unclear mortality benefit, PACs have been criticized for invasiveness and increased use of resources when there are potential alternatives, such as less invasive hemodynamic diagnostic devices.27

FloTrac/Vigileo MAP Pulse contour analysis CO/CI

Applanation tonometry CO/CI MAP Clearsight/CNAP MAP CO/CI PAWP correlate

*Noninvasive venous waveform analysis is not shown. CO/CI = cardiac output/cardiac index; CVP = central venous pressure; PAP = pulmonary artery pressure; PAWP = pulmonary artery wedge pressure; MAP = mean arterial pressure; NICOM = noninvasive cardiac output monitor; RVEDP = right ventricular end diastolic pressure; SvO2 = mixed venous oxygen saturation.

in differentiating shock etiology. As early as 1984, Eisenberg et al. noted the pitfalls of physical diagnosis when they reported that physicians could only accurately estimate a pulmonary artery wedge pressure (PAWP) by physical diagnosis 30% of the time compared with pulmonary artery catheter (PAC) monitoring.10 Similarly, a 1994 study by Mimoz et al. demonstrated 56% accuracy in predicting patient hemodynamic profiles by physical exam alone.11 More recent observational studies in adults and children have had similar diagnostic inaccuracy.12,13 Evidence to date suggests that while it is an important screening index for the presence and severity of shock, physical examination alone is not adequate to determine the cause of shock nor risk stratification.14

PAC is a diagnostic tool, not a treatment modality. As any other diagnostic tool, it cannot improve mortality by its mere placement. However, appropriate interpretation of real-time PAC hemodynamic profiles can easily capture hemodynamic changes while delineating the relative contributions and severity of right ventricular (RV) versus left ventricular (LV) failure in CS. Nuanced interpretation can then guide appropriate treatment strategy including initiation of inotropes as well as escalation to MCS therapy. Garan et al.’s analysis from the Cardiogenic Shock Working Group cohort found that complete PAC hemodynamic profiling in CS was associated with lower in-hospital mortality across all SCAI classifications even when adjusted for CS etiology, presence of MCS, and local PAC usage trends (adjusted OR: 1.57; 95% CI [1.06–2.33]). This study also found that an incomplete PAC hemodynamic profile portended similar inhospital mortality risk to having no PAC profiling at all, which they theorized may have been due to an underestimation of RV contribution to CS.28 Accordingly, the most recent European Society of Cardiology guidelines classify clinical presentations of acute HF not only by Forresterbased CO and PAWP, but also by the presence of elevated RV end diastolic pressure.29 The ESCAPE trial showed potential benefits of PAC in high volume centers, perhaps a reflection of its usefulness among those who are more experienced with hemodynamic evaluation.11 By allowing medical providers to make better informed decisions, PAC could ultimately

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NICOM versus CO (Fick and Td)

FloTrac versus LiDCO versus PAC (Td)

Off-pump CABG and liver transplant recipients

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FloTrac versus PAC (CoTd)

CNAP versus PAC

NICOM versus PAC (Fick and Td)

Cardiac surgery with CPB

Wagner et al. 201878 Post-cardiac surgery

Cardiogenic shock

Ambulatory heart failure

Lin et al. 201855

Rali et al. 202062

Alvis et al. 202188

84

50

51

32

21

None

None

None

None

None

None

None

None

Td vs AT-CO = 4.7 ± 1.2 versus 4.9 ± 1.1; % error = 34% AT-CO trend concordance 95%

• •

NICOM-Fick r=0.132, CC 0.101 (0.008–0.191) p=0.033, bias 0.763 NICOM-Td r=0.275, CC 0.133 (0.073–0.192), p<0.001, bias 0.484

Calibrated-CNCO – PAC-CO, -0.3 (SD ± 0.5; -1.2 to +0.7; 19% error) Uncalibrated-CNCO – PAC-CO +0.5 (SD +/- 1.3; 49% error)

• • • •

NIVA can risk-stratify HF patients

NICOM correlates poorly to Fick or Td derived via PAC in CS

CNAP requires frequent calibrations with PAC

Pre-CPB FloTrac versus PAC: % error 61.82; bias = 0.16 (−2.15, 2.47), Poor correlation between FloTrac and PAC concordance 64.10%.

Post-CPB FloTrac versus PAC: % error 51.80; bias = 0.48, concordance 62.16%

• •

PAC = 5.7 ±1.5 versus LiDCO = 6.0 ± 1.9 (bias −0.10, r=0.83, p=0.0028) Dynamic changes in CO trended congruently across devices but wide range of inter-device bias FloTrac = 5.9 ± 1.0 (bias −0.40, r=0.73, p=0.0258) PiCCO = 5.7 ± 1.8 (bias 0.18, r=0.85, p=0.0019) NICOM = 5.3 ± 1.0 (bias −0.71, r=0.87, p=0.0011)

• • • •

LiDCO better than FloTrac, but neither were within acceptable limits of error

FloTrac versus PAC: Bias = -0.44; % error = 74.4; R2 = 0.48 LiDCO versus PAC, Bias = -0.38; % error = 53.5; R2 = 0.75

• •

Bland and Altman analysis mean bias ± 2 SD of 0 ± 2.14 (% error = 34.5%) Poor correlation in septic shock

Noninvasive assessment of changes in CO

NICOM is precise and reliable in measuring CO at rest and with vasodilator challenge

Fick mean CO = 4.84 ± 1.39 versus Td 5.69 ± 1.74 (r=50.60, p,0.001) and NICOM 4.73 ± 1.15 (r=50.83, p=0.001) NICOM versus PAC-Fick coefficient of variance = 3.5 ± 0.3% versus 9.6 ± 6.1%, p=0.001

• •

Poor correlation in septic shock

Mean PAC versus NICOM (R = 0.64, slope = 0.71 (95% CI [0.70–0.72]). NICOM estimated CO with acceptable accuracy and Bias 0.06 ± 0.71 precision Fluid challenge PAC lag time (7.1 ± 3.1 min for negative challenge, 6.8 ± 3.2 min for positive challenge) versus NICOM (3.4 ± 1.3 min and 4.0 ± 2.2 min respectively; p=0.01, 0.003)

Clinical Significance

CC = 0.47 (p<0.01, r2 = 0.22)

•

•

Results

PAWP (mmHg) 30-day hospital admission NIVA score positively correlated with PAWP (r=0.92, n=106, p<0.0001) for heart failure Discharge NIVA score predicted 30-day admission with an AUC of 0.84, exacerbation a NIVA score >18 predicted admission with a sensitivity of 91% and specificity of 56%

CO (l/min)

CO (l/min)

CO (l/min)

CO (l/min)

Cardiac index None (l/min/m2)

CO (l/min)

CO (l/min)

CO (l/min)

Cardiac index None (l/min/m2)

CO (l/min)

Measured Clinical Primary Outcome Outcome/Endpoint

AT = applanation tonometry; AUC = area under curve; CABG = coronary artery bypass graft; CC = correlation coefficient; CNAP = continuous noninvasive arterial pressure waveform; CNCO = continuous noninvasive cardiac output; CO = cardiac output; CoTd = continuous thermodilution; CPB = cardiopulmonary bypass; LVEF = left ventricular ejection fraction; MCS = mechanical circulatory support; NICOM = noninvasive cardiac output monitor; PAC = pulmonary artery catheter; NIVA = noninvasive venous waveform analysis; PAWP = pulmonary artery wedge pressure; Td = bolus thermodilution; VCI = vena cava inferior.

NIVA versus PAC

Post-cardiac surgery PAC (Td) versus Pertinent exclusions: FloTrac/NICOM/ LVEF <45%, LiDCOplus/PiCCOplus arrhythmias, valvular dysfunction, and MCS

Lamia et al. 201838

Asamoto et al. 2017

21

FloTrac versus PAC (Td) 47

Septic shock

53

Ganter et al. 201652

50

AT versus PAC (Td)

50

18

110

n

Wagner et al. 201572 Post-cardiac surgery

Pulmonary hypertension

Rich et al.201361

NICOM versus PAC (Td)

FloTrac (VCI) versus PAC (Td)

Post-cardiac surgery

Squara 200760

Comparison Groups

Marque et al. 201354 Septic shock

Patient Population

Authors

Table 1: Comparison of Minimally Invasive and Noninvasive Hemodynamic Monitor to Pulmonary Artery Catheter-measured Cardiac Output

Hemodynamic Monitoring in the Critical Care Setting

Hemodynamic Monitoring in the Critical Care Setting improve mortality in patients with CS. In an observational study by Ranka et al. analyzing the National Readmissions Database for patients admitted with acute CS (n=236,156), PAC-guided therapy was associated with a significant (31%) reduction in mortality during index hospitalization, a 17% reduction in 30-day HF readmissions rate and sixfold increase in usage of an LV assist device and orthotopic heart transplants during readmission.30 Hernandez et al. also found that despite the recent decline in the use of PAC in patients with CS, treatment guided by PAC assessment resulted in lower mortality during index hospitalization (n=915,416; 35.1% versus 39.2%, OR 0.91, 95% CI [0.88–0.95]; p<0.001).31 These, among other recent studies, have certainly revived discussion and debate about the need for appropriately interpreted PAC profiles as a powerful tool in CS management.32,33 While these studies have advocated for the role of PAC hemodynamic assessment in CS, randomized controlled trials will help solidify it.

Minimally Invasive Hemodynamic Monitoring Pulse Index Continuous Cardiac Output Monitoring

Transpulmonary thermodilution or lithium dilution devices, such as the pulse contour CO (PiCCO) monitoring system (Pulsion Medical Systems/ Getinge) and the LiDCO system (LiD-COplus, LiDCO), estimate CO by transthoracic thermodilution and lithium indicator dilution, respectively.34,35 They are less invasive than PAC in that they do not transverse the heart, but they still require central access. PiCCO is performed by injecting a cold fluid bolus via a central venous catheter and measuring the resultant thermodilution via a thermistor-tipped femoral artery catheter.27 The thermodilution curve (blood temperature versus time) translates to estimated CO by the Stewart–Hamilton equation. CO measured by PiCCO has been shown to be within acceptable agreement (r=0.97, p<0.0001) with PAC-based intermittent bolus thermodilution estimation of CO in critically ill patients.36 Once calibrated with thermodilution, PiCCO algorithmically incorporates pulse contour analysis for continuous CO and stroke volume variation measurement, quantitative estimation of extravascular lung water (EVLW), and other calculated hemodynamic parameters. However, frequent recalibration is required.37 In a study of 20 patients admitted to the intesive care unit (ICU) after cardiac surgery with arterial line and PAC monitoring, cross-comparison of PAC derived CO was performed with PiCCO and LiDCO estimations; mean CO measurements were similar, though accuracy suffered during dynamic changes in CO.34 A newer cross-comparison between PAC, PiCCO, and LiDCO devices demonstrated tight inter-device measurement of dynamic CO trends in post-cardiac surgery patients without significant cardiac dysfunction, arrhythmia, or valvular abnormalities (PAC-PiCCO r=0.85, p=0.0019; PAC-LiDCO r=0.83, p=0.0028), suggesting that prior inaccuracies may have been algorithmically corrected.38 Among patients with CS, studies comparing PAC to PiCCO found adequate concordance with the cardiac index, including in patients with valvular abnormalities or arrhythmias.39,40 PiCCO has also been shown to demonstrate concordance with transthoracic echocardiography in estimating cardiac output.27,35 Location of central venous catheter as well as presence of MCS devices can affect the accuracy of PiCCO measurements. Herner et al. described significantly lower estimations in cardiac functional index when catheters were placed in a femoral location instead of gold standard jugular or subclavian venous access, though later iterations of PiCCO monitoring algorithms have some provisions to correct for venous catheter location.41 Thermodilutional-derived global ejection fraction has shown more accuracy to date than thermodilutional-derived cardiac functional index regardless of venous catheter location.41,42 PiCCO accuracy can also be

affected by MCS, such as intra-aortic balloon pump (IABP) counterpulsation.39 The device detects every augmentation during IABP support as a new systole, resulting in inaccurate estimation of heart rate. Literature regarding PiCCO monitoring with other forms of MCS such as ventricular assist devices or veno-arterial extracorporeal membrane oxygenation is sparse.

More recently, PiCCO monitoring has also been used with adjunct carotid tonometry in the measurement of effective arterial elastance (Ea), which is defined as the ratio between central end-systolic pressure and stroke volume. Ea has been proposed as an alternative to systemic vascular resistance when measuring LV afterload and measuring the ventriculararterial decoupling that occurs in shock states.6,43 The PiCCO system can provide a qualitative estimate of EVLW and has been proposed as a tool in management and prognostication of acute lung injury, acute respiratory distress syndrome (ARDS), and cardiogenic pulmonary edema.27,44 As the cold saline bolus is injected, the downslope of the thermodilution curve is used to estimate total pulmonary and thermal volumes, and EVLW is then estimated as the difference of intrathoracic blood volume and intrathoracic thermal volume.27,45 Targeting EVLW in sepsis and ARDS management has not revealed benefit. A multicenter randomized controlled trial of 350 patients demonstrated no mortality benefit of EVLW versus central venous pressure (CVP)-guided fluid balance in septic shock or ARDS.46 Indeed, little correlation is reported between EVLW estimates and shock subtype or ICU mortality.47,48 Given the evolution of fluid balance assessment in recent years, largerscale prospective studies will be critical in determining the utility of EVLW estimations with PiCCO monitoring in critically ill patients.

Similar to PiCCO, the LiDCO system provides CO measurements by lithium indicator dilution generating a curve of concentration over time. A lithium chloride indicator is injected in either a central or peripheral venous line, then arterial concentrations of the lithium are measured by serial blood draws through an arterial line sensor.49 With three sequential dilution measurements, the coefficient of error in measurement of CO is as low as 5% in hemodynamically stable, ventilated intensive care patients.50 Initial inaccuracies reported during dynamic CO shifts seem to have improved in later algorithms, though notably patients with severe cardiac dysfunction (LV ejection fraction [LVEF] <45%), MCS, valvular dysfunction, and arrhythmias were excluded.34,38 It remains unclear to what extent these hemodynamic assessments affect clinical outcomes. Furthermore, an important caveat is that these systems only assess CO and do not provide the complete hemodynamic picture (including pulmonary artery pressure, PAWP, etc.) which is more valuable than any one parameter alone.28

Uncalibrated Pulse Contour Analysis

The FloTrac/Vigileo system (Edwards Lifesciences) uses pulse contour analysis derived from the arterial line to estimate stroke volume. When combined the patient’s demographic data via the Vigileo monitor, it can also provide estimations of CO, cardiac index, and stroke volume variation with suboptimal accuracy.35 This technique does not require calibration with PAC-measured CO but also does not provide estimates of intracardiac pressures such as CVP, PAP, or pulmonary capillary wedge pressure.35,51 FloTrac has been criticized for poor correlation with PAC measured CO, with a widely variable percentage error (up to 68%) across all generations of monitors and across several studies and settings (ICU, postoperative, septic shock patients).51–56 While its utility in accurate estimation of cardiac

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Hemodynamic Monitoring in the Critical Care Setting index is limited, it may be useful in trending change in cardiac index as a mark of volume responsiveness.57–59

Noninvasive Hemodynamic Monitoring Noninvasive Cardiac Output Monitoring

Noninvasive Cardiac Output Monitor (NICOM, Cheetah Medical) measures intrathoracic bioimpedance by alternating AC currents through thoracic pulsatile blood flow. It then indirectly calculates the stroke volume as the derivative of the change in the NICOM signal amplitude between systole and diastole. This measurement is dependent upon the diffusion of oscillating electric currents through the thoracic cavity.

Studies evaluating the validity of the use of NICOM when compared with PAC have yielded mixed results. Squara et al. assessed CO in post-cardiac surgery patients by both NICOM and thermodilution by PAC and demonstrated that NICOM was a reliable method of measuring CO in this cohort.60 Rich et al. then demonstrated that NICOM was comparable to PAC in precision when assessing hemodynamics in patients with pulmonary artery hypertension.61 However, NICOM has not been reliable in assessing hemodynamics in patients with CS and acute decompensated HF. In a cross-sectional prospective clinical trial, Rali et al. found that NICOM correlated poorly with indirect Fick and thermodilution measurements of CO in patients with CS.62 It is plausible that these errors in measurement may be a result of interstitial and pulmonary edema and increased preload states in patients with chronic HF and low flow state in CS. The correlation did not improve with normalization of the cardiac index >2.2 l/min/m2 or with the achievement of euvolemic status (CVP <5 mmHg or pulmonary artery systolic pressure <25 mmHg).62

Arterial Applanation Tonometry

Arterial applanation tonometry noninvasively estimates the aortic pressure waveform as a correlate of cardiac hemodynamics. It is performed by securing a pressure sensor (tonometer) over the wrist to partially flatten the radial artery and capture the arterial pulse. The resultant pulse waveform then undergoes a Fourier transformation algorithm to estimate a central aortic pressure waveform.63 Since the arterial pressure waveform contour is primarily determined by the force and duration of ventricular ejection, aortic impedance, and peripheral vasculature resistance it can be calibrated to estimate hemodynamics including CO. The T-lineÒ system (Tensys® Medical) is a well-known applanation tonometer that estimates hemodynamics by formulaically auto-calibrating a pulse contour analysis of radial tonometry based on demographic and biometric patient data.35,64,65 Arterial tonometry has demonstrated accuracy in measuring beat-to-beat blood pressure variation and mean arterial pressure (MAP) in anesthetized surgical patients and critically ill non-cardiac patients.66–69 However, in critically ill patients with severe HF, arrhythmias, or valvular disorders, MAP estimations with arterial tonometry are less accurate than traditional arterial line monitoring, with a near 40% error reported.70 Small proof-ofconcept studies comparing CO estimations of arterial tonometry to PAC in critically ill patients found that appropriately positioned and calibrated arterial tonometers were able to estimate CO with a 23–34% margin of error.71,72 However, a follow-up study comparing arterial tonometry to PAC measurements in patients undergoing major abdominal surgery had an error rate of 43%.73 Applanation tonometry is strongly affected by vasoactive medications, obesity, and arrhythmias, and loses precision in large hemodynamic shifts or changes in vascular tone.69,70 Arterial tonometry is gaining traction for hemodynamic estimations in an ambulatory setting, with promising application in screening for

hypertension, obstructive sleep apnea, coronary artery disease, and LV hypertrophy, among other pathologies.63 It also has potential as an alternative to Doppler ultrasound to measure blood pressure in patients with an LV assist device and may be useful as a continuous wearable device.74,75 However, further improvements are needed for it to have consistently accurate arterial blood pressure and CO estimates in critically ill patients.

Volume Clamp Method-derived Pulse Contour Analysis

ClearSight (Edwards Lifesciences) and Continuous Noninvasive Arterial Pressure Waveform (CNAP, CNSystems) noninvasive hemodynamic measuring systems estimate CO via photoplethysmography of the finger pressure arterial waveform. In these volume clamp method devices, an occlusive band around the finger regulates the external pressure needed to keep a continuous arterial blood volume in the finger throughout systole and diastole.27 The resultant pulse contour analysis is then used to estimate CO and stroke volume variation.

In the surgical setting and in hemodynamically stable ICU patients, ClearSight and CNAP have demonstrated an approximate 25% margin of error when calibrated with thermodilution, and 25–45% error when autocalibrated.73,76–78 However, ClearSight and CNAP are not usually thermodilutionally calibrated in clinical practice, and larger ICU studies found much higher margins of error and standard deviations of measurement in auto-calibrated ClearSight measurements of undifferentiated shock patients.79,80 ClearSight and CNAP are particularly affected by hemodynamic shifts that require recalibration, vasopressor use, arrhythmias, and peripheral arterial disorders, which may limit their broad application in accurate hemodynamic assessment of critically ill patients.77,81 More recent data demonstrate that ClearSight and CNAP may be useful to track fluid responsiveness. Boisson et al. found that thermodilutionally calibrated ClearSight versus PiCCO in the operating room accurately trended increase in CO after 250 ml fluid boluses.77 In hemodynamically unstable patients, auto-calibrated ClearSight was able to trend increase in MAP and cardiac index over time with fluid resuscitation of patients in the emergency room or rapid response.82,83 Similarly finger photoplethysmography has been used to measure pulse amplitude ratio, defined as the ratio of pulse pressure at the end of a Valsalva maneuver to before the onset of Valsalva, which can estimate PAWP in HF patients as well as help identify hospitalized HF patients at increased risk of 30-day HF events.84,85

Noninvasive Venous Waveform Analysis

The high capacitance, low compliance venous system has not been widely studied in noninvasive hemodynamic monitors to date due to limitations in collecting and measuring low-frequency venous signals.

Noninvasive venous waveform analysis (NIVA) has recently been used to measure venous distension, and thereby estimate volume status and PAWP. NIVA technology uses piezoelectric sensing over the superficial wrist veins to detect and amplify venous signaling, then applies a Fourier transformation and algorithm to the signal to estimate PAWP.86 An initial study comparing NIVA estimates of PAWP to right heart catheterization measurements demonstrated a sensitivity of 80% and specificity of 53% in detecting a PAWP of >18 mmHg.87 With further refinement, NIVA technology may be used as an adjunct or alternative to implantable PAP

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Hemodynamic Monitoring in the Critical Care Setting monitoring systems such as CardioMEMS, which have in turn shown to be useful in ameliorating HF exacerbations and hospitalizations.87–89 NIVA has also been proposed as a method to direct volume removal during hemodialysis.86 However, inpatient application of NIVA is yet to be evaluated.

Transthoracic Echocardiography

Critical care echocardiography (CCE) has gained significant popularity with increased availability of mobile echocardiography machines and training opportunities.90 The noninvasive nature of CCE is especially appealing and echocardiography has long been validated as a reliable measure of hemodynamics.91,92 While the full scope of CCE application exceeds the limits of this review, it is worth noting that CCE can estimate all advanced hemodynamics with relative accuracy and tracking aortic velocity time index (VTI) is a reliable means to track change in CO over time or in response to fluid administration.93,94 CCE also adds vital information about cardiac structural details such as regional wall motion abnormality; valvular pathology; and diastolic dysfunction.93 Echocardiographic findings help with appropriate interpretation of hemodynamic data, such as tricuspid regurgitation affecting interpretation of CVP. Jentzer et al. recently discovered that LVEF at admission measured by formal transthoracic echocardiography in acute HF correlated to SCAI shock stages (p<0.001 across all stages) and independently predicted mortality based on LVEF and E/e’ ratio.95 This study prompted renewed discussion about the need for invasive hemodynamic monitoring if echocardiographic-derived hemodynamic 1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

Katz JN, Shah BR, Volz EM, et al. Evolution of the coronary care unit: clinical characteristics and temporal trends in healthcare delivery and outcomes. Crit Care Med 2010;38:375–81. https://doi.org/10.1097/ CCM.0b013e3181cb0a63; PMID: 20029344.

Sinha SS, Sjoding MW, Sukul D, et al. Changes in primary noncardiac diagnoses over time among elderly cardiac intensive care unit patients in the United States. Circ Cardiovasc Qual Outcomes 2017;10:e003616. https://doi. org/10.1161/CIRCOUTCOMES.117.003616; PMID: 28794121.

Miller PE, Thomas A, Breen TJ, et al. Prevalence of noncardiac multimorbidity in patients admitted to two cardiac intensive care units and their association with mortality. Am J Med 2021;134:653–61.e5. https://doi. org/10.1016/j.amjmed.2020.09.035; PMID: 33129785.

Bohula EA, Katz JN, van Diepen S, et al. Demographics, care patterns, and outcomes of patients admitted to cardiac intensive care units: the Critical Care Cardiology Trials Network prospective North American multicenter registry of cardiac critical illness. JAMA Cardiol 2019;4:928–35. https:// doi.org/10.1001/jamacardio.2019.2467; PMID: 31339509.

Berg DD, Bohula EA, van Diepen S, et al. Epidemiology of shock in contemporary cardiac intensive care units. Circ Cardiovasc Qual Outcomes 2019;12:e005618. https://doi. org/10.1161/CIRCOUTCOMES.119.005618; PMID: 30879324.

Hsu S, Fang JC, Borlaug BA. Hemodynamics for the heart failure clinician: a state-of-the-art review. J Card Fail 2022;28:133–48. https://doi.org/10.1016/j. cardfail.2021.07.012; PMID: 34389460.

Cecconi M, Hernandez G, Dunser M, et al. Fluid administration for acute circulatory dysfunction using basic monitoring: narrative review and expert panel recommendations from an ESICM task force. Intensive Care Med 2019;45:21–32. https://doi.org/10.1007/s00134-018-54152; PMID: 30456467.

De Backer D, Bakker J, Cecconi M, et al. Alternatives to the Swan-Ganz catheter. Intensive Care Med 2018;44:730–41. https://doi.org/10.1007/s00134-018-5187-8; PMID: 29725695.

Mello BH, Oliveira GB, Ramos RF, et al. Validation of the Killip-Kimball classification and late mortality after acute myocardial infarction. Arq Bras Cardiol 2014;103:107–17. https://doi.org/10.5935/abc.20140091; PMID: 25014060.

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measurements not only provide the above-mentioned benefits, but also demonstrate strong correlation to shock stage.96 However, echocardiography only provides a single snapshot into the hemodynamic profile of a patient which, while extremely valuable, may change rapidly in the intensive care setting. In complex cardiac patients, CCE and continuous invasive hemodynamic monitoring such as PAC may then serve the most value when used to both detect and diagnose shock evolution.

Appropriate training and competency among non-ultrasonographers remain the most significant limitation in widespread CCE usage. While there are CCE training programs provided by several professional organizations, there is no current formal consensus on number of training hours or exams needed to ensure competency.97 In response to this, the American Society of Echocardiography has recently developed a Critical Care Echocardiography board certification to attempt standardization of CCE skills.98

Conclusion

Several minimally invasive and noninvasive modalities exist to assess hemodynamic parameters. Most of these modalities still require optimization and validation for widespread usage. In the interim, comprehensive invasive hemodynamic profiling of patients in shock with echocardiography, and in select cases, PAC – which overall does not appear to improve clinical outcomes – remains pivotal in ensuring timely diagnosis and optimal treatment, especially in the increasingly complex patient population of the modern day CICU.

11. Mimoz O, Rauss A, Rekik N, et al. Pulmonary artery catheterization in critically ill patients: a prospective analysis of outcome changes associated with catheter-prompted changes in therapy. Crit Care Med 1994;22:573–9. https://doi. org/10.1097/00003246-199404000-00011; PMID: 8143466.

12. Nowak RM, Sen A, Garcia AJ, et al. The inability of emergency physicians to adequately clinically estimate the underlying hemodynamic profiles of acutely ill patients. Am J Emerg Med 2012;30:954–60. https://doi.org/10.1016/j. ajem.2011.05.021; PMID: 21802880.

13. Razavi A, Newth CJL, Khemani RG, et al. Cardiac output and systemic vascular resistance: clinical assessment compared with a noninvasive objective measurement in children with shock. J Crit Care 2017;39:6–10. https://doi.org/10.1016/j. jcrc.2016.12.018; PMID: 28088009.

14. Drazner MH, Hellkamp AS, Leier CV, et al. Value of clinician assessment of hemodynamics in advanced heart failure: the ESCAPE trial. Circ Heart Fail 2008;1:170–7. https://doi. org/10.1161/CIRCHEARTFAILURE.108.769778; PMID: 19675681.

15. Narang N, Thibodeau JT, Levine BD, et al. Inaccuracy of estimated resting oxygen uptake in the clinical setting.

Circulation 2014;129:203–10. https://doi.org/10.1161/ CIRCULATIONAHA.113.003334; PMID: 24077170.

16. Hoeper NM, Maier R, Tongers J, et al. Determination of cardiac output by the Fick method, thermodilution, and acetylene rebreathing in pulmonary hypertension. Am J Respir Crit Care Med 1998;160:535–41. https://doi.org/10.1164/ ajrccm.160.2.9811062; PMID: 10430725.

17. Opotowsky AR, Hess E, Maron BA, et al. Thermodilution vs estimated Fick cardiac output measurement in clinical practice: an analysis of mortality from the Veterans Affairs Clinical Assessment, Reporting, and Tracking (VA CART) program and Vanderbilt University. JAMA Cardiol 2017;2:1090–9. https://doi.org/10.1001/jamacardio.2017.2945; PMID: 28877293.

18. Hoeper MM, Bogaard HJ, Condliffe R, et al. Definitions and diagnosis of pulmonary hypertension. J Am Coll Cardiol 2013;62(25 Suppl):D42–50. https://doi.org/10.1016/j. jacc.2013.10.032; PMID: 24355641.

19. Stevens JH, Raffin TA, Mihm FG, et al. Thermodilution cardiac output measurement effect of the respiratory cycle on its reproducibility. JAMA 1985;253:2240–2. https://doi. org/10.1001/jama.253.15.2240; PMID: 3974116.

20. Forrester JS, Diamond G, Chatterjee K, Swan HJ. Medical therapy of acute myocardial infarction by application of hemodynamic subsets. N Engl J Med 1976;295:1404–13. https://doi.org/10.1056/NEJM197612162952505;

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PMID: 790194.

21. Richard C, Warszawski J, Anguel N, et al. Early use of the pulmonary artery catheter and outcomes in patients with shock and acute respiratory distress syndrome: a randomized controlled trial. JAMA 2003;290:2713–20. https://doi.org/10.1001/jama.290.20.2713; PMID: 14645314.

22. Sandham JD, Hull RD, Brant RF, et al. A randomized, controlled trial of the use of pulmonary-artery catheters in high-risk surgical patients. N Engl J Med 2003;348:5–14. https://doi.org/10.1056/NEJMoa021108; PMID: 12510037.

23. Reade MC, Angus DC. Pac-Man: game over for the pulmonary artery catheter? Crit Care 2006;10:303. https:// doi.org/10.1186/cc3977; PMID: 16420664.

24. Binanay C, Califf RM, Hasselblad V, et al. Evaluation study of congestive heart failure and pulmonary artery catheterization effectiveness: the ESCAPE trial. JAMA 2005;294:1625–33. https://doi.org/10.1001/jama.294.13.1625; PMID: 16204662.

25. Shah MR, Hasselblad V, Stevenson LW, et al. Impact of the pulmonary artery catheter in critically ill patients: metaanalysis of randomized clinical trials. JAMA 2005;294:1664– 70. https://doi.org/10.1001/jama.294.13.1664; PMID: 16204666.

26. Rajaram SS, Desai NK, Kalra A, et al. Pulmonary artery catheters for adult patients in intensive care. Cochrane Database Syst Rev 2013;2:CD003408. https://doi. org/10.1002/14651858.CD003408.pub3; PMID: 23450539.

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EDITORIAL

Lifetime Management of Patients with Aortic Valve Disease

The Final Word: Current Strategies for the Lifetime Management of Patients with Aortic Valve Stenosis Anne H Tavenier MD,1,2 Johny Nicolas MD, MSc, ,1 and Roxana Mehran MD,

1

1. The Zena and Michael A Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY; 2. Department of Cardiology, Isala Hospital, Zwolle, the Netherlands

Keywords

Aortic valve disease, transcatheter aortic valve replacement, surgical aortic valve replacement, aortic valve stenosis Disclosure: RM reports institutional research grants from Abbott, Abiomed, Applied Therapeutics, Arena, AstraZeneca, Bayer, Biosensors, Boston Scientific, BristolMyers Squibb, CardiaWave, CellAegis, CERC, Chiesi, Concept Medical, CSL Behring, DSI, Insel Gruppe AG, Medtronic, Novartis Pharmaceuticals, OrbusNeich, Philips, Transverse Medical, and Zoll; personal fees from ACC, Boston Scientific, California Institute for Regenerative Medicine (CIRM), Cine-Med Research, Janssen, WebMD, and SCAI; consulting fees paid to the institution from Abbott, Abiomed, AM-Pharma, Alleviant Medical, Bayer, Beth Israel Deaconess, CardiaWave, CeloNova, Chiesi, Concept Medical, DSI, Duke University, Idorsia Pharmaceuticals, Medtronic, Novartis, and Philips; equity <1% in Applied Therapeutics, Elixir Medical, STEL, and CONTROLRAD (spouse); Scientific Advisory Board for AMA and Biosensors (spouse). All other authors have no conflicts of interest to declare Received: February 15, 2022 Accepted: March 7, 2022 Citation: US Cardiology Review 2022;16:e13. DOI: https://doi.org/10.15420/usc.2022.07 Correspondence: Roxana Mehran, Center for Interventional Cardiovascular Research and Clinical Trials, The Zena and Michael A Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1030, New York, NY, 10029-6574. E: roxana.mehran@mountsinai.org Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Aortic valve stenosis (AS) is the most common form of valvular heart disease in developed countries, with a prevalence that increases exponentially with advancing age.1,2 Several etiologies, including congenital abnormalities (i.e. bicuspid aortic valve) and rheumatic heart disease, can lead to AS, although degenerative processes directly related to aging are the most common. The progressive fibrosis and calcification of the aortic valve obstruct blood flow from the left ventricle to the ascending aorta during systole. As a result of this decrease in cardiac output, patients complain of decreased exercise capacity that might progress to heart failure or even death if left untreated.

In addition to medical therapy, aortic valve replacement is often needed to limit disease progression, improve prognosis, and enhance the quality of life. Historically, surgical aortic valve replacement (SAVR) has been the mainstay therapy in most patients, while transcatheter aortic valve replacement (TAVR) has been limited to those at high risk for surgery.

Iterations in TAVR technologies and bioprosthetic valves’ design have expanded TAVR indications to patients across the spectrum of surgical risk. This editorial describes the pathophysiology and management strategies of AS, with a particular focus on the recent extension of TAVR to low-risk patients.

Pathophysiology of Aortic Valve Stenosis

Lipid deposition into intima cusps with subsequent oxidation constitutes the primary mechanism of pathogenesis of degenerative AS. This process triggers inflammation and oxidative stress that lead progressively to valve calcification.3 Hypercholesterolemia and high plasma levels of LDL particles are associated with an increase in oxidized LDL deposition in aortic valve leaflets, causing leaflet thickening, macrophage intrusion, and calcification.4 Another plausible mechanism is mediated by the renin–

angiotensin–aldosterone system through the promotion of monocytes infiltration, inflammatory cytokines production, and differentiation of aortic valve interstitial cells into osteoblast-like cells.5 Over time, all these processes lead to valve degeneration and calcification. Valve leaflet thickening, along with the resultant reduction in the aortic valve area, increase left ventricular afterload, which in turn leads to ventricular remodeling, fibrosis, and diastolic dysfunction. As valvular degeneration progresses in severity, systolic dysfunction ensues, and the risk of lethal arrhythmias rises. Therefore, different mechanisms are involved in the pathogenesis and progression of AS, and thus may be targeted by medical therapy. Ongoing clinical trials are currently testing the effects of medications that target calcium metabolic pathways on the progression of calcific aortic stenosis.

Medical Management of Aortic Stenosis

Previous studies have revealed an association between traditional cardiovascular risk factors, such as dyslipidemia, hypertension, and diabetes, and the development of severe AS.6 Therefore, optimal control of these risk factors may mitigate the likelihood or delay the onset of AS. Nonetheless, no medical treatment has been proven to prevent or treat AS efficaciously.7 For example, clinical trials evaluating the impact of statin therapy on valve-related outcomes in asymptomatic patients with mild-tomoderate AS showed no benefits, despite a significant reduction in the rates of ischemic events.8,9 Clinical guidelines provide no recommendations for the pharmacological treatment of AS beyond symptomatic relief and control of concomitant hypertension.10,11 Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers constitute a safe option for blood pressure control, and have been shown to have beneficial myocardial effects.12

© RADCLIFFE CARDIOLOGY 2022 www.USCjournal.com

Current Strategies in the Management of Aortic Stenosis When to Intervene?

Class 1 indications for aortic valve replacement are:10,11

• Severe AS with symptoms of exertional dyspnea, angina, or heart failure.

• Severe AS, asymptomatic, but with left ventricular ejection fraction <50%.

• Severe AS, asymptomatic, but undergoing cardiac surgery for other indications.

Extension of TAVR Indications to Low-risk Patients

Class 2a indications for aortic valve replacement are:10,11

• Severe AS, asymptomatic, and at least one of the following:

decreased exercise tolerance or ≥10 mmHg drop in blood pressure during exercise, a serum brain natriuretic peptide that is at least threefold the upper reference limit, or an increase of ≥0.3 m/s per year in blood flow velocity across the aortic valve.

• Severe AS with a transvalvular velocity of ≥5 m/s.

Class 2b indications for aortic valve replacement are:10

• Severe AS and a progressive decrease in left ventricular ejection fraction to <60% on three or more serial imaging studies.

• Moderate AS, asymptomatic, but undergoing cardiac surgery for other indications.

In general, symptomatic patients who undergo aortic valve replacement have a better prognosis, enhanced quality of life, and improved left ventricular systolic function.13

Timing and Mode of Intervention

The ideal timing of aortic valve replacement should be determined while considering several factors. First, delaying intervention in asymptomatic patients with severe AS carries a risk of adverse cardiac events (i.e. sudden cardiac death) and contributes to progressive left ventricular remodeling. Conversely, both surgical and transcatheter interventions have their own risks and complications, despite significant advances in the safety and efficacy of these therapies. In addition, all bioprosthetic valves are subject to deterioration over time, and carry a risk of endocarditis and thromboembolic events. Anticoagulation, especially with mechanical valves, is often required and is associated with bleedingrelated complications. Therefore, the ideal timing of the procedure is best described as the point in the disease course when the benefits of valve replacement outweigh the risks of the procedure and the untreated native disease.

The choice between SAVR and TAVR must be based upon careful evaluation of clinical, anatomical, and procedural factors by the Heart Team, weighing the risks and benefits of each approach for an individual patient. The Heart Team recommendation should be discussed with the patient, who can then make an informed treatment choice. According to the 2020 American College of Cardiology Guidelines for the management of valvular heart diseases, SAVR is recommended for patients who are aged <65 years or have a life expectancy >20 years.10 In patients aged between 65 and 80 years without any anatomical contraindication for 1.

Coffey S, Roberts-Thomson R, Brown A, et al. Global epidemiology of valvular heart disease. Nat Rev Cardiol 2021;18:853–64. https://doi.org/10.1038/s41569-02100570-z; PMID: 34172950.

2. Nkomo VT, Gardin JM, Skelton TN, et al. Burden of valvular

TAVR, both SAVR and TAVR are equivalent, and the choice should be made based on Heart Team discussion (i.e. to balance expected patient longevity and valve durability) and the patient’s preferences.10 Finally, in those who are aged >80 years or younger patients, but with a short life expectancy (i.e. <10 years), transfemoral TAVR is recommended over SAVR.10 To note, the 2021 European Society of Cardiology Guidelines for the management of valvular heart diseases consider age 75 years as a cut-off point, and surgical risk (low versus high) in guiding the choice between TAVR and SAVR. Early clinical trials have established TAVR as the best option for treating patients with symptomatic severe AS who are deemed to be at moderateto-high operative risk, and who cannot otherwise undergo surgical replacement. In contrast, the use of TAVR in patients at low operative risk remained limited due to the lack of robust evidence.

In 2019, two randomized clinical trials comparing TAVR versus SAVR in low-risk AS patients were published: the PARTNER 3 trial and the Evolut Low-Risk trial.14,15 The PARTNER 3 trial revealed the superiority of TAVR over SAVR at 1 year for the primary composite outcome of mortality, stroke, and rehospitalization.15 Similarly, the Evolut Low-Risk trial showed non-inferiority of TAVR versus SAVR in the primary composite endpoint of mortality or disabling stroke at a 2-year follow-up.14 As compared with SAVR, TAVR was associated with a higher incidence of perivalvular leak, new-onset left bundle-branch block, and need for implantation, especially with the Evolut bioprosthetic valve (Medtronic).

The clinical implications of these findings will be elucidated in the followup data that will be published over the next few years. In addition, patients with complex anatomy (i.e. bicuspid aortic valve, annular calcification, etc.) were excluded from these two studies, rendering the findings not generalizable to all low-risk patients with AS. In summary, the results from these two ground-breaking trials inform us that TAVR is superior to SAVR in the short term among low-risk patients with AS. The 5- and 10-year follow-up data will generate more insights on the efficacy of TAVR in these patients, and whether this less invasive approach is a true winner when compared with SAVR.

Conclusion

AS remains the leading etiology of valvular heart diseases requiring intervention in addition to medical therapy in developed countries. Over the past 20 years, multiple innovations have improved the safety and efficacy of invasive treatments for AS, with TAVR being the most notable invention. These revolutionary changes have led to recommendations for earlier intervention and expanded use of TAVR in patients with AS across the entire spectrum of surgical risk. Yet, the durability of transcatheter prosthetic valves and long-term outcomes following the procedure remain unknown. Within this context, well-conducted clinical trials with long-term follow-up are needed to better understand the optimal management of patients with AS in terms of optimal medical therapy, timing, and mode of intervention. Furthermore, current and future studies should explore the use of TAVR in patients with asymptomatic severe AS, patients with severe stenotic bicuspid aortic valve, and patients with moderate AS along with heart failure with reduced ejection fraction.

heart diseases: a population-based study. Lancet 2006;368:1005–11. https://doi.org/10.1016/S01406736(06)69208-8; PMID: 16980116.

3. Pawade TA, Newby DE, Dweck MR. Calcification in aortic stenosis: the skeleton key. J Am Coll Cardiol 2015;66:561–77.

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https://doi.org/10.1016/j.jacc.2015.05.066; PMID: 26227196.

4. Mohty D, Pibarot P, Després JP, et al. Association between plasma LDL particle size, valvular accumulation of oxidized LDL, and inflammation in patients with aortic stenosis.

Arterioscler Thromb Vasc Biol 2008;28:187–93. https://doi.

Current Strategies in the Management of Aortic Stenosis org/10.1161/ATVBAHA.107.154989; PMID: 17975118.

5. Kranzhöfer R, Schmidt J, Pfeiffer CA, et al. Angiotensin induces inflammatory activation of human vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 1999;19:1623–9. https://doi.org/10.1161/01.atv.19.7.1623; PMID: 10397679.

6. Yan AT, Koh M, Chan KK, et al. Association between cardiovascular risk factors and aortic stenosis: the CANHEART aortic stenosis study. J Am Coll Cardiol 2017;69:1523–32. https://doi.org/10.1016/j.jacc.2017.01.025; PMID: 28335833.

7. Marquis-Gravel G, Redfors B, Leon MB, Généreux P. Medical treatment of aortic stenosis. Circulation 2016;134:1766–84. https://doi.org/10.1161/CIRCULATIONAHA.116.023997; PMID: 27895025.

8. Cowell SJ, Newby DE, Prescott RJ, et al. A randomized trial of intensive lipid-lowering therapy in calcific aortic stenosis.

N Engl J Med 2005;352:2389–97. https://doi.org/10.1056/

NEJMoa043876; PMID: 15944423.

9. Rossebø AB, Pedersen TR, Boman K, et al. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med 2008;359:1343–56. https://doi.org/10.1056/ NEJMoa0804602; PMID: 18765433.

10. Otto CM, Nishimura RA, Bonow RO, et al. ACC/AHA guideline for the management of patients with valvular heart disease: executive summary: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice guidelines. J Am Coll Cardiol 2021;77:450– 500. https://doi.org/10.1016/j.jacc.2020.11.035; PMID: 33342587.

11. Vahanian A, Beyersdorf F, Praz F, et al. 2021 ESC/EACTS guidelines for the management of valvular heart disease.

Eur Heart J 2022;43:561–632. https://doi.org/10.1093/ eurheartj/ehab395; PMID: 34453165.

12. Bull S, Loudon M, Francis JM, et al. A prospective, double-

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blind, randomized controlled trial of the angiotensinconverting enzyme inhibitor ramipril in aortic stenosis (RIAS trial). Eur Heart J Cardiovasc Imaging 2015;16:834–41. https:// doi.org/10.1093/ehjci/jev043; PMID: 25796267.

13. Schwarz F, Baumann P, Manthey J, et al. The effect of aortic valve replacement on survival. Circulation 1982;66:1105–10. https://doi.org/10.1161/01.cir.66.5.1105; PMID: 7127696.

14. Popma JJ, Deeb GM, Yakubov SJ, et al. Transcatheter aorticvalve replacement with a self-expanding valve in low-risk patients. N Engl J Med 2019;380:1706–15. https://doi. org/10.1056/NEJMoa1816885; PMID: 30883053.

15. Mack MJ, Leon MB, Thourani VH, et al. Transcatheter aorticvalve replacement with a balloon-expandable valve in lowrisk patients. N Engl J Med 2019;380:1695–705. https://doi. org/10.1056/NEJMoa1814052; PMID: 30883058.

REVIEW

Interventional Cardiology

Age Considerations in the Invasive Management of Acute Coronary Syndromes Mansi Oberoi, MD, ,1 Nitesh Ainani, MD,2 J Dawn Abbott, MD, ,3 Mamas A Mamas, MBBCh, ,4 and Poonam Velagapudi, MD,

2

1. Department of Internal Medicine, Sanford School of Medicine, University of South Dakota, Sioux Falls, SD; 2. Division of Cardiovascular Medicine, University of Nebraska Medical Center, Omaha, NE; 3. Department of Internal Medicine, Division of Cardiology, The Warren Alpert Medical School of Brown University, Providence, RI; 4. Keele Cardiovascular Research Group, Institute of Applied Clinical Sciences, University of Keele, Stoke-on-Trent, UK

Abstract

The elderly constitute a major proportion of patients admitted with acute coronary syndrome (ACS) in the US. Due to pre-existing comorbidities, frailty, and increased risk of complications from medical and invasive therapies, management of ACS in the elderly population poses challenges. In patients with ST-elevation MI, urgent revascularization with primary percutaneous coronary intervention remains the standard of care irrespective of age. However, an early invasive approach in elderly patients with non-ST-elevation MI is based on individual evaluation of risks versus benefits.

In this review, the authors discuss the unique characteristics of elderly patients presenting with ACS, specific geriatric conditions that need to be considered while making treatment decisions in these situations, and available evidence, current guidelines, and future directions for invasive management of elderly patients with ACS.

Keywords

Acute coronary syndrome, non-ST-elevation MI, ST-elevation MI, elderly, invasive therapy Disclosure: JDA has served as a consultant for Medtronic and Philips and has conducted research for Boston Scientific, CSL Behring and MicroPort. PV has served on the Abiomed speakers bureau and advisory board for women’s health, OpSens speakers bureau, and Sanofi advisory board. All other authors have no conflicts of interest to declare.

Received: October 3, 2021 Accepted: February 23, 2022 Citation: US Cardiology Review 2022;16:e14. DOI: https://doi.org/10.15420/usc.2021.29 Correspondence: Poonam Velagapudi, Division of Cardiovascular Medicine, University of Nebraska Medical Center, 982265 Nebraska Medical Center, Omaha, NE 68198.

E: poonam.velagapudi@unmc.edu Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Due to increasing life expectancy and age being a significant factor in the development of coronary artery disease (CAD), people >65 years now constitute the majority of patients presenting with acute coronary syndromes (ACS). In the US more than 780,000 patients experience an ACS event each year, of whom 70% have non-ST-elevation MI (NSTEMI).1 About 60–65% of MI occurs in patients ≥65 years and 28–33% in patients ≥75 years of age.2 Furthermore, 80% of deaths related to MI occur in patients ≥65 years of age. Despite these numbers, elderly patients, particularly those aged ≥75 years have been underrepresented in ACS trials.

The management of ACS in the elderly can be challenging because they frequently present with atypical symptoms that delay diagnosis, preexisting multiple comorbidities, frailty, and increased risk of complications.3 Though an early invasive approach in high-risk ACS can result in a significant improvement in cardiovascular outcomes, elderly patients are often treated conservatively with medical management due to local physician practices, a dearth of evidence from randomized controlled trials (RCTs), and a lack of age-specific guidelines.4–7 Management decisions are therefore usually based on physician judgment and patient preference with significant consideration given to quality of life, risks and benefits of an invasive approach, life expectancy, and cognitive and functional status. In this review, we discuss the characteristics of elderly patients presenting with ACS, specific geriatric conditions that need to be considered while making treatment decisions in these situations, and

available evidence, guidelines, and future directions for invasive management of elderly patients with ACS.

Characteristics of Elderly Patients with Acute Coronary Syndrome

Age predisposes to the development of CAD due to various biological and functional changes, including increased oxidative stress, apoptosis, inflammation, and genomic instability that contribute to increased vascular stiffness, endothelial dysfunction, and thrombogenicity.3,8 Moreover, several established risk factors for CAD, including hypertension, hyperlipidemia, diabetes, and renal dysfunction are common in elderly patients (Table 1) leading to ACS being more common in this age group.3 The diagnosis and management of ACS in elderly patients is often challenging due to atypical presentation, polypharmacy, comorbidities, cognitive and functional status, and socio-economic factors.3,9 Atypical chest pain and dyspnea are common, while syncope, fatigue and confusion are less frequent presenting symptoms among elderly patients with ACS. Elderly patients who take multiple medications are prone to an increased risk of adverse drug interactions, and hence it is important to balance risks of polypharmacy with the benefit of taking guidelinedirected medications proven to be of benefit in the elderly.10 Multiple comorbidities commonly seen in elderly patients, such as chronic kidney disease (CKD), peripheral arterial disease (PAD), dementia, heart failure

© RADCLIFFE CARDIOLOGY 2022 www.USCjournal.com

ACS in the Elderly Table 1: Acute Coronary Syndrome in Elderly Patients: Risk Factors, Clinical Consideration, and Management Biological risk factors for CAD • Mitochondrial oxidative stress • Genomic instability • Epigenetic changes • Endothelial dysfunction • Inflammation • Impaired hemostasis

Nutritional status is another important consideration in the elderly since malnutrition adversely affects the prognosis of elderly patients and is often unrecognized and therefore untreated.25 A multi-center study showed that around 71% of hospitalized older patients are at nutritional risk or are malnourished which is associated with increased mortality.26 Another study classified 908 older patients hospitalized with ACS (mean age 82 ± 6 years) into malnutrition (4%), at high-risk of malnutrition (40%) and normal nutrition (56%) using the Mini Nutritional Assessment-Short Form (MNA-SF) score. During a 288-day follow-up period, 31%, 19% and 3% mortality rates were seen in malnourished subjects, at-risk patients and in patients with a normal nutritional status, respectively (p<0.001).

MNA-SF was found to be an independent predictor of all-cause mortality (HR 0.76; 95% CI [0.68–0.84]) in elderly ACS patients.27 As such, it is important that targeted nutritional interventions and rehabilitation programs that may improve the outcome in elderly patients with ACS be investigated in clinical trials and appropriate consideration be given to nutritional status while making decisions about management.

Clinical considerations • Atypical signs/symptoms • Polypharmacy and drug interactions • Frailty • Comorbidities: hypertension, diabetes, hyperlipidemia, CKD, anemia • Nutritional status • Ischemic and bleeding risk • Cognitive and functional status • Delirium • Goals of care and quality of life Management STEMI • Urgent revascularization (PCI or CABG) • Fibrinolysis if primary PCI not available NSTEMI • Individual assessment of risks and benefits of revascularization • Various scores/index can be used: - Ischemic and bleeding risk assessment: GRACE, TIMI, CRUSADE bleeding score - Frailty assessment: clinical frailty scale, FRAIL - Nutritional status: Mini Nutritional Assessment-Short Form - Cognitive status: MMSE - Quality of life: Seattle Angina Questionnaire:

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patients undergoing percutaneous coronary intervention (PCI) showed frailty to be associated with worse outcomes following the intervention.20–24 Thus, the assessment of frailty in elderly patients with ACS is essential to help physicians appraise the comprehensive prognostic risk of implementing appropriate management strategies.

Early invasive approach Guideline-directed medical therapy

ACS = acute coronary syndrome; CABG = coronary artery bypass graft; CAD = coronary artery disease; CKD = chronic kidney disease; CRUSADE = Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the ACC/AHA Guidelines; GRACE = Global Registry of Acute Coronary Events; MMSE = mini-mental state exam; NSTEMI = non-ST-elevation MI; PCI = percutaneous coronary intervention; STEMI = ST-elevation MI; TIMI = thrombolysis in MI.

(HF) or MI have a negative prognostic effect in patients with ACS.11 Diminished organ reserves and altered cognitive and functional status influence disease presentation, treatment, and recovery.12 In addition, older people living in impoverished and rural areas are more likely to have a delayed presentation, and may be farther away from medical facilities which delays timely care.13 There are several other important factors related to older age that need to be considered in patients presenting with ACS. Frailty, a state of diminished physiological reserve and increased vulnerability for poor resolution of homeostasis after a stressor event is seen more often in the elderly.14 In the US, prevalence of frailty ranges from 4–16% in men and women ≥65 years of age.15,16 In the 90+ study by Lee et al., prevalence of frailty was 24% and 39.5% among those aged 90–94 years and ≥95 years, respectively.17 Frailty is associated with increased risk of procedural complications, falls, disability, and is a strong independent predictor of 1-year mortality in elderly patients with ACS.18 A meta-analysis of 15 studies showed that frailty in elderly ACS patients increased the risk of all-cause mortality, any-type of cardiovascular disease, major bleeding and hospital readmissions by 2.65, 1.54, 1.51 and 1.51-fold, respectively.19 Several studies involving elderly ACS

Delirium, characterized by acute decline in attention and cognitive dysfunction, is a frequent complication during hospitalization in elderly patients associated with poor clinical outcomes and increased mortality.28 The incidence of delirium is reported to be 17.2% in patients ≥75 years admitted for acute cardiac diseases.29 Another study including 527 octogenarians with NSTEMI had a 7% incidence of delirium during hospitalization. The study also found delirium to be independently associated with mortality (HR 1.47, 95% CI [1.02–2.13]; p=0.04) and bleeding events (OR 2.87; 95% CI [1.98–4.16]; p<0.01) at 6 months.30 Thus, effective measures to prevent delirium, such as frequent orientation, cognitive stimulation, environmental modification and non-pharmacological sleep aids, early mobilization, visual and hearing aids, and avoiding medications precipitating delirium, especially benzodiazepines should be implemented in hospitalized elderly patients with ACS.31 Contrast-induced nephropathy (CIN), a form of acute kidney injury that occurs shortly after administration of iodinated contrast, is prevalent in elderly patients. Among at-risk patients, especially those with diabetes and CKD, the risk following coronary angiography with or without intervention is reported to be 10–30%. For all at-risk patients, preventive measures including use of low-osmolar or iso-osmolar contrast media with lower doses, hydration with 1 ml/kg/h of isotonic saline 6–12 hours pre-procedure, intra-procedure, and 6–12 hours post-procedure may be implemented.32,33 Finally, elderly patients with ACS are more likely to present with NSTEMI compared with ST-elevation MI (STEMI) and have higher rates of type 2 MI due to myocardial oxygen supply and demand mismatch. They are at increased risk of thrombotic, bleeding and PCI complications, and the rate of successful revascularization is lower due to more complex coronary disease.34 Given the high risk of bleeding complications, these patients need a carefully chosen anti-thrombotic with dose adjustment based on body weight and renal function.

ST-elevation MI

Studies have shown that 30% of patients admitted with STEMI are 75 years or older.2 There is an annual increase of >160,000 octogenarians in the

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ACS in the Elderly Table 2: Scores for Predicting Ischemic and Hemorrhagic Risks in Non-ST Elevation MI Score

Components of Score

Assessment

GRACE risk score 2.078

Age, heart rate, SBP, creatinine, cardiac arrest at admission, ST-segment deviation on ECG, abnormal cardiac enzymes, Killip class (signs/symptoms)

Estimates risk of in-hospital, 6-month mortality in ACS patients

Age ≥65, ≥3 CAD risk factors, known CAD, ASA use in past 7 days, severe angina (≥2 episodes in 24 h), ECG ST changes ≥0.5 mm, positive cardiac marker

Predicts 14-day all-cause death, new or recurrent MI, or severe recurrent ischemia requiring urgent revascularisation

Heart rate, SBP, hematocrit, creatinine clearance, sex, signs of congestive heart failure at presentation, history of vascular disease, history of diabetes

Predicts probability of major bleeding after NSTEMI

TIMI risk score79

CRUSADE bleeding score80

Score • 1–108 • 109–140 • 141–372 Score • 1–88 • 89–118 • 119–263

Score • 0–1 • 2 • 3 • 4 • 5 • 6–7 Score • 1–20 • 21–30 • 31–40 • 41–50 • >50

Risk category • Low • Intermediate • High Risk category • Low • Intermediate • High

In-hospital death (%) • <1 • 1–3 • >3 6-month post-discharge death (%) • <3 • 3–8 • >8

14-day event rate (%) • 4.7 • 8.3 • 13.2 • 19.9 • 26.2 • At least 40.9 Risk stratification • Very low • Low • Moderate • High • Very high

Major bleeding risk (%) • 3.1 • 5.5 • 8.6 • 11.9 • 19.5

ACS = acute coronary syndrome; AHA = American Heart Association; ASA = -acetylsalicylic acid; CAD = coronary artery disease; CRUSADE = Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the ACC/AHA Guidelines; GRACE = Global Registry of Acute Coronary Events; NSTEMI = non-ST elevation MI; SBP = systolic blood pressure; TIMI = thrombolysis in MI.

US, and the trend is estimated to increase by fivefold by 2040.35 Thus, the proportion of elderly patients with STEMI is also expected to increase over time. STEMI care in the elderly can often be challenging and delayed due to longer symptom onset to first medical contact, atypical symptoms, and ECG findings of STEMI being masked by pre-existing ECG changes, such as baseline left ventricular hypertrophy, changes from prior MI, conduction system disease with bundle branch block, or AF.2,36 Despite these challenges and high acuity, studies show elderly STEMI patients, including the very elderly ≥85 years, have reasonable long-term survival and excellent quality of life when treated aggressively with reperfusion therapy.37 Even patients >90 years treated with primary PCI have two- to threefold lower rate of inhospital and 12-month mortality compared with those treated medically.5,6 Early revascularization in elderly patients had an adjusted survival benefit as compared to delayed or no revascularization in the non-randomized SHOCK registry.38 Primary PCI is also superior to fibrinolysis, with the TRIANA trial demonstrating that PCI was superior to fibrinolysis (OR 0.64; 95% CI [0.45–0.91]) in reducing the composite of all-cause mortality, re-infarction or stroke at 30 days.2,39 When primary PCI is not readily available, the patient should be treated with thrombolysis, as supported by the STREAM trial.40 Thus, in elderly patients with STEMI, primary PCI is the preferred reperfusion strategy regardless of age, with fibrinolysis reserved for those patients where primary PCI is not immediately available. This recommendation is in accordance with 2013 American College of Cardiology (ACC)/American Heart Association (AHA) and 2017 European Society of Cardiology (ESC) guidelines (level of evidence A).41,42 Despite this benefit, elderly patients who are frail or have comorbidities, such as CKD, are often managed medically, leading to an increased risk of mortality.43

Elderly patients presenting with STEMI are more likely to have multivessel coronary disease compared to younger patients.44 The COMPLETE trial showed that multivessel PCI was superior to culprit-only PCI in reducing the risk of the composite of cardiovascular death, ischemia-driven revascularization, or MI in STEMI patients. However, these results cannot be generalized to elderly patients as a whole since the average age of patients enrolled in the COMPLETE trial was 62 years with <40% of patients being >65 years.45 A sub-study of DANAMI-3-PRIMULTI trial and a few other studies demonstrated no significant benefit to prophylactic complete revascularization of non-culprit lesions in elderly STEMI patients after treatment of the culprit lesion.46–48 Further RCTs including elderly patients are needed to understand the best management plan in elderly patients with STEMI and multivessel CAD.

Non-ST-elevation MI

The majority of patients admitted with NSTEMI are ≥70 years.49 The United Nations has projected that the proportion of the global population aged ≥80 years will triple over the next 20 years, and thus the proportion of elderly patients presenting with NSTEMI is expected to increase.50 The management of NSTEMI in elderly patients is based on the individual assessment of ischemic and bleeding risk. Age is an independent risk factor for both thrombotic and bleeding events in the setting of ACS.36 Several prognostic scores have been developed to predict the ischemic and hemorrhagic risks in patients with NSTEMI (Table 2). Risk stratification using these scores helps to make appropriate invasive or conservative management decisions. The Global Registry of Acute Coronary Events (GRACE) score has been validated to estimate the risk and survival in the acute phase of ACS in nonagenarians.51 The Thrombolysis in MI (TIMI) risk

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ACS in the Elderly Table 3: Randomized Controlled Trials Comparing Invasive and Conservative Groups in Elderly Study

Inclusion Criteria

Number of Mean Age Patients (IS; CS) (Years)

Follow-up Primary Endpoint

Outcomes

TACTICS-TIMI 18, 200456

Age >18 years with subgroup of ≥65 years

n=2,220 (1,114; 1,106) Age ≥65 n=962 (491; 471)

6 months

Early IS significantly improved ischemic outcomes compared with CS but at the expense of increased risk of major bleeding

72.9 ± 5.6

30-day and 6-month mortality, non-fatal MI, rehospitalization, stroke, and hemorrhagic complications

For >65 years, there was an absolute reduction of 4.8% (8.8% versus 13.6%; p=0.018) in death or MI at 6 months with IS compared to CS For >75 years, there was an absolute reduction of 10.8% (10.8% versus 21.6%, p=0.016) in death or MI at 6 months with IS compared with CS. The major bleeding rates were higher with IS (16.6% vs 6.5%; p=0.009) compared with CS Italian ACS elderly 201254 Age ≥75 years

313

82.5

1 year

Composite of all-cause mortality, non-fatal MI, disabling stroke, repeat hospital stay for cardiovascular causes or severe bleeding

There was no difference in the primary endpoint between IS and CS (HR 0.80; 95% CI [0.53–1.19]; p=0.26) in the overall study population There was a significant reduction in primary endpoint with IS compared with CS in patients with elevated troponin on admission (HR 0.43; 95% CI [0.23–0.80])

MOSCA 201655

Age ≥70 years 106 (52; 54) with at least two significant comorbidities

IS: 81 ± 5 CS: 83 ± 6

Median 2.5 years

Composite of all-cause mortality, There was no difference in primary reinfarction, and readmission for end point between IS and CS at cardiac cause long-term follow-up (2.5 years; HR 0.77; 95% CI: [0.48–1.24]; p=0.29

After Eighty 20167

Age ≥80 years

Median age Median 1.53 IS: 84.7 years (80–93; 84.7) CS: 84.9 (80–94)

Composite of MI, need for urgent IS was superior than CS in reducing revascularization, stroke, and the primary endpoint (40.6% versus death 61.4%; HR 0.53; 95% CI [0.41–0.69]; p<0.0001

457

There was no difference in bleeding complications between IS and CS CS = conservative strategy; IS = invasive strategy

score was shown to be a robust predictor of both in-hospital and postdischarge mortality in elderly women in a study by Furnaz et al.52 The predictive performance of the Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the ACC/AHA Guidelines (CRUSADE) bleeding score is less accurate in elderly patients than younger patients with ACS.53 There are several RCTs that compare outcomes between invasive and conservative approaches for ACS in the elderly population (Table 3). An Italian ACS study including patients ≥75 years with NSTEMI found no significant benefit of an early aggressive approach within 72 hours as compared to an initial conservative strategy in reducing the composite primary endpoint of death, MI, stroke, and repeat hospital stay for cardiovascular causes or severe bleeding within 1 year. However, in subgroup analysis, patients with elevated troponin levels had a lower primary endpoint from early invasive strategy (HR 0.43; 95% CI [0.23– 0.80]).54 The MOSCA trial is the first RCT which compared the outcomes of routine invasive versus conservative strategy in NSTEMI patients ≥70 years with at least two comorbidities (PAD, cerebral vascular disease, dementia, chronic pulmonary disease, CKD, or anemia). It reported that invasive management did not modify long-term outcomes (all-cause

mortality, reinfarction and readmission for cardiac cause) during the 2.5-year follow-up in elderly patients compared to a conservative approach (coronary angiogram only if recurrent ischemia or HF).

However, an invasive approach had better short-term outcomes at 3 months in terms of mortality (HR 0.348; 95% CI [0.122–0.991]; p=0.048), and mortality or ischemic events (HR 0.432, 95% CI [0.190–0.984]; p=0.046).55 The TACTICS-TIMI 18 trial found that early invasive strategy within 4 to 48 hours had better outcomes as compared to conservative management with an absolute reduction of 4.8% in death or MI at 6 months among NSTEMI patients >65 years and absolute reduction of 10.8% among patients >75 years. But major bleeding rates were higher with an invasive approach in patients >75 years (16.6% versus 6.5%; p=0.009).56 The After Eighty study including NSTEMI patients ≥80 years showed that an invasive approach was superior to a conservative strategy in reducing rates of MI, urgent revascularization, stroke, and death (40.6% versus 61.4%; HR 0.53; 95% CI [0.41–0.69]), with no significant difference in the rates of major and minor bleeding during a median of 1.53 years followup.7 Similar results were seen in the SENIOR-NSTEMI trial that estimated mortality in a non-randomized, propensity-matched analysis in NSTEMI

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ACS in the Elderly patients ≥80 years. The adjusted cumulative 5-year mortality was 36% in patients receiving invasive management within 3 days of peak troponin as compared to 55% in patients with a non-invasive approach (adjusted HR 0.68; 95% CI [0.55–0.84]).57 The SENIOR-RITA (NCT03052036) is an ongoing multicenter, open-label randomized trial comparing invasive and conservative strategies and the time to cardiovascular death or nonfatal MI within 1 year in type 1 NSTEMI patients ≥75 years. Overall, these RCTs included a very selective population, limiting the generalization of these results to the entire elderly population. Moreover, some of these trials studied the elderly population as the subgroup of a larger cohort and hence analysis may be underpowered for certain endpoint comparisons.

Table 4: Special Considerations During Invasive Approach for Acute Coronary Syndrome in Elderly Patients

A meta-analysis of six trials by Reano et al. compared the effectiveness of an early invasive strategy within 48–72 hours to a conservative approach in NSTEMI patients ≥65 years. Of a total of 3,768 patients, 1,986 were assigned to the invasive strategy and 1,782 to the conservative treatment group. The invasive strategy was defined as intervention either by PCI or coronary artery bypass graft within 48–72 hours of initial evaluation. The results showed a significant reduction in the need for revascularization during an average follow-up period of 2 years in the invasive group (2%) compared to the conservative treatment group (8%; RR 0.29; 95% CI [0.14–0.59]). However, there was no significant difference in the rate of all-cause mortality, cardiovascular mortality, stroke, and MI between the two groups with significant heterogeneity. The small number of events and sample sizes in addition to the different age cut-offs and different follow-up periods in the included studies may have been the sources of heterogeneity for death and MI outcomes.58

•

Another meta-analysis involving 13 studies (four RCTs and nine observational studies) by Ma et al. including a total of 832,007 elderly NSTEMI patients >75 years showed a significant decrease in the risk of death at follow-up from 6 months to 5 years in patients treated with an invasive approach compared to conservative treatment (RR 0.65; 95% CI [0.59–0.73]; p<0.001). This was mostly seen in observational studies.

However, there was a significant increase in bleeding risk in hospital patients treated with invasive strategy compared to conservative approach but no difference in major bleeding was observed between the two groups (RR 1.78; 95% CI [0.31–10.13]; p=0.514).59 In a meta-analysis of eight trials including 5,324 patients, overall, there was no significant mortality reduction in the early invasive group compared with the delayed invasive group. However, lower mortality was found with the early invasive strategy in some high-risk patients including patients with elevated cardiac biomarkers at baseline (risk reduction 24%), diabetes (risk reduction 33%), GRACE risk score >140 (risk reduction 30%), and those aged ≥75 years (risk reduction 35%).4 Based on available data, we recommend an early invasive approach in elderly patients with high-risk NSTEMI, considering the individual risks and benefits of revascularization in accordance with the 2014 AHA/ACC (level of evidence A) and 2020 ESC guidelines (level of evidence B).1,60

Special Considerations During Invasive Management of Elderly Patients with Acute Coronary Syndrome

There are several important things to consider for elderly patients undergoing PCI for ACS (Table 4). First, elderly patients with ACS have an increased risk of bleeding with use of anti-thrombotic therapies from the PCI access site, and are at risk of hemorrhagic stroke from fibrinolysis.2 On the other hand, under-prescription of appropriate anti-thrombotic agents in elderly patients increases the risk of ischemic events. Though

• • • • • • •

Shorter DAPT duration (3–6 months) post-PCI in HBR patients For patients requiring OAC, a P2Y12 inhibitor with OAC should be used without aspirin Prasugrel should be avoided due to increased bleeding risk Clopidogrel preferred in HBR patients Transradial approach preferred over transfemoral New generation drug-eluting stent preferred over bare metal stent Delirium prevention during hospitalization: frequent orientation, cognitive stimulation, environmental modification, non-pharmacological sleeping aids, early mobilization and avoid benzodiazepines Contrast-induced nephropathy prevention: adequate hydration, using low-osmolar or iso-osmolar contrast media with lower doses

Secondary prevention • Adequate control of cardiovascular risk factors: hypertension, diabetes, hyperlipidemia • Statins should be used in patients with clinical ASCVD • Cardiac rehabilitation ASCVD = atherosclerotic cardiovascular disease; DAPT = dual antiplatelet therapy; HBR = high bleeding risk; OAC = oral anticoagulation; PCI = percutaneous coronary intervention.

not specific to the elderly, the Predicting Bleeding Complications in Patients Undergoing Stent Implantation and Subsequent Dual Antiplatelet Therapy (PRECISE-DAPT) score can be used to predict the risk of bleeding in ACS patients on dual antiplatelet therapy (DAPT) post-PCI.61 A more conservative approach is recommended for patients who score ≥25. A study by Guerrero et al. showed that elderly patients ≥75 years have PRECISE-DAPT values above the cut-off point for high bleeding risk and recommend using different cut-off values for them.62 A shorter duration of 3–6 months instead of 12 months DAPT may be considered for elderly patients at high risk of bleeding post-PCI with newer generation drugeluting stents (DES). For patients requiring oral anticoagulation (OAC) post-PCI, a P2Y12 inhibitor with OAC should be used without aspirin to reduce the risk of bleeding.63 The right choice of P2Y12 inhibitor in elderly patients post-PCI is important to maximize ischemic benefit and reduce bleeding risk. Prasugrel must be avoided in elderly patients ≥75 years with ACS undergoing PCI due to the increased risk of bleeding, as seen in the TRITON TIMI 38 trial.64 The Elderly ACS 2 trial, which aimed to demonstrate superiority of lowdose prasugrel (5 mg) over clopidogrel (75 mg) in elderly patients with ACS, was prematurely interrupted because of futility for efficacy.65 Although, in the PLATO trial, the net clinical benefit favored the use of ticagrelor over clopidogrel even in the elderly despite increased bleeding risk, elderly patients ≥75 years with ACS constituted only 15% of the overall ACS trial population.66 Moreover, it is possible that patients with lower bleeding risk may have been included in the trial and hence overall net clinical benefit of ticagrelor compared with clopidogrel in elderly patients is not well defined. The POPular AGE trial showed that in patients ≥70 years with NSTEMI, clopidogrel is a favorable alternative to ticagrelor, especially where there is a high bleeding risk, because of reduced bleeding events without an increase in the combined endpoint of allcause death, MI, stroke, and bleeding.67 Thus, clopidogrel may be the P2Y12 of choice in elderly patients with ACS at high bleeding risk.

Second, although there is increased usage of the transradial approach (TRA) for PCI, its adoption is lowest in elderly patients despite similar reductions in mortality and major adverse cardiac and cerebrovascular

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ACS in the Elderly events outcomes (MACCE) associated with TRA use compared with younger patients.68 A meta-analysis of 17 studies showed decreased risk of stroke, vascular complications, and mortality benefit with TRA for PCI in elderly patients with STEMI.69 Although the access site crossover rate is higher in elderly people with TRA compared with the transfemoral approach (TFA), mainly due to an increased level of vascular calcification and arterial tortuosity, its use remains acceptably low considering the advantages associated with TRA.70 Given reduced bleeding and mortality with TRA compared with TFA, it should be the preferred access choice in elderly ACS patients undergoing PCI. Third, new generation DES must be preferred over bare metal stents (BMS) in elderly ACS patients post-PCI. The SENIOR RCT including patients ≥75 years undergoing PCI showed that DES and a short duration of DAPT have better outcomes for all-cause mortality, MI, stroke, and ischemiadriven target lesion revascularization at 1 year as compared to BMS with similar duration of DAPT (RR 0.71; 95% CI [0.52–0.94]; p=0.02).71 Fourth, elderly patients should be recruited in cardiac rehabilitation (CR) or a secondary prevention program after ACS. CR, a comprehensive lifestyle program promoting physical activity, education, diet, weight control, risk reduction and adherence reduces cardiovascular morbidity and mortality, and improves exercise capacity and quality of life in elderly patients with cardiovascular disease. For frail elderly patients, emphasis should be given to their physical efficiency assessed by aerobic capacity (cardiopulmonary exercise test, and 6-minute walking test), on functional autonomy and on improvement of muscular strength, balance and flexibility (short physical performance battery).72 Tailored CR programs based on individual functional status are needed to manage the complexities of elderly patients with frailty. MACRO (NCT03922529) is an ongoing RCT that is addressing issues related to aging as a means to better facilitate CR. Finally, pharmacological secondary prevention is an important part of management of elderly patients post ACS. Of note, there has been a decline in the rate of statin use in elderly patients post ACS with increasing age, particularly in those >75 years, reflecting differences in both prescribing and compliance.73 According to 2018 ACC/AHA guidelines, (level of evidence B–R) it is reasonable to initiate moderate or highintensity statin and to continue high intensity statin (level of evidence C– LD) in elderly patients (>75 years) with clinical atherosclerotic cardiovascular disease (ASCVD) for secondary prevention (class IIa recommendation).74 The decline in statin use in the elderly may be due to the adverse effects of statin especially myopathy which is more common in elderly patients due to increased drug interactions and comorbidities.

In such cases, using a lower dose, switching to an alternative statin or 1.

Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC guideline for the management of patients with non-STelevation acute coronary syndromes. Circulation 2014;130:e344–426. https://doi.org/10.1161/ CIR.0000000000000134; PMID: 25249585.

2. Alexander KP, Newby LK, Armstrong PW, et al. Acute coronary care in the elderly, part II: ST-segment-elevation myocardial infarction: a scientific statement for healthcare professionals from the American Heart Association council on clinical cardiology: in collaboration with the Society of Geriatric Cardiology. Circulation 2007;115:2570–89. https:// doi.org/10.1161/CIRCULATIONAHA.107.182616; PMID: 17502591.

3. Madhavan MV, Gersh BJ, Alexander KP, et al. Coronary artery disease in patients ≥80 years of age. J Am Coll Cardiol 2018;71:2015–40. https://doi.org/10.1016/j.jacc.2017.12.068; PMID: 29724356.

4. Jobs A, Mehta SR, Montalescot G, et al. Optimal timing of an

alternate-day dosing can be used which has shown equal efficacy in lowering LDL cholesterol with less risk of myopathy.75 Adequate control of blood pressure and diabetes is essential for secondary cardiovascular prevention. According to the 2017 ACC/AHA guideline on hypertension, (class IIa, level of evidence C – expert opinion) clinical judgement, patient preference, and a team-based approach to assess risks and benefits is reasonable for decisions regarding intensity of blood pressure-lowering therapy and choice of antihypertensive drugs for elderly patients ≥65 years with hypertension, a high burden of comorbidity, and limited life expectancy.76 Similarly, lenient HbA1c goals of 7–7.9% are recommended in elderly people ≥65 years, especially with frailty and multiple comorbidities.77

Current Guidelines and Future Guidance

The 2013 ACC/AHA and 2017 ESC guidelines do not include an age criterion for urgent reperfusion in STEMI.41,42 Thus, elderly patients with STEMI are treated with primary PCI where indicated regardless of age.

The 2014 ACC/AHA guidelines recommend that older patients with NSTEMI should be treated with guideline-directed medical therapy, an early invasive approach and revascularization as appropriate.1 The 2020 ESC guidelines recommend the management of elderly patients with NSTEMI should be based on evaluation of ischemic and bleeding risks, life expectancy, presence of other comorbidities, the need for non-cardiac surgery, quality of life, presence or absence of frailty, cognitive status and functional impairment, values and preferences of patients, as well as the estimated risks and benefits of revascularization.60 Despite these guidelines, elderly patients are less likely to undergo invasive procedures compared to the younger population due to concerns of increased risk of complications, and larger RCTs evaluating early invasive therapies are needed in elderly patients with ACS while accounting for their comorbidities, functional status, and quality of life.

Conclusion

Older people constitute an increasing proportion of patients presenting with ACS. Their management is often challenging due to several factors including increased risk of complications. Urgent reperfusion with primary PCI is the standard of care in patients with STEMI irrespective of age.

However, in elderly patients with NSTEMI, management depends on individual risk assessment. Recent studies have shown improved cardiovascular outcomes from an early invasive approach in these patients. However, these results are not generalizable to all elderly patients due to the very selective patient population included in these trials and confounding due to comorbidities and frailty. Future clinical trials including these parameters are needed to establish the definitive standard of care for management of elderly patients with NSTEMI.

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