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Volume 14, 2020

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Editor-in-Chief

Deputy Editor-in-Chief

Ankur Kalra, MD, FACP, FACC, FSCAI

Bill Gogas, MD, PhD

Case Western Reserve University School of Medicine, Cleveland, OH

Nanjing University, Jiangsu, China

Section Editor (Interventional/Structural)

Section Editor (Imaging)

Section Editor (Preventive Cardiology)

Rishi Puri, MD, PhD, FRACP

Akhil Narang, MD, FACC

Aditya Khetan, MD

Cleveland Clinic, Cleveland, OH

Northwestern University, Chicago, IL

Case Western Reserve University, Cleveland, OH

Section Editor (Electrophysiology)

Section Editor (Heart Failure)

Section Editor (Heart Failure)

Sourbha S Dani, MD, FACC

Amin Yehya, MD, MS, FACC, FHFSA

Andrew J Sauer, MD

Eastern Maine Medical Center, Bangor, ME

Sentara Heart, Norfolk, VA

The University of Kansas Medical Center, Kansas City, KS

Associate Editors Sahil Khera MD, MPH

Yogesh Reddy, MD, MSc

Bruce Stambler, MD

Columbia University, New York, NY

Mayo Clinic, Rochester, MN

Piedmont Healthcare, Atlanta, GA

Chad A Kliger, MD

Rajalakshmi Santhanakrishnan, MD, MBBS

Lenox Hill Heart and Vascular Institute, New York, NY

Wright State University, Dayton, OH

Editorial Board Ralph G Brindis, MD

University of California, San Francisco, CA

Leo Buckley, PharmD

Virginia Commonwealth University, Richmond, VA

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

Gregory J Dehmer, MD, MACC, FACP, FAHA, MSCAI Texas A&M University College of Medicine, Bryan, TX

NA Mark Estes III, MD

Tufts University School of Medicine, Boston, MA

Michael R Gold, MD

Duane Pinto, MD, MSc

Medical University of South Carolina, Charleston, SC

Harvard Medical School, Boston, MA

Dinesh K Kalra, MD, FACC, FSCCT, FSCMR

Krishna Pothineni, MD

Rush University Medical Center, Chicago, IL

University of Arkansas for Medical Sciences, Little Rock, AR

Morton J Kern, MD

Rahul Sharma, MD, FACP, FACC, FSCAI

University of California at Irvine, Orange, CA

Virginia Tech Carilion School of Medicine, Roanoke, VA

Jackson J Liang, MD, DO

W Douglas Weaver, MD

Hospital of the University of Pennsylvania, Philadelphia, PA

Wayne State University, Detroit, MI

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All information obtained by Radcliffe Cardiology and each of the contributors from various sources is as current and accurate as possible. However, due to human or mechanical errors, Radcliffe Cardiology and the contributors cannot guarantee the accuracy, adequacy or completeness of any information, and cannot be held responsible for any errors or omissions, or for the results obtained from the use thereof. Published content is for information purposes only and is not a substitute for professional medical advice. Where views and opinions are expressed, they are those of the author(s) and do not necessarily reflect or represent the views and opinions of Radcliffe Cardiology. Radcliffe Cardiology, Unit F, First Floor, Bourne End Business Park, Cores End Road, Bourne End, Buckinghamshire SL8 5AS, UK © 2020 All rights reserved ISSN: 1758-3896 • eISSN: 1758-390X

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Established: March 2016 | Volume 14, 2020

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Aims and Scope • US Cardiology Review is an international, English language, peerreviewed, open access journal that publishes articles continuously on www.USCjournal.com.

• US Cardiology Review aims to assist time-pressured physicians to stay abreast of key advances and opinion in cardiac failure practice.

• US Cardiology Review comprises balanced and comprehensive articles written by leading authorities, addressing the most pertinent developments in the field.

• US Cardiology Review provides comprehensive update on a range of salient issues to support physicians in continuously developing their knowledge and effectiveness in day-to-day clinical practice.

Structure and Format • US Cardiology Review publishes review articles, opinion pieces, guest editorials and letters to the editor.

• The structure and degree of coverage of the journal is determined by the Editor-in-Chief, with the support of the Deputy Editor-in-Chief and the Editorial Board.

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Online All published manuscripts are free to read at www.USCjournal.com.

They are also available at www.radcliffecardiology.com, along with articles from the other journals in Radcliffe Cardiology’s cardiovascular portfolio – Arrhythmia & Electrophysiology Review, Cardiac Failure Review, Interventional Cardiology Review and European Cardiology Review.

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Cardiology

Lifelong Learning for Cardiovascular Professionals

© R A D C L I F F E C AR DI OLOGY 2020

Contents

COVID-19 Pandemic and Cardiovascular Disease Aniket S Rali, MD, and Andrew J Sauer, MD DOI: https://doi.org/10.15420/usc.2020.14

Proximal Side Optimization: A Modification of the Double Kissing Crush Technique Francesco Lavarra, MD DOI: https://doi.org/10.15420/usc.2020.07

Intravascular Ultrasound-guided Versus Angiography-guided Percutaneous Coronary Intervention: Evidence from Observational Studies and Randomized Controlled Trials Xiao-Fei Gao, MD, Xiang-Quan Kong, MD, Guang-Feng Zuo, MD, Zhi-Mei Wang, MD, Zhen Ge, MD, and Jun-Jie Zhang, MD, FSCAI DOI: https://doi.org/10.15420/usc.2020.03

TWILIGHT: A Randomized Trial of Ticagrelor Monotherapy Versus Ticagrelor Plus Aspirin Beginning at 3 Months in High-risk Patients Undergoing Percutaneous Coronary Intervention Johny Nicolas, MD, Usman Baber, MD, and Roxana Mehran, MD DOI: https://doi.org/10.15420/usc.2019.02

Calcified Lesion Assessment and Intervention in Complex Percutaneous Coronary Intervention: Overview of Angioplasty, Atherectomy, and Lithotripsy Alexander G Truesdell, MD, Matheen A Khuddus, MD, Sara C Martinez, MD, PhD, and Evan Shlofmitz, DO DOI: https://doi.org/10.15420/usc.2020.16

Treatment of Secondary Mitral Regurgitation in Heart Failure: A Shifting Paradigm in the Wake of the COAPT Trial Kelly H Schlendorf, MD, MHS, Jared O’Leary, MD, and JoAnn Lindenfeld, MD DOI: https://doi.org/10.15420/usc.2020.05

Role of Intravascular Ultrasound in Guiding Complex Percutaneous Coronary Interventions Brandon Quintana, MS, and Akram Ibrahim, MD, FACC DOI: https://doi.org/10.15420/usc.2020.12

Clinical Trial Perspective: Cost-effectiveness of Transcatheter Mitral Valve Repair Versus Medical Therapy in Patients with Heart Failure and Secondary Mitral Regurgitation. Results From the COAPT Trial Suzanne J Baron, MD, MSc DOI: https://doi.org/10.15420/usc.2020.01

Overview of Quantitative Flow Ratio and Optical Flow Ratio in the Assessment of Intermediate Coronary Lesions Jelmer Westra, MD, and Shengxian Tu, PhD DOI: https://doi.org/10.15420/usc.2020.09

Pregnancy in Women with Congenital Heart Disease: A Guide for the General Cardiologist Catherine R Weinberg, MD, Amier Ahmad, MD, Boyangzi Li, MD, PhD, and Dan G Halpern, MD DOI: https://doi.org/10.15420/usc.2020.08

Percutaneous Coronary Intervention for Chronic Total Occlusion Giovanni Maria Vescovo, MD, Carlo Zivelonghi, MD, Benjamin Scott, MD, and Pierfrancesco Agostoni, MD, PhD DOI: https://doi.org/10.15420/usc.2020.10

Feasibility, Safety, and Clinical Performance of Self-apposing Stents for Left Main Stenosis Krzysztof Pujdak, MD, Jan Kähler, MD, and Marc Werner, MD DOI: https://doi.org/10.15420/usc.2020.11

The Role of Hemodynamic Support in High-risk Percutaneous Coronary Intervention Charles Simonton, MD, Craig Thompson, MD, Jason R Wollmuth, MD, D Lynn Morris, MD, and Thom G Dahle, MD DOI: https://doi.org/10.15420/usc.2020.18

Type and Duration of Dual Antiplatelet Therapy in Complex Percutaneous Coronary Intervention Dimitrios Alexopoulos, MD, Charalampos Varlamos, MD, and Despoina-Rafailia Benetou, MD DOI: https://doi.org/10.15420/usc.2020.13

© R A D C LIF F E CARDIOLOGY 2019

Expert Opinion

COVID-19 Pandemic and Cardiovascular Disease Aniket S Rali, MD,1 and Andrew J Sauer, MD2 1. Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Baylor College of Medicine, Houston, Texas; 2. Division of Advanced Heart Failure and Heart Transplantation, Department of Cardiovascular Medicine, University of Kansas Health System, Kansas City, Kansas.

Abstract There seems to be a unique interplay between 2019 novel coronavirus (SARS-CoV-2) and cardiovascular diseases, although it is predominantly a respiratory illness. Patients with pre-existing cardiovascular co-morbidities appear to be at highest risk for mortality from coronavirus disease 2019 (COVID-19) along with the elderly; COVID-19 also contributes to cardiovascular complications, including acute coronary syndromes, arrhythmias, myocarditis, acute heart failure, and, in the most severe cases, cardiogenic shock and death. Several medications proposed in the treatment of COVID-19 require cardiac monitoring owing to their cardiac-specific adverse effects. Ultimately, the COVID-19 pandemic has jeopardized the safety of heart transplantation and has placed transplant recipients on immunosuppressive therapies at significant risk. In this article, the authors summarize the rapidly emerging data on the cardiovascular implications of SARS-CoV-2 and COVID-19.

Keywords SARS-CoV-2, coronavirus, COVID-19, pandemic, cardiovascular diseases, myocarditis, heart transplantation Disclosure: The authors have no conflicts of interest to declare.

Received: March 20, 2020 Accepted: March 21, 2020 Citation: US Cardiology Review 2020;14:e01. DOI: https://doi.org/10.15420/usc.2020.14 Correspondence: Aniket S Rali, MD, 7200 Cambridge St, A 10.189, BCM 903, Houston, Texas, 77030. E: aniketrali@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.

In late December 2019, an outbreak of an unknown disease called a pneumonia of uncertain cause occurred in Wuhan, Hubei Province, China.1 Over the next few days, several independent laboratories identified the causative agent as a novel coronavirus.2–4 The WHO has temporarily named this virus severe acute respiratory syndrome coronavirus 2 (SARSCoV-2), and the related infectious disease coronavirus disease 2019 (COVID-19). According to the WHO’s daily report, there were 332,930 cases globally as of March 23, 2020, and there have been 14,509 deaths. The COVID-19 epidemic has evolved into a global health crisis.

The main reported symptoms of COVID-19 are fever (77–98%), fatigue (52–75%), and cough (60–81%).5–7 While it predominantly affects the respiratory system (Figure 1), SARS-CoV-2 has also been shown to affect other organ systems, including the gastrointestinal and cardiovascular systems. COVID-19 is only a few months old, and hence a lot remains unknown, but it appears that patients with cardiovascular disease (CVD) are among those with the highest risk for mortality and morbidity, along with the elderly. In a case series of 21 patients with COVID-19 requiring intensive care unit (ICU) level care in Washington State, congestive heart failure was the second most common baseline co-morbidity (42.9%), behind chronic kidney disease (47.6%).8 The purpose of this article is primarily to summarize the available literature on how this novel disease affects the cardiovascular system, especially in patients with pre-existing cardiovascular co-morbidities.

Access at: www.USCjournal.com

Cardiac Complications Published and anecdotal reports suggest that acute-onset heart failure, arrhythmias, acute cardiac injury including MI, myocarditis and cardiac arrest are among potential cardiovascular complications of COVID-19.5–7 It is likely that the pro-inflammatory state induced by this viral infection, and subsequently increased metabolic demand, lead to several of the aforementioned cardiac complications.

This has been well-established in patients with influenza infection and appears to be the case in those with SARS-COV-2 as well.9 There remains a paucity of data on whether the risk of cardiac complications is higher among patients with pre-existing cardiovascular co-morbidities compared with their CVD-naïve counterparts.

Cardiac Biomarkers and Acute Cardiac Injury In the recently published retrospective study of 191 COVID-19 patients from two separate hospitals in China, the incidence of elevation in highsensitivity cardiac troponin I (cTnI) (>28 pg/ml) was 17%, and it was significantly higher among non-survivors (46% versus 1%, p<0.001).10 Furthermore, elevation of this biomarker was noted to be a predictor of in-hospital death (univariable OR 80.07, 95% CI [10.34–620.36], p<0.0001).

The most abrupt increase in cTnI in non-survivors was noted beyond day 16 after the onset of disease. In the same study, the incidence of acute cardiac injury was 17% among all-comers, but significantly higher among non-survivors (59% versus 1%, p<0.0001).

© RADCLIFFE CARDIOLOGY 2020

COVID-19 and Cardiovascular Disease Figure 1: Chest Imaging of Patients with Confirmed SARS-CoV-2 Infection

A: The chest X-ray of a 33-year-old patient with acute respiratory failure due to confirmed SARS-CoV-2 infection. B: The classic CT chest findings of SAR-CoV-2 infection, peripheral ground-glass opacities, in a 72-year-old patient with acute respiratory failure.

Another study reported the incidence of acute cardiac injury to be 7% (10 out of 138 patients), but significantly higher among patients requiring ICU care (22.2% versus 2%, p<0.001).6 A meta-analysis of cardiac biomarkers in COVID-19 patients showed that the values of cardiac troponin I were significantly higher in patients with severe disease than in those without (standardized mean difference 25.6 ng/l; 95% CI [6.8â&#x20AC;&#x201C;44.5]).11 Most patients with COVID-19 only have a mild elevation in cTnI, and values exceeding the 99th percentile of the upper reference limit can only be seen in 8â&#x20AC;&#x201C;12% of positive cases.12 However, it appears that the magnitude of cTnI seems to be highest among patients with most severe disease. Hence, it is reasonable to suggest that initial measurement of cardiac biomarkers at the time of hospitalization, as well as longitudinal monitoring during the hospital stay, may help identify a subset of patients with evidence of acute cardiac injury and worse prognosis. Of note, in a case series of 140 COVID-19 patients from Wuhan, China, only a few (6.7%) patients had increased serum level of creatinine kinase, and there was no difference based on disease severity.5 The exact etiology of elevation in cardiac biomarkers among these patients has not been reported, but we must be cautious not to chalk it up to demand ischemia, because acute myocarditis and acute coronary syndromes (ACS) may also be potential causes. In fact, the angiotensinconverting enzyme 2 (ACE2) receptor, the binding point for SARS-CoV-2 is abundantly found in myocytes, and hence myocyte damage from a direct viral attack could very well be the predominant mechanism. A comprehensive work-up to identify the exact etiology of elevated biomarkers may not always be possible, especially in critically ill patients.

Furthermore, we shall have to balance the risks and benefits of pursuing invasive and noninvasive testing that could potentially expose providers and contaminate equipment, especially given the contagious nature of this illness, and the ability of this virus to survive on surfaces for multiple

US CARDIOLOGY REVIEW

days. A recent study showed that the median half-life of SARS-CoV-2 is 5.6 hours on stainless steel and 6.8 hours on plastic.13 In patients with suspected ACS as the etiology of elevated cardiac biomarkers, thrombolytics may be a valuable alternative treatment to primary percutaneous coronary intervention to minimize contamination of the catheterization laboratory.

Cardiac Arrhythmias In one of the earliest retrospective reviews of COVID-19 patients treated in China, Wang et al. found that of the 138 patients analyzed, 23 (17%) had cardiac arrhythmias and the incidence was significantly higher among those requiring ICU care (44.4% versus 6.9%, p<0.001), compared with those treated in non-ICU beds.6 The authors did not specify if these arrhythmias were atrial or ventricular or their median duration.

Another study reported that cardiac arrhythmias were significantly more common in patients with critical forms of COVID-19 than in mild and moderate cases.14 Telemetry monitoring for arrhythmias might be reasonable for all COVID-19 patients but especially recommended for those with pre-existing CVD, elevation in cardiac biomarkers, or with severe forms of COVID-19. In the absence of any evidence to the contrary, arrhythmias in COVID-19 patients should be treated with anti-arrhythmic drugs in the same manner as non-COVID-19 patients. In fact, amiodarone has been shown to inhibit in vitro spreading of SARS coronavirus.

Extrapolating from this data, some experts recommend administration of prophylactic intravenous amiodarone to mitigate the risk of late sudden cardiac arrest among patients infected with the novel SARS-COV-2.15

Myocarditis The exact incidence of COVID-19-related myocarditis is currently unknown. However, the pathogenicity of SARS-CoV-2 is similar to the

Expert Opinion Middle East respiratory syndrome coronavirus (MERS-CoV), which has been shown to cause acute myocarditis and heart failure.16 Hence, it is reasonable to hypothesize that as our understanding and reporting of SARS-CoV-2-related adverse cardiovascular events evolves, we can expect to see increasing cases of COVID-19-related acute myocarditis.

Elevated cardiac biomarkers, new-onset cardiac arrhythmias, and acuteonset heart failure symptoms in a SARS-CoV-2 patient should raise clinical suspicion for acute myocarditis. At the current time, the clinical utility of endomyocardial biopsy in confirming the diagnosis remains unclear. Noninvasive imaging such as cardiac PET or cardiac MRI to evaluate for myocardial inflammation might be helpful in cases of diagnostic uncertainty, if they can be performed with adequate isolation precautions.

One of the known adverse cardiac effects of lopinavir/ritonavir is hyperlipidemia (hypertriglyceridemia and hypercholesterolemia). In 2009, the US Food and Drug Administration warned about the potential of this drug to prolong QT and PR intervals, and recommended that caution be exercised when prescribing it in patients with structural heart disease. Therefore, patients being treated with this therapy for COVID-19 should undergo close cardiac monitoring, especially if they have pre-existing cardiac co-morbidities or develop them during the course of their illness. Oseltamivir is fairly cardio-benign, and in fact in animal models has been shown to reduce the risk of atrial and ventricular arrhythmias.22,23

Anti-malarial Drugs In a recent report of a 37-year-old patient with SARS-CoV-2-related fulminant myocarditis, Hu et al. showed successful treatment with a combination of methylprednisolone (200 mg/day, 4 days) and immunoglobulin (20 g/day, 4 days).17 Studies have shown that one of the most important mechanisms of clinical deterioration in COVID-19 is from a cytokine storm.18,19 This may explain why high-dose steroids may be effective in the treatment of fulminant myocarditis caused by this novel virus. There are some anecdotal reports of utilizing plasmapheresis and the extracorporeal cytokine absorber CytoSorb (CytoSorbents) in combating the cytokine storm, although there are no published studies on this as yet.

Acute Heart Failure and Cardiogenic Shock In one case series of COVID-19 patients, the incidence of acute heart failure was 23% (44 out of 191 patients) and significantly higher among non-survivors (52% versus 21%, p<0.0001).10 Multiple precipitating etiologies, including acute coronary syndrome, cardiac arrhythmias, stress-induced cardiomyopathy, and fulminant myocarditis, might result in acute heart failure or cardiogenic shock in this patient population.

Coronary CT angiogram and echocardiography may provide valuable non-invasive diagnostic evaluation that may be critical in guiding further therapies. The clinical threshold to obtain these tests should be low, especially a formal or bedside echocardiography in patients with severe COVID-19. Pulmonary artery catheters might be extremely useful tools for diagnosis and to guide therapy in these complex patients who are most likely to be suffering from mixed cardiogenic and vasodilatory shock, although the evidence is currently lacking for their use.

Investigational Therapies and Cardiac Concerns Anti-viral Drugs The combination of lopinavir and ritonavir (Kaletra, AbbVie) is a wellestablished antiretroviral therapy for HIV/AIDS. It was reported to have the potential to treat SARS infections, and hence has been thought to be useful in the treatment of SARS-CoV-2 virus as well.20 In a case series of 62 COVID-19 patients published by Xu et al., 46 patients received lopinavir/ ritonavir therapy, either alone or in conjunction with other therapies; one patient had been discharged from the hospital and no patients had died at the time of the publication.7 This combination was also a part of the treatment algorithm in the treatment of COVID-19 patients in at least one other case series from China.10 However, in a recently published open label randomized controlled trial comparing lopinavir/ritonavir (400 mg and 100 mg respectively) versus standard care in COVID-19 patients, the former was found to be no better.21 Oseltamivir is another antiviral that has been used in the treatment of SARS-CoV-2.6

Chloroquine, a widely used anti-malarial and autoimmune disease drug, has recently been reported as a potential broad-spectrum anti-viral drug.24,25 Chloroquine is known to block virus infection by increasing the endosomal pH required for virus/cell fusion and interfering with the glycosylation of cellular receptors of SARS-CoV.26 Hydroxychloroquine has the same mechanism of action as chloroquine, but its more tolerable safety profile makes it the preferred option. In a recent study examining the pharmacological activity of chloroquine and hydroxychloroquine, both drugs were tested using SARS-CoV2-infected Vero cells.27 In this laboratory study, hydroxychloroquine was found to be more potent than chloroquine at inhibiting SARS-CoV-2 in vitro. Based on these findings, the authors of the study propose an off-label use of hydroxychloroquine sulfate to treat SARS-CoV-2 infection. They suggest a loading dose of 400 mg twice daily for the first day, followed by a maintenance dose of 200 mg twice daily for 4 days.

Hydroxychloroquine-related cardiac adverse events are rare, but can be severe and occasionally life-threatening. A recent review of cardiac complications attributed to this medication found that most patients who developed cardiac symptoms had been on treatment for a long period of time (median 7 years), and had been exposed to large cumulative doses (median 1,235 g).28 The most common adverse event was conduction abnormalities (prolonged QT and PR intervals), which affected 85% of these patients. Although it appears that conduction abnormalities are a long-term sequela of high-dose and prolonged use of hydroxychloroquine, we recommend monitoring COVID-19 patients being treated with this drug for cardiac arrhythmias.

Angiotensin-converting Enzyme Inhibitors and Angiotensin Receptor Blockers There has been a tremendous amount of speculation surrounding the potential adverse effects of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) in COVID-19 patients.

Numerous social media posts have suggested that these commonly used drugs may not only increase the risk of infection, but also the severity of COVID-19.

The concern arises from the observation that, like the coronavirus causing SARS, the SARS-CoV-2 virus binds to a specific receptor called ACE2 to infect cells, and ACE2 levels are increased following treatment with ACEIs and ARBs. 29 However, any concerns regarding the safety of these drugs in COVID-19 patients lacks sound scientific evidence. In fact, there is evidence that ACEIs may be protective

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COVID-19 and Cardiovascular Disease against viral pneumonias. 30 –32 Similarly, there have been studies in animals infected with SARS-CoV-2 where these medications have been shown to be protective against serious lung complications, but to date human data are lacking. 33 Hence, we recommend that physicians and patients continue their treatments with ACEIs and ARBs because there is no clinical or scientific evidence that they cause or worsen COVID-19 infection. The European Society of Cardiology’s Council on Hypertension also recommends likewise in its recent position statement. 33

Extracorporeal Membrane Oxygenation Veno-arterial (VA) and veno-venous (VV) extracorporeal membrane oxygenation (ECMO) may both be extremely valuable in treatment of COVID-19 patients suffering from refractory cardiac and respiratory failure, respectively. Approximately 15–30% of COVID-19 patients develop acute respiratory distress syndrome (ARDS). 6,34 ECMO has been used in some patients with COVID-19 and ARDS in China, but detailed characteristics of these patients remain unknown at this time. 6 The WHO interim guidelines make general recommendations that patients in severe refractory ARDS should be referred to centers capable of providing ECMO support. 35 Generally, criteria for initiation of VV and VA ECMO in COVID-19 patients are the same as for nonCOVID-19 patients. The chief concern is protection of personnel involved in the implantation of ECMO. Anecdotal reports from South Korea, Japan, Italy and China have all shown mixed outcomes among patients initiated on ECMO, most likely owing to the severity of their disease necessitating treatment of ECMO. There is an ongoing ELSOCard registry study looking at outcomes on ECMO among COVID-19 patients, which shall be very telling. In the meantime, it is crucial to appreciate that ECMO is a resource-intensive, highly specialized, and expensive form of life support with the potential of significant complications, and hence should only be reserved for truly refractory cases. It is a finite resource, and must be used judiciously, especially in the midst of a pandemic where all resources are stretched thin.

Strategies to Minimize Potential Patient Exposure Much still remains unknown about the natural history of this novel virus.

Hence, the cliché of prevention is better than cure is true now more than ever. All the case series published to date have confirmed that patients with pre-existing cardiovascular co-morbidities have a higher risk of mortality with COVID-19.5–7 It is paramount that all measures to minimize patient exposure to SARS-CoV-2 be implemented broadly and effectively, including social distancing, proper hand hygiene and cancellation of elective clinic and hospital visits.

1.

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3.

4.

Wuhan Municipal Health Commission. Report of clustering pneumonia of unknown etiology in Wuhan City. Wuhan: Wuhan Municipal Health Commission, 2019 [in Chinese]. http://wjw. wuhan.gov.cn/front/web/showDetail/2019123108989 (accessed March 23, 2020).

Lu R, Zhao X, Li J et al. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet 2020;395:565–74. https:// doi.org/10.1016/S0140-6736(20)30251-8; PMID: 32007145.

Zhou P, Yang XL, Wang XG, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 2020;579:270–3. https://doi.org/10.1038/s41586-020-2012-7; PMID: 32015507.

Zhu N, Zhang D, Wang W, et al. A novel coronavirus from patients

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5.

6.

7.

As is eloquently discussed in a recent editorial by Dr Lisa Rosenbaum, we must learn from the tragedy in Italy to prevent our medical system in the US from being overwhelmed, and so we are not forced to make the heartbreaking decisions facing Italian providers.36 Indeed, as she says, the “best outcome of this pandemic would be being accused of having over prepared”.

Heart Transplantation One area of cardiovascular medicine that remains especially vulnerable in such pandemics is that of heart transplantation. Patients who are recipients of orthotopic heart transplantation, and those awaiting transplants are both at risk. The eminent risk for the former is more obvious owing to their immunocompromised state.

In an attempt to mitigate this risk, our institutions have instituted strict policies for COVID-19-suspected or confirmed patients to not be admitted in ICUs shared with our transplant patients.

A recently published survey of 87 heart transplant recipients during December 20, 2019 and February 25, 2020 in China showed that these patients had a low rate of infection with SARS-CoV-2, and transition to COVID-19, as long as they practiced social distancing.37 Only four patients had upper airway infections and three of them tested negative for SARSCoV-2; the fourth patient recovered well and did not need any testing.

The safety of patients awaiting heart transplantation has also been jeopardized by the COVID-19 pandemic due to potential transmission from the donor to the recipient. We know too little about this novel virus to reliably estimate the risk of transmission through donor organs.

Furthermore, until rapid testing for SARS-CoV-2 becomes readily available, there will be no way to definitively confirm negative status of the donor in a timely manner. It is reasonable to hypothesize that we may see a surge in implantations of durable left ventricular assist devices as bridge to transplantation until our understanding of the risk of transmission is more robust, or we have a definitive treatment for this novel virus, or until this pandemic has passed.

Conclusion Our knowledge of the novel coronavirus and its cardiovascular implications is evolving by the hour. It is critical that, as a medical community which is on the front lines of this pandemic, we share our experiences, the successes, and the failures, with one another at a rapid pace. In addition to published manuscripts, real-time anecdotal experiences shared by world experts on social media forums will remain a valuable tool as we continue to learn about this disease.

with pneumonia in China, 2019. N Engl J Med 2020;382:727–33. https://doi.org/10.1056/NEJMoa2001017; PMID: 31978945.

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10. Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 2020. https://doi.org/10.1016/ S0140-6736(20)30566-3; PMID: 32171076; epub ahead of press.

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Hui H, Zhang Y, Yang X, et al. Clinical and radiographic features of cardiac injury in patients with 2019 novel coronavirus pneumonia. MedRxiv 2020. https://doi.org/10.1101/2020.02.24.20 027052; epub ahead of press.

Stadler K, Ha HR, Ciminale V, et al. Amiodarone alters late endosomes and inhibits SARS coronavirus infection at a postendosomal level. Am J Respir Cell Mol Biol 2008;39:142–9. https:// doi.org/10.1165/rcmb.2007-0217OC; PMID: 18314540.

Alhogbani T. Acute myocarditis associated with novel Middle East respiratory syndrome coronavirus. Ann Saudi Med 2016;36:78–80. https://doi.org/10.5144/0256-4947.2016.78; PMID: 26922692.

Hu H, Ma F, Wei X, Fang Y. Coronavirus fulminant myocarditis saved with glucocorticoid and human immunoglobulin. Eur Heart J 2020. https://doi.org/10.1093/eurheartj/ehaa190; PMID: 32176300; epub ahead of press.

Chen C, Zhang XR, Ju ZY, He WF. Advances in the research of cytokine storm mechanism induced by corona virus disease 2019 and the corresponding immunotherapies]. Zhonghua Shao Shang Za Zhi 2020 [in Chinese]. https://doi.org/10.3760/ cma.j.cn501120-20200224-00088; PMID: 32114747; epub ahead of press.

Fung SY, Yuen KS, Ye ZW, et al. A tug-of-war between severe acute respiratory syndrome coronavirus 2 and host antiviral defence: lessons from other pathogenic viruses. Emerg Microbes Infect 2020;9:558–70. https://doi.org/10.1080/22221751.2020.173 6644; PMID: 32172672.

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Yan Y, Zou Z, Sun Y, et al. Anti-malaria drug chloroquine is highly effective in treating avian influenza A H5N1 virus infection in an animal model. Cell Res 2013;23:300–2. https://doi.org/10.1038/ cr.2012.165; PMID: 23208422.

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32. Caldeira D, Alarcão J, Vaz-Carneiro A, Costa J. Risk of pneumonia associated with use of angiotensin converting enzyme inhibitors and angiotensin receptor blockers: systematic review and metaanalysis. BMJ 2012;345:e4260. https://doi.org/10.1136/bmj.e4260; PMID: 22786934.

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March 13, 2020. https://www.who.int/publications-detail/clinicalmanagement-of-severe-acute-respiratory-infection-when-novelcoronavirus-(ncov)-infection-is-suspected (accessed March 23, 2020).

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Coronary Imaging & Complex Interventions

Proximal Side Optimization: A Modification of the Double Kissing Crush Technique Francesco Lavarra, MD Department of Cardiology, Jilin Heart Hospital, Changchun, China

Abstract Coronary bifurcations with significant lesions >10 mm in the side branch (SB) are likely to require two-stent treatment techniques. To date, double kissing Crush (DK-Crush) stenting has demonstrated higher rates of final kissing balloon inflation and better clinical outcomes. The technical iterations that lead to optimal clinical outcomes have been attributed to the first kissing balloon that repairs the distorted proximal segment and fully expands the orifice of the side stent. One potential caution, which relates to all Crush techniques, is the possibility of the guidewire crossing in an inappropriate position toward the Crushed SB stent. When this occurs, the SB stent may be further Crushed, leaving the ostium uncovered, which potentially negates the benefit of the Crush technique. In our experience, proximal side optimization (PSO) during DK-Crush stenting ensures stent size ‘accommodation’ to the larger vessel diameter in the proximal segment and better strut apposition to the wall, which is particularly important in the ostial segment. The benefits of this additional modification of the established DK-Crush technique are reduction or elimination of the risk of SB stent distortion, increase of the space of optimal wiring, and avoidance of guidewire advancement under the stent struts, even in unfavorable anatomies with extreme angulation. The author describes a step-by-step approach of a proposed PSO technique, which is easy to perform without any additional procedural time or costs.

Keywords Two-stent technique, double kissing Crush, proximal side optimization Disclosure: The author has no conflicts of interest to declare.

Received: February 26, 2020 Accepted: March 25, 2020 Citation: US Cardiology Review 2020;14:e02. DOI: https://doi.org/10.15420/usc.2020.07 Correspondence: Francesco Lavarra, Department of Cardiology, Jilin Heart Hospital, Jingyue Rd 5558, Changchun, Jilin Province 130117, China.

E: Lavarra@jlheart.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.

True coronary bifurcations (Medina 1,1,1 and most of 1,0,1 and 0,1,1) with side branch (SB) diameter of >2.25 mm and lesion length of >10 mm are likely to require two-stent treatment techniques (Figure 1A).1,2 The Crush technique underwent a series of technical iterations and modifications by Chen et al. before evolving into the so-called mini double kissing Crush (DK-Crush) technique.3,4 The conventional DK-Crush includes the following steps after adequate lesion preparation: • stenting the SB (with 1–2 mm protrusion in the main branch (MB); • removal of SB wire and balloon and MB balloon Crush; • proximal wiring of SB access through the Crushed stent and first kissing balloon inflation (KBI); • main vessel stenting; • first proximal optimization technique (POT); • SB rewiring access and strut dilation; • final KBI; and • final POT (Figure 1).

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The main difference between classic and DK-Crush is the use of the first KBI after balloon Crush of the implanted SB stent. Therefore, after MB stenting, one layer of metal struts remains at the ostial SB to cross through, which facilitates the second KBI. Contrary to the provisional SB stenting approach, where guidewire recrossing is suggested to be performed through the distal cells, the first recrossing of the SB during DK-Crush should be carried out through the most proximal cell to avoid malapposition of the SB stent at the carina.4 Compared to the provisional treatment, DK-Crush is superior to the classic Crush and Culotte strategies, because it leads to higher rates of successfully performed final KBI and to lower target lesion revascularizations (repeat interventions), as shown in the DK-CRUSH I, II, III, and V studies.5–8 This led to a class II recommendation for DK-Crush to be used as a treatment option for distal left main bifurcations in the European Association for Cardio-Thoracic Surgery/European Society of Cardiology guidelines.9 All Crush techniques have the limitation of the inappropriate guidewire crossing in the Crushed SB stent. When this occurs, the SB stent may be further Crushed, leaving the ostium uncovered. Furthermore, it yields

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Coronary Imaging & Complex Interventions Figure 1: Conventional Double Kissing Crush Steps

A

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A: Baseline angiography showing true bifurcation lesion of mid left anterior descending artery (LAD-D1; Medina 1,1,1). B: Side branch (SB) stenting with 1â&#x20AC;&#x201C;2 mm stent protrusion in the main vessel (MV).

C: Main branch balloon Crush. D: Proximal wiring of SB access through the Crushed stent and first kissing balloon inflation (KBI). E: MV stenting. F: First proximal optimization technique (POT). G: SB proximal rewire access and strut dilation. H: Second KBI. I: Final POT. J: Final angiography. KBI = kissing balloon inflation; MV = main vessel; POT = proximal optimization technique; SB = side branch.

Figure 2: Limitations of the Conventional Double Kissing Crush A

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SO A: Baseline angiography showing bifurcation lesion of the left anterior descending artery and first diagonal artery. B: Stent positioning. C: Stent deployment. D: Intravascular ultrasound pullback from the side branch immediately after deployment, showing reduced stent minimal luminal cross-sectional area due to stent underexpansion in the ostial position. E: Graphic representation showing the risk of stent underexpansion and malapposition to the artery wall in the ostial segment of the side branch. F: Graphic representation showing the risk of reduced SOW due to stent underexpansion.

SOW = space of optimal wiring.

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Proximal Side Optimization Figure 3: Proximal Side Optimization Modification of Double Kissing Crush Steps A

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SB stent with adequate protrusion

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Pull delivery balloon 3–4 mm back

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Dilate delivery at higher pressure across the bifurcation

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Dilate across bifurcation with NC balloon before Crush

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Crush from MV with final POT NC balloon

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SO A: Stent positioning in the side branch (SB). B: Stent implantation in the SB with adequate protrusion in the main vessel (MV), as conventional Crush and not as mini Crush. C: The delivery balloon is pulled halfway back into the MV, and higher than nominal pressure (12–14 atm) is applied for inflation. D: High-pressure post-dilatation with a non-compliant balloon (0.25–0.5 mm larger in diameter) is done across the bifurcation. E: Non-compliant balloon intended for final proximal optimization technique is used to Crush the SB stent from the MV. F: Graphic representation of stent implantation in the SB with adequate protrusion in the MV (as conventional Crush and not as mini Crush). G: Graphic representation of proximal side optimization (PSO); the delivery balloon is pulled halfway back into the MV, and higher than nominal pressure (12–14 atm) is applied for inflation. H: Intravascular ultrasound pullback from the SB before stent Crush shows increased minimal stent area and apposition to the vessel wall in the ostial segment. I: Intravascular ultrasound pullback from the MV after SB stent Crush shows increased space for optimal rewiring, eliminating the need for proximal strut rewiring. J: Graphic representation showing increased SOW (red line) after complete PSO modification. MV = main vessel; NC = non-compliant; POT = proximal optimization technique; PSO = proximal side optimization; SB = side branch; SOW = space of optimal wiring.

difficult SB rewiring after MB stent deployment, and potentially negates the benefit of the Crush technique, leaving the SB ostium uncovered (Figures 2A–2D). KBI may maximize SB access, but is unlikely to optimize SB stent apposition in the para-ostial segment.

The Proximal Side Optimization Technique We suggest a small modification to the established DK-Crush technique proposed by Chen et al.,4 which we call the proximal side optimization (PSO) technique. As the SB stent is sized based on the distal reference SB diameter, in long lesions there will be a definite size mismatch with the ostial SB diameter, thus it should be positioned and deployed with adequate protrusion in the MB (as conventional Crush and not as mini Crush; Figures 3A and 3B). In this way, the segment of SB stent is reliably Crushed and completely bent in only one direction in front of the SB, leaving one single layer of the stent struts to be further crossed by the guidewire and opened by the SB balloon (Figure 3H). The delivery balloon needs to be pulled back partially in the MB and deployed at a higher pressure (usually 4–6 atm above ‘nominal’ pressure; Figure 3C).

Subsequently, high-pressure dilatation with a non-compliant balloon (0.25–0.5 mm greater in size, or if intravascular ultrasound or optical coherence tomography is used, according to the dimensions of the proximal SB) is performed (Figure 3D). The SB stent is then Crushed from the MB using a big, short, high-pressure balloon designed for final POT (Figure 3E). The rest of the procedure follows the standard DK-Crush technique previously described.

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In our experience, the PSO leads to more reliable and considerably easier rewiring of the Crushed stent, most often increasing the area of optimal rewiring (space of optimal wiring, which is smaller before PSO, as with conventional DK-Crush [Figure 2F], and much larger after PSO [Figures 3I and 3J]), and by using the original workhorse soft-tipped guidewire in almost all of the cases. Notably, our modification excludes the necessity to rewire through the most proximal strut, which is discouraged in PSO to avoid the need to pass more layers of stents Crushed there. Similarly, in most cases, after first rewiring we utilize the same non-compliant balloon previously used for high-pressure SB stent post-dilatation to perform the KBI.

Conclusion The PSO modification ensures stent size ‘accommodation’ to the larger vessel diameter in the proximal segment and better strut apposition to the wall, which are particularly important in the ostial segment where size mismatch between proximal and distal SB dimensions in long lesions is greater (Figure 2E). It can be helpful in all Crush techniques and also in other stent techniques, such as T and protrusion (TAP) and Culotte.

Further serial clinical studies of optical coherence tomography, and bench tests of micro-CT and flow dynamics, need to be performed to demonstrate whether this iteration leads to optimal flow conditions in the carina, further reducing revascularization rates triggered by the restenotic process in the SB ostium.

Coronary Imaging & Complex Interventions 1.

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Kim HY, Doh JH, Lim HS, et al. Identification of coronary artery side branch supplying myocardial mass that may benefit from revascularization. JACC Cardiovasc Interv 2017;27;10:571–81. https://doi.org/10.1016/j.jcin.2016.11.033; PMID: 28259665.

Burzotta F, Lassen JF, Banning AP, et al. Percutaneous coronary intervention in left main coronary artery disease: the 13th consensus document from the European Bifurcation Club.

EuroIntervention 2018;14:112–20. https://doi.org/10.4244/EIJ-D-1800357; PMID: 29786539.

Colombo A, Stankovic G, Orlic D, et al. Modified T-stenting technique with Crushing for bifurcation lesions: immediate results and 30-day outcome. Catheter Cardiovasc Interv 2003;60:145–51. https://doi.org/10.1002/ccd.10622; PMID: 14517916.

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Chen SL, Zhang JJ, Ye F, et al. DK Crush (double-kissing and double-Crush) technique for treatment of true coronary bifurcation lesions: illustration and comparison with classic Crush. J Invasive Cardiol 2008;18:223–6. PMID: 17404406.

Chen SL, Zhang JJ, Ye F, et al. Study comparing the double kissing (DK) Crush with classical Crush for the treatment of coronary bifurcation lesions: the DKCRUSH-1 Bifurcation Study with drugeluting stents. Eur J Clin Invest 2008;38:361–71. https://doi. org/10.1111/j.1365-2362.2008.01949.x; PMID: 18489398.

Chen SL, Santoso T, Zhang JJ et al. A randomized clinical study comparing double kissing (DK) Crush with provisional stenting for treatment of coronary bifurcation lesions: the results from the DKCRUSH-II trial. J Am Coll Cardiol 2011;57:914–20. https://doi. org/10.1016/j.jacc.2010.10.023; PMID: 21329837.

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Chen SL, Xu B, Han YL, et al. Comparison of double kissing Crush versus Culotte stenting for unprotected distal left main bifurcation lesions: results from a multicenter, randomized, prospective DKCRUSH-III study. J Am Coll Cardiol 2013;61:1482–8. https://doi.org/10.1016/j.jacc.2013.01.023; PMID: 23490040.

Chen SL, Zhang JJ, Han Y, et al. Double kissing Crush versus provisional stenting for left main distal bifurcation lesions: DKCRUSH-V randomized trial. J Am Coll Cardiol 2017;70:2605–17. https://doi.org/10.1016/j.jacc.2017.09.1066; PMID: 29096915.

Neumann FJ, Sousa-Uva M, Ahlsson A, et al. ESC/EACTS guidelines on myocardial revascularization. Eur Heart J 2019;40:87–165. https://doi.org/10.1093/eurheartj/ehy855; PMID: 30615155.

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Coronary Imaging & Complex Interventions

Intravascular Ultrasound-guided Versus Angiography-guided Percutaneous Coronary Intervention: Evidence from Observational Studies and Randomized Controlled Trials Xiao-Fei Gao, MD, Xiang-Quan Kong, MD, Guang-Feng Zuo, MD, Zhi-Mei Wang, MD, Zhen Ge, MD, and Jun-Jie Zhang, MD, FSCAI Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China

Abstract Coronary angiography has been considered the gold standard for the diagnosis of coronary artery disease and guidance of percutaneous coronary intervention (PCI). However, 2D-projection angiography cannot completely reflect the 3D coronary lumen. Intravascular ultrasound (IVUS) can overcome a number of limitations of coronary angiography by providing more information about the dimensions of the vessel lumen, plaque characteristics, stent deployment, and the mechanisms of device failure. Growing data from observational studies and randomized controlled trials have confirmed the clinical benefit of IVUS guidance during PCI. This article summarizes the evidence regarding IVUS guidance to highlight its advantages and to support the use of IVUS during PCI.

Keywords Intravascular ultrasound, coronary angiography, percutaneous coronary intervention, stent, clinical trials Disclosure: The authors have no conflicts of interest to declare.

Received: January 21, 2020 Accepted: February 26, 2020 Citation: US Cardiology Review 2020;14:e03. DOI: https://doi.org/10.15420/usc.2020.03 Correspondence: Jun-Jie Zhang, MD, FSCAI, Department of Cardiology, Nanjing First Hospital, Nanjing Medical University; 68 Changle Rd, 210006 Nanjing, China.

E: jameszll@163.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.

Coronary angiography is widely used to diagnose coronary artery disease and to guide percutaneous coronary intervention (PCI). However, 2D projection angiography cannot completely reflect the 3D coronary lumen, with several inherent limitations in evaluating plaque composition, vessel diameter, diffuse reference vessel disease, lesion severity, as well as the result of stent deployment. In the past three decades, intravascular ultrasound (IVUS) has been increasingly used in clinical practice to overcome a number of limitations of coronary angiography by providing more details of coronary anatomy and stent implantation.

There is growing data from observational studies and randomized controlled trials (RCTs) to validate the value of IVUS guidance in PCI.1–19 IVUS guidance is not routinely performed in PCI, partly due to the increased procedural time, extra cost, and the potential neutral effect on cardiac death. This article summarizes the evidence for IVUS guidance in preprocedural, post-procedural, and follow-up assessment of PCI to highlight the advantage of using IVUS for patients undergoing stent implantation (Figure 1).

Preprocedural Assessment Basic IVUS Measurement There are three layers in the ultrasound image of coronary arteries (Figure 2).20 The inner layer frequently includes atheroma, intima, and the

© RADCLIFFE CARDIOLOGY 2020

internal elastic membrane. The middle layer is the media, which is less echogenic than the intima. The outer layer, bordering the external elastic membrane (EEM), consists of the adventitia and periadventitial tissues, which cannot be distinguished from each other in IVUS images. IVUS can be used to make the following basic measurements: • Minimum lumen diameter (MLD): the shortest diameter through the center point of the lumen.

• Minimum lumen area (MLA): the smallest area through the center point of the lumen.

• Lumen eccentricity: (maximum lumen diameter − minimum lumen diameter)/maximum lumen diameter.

• Area stenosis: (reference lumen area − stenosis lumen area)/reference lumen area.

• Plaque burden: (EEM area − lumen area)/EEM area.20

Assessment of Plaque Vulnerability Vulnerable plaque, sometimes called thin-cap fibroatheromas (TCFA), often associated with large plaque burden, spotty calcifications, attenuated plaque, and shallow echolucent zones shown by gray-scale IVUS, is a common cause of MI and cardiac death.21–25 In virtual histology (VH)-IVUS, TCFA was defined as focal, necrotic core-rich plaque (≥10% of the cross-sectional area) in contact with the lumen with atheroma

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Coronary Imaging & Complex Interventions volume ≥40%.26,27 The international, multicenter trial An Imaging Study in Patients with Unstable Atherosclerotic Lesions (PROSPECT) enrolled 697 patients with acute coronary syndrome undergoing coronary angiography, gray-scale and radiofrequency IVUS. It showed that three lesion-level independent predictors of major adverse cardiovascular events (MACE) at a median follow-up of 3.4 years were MLA ≤4 mm2 (HR 3.21; 95% CI [1.61–6.42]), plaque burden ≥70% (HR 5.03; 95% CI [2.51– 10.11]), and the presence of TCFA (HR 3.35; 95% CI [1.77–6.36]).28 In this study, TCFA was defined as the presence of >10% confluent necrotic core with more than 30% of the necrotic core abutting the lumen in ≥3 consecutive frames by VH-IVUS. Moreover, the VH-IVUS in Vulnerable Atherosclerosis (VIVA) study and the European Collaborative Project on Inflammation and Vascular Wall Remodeling in Atherosclerosis – Intravascular Ultrasound (ATHEROREMO-IVUS) study confirmed the finding that TCFA identified by VH-IVUS was associated with MACE.27,29 However, the PROSPECT trial also showed that the combination of these three high-risk plaque features only had an 18.2% predictive value for MACE, which might be due to the low resolution of IVUS, which makes it difficult to detect plaque composition.28

Figure 1: Uses of Intravascular Ultrasound When Guiding Percutaneous Coronary Intervention IVUS-guided PCI

Preprocedure

Post-procedure

Follow-up

• Assess plaque vulnerability • Assess functional significance • Identify reference segments • Choose stent size • Confirm landing zone

• Assess stent expansion • Identify edge dissection • Identify malapposition • Identify tissue protrusion • Identify stent thrombosis

Stent failure: • Stent restenosis • Device thrombosis

IVUS = intravascular ultrasound; PCI = percutaneous coronary intervention.

Figure 2: Common Morphologies of Intravascular Ultrasound

Assessment of Functional Significance There is always high inter-observer variability for angiographic estimation of the degree of coronary stenosis.30,31 Intermediate coronary lesions, defined by 40–70% stenosis by angiography assessment, cannot be accurately evaluated for their hemodynamic significance for MI even by experienced interventional cardiologists. Fractional flow reserve (FFR) has been regarded as the gold standard method of invasive MI assessment.32–34 Anatomic data for MLA has a relatively good correlation with FFR, which could be a liberal diagnostic application, though potential errors exist due to the variations of BMI and lesion complexity.

A comprehensive meta-analysis demonstrated that an IVUS-derived MLA of 2.8 mm2 for non-left main coronary lesions with an angiographic diameter >3 mm, and 2.4 mm2 for lesions with a diameter <3 mm, were cut-off values to detect functionally significant coronary stenosis.35 In isolated intermediate left main coronary lesions involving the ostium or shaft, an IVUS-derived MLA of 5.9 mm2 had the highest sensitivity (93%) and specificity (95%) for determining FFR less than 0.75 in Western populations, while an MLA <4.5 mm2 had good correlation with an FFR under 0.80 (77% sensitivity and 82% specificity) in Asian populations.36,37 The multicenter, prospective Spanish Working Group on Interventional Cardiology (LITRO) study also showed that an IVUS-derived MLA of more than 6 mm2 was a safe value to use to defer coronary revascularization of the left main lesions.38 Therefore, it seems reasonable to perform revascularization for left main coronary lesions when there is an MLA of <4.5 mm2, to defer revascularization if there is an MLA of >6 mm2 and to consider further invasive or non-invasive functional evaluation if there is an MLA of 4.5–6 mm2.

IVUS-guided Preprocedural Preparation A preprocedural IVUS check is important to assess calcium severity, to select stent size, to identify a reference segment and confirm the landing zone (Figure 3). Angiography is moderately sensitive for the detection of extensive calcific lesions, but it is less sensitive for mild calcium. One study has shown that IVUS could detect calcium in 841 of 1,155 (73%)

A: Normal artery: three-layered structure referring to intima (red arrow), media (yellow arrow), adventitia (green arrow). B: Fibrous plaque: intermediate echogenicity similar to the reference adventitia. C: Attenuated plaque: ultrasound attenuation behind plaque in the absence of calcium, which is associated with lipid pools, cholesterol crystals, microcalcification, and hyalinized fibrous tissue. D: Calcification: hyperechoic plaque brighter than the reference adventitia with shadowing. E: Thrombus: intra-luminal mass (relatively echolucent or scintillating echoes) with lobulated or layered structure. F: Intramural hematoma: an accumulation of blood within the medial space, resulting in external elastic membrane outward and internal elastic membrane inward. G: Edge dissection: the presence of a false lumen proximate to stent edges.

H: Acquired stent malapposition: the separation of stent struts from the vessel wall with blood flow (red arrow) behind the strut (yellow arrow). I: Stent restenosis: echogenic tissue similar to the reference adventitia.

stable patients, whereas angiography detected calcium in only 440 (38%) of them.39 The presence of severe calcium may require predilatation with a higher inflation pressure, larger balloon, cutting balloon angioplasty, or rotablator atherectomy.

Several potential IVUS-based stent diameter methods exist, including stent diameter according to EEM diameter at the site of MLA, the

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IVUS-guided Percutaneous Coronary Intervention Figure 3: Intravascular Ultrasound-guided Drug-eluting Stents Implantation in Left Main Bifurcation Lesion with Double Kissing Crush Technique

A 62-year-old man presented with unstable angina. Angiography showed medina 1,1,1 distal left main (LM) bifurcation lesion (A). A 3.5 × 29 mm Firehawk (MicroPort) stent was inflated in the left circumflex artery (LCX) with 1 mm protrusion into LM, and 3.5 × 12 mm Apollo (Brosmed) balloon was positioned in the left anterior descending artery (LAD) through a 6 Fr guiding catheter (B–C).

Balloon crush was performed immediately after stenting the LCX (D). Kissing inflation was performed with two 3.5 × 12 mm non-compliant balloons at 14 atm after rewiring LCX (E–F). A 3.5 × 33 mm Firehawk stent was deployed crossover from the LAD to LM (G). Proximal optimization technique (POT) was performed with a 4.0 × 12 mm Quantum stent (Boston Scientific; H). Sequential balloon inflations to 16 atm followed by second kissing balloon inflations to 12 atm after rewiring LCX (I–J), then a re-POT with 4.0 × 12 mm Quantum (K). An intravascular ultrasound (IVUS) check was performed at the final check after 2.5 × 15 mm Legend balloon (Medtronic) pre-dilatation. The lumen area at distal LM, ostial LAD and ostial LCX were 7.28 mm2, 4.45 mm2, and 3.52 mm2 (a–c). IVUS image showed two-layered struts at the ostial LCX after balloon crush (d). Rewiring the LCX from the proximal stent cell under IVUS guidance (e–f). The final IVUS images found struts well apposed (g–h), and no metal carina in IVUS image (i). The lumen area after the procedure at distal LM, ostial LAD and ostial LCX were 13.23 mm2, 8.9 mm2, and 7.43 mm2 (j–l).

smallest reference EEM diameter, the largest reference lumen, mean reference lumen, or the smallest reference lumen. Currently, the use of mean diameter of distal lumen with post-dilatation of the proximal and middle part of the stent is recommended.40 Stent length is determined by the distance from the distal to proximal reference site. Proximal and distal reference sites are set at cross-sections adjacent to the target lesion that have the largest lumen and a plaque burden of <50%.41 An appropriate landing zone is commonly considered as having residual plaque burden <50% without lipid-rich plaque at the stent edge, which is associated with subsequent stent restenosis.40–42 Overall, compared with angiography guidance, IVUS guidance could lead to more stents, larger stent diameter, longer stent length, and a greater post-procedural minimum stent area (MSA).12,19,43-45

procedural MSA has been considered the most important parameter to predict these adverse events.46–51 The current view is that the optimal MSA measured by IVUS is >5.5 mm2 for non-left main lesions, >7 mm2 for distal left main lesions, and >8 mm2 for proximal left main lesions.40,47,48,52,53 Acute stent malapposition after DES implantation without underexpansion does not translate into early or long-term adverse events regardless of the length and thickness of malapposition.54–56 An IVUS subgroup analysis from the Assessment of Dual AntiPlatelet Therapy With Drug Eluting Stents (ADAPT-DES) trial showed that 34.3% of lesions presented with tissue protrusion detected by IVUS after DES implantation. This was not associated with worse 2-year clinical outcomes, in part due to the larger lumen area of lesions treated with larger stent or post-dilatation balloon in the tissue protrusion group.57

Post-procedural Assessment Post-procedural IVUS assessment can detect stent underexpansion, acute stent malapposition, stent deformation, tissue protrusion through the stent struts, stent edge dissection, and residual disease at stent edge (Figures 2 and 3). Several studies have demonstrated that stent underexpansion was associated with early stent thrombosis and restenosis after implantation of a drug-eluting stent (DES).46–49 Post-

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However, a substudy of the Bivalirudin in Patients Undergoing Primary Angioplasty for Acute Myocardial Infarction (HORIZONS-AMI) trial demonstrated that significant tissue protrusion (plaque/thrombus), defined as residual lumen area <4mm2 by IVUS detection, was associated with early stent thrombosis.46 Moreover, post-procedural large edge dissections – characterized by IVUS as deep depth (at least disrupting the

Coronary Imaging & Complex Interventions Table 1. Key Randomized Trials of Intravascular Ultrasound Versus Angiography-guided Drug-eluting Stent Implantation Trials

Sample Size (n)

Center

Key Inclusion Criteria

Follow-up Primary Endpoint (months)

HOME DES IVUS13

105

Single center

Type B2/C proximal LAD, LM, RVD <2.5 mm, lesion length >20 mm, ISR, diabetes and ACS

18

MACE: 11% versus 12%, p=NS

AVIO 201311

142

Multicenter

Long lesions (>28 mm), CTO, bifurcation lesions, small vessels (≤2.5 mm), ≥4 stents

24

Post-PCI MLD: 2.70 ± 0.46 mm versus 2.51 ± 0.46 mm, p=0.0002

RESET 201316

269/274

Multicenter

Long lesions (stent length ≥28 mm)

12

MACE: 4.5% versus 7.3%, p=0.16

AIR-CTO 201518

115

Multicenter

CTO

24

In-stent late lumen loss: 0.28 ± 0.48 mm versus 0.46 versus 0.68 mm, p=0.025

CTO-IVUS 201515

201

Multicenter

CTO

12

Cardiac death: 0% versus 1%, p=0.16

Tan et al. 201517

61/62

Single center

Unprotected LM

24

MACE: 13.1% versus 29.3%, p=0.031

12

700

Multicenter

Long lesions (stent length ≥28 mm)

12

MACE: 2.9% versus 5.8%, p=0.007

Zhang et al. 201614

42

Single center

Small vessel disease (2.25–2.75 mm)

12

Post-PCI MLD: 2.77 ± 0.19 mm versus 2.53 ± 0.21 mm, p<0.001

ULTIMATE 201819

724

Multicenter

All comers

12

TVF: 2.9% versus 5.4%, p=0.019

IVUS-XPL 2015

ACS: acute coronary syndrome; B2/C: Stenosis grade as defined by American College of Cardiology/American Heart Association; CTO: chronic total occlusion; DES: drug-eluting stent; ISR: in-stent restenosis; LAD: left anterior descending artery; LM: left main disease; MACE: major adverse cardiac events; MLD: minimum lumen diameter; PCI: percutaneous coronary intervention; RVD: reference vessel diameter; TVF: target vessel failure.

media layer) great lateral extension (>60°C), and long length (>2 mm) – could result in early stent thrombosis.46,58 The optimal criteria of IVUS-guided bare-metal stent deployment in the Multicenter Ultrasound Stenting in Coronaries Study (MUSIC) included: • complete apposition of stent; • adequate stent expansion: MSA ≥90% of average reference lumen area or ≥100% of the smaller reference segment area if the MSA <9 mm2, or MSA ≥80% of average reference lumen area or ≥90% of the smaller reference segment area if the MSA >9 mm2; and • symmetrical stent expansion: MLD/maximum lumen diameter ≥0.7.

The MUSIC study found that 81% of 155 patients undergoing bare metal Palmaz-Schatz stents met IVUS optimal criteria, and the overall risk of target lesion revascularization was 4.5% at 6 months.59 In the DES era, evidence derived from observational studies, RCTs (Table 1) and meta-analyses all demonstrated that IVUS-guided DES implantation was associated with a lower risk of MACE and target vessel revascularization (TVR) in complex lesions, such as unprotected left main disease, bifurcation lesions, chronic total occlusion, and long lesions.1–5,8,10–18,43,44,60–65 More importantly, several optimal IVUS-guided criteria have been proposed through RCTs rather than observational studies. The Angiography Versus (vs) IVUS Optimisation (AVIO) RCT, proposed a new optimal IVUS-guided criterion: MSA >70% of the postdilatation balloon cross-sectional area (CSA), and the non-compliant postdilatation balloon size to be determined by the average of the media-tomedia diameters of distal in-stent segment, proximal in-stent segment, and maximal in-stent narrowing.11 Another randomized trial – the Impact of Intravascular Ultrasound Guidance on Outcomes of Xience Prime Stents in Long Lesions (IVUS-XPL) study – presented an IVUS-guided optimal criterion for long lesions as the MLA greater than the lumen CSA at distal reference segments.12,65 Most

RCTs have enrolled people with complex coronary lesions, and only the Intravascular Ultrasound Guided Drug Eluting Stents Implantation in ‘AllComers’ Coronary Lesions (ULTIMATE) trial recruited all-comer patients and showed that IVUS guidance was associated with significant lower risk of target vessel failure (TVF) compared with angiography guidance in allcomers undergoing second-generation DES implantation.19 In this trial, the novel criteria of IVUS-guided optimal DES deployment were: • the MLA in the stented segment >5.0 mm2, or 90% of the MLA at the distal reference segments; • plaque burden of 5 mm proximal or distal to the stent edge <50%; and • no edge dissection involving media with a length >3 mm.

A total of 53% of the 1,448 participants met these three criteria and they were associated with a lower rate of TVF at 12 months compared with those with a suboptimal PCI procedure. An updated meta-analysis that included the ULTIMATE trial demonstrated that IVUS guidance could reduce the risk of cardiac death.66 A 5-year clinical follow-up of the IVUSXPL trial has shown the long-term benefit of IVUS guidance in optimizing DES implantation in long lesions.65 However, further RCTs are warranted to explore the difference in clinical relevance when using different optimal IVUS guidance criteria.67

Follow-up Assessment IVUS at follow-up is used to detect chronic stent expansion, stent fracture, neointimal hyperplasia, stent malapposition, and positive remodeling of vessel wall. Current guidelines and expert consensus recommend intracoronary imaging should be used to identify the mechanisms of stent failure (restenosis and thrombosis) at follow-up.32,40,68 The common causes of stent restenosis, apart from intimal hyperplasia, are chronic underexpansion, stent fracture, and neoatherosclerosis.47,69 Chronic underexpansion and stent fracture could be assessed easily by IVUS, but the detection of neoatherosclerosis may need a higher resolution intracoronary modality. A prospective, multicenter study

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IVUS-guided Percutaneous Coronary Intervention showed that stent fracture could be found in 803 (12.3%) patients, 3,630 (22.0%) stents, and 1,852 (17.2%) diseased vessels, which was associated with higher risk of stent restenosis and definite stent thrombosis.70 In this study, a novel classification of stent fracture was proposed, identifying five types: • • • • •

type IA: single strut fracture; type IB: gap between 2 struts >2 times a 2.5mm cell; type II: incomplete transverse, V gap; type III: complete transverse, no displacement; and type IV: complete transverse with displacement.

Of 3,630 fractured stents in this study 2,963 were detected by angiography and the remaining 640 had to be identified by IVUS. Stent malapposition at

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follow-up should be divided into two types: persistent malapposition since stent implantation and late acquired malapposition, which may be caused by plaque/thrombus resolution and positive remodeling.54

Conclusion IVUS can provide important information about vessel lumen, dimensions, plaque characteristics, and stent deployment, as well as the mechanisms of device failure. Clinical studies have demonstrated that IVUS-guided PCI could improve the clinical outcomes in patients with DES implantation, especially for complex coronary lesions and high-risk patients. But IVUS guidance is not routinely performed in the real-world daily practice of PCI, partly due to the increased procedural time and extra cost. The next step should be to reduce the cost of IVUS, educate interventional cardiologists, and promote the use of IVUS as much as possible during PCI.

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48. Song HG, Kang SJ, Ahn JM, et al. Intravascular ultrasound assessment of optimal stent area to prevent in-stent restenosis after zotarolimus-, everolimus-, and sirolimus-eluting stent implantation. Catheter Cardiovasc Interv 2014;83:873–8. https://doi. org/10.1002/ccd.24560; PMID: 22815193.

49. Sonoda S, Morino Y, Ako J, et al. Impact of final stent dimensions on long-term results following sirolimus-eluting stent implantation: serial intravascular ultrasound analysis from the sirius trial. J Am Coll Cardiol 2004;43:1959–63. https://doi. org/10.1016/j.jacc.2004.01.044; PMID: 15172398.

50. Liu X, Doi H, Maehara A, et al. A volumetric intravascular ultrasound comparison of early drug-eluting stent thrombosis versus restenosis. JACC Cardiovasc Interv 2009;2:428–34. https:// doi.org/10.1016/j.jcin.2009.01.011; PMID: 19463466.

51. Moussa I, Moses J, Di Mario C, et al. Does the specific intravascular ultrasound criterion used to optimize stent expansion have an impact on the probability of stent restenosis?

Am J Cardiol 1999;83:1012–7. https://doi.org/10.1016/S00029149(99)00006-5; PMID: 10190511.

52. Doi H, Maehara A, Mintz GS, et al. Impact of post-intervention minimal stent area on 9-month follow-up patency of paclitaxeleluting stents: an integrated intravascular ultrasound analysis from the TAXUS IV, V, and VI and TAXUS ATLAS Workhorse, Long Lesion, and Direct Stent Trials. JACC Cardiovasc Interv 2009;2:1269–75. https://doi.org/10.1016/j.jcin.2009.10.005; PMID: 20129555.

53. Hong MK, Mintz GS, Lee CW, et al. Intravascular ultrasound predictors of angiographic restenosis after sirolimus-eluting stent implantation. Eur Heart J 2006;27:1305–10. https://doi. org/10.1093/eurheartj/ehi882; PMID: 16682378.

54. Guo N, Maehara A, Mintz GS, et al. Incidence, mechanisms, predictors, and clinical impact of acute and late stent malapposition after primary intervention in patients with acute myocardial infarction: an intravascular ultrasound substudy of the Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial. Circulation 2010;122:1077–84. https://doi.org/10.1161/ CIRCULATIONAHA.109.906040; PMID: 20805433.

55. Romagnoli E, Gatto L, La Manna A, et al. Role of residual acute stent malapposition in percutaneous coronary interventions.

Catheter Cardiovasc Interv 2017;90:566–75. https://doi. org/10.1002/ccd.26974; PMID: 28295990.

56. Wang B, Mintz GS, Witzenbichler B, et al. Predictors and longterm clinical impact of acute stent malapposition: an assessment of dual antiplatelet therapy with drug-eluting stents (ADAPT-DES) intravascular ultrasound substudy. J Am Heart Assoc 2016;5:pii:e004438. https://doi.org/10.1161/JAHA.116.004438; PMID: 28007741.

57. Qiu F, Mintz GS, Witzenbichler B, et al. Prevalence and clinical impact of tissue protrusion after stent implantation: an ADAPTDES intravascular ultrasound substudy. JACC Cardiovasc Interv 2016;9:1499–1507. https://doi.org/10.1016/j.jcin.2016.05.043; PMID: 27478119.

58. Cheneau E, Leborgne L, Mintz GS, et al. Predictors of subacute stent thrombosis: results of a systematic intravascular ultrasound study. Circulation 2003;108:43–7. https://doi. org/10.1161/01.CIR.0000078636.71728.40; PMID: 12821553.

59. de Jaegere P, Mudra H, Figulla H, et al. Intravascular ultrasoundguided optimized stent deployment. Immediate and 6 months clinical and angiographic results from the Multicenter Ultrasound Stenting in Coronaries Study (MUSIC Study). Eur Heart J 1998;19: 1214–23. https://doi.org/10.1053/euhj.1998.1012; PMID: 9740343.

60. Zhang J, Gao X, Ge Z, et al. Impact of intravascular ultrasoundguided drug-eluting stent implantation on patients with chronic kidney disease: results from ULTIMATE trial. Catheter Cardiovasc Interv 2019;93:1184–93. https://doi.org/10.1002/ccd.28308;

PMID: 31116913.

61. Buccheri S, Franchina G, Romano S, et al. Clinical outcomes following intravascular imaging-guided versus coronary angiography-guided percutaneous coronary intervention with stent implantation: a systematic review and bayesian network meta-analysis of 31 studies and 17,882 patients. JACC Cardiovasc Interv 2017;10:2488–98. https://doi.org/10.1016/j. jcin.2017.08.051; PMID: 29153502.

62. Shin DH, Hong SJ, Mintz GS, et al. Effects of intravascular ultrasound-guided versus angiography-guided new-generation drug-eluting stent implantation: meta-analysis with individual patient-level data from 2,345 randomized patients. JACC Cardiovasc Interv 2016;9:2232–9. https://doi.org/10.1016/j. jcin.2016.07.021; PMID: 27744039.

63. Steinvil A, Zhang YJ, Lee SY, et al. Intravascular ultrasound-guided drug-eluting stent implantation: an updated meta-analysis of randomized control trials and observational studies. Int J Cardiol 2016;216:133–9. https://doi.org/10.1016/j.ijcard.2016.04.154; PMID: 27153138.

64. Fan ZG, Gao XF, Li XB, et al. The outcomes of intravascular ultrasound-guided drug-eluting stent implantation among patients with complex coronary lesions: a comprehensive metaanalysis of 15 clinical trials and 8,084 patients. Anatol J Cardiol 2017;17:258–68. https://doi.org/10.14744/ AnatolJCardiol.2016.7461; PMID: 28344214.

65. Hong SJ, Mintz GS, Ahn CM, et al. Effect of intravascular ultrasound-guided drug-eluting stent implantation: 5-year followup of the IVUS-XPL randomized trial. JACC Cardiovasc Interv 2020;13:62–71. https://doi.org/10.1016/j.jcin.2019.09.033; PMID: 31918944.

66. Gao XF, Wang ZM, Wang F, et al. Intravascular ultrasound guidance reduces cardiac death and coronary revascularization in patients undergoing drug-eluting stent implantation: results from a meta-analysis of 9 randomized trials and 4,724 patients.

Int J Cardiovasc Imaging 2019;35:239–47. https://doi.org/10.1007/ s10554-019-01555-3; PMID: 30747368.

67. Zhang JJ, Chen SL. IVUS guidance for coronary revascularization: when to start, when to stop? JACC Cardiovasc Interv 2020;13:72–3. https://doi.org/10.1016/j.jcin.2019.11.002; PMID: 31918945.

68. Johnson TW, Raber L, di Mario C, et al. Clinical use of intracoronary imaging. Part 2: acute coronary syndromes, ambiguous coronary angiography findings, and guiding interventional decision-making: an expert consensus document of the European Association of Percutaneous Cardiovascular Interventions. Eur Heart J 2019;40:2566–84. https://doi. org/10.1093/eurheartj/ehz332; PMID: 31112213.

69. Goto K, Zhao Z, Matsumura M, et al. Mechanisms and patterns of intravascular ultrasound in-stent restenosis among bare metal stents and first- and second-generation drug-eluting stents. Am J Cardiol 2015;116:1351–7. https://doi.org/10.1016/j. amjcard.2015.07.058; PMID: 26341188.

70. Kan J, Ge Z, Zhang JJ, et al. Incidence and clinical outcomes of stent fractures on the basis of 6,555 patients and 16,482 drug-eluting stents from 4 centers. JACC Cardiovasc Interv 2016;9:1115–23. https://doi.org/10.1016/j.jcin.2016.02.025; PMID: 27009464.

US CARDIOLOGY REVIEW

Dual Antiplatelet Therapy

TWILIGHT: A Randomized Trial of Ticagrelor Monotherapy Versus Ticagrelor Plus Aspirin Beginning at 3 Months in High-risk Patients Undergoing Percutaneous Coronary Intervention Johny Nicolas, MD, Usman Baber, MD, and Roxana Mehran, MD The Zena and Michael A Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York City, NY

Abstract A P2Y12 inhibitor-based monotherapy after a short period of dual antiplatelet therapy is emerging as a plausible strategy to decrease bleeding events in high-risk patients receiving dual antiplatelet therapy after percutaneous coronary intervention. Ticagrelor With Aspirin or Alone in High-Risk Patients After Coronary Intervention (TWILIGHT), a randomized double-blind trial, tested this approach by dropping aspirin at 3 months and continuing with ticagrelor monotherapy for an additional 12 months. The study enrolled 9,006 patients, of whom 7,119 who tolerated 3 months of dual antiplatelet therapy were randomized after 3 months into two arms: ticagrelor plus placebo and ticagrelor plus aspirin. The primary endpoint of interest, Bleeding Academic Research Consortium type 2, 3, or 5 bleeding, occurred less frequently in the experimental arm (HR 0.56; 95% CI [0.45–0.68]; p<0.001), whereas the secondary endpoint of ischemic events was similar between the two arms (HR 0.99; 95% CI [0.78–1.25]). Transition from dual antiplatelet therapy consisting of ticagrelor plus aspirin to ticagrelor-based monotherapy in high-risk patients at 3 months after percutaneous coronary intervention resulted in a lower risk of bleeding events without an increase in risk of death, MI, or stroke.

Keywords Aspirin, ticagrelor, bleeding, dual antiplatelet therapy, TWILIGHT, drug-eluting stent Disclosure: UB received institutional research funding and advisory board/personal fees from AstraZeneca. RM received institutional research funding from AstraZeneca. JN has no conflicts of interest to declare.

Received: 17 December 2019 Accepted: 6 March 2020 Citation: US Cardiology Review 2020;14:e04. DOI: https://doi.org/10.15420/usc.2019.02 Correspondence: Roxana Mehran, The Zena and Michael A Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, 1 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.

Seminal clinical trials conducted in the balloon angioplasty and bare metal stent era established the superiority of dual antiplatelet therapy (DAPT) as compared with aspirin monotherapy or anticoagulation with respect to the prevention of thrombotic events.1,2 Other studies found that the benefits of DAPT are durable for at least 1 year and extend to patients with acute coronary syndromes.3–5 However, iterative advances in stent design lowered the thrombotic potential of these devices, thereby altering the risk–benefit calculus for prolonged durations of DAPT.6,7 Moreover, numerous studies have shown that bleeding confers a strong and independent risk for mortality after percutaneous coronary intervention (PCI), thus rendering the prevention of bleeding an important clinical priority.8–10 While several studies have shown that short DAPT durations followed by aspirin monotherapy may be safe and feasible in relatively low-risk patients, extension to higher-risk patient and lesion subsets remains less certain.11,12 An alternative approach that might preserve the benefits of strong P2Y12 inhibition while lowering bleeding involves the cessation of aspirin and continuation of a potent P2Y12 inhibitor after an initial course of DAPT.

© RADCLIFFE CARDIOLOGY 2020

Rationale of the Trial The What is the Optimal antiplatElet and anticoagulant therapy in patients with oral anticoagulation and coronary StenTing (WOEST) trial was the first study to examine the effect of an aspirin-free strategy in the context of PCI by comparing warfarin, clopidogrel, and aspirin with warfarin and clopidogrel over a period of 1 year among patients with AF.13 In this study, the withdrawal of aspirin led to a significant reduction in bleeding with no change in thrombotic events.13 Other studies using alternative direct oral anticoagulants recapitulated these observations, and an initial aspirin-free approach is considered optimal in most patients receiving oral anticoagulation and clopidogrel after PCI.13–16 In contrast, the GLOBAL LEADERS trial was the first examination of an aspirin-free strategy in a large, all-comer PCI population not receiving an oral anticoagulant.17 In this trial, ticagrelor monotherapy for 23 months was compared with conventional DAPT followed by aspirin alone. The experimental approach did not significantly reduce the risk for death or

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Dual Antiplatelet Therapy Table 1: Clinical and Angiographic Characteristics that Satisfy the High-risk Criteria High-risk Criteria* Clinical Criteria

Angiographic Criteria

Age ≥65 years

Multi-vessel coronary artery disease

Female sex

Total stent length of >30 mm

Troponin-positive acute coronary syndrome

Thrombotic target lesion

Established vascular disease

Bifurcation lesion treated with two stents

Diabetes treated with medications

Obstructive left main or proximal left anterior descending lesion

Chronic kidney disease

Calcified target lesion treated with atherectomy

* Patients should have at least one clinical and one angiographic criteria to be considered high risk.

Table 2: Definition of Primary Endpoint Bleeding Academic Research Consortium Bleeding Criteria Type

Definition of BARC Bleeding (Primary Endpoint)

0

No evidence of bleeding.

1

Bleeding that is not actionable.

2

Any clinically overt sign of hemorrhage that is actionable, but does not meet criteria for type 3, 4, or 5 bleeding. It must meet at least one of the following criteria: • Requiring medical or percutaneous intervention guided by a healthcare professional • Leading to hospitalization or an increased level of care • Prompting evaluation (laboratory or imaging)

3 3a

Clinical, laboratory, and/or imaging evidence of bleeding with healthcare responses, as listed below: • Any transfusion with overt bleeding • Overt bleeding plus hemoglobin (Hb) drop ≥3 to <5 g/dl (provided Hb drop is related to bleeding)

3b

Overt bleeding plus Hb drop ≥5 g/dl Cardiac tamponade Bleeding requiring surgical intervention for control Bleeding requiring intravenous vasoactive drugs

3c

Intracranial hemorrhage Intraocular bleed compromising vision

4

CABG-related bleeding • Perioperative intracranial bleeding within 48 hours • Reoperation following closure of sternotomy for the purpose of controlling bleeding • Transfusion of ≥5 units of whole blood or packed red blood cells within a 48-hour period • Chest tube output ≥2 l within a 24-hour period

5

Fatal bleeding. Bleeding directly causes death with no other explainable cause.

Categorized further as either definite or probable:

5a

Probable fatal bleeding that is clinically suspicious as the cause of death, but the bleeding is not directly observed

5b

Definite fatal bleeding that is directly observed.

BARC = Bleeding Academic Research Consortium; CABG = coronary artery bypass grafting; Hb = hemoglobin.

Q-wave MI over a period of 2 years, a null result that has been attributed to the inclusion of relatively low-risk patients, variable levels of drug adherence, or the lack of central adjudication.17 Hence, the benefits, or harms, of ticagrelor monotherapy in patients at higher risk for either ischemic or bleeding complications remain unclear.

In addition, it is plausible that higher-risk patients will derive a larger benefit from a therapeutic intervention aimed at lowering bleeding.

Accordingly, we designed the Ticagrelor With Aspirin or Alone in High-Risk Patients After Coronary Intervention (TWILIGHT) trial to test the hypothesis that ticagrelor monotherapy would yield a significant reduction in clinically relevant bleeding while not increasing ischemic risk, as compared with ticagrelor plus aspirin among high-risk patients undergoing PCI who had already completed a 3-month course of DAPT.

Study Design TWILIGHT (NCT02270242) is a randomized and double-blind trial conducted in 187 medical centers across 11 countries.18,19 The patients selected for participation underwent successful implantation of at least one drugeluting stent, followed by discharge on a regimen of ticagrelor plus aspirin, as intended by the treating physician. Selected patients were high risk, as defined by at least one clinical and one angiographic feature (Table 1).

Patients with ST-segment elevation MI, cardiogenic shock, ongoing longterm treatment with oral anticoagulants, or contraindication to antiplatelet therapy were excluded.

All enrolled patients received DAPT, consisting of ticagrelor (90 mg twice daily) and enteric-coated aspirin (81–100 mg daily) for 3 months after index PCI. Patients who showed adherence and did not have a major bleeding or ischemic event (stroke, MI, or coronary revascularization) at 3 months were randomized in a 1:1 fashion to either aspirin or placebo in addition to continuation of open label ticagrelor for an additional 12 months.

A secure web-based system was used to perform the randomization.

Sequences were randomly generated by blocks of four, six, and eight patients, and were stratified according to treatment site. Randomized patients were followed up by phone at 1 month and in person at 6 and 12 months after randomization. Adherence to medications was evaluated using manual pill counts.

The primary outcome of interest was bleeding events, defined as type ≥2 according to the Bleeding Academic Research Consortium (BARC) criteria (Table 2).20 The secondary outcomes were mainly ischemic events, including death from any cause, non-fatal MI or stroke, and thrombosis.

Both primary and secondary outcomes were observed between randomization and the 1-year follow-up period using a time-to-event analysis. All clinical events were externally adjudicated by an independent committee whose members were blinded to therapy assignment.

The study was powered to detect a difference in the primary endpoint of BARC type 2, 3, or 5 bleeding, based on a superiority assumption. A sample size of 8,200 patients was required to achieve 80% power in the detection of a 28% lower incidence of bleeding in the experimental group, assuming an incidence of 4.5% at 1 year in the control group (type I error rate of 0.05). Similarly, for the secondary endpoints, 8,200

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Ticagrelor Monotherapy Versus Ticagrelor Plus Aspirin patients were required to achieve a power of 80% in ruling out an absolute difference in risk of 1.6 percentage points (one-sided type I error rate of 0.025).

Figure 1: Kaplan–Meier Curves for the Primary and Secondary Outcomes

Out of 9,006 patients selected for participation, 7,119 were randomly assigned in a 1:1 fashion at 3 months to either ticagrelor plus placebo or ticagrelor plus aspirin with an intention-to-treat. The baseline demographic and clinical characteristics were very similar between the two arms: the mean age was 65 years, women represented 24% of participants, and the prevalence of diabetes and chronic kidney disease was approximately 40% and 17%, respectively. Multivessel coronary artery disease was prevalent in 63.9% of patients in the experimental arm, and 61.6% of those in the control arm.

The primary endpoint, bleeding events (BARC type 2, 3, or 5), occurred in 7.1% of patients who received ticagrelor plus aspirin, and 4.0% of those who received ticagrelor plus placebo (HR 0.56; 95% CI [0.45–0.68]; p<0.001; Figure 1A). Secondary endpoints, mainly ischemic events (including all-cause death, non-fatal MI, or non-fatal stroke), occurred similarly in the two arms: 3.9% in those who received ticagrelor plus placebo, and 3.9% in those who received ticagrelor plus aspirin (HR 0.99; 95% CI [0.78–1.25]; Figure 1B). These findings were consistent across all subgroups analyzed (age, sex, race/ethnicity, diabetes, chronic kidney disease, BMI, indication for PCI, total stent length, prior MI, and multivessel disease).

In contrast, ischemic events occurred similarly in both arms, indicating that dual therapy does not confer additional protection from death, MI, and stroke. In other words, ticagrelor monotherapy led to a lower bleeding events rate without compromising the protection from ischemic events, as compared with a dual therapy regimen. These findings were consistent with some previously published studies, but conflicted with others. The differences are mainly due to variations in clinical trial design and execution (Table 3).

Two randomized clinical trials, ShorT and OPtimal Duration of Dual AntiPlatelet Therapy-2 (STOPDAPT-2) and Smart Angioplasty Research Team: Comparison Between P2Y12 Antagonist Monotherapy vs Dual Antiplatelet Therapy in Patients Undergoing Implantation of Coronary

US CARDIOLOGY REVIEW

10

80

8

Ticagrelor + aspirin Ticagrelor + placebo Placebo versus aspirin HR 0.56 (95% CI 0.45–0.68) p<0.001

6

60 4

40

2 0

20

0

0

3

6

9

12

3

6

9

12

Months since randomization Number at risk Ticagrelor + aspirin Ticagrelor + placebo

3,564 3,555

3,454 3,474

3,357 3,424

3,277 3,336

3,213 3,321

Death, MI, or stroke 100

10

Ticagrelor + aspirin Ticagrelor + placebo

8

80

6

Placebo versus aspirin HR 0.99 (95% CI 0.78–1.25)

60 4

40

2

20

0 0

3

6

9

12

0 0

Discussion Transition to ticagrelor monotherapy after 3 months of DAPT in high-risk patients who received a drug-eluting stent was associated with a significant decrease in the incidence of bleeding events (44% lower risk of BARC type 2, 3, or 5 bleeding). The benefits of aspirin withdrawal at 3 months extended to severe bleeding events (BARC type 3 or 5) and across different bleeding scales (Thrombolysis in Myocardial Infarction [TIMI], Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries [GUSTO], and the International Society on Thrombosis and Haemostasis [ISTH]).21–23

100

0

Cumulative incidence (%)

Results

Cumulative incidence (%)

BARC 2, 3, or 5 bleeding

The primary endpoint of bleeding was analyzed using an intention-totreat approach. In contrast, the analysis of ischemic events was completed by only including randomized patients who completed the treatment originally allocated (per-protocol approach).

3

6

9

12

Months since randomization Number at risk Ticagrelor + aspirin Ticagrelor + placebo

3,515 3,524

3,466 3,457

3,415 3,412

3,361 3,365

3,320 3,330

A: Kaplan–Meier estimates of the incidence of BARC type 2, 3, or 5 bleeding 1 year after randomization (intention-to-treat population). B: Kaplan–Meier estimates of the incidence of death from any cause, non-fatal MI, or non-fatal stroke 1 year after randomization (per-protocol population). BARC = Bleeding Academic Research Consortium. Source: Mehran et al. 2019.19 Reproduced with permission from Massachusetts Medical Society.

Drug-Eluting Stents (SMART-CHOICE), showed a significant bleeding risk reduction without a change in ischemic events when switched to clopidogrel monotherapy after 1–3 months of DAPT.24,25 In contrast, GLOBAL LEADERS showed that 1 month of DAPT followed by 23 months of ticagrelor monotherapy did not reduce the risk of bleeding as compared to dual therapy.17 The contradictory results between TWILIGHT and GLOBAL LEADERS can be explained by differences in study design: the first is double-blind, a high-risk population who received monotherapy for 12 months; whereas the second trial is open-label, an all-comers population who received therapy for 23 months. In addition, the control arm in GLOBAL LEADERS was maintained on aspirin, whereas in TWILIGHT it was maintained on ticagrelor plus aspirin. Finally, bleeding events were self-reported in GLOBAL LEADERS, whereas adjudication committees evaluated events in TWILIGHT.

Dual Antiplatelet Therapy Table 3: Comparison Between TWILIGHT and Other Randomized Trials

Sample size

GLOBAL LEADERS17

STOPDAPT-224

SMART-CHOICE25

TWILIGHT19

15,968

3,045

2,993

7,119

Case mix

All-comers

All-comers

All-comers

Enriched with high-risk features

Design

Open-label

Open-label

Open-label

Double-blind

Primary endpoint

Death or Q-wave MI

Death, MI, stroke, ST, bleeding

Death, MI, stroke

BARC 2, 3, 5

Hypothesis

Superiority

Non-inferiority

Non-inferiority

Superiority

BARC = Bleeding Academic Research Consortium; ST = stent thrombosis.

Figure 2: TWILIGHT Trial

Ticagrelor with or without aspirin in high-risk patients after PCI Inclusion criteria

Multicenter, randomized, double-blind, placebo-controlled clinical trial

High ischemia/bleeding risk patients who underwent PCI with at least one locally approved DES and had successfully tolerated DAPT for 3 months post-PCI without an ischemic or bleeding event

Study objective

Assess efficacy of ticagrelor monotherapy in patients undergoing PCI who are at high risk for ischemic or hemorrhagic complications maintained on DAPT for 3 months

Primary outcome 3 months

12 months

Secondary outcome

BARC 2, 3, or 5

Death, MI, stroke

Stent thrombosis

7.1%

3.9%

0.6%

HR 0.56 95% CI [0.45–0.68] p<0.001

HR 0.99 95% CI [0.78–1.25]

HR 0.74 95% CI [0.37–1.47]

4.0%

3.9%

n=3,564 Ticagrelor (90 mg twice daily)

Aspirin (81–100 mg daily)

Randomization 1:1

n=3,555 Ticagrelor (90 mg twice daily)

Drop aspirin

0.4%

Placebo

Among high-risk patients who underwent PCI and completed 3 months of DAPT, ticagrelor monotherapy for 12 months was associated with lower incidence of bleeding and similar ischemic events rate as ticagrelor plus aspirin BARC = Bleeding Academic Research Consortium; DAPT = dual antiplatelet therapy; DES = drug-eluting stent; PCI = percutaneous coronary intervention.

All these differences could explain the attenuated beneficial effect of aspirin withdrawal in GLOBAL LEADERS as compared with TWILIGHT. Indeed, in patients maintained on ticagrelor monotherapy, the relative incidence of BARC type 3 or 5 bleeding was 14% lower in GLOBAL LEADERS compared with 51% in TWILIGHT.17 The main strength of the TWILIGHT trial is mainly in including high-risk patients who are highly prone to primary or secondary endpoints at 12 months follow-up. Consequently, shortening exposure to dual antiplatelet agents in this vulnerable population has a great impact on bleeding reduction without compromising the ischemic protection. Nevertheless, the TWILIGHT results are only applicable to patients satisfying prespecified clinical and angiographic features (Table 1), and cannot be generalized to patients with ST-segment elevation MI or non-acute coronary syndrome on presentation.

Moreover, 36% of all patients included in the study were either asymptomatic or had stable angina. A dual antiplatelet regimen consisting of aspirin and clopidogrel is usually recommended by all guidelines for such patients.11,26 Hence, it is expected that the use of ticagrelor rather than clopidogrel in non-acute coronary syndrome patients results in a higher incidence of bleeding events without a significant change in ischemic events.

Consequently, one might assume that the beneficial effect of ticagrelor monotherapy should not be extended to all PCI patients, and especially to those with stable disease. However, all patients enrolled in TWILIGHT, including those with stable disease, had at least one clinical and one angiographic characteristic that placed them at high risk for complications following PCI, and hence they were prescribed a more potent P2Y12 inhibitor (ticagrelor rather than clopidogrel).

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Ticagrelor Monotherapy Versus Ticagrelor Plus Aspirin The present study had several limitations. First, the lack of power to detect differences in the risk of stent thrombosis and stroke (considered as rare events). Second, only high-risk patients were included; hence, the results may not be applicable to low-to-intermediate-risk patients. Furthermore, the results are also not applicable to patients who satisfied the high-risk criteria but did not tolerate DAPT in the first 3 months. Third, more ischemic cerebrovascular events were recorded in patients receiving ticagrelor monotherapy; however, because of the low number of events (24), no conclusion can be made. Fourth, the primary endpoint included bleeding events of different severity, which might affect the risk–benefit calculation for ticagrelor monotherapy. Fifth, a lower than expected incidence of the composite endpoint for the secondary outcomes may have biased the study results toward the null. Sixth, patients with ST-segment elevation MI

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6. Palmerini T, Biondi-Zoccai G, Della Riva D, et al. Stent thrombosis with drug-eluting stents: is the paradigm shifting? J Am Coll Cardiol 2013;62:1915–21. https://doi.org/10.1016/j. jacc.2013.08.725; PMID: 24036025.

7. Kereiakes DJ, Yeh RW, Massaro JM, et al. Stent thrombosis in drug-eluting or bare-metal stents in patients receiving dual antiplatelet therapy. JACC Cardiovasc Interv 2015;8:1552–62. https://doi.org/10.1016/j.jcin.2015.05.026; PMID: 26493248.

8. Baber U, Mehran R, Giustino G, et al. Coronary thrombosis and major bleeding after PCI with drug-eluting stents: risk scores from PARIS. J Am Coll Cardiol 2016;67:2224–34. https://doi. org/10.1016/j.jacc.2016.02.064; PMID: 27079334.

9. Généreux P, Giustino G, Witzenbichler B, et al. Incidence, predictors, and impact of post-discharge bleeding after percutaneous coronary intervention. J Am Coll Cardiol 2015;66:1036–45. https://doi.org/10.1016/j.jacc.2015.06.1323; PMID: 26314532.

10. Valle JA, Shetterly S, Maddox TM, et al. Postdischarge bleeding after percutaneous coronary intervention and subsequent mortality and myocardial infarction: insights from the HMO

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11.

12.

13.

14.

15.

16.

17.

18.

on presentation were excluded, which could affect the generalizability of the results to this high-risk population.

Conclusion Transition from dual antiplatelet therapy consisting of ticagrelor plus aspirin to ticagrelor-based monotherapy in high-risk patients at 3 months after PCI resulted in a lower bleeding events rate without an increase in death, MI, or stroke (Figure 2). The ongoing challenge will be in integrating the findings of TWILIGHT with the abundant evidence from previous studies supporting long-term DAPT in patients with low bleeding but high ischemic risk. Nonetheless, the decision to switch from DAPT to ticagrelor monotherapy remains at the discretion of each physician’s clinical judgment and the patient’s specific baseline characteristics.

Research Network-Stent Registry. Circ Cardiovasc Interv 2016;9:e003519. https://doi.org/10.1161/ CIRCINTERVENTIONS.115.003519; PMID: 27301394.

Levine GN, Bates ER, Bittl JA, et al. 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2016;68:1082–115. https://doi.org/10.1016/j.jacc.2016.03.513; PMID: 27036918.

Bhatt DL, Fox KA, Hacke W, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events.

N Engl J Med 2006;354:1706–17. https://doi.org/10.1056/ NEJMoa060989; PMID: 16531616.

Dewilde WJ, Oirbans T, Verheugt FW, et al. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an openlabel, randomised, controlled trial. Lancet 2013;381:1107–15. https://doi.org/10.1016/S0140-6736(12)62177-1; PMID: 23415013.

D’Ascenzo F, Taha S, Moretti C, et al. Meta-analysis of randomized controlled trials and adjusted observational results of use of clopidogrel, aspirin, and oral anticoagulants in patients undergoing percutaneous coronary intervention. Am J Cardiol 2015;115:1185–93. https://doi.org/10.1016/j. amjcard.2015.02.003; PMID: 25799015.

Gibson CM, Mehran R, Bode C, et al. Prevention of bleeding in patients with atrial fibrillation undergoing PCI. N Engl J Med 2016;375:2423–34. https://doi.org/10.1056/NEJMoa1611594; PMID: 27959713.

Cannon CP, Bhatt DL, Oldgren J, et al. Dual antithrombotic therapy with dabigatran after PCI in atrial fibrillation. N Engl J Med 2017;377:1513–24. https://doi.org/10.1056/NEJMoa1708454; PMID: 28844193.

Vranckx P, Valgimigli M, Jüni P, et al. Ticagrelor plus aspirin for 1 month, followed by ticagrelor monotherapy for 23 months vs aspirin plus clopidogrel or ticagrelor for 12 months, followed by aspirin monotherapy for 12 months after implantation of a drugeluting stent: a multicentre, open-label, randomised superiority trial. Lancet 2018;392:940–9. https://doi.org/10.1016/S01406736(18)31858-0; PMID: 30166073.

Baber U, Dangas G, Cohen DJ, et al. Ticagrelor with aspirin or alone in high-risk patients after coronary intervention: rationale

and design of the TWILIGHT study. Am Heart J 2016;182:125–34. https://doi.org/10.1016/j.ahj.2016.09.006; PMID: 27914492.

19. Mehran R, Baber U, Sharma SK, et al. Ticagrelor with or without aspirin in high-risk patients after PCI. N Engl J Med 2019;381:2032–42. https://doi.org/10.1056/NEJMoa1908419; PMID: 31556978.

20. Mehran R, Rao SV, Bhatt DL, et al. Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium. Circulation 2011;123:2736-2747. https://doi.org/10.1161/ CIRCULATIONAHA.110.009449; PMID: 21670242.

21. Rao AK, Pratt C, Berke A, et al. Thrombolysis in Myocardial Infarction (TIMI) trial – phase I: hemorrhagic manifestations and changes in plasma fibrinogen and the fibrinolytic system in patients treated with recombinant tissue plasminogen activator and streptokinase. J Am Coll Cardiol 1988;11:1–11. https://doi. org/10.1016/0735-1097(88)90158-1; PMID: 3121710.

22. GUSTO investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med 1993;329:673–82. https://doi.org/10.1056/ NEJM199309023291001; PMID: 8204123.

23. Rodeghiero F, Tosetto A, Abshire T, et al. ISTH/SSC bleeding assessment tool: a standardized questionnaire and a proposal for a new bleeding score for inherited bleeding disorders.

J Thromb Haemost 2010;8:2063–5. https://doi.org/10.1111/ j.1538-7836.2010.03975.x; PMID: 20626619.

24. Watanabe H, Domei T, Morimoto T, et al. Effect of 1-month dual antiplatelet therapy followed by clopidogrel vs 12-month dual antiplatelet therapy on cardiovascular and bleeding events in patients receiving PCI: the STOPDAPT-2 randomized clinical trial.

JAMA 2019;321:2414–27. https://doi.org/10.1001/jama.2019.8145; PMID: 31237644.

25. Hahn JY, Song YB, Oh JH, et al. Effect of P2Y12 inhibitor monotherapy vs dual antiplatelet therapy on cardiovascular events in patients undergoing percutaneous coronary intervention: the SMART-CHOICE randomized clinical trial. JAMA 2019;321:2428–37. https://doi.org/10.1001/jama.2019.8146; PMID: 31237645.

26. Knuuti J, Wijns W, Saraste A, et al. 2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes. Eur Heart J 2019;41:407–77. https://doi.org/10.1093/eurheartj/ehz425; PMID: 31504439.

Coronary Imaging & Complex Interventions

Calcified Lesion Assessment and Intervention in Complex Percutaneous Coronary Intervention: Overview of Angioplasty, Atherectomy, and Lithotripsy Alexander G Truesdell, MD,1,2 Matheen A Khuddus, MD,3 Sara C Martinez, MD, PhD,4 and Evan Shlofmitz, DO5 1. Virginia Heart, Falls Church, VA; 2. Inova Heart and Vascular Institute, Falls Church, VA; 3. The Cardiac and Vascular Institute, Gainesville, FL; 4. Providence St Peter Hospital, Olympia, WA; 5. MedStar Washington Hospital Center, Washington, DC

Abstract Calcific coronary artery disease intervention is associated with uniformly worse short-term procedural and long-term clinical results compared with treatment of non-calcified lesions. Multiple intravascular imaging tools currently exist to aid the identification and detailed characterization of intracoronary calcium, and guide appropriate follow-on management strategies. Several unique device therapies, to include angioplasty, atherectomy, and lithotripsy may be employed to enhance lesion preparation, stent implantation and optimization, and improve patient outcomes.

Current low use of both imaging and ablative technologies in the US offers significant future opportunities for improving the comprehensive evaluation and management of these complex lesion subsets and patients.

Keywords Coronary calcification, intravascular imaging, angioplasty, atherectomy, lithotripsy Disclosure: AGT is a consultant and on the speakers bureau at Abiomed. MAK is a consultant and on the speakers bureau at Abbott Vascular and Merit Medical, is a consultant at Microvention, and is on the advisory board at Procyrion. ES is a consultant at Opsens Medical and Abbott Vascular. SCM has no conflicts of interest to declare.

Received: March 29, 2020 Accepted: April 28, 2020 Citation: US Cardiology Review 2020;14:e05. DOI: https://doi.org/10.15420/usc.2020.16 Correspondence: Alexander G Truesdell, Virginia Heart, Inova Heart and Vascular Institute, 2901 Telestar Court, Falls Church, VA 22042.

E: agtruesdell@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.

“When you fail to prepare, you’re preparing to fail.”

– Coach John Wooden

Ongoing technological and procedural innovations increasingly permit the safe and effective performance of ever more high-risk and complex percutaneous coronary interventions (PCI) in the modern cardiac catheterization laboratory. Anatomic characteristics of higher risk include unprotected distal left main stenosis, bifurcation and trifurcation lesions, chronic total occlusions, vein graft lesions, last remaining vessels supplying large myocardial territories, and heavily calcified lesions.1–3 Moderate-to-severe coronary calcification is encountered in up to one-third of coronary lesions, is commonly associated with a greater degree of lesion complexity to include coronary bifurcations and chronic total occlusions, and is expected to increase in prevalence with increasing patient age, chronic kidney disease, and diabetes.4–6 Patients with severely calcific coronary lesions have overall higher mortality, worse outcomes independent of clinical presentation, and are less likely to receive complete revascularization. 2,7,8 Heavily calcified lesions are difficult to dilatate, and are more commonly

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associated with coronary dissection and perforation, failure to deliver stents, stent underexpansion and malapposition, polymer disruption and impaired drug delivery with drug-eluting stents, and higher rates of target lesion failure, restenosis, stent thrombosis, MI, and death. 2,4,9–11 Technologies to include high-pressure non-compliant balloons, ultrahigh-pressure balloons, cutting balloons, and various forms of atherectomy are all designed to facilitate PCI in severely calcified coronary arteries (Table 1). Over time, atherectomy has evolved from a stand-alone debulking therapy to a bail-out technique in undilatatable stenoses or an adjunct to balloon angioplasty, and finally into a primary approach of intentional lesion preparation.12–15 The contemporary objective of atherectomy is plaque modification to disrupt the continuity of calcium, and enable balloon inflation and stent implantation and expansion while also minimizing side branch compromise.16 Up-front versus bail-out atherectomy is also associated with decreased fluoroscopy dose, shorter procedural times, lower contrast volume, and the use of fewer predilatation balloons.17 Despite such advantages, atherectomy is employed infrequently in the US, and its use remains highly variable across operators and hospitals.1

© RADCLIFFE CARDIOLOGY 2020

Angioplasty, Atherectomy, and Lithotripsy Table 1: Angioplasty, Atherectomy, and Lithotripsy Device Comparison Atherectomy and Laser Lesion Modification

Balloon-based Lesion Modification

Device

Rotational atherectomy

Orbital atherectomy

Excimer laser coronary atherectomy

Intravascular lithotripsy

Cutting balloon

Scoring balloon

Super high-pressure non-compliant balloon

Mechanism of action

Differential cutting with mechanical ablation of inelastic plaque by concentric rotation and antegrade movement of an elliptical burr

Differential sanding of calcified plaque by elliptical rotation and antegrade and retrograde movement of an eccentrically mounted crown

Ablation and modification of recalcitrant lesions by catheter emitted pulses of ultraviolet light

Disruption of calcified lesions with unfocused circumferential pulsatile mechanical energy during lowpressure balloon inflation63

Creation of discrete incisions in fibrocalcific tissue by multiple longitudinally placed atherotomes

Controlled expansion with low dissection rates using a balloon with external nitinol scoring wires6

Uniform lesion expansion using a twin layer balloon design to very high pressure29

Device sizes

Burrs (mm): 1.25, 1.50, 1.75, 2.00, 2.15, 2.25, 2.38, and 2.50

Crown (mm): 1.25

Catheters (mm): 0.9, 1.4, 1.7, and 2.0

Balloons (mm): 2.5–4.0 diameter (in 0.25 mm increments) in 12 mm length

Balloons (mm): 2.0–4.0 (in 0.25 mm increments) in 6, 10, and 15 mm lengths

Balloons (mm): 2.0–3.5 (in 0.5 mm increments) in 6, 10, and 15 mm lengths

Balloons (mm): 1.5–4.5 (in 0.5 mm increments) in 10, 15, and 20 mm lengths

Guide catheter compatibility

6 Fr: 1.25 mm and 6 Fr 1.50 mm burr 7 Fr: 1.75 mm burr 8 Fr: 2.00 mm and 2.15 mm burr 9 Fr: 2.25 mm and 2.38 mm burr 10 Fr: 2.50 mm burr

6 Fr: 0.9, 1.4 mm 7 Fr: 1.7 mm 8 Fr: 2.0 mm

6 Fr

6 Fr

6 Fr

5 Fr

Device sizing

Burr-to-artery ratio: Single size crown 0.4–0.634

Catheter-to-vessel ratio: 0.5–0.6

1:1 sizing63

≤1:1 sizing

≤1:1 sizing

≤1:1 sizing

Technique

Rotational speed of 140,000–180,000 rpm using a ‘pecking’ motion with gradual burr advancement, short ≤30 s runs, and avoidance of decelerations >5,000 rpm31,34

Rotational speed options of 80,000 and 120,000 rpm with higher speed translating to a larger crown orbit, slow crown advancement (1–3 mm/s), short ≤30 s runs32

Laser activation of 10 s with a 5 s pause prior to next pulse, very slow catheter advancement (0.5 mm/s), manual flush saline infusion before and during ablation required47

Delivery of 1 cycle of 10 pulses (1 pulse/s) for total of 8 cycles per catheter63

Rapid exchange balloon with very slow and controlled inflation and deflation

Rapid exchange balloon with very slow and controlled inflation and deflation

Rapid exchange balloon designed to deliver high-pressure inflation ≥35 atm47

Complications

No-reflow, dissection, perforation, burr entrapment, AV block34

No-reflow, dissection, perforation, abrupt closure44

Dissection, perforation7

Dissection, electric signals similar to pacing spikes, asynchronous cardiac pacing63

Dissection, perforation6

Dissection32

Dissection29

Wire

RotaWire Floppy (0.014/0.009"), RotaWire Extra Support (0.014/0.009")

ViperWire (0.014/0.012"), ViperWire Advance with Flex Tip (0.014/0.012")

Standard 0.014" Standard 0.014" Standard 0.014" Standard 0.014" Standard 0.014" coronary guidewire coronary guidewire coronary guidewire coronary guidewire coronary guidewire

Particle size

5−10 µm

<2 µm

<10 µm

–

–

–

–

Regulatory approval

FDA, CE mark

FDA, CE mark

FDA, CE mark

CE mark

FDA, CE mark

FDA, CE mark

CE mark

CE = Conformitè Europëenne; ELCA = excimer laser coronary atherectomy; FDA = Food and Drug Administration; IVL = intravascular lithotripsy.

Lesion Assessment Accurate characterization of calcium distribution and morphology is key to successful treatment. Coronary angiography grossly underestimates the presence, extent, severity, and depth of coronary calcification (Figure 1).18,19 Advanced intravascular imaging techniques enhance

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identification of calcium, and permit comprehensive assessment of calcium burden, eccentricity, depth, distribution, and the presence or absence of a calcified nodule, thereby facilitating a tailored strategy for lesion preparation and appropriate atherectomy device selection (Figure 2).20 Intravascular imaging simplifies complex decision-making,

Coronary Imaging & Complex Interventions Figure 1: Intravascular Imaging Assessment of Calcium Characteristics and Morphology Deep calcium

Calcified nodule

A

Superficial calcium

B

C

Optical coherence tomography cross-sections demonstrating eccentric deep calcium (A), a calcified nodule protruding into the vessel lumen (B), and concentric superficial calcium (C).

Figure 2: Algorithmic Approach to the Treatment of Heavily Calcified Coronary Lesions OCT/IVUS to assess calcified plaque

Deep

Uncrossable

Superficial

Mildâ&#x20AC;&#x201C;moderate

Nodular

Moderateâ&#x20AC;&#x201C;severe

Balloon crossable

NC/scoring/cutting balloon-based lesion preparation

Balloon uncrossable

Intravascular lithotripsy, orbital atherectomy or rotational atherectomy

Orbital atherectomy or rotational atherectomy

Calcium fracture present on OCT/IVUS

Final OCT/IVUS

Stent No

Yes

Stent

Final OCT/IVUS

Intravascular imaging permits identification of calcified plaque characteristics and morphology to guide optimal lesion preparation. Following lesion preparation, intravascular imaging facilitates identification of the adequacy of calcium fracture and plaque modification, and guides appropriate stent sizing. Final postintervention imaging is recommended to ensure adequate stent expansion.

IVUS = intravascular ultrasound; NC = non-compliant; OCT = optical coherence tomography.

reduces radiation and contrast exposure, provides accurate measurement of luminal size, lesion length, and reference vessel diameter, offers visualization of projected stent landing zones, and ensures that adequate postprocedure endpoints, to include stent expansion and apposition, and the absence of edge dissections, have been achieved (Figure 3).21 As is the case with atherectomy, despite an association with improved clinical

outcomes, the use of intravascular imaging remains low in the US, with substantial interoperator and interhospital variability.22,23 Intravascular ultrasound (IVUS) is the most reliable diagnostic tool to detect coronary calcium with high tissue penetration. However, due to acoustic shadowing, IVUS reveals the calcific arc without defining its

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Angioplasty, Atherectomy, and Lithotripsy Figure 3: Lesion Preparation and Percutaneous Coronary Intervention Rotational atherectomy

A

Orbital atherectomy

B

Intravascular lithotripsy

C

Optical coherence tomography demonstrating fracture of calcified plaque (white arrow) following lesion preparation and stent implantation with rotational atherectomy (A), orbital atherectomy (B), and intravascular lithotripsy (C).

thickness. Despite more limited depth penetration, optical coherence tomography, with its higher spatial (axial and longitudinal) resolution, offers more accurate quantification of calcific plaque, such as calcium area, thickness, length, and 3D volume, all of which better predict response to balloon dilatation.24â&#x20AC;&#x201C;26 Optical coherence tomography also has higher sensitivity compared with IVUS in detecting both stent malapposition and underexpansion.27

Balloon Angioplasty Balloon-based techniques do not remove calcium, but aim to increase plaque elasticity and allow stent expansion by cracking calcified zones in one or multiple areas. Standard balloon dilatation of calcified lesions often results in non-uniform balloon expansion and consequent overexpansion of, and injury to, more compliant vessel segments. Non-compliant balloons apply higher inflation forces and facilitate more uniform balloon expansion. The newer OPN noncompliant balloon (SIS Medical) permits uniform expansion up to super high pressures of 40 atm, but may still be biased toward noncalcified vessel segments leading to dissection at the fibrocalcific interface. 28,29 Cutting balloons utilize multiple atherotomes placed longitudinally on the balloon surface to concentrate dilatation forces along the blades to create radial incisions with more controlled intimal and medial dissections. 30 However, they are often too bulky to cross undilatable lesions and may further fail to expand lesions with significant calcification, even at high pressures.

Rotational Atherectomy Rotational atherectomy (RA; Boston Scientific) employs a diamondcoated elliptical burr to rotate concentrically while advancing in a forward direction. Differential cutting permits mechanical ablation of inelastic fibrocalcific plaque while sparing adjacent compliant elastic vessel tissue.31,32 The effect of RA on severely calcified lesions depends on the calcium eccentricity, luminal area, burr size, and degree of guidewire bias.33 When circumferential calcium is present and the minimal luminal area is smaller than the burr size, RA effectively drills a circular lumen inside the calcium.34 When the burr used is smaller than

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the luminal area, calcium modification is only seen in areas where guidewire bias directs the burr toward the vessel wall.

Most operators use standard workhorse coronary wires for lesion crossing followed by microcatheter wire exchange, as both versions of the RotaWire are limited by poor lesion crossability. The Floppy RotaWire is most commonly used for RA, although the Extra Support wire may preferentially be employed to alter wire bias and ablate plaque at the lesser curvature (versus greater curvature) of angulated lesions, or for aorto-ostial or distal vessel lesions.35 Cutting balloons may sometimes also be deployed after RA to facilitate more complete calcium fracture and greater stent expansion.36 Contemporary best practices, to include appropriate lesion selection, proper burr-sizing, optimal atherectomy speed and duration, integration of visual, tactile, and auditory feedback and strategies to anticipate, prevent and manage adverse events are well reviewed elsewhere.31,34 Procedural complications, such as no-reflow, and vessel dissection and perforation, are largely preventable with optimal technique. Transient conduction disturbances may likewise be prevented by shorter RA runs, longer breaks between runs, and prophylactic pharmacological measures, thereby avoiding the risks associated with temporary pacemaker implantation.37

Orbital Atherectomy Orbital atherectomy (OA; Cardiovascular Systems) has a crown design with diamond chips on both the front and back to allow ablation during both antegrade and retrograde motion while facilitating continuous blood flow during both rest and ablation, thereby reducing thermal injury, transient heart block, no reflow, and the risks of crown entrapment.38â&#x20AC;&#x201C;41 OA utilizes differential sanding during fast elliptical rotation of the crown using centrifugal force to ablate hard noncompliant calcium while sparing normal healthy vascular tissue, and demonstrates deeper tissue ablation compared with RA.42 Increased orbit diameter and deeper ablation arcs are created using a single-sized crown by decreasing advancement speed and increasing contact time

Coronary Imaging & Complex Interventions Table 2: Angioplasty, Atherectomy, and Lithotripsy Clinical Trial Data Trial

Study Design

Sample Size

Study Arms

LAVA Study (1997)49

Randomized controlled trial

215

117 laser versus 98 PTCA No difference in procedural alone success or diameter stenosis after treatment

No benefits of laser-facilitated PTCA versus stand-alone PTCA Procedural complications significantly increased with laser

STRATAS (2001)13

Randomized controlled trial

497

249 aggressive RA burr sizing (burr/artery ratio >0.70) versus 248 routine RA burr sizing (burr/artery ratio <0.70)

6-month TLR 31% with aggressive RA strategy versus 22% with routine RA strategy Restenosis 58% with aggressive RA strategy versus 52% with routine RA strategy

Aggressive RA with burr/artery ratio >0.70 offers no advantage over routine RA strategy A decrease in rpm >5,000 from baseline associated with CK-MB elevation, and restenosis

CARAT (2001)12

Randomized controlled trial

222

104 RA burr/artery ratio >0.7 (lesion debulking) and 118 RA burr/artery ratio <0.7 (lesion modification)

Diameter stenosis at procedure end

No differences in procedural success, extent of immediate lumen enlargement, or late TVR Large burrs had more serious angiographic complications (12.7% versus 5.1%)

ROTAXUS (2013)67

Randomized controlled trial

240

120 RA + DES versus 120 PTCA + DES

9-month in-stent late lumen loss Balloon dilation with provisional RA 0.44 RA versus 0.31 PTCA, despite preferred over routine RA higher acute lumen gain with RA

LEONARDO Study (2015)50

Prospective, single-arm

80

100 lesions (96 treated with ELCA)

Laser success 93.7%, procedural success 91.7%, clinical success 90.6% No major complications

LA is simple, safe, and effective for complex lesions

ROTATE (2016)17

Registry

985

1167 lesions treated with RA

In-hospital MACE 8.3%, driven by periprocedural MI

RA is safe and effective in severely calcified lesions

ORBIT II (2016)40

Prospective, single-arm

443

OA + BMS (43), OA + first-generation DES (74), OA + second-generation DES (312)

2-year MACE, 19.4% (BMS), 4.3% (first-generation DES), 8.1% (second-generation DES)

OA is safe and effective in de novo, severely calcified lesions

Registry of OA (2016)44

Multicenter registry

458

OA + DES

30-day MACCE 1.7%

Real-world patients to include high-risk and surgical turn-down Acute and short-term adverse rates were low

120

IVL on calcified coronary lesions

Calcium fracture identified in 78.7% of lesions In-hospital MACE, 5.8% with non-Q-wave MI

IVL safely performed with high procedural success

No significant differences between OA versus RA except fluoroscopy time

Disrupt CAD II Study Prospective, multicenter, single-arm (2019)52

Outcomes/Results

OA versus RA meta-analysis (2020)58

Meta-analysis

1,872

535 OA versus 1,337 RA

OA lower fluoroscopy times No difference in 30-day MI, complications, mortality, TVR, or MACE

ECLIPSE Trial NCT03108456 (ongoing)

Randomized controlled trial

2,000 (planned enrollment)

OA versus PTCA prior to DES implantation

Acute minimum stent area, procedural success, and 1-year TVF

DISRUPT CAD III NCT03595176 (ongoing)

Prospective multicenter single-arm

392 (planned enrollment)

IVL prior to DES implantation

Adverse events, procedural success (residual stenosis <50%)

Conclusions

BMS = bare-metal stent; DES = drug-eluting stent; ELCA = excimer laser coronary atherectomy; IVL = intravascular lithotripsy; MACE = major adverse cardiovascular events; MACCE = major adverse cardiovascular and cerebrovascular events; MB = modified balloon-cutting or scoring balloon; OA = orbital atherectomy system; PTCA = percutaneous coronary angioplasty; RA = rotational atherectomy; RCT = randomized clinical trial; TLR = target lesion revascularization; TVF = target vessel failure.

between crown and plaque, increasing the number of passes, increasing rotation speed, and altering wire bias.43,44

Laser Atherectomy Excimer laser coronary atherectomy (ELCA; Philips) modifies tissue by three distinct mechanisms: photochemical, photothermal, and photomechanical effects.45,46 Laser interaction with calcium occurs

primarily via the photomechanical component, and is increased if laser is applied directly through blood (without saline) and even more so if used with contrast injection.33,47 Excimer laser catheters are compatible with standard coronary guidewires, and may also be used to create a pilot channel to permit subsequent microcatheter passage for follow-on RA (“RASER” technique) or OA to leverage the combined benefits of each individual technology.48–50

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Angioplasty, Atherectomy, and Lithotripsy Intravascular Lithotripsy The intravascular lithotripsy (IVL) system (Shockwave Medical) is a novel balloon catheter-based device that utilizes pulsatile mechanical energy to disrupt calcified lesions. Miniature emitters placed along the length of a semicompliant balloon convert electrical energy into transient acoustic circumferential pressure pulses that disrupt both superficial and deep calcium within vascular plaque. 51,52 The balloon is typically sized 1:1 to the reference vessel diameter, and inflated to subnominal pressures to permit contact with the vessel wall while minimizing static barotrauma.

IVL uniquely modifies calcium both circumferentially and transmurally, and has a preferential effect on deep calcium compared with other ablation techniques.51 In contrast to both RA and OA, which generate nanoparticles that may embolize distally and impair microcirculatory function, larger calcium fragments generated by lithotripsy remain in situ. As a balloon-based technique, it is also user-friendly with a short learning curve. Balloon uncrossable lesions remain the primary limitation of IVL, and sometimes balloon predilatation or alternative atherectomy (such as RA, OA, or ELCA) may be required to facilitate balloon delivery.

Special Situations PCI in heavily calcified lesions may be performed safely via radial access with standard use of 7.0–8.5 Fr sheathless guide catheters.53 Adjunctive devices and techniques to include guide extension catheters, anchor balloon techniques, and specialty wires may be required for equipment delivery for all angioplasty, atherectomy, and lithotripsy devices.54,55 There are no randomized controlled trials directly comparing different atherectomy technologies (Table 2). Device choice should consider patient and angiographic characteristics, local availability, and operator comfort and institutional expertise. Although there may exist specific advantages in certain lesion subtypes and clinical scenarios, the principal objective is to ensure adequate lesion preparation regardless of the device utilized.56–58 New mobile apps, such as CalcificAid (https:// cardiologyapps.com/calcificaid), are also now available to guide device selection and procedural techniques.

OA has the potential advantage of ease of use and compatibility of a single-size device with a 6 Fr guide or 7 Fr guide/extension combination.

1.

2.

3.

4.

Beohar N, Kaltenbach LA, Wojdyla D, et al. Trends in usage and clinical outcomes of coronary atherectomy: a report from the National Cardiovascular Data Registry CathPCI Registry. Circ Cardiovasc Interv 2020;2:e008239. https:// doi.org/10.1161/CIRCINTERVENTIONS.119.008239; PMID: 31973557.

Bourantas CV, Zhang YJ, Garg S, et al. Prognostic implications of coronary calcification in patients with obstructive coronary artery disease treated by percutaneous coronary intervention: a patient-level pooled analysis of 7 contemporary stent trials. Heart 2014;100:1158–64. https://doi.org/10.1136/heartjnl-2013-305180; PMID: 24846971.

Kirtane AJ, Doshi D, Leon MB, et al. Treatment of higher-risk patients with an indication for revascularization. Circulation 2016;134:422–31. https://doi.org/10.1161/ CIRCULATIONAHA.116.022061; PMID: 27482004.

Généreux P, Madhavan MV, Mintz GS, et al. Ischemic outcomes after coronary intervention of calcified vessels in acute coronary syndromes: pooled analysis from the HORIZONS-AMI (Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction) and ACUITY (Acute Catheterization

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5.

6.

7.

8.

RA has higher penetration power, as the device ablative interface sits immediately at the burr tip (whereas the OA ablative crown is located 6.5 mm proximal to the tip), and may therefore have theoretical advantages in ostial lesions, balloon uncrossable lesions, and chronic total occlusions (even in the presence of dissections).34,59 ELCA may be uniquely used for chronic total occlusion cap modification by expert operators.45 IVL has the distinct advantage of permitting plaque modification without surrendering wire position, which may be especially attractive in bifurcation lesions or lesions with high risk of side branch compromise. Finally, in instances of underexpanded stents due to failure to adequately perform lesion preparation in heavy concentric calcification during the index procedure, RA (‘stentablation’), OA, ELCA with contrast medium (‘laser bomb’), or IVL may all be utilized.60–64

Future Directions Intravascular imaging and lesion preparation therapies remain underused technologies in the face of progressively increasing patient and lesion complexity. Several ongoing randomized clinical trials evaluating the most appropriate and cost-effective use of various intravascular imaging, angioplasty, atherectomy, and lithotripsy technologies are currently underway, including Evaluation of Treatment Strategies for Severe CaLcIfic Coronary Arteries: Orbital Atherectomy versus Conventional Angioplasty Technique Prior to Implantation of Drug-Eluting StEnts (ECLIPSE; NCT03108456) and Disrupt Coronary Artery Disease (DISRUPT CAD III; NCT03595176). Future efforts should target consensus imaging guidelines and operator training pathways to guide the best selection of appropriate therapies, and ensure adequate stent implantation, and optimal short- and long-term outcomes in patients with heavy vessel calcification.3,25,65,66

Conclusion Coronary artery calcification continues to increase in prevalence in parallel with an aging patient population, and rising rates of diabetes and renal disease. PCI of increasingly complex calcified coronary artery lesions remains a persistent challenge in contemporary interventional practice. Growing use of intravascular imaging to inform a strategic treatment algorithm is proving critical to optimal patient management.

Newer device technologies increasingly facilitate more complete and effective revascularization with superior short-term procedural results and long-term patient outcomes.

and Urgent Intervention Triage Strategy) trials. J Am Coll Cardiol 2014;63:1845–54. https://doi.org/10.1016/j.jacc.2014.01.034; PMID: 24561145.

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De Maria GL, Scarsini R, Banning AP. Management of calcific coronary artery lesions. JACC Cardiovasc Interv 2019;12:1465–78. https://doi.org/10.1016/j.jcin.2019.03.038; PMID: 31395217.

Mariani J, Guedes C, Soares P, et al. Intravascular ultrasound guidance to minimize the use of iodine contrast in percutaneous coronary intervention the MOZART (Minimizing cOntrast utiliZation With IVUS Guidance in coRonary angioplasTy) randomized controlled trial. JACC Cardiovasc Interv 2014;7:1287– 93. https://doi.org/10.1016/j.jcin.2014.05.024. PMID: 25326742.

Smilowitz NR, Mohananey D, Razzouk L, et al. Impact and trends of intravascular imaging in diagnostic coronary angiography and percutaneous coronary intervention in inpatients in the United States. Catheter Cardiovasc Interv 2018;92:E410–5. https://doi. org/10.1002/ccd.27673; PMID: 30019831.

Buccheri S, Franchina G, Romano S, et al. Clinical outcomes following intravascular imaging-guided versus coronary angiography-guided percutaneous coronary intervention with stent implantation: a systematic review and Bayesian network meta-analysis of 31 studies and 17,882 patients. JACC Cardiovasc Interv 2017;10:2488–98. https://doi.org/10.1016/j. jcin.2017.08.051; PMID: 29153502.

Tearney GJ, Regar E, Akasaka T, et al. Consensus standards for acquisition, measurement, and reporting of intravascular optical coherence tomography studies. J Am Coll Cardiol 2012;59:1058– 72. https://doi.org/10.1016/j.jacc.2011.09.079; PMID: 22421299.

Räber L, Mintz GS, Koskinas KC, et al. Clinical use of intracoronary imaging. Part 1: guidance and optimization of coronary interventions. An expert consensus document of the European Association of Percutaneous Cardiovascular Interventions. Eur Heart J 2018;39:3281–3300. https://doi. org/10.1093/eurheartj/ehy285; PMID: 29790954.

Fujino A, Mintz GS, Matsumura M, et al. A new optical coherence tomography-based calcium scoring system to predict stent underexpansion. EuroIntervention 2018;13:e2182–9. https://doi. org/10.4244/EIJ-D-17-00962; PMID: 29400655.

Gudmundsdottir I, Adamson P, Gray C, et al. Optical coherence tomography versus intravascular ultrasound to evaluate stent implantation in patients with calcific coronary artery disease.

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Secco GG, Ghione M, Mattesini A, et al. Very high-pressure dilatation for undilatable coronary lesions: Indications and results with a new dedicated balloon. EuroIntervention 2016;12:359–65. https://doi.org/10.4244/EIJY15M06_04; PMID: 26111405.

Felekos I, Karamasis GV, Pavlidis AN. When everything else fails: high-pressure balloon for undilatable lesions. Cardiovasc Revascularization Med 2018;19:306–3. https://doi.org/10.1016/j. carrev.2017.11.004; PMID: 29221960.

Abdel-Wahab M, Toelg R, Byrne RA, et al. High-speed rotational atherectomy versus modified balloons prior to drug-eluting stent implantation in severely calcified coronary lesions: The randomized prepare-CALC trial. Circ Cardiovasc Interv 2018;11:e007415. https://doi.org/10.1161/ CIRCINTERVENTIONS.118.007415; PMID: 30354632.

31. Barbato E, Carrié D, Dardas P, et al. European expert consensus on rotational atherectomy. EuroIntervention 2015;11:30–6. https:// doi.org/10.4244/EIJV11I1A6; PMID: 25982648.

32. Shavadia JS, Vo MN, Bainey KR. Challenges with severe coronary artery calcification in percutaneous coronary intervention: a narrative review of therapeutic options. Can J Cardiol 2018;34:1564–72. https://doi.org/10.1016/j.cjca.2018.07.482; PMID: 30527144.

33. Mehanna E, Abbott JD, Bezerra HG. Optimizing percutaneous coronary intervention in calcified lesions. Circ Cardiovasc Interv 2018;11:e006813. https://doi.org/10.1161/ CIRCINTERVENTIONS.118.006813; PMID: 29743161.

34. Sharma SK, Tomey MI, Teirstein PS, et al. North American expert review of rotational atherectomy. Circ Cardiovasc Interv 2019;12:e007448. https://doi.org/10.1161/ CIRCINTERVENTIONS.118.007448; PMID: 31084239.

35. Gupta T, Weinreich M, Greenberg M, et al. Rotational atherectomy: a contemporary appraisal. Interv Cardiol 2019;14:182–9. https://doi.org/10.15420/icr.2019.17.R1; PMID: 31867066.

36. Amemiya K, Yamamoto MH, Maehara A, et al. Effect of cutting balloon after rotational atherectomy in severely calcified coronary artery lesions as assessed by optical coherence tomography. Catheter Cardiovasc Interv 2019;94:936–44. https://doi.org/10.1002/ccd.28278; PMID: 30977278.

37. Megaly M, Sandoval Y, Lillyblad MP, Brilakis ES. Aminophylline for preventing bradyarrhythmias during orbital or rotational atherectomy of the right coronary artery. J Invasive Cardiol 2018;30:186–9. PMID: 2944062 38. Chambers JW, Feldman RL, Himmelstein SI, et al. Pivotal trial to evaluate the safety and efficacy of the orbital atherectomy system in treating de novo, severely calcified coronary lesions (ORBIT II). JACC Cardiovasc Interv 2014;7:510–8. https://doi. org/10.1016/j.jcin.2014.01.158; PMID: 24852804.

39. Lee M, Généreux P, Shlofmitz R, et al. Orbital atherectomy for treating de novo, severely calcified coronary lesions: 3-year results of the pivotal ORBIT II trial. Cardiovasc Revascularization Med 2017;18:261–4. https://doi.org/10.1016/j.carrev.2017.01.011; PMID: 28162989.

40. Généreux P, Bettinger N, Redfors B, et al. Two-year outcomes after treatment of severely calcified coronary lesions with the orbital atherectomy system and the impact of stent types: insight from the ORBIT II trial. Catheter Cardiovasc Interv 2016;88:369–77. https://doi.org/10.1002/ccd.26554; PMID: 27084293.

41. Lee MS, Shlofmitz E, Kaplan B, et al. Real-world multicenter registry of patients with severe coronary artery calcification undergoing orbital atherectomy. J Interv Cardiol 2016;29:357–62. https://doi.org/10.1111/joic.12310; PMID: 27358246.

42. Kini AS, Vengrenyuk Y, Pena J, et al. Optical coherence tomography assessment of the mechanistic effects of rotational and orbital atherectomy in severely calcified coronary lesions.

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43. Shlofmitz E, Martinsen BJ, Lee M, et al. Orbital atherectomy for the treatment of severely calcified coronary lesions: evidence, technique, and best practices. Expert Rev Med Devices 2017;14:867–79. https://doi.org/10.1080/17434440.2017.1384695; PMID: 28945162.

44. Lee MS, Gordin JS, Stone GW, et al. Orbital and rotational atherectomy during percutaneous coronary intervention for coronary artery calcification. Catheter Cardiovasc Interv 2018;92:61–7. https://doi.org/10.1002/ccd.27339; PMID: 29045041.

45. Egred M, Brilakis ES. Excimer laser coronary angioplasty (ELCA): fundamentals, mechanism of action, and clinical applications. J Invasive Cardiol 2020;32:E27–35. PMID: 32005787 46. Karacsonyi J, Armstrong EJ, Truong HTD, et al. Contemporary use of laser during percutaneous coronary interventions: insights from the Laser Veterans Affairs (LAVA) multicenter registry. J Invasive Cardiol 2018;30:195–201. https://doi.org/10.1016/S07351097(18)31656-5; PMID: 29543185.

47. Farag M, Costopoulos C, Gorog DA, et al. Treatment of calcified coronary artery lesions. Expert Rev Cardiovasc Ther 2016;14:683– 90. https://doi.org/10.1586/14779072.2016.1159513; PMID: 26924773.

48. Fernandez JP, Hobson AR, McKenzie DB, et al. Treatment of calcific coronary stenosis with the use of excimer laser coronary atherectomy and rotational atherectomy. Interv Cardiol 2010;2:801–6 https://doi.org/10.2217/ica.10.83.

49. Stone GW, De Marchena E, Dageforde D, et al. Prospective, randomized, multicenter comparison of laser-facilitated balloon angioplasty versus stand-alone balloon angioplasty in patients with obstructive coronary artery disease. J Am Coll Cardiol 1997;30:1714–21. https://doi.org/10.1016/S0735-1097(97)003872; PMID: 9385898.

50. Ambrosini V, Sorropago G, Laurenzano E, et al. Early outcome of high energy laser (Excimer) facilitated coronary angioplasty on hard and complex calcified and balloon-resistant coronary lesions: LEONARDO Study. Cardiovasc Revascularization Med 2015;16:141–6. https://doi.org/10.1016/j.carrev.2015.02.002; PMID: 25708003.

51. Serruys PW, Katagiri Y, Onuma Y. Shaking and breaking calcified plaque: lithoplasty, a breakthrough in interventional armamentarium? JACC Cardiovasc Imaging 2017;10:907–11. https://doi.org/10.1016/j.jcmg.2017.05.011; PMID: 28797413.

52. Ali ZA, Nef H, Escaned J, et al. Safety and effectiveness of coronary intravascular lithotripsy for treatment of severely calcified coronary stenoses: the Disrupt CAD II study. Circ Cardiovasc Interv 2019;12:e008434. https://doi.org/10.1161/ CIRCINTERVENTIONS.119.008434; PMID: 31553205.

53. Tada N, Takizawa K, Kahata M, et al. Sheathless guide catheter coronary intervention via radial artery: single-center experience with 9658 procedures. J Invasive Cardiol 2015;27:237–41.

PMID: 25929300 54. Fairley S, Spratt J, Rana O, et al. Adjunctive strategies in the management of resistant, ‘undilatable’ coronary lesions after successfully crossing a CTO with a guidewire. Curr Cardiol Rev 2014;10:145–57. https://doi.org/10.2174/157340 3X10666140331124954; PMID: 24694106.

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56. Meraj PM, Shlofmitz E, Kaplan B, et al. Clinical outcomes of atherectomy prior to percutaneous coronary intervention: a comparison of outcomes following rotational versus orbital atherectomy (COAP-PCI study). J Interv Cardiol 2018;31:478–85. https://doi.org/10.1111/joic.12511; PMID: 29707807.

57. Aggarwal D, Seth M, Perdoncin E, et al. Trends in utilization, and comparative safety and effectiveness of orbital and rotational atherectomy. JACC Cardiovasc Interv 202013:146-8. https://doi. org/10.1016/j.jcin.2019.09.027; PMID: 31918938.

58. Goel S, Pasam RT, Chava S, et al. Orbital atherectomy versus rotational atherectomy: a systematic review and meta-analysis.

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59. Brinkmann C, Eitan A, Schwencke C, et al. Rotational atherectomy in CTO lesions: too risky? Outcome of rotational atherectomy in CTO lesions compared to non-CTO lesions.

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60. Ashikaga T, Yoshikawa S, Isobe M. The effectiveness of excimer laser coronary atherectomy with contrast medium for underexpanded stent: The findings of optical frequency domain imaging. Catheter Cardiovasc Interv 2015;86:946–9. https://doi. org/10.1002/ccd.25915; PMID: 25754354.

61. Whiteside HL, Nagabandi A, Kapoor D. Safety and efficacy of stentablation with rotational atherectomy for the management of underexpanded and undilatable coronary stents.

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62. Alfonso F, Bastante T, Antuña P, et al. Coronary lithoplasty for the treatment of undilatable calcified de novo and in-stent restenosis lesions. JACC Cardiovasc Interv 2019;12: 497–9. https:// doi.org/10.1016/j.jcin.2018.12.025; PMID: 30772288.

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65. Johnson TW, Räber L, Di Mario C, et al. Clinical use of intracoronary imaging. Part 2: acute coronary syndromes, ambiguous coronary angiography findings, and guiding interventional decision-making: an expert consensus document of the European Association of Percutaneous Cardiovascular Interventions. Eur Heart J 2019;40:2566–84. https://doi. org/10.1093/eurheartj/ehz332; PMID: 31112213.

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67. Abdel-Wahab M, Richardt G, Joachim Büttner H, et al. High-speed rotational atherectomy before paclitaxel-eluting stent implantation in complex calcified coronary lesions: the randomized ROTAXUS (Rotational Atherectomy Prior to Taxus Stent Treatment for Complex Native Coronary Artery Disease) trial. JACC Cardiovasc Interv 2013;6:10–9. https://doi:10.1016/j. jcin.2012.07.017; PMID: 23266232.

US CARDIOLOGY REVIEW

Valvular Heart Disease & Heart Failure

Treatment of Secondary Mitral Regurgitation in Heart Failure: A Shifting Paradigm in the Wake of the COAPT Trial Kelly H Schlendorf, MD, MHS, Jared O’Leary, MD, and JoAnn Lindenfeld, MD Vanderbilt University Medical Center, Nashville, TN

Abstract Secondary mitral regurgitation (MR) is common in patients with left heart dysfunction and it is associated with poor outcomes. Findings from the Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation (COAPT) trial, published in 2018, suggest that in a subset of people with heart failure with secondary MR that persists despite optimization of guidelinedirected medical therapies, there is now a role for percutaneous mitral valve repair using the MitraClip device. Defining which patients are most likely to benefit from MitraClip, and when, requires both a multidisciplinary approach centered on heart failure, as well as a recognition of the need for further research in this area.

Keywords Mitral regurgitation, heart failure, COAPT, transcatheter mitral valve repair, MITRA.FR Disclosure: JL is co-principal investigator of COAPT and has a consulting income from Abbott. All other authors have no conflicts of interest to declare.

Received: February 19, 2020 Accepted: April 30, 2020 Citation: US Cardiology Review 2020;14:e06. DOI: https://doi.org/10.15420/usc.2020.05 Correspondence: Kelly Schlendorf, Room 5209, Vanderbilt University Medical Center, 1215 21st Avenue S, Nashville, TN 37232. E: kelly.h.schlendorf@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.

Mitral regurgitation (MR) is common in industrialized countries, with a prevalence of about 2% in the general population and about 9% in people over 75 years old.1,2 MR is classified as primary/degenerative when it results from a structural abnormality of the valve apparatus, or secondary/functional when it results from a disturbance of ventricular or annular geometry and/or function that impairs leaflet coaptation.3 Secondary MR (SMR) represents the majority of MR and accompanies left heart dysfunction, where its presence has been strongly associated with decreased quality of life, increased heart failure hospitalizations, and increased mortality.4–8 The prevalence of SMR in patients with heart failure is high. Robbins et al. reported a prevalence of moderate or greater SMR of 45% in outpatients and 63% in inpatients with heart failure with reduced ejection fraction.5 In a series of 558 outpatients with heart failure and a left ventricular ejection fraction (LVEF) of ≤35%, 39% had at least moderate MR and 17% had moderately severe to severe MR.6 In a meta-analysis of 53 studies and 45,900 patients, SMR was associated with increased risk of cardiac mortality, heart failure hospitalizations, and a composite endpoint of death, heart failure or transplant.7 In patients on guideline-directed medical therapy (GDMT), severe SMR may improve over time but may also persist or appear in those with less than severe SMR at baseline. Whereas mortality in the former group is comparable to that of patients who never develop severe SMR, the presence of sustained severe SMR or worsening SMR in the latter groups has been shown to be independently predictive of poor outcomes.8

© RADCLIFFE CARDIOLOGY 2020

The surgical correction of primary MR with either repair or replacement has strong support in European and US valvular heart disease guidelines with several level 1 recommendations.9,10 Surgical intervention to reduce SMR, however, has not been shown to improve outcomes and, despite the prevalence of SMR and its association with poor prognosis, the same guidelines provide no class 1 recommendations for the treatment of SMR. However, mounting evidence suggests an important role for percutaneous intervention to reduce SMR. The MitraClip device (Abbott) is placed via a percutaneous, transseptal procedure and is used to approximate the edges of the anterior and posterior mitral leaflets, in a manner similar to the Alfieri stitch surgical procedure. In the Pivotal Study of a Percutaneous Mitral Valve Repair System (EVEREST II) which enrolled patients with primary and secondary MR, patients randomized to the MitraClip device had improved safety profiles but there was less of a reduction in MR severity compared with those randomized to mitral valve repair.11 However, in a sub-group analysis of EVEREST II patients with SMR, transcatheter mitral valve repair and surgical mitral valve repair were similarly effective in reducing MR. These findings led to Food and Drug Administration approval of MitraClip for treatment of symptomatic primary/degenerative MR in surgically high-risk patients, and to a call for randomized controlled trials of transcatheter mitral valve repair for SMR. The Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation

Access at: www.USCjournal.com

Valvular Heart Disease & Heart Failure Figure 1: Heart Valve Team Approach for Evaluation of Secondary Mitral Regurgitation with Integration of the Heart Failure Cardiologist

Secondary MR

Heart valve team: Interventional cardiologist Cardiac surgeon Imaging specialist

Heart failure cardiologist: GDMT Cardiac synchronization

Heart failure referrals with MR

Remain symptomatic Surgery not preferred EROA ≥30 mm2 Technically feasible

Relative contraindications: LV end-systolic diameter >7 cm LVEF <20% Resting inotrope support EROA <40 mm2 with reduced LVEF

Yes

Consider advanced heart failure therapies

No MitraClip EROA: effective regurgitant orifice area; GDMT: guideline-directed medical therapy; LV = left ventricular; LVEF = Left ventricular ejection fraction; MR = mitral regurgitation.

(COAPT) trial, published in 2018, tested the hypothesis that percutaneous mitral valve repair to correct SMR in patients with heart failure would lead to improved outcomes and be safe.12 Its results were resoundingly positive and have reshaped the cardiology community’s approach to treatment of heart failure and SMR. Between 2012 and 2017, the COAPT investigators enrolled a total of 614 patients with New York Heart Association (NYHA) class II–IV heart failure, an LVEF of 20–50%, and moderately-severe to severe SMR who remained symptomatic despite the use of maximally tolerated GDMT. Patients with left ventricular end-systolic diameters of >7 cm shown by echocardiography were excluded. Patients were randomized to either transcatheter mitral valve repair plus GDMT (device group) or GDMT alone (control group). Baseline characteristics, including NYHA class, mean LVEF and severity of SMR, were similar in both trial arms. Compared with patients in the control group, patients randomized to the device group exhibited a significant reduction in the primary effectiveness endpoint of heart failure hospitalizations within 24 months (35.8% per patient year versus 67.9% per patient year, p<0.001) as well as a 96.6% rate of freedom from device-related complications at 12 months.

Moreover, the prespecified secondary endpoint of all-cause mortality within 24 months was significantly lower with device-based therapy than with medical therapy alone (29.1% versus 46.1%, p<0.001). In addition, all secondary endpoints were positive including a 16-point difference in the Kansas City Cardiomyopathy Questionnaire (KCCQ) and a 58 m improvement in the 6-minute walk distance, both favoring transcatheter mitral valve repair.12 These differences were both highly statistically significant but also clinically significant, given data suggesting that a 5-point difference in the KCCQ predicts improvements in clinical endpoints, such as heart failure hospitalizations and mortality.13

The results of COAPT have been met with a combination of excitement and confusion, the latter stemming in part from the findings of the Percutaneous Repair with the MitraClip Device for Severe Functional/ Secondary Mitral Regurgitation (Mitra.FR) trial, a similarly designed study published shortly before COAPT, in which heart failure patients with severe SMR treated with MitraClip had similar rates of the composite primary outcome of death from any cause or unplanned heart failure hospitalization at 12 months, compared with patients treated with medical therapy alone.14 While the discordant results from COAPT and Mitra.FR have yet to be fully reconciled, several key points are worth noting. 15,16 First, patient enrollment in COAPT was contingent on confirmation by a central eligibility committee that patients with reduced left ventricular function were taking maximally tolerated doses of GDMT. This requirement was not the case in Mitra.FR. Given that nearly 40% of patients with reduced ejection fraction and severe SMR may have significant reduction in MR with GDMT, it is possible that many patients enrolled in Mitra.FR and randomized to MitraClip had not had adequate medical treatment at the time of device therapy.9 Second, patients enrolled in COAPT compared with those enrolled in Mitra.FR had disproportionately greater degrees of MR as measured by effective regurgitant orifice area (EROA) relative to their left ventricular volumes raising the possibility, as suggested by others, that ‘disproportionate’ MR may be more responsive than ‘proportionate’ MR to device-based treatment.17 While rates of residual 3+ or higher MR immediately following device therapy in both trials were <10%, rates at 1 year were substantially higher in Mitra.FR compared with COAPT (17% versus 5%). Although concerns have been raised by Mitra.FR investigators

US CARDIOLOGY REVIEW

Treating Mitral Regurgitation in the Wake of COAPT about baseline differences in use of renin–angiotensin–aldosterone inhibitors among COAPT-enrolled patients, which were marginally significant by chance, a multivariable analysis published in the original COAPT manuscript demonstrated that the point estimates for benefit were similar after accounting for this consideration.12,16 Similarly, while Mitra.FR investigators have expressed concerns about potential differences in baseline heart rate and blood pressure among COAPTenrolled patients, these parameters have been recently reported, demonstrating no significant differences between GDMT and GDMT+MitraClip.15,16 One final difference is that COAPT enrolled only NYHA class IV ambulatory patients, whereas Mitra.FR did not require NYHA class IV patients to be ambulatory.12,14 Whatever the explanation for the discordant results from the two trials, the statistically robust COAPT results (p=0.000006 for the primary effectiveness endpoint) have ignited interest in percutaneous therapies for SMR and highlighted the importance of a multidisciplinary approach that begins with the heart failure cardiologist and relies heavily on expertise from interventionalists, surgeons and cardiac imaging experts.

At our center, these clinicians comprise a structural heart and valve team (Figure 1). The primary role of the heart failure cardiologist is to ensure that prior to consideration of MitraClip, patients are decongested and those with ejection fractions <40% are adequately treated with maximally tolerated GDMT and, when indicated, cardiac resynchronization therapy (CRT), all of which have been shown to improve SMR.18–21 In a patient who

1.

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8.

Nkomo VT, Gardin JM, Skelton TN, et al. Burden of valvular heart diseases: a population-based study. Lancet 2006;368:1005–11. https://doi.org/10.1016/S0140-6736(06)69208-8; PMID: 16980116. d’Arcy JL, Coffey S, Loudon MA, et al. Large-scale community echocardiographic screening reveals a major burden of undiagnosed valvular heart disease in older people: the OxVALVE Population Cohort Study. Eur Heart J 2016;37:3515–22. https://doi.org/10.1093/eurheartj/ehw229; PMID: 27354049.

Asgar AW, Mack MJ, Stone GW. Secondary mitral regurgitation in heart failure: pathophysiology, prognosis, and therapeutic considerations. J Am Coll Cardiol 2015;65:1231–48. https://doi. org/10.1016/j.jacc.2015.02.009; PMID: 25814231. de Marchena E, Badiye A, Robalino G, et al. Respective prevalence of the different Carpentier classes of mitral regurgitation: a stepping stone for future therapeutic research and development. J Card Surg 2011;26:385–92. https://doi. org/10.1111/j.1540-8191.2011.01274.x; PMID: 21793928.

Robbins JD, Maniar PB, Cotts W, et al. Prevalence and severity of mitral regurgitation in chronic systolic heart failure. Am J Cardiol 2003;91:360–2. https://doi.org/10.1016/S0002-9149(02)03172-7; PMID: 12565101.

Patel JB, Borgeson DD, Barnes ME, et al. Mitral regurgitation in patients with advanced systolic heart failure. J Card Fail 2004;10:285–91. https://doi.org/10.1016/j.cardfail.2003.12.006; PMID: 15309693.

Sannino A, Smith RL II, Schiattarella GG, et al. Survival and cardiovascular outcomes of patients with secondary mitral regurgitation: a systematic review and meta-analysis. JAMA Cardiol 2017;2:1130–9. https://doi.org/10.1001/ jamacardio.2017.2976; PMID: 28877291.

Nasser R, Van Assche L, Vorlat A, et al. Evolution of functional mitral regurgitation and prognosis in medically managed heart

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develops worsening signs and symptoms of heart failure, it is also important that the heart failure cardiologist and other team members recognize that the development of SMR may be the cause, especially now that there is evidence that transcatheter mitral valve repair may improve prognosis. Thus, patients in whom SMR persists or develops despite GDMT and/or CRT may benefit from MitraClip if they meet the criteria for COAPT enrollment, including an LVEF of 20–50%, a left ventricular end systolic diameter <7 cm, and an EROA ≥0.3 cm2 (or other criteria for severe MR if EROA cannot be determined).22 Markedly dilated ventricles may not benefit regardless of the severity of MR although this contention requires further examination.

Ongoing investigation is needed to further refine which patients with left ventricular dysfunction will most benefit from MitraClip. Despite the beneficial effects on heart failure hospitalizations, mortality, quality of life and functional capacity, mortality in COAPT was 29% at 24 months. Some of this may be accounted for by age – patients in COAPT had an average age of 72 years, which is about 8 years older than most heart failure trials.

The MITRA.FR and COAPT investigators have combined data from both trials that will allow analyses to answer many outstanding questions, including whether those with ‘disproportionate’ SMR should undergo transcatheter mitral valve repair prior to receiving maximally tolerated GDMT and whether patients with more advanced heart failure might stabilize enough with MitraClip to avoid the need for a left ventricular assist device or heart transplantation.

failure patients with reduced ejection fraction. JACC Heart Fail 2017;5:652–9. https://doi.org/10.1016/j.jchf.2017.06.015; PMID: 28859754.

Nishimura RA, Otto CM, Bonow RO, et al. 2017 AHA/ACC focused update of the 2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2017;70:252–89. https://doi.org/10.1016/j.jacc.2017.03.011; PMID: 28315732.

Baumgartner H, Falk V, Bax JJ, et al. 2017 ESC/EACTS guidelines for the management of valvular heart disease. Eur Heart J 2017;38:2739–91. https://doi.org/10.1093/eurheartj/ehx391; PMID: 28886619.

Feldman T, Foster E, Glower DD, et al. Percutaneous repair or surgery for mitral regurgitation. N Engl J Med 2011;364:1395–1406. https://doi.org/10.1056/NEJMoa1009355; PMID: 21463154.

Stone GW, Lindenfeld J, Abraham WT, et al. Transcatheter mitralvalve repair in patients with heart failure. N Engl J Med 2018;379:2307–18. https://doi.org/10.1056/NEJMoa1806640; PMID: 30280640.

Kosiborod M, Soto GE, Jones PG, et al. Identifying heart failure patients at high risk for near-term cardiovascular events with serial health assessments. Circulation 2007;115:1975–81. https://doi.org/10.1161/CIRCULATIONAHA.106.670901; PMID: 17420346.

Obadia JF, Messika-Zeitoun D, Leurent G, et al. Percutaneous repair or medical treatment for secondary mitral regurgitation.

N Engl J Med 2018;379:2297–306. https://doi.org/10.1056/ NEJMoa1805374; PMID: 30145927.

Schlendorf K, Stone GW, Abraham WT, et al. Who and when to clip: that is the question. Eur J Heart Fail 2020;22:20–2. https://doi. org/10.1002/ejhf.1598; PMID: 32003137.

16. Mewton N, Cucherat M. To clip, or not to clip heart failure patients, that is the question. Eur J Heart Fail 2020;22:16–9. https://doi.org/10.1002/ejhf.1612; PMID: 32003134.

17. Grayburn PA, Sannino A, Packer M. Proportionate and disproportionate functional mitral regurgitation: a new conceptual framework that reconciles the results of the MITRA-FR and COAPT trials. JACC Cardiovasc Imaging 2019;12:353–62. https://doi.org/10.1016/j.jcmg.2018.11.006; PMID: 30553663.

18. Capomolla S, Febo O, Dnemmi M, et al. Beta-blockade therapy in chronic heart failure: diastolic function and mitral regurgitation improvement by carvedilol. Am Heart J 2000;139:596–608. https:// doi.org/10.1016/S0002-8703(00)90036-X; PMID: 10740140.

19. Seneviratne B, Moore GA, West PD. Effect of captopril on functional mitral regurgitation in dilated heart failure: a randomized double blind placebo controlled trial. Br Heart J 1994:72:63–8. https://doi.org/10.1136/hrt.72.1.63; PMID: 8068472.

20. Kang DH, Park SJ, Shin SH, et al. Angiotensin receptor neprilysin inhibitor for functional mitral regurgitation. Circulation 2019;139:1354–65. https://doi.org/10.1161/ CIRCULATIONAHA.118.037077; PMID: 30586756.

21. Mihos CG, Capoulade R, Orencole MR, et al. Impact of cardiac resynchronization therapy on mitral valve apparatus geometry and clinical outcomes in patients with secondary mitral regurgitation. Echocardiography 2017;34:1561–7. https://doi. org/10.1111/echo.13690; PMID: 28895197.

22. Asch FM, Grayburn PA, Siegel RJ, et al. Echocardiographis outcomes after transcatheter leaflet approximation in patients with secondary mitral regurgitation: the COAPT Trial. J Am Coll Cardiol 2019;17:2969–79. https://doi.org/10.1016/j. jacc.2019.09.017; PMID: 31574303.

Coronary Imaging & Complex Interventions

Role of Intravascular Ultrasound in Guiding Complex Percutaneous Coronary Interventions Brandon Quintana, MS,1 and Akram Ibrahim, MD, FACC2,3 1. Philadelphia College of Osteopathic Medicine, Philadelphia, PA; 2. Southeastern Cardiology Associates, Columbus, GA; 3. Emory University School of Medicine, Atlanta, GA

Abstract Complex percutaneous coronary interventions (PCIs) are increasing in frequency due to the rapid advances in interventional cardiology. This has had a favorable impact on patients with extensive coronary artery disease and multiple comorbidities with regard to symptomatic relief and mortality.

With this increase, cardiologists must develop a standardized way to approach complex PCI in an era in which angiographic guidance alone yields suboptimal results. Intravascular ultrasound (IVUS) has been shown to improve outcomes with better preprocedural planning, improved stent placement, and larger stent diameters. Considering the supportive data, the use of IVUS is crucial in all cases of complex PCI.

Keywords Intravascular ultrasound, percutaneous coronary intervention, optical coherence tomography, coronary artery disease, complex coronary intervention, chronic total occlusion, left main, bifurcation, in-stent restenosis, stent thrombosis.

Disclosure: The authors have no conflicts of interest to declare.

Received: March 6, 2020 Accepted: June 25, 2020 Citation: US Cardiology Review 2020;14:e07. DOI: https://doi.org/10.15420/usc.2020.12 Correspondence: Akram Ibrahim, Southeastern Cardiology Associates, 2121 Warm Springs Rd, Columbus, GA 31904. E: awibrah@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.

Percutaneous coronary intervention (PCI) has been rapidly evolving since its initial application in 1977. Over the years, it has become a mainstay of the treatment of coronary artery disease, including acute coronary syndromes and stable ischemic heart disease.

With the advent of novel ancillary technologies, such as intravascular ultrasound (IVUS) and optical coherence tomography (OCT), it has become imperative that routine upfront intravascular imaging be incorporated in PCI procedures to improve efficiency and achieve superior clinical outcomes.

As the interventional cardiology community tackles the more complex issues of the coronary artery disease spectrum, and with the introduction of complex and high-risk coronary intervention fellowship programs, the use of intravascular imaging is an important step along the road to a successful PCI procedure.

Systems, such as the Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery (SYNTAX) score and the American College of Cardiology/American Heart Association lesion classification system, have been developed to characterize and quantify lesion complexity.1,2 Comorbidities, such as congestive heart failure, diabetes, and chronic kidney disease, as well as lesion anatomic factors, such as chronic total occlusion (CTO), bifurcation disease, unprotected left main disease, long lesions, and calcified lesions, have all increased the

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complexity of the PCI necessary to achieve revascularization.2 Similarly, anatomically complex lesions are associated with lower success rates and higher rates of postprocedural complications when compared with less complex anatomic lesions.2,3 Coronary artery bypass grafting has been shown to be superior to PCI or medical therapy in the case of intermediateâ&#x20AC;&#x201C; high SYNTAX scores; however, with the advances in PCI technology, interventional cardiologists hope to close that gap and successfully address more complex cases.4 In the past decade, there has already been a twofold increase in the rate of complex PCI, providing better outcomes to more elderly and sicker patients.5 However, considering that there is an inverse relationship between operator volume and in-hospital mortality for PCI patients, there will likely be an additional emphasis on operator experience and high-volume centers for complex PCI.1,6 In the past 30 years, the field of interventional cardiology has witnessed major technological advancements in the field of intravascular imaging.

The two modalities of note, IVUS and OCT, are used as adjunctive tools to conventional angiography in order to provide an optimized and precise procedural outcome.

Traditionally, PCI is guided through coronary angiography, which uses a radiopaque contrast dye to visualize the circulation and subsequently quantify any significant intraluminal stenosis. For intermediate complexity lesions, angiography alone may provide sufficient guidance, but coronary angiography has well-known limitations. These include significant

Š RADCLIFFE CARDIOLOGY 2020

Role of IVUS in Complex PCI intra- and interobserver variability, and limited plaque morphology visualization. IVUS uses a 20–60 MHz frequency ultrasound probe-tipped catheter, particularly useful in situations in which angiography alone provides inadequate visualization. The image created is a 360°, 2D view of the vessel wall. The resolution is around 100 µm axially and 200–250 µm laterally. The image properties are typical of ultrasound-generated images; the image is generated based on the reflection of ultrasound waves, which depend on the physical properties of the vessel components. This technology allows interventionalists to visualize plaque morphology, extent, and composition, as well as stent positioning, stent wall apposition, and stent border characteristics. IVUS can be used before, during, and after the procedure to optimize PCI and improve outcomes.

Figure 1: Acute Incomplete Stent Apposition

In clinical use, two types of IVUS systems are available: the solid-state electronic phased array transducer and the mechanical single-element rotating transducer. The 6 Fr compatible mechanical systems offer a more uniform pullback and greater resolution due to the higher ultrasound frequency. Mechanical systems are available commercially as the 60 MHz OptiCross (with or without high definition) catheter (Boston Scientific), the Revolution 45 MHz catheter (Philips), and the 40 MHz LipiScan IVUS (InfraReDx). The solid-state phased array transducer has 64 stationary transducer elements around the tip that image at 20 MHz, and it is commercially available as the 5 Fr-compatible Eagle Eye Catheter (Volcano). Benefits of the solid-state catheter include superior deliverability due to the coaxial design and lack of non-uniform rotational distortion artifacts seen with rotational systems.7

Acute incomplete stent apposition (A) found immediately after stent implantation on intravascular ultrasound in the left anterior descending coronary artery as well as (B) on post-dilation intravascular ultrasound of the same location. Source: McDaniel et al. 2011.7 Reproduced with permission from Elsevier.

Another novel imaging modality in the armamentarium of interventional cardiologists is OCT. OCT uses near-infrared light (1,300 nm wavelength) to image the lumen–wall interface of coronary arteries. Image generation depends on the time delay of light wave reflection. While OCT has a superior spatial resolution, it has a few important drawbacks. These include a low tissue penetration of around 1–2 mm and the need to create a blood-free zone to properly image the vessel wall. The wavelength of light is smaller than the diameter of a red blood cell, thus a blood-free zone is needed to prevent interference. This is accomplished by crystalloid or contrast flush of the vessel, followed by a constant pullback to acquire the image.8 There are limited trials comparing IVUS and OCT use in guiding lesionspecific complex PCI. Several studies have compared their use in PCI in general. OCT has better reproducibility in measuring lumen parameters, although its relatively lower penetration does not allow optimal vessel size measurement.9,10 This limits the operator to sizing stents based on luminal size rather than vessel size, yielding smaller stent diameters.9,10 IVUS and OCT are excellent for detecting calcifications, which is important in determining whether atherectomy is necessary prior to stent implantation. However, IVUS cannot visualize fibrocalcific lesions as well as OCT, due to the acoustic shadowing caused by the reflection of ultrasound waves on the calcium.11 The finer resolution provided by OCT is also able to detect smaller stent edge dissections compared with IVUS.12 The Observational Study of Optical Coherence Tomography (OCT) in Patients Undergoing Fractional Flow Reserve and Percutaneous Coronary Intervention – Stage II (ILUMIEN II) trial retrospectively compared OCT-guided and IVUS-guided PCI, and found that OCT detected a higher

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A

B

Figure 2: Stent Fracture and Neoatherosclerosis From Different Cases A

B

C

A’

B’

C’

In (A) and (A’), the overlapped stent struts (arrowheads) were consistent with stent fracture on optical coherence tomography and intravascular ultrasound (IVUS), respectively. In (B), there is in-stent (white asterisks) restenosis with neointimal hyperplasia. The cause of restenosis is stent cstent (black asterisks) is well-expanded with neointimal calcification on IVUS (white arrowheads). In (C), optical coherence tomography shows neointimal rupture in the lipidic plaque within the stent struts (white asterisks). This was not clearly seen on IVUS in (C’). Source: Maehara et al. 2017.9 Reproduced with permission from Elsevier.

prevalence of post-PCI stent malapposition, edge dissections, and tissue protrusion (Figures 1–4).12 Although the higher resolution can make up for the low tissue penetration with OCT, one disadvantage of OCT is the higher dose of contrast needed to create a blood-free zone. This amount was determined by the ILUMIEN III study to be around 32 ml additional contrast use, on average.13 This need for clearance limits the ability to image ostial left main lesions and the additional contrast is worrisome for patients with poor renal function.

IVUS plays an important role in many aspects of complex, PCI whether it is preoperative planning, intraoperative positioning, or postoperative assessment. Its use is imperative in a myriad of clinical subsets including CTO, in-stent restenosis, complex coronary bifurcation stenosis, left main PCI, and saphenous vein graft stenoses.

Coronary Imaging & Complex Interventions Figure 3: Stent Underexpansion

A

coronary artery (LMCA) above the polygon of confluence (so-called 5–6– 7–8 rule).14 It is noted that the population was Asian, and that left main cut-off values are larger in white patients.

B Additionally, Patel et al. found that at 2.5 years after complex PCI, IVUS use was associated with a decreased incidence of death, MI, stent thrombosis, target lesion revascularization (TLR) and target vessel revascularization (TVR).15 Another study found similar results with regard to reduced revascularization, MI, and cardiac death for IVUS-guided drug-eluting stent (DES) implantation in patients with unstable angina and true bifurcation lesions.16

A: The proximal stent illustrates symmetrical stent expansion. B: An example of stent underexpansion in the mid-stent at an area of calcified plaque. Source: McDaniel et al. 2011.7 Reproduced with permission from Elsevier.

Figure 4: Stent Edge Dissection, Stent Malapposition, and Tissue Protrusion Through Stent Struts on IVUS and OCT A’

A’’

B’

B’’

C’

C’’

Medial dissection flap (A’,A’’), stent malapposition (B’,B’’) and tissue protrusion through stent strut (C’,C’’) on optical coherence tomography and intravascular ultrasound, respectively.

Source: Maehara et al. 2017.9 Reproduced with permission from Elsevier.

In coronary bifurcation PCI, IVUS has been shown to be useful in determining stenting strategies, stent placement, and has even demonstrated improved long-term clinical outcomes.7 For instance, selection of provisional or complex two-stent bifurcation techniques in the distal left main bifurcation lesions should be based on disease status of the ostium of the left circumflex artery. In this setting, IVUS provides accurate information for both main-branch and side-branch disease patterns and the status of vascular positive or negative remodeling in these lesions.7 In addition to the assistance in the choice of stenting strategy, IVUS has a role in optimizing stent mechanics intraoperatively. It provides valuable information on stent expansion and adequate apposition. Risk factors for stent thrombosis and restenosis include stent malapposition and underexpansion. IVUS evaluation ensures achievement of larger stent diameters and simultaneously provides information on acute incomplete stent malapposition. IVUS criteria for minimum stent area predicting angiographic restenosis were 5.0 mm2 for the left circumflex artery ostium, 6.3 mm2 for the left anterior descending artery ostium, 7.2 mm2 for the polygon of confluence, and 8.2 mm2 for the proximal left main

In the CTO subset of lesions, the role of IVUS has yet to be solidified with hard clinical endpoints. Its utility in CTO lesions has been limited to some preprocedural planning and lesion characterization as well as guiding the reverse controlled antegrade and retrograde tracking technique of revascularization.17,18 Although a reduction in major adverse cardiac events was found, one study failed to show a significant reduction in mortality with IVUS-guided versus angiography-guided PCI in CTO.19 This highlights the difficulty of the procedure as well as the further research needing to be done with IVUS use in CTO PCI. Perhaps the most extensively researched IVUS use in complex PCI would be its application in unprotected LMCA PCI. Due to the large vascular territory subtended by the left main and its association with high mortality rates, coronary artery bypass grafting has been the standard approach to revascularization. However, due to the advent of improved stent engineering and the utilization of intravascular imaging, PCI outcomes have been shown to be favorable in multiple clinical trials involving this subset of patients.

The Evaluation of XIENCE versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization (EXCEL) trial is one example of the advancement made in left main PCI over the years.20 Numerous other small studies have demonstrated benefits of IVUS, but one of the largest, conducted by Andell et al., found that IVUS-guided PCI in unprotected LMCA was associated with significantly lower occurrence of all-cause mortality, restenosis, and definite stent thrombosis compared with unprotected LMCA PCI without IVUS guidance.21 The IVUS patients in that study had significantly larger stent diameters, which were independently associated with improved outcome.22 It is hypothesized that stent underexpansion may contribute to stent thrombosis or in-stent restenosis, thus emphasizing the importance of the increased stent diameters achieved with the use of IVUS. Additionally, a recent meta-analysis found significant reduction in major adverse cardiac events, TLR, and TVR in IVUS-guided DES implantation compared with angiography-guided implantation in patients with complex coronary lesions.22 That study used a broad and appropriate definition of complex lesions, and used cardiac death during 64 months of median follow-up as its primary endpoint. The greatest benefits were seen in the left main group. Lending credence to the aforementioned literature, the role of IVUS in LMCA PCI is essential and a cornerstone of the revascularization process. More randomized clinical trials involving LMCA revascularization need to incorporate the use of intravascular imaging for a true measure of clinical benefit.

US CARDIOLOGY REVIEW

Role of IVUS in Complex PCI Table 1: Summary of Trials Supporting Use of Intravascular Ultrasound in Complex Percutaneous Coronary Intervention Study

Sample Size

Focus

Findings

Limitations

Patel et al. 201215

449 (247 with IVUS, 202 without)

Long-term outcomes associated with using IVUS for treatment of bifurcation lesions

IVUS associated with lower rates of death, MI, TVR, and TLR

Selection bias by operators No prespecified stenting criteria

Chen et al. 201816

1,465 (310 with IVUS, 1,155 Composite MACE (cardiac death, without) MI, TVR) at 1 and 7 years after treatment of bifurcation lesions with IVUS versus angiography

IVUS was associated with lower rate of MACE at 1 and 7 years, with a more significant difference at 7 years.

IVUS was also associated with lower rates of revascularization compared with angiography-guided PCI

Non-randomized Relatively lower rate of angiographic follow-up at 1 year

Kim et al. 201519

402 (201 with IVUS, 201 without)

Cardiac death was not significantly lower, but MACE rates were significantly lower in IVUS group than in angiography group

Minimum stent areas used may have been too small No clear reason for improved clinical outcomes

Andell et al. 201721

2,468 (621 with IVUS, 1,847 Composite endpoint of all-cause without) mortality, restenosis, or definite stent thrombosis in IVUS-guided versus angiography-guided PCI for unprotected left main disease

IVUS group had significantly lower rates of primary composite endpoint and mortality compared with angiography group

Comorbidities and age difference in non-IVUS group Registry does not include whether IVUS used before PCI, after PCI, or both Not able to account for skill differences in operators

Choi et al. 201922

6,005 (1,674 with IVUS, 4,331 Long-term cardiac death risk in without) patients with complex lesions using IVUS-guided versus angiographyguided PCI

IVUS-guided PCI associated with significantly lower risk of cardiac death, as well as all-cause death, MI, ST, TLR compared with angiographyguided PCI on complex lesions

Non-randomized Selection bias by operators Confounding comorbidities in angiography group

Cardiac death and composite MACE (cardiac death, MI, TVR) rates in CTO using IVUS-guided versus angiography-guided PCI

CTO = chronic total occlusion; IVUS = intravascular ultrasound; MACE = major adverse cardiac events; PCI = percutaneous coronary intervention; ST = stent thrombosis; TLR = target lesion revascularization; TVR = target vessel revascularization.

Finally, the incremental benefit of IVUS in the PCI realm was noted to have different etiologies in the bare-metal stent (EMS) versus DES categories.

In the former, it is noted that IVUS leads to decreased TVR by virtue of decreasing restenosis and increasing minimum stent areas on imaging.

As mentioned, stent underexpansion is a major risk factor in the development of restenosis, ultimately leading to TVR.

with an angiography-guided strategy in a propensity-matched analysis of 884 patients undergoing PCI with DES.2,4 The proposed hypothesis behind this benefit is that IVUS aids in the detection of many of the risk factors of stent thrombosis including edge dissections, stent underexpansion, incomplete stent apposition, incomplete lesion coverage, geographic miss, residual thrombus and tissue protrusion.28,29

One meta-analysis of 2,193 patients from seven randomized trials, in which an IVUS-guided PCI strategy was utilized with EMS, found a reduction in TVR (13% versus 18%, p<0.001) in the IVUS-guided subgroup compared with the angiography-guided PCI strategy, with similar rates of death (2.4% versus 1.6%, p=0.18) and MI (3.6% versus 4.4%, p=0.51).23 As mentioned above, clinically significant benefits in death or MI have not been demonstrated in these trials.

Conclusion

In contrast, IVUS guidance in the early DES era has not been shown to influence the rates of restenosis. The contemporary literature, however, indicates reduced TVR with DES and IVUS specifically in the complex lesion subset (Table 1). Larger IVUS MSA cut-offs were also associated with non-ischemic fractional flow reserve.24–27 Additionally, there is mounting evidence that IVUS may reduce the rates of stent thrombosis. Also, an IVUS-guided approach was associated with reduced rates of stent thrombosis at both 30 days (0.5% versus 1.4%, p=0.046) and at 12 months (0.7% versus 2.0%, p=0.014) when compared

US CARDIOLOGY REVIEW

While there are limited studies on the use of IVUS versus OCT in complex PCI, the benefit of IVUS-guided PCI over conventional angiographically guided PCI has been well-delineated in the literature involving multiple clinical subsets including the complex PCI population. It is imperative that routine upfront utilization of intravascular imaging be used in complex PCI procedures, including the left main subset, due to the overwhelming evidence for and benefits of superior clinical outcomes and lower incidences of restenosis and stent thrombosis. Conventional angiography alone cannot ensure proper stent expansion and apposition needed for the superior outcomes and reduced complications provided

by IVUS-guided PCI.29 Finally, we await the results of the upcoming IMPact on Revascularization Outcomes of intraVascular Ultrasound Guided Treatment of Complex Lesions and Economic Impact (IMPROVE; NCT04221815) randomized controlled trial that is specifically assessing the impact of IVUS in PCI of complex coronary stenoses in an estimated sample size of 3,100 patients.30

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2. Werner N, Nickenig G, Sinning J-M. Complex PCI procedures: challenges for the interventional cardiologist. Clin Res Cardiol 2020;2:64–73. https://doi.org/10.1007/s00392-018-1316-1; PMID: 29978353.

3. Kirtane AJ, Doshi D, Leon MB, et al. Treatment of higher-risk patients with an indication for revascularization: evolution within the field of contemporary percutaneous coronary intervention.

Circulation 2016;134:422–31. https://doi.org/10.1161/ CIRCULATIONAHA.116.022061; PMID: 27482004.

4. Mohr FW, Morice MC, Kappetein AP, et al. Coronary artery bypass graft surgery versus percutaneous coronary intervention in patients with three-vessel disease and left main coronary disease: 5-year follow-up of the randomized, clinical SYNTAX trial. Lancet 2013;381:629–38. https://doi.org/10.1016/S01406736(13)60141-5; PMID: 23439102.

5. Landes U, Bental T, Levi A, et al. Temporal trends in percutaneous coronary interventions thru the drug eluting stent era: insights from 18,641 procedures performed over 12-year period. Catheter Cardiovasc Interv 2018;92:e262–70. https://doi.org/10.1002/ ccd.27375; PMID: 29027735.

6. Fanaroff AC, Zakroysky P, Wojdyla D, et al. Relationship between operator volume and long-term outcomes after percutaneous coronary intervention. Circulation 2019;139:458–72. https://doi. org/10.1161/CIRCULATIONAHA.117.033325; PMID: 30586696.

7. McDaniel MC, Eshtehardi P, Sawaya FJ, et al. Contemporary clinical applications of coronary intravascular ultrasound. JACC Cardiovasc Interv 2011;4:155–67. https://doi.org/10.1016/j. jcin.2011.07.013; PMID: 22115655.

8. Longobardo L, Mattesini A, Valente S, et al. OCT-guided percutaneous coronary intervention in bifurcation lesions. Interv Cardiol 2019;14:5–9. https://doi.org/10.15420/icr.2018.17.2; PMID: 30858885.

9. Maehara A, Matsumura M, Ali ZA, et al. IVUS-guided versus OCTguided coronary stent implantation: a critical appraisal. JACC Cardiovasc Imaging 2017;10:1487–503. https://doi.org/10.1016/j. jcmg.2017.09.008; PMID: 29216976.

10. Gerbaud E, Weisz G, Tanaka A, et al. Multi-laboratory interinstitute reproducibility study of IVOCT and IVUS assessments using published consensus document definitions. Eur Heart J Cardiovasc Imaging 2016;17:756–64. https://doi.org/10.1093/ehjci/ jev229; PMID: 26377904.

11. Giavarini A, Kilic ID, Diéguez AR, et al. Intracoronary imaging.

Heart 2017;103:708–25. https://doi.org/10.1136/ heartjnl-2015-307888; PMID: 28057798.

12. Maehara A, Ben-Yehuda O, Ali Z, et al. Comparison of stent expansion guided by optical coherence tomography versus intravascular ultrasound: The ILUMIEN II study (Observational Study of Optical Coherence Tomography [OCT] in Patients Undergoing Fractional Flow Reserve [FFR] and Percutaneous Coronary Intervention). JACC Cardiovasc Interv 2015;8:1704–14. https://doi.org/10.1016/j.jcin.2015.07.024; PMID: 26585621.

13. Ali ZA, Maehara A, Genereux P, et al. Optical coherence tomography compared with intravascular ultrasound and with angiography to guide coronary stent implantation (ILUMIEN III: OPTIMIZE PCI): a randomised controlled trial. Lancet 2016;388:2618–28. https://doi.org/10.1016/S0140-6736(16)319225; PMID: 27806900.

14. Kang SJ, Ahn JM, Song H, et al. Comprehensive intravascular ultrasound assessment of stent area and its impact on restenosis and adverse cardiac events in 403 patients with unprotected left main disease. Circ Cardiovasc Interv 2011;4:562– 9. https://doi.org/10.1161/CIRCINTERVENTIONS.111.964643; PMID: 22045969.

15. Patel Y, Depta JP, Novak E, et al. Long-term outcomes with use of intravascular ultrasound for the treatment of coronary bifurcation lesions. Am J Cardiol 2012;109:960–5. https://doi. org/10.1016/j.amjcard.2011.11.022; PMID: 22296739.

16. Chen L, Xu T, Xue XJ, et al. Intravascular ultrasound-guided drugeluting stent implantation is associated with improved clinical outcomes in patients with unstable angina and complex coronary artery true bifurcation lesions. Int J Cardiovasc Imaging 2018;34:1685–96. https://doi.org/10.1007/s10554-018-1393-2; PMID: 29981016.

17. Fujii K, Ochiai M, Mintz GS, et al. Procedural implications of intravascular ultrasound morphologic features of chronic total coronary occlusions. Am J Cardiol 2006;97:1455–62. https://doi. org/10.1016/j.amjcard.2005.11.079; PMID: 16679083.

18. Yamamoto MH, Maehara A, Poon M, et al. Morphological assessment of chronic total occlusions by combined coronary computed tomographic angiography and intravascular ultrasound imaging. Eur Heart J Cardiovasc Imaging 2017;18:315–22. https://doi.org/10.1093/ehjci/jew077; PMID: 27099278.

19. Kim BK, Shin DH, Hong MK, et al. Clinical impact of intravascular ultrasound-guided chronic total occlusion intervention with zotarolimus-eluting versus biolimus-eluting stent implantation: randomized study. Circ Cardiovasc Interv 2015;8:e002592. https:// doi.org/10.1161/CIRCINTERVENTIONS.115.002592; PMID: 26156151.

20. Stone GW, Sabik JF, Serruys PW, et al. Everolimus-eluting stents or bypass surgery for left main coronary artery disease. N Engl J Med 2016;375:2223–35. https://doi.org/10.1056/NEJMoa1610227; PMID: 27797291.

21. Andell P, Karlsson S, Mohammad MA, et al. Intravascular

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ultrasound guidance is associated with better outcome in patients undergoing unprotected left main coronary artery stenting compared with angiography guidance alone. Circ Cardiovasc Interv 2017;10:e004813. https://doi.org/10.1161/ CIRCINTERVENTIONS.116.004813; PMID: 28487356.

Choi KH, Song YB, Lee JM, et al. Impact of intravascular ultrasound-guided percutaneous coronary intervention on longterm clinical outcomes in patients undergoing complex procedures. JACC Cardiovasc lnterv 2019;12:607–20. https://doi. org/10.1016/j.jcin.2019.01.227; PMID: 30878474.

Parise H, Maehara A, Stone GW, et al. Meta-analysis of randomized studies comparing intravascular ultrasound versus angiographic guidance of percutaneous coronary intervention in pre-drug-eluting stent era. Am J Cardiol 2011;107:374–82. https://doi.org/10.1016/j. amjcard.2010.09.030; PMID: 21257001.

Malik AH, Yandrapalli S, Aronow WS, et al. Intravascular ultrasound-guided stent implantation reduces cardiovascular mortality: updated meta-analysis of randomized controlled trials.

Int J Cardiol 2020;299:100–5. https://doi.org/10.1016/j. ijcard.2019.07.033; PMID: 31345647.

Hong SJ, Mintz GS, Ahn CM, et al. Effect of intravascular ultrasound-guided drug-eluting stent implantation: 5-year followup of the IVUS-XPL randomized trial. JACC Cardiovasc Interv 2020;13:62–71. https://doi.org/10.1016/j.jcin.2019.09.033; PMID: 31918944.

Zhang J, Gao X, Kan J, et al. Intravascular ultrasound versus angiography-guided drug-eluting stent implantation: the ULTIMATE Trial. J Am Coll Cardiol 2018;72:3126–37. https://doi. org/10.1016/j.jacc.2018.09.013; PMID: 30261237.

Shlofmitz E, Torguson R, Zhang C, et al. Impact of Intravascular Ultrasound on Outcomes Following PErcutaneous Coronary InterventioN in Complex Lesions (iOPEN Complex). Am Heart J 2020;221:74–83. https://doi.org/10.1016/j.ahj.2019.12.008; PMID: 31951847.

Roy P, Steinberg DH, Sushinsky SJ, et al. The potential clinical utility of intravascular ultrasound guidance in patients undergoing percutaneous coronary intervention with drugeluting stents. Eur Heart J 2008;29:1851–7. https://doi. org/10.1093/eurheartj/ehn249; PMID: 18550555.

Gao X-F, Kong X-Q, Zuo G-F, et al. Intravascular ultrasound-guided versus angiography-guided percutaneous coronary intervention: evidence from observational studies and randomized controlled trials. US Cardiol 2020;14:e03. https://doi.org/10.15420/ usc.2020.03.

IMPact on Revascularization Outcomes of intraVascular Ultrasound Guided Treatment of Complex Lesions and Economic Impact (IMPROVE). https://clinicaltrials.gov/ct2/show/ NCT04221815 (accessed August 3, 2020).

US CARDIOLOGY REVIEW

Interventional Cardiology

Clinical Trial Perspective: Cost-effectiveness of Transcatheter Mitral Valve Repair Versus Medical Therapy in Patients with Heart Failure and Secondary Mitral Regurgitation. Results From the COAPT Trial Suzanne J Baron, MD, MSc Lahey Hospital and Medical Center, Burlington, MA

Abstract Treatment of secondary (or functional) mitral regurgitation had traditionally been limited to optimal medical therapy because studies have failed to show a survival benefit with mitral valve surgery for this condition. However, recently the Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation (COAPT) trial demonstrated a significant decrease in heart failure hospitalizations and mortality in patients with severe secondary mitral regurgitation treated with percutaneous edge-to-edge mitral valve repair (TMVr) using the MitraClip device compared with medical therapy. Based on the results of the COAPT trial, the Food and Drug Administration granted approval for MitraClip treatment of patients with severe secondary mitral regurgitation in March 2019. In an attempt to understand the economic impact of treating this patient population with TMVr using the MitraClip device, a formal cost-effectiveness analysis was performed alongside the COAPT trial. This review summarizes the methods and results of the economic substudy of the COAPT trial and discusses the value of the MitraClip device from the perspective of the US healthcare system in the treatment of patients with symptomatic heart failure and secondary mitral regurgitation.

Keywords Transcatheter mitral valve repair, secondary mitral regurgitation, cost-effectiveness, heart failure, mitral valve insufficiency, heart valve prosthesis implantation, percutaneous coronary intervention Sources of Funding: The COAPT trial and economic substudy were funded by Abbott.

Disclosure: SJB has sat on an advisory board for and received funding from Boston Scientific, and has sat on an advisory board for Abiomed.

Received: January 1, 2020 Accepted: April 30, 2020 Citation: US Cardiology Review 2020;14:e08. DOI: https://doi.org/10.15420/usc.2020.01 Correspondence: Suzanne J Baron, Lahey Hospital and Medical Center, 41 Mall Rd, Burlington, MA 01805. E: suzanne.j.baron@lahey.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.

In the wake of transcatheter aortic valve replacement revolutionizing the treatment of aortic stenosis, sizeable interest has arisen in the development of percutaneous technologies to treat patients with mitral valve disease. Thus, when a percutaneous method of edge-to-edge mitral valve repair (TMVr) using the MitraClip device (Abbott Vascular) was introduced, this device was met with considerable enthusiasm. TMVr was first studied in the Endovascular Valve Edge-to-edge REpair STudy (EVEREST II), which randomized patients with severe mitral regurgitation to treatment with conventional mitral valve surgery or TMVr.1 However, the results of the EVEREST II trial were mixed: TMVr demonstrated a good safety profile, but proved to be less effective than surgery in reducing mitral regurgitation.1 Nevertheless, subgroup analyses suggested that TMVr may be more effective than surgery in the subset of patients with secondary (or functional) mitral regurgitation (SMR).1 Hence, the Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation (COAPT) trial was designed to evaluate the effectiveness of

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TMVr using the MitraClip in the treatment of patients with symptomatic heart failure, reduced left ventricular ejection fraction (LVEF; 20–50%), and severe SMR.2 Just over 600 patients were randomized 1:1 to either guideline-directed medical therapy (GDMT) or GDMT in addition to TMVr. At 2 years, treatment with TMVr led to a significant decrease in the primary endpoint of hospitalizations for heart failure (35.8% versus 67.9% per patient-year, p<0.001).2 Furthermore, although rates of all-cause mortality were high in both groups (thereby reflecting the significant comorbidity of this patient population), patients treated with TMVr had substantially lower rates of death from any cause (29.1% versus 46.1%, p<0.001), as well as significantly better health status at 2 years (mean between-group difference in Kansas City Cardiomyopathy QuestionnaireOverall Summary Score 12.8 points, 95% CI [7.5–18.2 points]), than patients treated with GDMT only.2,3 Reassuringly, the efficacy of TMVr appeared to be largely sustained at the 3-year follow-up in the intentionto-treat population (all-cause death 42.8% versus 55.5%, p=0.001; heart failure hospitalizations 46.5% versus 81.5%, p<0.001).4 Given the rising cost of healthcare and the large patient population affected by severe

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Interventional Cardiology SMR and heart failure, a formal economic analysis was conducted alongside the COAPT trial to assess the potential effect on the US healthcare system of TMVr treatment in this population.

Clinical Trial Summary The COAPT economic analysis included all randomized patients and was performed from the perspective of the US healthcare system. In-trial medical costs were assessed using a combination of resource-based accounting for procedural costs and hospital billing data for nonprocedural costs. As the long-term efficacy and associated costs of TMVr beyond the 2-year trial period were unknown, observed in-trial data were used to project healthcare costs as well as patient-level quality-adjusted survival over a lifetime perspective. Lifetime survival was estimated using US life tables, which were recalibrated based on observed trial data so as to reflect the COAPT population. Future inpatient and outpatient healthcare costs were estimated using a regression model, which was derived from observed in-trial costs accrued 1 year after randomization.

Incremental cost-effectiveness ratios (ICERs) were then calculated as the difference in mean lifetime healthcare costs divided by the difference in mean quality-adjusted life-years (QALYs) gained between the two treatment groups. Consistent with current American College of Cardiology and American Heart Association guidelines, ICERs of <$50,000, $50,000â&#x20AC;&#x201C; 150,000, and >$150,000 per QALY gained were considered to represent high, intermediate, and low economic value, respectively, within the US healthcare system.5 Although follow-up costs over the 2-year in-trial period were significantly lower in the TMVr than GDMT group ($26,654 versus $38,345, p=0.018), overall 2-year costs were substantially higher by approximately $35,000 with TMVr due to the high cost of the TMVr index hospitalization ($48,198).6 Due to the higher initial costs of the TMVr procedure, in addition to a projected increase in quality-adjusted life expectancy of 0.82 years with TMVr, overall lifetime costs were estimated to be $45,648 higher with TMVr.6 Accordingly, the ICER for TMVr versus GDMT was $55,600/QALY gained, consistent with TMVr therapy providing intermediate to high economic value. Further analyses did not reveal any patient subgroups (including advanced age, moderate to severe baseline tricuspid regurgitation, or severely depressed LVEF) in whom TMVr would be considered poor economic value. In addition, the ICER for TMVr remained below a threshold of $100,000/QALY gained over a range of sensitivity analyses, in which the durability of survival, quality of life, and cost benefits associated with TMVr were varied.

Discussion of Results The results of the COAPT economic analysis demonstrated that TMVr using the MitraClip device is a cost-effective strategy by current US standards for the treatment of patients with heart failure and severe, symptomatic SMR. Although this treatment strategy is clearly not inexpensive, it is important to note that these findings are comparable to the results of cost-effectiveness analyses of other cardiovascular therapies used for the treatment of heart failure and/or valvular heart disease. For example, when transcatheter aortic valve replacement (TAVR) was compared to medical therapy in patients at extreme surgical risk in the Placement of AoRTic TraNscathetER Valve Trial (PARTNER) 1B trial, the ICER for TAVR versus medical therapy was $61,899/QALY gained.7 Similarly, in the Multicenter Automatic Defibrillator Implantation

With Cardiac Resynchronization Therapy (MADIT-CRT) trial, cardiac resynchronization therapy in addition to implantable cardiac defibrillators was associated with an ICER of $58,330/QALY gained compared with implantable cardiac defibrillators alone in patients with wide QRS complexes and reduced LVEF.8 Although it may seem counterintuitive that TMVr (or other cardiac device therapies) would not be cost saving in the long run, given the reduction in heart failure hospitalizations seen in follow-up, the higher long-term costs are due to a combination of factors. Certainly, the price of the MitraClip technology (estimated at $30,000 per procedure in the analysis) contributes substantially to the upfront cost of the therapy. That said, even if the device cost was assumed to be $0, TMVr would be cheaper, but still not cost saving, as demonstrated in sensitivity analyses (ICER = $20,754/QALY gained when MitraClip cost is assumed to be $0). In addition to the cost of the device, the persistently elevated long-term cost is also likely due to the substantial mortality benefit associated with TMVr and the high healthcare expenditures associated with improved survival.

Indeed, researchers have estimated that the average adult over 70 years of age who reports a limitation in an activity of daily living spends approximately $22,000/year in 2018 for healthcare.9 Thus, as long as treatment with TMVr results in prolonged survival, it is unlikely that this treatment strategy would ever result in cost savings in this complex population of patients with heart failure and other comorbidities.

There is also no guarantee that TMVr will be cost-effective in every patient with severe mitral regurgitation. The Percutaneous Repair with the MitraClip Device for Severe Functional/Secondary Mitral Regurgitation (MITRA-FR) trial failed to show any mortality benefit or reduction in heart failure hospitalizations in another population of patients with severe SMR.10 Consequently, it follows that TMVr would not have been found to be cost-effective in an economic analysis based on MITRA-FR trial data given the lack of efficacy and the known costs of the MitraClip procedure.

Despite both trials enrolling patients with severe SMR, examination of the COAPT and MITRA-FR trials side by side has suggested that the populations of patients differed in important ways, with COAPT patients having more severe SMR relative to their left ventricular dysfunction and receiving more aggressive medical therapy, whereas MITRA-FR patients had more severe left ventricular dysfunction relative to their SMR and received less robust medical therapy prior to trial enrollment.11,12 As these subtle differences in patient characteristics and treatment regimens may have led to opposing and dissimilar clinical results, which, in turn, would have different economic implications for TMVr, it follows that the acceptable economic value of TMVr can only be assumed in patients with SMR who closely mimic those enrolled in the COAPT trial.

In addition, the findings of the COAPT trial cannot necessarily be extrapolated to patients with primary mitral regurgitation or when TMVr is compared to treatments other than GDMT. In a 12-month costeffectiveness analysis of EVEREST II (which included patients with both primary mitral regurgitation and SMR who were treated with either surgery or TMVr), researchers estimated that TMVr was decidedly not cost-effective (ICER >$400,000/QALY gained) compared to surgery in a modified intention-to-treat population.13 Interestingly though, when the analysis was limited only to patients with acute procedural success, the cost-effectiveness of TMVr was found to be of good economic value, with

US CARDIOLOGY REVIEW

Clinical Trial Perspective: COAPT Cost-effectiveness Analysis an ICER estimated at approximately $54,000/QALY gained compared with surgery.13 As such, this further suggests that the economic value of TMVr in the treatment of mitral regurgitation is exceptionally reliant on its use in a highly selected patient population.

Study Limitations The findings of the COAPT economic analysis should be considered in the context of several limitations. First, because billing data were not collected for follow-up costs, various costing methodologies were used to assign follow-up costs. As such, it is likely that these methods resulted in some underestimation of the total costs for both the GDMT and TMVr groups. In addition, the projections of lifetime costs and quality-adjusted survival were uncertain and were based on data through 2 years. As the COAPT trial allowed patients treated with GDMT to crossover to TMVr after 2 years, the accuracy of the lifetime assumptions in this analysis cannot be ascertained in future analyses. That said, sensitivity analyses, in which

1.

2.

3.

4.

5.

Feldman T, Foster E, Glower DD, et al. Percutaneous repair or surgery for mitral regurgitation. N Engl J Med 2011;364:1395–406. https://doi.org/10.1056/NEJMoa1009355; PMID: 21463154.

Stone GW, Lindenfeld J, Abraham WT, et al. Transcatheter mitralvalve repair in patients with heart failure. N Engl J Med 2018;379:2307–18. https://doi.org/10.1056/NEJMoa1806640; PMID: 30280640.

Arnold SV, Chinnakondepalli KM, Spertus JA, et al. Health status after transcatheter mitral-valve repair in heart failure and secondary mitral regurgitation: COAPT trial. J Am Coll Cardiol 2019;73:2123–32. https://doi.org/10.1016/j.jacc.2019.02.010; PMID: 30894288.

Mack MJ. COAPT: three-year outcomes from a randomized trial of the MitraClip in patients with heart failure and severe secondary mitral regurgitation. Presented at TCT 2019, San Francisco, US, September 28, 2019.

Anderson JL, Heidenreich PA, Barnett PG, et al. ACC/AHA statement on cost/value methodology in clinical practice guidelines and performance measures: a report of the American College of Cardiology/American Heart Association Task Force on

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6.

7.

8.

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the duration of clinical and economic benefits associated with TMVr were varied, did demonstrate that TMVr provided at least intermediate economic value even under the most conservative of assumptions. Finally, as discussed above, these economic results only apply to patients who fit the inclusion and exclusion criteria for the COAPT trial because the same benefit of TMVr treatment versus GDMT was not observed in the MITRAFR trial, which included patients with very poor left ventricular function, non-optimized medical therapy, and lesser degrees of mitral regurgitation.10

Clinical Practice Implications For symptomatic heart failure patients with severe SMR despite optimal GDMT, TMVr using the MitraClip device increases quality-adjusted life expectancy at a cost that represents intermediate to high economic value in the US healthcare system. As such, TMVr represents a reasonable treatment strategy from both from a clinical and economic perspective in patients with severe SMR, similar to those enrolled in the COAPT trial.

Performance Measures and Task Force on Practice Guidelines.

J Am Coll Cardiol 2014;63:2304–22. https://doi.org/10.1016/j. jacc.2014.03.016; PMID: 24681044.

Baron SJ, Wang K, Arnold SV, et al. Cost-effectiveness of transcatheter mitral valve repair versus medical therapy in patients with heart failure and secondary mitral regurgitation: results from the COAPT trial. Circulation 2019;140:1881–91. https://doi.org/10.1161/CIRCULATIONAHA.119.043275; PMID: 31564137.

Reynolds MR, Magnuson EA, Wang K, et al. Cost-effectiveness of transcatheter aortic valve replacement compared with standard care among inoperable patients with severe aortic stenosis: results from the placement of aortic transcatheter valves (PARTNER) trial (cohort B). Circulation 2012;125:1102–9. https:// doi.org/10.1161/CIRCULATIONAHA.111.054072; PMID: 22308299.

Noyes K, Veazie P, Hall WJ, et al. Cost-effectiveness of cardiac resynchronization therapy in the MADIT-CRT trial. J Cardiovasc Electrophysiol 2013;24:66–74. https://doi.org/10.1111/ j.1540-8167.2012.02413.x; PMID: 22913474.

Lubitz J, Cai L, Kramarow E, Lentzner H. Health, life expectancy,

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and health care spending among the elderly. N Engl J Med 2003;349:1048–55. https://doi.org/10.1056/NEJMsa020614; PMID: 12968089.

Obadia JF, Messika-Zeitoun D, Leurent G, et al. Percutaneous repair or medical treatment for secondary mitral regurgitation.

N Engl J Med 2018;379:2297–306. https://doi.org/10.1056/ NEJMoa1805374; PMID: 30145927.

Nishimura RA, Bonow RO. Percutaneous repair of secondary mitral regurgitation – a tale of two trials. N Engl J Med 2018;379:2374–6. https://doi.org/10.1056/NEJMe1812279; PMID: 30575469.

Grayburn PA, Sannino A, Packer M. Proportionate and disproportionate functional mitral regurgitation: a new conceptual framework that reconciles the results of the MITRAFR and COAPT trials. JACC Cardiovasc Imaging 2019;12:353–62. https://doi.org/10.1016/j.jcmg.2018.11.006; PMID: 30553663.

Reynolds M, Galper B, Apruzzese P, et al. Cost effectiveness of the MitraClip compared with mitral valve surgery: 12-month results from the EVEREST II randomized controlled trial. J Am Coll Cardiol 2012;60(17 Suppl):B229. https://doi.org/10.1016/j.jacc.2012.08.831

Complex Coronary Interventions

Overview of Quantitative Flow Ratio and Optical Flow Ratio in the Assessment of Intermediate Coronary Lesions Jelmer Westra, MD,1 and Shengxian Tu, PhD2 1. Department of Cardiology, Aarhus University Hospital, Skejby, Denmark; 2. School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China

Abstract Fractional flow reserve (FFR)-guided percutaneous coronary intervention (PCI) improves clinical outcome compared with angiography-guided PCI. Advances in computational technology have resulted in the development of solutions, enabling fast derivation of FFR from imaging data in the catheterization laboratory. The quantitative flow ratio is currently the most validated approach to derive FFR from invasive coronary angiography, while the optical flow ratio allows faster and more automation in FFR computation from intracoronary optical coherence tomography. The use of quantitative flow ratio and optical flow ratio has the potential for swift and safe identification of lesions that require revascularization, optimization of PCI, evaluation of plaque features, and virtual planning of PCI.

Keywords Coronary angiography, fractional flow reserve, optical coherence tomography, ST-elevation MI, multivessel disease, optical flow ratio, quantitative flow ratio Disclosure: The project was funded by the Natural Science Foundation of China (grant no. 81871460), the Shanghai Technology Research Leader Program, and the Shanghai Science and Technology Commission (grant no. 19DZ1930600). ST received a research grant from Pulse Medical Imaging Technology. JW has no conflicts of interest to declare.

Received: February 28, 2020 Accepted: June 2, 2020 Citation: US Cardiology Review 2020;14:e09. DOI: https://doi.org/10.15420/usc.2020.09 Correspondence: Shengxian Tu, Med-X Research Institute, Room 123, Shanghai Jiao Tong University, no 1954, Huashan Rd, Shanghai 200030, China.

E: sxtu@sjtu.edu.cn 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.

Physiological lesion assessment is recommended for the identification of intermediate coronary lesions that might benefit from percutaneous coronary intervention (PCI).1 The quantitative flow ratio (QFR) was developed to derive coronary physiology from angiographic images, whereas the optical flow ratio (OFR) is a more recent approach for the rapid and automated assessment of coronary physiology from intracoronary optical coherence tomography (OCT).2–5 The aim of this article is to present an overview of the evidence, clinical applications, and future perspectives supporting the use of QFR and OFR for the physiologic assessment of intermediate coronary lesions in the catheterization laboratory.

Indication and Use of Physiologic Lesion Assessment in the Catheterization Laboratory Visual estimation limitations of the severity and extent of epicardial coronary artery disease have been acknowledged for more than two decades.6,7 Fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR) are indices that reveal the extent to which an epicardial coronary stenosis causes a pressure drop as a surrogate for compromised coronary flow.8,9 FFR and iFR assessment have a class 1A recommendation in the 2019 European Guidelines on Chronic Coronary

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Syndromes for high-risk patients without documented ischemia and for whom revascularization is considered.1 The use of wire-based physiologic assessment is improving, but is still underutilized because of a lack of confidence in visual assessment, prolonged procedure time, high cost, and risks related to pressure wires.10,11

Emerging Tools for Image-based Derivation of Fractional Flow Reserve Multiple efforts were recently made to develop post-processing computational methods to derive FFR from imaging data.12–16 Invasive coronary angiography (ICA)-derived FFR solutions have the potential to expand the use of physiologic-guided PCI and reduce the amount of pressure wires needed. Intracoronary imaging-derived FFR solutions are able to integrate physiologic and morphologic information in a one-step approach. The current review focuses on the ICA-derived QFR and OCTderived OFR.

Quantitative Flow Ratio The backbone of FFR computation is based on accurate reconstruction of the coronary geometry and hemodynamic modeling. To reconstruct the coronary geometry, 3D quantitative coronary angiography (3D-QCA)

© RADCLIFFE CARDIOLOGY 2020

Quantitative Flow Ratio and Optical Flow Ratio Figure 1: Derivation of Quantitative Flow Ratio and Optical Coherence Tomography-derived Fractional Flow Reserve

A

B

C

Cons Single-vessel analysis Learning curve ICA quality (overlap, foreshortening) Pros No pressure wire No hyperemia induction Computation time <5 minutes

D

E

1.00

0.00 QFR = 0.81

F1

Cons Invasive (need for OCT) OCT is not routinely used Dependent on pullback length Pros Bifurcation lesion analysis Physiology and morphology in one Stent assessment

F2 1.00

0.60

OFR = 0.83

A: To compute QFR, two angiographic acquisitions, separated by >25°, are acquired. B: Pros and cons of QFR. C: The QFR value is superimposed on the 3D vessel reconstruction as a color-coded representation. D: For derivation of the OFR, the OCT scan (D) is acquired according to recommended clinical practice. E: Pros and cons of OFR. F1: The main-vessel lumen is automatically reconstructed in 3D, whereas the lumen of the side-branch ostias is derived by automatic reconstruction of cut planes. F2: The OFR value is color coded and superimposed on the 3D vessel.

ICA = invasive coronary angiography; OCT = optical coherence tomography; OFR = optical flow ratio; QFR = quantitative flow ratio.

is performed with the use of a minimum of two angiographic acquisitions, usually separated by ≥25° (Figure 1). For the calculation of pressure drop and flow reserve, initial ICA-derived FFR computation approaches were based on complex and time-consuming computational fluid dynamic solutions.17,18 To facilitate implementation in routine clinical workflow, QFR was developed. Empiric fluid dynamic equations were applied to shorten the computation time.2 Three different blood flow models are available for QFR. The first uses a fixed hyperemic flow velocity of 0.35 m/s (fQFR). The second uses contrast-flow velocity as derived by the thrombolysis in MI (TIMI) frame count from diagnostic coronary angiography to predict hyperemic flow velocity (cQFR). Finally, hyperemic flow velocity can be derived with TIMI frame counting during adenosine infusion. In clinical practice, the use of cQFR is recommended. Despite the need for manual interaction, the total cQFR in-procedure computation time is on average 5 minutes.19,20 QFR computation is commercially available from QAngio XA 3D software (Medis Medical Imaging Systems), as well as AngioPlus (Pulse Medical Imaging Technology), which uses the same QFR computational algorithm.

Optical Coherence Tomography-derived Fractional Flow Reserve Intravascular imaging visualizes the coronary artery lumen with high resolution. Tools have improved substantially with regard to automated lumen and stent detection.21 Consequently, several groups have attempted to derive FFR-based geometric reconstructions from intracoronary imaging.16 OCT can visualize the vessel structure with a resolution much higher than that of ICA and resolve the limitation of vessel overlap and foreshortening by ICA. Therefore, a computational approach similar to QFR was applied to OCT images for the derivation of

US CARDIOLOGY REVIEW

OFR.4 Following the acquisition of an OCT pullback according to routine clinical practice, the lumen contours are automatically delineated and stacked in 3D. The cut planes of the side-branches ostia are reconstructed to quantify the side-branch areas. The latter allows for an accurate derivation of the step-down reference lumen as if there were no stenosis (Figure 1). Finally, the volumetric flow rate is derived by multiplying a fixed-flow rate of 0.35 m/s with the reference lumen size, and OFR at every cross-section is computed and superimposed with the OCT images. OFR computation is commercially available from OctPlus software (Pulse Medical Imaging Technology). A recent study showed that the diagnostic performance of OFR was superior to QFR, likely due to the incorporation of side-branches and accurate OCT-derived lumen dimensions.5

Clinical Applications Identification of Coronary Artery Stenosis with Indication for Revascularization It is widely accepted that an FFR ≤0.80 is a good indicator for vessels to benefit from revascularization.1 Therefore, FFR was routinely used as a reference standard in diagnostic studies evaluating new physiologic indices. QFR and OFR have good diagnostic and numerical agreement with FFR in retrospective, prospective offline, and prospective inprocedure studies (Table 1).2,4,5,19,20,22–26 The Functional Assessment by Virtual Online Reconstruction (FAVOR) II trials compared the diagnostic performance of in-procedure QFR, with the FFR as a reference standard, and found high diagnostic accuracy. Importantly, QFR was measured within the time of conventional FFR measurements. The diagnostic certainty drops close to the FFR 0.80 cut-off point, where the benefit of revascularization is questionable (Figure 2).27,28 Observational data show

Complex Coronary Interventions Table 1: Key Quantitative Flow Ratio and Optical Flow Ratio Studies Patients (Vessels)

Mean FFR

QFR–FFR Agreement

AUC [95% CI]

QFR Core laboratory measurements FAVOR pilot study2

73 (84)

0.84 ± 0.08

0.00 ± 0.06

0.92 [0.84–0.97]

WIFI II22

172 (240)

0.82 ± 0.11

0.01 ± 0.08

0.86 [0.81–0.91]

308 (328)

0.82 ± 0.12

−0.01 ± 0.06

0.96 [0.94–0.98]

272 (317)

0.83 ± 0.09

0.01 ± 0.06

0.92 [0.89–0.96]

65 (83)

0.81 ± 0.11

−0.03 ± 0.08

0.88 [0.79–0.94]

75 (75)

0.79 ± 0.11

−0.02 ± 0.06

0.93 [0.86–0.97]

66 (82)

0.85 ± 0.07

0.01 ± 0.05

0.91 [0.84–0.99]

115 (138)

—

—

0.67 [0.46–0.84]

0.82 ± 0.09

—

0.91 [0.85–0.97]

0.81 (0.71-0.88)

0.02 ± 0.10

0.89 [0.82–0.95]

In-procedure measurements FAVOR II China19 FAVOR II E-J

20

Microvascular dysfunction Mejía-Rentería et al.23 Previous MI Emori et al.24 Diabetes Smit et al.25 Severe aortic stenosis Mejía-Rentería et al.30

Non-culprit lesions in ST-elevation MI patients with multivessel disease Lauri et al.37 Sejr-Hansen et al.

82 (91) 36

— (103)

OFR Core laboratory measurements Yu et al.4

118 (125)

0.80 ± 0.09

0.00 ± 0.07

0.93 [0.87–0.97]

Huang et al.5

181 (212)

0.82 ± 0.10

0.00 ± 0.05

0.97 [0.88–0.95]

Gutiérrez-Chico et al.26

59 (74)

0.83 ± 0.09

0.00 ± 0.05

0.95 [0.86–0.99]

AUC = area under the curve; FFR = fractional flow reserve; OFR = optical flow ratio; QFR = quantitative flow ratio.

Physiologic Lesion Assessment in ST-elevation MI Patients with Multivessel Disease Current guidelines recommend the use of functional testing to identify non-culprit lesions with an indication for revascularization.34 However, the validity of invasive physiology in the setting of ST-elevation MI (STEMI) remains a subject of debate.35 Transient changes in the downstream resistance and resting versus hyperemic flow could affect indices, such as FFR and iFR, differently depending on the time of measurement (acute/ staged). The evaluation of non-culprit lesions with QFR in the acute setting of STEMI has been found to be comparable to the evaluation of the same lesions using QFR or FFR in a staged setting.36,37 The use of QFR in the

Figure 2: Diagnostic Accuracy of Quantitative Flow Ratio 100

90

Accuracy (%)

more discordance between QFR–FFR in patients with chronic kidney disease, diabetes, previous MI, microcirculatory dysfunction, severe stenosis (high percentage diameter stenosis or long lesion length), and severe aortic stenosis (aortic valve area <0.60 m2).3,23,24,29,30 However, the overall validation results appear comparable and promising (Table 1). QFR was further compared to non-invasive imaging with heterogeneous results.31,32 An increased distal microvascular resistance and impaired ability to dilate the microvasculature could contribute to the described QFR–FFR discordance rate observed in patients with diabetes, previous MI, and microcirculatory dysfunction. However, it is unclear which index provides a ‘true’ measure of the epicardial lesion severity in the setting of increased microvascular resistance, because FFR is inherently affected by microvascular dysfunction.33

80

70

60

50 <0.55

0.55

0.60

0.65

0.70

0.75

0.80

0.85

0.90 >=0.95

FFR

The per-vessel diagnostic accuracy of QFR derived from pooled analysis based on four prospective studies is 87% (95% CI [85–89]). The diagnostic accuracy of QFR is impaired when FFR approaches the 0.80 cut-off point. FFR = fractional flow reserve; QFR = quantitative flow ratio. Source: Westra et al. 2019.3 Reproduced with permission from Wiley.

setting of STEMI and multivessel could reduce the acute procedure length (e.g. QFR can be computed both in-procedure or post-hoc based on the acute angiography) and decrease the need for further downstream evaluation of non-culprit lesions.

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Quantitative Flow Ratio and Optical Flow Ratio Figure 4: Example of Virtual PCI and Stepwise Optimization Using OFR

Figure 3: Prognostic Value of Post-percutaneous Coronary Intervention Assessment of Quantitative Flow Ratio 50

Cumulative occurrence of VOCE (%)

QFR ≤0.89 (n=123) QFR >0.89 (n=628)

40

30

20

10

0

0

100

200

300

400

500

600

700

800

Time since PCI procedure (days) Vessels at risk 123 628

106 609

100 604

61 442

31 205

Cumulative incidence of a vessel-oriented composite endpoint (VOCE) stratified according to QFR. VOCE consists of vessel-related cardiovascular death, vessel-related MI, and ischemiadriven target vessel revascularization. Post-PCI quantitative flow ratio ≤0.89 was associated with a threefold increase VOCE risk (adjusted HR: 2.91; 95% CI [1.63–5.19]; p<0.001). Black line shows vessels with values of post-PCI quantitative flow ratio ≤0.89. Blue dotted line shows vessels with QFR values >0.89. PCI = percutaneous coronary intervention; QFR = quantitative flow ratio; VOCE = vessel-oriented composite endpoint. Source: Biscaglia et al. 2019.43 Reproduced with permission from Elsevier.

Physiologic Lesion Assessment in Patients with Severe Aortic Stenosis Patients with symptomatic severe aortic stenosis often have concomitant coronary artery disease warranting revascularization.38 The identification of flow-limiting stenosis in the setting of severe aortic stenosis could be challenging, because wire-based physiologic indices are susceptible to changes in coronary hemodynamics induced by aortic stenosis.39 However, despite that, the variations in FFR pre-transcatheter aortic valve replacement (TAVI) versus post-TAVI are potentially small, and the hemodynamic effects related to the administration of vasodilators in the setting of severe aortic stenosis might hamper its use.40 Therefore, QFR appears to be superior to quantitative coronary angiography for the identification of flow-limiting lesions in patients with coronary artery disease and aortic stenosis scheduled for TAVI.30

Optimizing Percutaneous Intervention Recent data from the Physiologic Assessment of Coronary Stenosis Following PCI (DEFINE PCI) study illustrated that a residual pressure drop (as measured with iFR) is present in one in five cases with angiographicsuccessful PCI.41 Importantly, four of five cases had residual focal lesions with the potential for further optimization by PCI. Furthermore, multiple large studies confirmed that post-PCI FFR is a predictor of clinical outcome.42 Low post-PCI QFR after successful revascularization was found to predict a vessel-oriented composite endpoint consisting of vessel-related death, vessel-related MI, and ischemia-driven target vessel revascularization in the Angio-based Fractional Flow Reserve to Predict Adverse Events After Stent Implantation (HAWKEYE) study (Figure 3).43 Therefore, the routine use of post-PCI QFR might be a swift and

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A: Pre-PCI OFR computation illustrating a total vessel pressure drop of 0.28 (vessel OFR 0.72).

Pressure drop at the target segment is 0.17, suggesting that the vessel OFR will increase to 0.89 if the target segment is completely revascularized. B: Post-PCI vessel OFR after actual PCI treatment is 0.82 with an in-stent pressure drop of 0.06 caused by stent malapposition and underexpansion. C: After post-optimization, in-stent pressure drop reduces to 0.02, resulting in an increase in the vessel OFR from 0.82 to 0.86. OFR = optical flow ratio; PCI = percutaneous coronary intervention.

straightforward solution for the identification of suboptimal PCI results, as the measurements can easily be acquired using two standard post-PCI angiographic acquisitions. Nevertheless, it should be noted that post-PCI QFR cannot completely assess the impact of stent malapposition in computational physiology, as coronary angiography fails to visualize instent conditions.

The role of intracoronary imaging for procedural guidance is increasingly acknowledged, given the ambiguity of angiography in several clinical settings, such as left main coronary artery disease and coronary artery disease involving bifurcations.44 In a large meta-analysis, the use of intravascular ultrasound or OCT was associated with a reduction in cardiovascular mortality when compared to ICA-guided PCI.45 Therefore,

Complex Coronary Interventions the structured, stepwise use of OCT with OFR as an add-on modality could provide instant evaluation of physiology, lumen dimensions, dissections, stents, and wires, potentially improving the final PCI results (Figure 4).

Virtual Percutaneous Intervention Planning Similar to lumen dimensions measured by OCT, 3D-QCA provides the operator with detailed vessel dimensions, which are useful for treatment planning.46 Furthermore, QFR software enables the calculation of residual QFR, predicting the effect of stenting individual lesions that might be useful in cases with tandem lesions or diffuse disease.

However, there are insufficient data on the current application. Initial pilot data from the Does Optical Coherence Tomography Optimize Results of Stenting (DOCTORS) study found a correlation between prePCI residual QFR (virtual PCI) and the actual post-PCI FFR results.47,48 Of note, such a correlation might be reduced by the presence of in-stent pressure drop as result of suboptimal PCI. That is, virtual PCI assumes that the target vessel segment is completely revascularized (Figure 4).

Additionally, QFR and OFR provide the user with a pressure pullback, as known from FFR, that can be useful for differentiating focal disease from diffuse disease. The pullback pressure gradient was recently introduced to identify arteriosclerotic disease patterns with motorized FFR pullbacks.49 This might enable more individualized patient decisionmaking by identifying diffuse disease that can often be managed with optimal medical therapy or coronary artery bypass graft. Given the concordance of QFR and OFR with FFR, the virtual pullbacks derived from QFR and OFR might be similarly suitable for this purpose and will be subject to future study.

Identification of Microvascular Dysfunction Epicardial coronary artery disease and coronary microvascular disease (MVD) can be difficult to differentiate, but can co-exist.50 Therefore, it is important to look for MVD, as it could explain persistent symptoms in a large proportion of symptomatic patients that undergo ICA without obvious disease or persistent symptoms after successful PCI in obstructive epicardial disease. Contrary to the fixed-flow QFR algorithm, the contrast-flow QFR incorporates the TIMI frame count to estimate the hyperemic flow velocity. It was therefore hypothesized that a large difference between contrast-flow QFR and fixed-flow QFR could occur in the setting of MVD. In a proof-of-concept study, a >0.07 difference between cQFR and fQFR was considered an independent predictor of MVD, as assessed with contrast-enhanced cardiovascular magnetic resonance after PCI.51 If future studies confirm these findings in various patient settings, an approach integrating all QFR algorithms might be applicable for differentiating epicardial and microvascular disease.

1.

2.

3.

Neumann FJ, Sousa-Uva M, Ahlsson A, et al. 2018 ESC/EACTS guidelines on myocardial revascularization. Eur Heart J 2019;40:87–165. https://doi.org/10.1093/eurheartj/ehy394; PMID: 30165437.

Tu S, Westra J, Yang J, et al. Diagnostic accuracy of fast computational approaches to derive fractional flow reserve from diagnostic coronary angiography: the International multicenter FAVOR pilot study. JACC Cardiovasc Interv 2016;9:2024–35. https:// doi.org/10.1016/j.jcin.2016.07.013; PMID: 27712739.

Westra J, Tu S, Campo G, et al. Diagnostic performance of quantitative flow ratio in prospectively enrolled patients: an individual patient-data meta-analysis. Catheter Cardiovasc Interv 2019;94:693–701. https://doi.org/10.1002/ccd.28283; PMID: 30963676.

4.

5.

6.

Perspectives Toward Patient-tailored Treatment Strategies: Combination of Physiology and Morphology Patients with recurrent acute coronary syndrome have a greater prevalence of high-risk plaque features, such as thin-cap fibroartheromas when compared to stable patients.52 Approximately half of all patients presenting with STEMI and multivessel disease have vulnerable plaque morphology, as detected by OCT in obstructive non-culprit lesions. The latter findings were presented in the COMPLETE-OCT substudy, and might explain the favorable clinical outcome found in the Complete vs Culpritonly Revascularization to Treat Multi-vessel Disease After Early PCI for STEMI (COMPLETE) study.53,54 In the COMPLETE study, a small proportion of patients underwent FFR-guided revascularization (<1%). Therefore, the question remains of whether physiology-guided complete revascularization has a benefit in the setting of STEMI and multivessel disease.55 OFR could play a future role by providing vessel morphology with the identification of high-risk plaque features, whereas the physiology component is able to identify flow-limiting lesions. This synergy could potentially enable the treating physician to provide better patient-tailored treatment.

Outcome Trials It is unknown whether the concordance of QFR (and OFR) with FFR translates into comparable clinical outcomes. Three major randomized clinical outcome trials are currently ongoing. The FAVOR III (China) trial is testing the hypothesis that a QFR-guided PCI strategy results in a superior clinical outcome compared to a standard angiography-guided PCI strategy after 12 months (NCT03656848). The FAVOR III E-J trial is testing the hypothesis that a QFR-based diagnostic strategy results in a non-inferior clinical outcome when compared to a FFR guided strategy after 12 months (NCT03729739). The QFR Guided Revascularization Strategy for Patients Undergoing Primary Valve Surgery With Comorbid Coronary Artery Disease (FAVOR IV-QVAS) is testing the hypothesis that a QFRguided strategy can reduce the incidence of a composite outcome within 30 days after surgery, as compared to an ICA-guided strategy in patients with planned primary valvular surgery and concomitant coronary artery disease (NCT03977129).

Conclusion QFR and OFR have the potential to improve clinical practice by providing detailed coronary anatomy and imaging derived physiology. The integration of anatomy and physiology could inform clinical decisionmaking for treatment and optimize subsequent revascularization if indicated. Validation of the techniques through ongoing randomized outcome trials are needed to prove the efficacy of these solutions when applied by users outside highly trained core laboratories.

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Huang J, Emori H, Ding D, et al. Comparison of diagnostic performance of intracoronary optical coherence tomographybased and angiography-based fractional flow reserve for evaluation of coronary stenosis. EuroIntervention 2020. https://doi.org/10.4244/EIJ-D-19-01034; PMID: 31951207; epub ahead of press.

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Davies JE, Sen S, Dehbi HM, et al. Use of the instantaneous wave-free ratio or fractional flow reserve in PCI. N Engl J Med 2017;376:1824–34. https://doi.org/10.1056/NEJMoa1700445; PMID: 28317458.

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Puymirat E, Simon T, de Bruyne B, et al. Rationale and design of the Flow Evaluation to Guide Revascularization in Multivessel ST-Elevation Myocardial Infarction (FLOWER-MI) trial. Am Heart J 2020;222:1–7. https://doi.org/10.1016/j.ahj.2019.12.015; PMID: 32000067.

Pregnancy

Pregnancy in Women with Congenital Heart Disease: A Guide for the General Cardiologist Catherine R Weinberg, MD,1 Amier Ahmad, MD,2 Boyangzi Li, MD, PhD,2 and Dan G Halpern, MD2 1. Department of Cardiovascular Medicine, Lenox Hill Hospital, Northwell Health, New York, NY; 2. Leon H Charney Division of Cardiology, NYU Langone Health, New York, NY

Abstract Remarkable advances in the care and survival of congenital heart disease (CHD) patients have led to increasing numbers of young women with CHD who carry a pregnancy with significant risk. The profound hemodynamic changes that naturally occur during gestation may unmask CHD or exacerbate an existing condition and place both the woman and fetus in jeopardy. The caring cardiologist should be familiar with the specific lesion and anticipate complications. Pregestational counseling and a multidisciplinary team approach during pregnancy are key for a successful pregnancy and favorable outcomes. In this review we discuss the evaluation of the expecting CHD patient and focus on the commonly encountered lesions.

Keywords Congenital heart disease, pregnancy, risk stratification, aortic stenosis, coarctation, atrial septal defect, tetralogy of Fallot, transposition of great arteries Disclosure: The authors have no conflicts of interest to declare.

Received: 20 May 2019 Accepted: 17 March 2020 Citation: US Cardiology Review 2020;14:e10. DOI: https://doi.org/10.15420/usc.2020.08 Correspondence: Catherine R Weinberg, Department of Cardiovascular Medicine, Lenox Hill Hospital, Northwell Health, 130 E 77th St, New York, NY 10075.

E: CWeinberg@northwell.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.

Dyspnea, palpitations, edema, and fatigue are common symptoms during pregnancy. For women with congenital heart disease (CHD), it may be difficult to discern whether symptoms are due to normal pregnancy or underlying cardiac disease. Although most women with CHD tend to experience successful pregnancies, morbidity and mortality are significantly increased with more complex CHD lesions.1–6 Women with CHD are at risk for arrhythmias, heart failure (HF), thromboembolic complications, and preeclampsia.1–6 Risks to the fetus also exist, including premature birth, small for gestational age (SGA), neonatal death, and the risk of recurrence of CHD.1–3 Many of these maternal complications can be treated, and perhaps even anticipated. As the number of maternal CHD pregnancies rises,4 clinical cardiologists should understand the complications with specific CHD conditions and know when to refer women for more specialized care. This review discusses common clinical case scenarios seen by the general cardiologist.

Physiology of Pregnancy

of the renin–angiotensin–aldosterone system results in plasma volume expansion. A disproportional stimulation of erythrocyte mass occurs compared with volume expansion, resulting in dilutional anemia. Further modulation of hormones produces systemic vasodilation to accommodate this volume expansion. As the placenta matures, systemic vascular resistance decreases until the third trimester, during which it rises slightly. Concurrently, pulmonary vascular resistance decreases to allow for the increase in pulmonary flow. A fall in blood pressure occurs until the third trimester, after which blood pressure begins to rise gradually. Importantly, cardiac output increases as much as 50% by around 24 weeks to allow for these hemodynamic changes. The early increase in cardiac output is due to increasing circulating volume. Later, the output is augmented by increased heart rate. Importantly, pregnancy is a hypercoagulable state, increasing the risk of thromboembolic complications fivefold by the third trimester and peaking early postpartum.9 Multiple gestations can intensify these consequences.

Pregnancy encompasses rapid and profound anatomical and physiological changes (Figure 1). Healthy women compensate for significant hemodynamic changes during pregnancy. However, in women with underlying CHD, the hemodynamic adaptations of pregnancy may cause further burden to both the mother and fetus.

Conception initiates physiological adaptations, which persist for several months postpartum.7,8 Estrogen, progesterone, and activation

Labor and delivery cause marked increases in heart rate, cardiac output, and central venous pressures.7,8 Cardiac output increases 60–80% immediately postpartum due to the uteroplacental autotransfusion and vena cava decompression. Changes in hydrostatic and colloid osmotic pressure increase the risk of pulmonary edema at the time of delivery and immediately postpartum. Within the next 24–72 hours, heart rate and

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© RADCLIFFE CARDIOLOGY 2020

Pregnancy in Women with CHD cardiac output fall. By 2 weeks postpartum, most of the hemodynamic changes return to their prepregnancy state; however, it may take up to 6 months for cardiac remodeling to resolve. Due to the significant and rapid hemodynamic changes of labor and in the early postpartum period, women with underlying cardiovascular disease are at increased risk of decompensation during delivery and postpartum, especially within the first 48 hours.

Figure 1: Hemodynamic Changes Throughout Pregnancy

50 40 30

Medications

Preconception counseling regarding the risks and benefits of anticoagulation including warfarin and heparin by an experienced provider is essential because all pose an increased risk of gestational complications.7,8,10 Warfarin crosses the placenta and is associated with embryopathy, miscarriage, and stillbirth, with increasing complications at doses >5 mg. Despite these risks in women with mechanical valve, warfarin is associated with the lowest risk of adverse maternal outcomes and should be recommended as per guidelines.

Low-molecular-weight heparin (LMWH), which does not cross the placenta, is associated with the lowest risk of adverse fetal outcomes, but higher maternal risk in those with mechanical valves. LMWH is the preferred agent for all other indications. In addition, frequent monitoring of levels, conversion between medications as an inpatient, and a planned delivery are necessary.

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20 Change (%)

Cardiovascular medications are frequently necessary during pregnancy in women with underlying heart disease. The risks and benefits to both the mother and fetus must be considered when determining the use and safety of medications during pregnancy.7,8,10 Exposure to medications during the first 2 weeks after conception can result in fetal demise, whereas teratogenicity usually occurs between 4 and 12 weeks of gestation. An extensive review of the safety of medications for cardiovascular disease during pregnancy has been published previously. 10 Beta-blockers are the most widely used cardiac medication during pregnancy. With the exception of atenolol, betablockers have a favorable safety profile; however, they are associated with an increase in SGA births, neonatal bradycardia, and hypoglycemia.

Calcium channel blockers, nifedipine for hypertension and verapamil for arrhythmias, are the preferred agents. Calcium channel blockers can be associated with prematurity, intrauterine growth restriction (IUGR), fetal bradycardia, and suspected neonatal seizures if used in the third trimester. Pulmonary edema necessitates judicious diuresis with loop diuretics, weighing the risk of oligohydramnios, decrease in placental perfusion, and fetal electrolyte abnormalities. Angiotensinconverting enzyme inhibitors, angiotensin receptor blockers, direct renin inhibitors, and spironolactone are all contraindicated during pregnancy and should be discontinued prior to conception. Hydralazine and oral isosorbide dinitrate may be used as substitutes for afterloadreducing medication. Of note, captopril, benazepril, and enalapril may be considered during lactation. Amiodarone is associated with fetal hypothyroidism and IUGR unrelated to duration or dose, and therefore should be reserved for life-threatening refractory arrhythmias. Instead, adenosine, digoxin, or lidocaine, and, used with caution, sotalol, flecainide, or propafenone may be considered for arrhythmia management. Drugs such as endothelin receptor antagonists, statins and direct oral anticoagulants are contraindicated during pregnancy and appropriate alternatives should be discussed.

10 0 0

7

14

21

28

35

42

–10 –20 –30 Delivery –40

Duration of pregnancy (weeks) Plasma volume

HR

CO

MAP

SVR

SV

CO = cardiac output; HR = heart rate; MAP = mean arterial pressure; SV = stroke volume; SVR = systemic vascular resistance. Source: Halpern et al.21 Reproduced with permission from McGraw Hill.

Cases Case 1: Prepregnancy Evaluation of a Woman with Bicuspid Aorta with Moderate Aortic Stenosis and Repaired Coarctation Prepregnancy counseling and evaluation is essential in woman with CHD, especially those at highest risk.7,8 Unfortunately, most women do not receive appropriate counseling and optimization of their CHD. Without appropriate prepregnancy counseling and optimization of their CHD, women have double the risk of maternal mortality and HF.2 One of the first steps in counseling a patient with CHD is to determine their risk with the modified WHO (mWHO) classification.8 Women with mWHO I, such as those with mild pulmonary stenosis or a repaired simple atrial septal defect (ASD), have a small increase in morbidity and no increase in mortality compared with the general population. Conversely, mWHO IV, such as woman with symptomatic severe aortic stenosis or severe systemic ventricular dysfunction, have the highest risk of maternal complications, with cardiac event rates of 40–100%. mWHO IV individuals should be counseled against pregnancy and, if pregnancy occurs, discussions regarding termination are essential. Women with stenotic bicuspid aortic valve and repaired coarctation without significant residual narrowing or aneurysm are classified as mWHO II–III and have an intermediate risk of morbidity and mortality with a cardiac event rate of 10–19%. Other risk scores, such as CARdiac disease in PREGnancy (CARPREG I and II) and Zwangerschap bij vrouwen met een Aangeboren HARtAfwijking (ZAHARA), further assist in stratifying a patient’s risks (Table 1).11–13 The latter risk score is focused on CHD. The next step in risk stratification is to determine the anatomic and physiological complexity of the defect.7,8 Reviewing prior surgical and

Pregnancy Table 1: Predictors of Adverse Maternal Cardiovascular Events During Pregnancy Modified WHO8 (Maternal Cardiac Event Rate)

ZAHARA13

CARPREG II12

Class I • No detectable increased risk of maternal mortality and no or mild increased risk in morbidity (2.5–5%), follow-up once or twice during pregnancy

Risk factors • History of arrhythmias (1.5 points)

Risk factors • Prior CV events or arrhythmia (3 points)

• Small or mild PS, PDA, mitral valve prolapse

• Cardiac medications before pregnancy (1.5 points)

• Successfully repaired simple lesions (ASD, VSD, PDA, anomalous pulmonary venous • NYHA class >II (0.75 points) drainage) • LVOT with peak >50 mmHg or AV • Atrial or ventricular ectopic beats, isolated area <1 cm2 (2.5 points) Class II • Small increased risk of maternal mortality or moderate increase in morbidity (5.7–10.5%), follow-up once a trimester

• NYHA class >II or cyanosis (resting oxygen saturation <90% at rest; 3 points) • Mechanical valve (3 points)

• Moderate or severe systemic AV valve regurgitation (0.75 points)

• Systemic ventricular dysfunction with LVEF <49% (2 points)

• Pulmonary AV valve regurgitation (0.75 points)

• Most arrhythmias (supraventricular arrhythmias)

• Mechanical valve prosthesis (4.25 points)

• High-risk left-sided obstruction (peak LVOT >30 mmHg, mitral valve area <2 cm2, aortic valve area <1.5 cm2; 2 points)

• Turner syndrome without aortic dilatation

• Cyanotic heart disease (1.0 point)

• Pulmonary hypertension (2 points)

• Unoperated ASD, VSD • Repaired TOF

Score → CV risk: Class II–III • Intermediate increased risk of maternal mortality or moderate to severe increase in • 0–0.5 → 2.9% • 0.51–1.50 → 7.5% morbidity (10–19%), follow-up bimonthly • Mild LV impairment (LVEF >45%)

• 1.51–2.50 → 17.5%

• Hypertrophic cardiomyopathy

• 2.52–3.50 → 43.1%

• Native or tissue valve disease not considered WHO I or IV (mild MS, moderate AS)

• ≥3.51 → 70.0%

• Marfan or other HTAD syndrome without aortic dilatation • Aorta <45 mm in bicuspid aortic valve pathology • Repaired coarctation • AV septal defect Class III • Significantly increased risk of maternal mortality or severe morbidity (19–27%), follow-up monthly or bimonthly

• Coronary artery disease (2 points) • High-risk aortopathy (2 points) • No prior cardiac intervention (1 point) • Later pregnancy assessment (2 points) Score → CV risk • 0–1 → 5% • 2 → 10% • 3 → 15% • 4 → 22% • ≥4 → 41%

• LVEF 30–45% • Previous peripartum cardiomyopathy without residual LV impairment • Mechanical valve • Systemic RV with good or mildly decreased ventricular function • Fontan circulation • Patient is well and cardiac condition uncomplicated • Unrepaired cyanotic heart disease • Other complex heart disease • Moderate MS • Severe asymptomatic AS • Moderate aortic dilatation (40–45 mm in Marfan syndrome or other HTAD; 45–50 mm in bicuspid aortic valve, Turner syndrome) Class IV • Extremely high risk of maternal mortality or severe morbidity (40–100%), follow-up monthly • Pulmonary arterial hypertension • Severe systemic ventricular dysfunction (LVEF <30% or NYHA class III–IV) • Previous peripartum cardiomyopathy with any residual LV impairment • Severe MS • Severe symptomatic AS • Systemic RV with moderate or severely decreased ventricular function • Severe aortic dilatation (>45 mm in Marfan syndrome or other HTAD, >50 mm in bicuspid aortic valve, Turner syndrome ASI >25 mm/m2, TOF >50 mm) • Vascular Ehlers–Danlos • Severe (re)CoA • Fontan with any complication ASI = aortic size index; AS= aortic stenosis; ASD= atrial septal defect; CV=cardiovascular; CoA= coarctation; EF = ejection fraction; HTAD = heritable thoracic aortic disease; LV= left ventricle; MS = mitral stenosis; NYHA = New York Heart Association; PDA= patent ductus arteriosus; pts= points; RV=right ventricle; TOF = tetralogy of Fallot; VSD = ventricular septal defect. Adapted from: Halpern et al. 2019.21 Used with permission from McGraw Hill Education.

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Pregnancy in Women with CHD catheterization reports assists in understanding the underlying anatomy and potential complications. Echocardiography further determines the underlying anatomy and spectrum of CHD (e.g. from mild to severe aortic stenosis). However, an echocardiogram may not reveal the true extent of an aortic aneurysm or stenosis of the aorta. Therefore, women with coarctation of the aorta (CoA) should undergo an MRI or ECG-gated CT scan prior to pregnancy. If the woman is pregnant at the time of presentation, an MRI without gadolinium after the first trimester may be performed. Women with hemodynamically significant CoA are advised to undergo stent placement prior to pregnancy. In addition to anatomic evidence seen on imaging, significant CoA is defined as: upper or lower extremity resting peak-to-peak gradient >20 mmHg or mean Doppler systolic gradient >20 mmHg; upper or lower extremity gradient >10 mmHg or mean Doppler gradient >10 mmHg plus either decreased LV systolic function, aortic regurgitation or with collateral flow.7,8,14 Aneurysms may also be seen on imaging, and careful indexing of the absolute aortic dimensions to the patient’s size (i.e. body surface area) is crucial to clinical decision making.7,8,14 Patients with smaller body habitus may be erroneously judged to have normal aortic dimensions by their absolute measurements. Thus, individuals with a smaller body habitus, such as patients with Turner syndrome who become pregnant, commonly by assisted reproductive therapy techniques or by being Turner mosaic, are advised to undergo aortic replacement when the aorta exceeds 25 mm/m2. Non-Turner patients with bicuspid aortic valves are advised to undergo aorta replacement when the absolute aortic size exceeds 50 mm or 27 mm/m2. In those with genetic aortopathies, such as Marfan syndrome, replacement at smaller sizes is advisable. Even with ascending aortic root replacement, women with aortopathies remain at risk of type B dissection. In addition, intracranial aneurysm in adults with CoA occur, and women should be screened for as per guidelines.

Women with coarctation are at increased risk of hypertension disorders, including preeclampsia.7,8 Low-dose aspirin should be considered after 12 weeks of gestation to decrease the risk of severe preeclampsia. 15 Hypertensive medication should be appropriately adjusted prior to pregnancy and titrated during pregnancy. Betablockers are the first-line choice to treat hypertension. 7,8,10 Aggressive blood pressure lowering should be avoided in women with residual or native coarctation because this may result in uterine hypoperfusion.

Rarely, catheter-based interventions during pregnancy are required for maternal or fetal compromise. If a catheter-based intervention is deemed necessary, caution should be used because hormonal changes of pregnancy and the hyperkinetic circulation increase the risks of dissection and dilation of the aorta.

After appropriate counseling and optimization, if pregnancy occurs vaginal delivery with an expedited second stage and regional anesthesia should be considered in women with asymptomatic stenosis or aneurysm 40–45 mm.7,8 In those women with symptomatic aortic stenosis, aortic aneurysm >45 mm, or progression of an aneurysm, a cesarean section is indicated. A cesarean section can be considered in women with unrepaired coarctation and aneurysms.

Case 2: Woman with a Newly Diagnosed Murmur at 24 Weeks Found to have an Atrial Septal Defect With Mildly Dilated Right Ventricle and Normal Systolic Function

Prepregnancy exercise testing is also an important screening tool because many women under-report or under-recognize the degree of their limitation.7,8,14 Exercise testing reveals symptom burden and identifies high-risk exercise test features, including reduced exercise capacity (peak oxygen consumption, VO2), abnormal blood pressure response, ischemic changes, or arrhythmias. If a woman is found to have symptomatic severe aortic stenosis, asymptomatic severe aortic stenosis with left ventricular (LV) dysfunction, or high-risk exercise test features, she should be advised against pregnancy and referred for valve replacement as per guidelines.

Further, women with hemodynamically significant CoA are advised to undergo stent placement prior to pregnancy, and aneurysms should be repaired at sizes as specified above.

Atrial septal defects (ASDs) are one of the most common CHDs in pregnancy. ASDs may be newly diagnosed in pregnancy because the hemodynamic changes exaggerate right ventricular (RV) volume and may unmask an undiagnosed ASD.7–9 Unrepaired (mWHO Class II) or repaired (mWHO Class I), ASDs are usually well tolerated in pregnancy unless associated with cyanosis or pulmonary hypertension. Women are at a <5% risk of arrhythmias, which occur more frequently in those with unrepaired shunts or those with shunts repaired at older ages.

There is also a small risk of paradoxical emboli; thus, any signs of deep venous thrombosis should be investigated. Aspirin should be considered after 12 weeks because there is an increased rate of preeclampsia. Other complications include SGA and higher fetal or perinatal mortality. Rarely will ASD closure be required during pregnancy unless cyanosis occurs without significantly elevated pulmonary vascular resistance. Similarly, women with repaired small ventricular septal defects (VSDs) or small patent ductus arteriosus without an increase in pulmonary vascular resistance tolerate pregnancy well. Vaginal delivery is usually well tolerated with a consideration for IV air filters to prevent air embolisms.

Woman with aortic stenosis should be counseled on and assessed for HF, angina, and syncope.7,8 As pregnancy progresses, the decline in afterload and increase in volume increases the aortic gradient and limits the ability to augment cardiac output appropriately. These changes in hemodynamics increase the risk of HF, arrhythmias, and angina, even if not present prior to conception. If a complication arises, such as HF, medical management with diuretics may be required with caution, given fixed cardiac output, and concern for fetal hypoperfusion.

If these attempts fail, patients should be evaluated for possible balloon aortic valvuloplasty or surgery.

If an ASD or other shunt results in Eisenmenger syndrome (i.e. irreversible pulmonary vascular disease with reversal of the shunt direction and cyanosis; mWHO Class IV), maternal mortality has been reported to be as high as 20–50%.16,17 These individuals should be counseled strongly against pregnancy and, if needed, should undergo early termination.8 If resting arterial oxygen saturation is <85%, the likelihood of a live birth is 12%. Pregnant women with Eisenmenger syndrome or cyanotic heart disease should be referred to advanced CHD centers for further care given their significant morbidity and mortality risk.

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Pregnancy Case 3: Palpitations in a Pregnant Woman with Tetralogy of Fallot Status, Severe Pulmonary Regurgitation, Dilated and Hypokinetic Right Ventricle Eight per cent of women with repaired tetralogy of Fallot (TOF), mWHO II, endure cardiac complications such as arrhythmias and HF during pregnancy.8,18 Given the increased risk of arrhythmias, woman who complain of palpitations should be evaluated with a Holter or event monitor.

Extra volume load, enhanced adrenergic receptor excitability, and surgical scars all increase a woman’s risk of both atrial and ventricular arrhythmias.19 When AF occurs, rhythm control with cardioversion is preferred over rate control with beta-blockers with concurrent anticoagulation.7,8 Electrical cardioversion should be performed in women with hemodynamic instability.

In addition to arrhythmias, RV dilation and HF can occur in women with repaired TOF, especially in those with underlying severe pulmonic regurgitation with RV dysfunction, left ventricular dysfunction, and pulmonary hypertension.1,14 Therefore, prior to pregnancy, in addition to an echocardiogram, cardiac MRI is recommended to evaluate pulmonary regurgitation, RV dilation, and ventricular function in women with repaired TOF.8,14 Optimal timing of pulmonary valve replacement prior to pregnancy should be as per the American College of Cardiology/American Heart Association guidelines.14 As with all women with CHD, close monitoring throughout pregnancy is required because it is difficult to distinguish symptoms and signs of normal pregnancy from those that may reflect hemodynamic compromise of HF. Screening with N-terminal pro B-type natriuretic peptide (NT-proBNP) at 20 weeks of gestation has a good negative predictive value regarding cardiovascular events.20 Echocardiograms should be performed at a minimum of every trimester.8 If RV HF occurs, medical management with diuretics is indicated. Very rarely, trans-catheter pulmonary valve implantation is required in those not responding to medical management with severe pulmonary regurgitation and RV HF. Thromboembolism and endocarditis have seldom been reported.

In addition to maternal echocardiograms, woman with TOF and other forms of CHD should be offered a fetal echocardiogram at 18–22 weeks of pregnancy because it identifies 45% of congenital cardiac malformations.7,8 Parents should also be offered 22q11 deletion testing and genetic counseling. In those whose disease arises de novo, CHD recurrence in offspring is 3–5%.

Given the risks associated with pregnancy in TOF, a clear plan for labor, delivery, and postpartum care should be developed by the end of the second trimester and distributed to all members of the care team.7,8 As with all complex congenital heart diseases, careful cardiac monitoring is recommended because the odds of an adverse maternal cardiac event, including HF, arrhythmia, and thromboembolic events, during delivery are 2.4- to 27.6-fold higher for women with than without CHD.3 Obstetric complications are also higher in these women, including preeclampsia, preterm delivery, hemorrhage, and placental abruption. Higher rates of comorbidities, such as pulmonary hypertension, coronary artery disease, conduction and rhythm disorders, mental health, neurological, and pulmonary conditions, accompany women with CHD and require consideration during delivery.

Vaginal delivery should be encouraged in women with CHD because it has less blood loss and lower risks of infection, venous thrombosis, and

embolism.7,8 Elective cesarean sections have no maternal benefit and result in earlier delivery and lower birth weight. Therefore, cesarean sections are reserved for obstetric indications and specific cardiac indications, including current warfarin therapy, dilated aortic root, aortic dissection, and intractable HF. An early epidural should be carefully titrated during labor and delivery. An epidural minimizes pain and intrapartum fluctuations in cardiac output, but can cause systemic hypotension in those with obstructive valve lesions or diminished ventricular function. Fluids should be meticulously titrated. Hemorrhage causing tachycardia and decreased stroke volume is poorly tolerated, especially in women with preload-dependent hearts. Thus, to prevent hemorrhage, a slow infusion of oxytocin may be safely used, whereas vasodilatation and pulmonary vasoconstriction can occur with an intravenous bolus.

Due to the rapid and significant hemodynamic adaptations, postpartum women with complex CHD should be closely monitored, including telemetry for a minimum of 24–48 hours. After discharge, women should be seen intermittently as outpatients for at least 6 months.

Case 4: Postpartum Heart Failure in a Woman With Transposition of the Great Arteries Status After Repair Many women of reproductive age with dextro transposition of the great arteries (D-TGA) have undergone the atrial switch operation (i.e. Mustard or Senning), with redirection of the systemic and pulmonary venous return at the atrial level resulting in a systemic RV (mWHO III).7,8,14 Pregnancy can be relatively well tolerated if there is less than moderate impairment of RV function or moderate tricuspid regurgitation. However, the systemic RV is prone to failure and worsening tricuspid regurgitation in the setting of the hemodynamic changes of pregnancy, requiring HF therapy with diuretics.7,8 In addition, atrial baffles, as part of the atrial switch operation, may narrow or leak, resulting in shunting with the potential for systemic cyanosis and paradoxical emboli. Further, women are at risk of sinus node dysfunction and atrial or ventricle arrhythmias.

Therefore, monthly or bimonthly surveillance with echocardiograms and arrhythmia monitoring is necessary during pregnancy and postpartum.

Since the late 1980s, an alternative to the atrial switch has been an arterial switch, which is now performed more frequently.14 The surgery for an arterial switch consists of transection of the pulmonary artery and moving it anteriorly (LeCompte maneuver), and translocation of the coronary arteries to the neoaorta (previous pulmonary root). Long-term complications include stenosis of the great arteries or coronaries at the reimplantation sites, and neoaortic root dilatation. A prepregnancy evaluation of ischemia, supravalvular obstruction, dysfunction, and aneurysm of the neoaortic valve is recommended.7,8 If there is an aneurysm of the neoaorta, echo surveillance during pregnancy is advised.

In the absence of residual structural abnormalities, women with a prior arterial switch procedure do well; however, data are limited.

Systemic RV also occurs in women with congenitally corrected transposition (levo transposition of the great arteries [L-TGA]). L-TGA can be associated with pulmonary stenosis and VSD precipitating surgical intervention (mWHO III).7,8,14 Cardiac complications can include heart block, atrioventricular valve regurgitation, and HF. Importantly, as many as 10% will have an irreversible fall in RV function during pregnancy. Therefore, echo surveillance of the systemic RV function should be performed every 4–8 weeks.

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Pregnancy in Women with CHD Women with systemic RV with either d-TGA with atrial switch or L-TGA with underlying ventricular dysfunction, left-sided obstructive lesions, or Eisenmenger syndrome are at highest risk for HF.1,6 Ventricular dysfunction, even if mild, can be further impaired due to increasing demands of pregnancy. Pregnancy may worsen systemic tricuspid regurgitation, which may persist postpartum. In women with structural heart disease, preeclampsia can also increase the risk of developing HF. Symptoms of HF may occur during pregnancy or up to 6 months postpartum, warranting vigilant postpartum evaluation. If RV dysfunction or worsening tricuspid regurgitation occurs, it may be irreversible, and future pregnancies should be discouraged with any dysfunction beyond the mild range. When HF occurs, management is guideline-directed therapy.7,8,14

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Conclusion Advances in medicine have resulted in improved survival in women with CHD who desire pregnancies. General cardiologists are now being tasked with caring for these women, and it is important to have a thorough understanding of these unique hemodynamics and the potential complications that can arise. Although the majority of these women can expect to tolerate pregnancy well, it is imperative that physicians engage in prepregnancy counseling and remain vigilant for issues such as HF, arrhythmia, and thromboembolic complications that may require more specialized care. A team approach, which includes the primary cardiologist, adult congenital heart disease specialist, and maternal–fetal medicine, is proving to improve the care of such complex patients.

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Bredy C, Mongeon FP, Leduc L, et al. Pregnancy in adults with repaired/unrepaired atrial septal defect. J Thorac Dis 2018;10(Suppl 24):S2945–52. https://doi.org/10.21037/ jtd.2017.10.130; PMID: 30305955.

Halpern DG, Weinberg CR, Pinnelas R, et al. Use of medication for cardiovascular disease during pregnancy: JACC state-of-theart review. J Am Coll Cardiol 2019;73:457–76. https://doi. org/10.1016/j.jacc.2018.10.075; PMID: 30704579.

Siu SC, Sermer M, Colman JM, et al. Prospective multicenter study of pregnancy outcomes in women with heart disease.

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Drenthen W, Boersma E, Balci A et al. Predictors of pregnancy complications in women with congenital heart disease. Eur Heart J 2010;31:2124–32. https://doi.org/10.1093/eurheartj/ehq200; PMID: 20584777.

Stout KK, Daniels CJ, Aboulhosn JA, et al. 2018 AHA/ACC guideline for the management of adults with congenital heart disease: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2019;73:1494–

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16. Yentis SM, Steer PJ, Plaat F. Eisenmenger’s syndrome in pregnancy: maternal and fetal mortality in the 1990s. Br J Obstet Gynaecol 1998;105:921–2. https://doi.org/10.1111/ j.1471-0528.1998.tb10240.x; PMID: 9746388.

17. Presbitero P, Somerville J, Stone S, et al. Pregnancy in cyanotic congenital heart disease. Outcome of mother and fetus.

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CIR.89.6.2673; PMID: 8205680.

18. Veldtman GR, Connolly HM, Grogan M, et al. Outcomes of pregnancy in women with tetralogy of Fallot. J Am Coll Cardiol 2004;44:174–80. https://doi.org/10.1016/j.jacc.2003.11.067; PMID: 15234429.

19. Escudero C, Khairy P, Sanatani S. Electrophysiologic considerations in congenital heart disease and their relationship to heart failure. Can J Cardiol 2013;29:821–9. https://doi. org/10.1016/j.cjca.2013.02.016; PMID: 23642334.

20. Kampman MA, Balci A, van Veldhuisen DJ, et al. N-Terminal proB-type natriuretic peptide predicts cardiovascular complications in pregnant women with congenital heart disease. Eur Heart J 2014;35:708–15. https://doi.org/10.1093/eurheartj/eht526; PMID: 24334717.

21. Halpern DG, Sarma A, Economy KE, Valente AM. Heart disease in pregnancy. In: Fuster V, Harrington RA, Narula J, Eapen ZJ, eds.

Hurst’s the Heart. 14th ed. New York: McGraw Hill Education; 2019.

Complex Coronary Intervention

Percutaneous Coronary Intervention for Chronic Total Occlusion Giovanni Maria Vescovo, MD, Carlo Zivelonghi, MD, Benjamin Scott, MD, and Pierfrancesco Agostoni, MD, PhD Department of Cardiology, Hartcentrum, Ziekenhuis Netwerk Antwerpen Middelheim, Antwerp, Belgium

Abstract Treatment of coronary chronic total occlusions represents one of the major challenges in the field of interventional cardiology. This is due to the complexity of these procedures and to the relatively higher risk of complications. In recent years, the development of innovative techniques and the evolution of materials have produced significant progress in this field. Better procedural outcomes have been achieved, with fewer complications.

This article highlights the most recent scientific evidence and techniques, with the intention to guide interventional cardiologists in optimal patient selection and procedure choice.

Keywords Chronic total occlusion, angina, quality of life, antegrade approach, retrograde approach, dissection and re-entry technique Disclosure: The authors have no conflicts of interest to declare.

Received: February 28, 2020 Accepted: July 7, 2020 Citation: US Cardiology Review 2020;14:e11. DOI: https://doi.org/10.15420/usc.2020.10 Correspondence: Pierfrancesco Agostoni, Department of Cardiology, Hartcentrum, Ziekenhuis Netwerk Antwerpen Middelheim, Lindendreef 1, 2020 Antwerp, Belgium. E: agostonipf@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.

Coronary chronic total occlusion (CTO), defined as complete occlusion of a coronary artery for at least 3 months with thrombolysis in myocardial infarction (TIMI) grade 0 flow, represents one of the most complex situations in the field of interventional cardiology.1 Despite an incidence of CTO in patients with stable coronary artery disease (CAD) undergoing coronary angiography of 18–46%, the number of percutaneous coronary interventions (PCIs) for CTO is still less than 4% of all percutaneous revascularizations.2–4

circulation. To do this, it is necessary to obtain accurate coronary angiography. Several authors suggest the use of simultaneous double coronary injection every time contralateral collateral circulation is present.

This consists of injecting the contrast at the level of the donor vessel, followed 2–3 seconds later by injection into the CTO target vessel. During dual injection angiographic film exposure should be prolonged and the image acquired at low magnification avoiding panning, in order to gain a precise definition of both the lesion and collateral vessels.10

In fact, the high rate of complications and failures of CTO revascularization, together with the lack of supporting data from randomized clinical trials, discourage interventional cardiologists from embracing this procedure.

However, thanks to the progress of technology and to greater operator experience, the percentage of successful revascularizations has increased over the years, reaching approximately 90% in specialized centers.5 In addition, the number of procedural complications and adverse clinical events has also decreased significantly.6 Although randomized trials conducted so far have failed to demonstrate superiority of CTO revascularization strategies over medical therapy alone in terms of hard endpoints, observational studies and meta-analysis suggest a wide range of benefits of interventional treatment.7–9

CTO consists of an atherosclerotic plaque and a thrombotic component that can be homogeneous or made up of several layers of differently organized tissues as a result of multiple thrombotic episodes occurring at different times.11 The proximal endoluminal part of the plaque (proximal cap) can be more or less hard depending on the age of the occlusion.

Usually older lesions have a calcific cap that is more difficult to cross.

Conversely, more recent occlusions are characterized by a softer cap that is easier to cross. The proximal cap is morphologically classified in three ways: blunt, tapered, and ambiguous. A tapered cap is usually less resistant to penetration than a blunt cap, making it crossable with low penetration force guidewires. In the case of proximal cap ambiguity, defined as the inability to accurately define the subsequent course of the vessel, it may be necessary to use a selective contrast injection with microcatheter, intravascular ultrasound (IVUS), or coronary CT angiography (CCTA) in order to better define the cap anatomy.12,13

Anatomy of Chronic Total Occlusion In the context of CTO treatment, the assessment of risks and benefits of the intervention and the planning of the procedure are essential to achieve a successful revascularization. The first step is to carefully analyze the anatomy of the occlusion and the presence of collateral

Access at: www.USCjournal.com

To correctly define the complexity of the lesion, other characteristics such as length, tortuosity and composition of the occlusion should be defined.

© RADCLIFFE CARDIOLOGY 2020

PCI for Chronic Total Occlusion Table 1: Randomized Controlled Trials on the Efficacy of Percutaneous Coronary Intervention in Chronic Total Occlusion Versus Medical Therapy Study

Design

Population

Patients (n)

Primary Endpoint

Follow-up Results

CTO Success Rate (%)

DECISION-CTO14

Multicenter

Silent ischemia, stable angina, ACS

834

Composite of death from any cause, MI, stroke, or any revascularization.

4 years

No differences between groups (p=0.86)

91

EuroCTO15

Multicenter

Symptoms and/or ischemia and viability

396

Change in health status 12 months assessed on the SAQ

Greater improvements in health status in the PCI group (p=0.007)

87

IMPACTOR-CTO16 Single center RCT RCA CTO and stable angina

72

Decrease in MIB from baseline to 12-month control

12 months

Decrease in MIB was significantly higher in the PCI group (p<0.01)

83

EXPLORE20

Multicenter RCT

STEMI with coexisting CTO

304

LVEF and LVEDV on cMRI after 4 months

4 months

No differences between groups (LVEF: p=0.60; LVEDV: p=0.70)

73

REVASC22

Single center

Symptoms and/or non-invasive functional testing

205

Change in SWT in the CTO territory

12 months

No differences between groups (p=0.57)

97

ACS = acute coronary syndrome; cMRI = cardiovascular MRI; CTO = chronic total occlusion; LVEDV = left ventricular end-diastolic volume; LVEF = left ventricular ejection fraction; LVEDV = left ventricular end-diastolic volume; MIB = myocardial ischemia burden; PCI, percutaneous coronary intervention; RCA = right coronary artery; RCT = randomized controlled trial; SAQ = Seattle Angina Questionnaire; STEMI = ST-elevation MI; SWT = segmental wall thickening.

Long (>20 mm), tortuous, and calcified chronic occlusions make lesion crossing more difficult. They are also associated with a higher complication rate. Finally, the presence, size, and course of collateral vessels are fundamental to the planning of a retrograde approach, which may be the strategy of choice in the case of ambiguous lesions or antegrade technique failure.

Rationale for Revascularization of Chronic Total Occlusion Symptoms and Quality of Life It is widely established that CTO PCI carries advantages in terms of improving symptoms compared with drug therapy alone. Looking at randomized trials in which angina and quality of life (QoL) were taken as endpoints, only the Drug-Eluting stent Implantation versus optimal Medical Treatment in patients with ChronIc Total OccluSION (DECISION CTO) study failed to demonstrate superiority of PCI compared with pharmacological treatment.14 In contrast, the Randomized Multicentre Trial to Evaluate the Utilization of Revascularization or Optimal Medical Therapy for the Treatment of Chronic Total Coronary Occlusions (EuroCTO study) and the Impact on Inducible Myocardial Ischemia of PercutAneous Coronary InTervention versus Optimal Medical TheRapy in Patients with Right Coronary Artery Chronic Total Occlusion (IMPACTOR CTO study) showed, at 1-year follow-up, advantages of percutaneous revascularization in reducing angina and improving QoL, assessed with the Seattle Angina Questionnaire (SAQ; Table 1).15,16 These differences could be due to the limitations found in the DECISION CTO trial, such as the slow and early termination of enrollment, the high percentage of cross-over in both arms, the high frequency of PCI for nonCTO lesions and the inclusion of patients with mild or absent symptoms.14 Moreover, the study was not focused specifically on CTO-only lesions: many patients with multivessel disease and one CTO were randomized to PCI of all vessels besides CTO, versus PCI of everything including CTO

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(thus the real impact of CTO on symptoms was not assessed). Finally, in the first days after randomization there was a cross-over rate of approximately 20% from the conservative to the PCI treatment, which may also have affected the final results.14 A recent study conducted by Hirai et al. analyzed 1,000 consecutive patients with high-grade refractory angina undergoing CTO PCI and showed that successful revascularization leads to higher improvement in the SAQ Angina Frequency and SAQ Summary Scores compared with unsuccessful PCI (35.0 ± 26.8 versus 18.8 ± 28.9, p<0.01; and 34.2 ± 19.4 versus 22.5 ± 20.8, p<0.01, respectively).17 This suggests that patients who may receive greater benefit from CTO revascularization are those with the highest degree of ischemia.

Further confirmation of the efficacy of percutaneous revascularization in terms of improvement of symptoms was obtained from a meta-analysis conducted by Joyal et al., with a lower persistence of angina in the group of patients who underwent successful revascularization.18 A better QoL, due to improvement of the depression-related symptoms common in patients with CAD, was also seen.19 The presence of refractory angina can lead to psychological distress and a depressive state. From this point of view, revascularization of CTO could lead to an improvement in health status in patients with angina and depression, as reported by Yeh et al.19

Regional and Global Left Ventricular Dysfunction The improvement of left ventricular (LV) systolic function in patients undergoing CTO PCI is one of the most explored outcomes. In the randomized controlled multicenter trial Evaluating Xience and Left Ventricular Function in Percutaneous Coronary Intervention on Occlusions After ST-Elevation Myocardial Infarction (EXPLORE), 304 patients with STelevation MI (STEMI) and coexisting CTO in a non-infarct-related vessel were enrolled.20 The aim of the study was to evaluate, using MRI, the improvement of LV function and the reduction of LV end-diastolic volume

Complex Coronary Intervention Table 2: Chronic Total Occlusion Scoring Systems Score

J-CTO34

RECHARGE36

PROGRESS CTO39

CL37

CASTLE35

Characteristics Blunt stump (1) assessed Length >20 mm (1) Intralesion bending ≥45° (1) Mild–severe calcification (1) Previous CTO failure (1)

Blunt stump (1) Length >20 mm (1) Intralesion bending ≥45° (1) Visible calcification in the CTO segment (1) Bypassed on the CTO target vessel (1) Diseased distal landing zone (1)

Ambiguous proximal cap (1) Circumflex target vessel (1) Moderate/severe proximal tortuosity (1)* Lack of interventional collateral vessels (1)

Blunt stump (1) Length >20 mm (1.5) Non-left anterior descending artery (1) Severe calcification (2) Previous CABG or MI (1.5)

Blunt or no stump (1) Length >20 mm (1) Severe/unseen tortuosity (1)† Severe calcification (1) Age >70 years (1) Previous CABG (1)

Probability of success or failure

Technical success 0–1: 98% 2: 90% 3: 73% 4: 69% 5: 44% 6: 14%

Technical success 0: 98.2% 1: 97.5% 2: 91.6% ≥3: 76.7%

Technical success 0–1: 88.3% 1.5–2.5: 73.1% 3–4.5: 59.4% ≥5%: 46.2%

CTO failure 0: 5.8% 1: 9.3% 2: 14.5% 3: 22.1% 4: 32.3% 5: 44.7% 6: 56.5%

Successful guidewire crossing in <30 min 0: 92.3% 1: 58.3% 2: 34.8% ≥3: 22.2%

* Moderate/severe tortuosity = 2 bends >70° or 1 bend >90°. †Severe = ≥2 pre-occlusive bends >90° or ≥1 bend >120°. CABG = coronary artery bypass grafting; CL score = clinical and related lesion score; CTO = chronic total occlusion.

in patients treated with PCI compared with those on medical therapy alone. The study showed, no advantages of PCI compared with drug treatment at 4 months after the acute event. However, the slow enrollment (leading to potential selection bias) and the relatively low PCI success rate (73%) may have affected the results. Moreover, the evaluation of the outcome only 4 months after randomization could have represented a further limitation. And, as evidenced by Bondarenko et al., myocardial recovery in many cases may be delayed.21 Similarly to the EXPLORE trial, the Recovery of Left Ventricular Function After Stent Implantation in Chronic Total Occlusion of Coronary Arteries (REVASC) trial at 1 year showed no differences between the two groups (CTO PCI versus medical therapy) in terms of changes in segmental wall thickening (SWT) in the CTO territory.22 However, the result could have been influenced by the revascularization of non-CTO stenosis in the group treated with medical therapy. Also, PCI for non-CTO lesions may have increased the flow in the collateral circulation, leading to recovery of areas of hibernating myocardium even in the group of patients without CTO PCI. This speculation arose from subgroup analysis that showed, in patients with less complex CAD (SYNTAX score <13), an improvement in SWT only in patients undergoing CTO revascularization. A further limitation of the study was the lack of assessment of myocardial viability on MRI. SWT was shown to improve significantly only in segments with <75% transmural infarct, with a significant remaining viable myocardium.23 Finally, in patients included in the study, mean LV ejection fraction (LVEF) was normal.22 A recent meta-analysis of 34 studies with a total of 2,804 patients, by Megaly et al., showed that successful revascularization of a CTO is associated with a significant increase in LVEF, especially in those with lower baseline values.24

Arrhythmic Events and Sudden Cardiac Death Chronic total occlusion of an infarct-related coronary artery has been associated with higher risk of ventricular arrhythmia or appropriate ICD shock.25 Ventricular arrhythmias in patients with previous infarction arise in the myocardial area surrounding the fibrous scar.26 At this level, in patients with CTO, hypoperfusion could represent an arrhythmic substrate and favor the occurrence of ventricular tachycardia. Therefore, CTO revascularization,

by restoring blood flow in the area close to the fibrotic scar, may generate positive electrical remodeling and reduce arrhythmias. A recent metaanalysis that assessed ventricular arrhythmias in patients with CTO has shown that CTO is associated with an increased risk of ventricular arrhythmia and all-cause mortality.27 Therefore, it is reasonable to consider defibrillator implantation in patients with an infarct-related CTO.

Mortality and Major Adverse Cardiac Events There is a great discordance in the literature between observational studies and randomized clinical trials, regarding hard endpoints such as mortality and major adverse cardiac events (MACE). In the DECISION CTO trial, which assessed all-cause mortality, MI, revascularization, stroke and MACE, no advantages were found in the PCI group compared with medical treatment alone. One of the weaknesses of the study, in addition to those already mentioned above, was the exclusion of patients with LVEF <30% who appear to benefit more from revascularization.28 In contrast, data from several registries showed an increase in survival in patients undergoing successful recanalization compared with those with unsuccessful PCI.29,30 A meta-analysis of 25 studies (28,486 patients) conducted by Christakopoulos et al. showed that compared with failed procedures, successful CTO PCIs were associated with a lower incidence of death, stroke, coronary artery bypass grafting (CABG) and less recurrent angina.31 Furthermore, another more recent meta-analysis suggested possible advantages of revascularization of CTOs, compared with medical therapy, in terms of allcause mortality, cardiac death and MACE.7 Finally, the REVASC study evaluated MACE, defined as total mortality, MI and any clinically driven repeat revascularization, at 12 months as a secondary endpoint. Although the trial was not powered for clinical endpoints, the CTO PCI group had a lower risk of MACE than the group with medical therapy alone.22

Recommendations for Revascularization of Chronic Total Occlusions Current European and US recommendations for percutaneous revascularization of CTOs are derived from the randomized clinical trials conducted so far. The European guidelines recommend CTO PCI (Class IIa,

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PCI for Chronic Total Occlusion level of evidence B), in patients with expected reduction of ischemia in a tributary territory and/or angina relief.32 At variance with US guidelines, CTO revascularization should be performed by an expert operator in patients with appropriate clinical indication and suitable anatomy.33

Figure 1: Crossing a Chronic Total Occlusion: Antegrade Approach

Risk Scores In order to define the degree of lesion complexity and predict the technical success of CTO, several scores have been proposed (Table 2).

The Japan-CTO (Multicenter CTO Registry of Japan) score (J-CTO score) was developed to estimate the likelihood of successful guidewire passage of the CTO body within 30 minutes.34 The score consists of five variables, and 1 point is assigned to each: previous CTO failure; blunt stump of proximal cap; mild–severe calcification; intralesion bending ≥45°; and occlusion length >20 mm. Patients are classified into four grades of difficulty: easy (J-CTO score 0); intermediate (J-CTO score 1); difficult (J-CTO score 2); and very difficult (J-CTO score ≥3).34 In the EuroCTO (CASTLE) score the variables considered are: CABG history; age (70 years); stump anatomy (blunt or invisible); tortuosity; length of occlusion >20 mm; and extent of calcification.35 Tortuosity is defined as severe when the CTO vessel contains either two or more pre-occlusive bends >90° or at least one bend >120°; and moderate when it contains two bends >70° or one bend >90°. The CTO is defined as straight if the pre-occlusive segment contains a bend <70°.

Other popular scores are the Prospective Global Registry for the Study of Chronic Total Occlusion Intervention (PROGRESS CTO), the Registry of CrossBoss and Hybrid Procedures in France, the Netherlands, Belgium and United Kingdom (RECHARGE), and the clinical and lesion-related (CL) scores, which have been widely validated, as demonstrated in a metaanalysis by Karatasakis et al.36–39

Strategies to Cross a Chronic Total Occlusion There are four strategies to cross a CTO: two antegrade and two retrograde. In both approaches, the lesion can be crossed by passing through the true lumen of the vessel or through the subintimal space (using dissection and re-entry techniques). They are therefore defined as follows: antegrade wire escalation (AWE), antegrade dissection and reentry (ADR), retrograde wire escalation (RWE), and retrograde dissection and re-entry (RDR).

Antegrade Approach The antegrade wire (or AWE) technique consists of advancing various guidewires in an antegrade direction to cross the CTO while remaining within the true lumen of the vessel (true to true). Usually, for proximal cap penetration, tapered polymer guidewires with a low-penetration power soft-tip (Fielder family guidewires; Ashai Intecc), allowing advancement along visible or invisible microchannels, are the preferred first choice. If the operator encounters difficulties in crossing the lesion, they can switch to guidewires with greater penetration force. In general, when the proximal cap is blunt, guidewires with intermediate penetration force (Gaia 2nd–3rd [Ashai Intecc] or Pilot 200 [Abbott Vascular]) are used. If ineffective, guidewires with high penetration force (Conquest Pro 9-12 [Ashai Intecc] or Hornet 10-14 [Boston Scientific]) are used. In addition, the use of a microcatheter, placed near the lesion, may be helpful to increase the support and the penetration power of the guidewire (Figure 1).

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A: Antegrade wire escalation. B: Antegrade dissection and re-entry with knuckle technique.

Modified from Servier Medical Art, licensed under a Creative Common Attribution 3.0 Generic License. https://smart.servier.com/smart_image/atherosclerosis-34/

Once the proximal cap has been penetrated, de-escalation to less penetrating guidewires can be carried out (quick and precise changing of guidewires is made easier by the presence of a microcatheter, because the path already run by the guidewire followed by a microcatheter does not need to be run again by the new guidewire, which can instead be used immediately at the level where the previous guidewire stopped).

There are several methods for advancing the guidewire in the true-to-true lumen technique. In the sliding technique, using tapered polymer guidewires with soft tips, slight rotational movements and cautious advances are used to cross the lesion. The drilling technique, performed when there are harder caps, consists of advancing the guidewire, making rotational movements less than 90°. In the presence of more calcified lesions the operator may proceed with the penetration technique in which stiff guidewires are pushed without rotational movements.

Finally, in the push and torque technique the operator advances and rotates the guidewire until the hardest portion of the plaque is reached and then redirects it to a softer part. Once the lesion is crossed, in order to understand where the guidewire is located, it is necessary to perform the contralateral injection with the acquisition of at least two orthogonal projections. If during the wiring escalation technique, the guidewire accidentally reaches the subintimal space, it is possible to proceed with the dissection and re-entry technique. Alternatively, the guidewire can be left in the subintimal space as a reference, and a second guidewire advanced through the plaque (parallel guidewire technique).40 The first dissection and re-entry technique to be described was the subintimal tracking and re-entry (STAR) with a knuckled guidewire advanced in the subintimal space (Figure 1B).

The subsequent re-entry into the distal lumen was unpredictable and uncontrollable.41 This implies that the stent is implanted in a long subintimal tract with higher risk of branch occlusion and vessel restenosis.

A more recent technique with a particular flat balloon characterized by the presence of two juxtaposed holes (Stingray; Boston scientific) has been developed, allowing a controlled re-entry and collateral preservation.

Complex Coronary Intervention Figure 2: Re-entry Into the Distal Lumen: Controlled Dissection and Re-entry Technique Using Stingray Re-entry System

A: Stingray balloon is placed into the subintimal space beyond the distal cap of the chronic total occlusion. B: A stiff guidewire is advanced through the hole of the Stingray balloon into the distal lumen of the vessel.

Figure 3: Crossing a Chronic Total Occlusion: Retrograde Approach

perforation, which may occur also during attempts to cross collaterals: specifically, epicardial collaterals are at higher risk for this type of complication due to their anatomical position close to the pericardium.

Conversely, the risk of perforation is lower (but still present) in the case of crossing septal collaterals. Once the collaterals are passed with guidewire (usually soft dedicated guidewires such as Fielder XT-R [Ashai Intecc], Sion [Ashai Intecc], Suoh03 [Ashai Intecc]) and with microcatheter, the next step is to pass in a retrograde fashion the CTO body, from the distal cap to the proximal cap. It is important to note that usually the distal CTO cap is anatomopathologically softer than the proximal cap because it is exposed to lower arterial pressures. This helps for an easier passage of guidewires through the distal CTO cap. In the RWE technique, as well in the AWE technique, guidewires with higher penetration power are progressively inserted into the distal cap (Figure 3A). In the case of failure of the true lumen to true lumen retrograde approach, or when a long lesion is present, it is necessary to use a dissection and re-entry technique such as the reverse controlled antegrade and retrograde tracking (CART; Figure 3B). With this technique the subintimal space is reached with an antegrade guidewire that is subsequently expanded with a balloon in order to permit the advancement of the retrograde guidewire from the subintimal space back to the true lumen.44

Chronic Total Occlusion Equipment A deep knowledge of guidewire and microcatheter properties is crucial for any attempt at CTO revascularization.

Guidewires To better understand the peculiarities of each guidewire, it is necessary to analyze every single component. Guidewires are composed of four elements, as follows.

A: Retrograde wire escalation. B: Reverse controlled antegrade and retrograde tracking. Modified from Servier Medical Art, licensed under a Creative Common Attribution 3.0 Generic License. https://smart.servier.com/smart_image/atherosclerosis-34/

Once the balloon has reached the subintimal space beyond the CTO segment, a very stiff guidewire (or the dedicated Stingray guidewire [Boston Scientific] or a Hornet 14 [Boston Scientific] or a Confianza PRO 12 [Ashai Intecc]) is advanced through the hole in the luminal side, to regain the lumen of the distal vessel (Figure 2). A recent study conducted by Karatasakis et al. showed that limited dissection and re-entry techniques can lead to a lower risk of restenosis and target vessel revascularization.42

Retrograde Approach The retrograde approach is mainly used in complex anatomical settings or when antegrade methods have failed. The introduction of the retrograde approach has led to a successful rate of revascularization of approximately 90%.43 The first step in the retrograde approach is to pass the collaterals.

There are several types of collaterals depending on the anatomy of the coronary tree and the specific occlusion: epicardial or septal, contralateral or ipsilateral. Moreover, in post-bypass patients the bypass itself can be used as a conduit to tackle the CTO using a retrograde approach. The careful assessment of collaterals is fundamental to the choice of the most appropriate collateral to cross. The passage of guidewires and microcatheters through the collateral channels is not without risk. One of the most frequent complications of CTO revascularization is coronary

The first element is the core: it is the inner part of the guidewire, which is usually composed of stainless steel, nitinol or both (dual core). In general, a stainless core provides excellent support, pushability (amount of force needed to advance the guidewire once it has penetrated a lesion) and torqueability (ability of the guidewire to transmit efficiently a rotation from the proximal to the distal end). Conversely, the nitinol core has excellent flexibility and trackability (ability of the guidewire to follow the tip around bends and tortuous vessels). Beyond the composition of the core, its thickness is directly related to the support of the guidewire.

The second element is the tip: this is the distal part of the guidewire and has two different designs depending on the extension of the core to the tip. The core-to-tip design consists of a direct connection between the two parts, allowing great torqueability and good tactile feedback. In contrast, when the core is shorter and does not reach the tip a small metal ribbon bridges the gap, ensuring flexibility and good shape retention.

The tip is also responsible for the penetration power (penetrability), defined as the force needed to bend the tip against resistance. Penetration power is directly related to tip stiffness and inversely related to the tip area. Therefore, tapered guidewires have a greater penetration power compared with guidewires with a non-tapered tip. Guidewires with high penetration force are used for crossing calcified lesions when softer guidewires have failed.

US CARDIOLOGY REVIEW

PCI for Chronic Total Occlusion Table 3: Overview of the Most Commonly Used Guidewires Indication

Guidewire Manufacturer

Coating

Tip Tip morphology load (g)

Tip diameter (inches)

Shaft diameter (inches)

Penetration Properties force

Asahi Intecc

Hydrophilic Polymer jacketed

Non-tapered

0.8

0.014

/

Low

Asahi Intecc

Hydrophilic Polymer jacketed

Tapered

0.8

0.009

0.014

Low

Fielder XTA

Asahi Intecc

Hydrophilic Polymer jacketed

Tapered

1

0.009

0.014

Low

Higher tip load than Fielder XT and XT-R, facilitating entry into the chronic occluded lesion

Fielder XTR

Asahi Intecc

Hydrophilic Polymer jacketed

Tapered

0.6

0.009

0.014

Low

Extremely low friction and high flexibility Less support than XT-A

Miracle 6

Asahi Intecc

Hydrophobic

Non-tapered

6

0.014

/

Intermediate

Good tactile feedback (hydrophobic tip)

Ultimate Bros Asahi Intecc 3

Hydrophilic Polymer jacketed

Non-tapered

3

0.014

/

Intermediate

High maneuverability Good pushability Reduced risk of false lumen expansion

Miracle 12

Hydrophobic

Non-tapered

12

0.014

/

High

Good tactile feedback (hydrophobic tip) High lateral support.

Conquest Pro Asahi Intecc 9

Hydrophilic

Tapered

9

0.009

0.014

High

Conquest Pro Asahi Intecc 12

Hydrophilic

Tapered

12

0.009

0.014

High

Stiff and tapered tip allows penetration of heavily calcified lesions High pushability Uncoated tip provides good tactile feedback

Hornet 10

Boston Scientific

Hydrophilic

Tapered

10

0.008

0.014

High

Hornet 14

Boston Scientific

Hydrophilic

Tapered

14

0.008

0.014

High

Sliding Fielder FC technique (crossing microchannels) Fielder XT

Drilling technique

Penetrating technique

Push and torque technique

Knuckle technique (dissection)

Knuckle technique (dissection)

Asahi Intecc

Excellent lubricity and trackability in tortuous vessels Moderate support

High torqueability, penetrability and pushability

Gaia First

Asahi Intecc

Hydrophilic

Tapered

1.5

0.010

0.014

Low

Gaia Second

Asahi Intecc

Hydrophilic

Tapered

3.5

0.011

0.014

Intermediate

Gaia Third

Asahi Intecc

Hydrophilic

Tapered

4.5

0.012

0.014

High

Pilot 50

Abbott Vascular

Hydrophilic Polymer jacketed

Non-tapered

1.5

0.014

/

Low

Good steerability and flexibility

Pilot 150

Abbott Vascular

Hydrophilic Polymer jacketed

Non-tapered

2.7

0.014

/

Intermediate

Excellent torqueability Moderate support

Pilot 200

Abbott Vascular

Hydrophilic Polymer jacketed

Non-tapered

4.1

0.014

/

Intermediate

Excellent torqueability Moderate support Higher penetration force compared with Pilot 150 Makes larger knuckles than the Fielder XT

Sion Black

Asahi Intecc

Hydrophilic Polymer jacketed

Non-tapered

0.8

0.014

/

Low

Excellent torqueability Very low friction due to polymer jacket

Fielder XT

Asahi Intecc

Hydrophilic Polymer jacketed

Tapered

0.8

0.009

0.014

Low

Excellent lubricity and trackability in tortuous vessels Moderate support

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High maneuverability and torqueability Tip designed (micro-cone tip) to improve penetrability

Complex Coronary Intervention Table 3: Cont.

Indication

Guidewire Manufacturer

Coating

Tip Tip morphology load (g)

Tip diameter (inches)

Shaft diameter (inches)

Penetration Properties force

Crossing collateral channel

Sion

Asahi Intecc

Hydrophilic

Non-tapered

0.7

0.014

/

Low

High lubricity (hydrophilic tip)

Sion Blue

Asahi Intecc

Hydrophilic

Non-tapered

0.5

0.014

/

Low

High torqueability and flexibility

Sion Black

Asahi Intecc

Hydrophilic Polymer jacketed

Non-tapered

0.8

0.014

/

Low

Excellent torqueability Very low friction due to polymer jacket

Suoh03

Asahi Intecc

Hydrophilic

Non-tapered

0.3

0.014

/

Low

High trackability, torqueability and flexibility

Fielder XTR

Asahi Intecc

Hydrophilic Polymer jacketed

Tapered

0.6

0.009

0.014

Low

Extremely low friction and high flexibility Less support than XT-A

Stingray guidewire

Boston Scientific

Hydrophilic

Tapered

12

0.0035

0.014

High

Dedicated guidewire advanced into the Stingray balloon

Hornet 14

Boston Scientific

Hydrophilic

Tapered

14

0.008

0.014

High

High torqueability, penetrability and pushability

Conquest Pro Asahi Intecc 12

Hydrophilic

Tapered

12

0.009

0.014

High

High pushability Uncoated tip provides good tactile feedback

Pilot 200

Abbott Vascular

Hydrophilic Polymer jacketed

Non-tapered

4.1

0.014

/

Intermediate

Excellent torqueability Moderate support More penetrability compared with Pilot 150

RG3

Asahi Intecc

Hydrophilic

Non-tapered

3

0.010

/

Intermediate

Optimal inside-catheter pushability

R350

Vascular solutions Hydrophilic

Non-tapered

3

0.013

/

Intermediate

Nitinol core for flexibility Excellent deliverability during advancement through tortuous vessels

Re-entry

Externalization

The third element is the body: this is the part of the guidewire that surrounds the core. It may be composed entirely of spring coils or a combination of spring coils and polymers (plastic). Polymer-jacketed guidewires provide advanced slip performance and good deliverability.

Fourth, the coating: the guidewires can be coated with hydrophobic or hydrophilic material. Hydrophobic coating (silicone based) gives the advantage of greater tactile feedback and a lower risk of unintentionally ending up in the subintimal space. Hydrophilic-coated guidewires are more slippery and are suitable to cross microchannels, tortuous vessels and small collaterals. Sometimes guidewires are coated with hydrophilic material with the exception of the tip, which is hydrophobic, providing at the same time slipperiness and optimal tactile feedback.45 Table 3 summarizes the main properties and indications of the guidewires most used in the treatment of CTOs.

Microcatheters Microcatheters are an essential tool in the treatment of CTOs. Basically, these are used in order to increase guidewire support and penetration power, to allow easy guidewire exchange and to perform selective

contrast injection. Microcatheters have several features that differentiate them from each other, making them specific for precise situations. In general, large-diameter microcatheters are used to increase guidewire tip stiffness during the AWE technique. Conversely, small microcatheters are more useful in the case of tortuosity. Dual lumen microcatheters are used to perform the parallel guidewire technique and wire escalation when the side branch originates near the proximal cap, to wire the side branch of a bifurcation and to gain the main distal vessel when the guidewire achieves the side branch located near the distal cap. In the latter case, the pullback performed in order to redirect the guidewire from the side branch to the main vessel could lead to loss of the path already gained.46 Table 4 summarizes the main properties of and indications for the microcatheters most used in the treatment of CTOs.

Role of Intravascular Ultrasound in Chronic Total Occlusion In the treatment of CTOs, IVUS may be a useful tool to deal with some complex scenarios. One of its main uses is in the case of proximal cap ambiguity. In this condition, if a good-sized collateral branch originates near the lesion, the IVUS catheter can be inserted in the proximal segment

US CARDIOLOGY REVIEW

PCI for Chronic Total Occlusion Table 4: Overview of the Most Commonly Used Microcatheters Microcatheter

Manufacturer

Lumen

Coating

Crossing profile (Fr)

Length (cm)

Advancement

Properties

Finecross

Terumo

Single

Distal hydrophilic coating

1.8

130–150

Forward push (no rotation at all)

Floppy distal segment ultra-flexible for improved trackability around bends and tortuous vessels

Corsair Pro

Ashai Intecc

Single

Distal hydrophilic coating

2.6

135–150

Counter-clockwise rotation

Increased tip flexibility Developed as a septal channel dilator

Turnpike

Teleflex

Single

Distal hydrophilic coating

2.6

135–150

Rotation in both directions

Flexible and tapered tip for improved trackability

Turnpike LP

Teleflex

Single

Distal hydrophilic coating

2.2

135–150

Rotation in both directions

Lower distal shaft profile than standard Turnpike Increased flexibility Excellent for navigating tortuous vessels (150 cm for retrograde; 135 cm for antegrade)

Turnpike Spiral

Teleflex

Single

Distal hydrophilic coating

2.9

135

Clockwise rotation

Great support 2 cm outer nylon coil to improve rotational advancement Used for antegrade approach mainly with fibrotic or calcific lesions

Turnpike Gold

Teleflex

Single

Distal hydrophilic coating

2.9

135

Clockwise rotation

Gold-plated tip for additional guidewire support Used for antegrade approach with highly calcific lesions

SuperCross

Teleflex

Single

Distal hydrophilic coating

1.8 (Straight, flexible)

130–150

Forward push Rotation (in both directions) possible for SuperCross straight tip.

Straight tip or angled tip with multiple tip degree options: 45°, 90°, 120° Provides increased pushability Flexible tip provides increased trackability Excellent torqueability and flexibility (dual coil design) Used as workhorse and for tortuous anatomy Specific use of angled tip design to access sharp angles

2.4 (45°, 90°, 90° XT, 120°)

Mamba

Boston Scientific

Single

Distal hydrophilic coating

2.4

135

Rotation in both directions

Three coil taper zones that provide excellent pushability and support Used to increase support during antegrade approach

Mamba Flex

Boston Scientific

Single

Distal hydrophilic coating

2.1

135–150

Rotation in both directions

Five coil taper zones for enhanced flexibility Used to cross tortuosity and collateral channels

Caravel

Ashai Intecc

Single

Distal hydrophilic coating

1.9

135–150

Forward push (no rotation at all)

Very low distal profile Developed to advance through tortuous vessels

FineDuo

Terumo

Dual

Distal hydrophilic coating

2.9

140

Forward push

Increased tip flexibility Excellent trackability and strong penetration force Used for guidewires placement, parallel guidewire technique and wiring CTO with side branch at the level of proximal or distal cap

Twin Pass

Vascular solutions

Dual

Distal hydrophilic coating

3.5

135

Forward push

Proximal embedded stainless steel rod for support and pushability Used for guidewire placement, parallel guidewire technique and wiring CTO with side branch at the level of proximal or distal cap

CTO = chronic total occlusion.

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Complex Coronary Intervention of the side branch, thereby visualizing the exact location of the CTO cap.

This allows correct puncture of the proximal cap, reducing the risk of inadvertent advancement of the guidewire into the subintimal space or even outside the vessel structure. Sometimes during AWE techniques, the guidewire can accidentally end up in the subintimal space, creating a large dissection and leading to collapse of the distal true lumen. For this reason, the distal part of the vessel cannot be seen on simple angiography, making the following part of the procedure dangerous. In this situation, the IVUS catheter may help to identify the distal true lumen and allow safe and successful re-entry. The operator, after pre-dilation of the subintimal space with a small balloon (1.5 mm), advances the IVUS catheter into the false lumen, identifying the point of re-entry proximal to the distal cap.

Then, under the guidance of IVUS, a second guidewire with high penetration support is advanced to gain the true lumen. IVUS can be particularly useful to tackle ostial lesions with the RDR technique. In this situation the IVUS catheter is placed proximal to the occluded ostium, at the level of the bifurcation, guiding the retrograde passage of the guidewire from the subintimal space to the proximal true lumen. Finally, IVUS is widely used for stenting optimization. Although the randomized studies conducted so far have not shown clear advantages of IVUSguided revascularization compared with angiography alone, the use of this technique could reduce the risk of complications, especially in selected complex settings.47,48

Algorithm for Crossing Chronic Total Occlusions Although the antegrade approach is generally preferred because it is associated with a lower risk of complications, the retrograde technique is necessary to achieve successful PCI in many procedures. Sometimes retrograde techniques may represent the first strategy in the presence of a complex anatomy or ambiguity of the proximal cap. Several algorithms have been proposed to simplify the revascularization and to choose the best approach. The most frequently used are the hybrid approach and the Asia Pacific algorithm.5,49 The hybrid approach consists of positioning two guide catheters in the right and left coronary arteries for complete assessment of the CTO, by doing simultaneous double injection with two guiding catheters. The main criteria to assess the CTO are: type of proximal CTO cap (well defined or ambiguous), length of the CTO segment (less or more than 20 mm), presence of collaterals that can be used for retrograde procedures (so called ‘interventional collaterals’), and quality of the distal vessel after the CTO (diseased distal vessel, distal CTO cap at bifurcation). According to all possible combinations of these four parameters, one of the four techniques (AWE, ADR, RWE or RDR) is chosen as the first strategy. Having the set up with double guiding catheters allows the switch from one technique to another during the procedure in the case of failure of the previous one. Thus the CTO is tackled from every perspective possible.

Several registries have highlighted the importance of the hybrid algorithm, which has a high PCI success rate (86–91%) and a relatively low percentage of procedural complications (1.7–2.6%).50,51 The Asia Pacific algorithm maintains some common features with the hybrid algorithm such as the evaluation of the proximal cap, the quality of the distal vessel and the presence of collaterals. In contrast, the length of the occlusive stenosis is not considered. Furthermore, it is recommended to use the CrossBoss catheter (Boston Scientific) in the

presence of intrastent occlusive restenosis, the Stingray system (Boston Scientific) in the case of failure of the antegrade approach, and the parallel guidewire technique and IVUS-guided wiring as a bail-out strategy in the antegrade arm.

Complications of Chronic Total Occlusion Percutaneous Coronary Intervention Recent advances in the field of CTO have increased the rate of successful revascularization and reduced periprocedural complications. A report from the National Cardiovascular Data Registry showed that the incidence of MACE in CTO percutaneous procedures, although decreasing over time, is still higher compared with non CTO PCI.4 Furthermore, the development of procedural complications has also been associated with a worse long-term health status that has further discouraged interventional cardiologists from actively dealing with CTO percutaneous revascularization. Registry data show a total complication rate ranging from 2.6% to 9.7%.52–54 Several complications may occur during CTO PCI, including coronary perforation, periprocedural MI, arrhythmias, cardiogenic shock, stroke, major bleeding, donor vessel thrombosis, contrast-induced nephropathy, radiation damage and death.53 These have been independently associated with a retrograde approach, advanced age and lesion complexity defined according to the J-CTO score.

One of the most frequent and feared complications of CTO PCI is coronary perforation. 55 This usually occurs as a result of collateral channel damage during a retrograde crossing attempt or due to an accidental exit of the guidewire during wire escalation (both antegrade and retrograde) using high penetration force guidewires. Perforation can occur at the level of epicardial vessels, with an increased risk of cardiac tamponade, or at the level of septal collaterals, and is usually self-limited and does not require specific treatment. In the presence of coronary perforation that is not self-limited, it is crucial to stop the bleeding promptly.

The first step should involve the placement of a balloon close to the perforation. In the majority of cases this may be enough to resolve the complication and prevent cardiac tamponade. However, if it is not sufficient, it becomes necessary to implement additional strategies such as positioning a covered stent or coils or injecting autologous fat, thrombin or microbeads at the level of the perforation.56 Of note, the injection of these substances should never be performed in the case of connection between the perforation and the left chamber, because of the high risk of embolization and stroke. Pericardiocentesis is needed in cases of cardiac tamponade. However, in most cases coronary perforations do not cause hemodynamically significant pericardial effusion.57 Finally, cardiac surgery may be required as a bailout option for percutaneously unresolvable bleeding.

Another complication due to coronary perforation is the intramural hematoma, also called ‘dry tamponade’.58 Vessel perforation may occasionally lead to an important blood extravasation within the myocardial wall or in localized structures next to the heart itself (typically in post-CABG patients in whom the pericardium has several adhesions), causing ventricular or atrial compression and stiffening and subsequent risk of cardiogenic shock. The treatment of this complication is complex: the first step is to stop the bleeding; second, the blood extravasation

US CARDIOLOGY REVIEW

PCI for Chronic Total Occlusion Figure 4: Minimalistic Hybrid Algorithm for Crossing a Chronic Total Occlusion Single transradial 6 Fr for retrograde approach

Success

Second transradial 6 Fr RWE or R-CART

Yes Interventional collaterals?

Complex CTO scenario J-CTO score >1

Failure No

Failure

Possible ADR: 7 or 8 Fr for antegrade approach and 6 Fr transradial for contralateral injections

Simple CTO scenario J-CTO score ≤1

Yes Single 6 Fr transradial for AWE (no contralateral injections): soft wires

Failure

Attempted collateral crossing

Interventional collaterals?

Success

Failure No

Second transradial 6 Fr RWE or R-CART

Failure

Possible ADR: 7 or 8 Fr for antegrade approach and 6 Fr transradial for contralateral injections

ADR = antegrade dissection and re-entry; AWE = antegrade wire escalation; CTO = chronic total occlusion; R-CART = reverse controlled antegrade and retrograde tracking; RWE = retrograde wire escalation. Source: Zivelonghi et al. 2019.60 Reproduced with permission from Elsevier.

should be decompressed, but these localized blood collections may be difficult to reach percutaneously. Sometimes only supportive measures to generate increased intracardiac pressure (such as hydration) in order to compensate for the external pressure, are sufficient to bridge the patient to a stable situation that then allows the hematoma to reabsorb by itself. In the case of development and persistence of hemodynamic compromise, ventricular assist device could be used to stabilize the patient as a bridge to recovery.

Periprocedural infarction still represents one of the feared complications of CTO PCI. This can occur as a consequence of collateral branch occlusion (in particular during uncontrolled dissection and re-entry technique) or in the case of thrombotic occlusion of the donor vessel. The former may be avoided through the use of more controlled re-entry systems, the latter by means of excellent anticoagulation with an activated clotting time >300–350 seconds. Finally, of the most frequent extra-cardiac periprocedural complications, those related to vascular access are notable. In recent years, attention has been paid to the type of access, with the aim of minimizing the use of femoral access and of large introducer sheaths (8 Fr).24

Importance of Access and the Minimalistic Hybrid Algorithm The choice of arterial access plays an important role in the procedure. The type of access depends on operator preference and on the anatomical characteristics of the CTO. In general, complex lesions, such as those with a very resistant proximal cap, require large guide catheters (7 or 8 Fr) for greater passive support. Consequently, femoral access is usually

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preferred. In contrast, radial access, which is now increasingly used for CTO PCI, is associated with similar procedural success but with a lower risk of major bleeding compared with femoral access.59 We recently proposed an approach based on the use of all four possible hybrid strategies to cross the CTO, but with the aim of reducing the rate of femoral approach, double access and periprocedural complications.60 This approach, called the minimalistic hybrid algorithm, has shown promising results, ensuring a high revascularization success rate using the radial approach in 90% of cases and a single catheter approach in nearly 60% of procedures (Figure 4).61

Conclusion CTO treatment represents one of the most challenging and complex procedures in the field of interventional cardiology. International guidelines based on the results of the available randomized controlled trials (RCTs), support CTO revascularization only in selected cases. It is a generally accepted opinion that in patients with refractory angina, CTO PCI improves QoL. Its effect on ventricular function and other hard endpoints such as mortality and MACE, however, is still debated; although RCTs and observational studies have consistently suggested the possible advantages of CTO PCI when compared with optimal medical treatment in some subgroups of patients, for instance in those with depressed EF and/ or evidence of myocardial hibernation. Therefore, despite improvement in technique and greater operator skill, CTO PCI remains a complex procedure with a non-negligible incidence of complications. For this reason, accurate selection of patients who may benefit from this procedure is needed, and specific algorithms leading to a systematic approach to this type of procedure, are welcome.

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46. Vemmou E, Nikolakopoulos I, Xenogiannis I, et al. Recent advances in microcatheter technology for the treatment of chronic total occlusions. Expert Rev Med Devices 2019;16:267–73. https://doi.org/10.1080/17434440.2019.1602039; PMID: 30929525.

47. Kim BK, Shin DH, Hong MK, et al. Clinical impact of intravascular ultrasound-guided chronic total occlusion intervention with zotarolimus-eluting versus biolimus-eluting stent implantation: randomized study. Circ Cardiovasc Interv 2015;8:e002592. https:// doi.org/10.1161/CIRCINTERVENTIONS.115.002592; PMID: 26156151.

48. Chieffo A, Latib A, Caussin C, et al. A prospective, randomized trial of intravascular-ultrasound guided compared to angiography guided stent implantation in complex coronary lesions: the AVIO trial. Am Heart J 2013;165:65–72. https://doi.org/10.1016/j. ahj.2012.09.017; PMID: 23237135.

49. Harding SA, Wu EB, Lo S, et al. A new algorithm for crossing chronic total occlusions from the Asia Pacific Chronic Total Occlusion Club. JACC Cardiovasc Interv 2017;10:2135–43. https:// doi.org/10.1016/j.jcin.2017.06.071; PMID: 29122129.

50. Christopoulos G, Karmpaliotis D, Alaswad K, et al. Application and outcomes of a hybrid approach to chronic total occlusion percutaneous coronary intervention in a contemporary multicenter US registry. Int J Cardiol 2015;198:222–8. https://doi. org/10.1016/j.ijcard.2015.06.093; PMID: 26189193.

51. Sapontis J, Salisbury AC, Yeh RW, et al. Early procedural and health status outcomes after chronic total occlusion angioplasty: a report from the OPEN-CTO Registry (Outcomes, Patient Health Status, and Efficiency in Chronic Total Occlusion Hybrid Procedures). JACC Cardiovasc Interv 2017;10:1523–34. https://doi. org/10.1016/j.jcin.2017.05.065; PMID: 28797429.

52. Danek BA, Karatasakis A, Karmpaliotis D, et al. Development and validation of a scoring system for predicting periprocedural complications during percutaneous coronary interventions of chronic total occlusions: the Prospective Global Registry for the Study of Chronic Total Occlusion Intervention (PROGRESS CTO) complications score. J Am Heart Assoc 2016;5:e004272. https:// doi.org/10.1161/JAHA.116.004272; PMID: 27729332.

53. Riley RF, Sapontis J, Kirtane AJ, et al. Prevalence, predictors, and health status implications of periprocedural complications during coronary chronic total occlusion angioplasty.

EuroIntervention 2018;14:e1199–e1206. https://doi.org/10.4244/ EIJ-D-17-00976; PMID: 29808821.

54. Konstantinidis NV, Werner GS, Deftereos S, et al. Temporal trends in chronic total occlusion interventions in Europe. Circ Cardiovasc Interv 2018;11:e006229. https://doi.org/10.1161/ CIRCINTERVENTIONS.117.006229; PMID: 30354635.

55. Patel VG, Brayton KM, Tamayo A, et al. Angiographic success and procedural complications in patients undergoing percutaneous coronary chronic total occlusion interventions: a weighted metaanalysis of 18,061 patients from 65 studies. JACC Cardiovasc Interv 2013;6:128–36. https://doi.org/10.1016/j.jcin.2012.10.011; PMID: 23352817.

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PCI for Chronic Total Occlusion 56. Azzalini L, Poletti E, Ayoub M, et al. Coronary artery perforation during chronic total occlusion percutaneous coronary intervention: epidemiology, mechanisms, management, and outcomes. EuroIntervention 2019;15:e804–11. https://doi. org/10.4244/EIJ-D-19-00282; PMID: 31217142.

57. Danek BA, Karatasakis A, Tajti P, et al. Incidence, treatment, and outcomes of coronary perforation during chronic total occlusion percutaneous coronary intervention. Am J Cardiol 2017;120:1285– 92. https://doi.org/10.1016/j.amjcard.2017.07.010; PMID: 28826896.

58. Vetrugno V, Sharma H, Townend JN, Khan SQ. What is the cause

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of hypotension? A rare complication of percutaneous coronary intervention of a chronic total occlusion: a case report. Eur Heart J Case Rep 2019;3:1–5. https://doi.org/10.1093/ehjcr/ytz184; PMID: 32123803.

59. Bakker EJ, Maeremans J, Zivelonghi C, et al. Fully transradial versus transfemoral approach for percutaneous intervention of coronary chronic total occlusions applying the hybrid algorithm: insights from RECHARGE Registry. Circ Cardiovasc Interv 2017;10:e005255. https://doi.org/10.1161/ CIRCINTERVENTIONS.117.005255; PMID: 28851720.

60. Zivelonghi C, van Kuijk JP, Suttorp MJ, et al. Implementing a

minimally invasive approach (combining radial approach, small guiding catheters and minimization of double access) for coronary chronic total occlusion intervention according to the hybrid algorithm: the minimalistic hybrid algorithm. Int J Cardiol 2019;283:84–7. https://doi.org/10.1016/j.ijcard.2018.11.021; PMID: 30449693.

61. Zivelonghi C, van Kuijk JP, Poletti E, et al. A “minimalistic hybrid algorithm” in coronary chronic total occlusion revascularization: procedural and clinical outcomes. Catheter Cardiovasc Interv 2020;95:97–104. https://doi.org/10.1002/ccd.28213; PMID: 30919577.

Complex Coronary Intervention

Feasibility, Safety, and Clinical Performance of Self-apposing Stents for Left Main Stenosis Krzysztof Pujdak, MD, Jan Kähler, MD, and Marc Werner, MD Department of Cardiology, Klinikum Herford, Herford, Germany

Abstract Drug-eluting stents (DES) are the gold standard for percutaneous coronary interventions (PCI); however, technical and anatomical challenges need to be addressed to ensure optimal apposition and prevent late adverse events. Complex vessel anatomies, including ectatic or aneurysmatic vessels, or significant differences in diameter in left main stenosis of the coronary artery, are clinical indications in which current PCI techniques attempt to shape conventional DES to follow vessel anatomy, thus modifying the original stent scaffold and its properties. However, due to their design, balloon-expandable cobalt–chromium and cobalt–nickel DES have limitations regarding their expansion capacity, which can result in undersizing and malapposition. New stent scaffolds have recently been introduced into clinical practice to address these challenging anatomies, including a drug-eluting nitinol stent platform. The nature of the nitinol device allows conformability to the native vessel, covering complex anatomies without manual adaptation. In this article, the authors present the rationale and current data on self-apposing nitinol DES in left main stenosis, and suggest that the device may be safely and effectively used with comparable rates of adverse cardiovascular events, as seen with second-generation balloon-expandable DES.

Keywords Left main stenosis, self-apposing stents, percutaneous coronary intervention, complex vessel anatomies, drug-eluting stents Disclosure: KP has received fees from STENTYS. All other authors have no conflicts of interest to declare.

Received: March 3, 2020 Accepted: June 22, 2020 Citation: US Cardiology Review 2020;14:e12. DOI: https://doi.org/10.15420/usc.2020.11 Correspondence: Krzysztof Pujdak, Department of Cardiology, Klinikum Herford, Schwarzenmoorstr. 70, Herford 32049, Germany.

E: Krzysztof.Pujdak@klinikum-herford.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.

Significant stenosis of the left main (LM) coronary artery is observed in 7% of coronary angiographies.1 Coronary artery bypass grafting has traditionally been the treatment of choice. In recent years, percutaneous coronary intervention (PCI) has evolved as an alternative, especially for low and intermediate SYNTAX score patients.2 However, during PCI of bifurcation lesions, approximately 50% of LM stenoses are associated with worse outcomes compared to ostial or mid-portion LM shaft lesion treatment.3 A particular technical challenge related to interventions of the distal LM stem is a major difference in diameter between the LM coronary artery and its branches (left anterior descending artery [LAD], left circumflex [LCX] artery, or intermediate branch). This can result either in oversizing the LM coronary artery in relation to the diameter of the distal branch, or in undersizing the LM coronary artery in which it was implanted, which can affect the distal reference diameter. The first is potentially associated with distal stent-edge dissection or perforation; the latter can result in malapposition of the stent. Both phenomena result in unfavorable angiographic and clinical outcomes.

the materials used, their maximal expansion capacity can be a limiting factor, particularly in patients with large ectatic or aneurysmatic vessels and major fractal differences in diameters; for example, between the LM coronary artery and LAD, or between the LM coronary artery and LCX artery.

Self-apposing Stents

Characteristics of Self-apposing Stents

Conventional balloon-expandable, drug-eluting stents (DES) are the gold standard for the interventional treatment of hemodynamically significant coronary artery stenoses. However, due to their design and

Conventional balloon-expandable stent platforms do not have any expansion force, and their expansion and apposition are the result of deployment pressure and post-dilation.

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This limitation has led to the development to various stent designs, and many materials have been tested in order to improve the physical properties of DES. One of these materials is nitinol, a nickel–titanium alloy, which has been used for many years for devices, such as those used for patent foramen ovale closure. Nitinol has memory properties that allow it to actively expand to a predetermined diameter at body temperature, including in a self-apposing manner (with the outward force to take the shape of the vessel). The device has the ability to match differing vessel diameters along the length of the vessel and to adapt to any changes in the vessel diameter over time; for example, resolution of vascular spasm or negative remodeling in the course of atherosclerosis.

© RADCLIFFE CARDIOLOGY 2020

Self-apposing Stents for Left Main Stenosis Figure 1: Design of Xposition Self-apposing Stent

Figure 2: Xposition S-stent Deployment Disconnectable

1. Stent is mounted on a semi-compliant balloon and is restrained by a splittable sheath.

2. Balloon inflation splits the sheath and releases the self-apposing stent.

Disconnection

3. The balloon is then deflated, leaving the 0.0032" sheath between the stent and the vessel wall.

Reproduced with permission from Stentys.

In contrast, self-apposing stents have an inherent expansion force that allows the stent to conform to the vessel diameter without the risk of overexpansion. The expansion force is relatively low and inadequate to replace meticulous lesion preparation. If there is insufficient in predilatation and post-dilatation of the lesion, there is a substantial risk of underexpansion of the stent, which, similar to conventional balloonexpandable stents, is a relevant factor for stent thrombosis (ST) and instent restenosis.

As the expansion force exponentially decreases as the stent diameter increases, it is crucial to select the proper stent size and avoid oversizing the device in order to ensure good apposition to the vessel wall.

Self-apposing stents can conform to the vessel, even in the presence of variance in vessel diameter and changes in vessel diameter over time.

Self-apposing stents have shown more complete and continual apposition against the vessel wall than balloon-expandable stents.4 Stent strut malapposition has been found to be a key mechanism for acute and subacute ST.5 This ability to conform to varying diameters also reduces the need for the high pressure, oversized post-dilation, and the risk of subsequent dissection. In vessels with diameter variance, this means that all balloon dilations can focus on treating the lesion rather than on making the stent fit the vessel. In bifurcations, there is also no need to use the kissing balloon technique or the proximal optimization technique (POT) to ensure good apposition, simplifying the treatment of bifurcation lesions.6 Most of the available clinical data relate to a single device, the Xposition S self-apposing sirolimus-eluting stent (Stentys SA). The Xposition S stent is laser cut from a nitinol tube, with short Z-shaped rows of stent struts joined together with S-shaped connectors. These short-stent elements enable the stent to accurately conform to the vessel wall, whereas the S-shaped connecting elements are disconnectable to allow side-branch access, facilitating a provisional approach to bifurcation lesions. Disconnection is triggered by passing a balloon though the distal cell covering the ostium of the side-branch, and subsequent inflation of the balloon induces a rotational torque force that causes the elements to disconnect (Figure 1). However, proper balloon size

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4. The balloon and sheath are then withdrawn, leaving the stent apposed to the vessel wall.

The two radio-opaque stent markers are located at the stent edges.

Reproduced with permission from Stentys.

selection is crucial to ensure good apposition of the disconnected element. Gold markers are embedded in paddles at either end of the stent, allowing accurate visualization of the stent once implanted. The stent is coated with a polymer of polysulfone that contains both the drug (1.4 µg/mm² sirolimus) and the excipient (polyvinylpyrrolidone), resulting in a highly biocompatible and non-thrombogenic surface.

The stent is compatible with a 6 Fr guiding catheter, and the current monorail delivery system makes it deployable by withdrawal of a retractable sheath. It is mounted onto a semi-compliant balloon. The stent is covered by a splittable sheath that keeps the stent compressed. When the balloon is inflated, the sheath is split, which results in stent release.

The device is available in four lengths (17, 22, 27, and 37 mm) and three sizes 2.5–3.0 mm (small), 3.0–3.5 mm (medium), and 3.5–4.5 mm (large).

The theoretical maximum diameter reached with the medium-sized device is 5 mm, and 6.5 mm with the large-sized device.

Using a Self-apposing Stent Lesion Preparation Predilatation is mandatory in every case prior to stent deployment.

However, in the case of heavily calcified vessels, it is crucial that the lesion is prepared with high-pressure predilatation, cutting or scoring balloon, or atherectomy to achieve a diameter of <30% residual stenosis or a 2 mm lumen diameter. Poor lesion preparation will result in a higher retraction force upon withdrawal of the delivery system, and possible migration of the stent (Figure 2).

Device Deployment The device is positioned using the proximal and distal markers of the balloon; however, as the balloon expands 4 mm proximally to the marker, care should be taken to ensure the guide catheter is not covering this segment. The stent will deploy at approximately 8 atm, but inflation should always be at a minimum of 12 atm.

Complex Coronary Intervention Figure 3: Coronary Angiogram

Reproduced with permission from Stentys.

Figure 4: Three-month Follow-up Showing a Favorable Angiographic Result

Reproduced with permission from Stentys.

Device Withdrawal During delivery, the splittable sheath is trapped between the stent and the vessel wall; therefore, during withdrawal, care must be taken to avoid advancement of the guide catheter. To avoid interaction of the guiding catheter with the stent and sheath and a consecutive increase of retraction force or stent damage, it is strongly recommended that the guide catheter is withdrawn so that it is 2 cm from the proximal stent marker, and that this position is maintained.

Post-dilatation As a self-apposing stent only has an expansion force to conform to the vessel, the use of post-dilatation with a non-compliant balloon is strongly recommended to ensure that the lesion is fully expanded.

Current Evidence on the Use of Self-apposing Stents in Left Main Coronary Artery Disease In a propensity score analysis from the Self-apposing Stentys Stents Registry (SPARTA) and Failure in Left Main Study with Second-generation Stents – Cardiogroup III (FAILS-2) registries, 151 patients with LM coronary artery disease treated with the XPosition S device and 1,270 treated with

second-generation balloon-expandable DES were included.7 No differences in the rate of major adverse cardiovascular events (MACE) rate at 250 days were observed (9.8% versus 11.5%, p=0.54). After propensity score matching, 129 patients treated with sirolimus-eluting stents and 258 patients with DES (approximately one-third were women) were compared. After a follow-up of 250 days, the MACE rate was not found to differ between the two groups (9.9% versus 8.5%, p=0.66), nor did the rate of LM target lesion revascularization (TLR; 1.6% versus 3.1%, p=0.36) and definite ST (0.8% versus 1.2%, p=0.78). These results were also consistent when controlling for treatment with provisional versus two-stent strategies for unprotected LM bifurcation.

In the LM-STENTYS registry, 175 consecutive patients were treated with Stentys DES implanted to the LM coronary artery. The primary endpoint was major adverse cardiac and cerebral events (MACCE), defined as cardiac death, MI, TLR, and stroke assessed after 1 year. 8 The secondary endpoint was ST at 1 year. In 117 (66.9%) and 58 (33.1%) patients, stable acute coronary syndrome (ACS) and angina were the initial diagnoses, respectively. The median SYNTAX score was 23.0 (interquartile range [IQR] 18.7–32.2) in the stable angina group and 25.0 (IQR 20.0–30.7) in the ACS group. During 1-year follow-up in the stable angina group, two (3.4%) MACCE occurred; both were cardiac deaths. Among the ACS patients, there were 19 (16.2%) MACCE, nine (7.7%) cardiac deaths, 11 (9.4%) MI, 11 (9.4%) TLR, one (0.9%) stroke. In total, there were three (1.7%) cases of acute ST, all in the ACS subset.

It is worth noting that no intravascular imaging was utilized in either the SPARTA or FAILS-2 registries.

The Clinical Study to Evaluate the STENTYS Xposition S for Treatment of Unprotected Left Main Coronary Artery Disease (TRUNC) study included 205 patients between June 2016 and July 2017 at 18 locations in Europe.9 Patients with a SYNTAX score >32 or recent ST-elevation MI were excluded. Distal LM stenosis was present in 92.7% of patients treated using the provisional approach (in 79.4% of cases). Remarkably, POT and kissing balloon inflation were performed in 56.3% and 26.6% cases, respectively. The target lesion failure rate, defined as a composite of cardiac death (2.4%), target vessel MI (3.9%), and TLR (7.3%), was 8.3% at 12 months and 11.7% at 24 months. Most TLR events were due to stenosis located in the side-branch, outside the XPosition S-stent location at the side-branch level (irrespective of the type of SB treatment during index procedure), which is commonly observed when treating coronary bifurcation lesions. Only one probable/subacute ST was reported (death of unknown cause within 30 days) with no late or very late ST event. The TRUNC study confirmed that the Xposition S selfapposing stent is a valid and feasible option for the treatment of LM coronary artery disease. Such results were reached without the systematic need of stent optimization techniques, focusing mainly on lesion treatment.

Case Report A 64-year-old male with previously diagnosed arterial hypertension and dyslipidemia was admitted to our emergency department with hypotonia, tachycardia, and angina at rest. ECG revealed ST-elevation in aVR, and ST-depression in leads I, aVL, and V2–V6. A coronary angiogram was immediately performed and showed subtotal stenosis of a relatively short LM coronary artery with the presence of general

US CARDIOLOGY REVIEW

Self-apposing Stents for Left Main Stenosis Figure 5: Optical Coherence Tomography Showing Good Apposition and Expansion of the Well-endothelialized Stent

1 mm

10

20

30

40

50

Reproduced with permission from Stentys.

ectasia of the dominant left coronary system (Figure 3). After administration of dual antiplatelet therapy and tirofiban, both main

1.

2.

3.

DeMots H, Rosch J, McAnulty JH, Rahimtoola SH. Left main coronary artery disease. Cardiovasc Clin 1977;8:201–21.

PMID: 302748.

Thuijs DJFM, Kappetein AP, Serruys PW, et al. Percutaneous coronary intervention versus coronary artery bypass grafting in patients with three-vessel or left main coronary artery disease: 10-year follow-up of the multicentre randomised controlled SYNTAX trial. Lancet 2019;394:1325–34. https://doi.org/10.1016/ S0140-6736(19)31997-X; PMID: 31488373.

Puri R, Kapadia SR, Nicholls SJ, et al. Optimizing outcomes during left main percutaneous coronary intervention with intravascular ultrasound and fractional flow reserve: the current state of evidence. JACC Cardiovasc Interv 2012;5:697–707. https://doi.org/10.1016/j.jcin.2012.02.018; PMID: 22814774.

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4.

5.

6.

7.

branches of the left coronary artery were wired, and predilatation with a 3.0/12 mm balloon was performed. Because of difficulties in assessing the true lumen of the LM coronary artery due to thrombotic burden in the vessel and possible spasm related to cardiogenic shock with vasopressor therapy, we decided to implant a Stentys X-Position S 22 mm long stent (large size) from the LM coronary artery to the LAD. After rewiring the LCX artery, the stent cell was opened with a 3.0/12 mm balloon, and post-dilation of the LM coronary artery (POT) was performed. The patient was scheduled for elective re-angiography with optical coherence tomography (OCT) 3 months later. OCT revealed good apposition and endothelization of the implanted device (Figures 4 and 5). Dual antiplatelet therapy was continued for 12 months after initial PCI.

Conclusion Self-apposing stents are a new option for the treatment of LM disease in clinical practice when vessel anatomy requires a stent that is able to adapt to the fractal geometry of the vessel. However, it should be stressed that the low expansion force of the device requires meticulous lesion preparation. Similar to conventional balloon-expandable stents, the use of intravascular imaging is encouraged to detect possible underexpansion of the device or residual stenosis of untreated sidebranches when a provisional strategy has been chosen.

van Geuns RJ, Yetgin T, La Manna A, et al. STENTYS self-apposing sirolimus-eluting stent in ST-segment elevation myocardial infarction: results from the randomised APPOSITION IV trial.

EuroIntervention 2016;11:e1267–74. https://doi.org/10.4244/ EIJV11I11A248; PMID: 26865444.

Nakano M, Yahagi K, Otsuka F, et al., Causes of early stent thrombosis in patients presenting with acute coronary syndrome: an ex vivo human autopsy study. J Am Coll Cardiol 2014;63:2510– 20. https://doi.org/10.1016/j.jacc.2014.02.607; PMID: 24768883.

Naber CK. Self-expanding drug-eluting stent in coronary bifurcation lesions at 48 months follow-up: results from the OPEN II Trial. Presented at EuroPCR 2017, Paris, France, May 16–19, 2017.

Montefusco A, D’Ascenzo F, Gili S, et al. Self-expandable sirolimus-eluting stents compared to second-generation drug-

8.

9.

eluting stents for the treatment of the left main: a propensity score analysis from the SPARTA and the FAILS-2 registries.

Catheter Cardiovasc Interv 2019;93:208–15. https://doi. org/10.1002/ccd.27809; PMID: 30298593.

Wańha W, Mielczarek M, Smolka G, et al. Safety and efficacy of self-apposing Stentys drug-eluting stent in left main coronary artery PCI: Multicentre LM-STENTYS registry. Catheter Cardiovasc Interv 2019;93:574–82. https://doi.org/10.1002/ccd.27876; PMID: 30311397.

Briguori C, Tamburino C, Jessurun GAJ, et al. Prospective evaluation of drug eluting self-apposing stent for the treatment of unprotected left main coronary artery disease: 1-year results of the TRUNC study. Catheter Cardiovasc Interv 2020;96:e142–8. https://doi.org/10.1002/ccd.28584; PMID: 3169661.

Complex Coronary Intervention

The Role of Hemodynamic Support in High-risk Percutaneous Coronary Intervention Charles Simonton, MD,1 Craig Thompson, MD,2 Jason R Wollmuth, MD,3 D Lynn Morris, MD,4 and Thom G Dahle, MD5 1. PCICHUCK LLC, Charlotte, NC; 2. NYU Langone Health System, New York, NY; 3. Providence Heart Institute, Portland, OR; 4. East Carolina Heart Institute Brody School of Medicine, Greenville, NC; 5. Centracare Heart and Vascular Center, St Cloud, MN

Abstract Patients with advanced age, complex coronary anatomy, and multiple comorbidities are often unsuitable for surgical revascularization. In this setting, hemodynamic support devices are used as an adjunct to percutaneous coronary intervention to maintain hemodynamic stability and enable optimal revascularization. This article provides an overview of percutaneous hemodynamic support devices currently used in clinical practice for high-risk percutaneous coronary intervention. These include the intra-aortic balloon pump, centrifugal pumps (TandemHeart, venous arterial extracorporeal membrane oxygenation), and micro-axial Impella pump. The hemodynamic effects, clinical evidence supporting improved outcomes and recovery of heart function, and associated complications with these devices are highlighted, with a special focus on Impella pumps.

Keywords Percutaneous coronary intervention, high-risk percutaneous coronary intervention, hemodynamic support devices, percutaneous left ventricular assist devices, balloon pump, Impella, extracorporeal membranous oxygenation Disclosure: CS is a consultant for Abiomed. CT is a consultant for Boston Scientific and Abiomed. JRW is a consultant, proctor, speaker, and advisory board member for Boston Scientific and Abbott Vascular; a consultant, speaker, and advisory board member and has received research support for Abiomed; is on an advisory board for Phillips, and is a proctor for Asahi Intecc. DLM is a consultant and speaker, and has received research support from Abiomed. TGD is a speaker and proctor for Abiomed.

Acknowledgement: The authors acknowledge Uma Chandrasekaran, PhD, for her contribution to the writing of this manuscript. They also acknowledge Alexander Smith and Michael Perry for their contribution in creating figures in this manuscript.

Received: May 10, 2020 Accepted: June 11, 2020 Citation: US Cardiology Review 2020;14:e13. DOI: https://doi.org/10.15420/usc.2020.18 Correspondence: Charles A Simonton, 8508 Park Rd, #104, Charlotte, NC 28210. E: pcichuck@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.

Coronary artery disease (CAD) is a leading cause of morbidity and mortality globally, despite advances in medical and preventive therapy. It is estimated that 18.2 million adults in the US have CAD, with 720,000 Americans projected to have a first hospitalization for MI or CAD death this year.1 Treatment of patients with symptomatic CAD includes guidelinedirected medical therapy and coronary revascularization procedures, percutaneous coronary intervention (PCI) and coronary bypass grafting (CABG), to reduce adverse clinical events and improve quality of life.2–5 The evolution in PCI technology and technique has improved the risk– benefit ratio and resulted in a greatly expanded population eligible for PCI, including high-risk patients with older age, complex anatomic lesions, and multiple comorbidities that preclude surgical revascularization.6 According to 2020 American Heart Association statistics, PCI is the most common revascularization modality and is applied to patients with increased lesion complexity and comorbidities, with about 50% of all PCI performed in patients ≥65 years of age.1 Recent analyses report numerical doubling of unprotected left main PCI from 2009 to 2016, an increase in PCI for baseline left ventricular (LV) systolic dysfunction from 13% in 2004 to 17% in 2016, and for chronic total occlusion from 0.1% in 2012 to 3.4%

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in 2016.7–9 Thus, high-risk PCI (HR-PCI) is emerging as a valuable therapeutic modality in the growing patient population referred to as ‘complex high-risk and indicated patients’ (CHIP).

A confluence of characteristics, including complex CAD (multivessel or left main disease and anatomically complex coronary lesions), hemodynamic status (severely depressed LV function), and clinical comorbidities such as advanced age, diabetes, peripheral vascular disease, heart failure, acute coronary syndromes, or previous cardiac surgery define CHIP, although none are absolute (Figure 1). Acknowledging the variable definition of CHIP, many patients with angina refractory to guideline-directed medical therapy or heart failure are candidates for HR-PCI after review by the heart team, per the appropriate use criteria for coronary revascularization.10,11 However, studies suggest underuse of revascularization in >30% of appropriate use criteria patients, which is associated with adverse outcomes.12 While CHIP are least likely to be offered PCI, they are the group most likely to benefit from revascularization.6 Registry data and retrospective analysis of randomized trials suggest that complete revascularization leads to superior outcomes.13,14 However,

© RADCLIFFE CARDIOLOGY 2020

Circulatory Support Devices for High-risk PCI given the increased risk of procedural complications induced by multiple balloon inflations and plaque modification procedures, such as atherectomy, CHIP frequently undergo incomplete revascularization or a staged PCI strategy with a higher incidence of adverse clinical outcomes.14–16 Over the last 20 years, multiple percutaneously implanted hemodynamic support devices have become available for use during HRPCI to prevent hemodynamic collapse and enable complete and optimal revascularization. In this review, we provide an overview of percutaneous hemodynamic support devices currently used in clinical practice for HRPCI (Figure 2). These include the intra-aortic balloon pump (IABP), centrifugal pumps (TandemHeart [CardiacAssist], venous arterial extracorporeal membrane oxygenation [VA-ECMO]), and micro-axial Impella pumps (Abiomed). Specifically, we discuss the hemodynamic effects of the support devices and clinical evidence of safety and efficacy with a special focus on Impella pumps.

Figure 1: Growing Population of Complex And High-risk Patients Who Could Benefit From Hemodynamic Support

• • • • • •

Surgical ineligibility Prior cardiac surgery Heart failure Diabetes Advanced age Unstable angina/ NSTEMI • Renal insufficiency

Patient comorbidities

Complex CAD Complex/ high-risk PCI

• Multi-vessel disease • Distal left main disease • Complex lesions (bifurcation, calcification) • CTO retrograde

Hemodynamic compromise Mild, moderate and severely depressed ejection fraction High LVEDP

CAD = coronary artery disease; CTO = chronic total occlusion; LVEDP = left ventricular end-diastolic pressure; NSTEMI = non-ST elevation MI; PCI = percutaneous coronary intervention.

Adapted with permission from Abiomed ‘Protected PCI’ Clinical Dossier 2020.

Percutaneous Hemodynamic Support Devices In their seminal 1991 publication, Lincoff et al. listed multiple mechanical support devices and their potential application as an adjunct to HR-PCI.17 It is remarkable that the range of adjunctive PCI tools currently available for disposal in the catheterization lab are mostly iterative developments of the devices proposed previously (Table 1). The goal of hemodynamic support during HR-PCI is to maintain mean arterial pressure to ensure end-organ perfusion and decrease myocardial oxygen demand while maintaining or increasing the cardiac output. In addition, an ideal hemodynamic support device would facilitate complete revascularization in a single setting, aiding LV remodeling and recovery of LV ejection fraction in the long-term.

Despite the ability for optimization of hemodynamics, the risks associated with the large-bore access for all these mechanical support devices include bleeding and vascular complications.18–22

Intra-aortic Balloon Pump The first case report of successful treatment with an IABP was reported in a 45-year-old woman with acute MI with cardiogenic shock in 1968.23 Since then, IABP has evolved as prophylactic support during HR-PCI. IABP provides circulatory support by displacing blood volume in the descending aorta by inflating during diastole and reducing resistance to systolic output through presystolic deflation of the balloon.24 The overall effect of the IABP is to reduce myocardial work and oxygen demand by 10–20% by decreasing the duration of isometric phase of LV contraction.17 Hemodynamically, IABP reduces LV end-diastolic pressure (LVEDP) by up to 30% and systolic pressure by 10%.24 Nonetheless, the IABP only provides a modest increase in cardiac output of 0.5–1 l/min and requires a stable electrical rhythm or pressure tracing for optimal timing and function. Consequently, the use of IABP is of limited hemodynamic benefit in CHIP, particularly those with depressed LV function or contractility.17 Several observational studies have suggested a reduction in mortality and major complications with the elective use of IABP during HR-PCI.25–28 The Balloon Pump-Assisted Coronary Intervention Study (BCIS-1) was the first randomized trial to evaluate the safety and effectiveness of elective IABP use in HR-PCI. A similar incidence of the primary endpoint of major cardiac and cerebrovascular events (MACCE) at hospital discharge (capped at 28 days) was observed among patients undergoing HR-PCI with elective IABP support versus without planned IABP support.29 A posthoc long-term follow-up study of BCIS-1 suggested a 34% reduction in

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all-cause mortality with elective IABP use than unsupported PCI, though did not provide any mechanistic explanation of the effect based on LV function and remodeling.30 Romeo et al. performed a meta-analysis including 11 studies and found no correlation of elective IABP use in HRPCI with a reduction in the risk ratio for in-hospital death or major adverse cardiovascular events (MACE).31

Centrifugal Pumps TandemHeart The TandemHeart is an extracorporeal left atrium to femoral artery bypass system. It consists of a 21 Fr venous transseptal inflow cannula containing 14 side holes and a large end hole, a continuous flow centrifugal pump, and a 15–17 Fr arterial outflow cannula.15 The device delivers up to 4 l/min of blood flow and is dependent on left atrium volume and right ventricular (RV) function for optimal function. It is approved for use in cardiogenic shock for up to 14 days, and an oxygenator can be added to the circuit allowing for concomitant circulatory and oxygenation support.32 Hemodynamic effects include a reduction in LV preload and workload, filling pressures, myocardial oxygen demand, and increased arterial blood pressure, and cardiac output.

Limited data on the use of TandemHeart for HR-PCI suggest the feasibility and effectiveness of support (Table 2).22,33–35 However, limitations include transseptal puncture and higher complication rates.

Extracorporeal Membrane Oxygenation ECMO is a portable modification of heart-lung bypass machine that consists of a centrifugal pump, heat exchanger, and membrane oxygenator.18 This device drains venous blood through one or multiple outflow cannula into the external centrifugal pump, where it is sent to the oxygenator for gaseous exchange and the oxygenated blood is returned to the venous (VV) or arterial (VA) circulation through an inflow cannula.

While VV-ECMO provides respiratory support, VA-ECMO provides both respiratory and hemodynamic support. VA-ECMO can provide cardiac flow of 4–6 l/min and be used for managing both RV and LV dysfunction.

The main indications for ECMO include profound cardiogenic shock with respiratory failure and cardiac arrest.18 The primary hemodynamic effects of VA-ECMO are decreased preload and increased afterload. The increase in afterload may contribute to LV distention, elevated LVEDP, increased myocardial oxygen demand, and

Complex Coronary Intervention Figure 2: Percutaneous Mechanical Circulatory Support Devices Currently Used For High-risk Percutaneous Coronary Intervention

LV support

IABP

TandemHeart

VA-ECMO

Impella 2.5/CP

Mechanism

Counterpulsation

Centrifugal flow continuous pump (LA to aorta)

Centrifugal flow continuous pump (RA to aorta)

Axial flow continuous pump (LV to aorta)

Flow/output

0.5–1.0 l/min

2.5–4.0 l/min

4.0–6.0 l/min

2.5–4.3 l/min

Sheath size

7–8 Fr arterial

21 Fr inflow (venous) 15–17 Fr outflow (arterial)

18–21 Fr inflow (venous) 15–22 Fr outflow (arterial)

12–14 Fr

Coronary perfusion

Yes+

No

No

Yes+++

Reduced work/O2 demand

Minor

Yes

No

Yes

510 (k) clearance

510 (k) clearance

510 (k) clearance

Premarket approval

FDA approval safe and effective

No

No

No

Yes

FDA indication

NA

NA

NA

High-risk PCI, AMI and other cardiogenic shock

Short days

<6 hours

<6 hours

Up to 6 days

None

Yes

None

Yes, multiple

0%

0%

Unknown

0%

2–6%

0–1%

12%

0–1%

+

+++

+++++

++

Device

FDA clearance/approval

Approved duration of use FDA clinical trials Safety – aortic valve Safety – stroke Leg ischemia

IABP = intra-aortic balloon pump; LA = left atrium; LV = left ventricle; NA = not applicable; PCI = percutaneous coronary intervention; RA = right atrium; VA-ECMO = venous arterial extracorporeal membrane oxygenation. Adapted from: Thiele et al. 2019.69 Used with permission from Oxford University Press.

an ultimate decline in myocardial perfusion in patients with significant LV dysfunction.36 Limited data for VA-ECMO use in HR-PCI suggest feasibility,37–41 although vascular and renal complications remain a significant concern (Table 3).

Impella The Impella is a non-pulsatile micro-axial flow Archimedes screw device that is placed across the aortic valve and designed to pump blood from the LV into the ascending aorta, in sync with the normal physiology.

Impella devices (2.5 and CP) are placed percutaneously via peripheral arterial approach, femoral or axillary arteries. Impella 2.5 and CP have motors that are 12 Fr and 14 Fr and provide blood flow rates of 2.5 and 4.3 l/min, respectively. Impella continuously pumps blood directly from the LV, independent of the cardiac cycle, resulting in LV unloading (LV volume dependent).32 With increasing pump flow rate, the LV becomes increasingly unloaded, leading to reduced LVEDP, decreasing LV work, and

myocardial oxygen demand. Also, the greater degree of unloading results in increased dissociation of LV peak pressure and aortic pressure, referred to as ventriculoarterial uncoupling.36,42 Impella improves distal coronary pressure and coronary perfusion pressure in the presence of critical stenoses, lessening the ischemic burden.43 The Impella 2.5 pump has been commercially available since 2008, upon receipt of the Food and Drug Administration (FDA) 510 (k) clearance in the US. The Impella 2.5 and Impella CP heart pumps received FDA premarket approval as safe and effective ventricular support devices for HR-PCI, referred to as Protected PCI, in 2015 and 2016, respectively.32 The clinical evidence supporting the safety and effectiveness of Impella support in HR-PCI includes a prospective single-arm feasibility study (Prospective Feasibility Trial Investigating the Use of the IMPELLA RECOVER LP 2.5 System in Patients Undergoing High Risk PCI; PROTECT I), a randomized controlled trial (Prospective, Randomized Clinical Trial of

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Circulatory Support Devices for High-risk PCI Table 1: Evolution of Hemodynamic Support Devices For Use in High-risk Percutaneous Coronary Intervention Device Listed in Lincoff et al.17

Proposed Application

Current Device

Hemodynamic and Clinical Effects

Intra-aortic balloon counterpulsation

Prophylactic placement in select HR-PCI patients IABP Prolonged support for severe hemodynamic compromise post-PCI

Based on BCIS-1 randomized trial,routine prophylactic use of IABP not recommended during HR-PCI29

Hemopump

Investigational

Impella devices (Impella 2.5, Impella CP)

Superior hemodynamic support during HR-PCI45 Supports longer rotational atherectomy procedures during HR-PCI48 Improved clinical outcomes up to 90 days after HR-PCI45,49–51 Extensive revascularization with Impella associated with improved outcomes53 Protects against in-hospital acute kidney injury55,56 Improved survival and ejection fraction in the long term21,57–59 Beneficial in patients with LVEF >35% undergoing HR-PCI61

Partial left heart bypass

Investigational

TandemHeart

Select observational studies showing feasibility of use in HR-PCI Requires transseptal puncture and associated with increased risk of complications15

Cardiopulmonary support

Prophylactic placement in select HR-PCI patients Severe hemodynamic compromise after post-PCI complication

ECMO

Increased afterload leading to inefficient LV unloading Limited evidence of use in HR-PCI, based on few observational studies Vascular and bleeding complications remain of significant concern

Coronary sinus retroperfusion

Prolonged balloon inflations during HR-PCI

Investigational

Anterograde perfusion

Prolonged balloon inflations Support post-PCI after abrupt closure

Obviated due to intracoronary stents

Other

HR-PCI = high-risk percutaneous coronary intervention; IABP = intra-aortic balloon pump; ECMO = extracorporeal membrane oxygenation; LVEF = left ventricular ejection fraction; PCI = percutaneous coronary intervention. Adapted from Lincoff et al. 1991.17 Used with permission from Elsevier.

Hemodynamic Support With Impella 2.5 Versus Intra-Aortic Balloon Pump in Patients Undergoing High-Risk PCI; PROTECT II), an FDA post-approval study (PROTECT III), and several observational multicenter registries including the Roma-Verona Registry, the Observational Multicenter Registry of Patients Treated with IMPella Mechanical Circulatory Support Device in ITaly (IMP-IT), and German Impella registry (Table 4).

PROTECT I was a prospective, single-arm, multi-center feasibility study examining the safety and feasibility of Impella 2.5 in HR-PCI.44 Between 2006 and 2007, 20 patients with LV ejection fraction (LVEF) ≤35% undergoing PCI on an unprotected left main lesion or last patent conduit were enrolled. The study showed an excellent safety profile of the device, with MACE at 30 days in 20% of patients (two MIs and two deaths). None of the patients developed hemodynamic compromise during PCI. Also, significant improvement in LVEF was observed with the use of Impella 2.5 during HR-PCI (LVEF pre-PCI: 26 ± 6% versus post-PCI at 30 days: 34 ± 11%; p=0.003). Based on these results, Impella 2.5 received the US FDA 510 (k) clearance in 2008 for partial circulatory support for up to 6 hours during cardiac procedures and led to the pivotal PROTECT II trial.

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PROTECT II was a prospective randomized controlled trial comparing hemodynamic support with Impella 2.5 versus IABP in patients undergoing HR-PCI (2007–2010).45 Patients with complex three-vessel disease or unprotected left main and LVEF ≤35% were randomized to an Impella 2.5 (n=216) or IABP (n=211) support. The primary endpoint was a composite of 10 major adverse events (MAE) at discharge or 30 days with a follow-up at 90 days: death, stroke/transient ischemic attack, MI, repeat revascularization, need for cardiac or vascular operation, acute renal dysfunction, cardiopulmonary resuscitation or ventricular arrhythmia requiring cardioversion, increase in aortic insufficiency >1 grade, severe hypotension, and failure to achieve angiographic success. The trial was stopped prematurely, based on an interim review of the primary endpoint, following enrollment of 452 of the planned 654 patients. However, a prespecified subgroup analysis revealed a learning curve with Impella 2.5 during the first half of the trial, leading to underestimation of the potential benefit of Impella at the interim review.45,46 PROTECT III is an ongoing, prospective, FDA post-approval study of Impella-supported HR-PCI patients. Between 2017 and 2019, a total of 898

Complex Coronary Intervention Table 2: Select Clinical Evidence of TandemHeart in High-risk Percutaneous Coronary Intervention Study

High-risk Features

Clinical Effects

Kovacic et al. 201333

32

n

Mean EF, 35.7 ± 18.2% LM lesion in seven patients MVD in 28 patients RA in nine patients

Procedural success in 99% No death, stroke, or renal failure until discharge Large hematoma requiring transfusion in two patients Left atrial perforation with cardiac tamponade in one patient

Alli et al. 201234

54

Mean EF, 30 ± 2.5% LM lesion in 34 patients MVD in 34 patients RA in 26 patients

Procedural success in 97% Mortality of 13% at 6 months Major vascular complication in seven with surgical repair in five Thrombocytopenia in five patients Worsening renal function in one patient

Schwartz et al. 201122

32

EF <35% in 21 patients EF <25% in 14 patients UPLM in 17 patients MVD in four patients

Angiographic and procedural success in 97% Mean increase in EF, 5.7 ± 11.7% after HR-PCI No death or MI at 30 days Recurrent ischemia and stroke in one patient each Limb ischemia in two patients Blood transfusion in 20 patients

Gimelli et al. 200835

11

Mean EF, 25 ± 8% RA in two patients LM or LM equivalent lesion in two patients

No in-hospital MACE, one vascular complication requiring blood transfusion Increase in EF to 41 ± 9% at minimum follow-up of 15 ± 15 months

EF = ejection fraction; HR-PCI = high-risk percutaneous coronary intervention; LM = left main; UPLM = unprotected left main; MACE = major adverse cardiovascular events; MVD = multivessel disease; RA = rotational atherectomy.

Table 3: Select Clinical Evidence of Venous Arterial Extracorporeal Membrane Oxygenation in High-risk Percutaneous Coronary Intervention Study

n

High-risk Features

Clinical Effects

van den Brink et al. 202037

14

EF <35% in 10 patients LM lesion in 10 patients CTO in 11 patients

Complete revascularization in all patients Mortality at discharge in one patient Re-infarction in one patient Thromboembolic complication in two patients Renal insufficiency post-procedure in three patients

Shaukat et al. 201838

5

EF <35% in four patients UPLM in four patients CTO in one patient

Successful PCI with weaning of ECMO in all patients No MACCE in-hospital and at 1-year follow-up Mean increase in EF, 24.3 ± 10.8% at 1-year follow-up in four patients with LV dysfunction Femoral artery surgical repair in one patient

Tomasello et al. 201539

12

Mean EF 34 ± 12.6% LM lesion in 10 patients CTO in four patients

Complete revascularization in 42% with successful PCI in all No in-hospital MACCE Repeat revascularization in two patients at 6-month follow-up Chronic hemodialysis in one patient

Cho et al. 201140

10

Mean EF 23 ± 10%

At mean follow-up of 541 days - No procedural or cardiac mortality - Non cardiac-related mortality in two patients

Vainer et al. 200741

15

Mean EF 34 ± 15%

No in-hospital death or periprocedural MI Procedural success in 14 patients Blood transfusion in eight patients Three cardiac deaths during mean follow-up of 15 months

CTO = chronic total occlusion; EF = ejection fraction; LM = left main; MACCE = major adverse cardiac and cerebral event; PCI = percutaneous coronary intervention; UPLM = unprotected left main.

patients have been enrolled, including 571 supported with Impella CP.47 Compared to Protect II, patients in PROTECT III are older, include more women, and receive more complex procedures.

were discharged from the catheterization lab on the device, compared to 37% of IABP patients. Consequently, the duration of hemodynamic support was longer in the IABP arm than with Impella 2.5 (8.4 ± 21.8 hours versus 1.9 ± 2.7 hours; p<0.001).

Effect of Impella Support During High-risk PCI Superior Hemodynamic Support of Impella 2.5

Supports Longer Rotational Atherectomy Procedures

In Protect II, Impella provided superior hemodynamic support compared to IABP (maximal decrease in cardiac power of 0.04 ± 0.24 W with Impella versus 0.14 ± 0.27 W with IABP; p=0.001).45 Only 6% of Impella patients

Rotational atherectomy (RA) is used for treating complex, heavily calcified lesions and is associated with increased risk of hypotension and periprocedural MI. In PROTECT II, RA was used more frequently and aggressively in the Impella

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Circulatory Support Devices for High-risk PCI Table 4: Select Clinical Evidence of Impella in High-risk Percutaneous Coronary Intervention Study

n

High-risk Features

Clinical Effects

PROTECT Series Dixon et al. 200944 (PROTECT I, 2006–2007)

20

Mean EF, 26 ± 6% LVEF ≤35% and PCI on UPLM or LPC in all patients

MACE in 20% (death and MI in two patients each) Transient hemolysis in two patients Femoral hematoma in eight patients No hemodynamic compromise during PCI Significant improvement in LVEF (LVEF pre-PCI: 26 ± 6% versus post-PCI at 30 days: 34 ± 11%; p=0.003)

O’Neill et al. 201245 (PROTECT II RCT, 2007–2010)

452

Mean EF, 24 ± 6% Surgical ineligibility in 64% UPLM/LPC in 106 patients Three-vessel disease in 337 patients

Patients randomized to Impella 2.5 (n=216) versus IABP (n=211) Similar rates of MAE at 30 days (35% with Impella versus 40% with IABP; p=0.23 in the ITT population) Trend of lower MAE at 90 days (41% with Impella versus 49% with IABP; p=0.06 in the ITT population) Significant learning curve with lower 90-day MAE with Impella 2.5 in second half of the trial

Popma et al. 201947 (PROTECT III, 2017–2019)

898

Mean EF, 32 ± 15% LM lesion in 16% Three-vessel disease in 30% Atherectomy use in 43%

MACCE at 90 days in 17% of 469 patients supported with Impella Lower rate of acute kidney injury in Impella treated patients versus propensity-matched control group with no Impella support

Azzalini et al. 202021 (2009-2018)

500

Mean LVEF, 26 ± 15% LM stenosis in 19% CTO in 15% Rotational atherectomy in 41%

Patients supported with Impella (n=250) propensity matched to controls without support (n=250) In hospital MACCE, 27% versus 13% (p<0.001) No difference in MACCE at 1 year, 31% versus 27% (p=0.8)

Chieffo et al. 202058 (IMP-IT registry, 2004–2018)

177

Mean EF, 31 ± 10% 3-vessel disease in 68% LM lesion in 48%

In-hospital death in 6%, severe bleeding in 5%, limb ischemia in 3% At 1-year, All-cause death in 16% Death, hospitalization for heart failure, LVAD or heart transplant in 23%

Baumann et al. 201957 German Impella registry

157

Median EF, 39% (IQR 25-50) LM stenosis in 71% CTO in 14% Surgical turndown in 34%

In hospital MACE in 13%, bleeding in 6.5%, leg ischemia in 2% 180-day MACE in 23%, death in 18%, stroke in 3%, STEMI in 6%

Burzotta et al. 201959 (Roma-Verona registry, 2007–2016)

86

Mean LVEF, 31 ± 9% MVD and surgical ineligibility in 100% LM lesion in 44%

Bleeding in 14% and vascular complications in 2% All-cause mortality 10.5% at mean follow-up of 14 months Extent of revascularization achieved during Impella supported PCI associated with LVEF recovery and survival

Other observational studies

CTO = chronic total occlusion; EF = ejection fraction; ITT = intention to treat; LM = left main; LPC = last patent conduit; LVAD = left ventricular assist device; MACE = major adverse cardiovascular event; MACCE = major adverse cardiac and cerebral event; MVD = multivessel disease; PCI = percutaneous coronary intervention; RCT = randomized controlled trial; STEMI = ST-segment elevation MI; UPLM = unprotected left main.

arm with more RA passes per lesion and longer duration of use than IABP.48 This treatment imbalance likely resulted in a higher rate of periprocedural MI (creatine kinase myocardial band [CK-MB] >3 times the upper limit of normal [ULN]) in the Impella group at 30 days (34.4% versus 5%; p=0.014) with no difference in mortality. Notably, the rates of repeat revascularization were lower with Impella at 30 and 90 days.

Short-term Clinical Outcomes with Impella Support During High-risk PCI Improved Clinical Outcomes up to 90 Days In PROTECT II, no difference in the composite of MAE was observed between the groups at 30 days (35% with Impella 2.5 versus 40% with IABP; p>0.05). The 90-day MAE was lower in the Impella arm than IABP in the per-protocol comparison (40% versus 51%; p<0.05).45 This difference

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in MAE was driven by fewer repeat revascularization events with Impella 2.5 at 90 days.

In a post-hoc analysis based on a periprocedural MI definition of CK-MB >8 × ULN, the 90-day MAEs were lower with Impella due to less repeat revascularization and MI.49 The lower 90-day MAE rates with Impella supported PCI was maintained in the subgroup of patients with threevessel disease and LVEF <30% (40% versus 51%; p<0.05)50 and those <80 years of age (40% versus 52%; p<0.05).51 The lower MAE also led to lower readmission and length of stay costs with Impella 2.5 (5 days versus 7 days and $11,007 versus $21,834; p<0.001), thus being more costeffective than IABP.52 Consistent improved outcomes with Impella were observed with lower MACCE rates at 90 days in PROTECT III (16.8%) than in the PROTECT II Impella arm (21.9%).47

Complex Coronary Intervention Extensive Revascularization with Impella Associated with Improved Outcomes

Impella Support Beneficial in Patients with LVEF >35% Undergoing High-risk PCI

Burke et al. evaluated the benefit of Impella 2.5 versus IABP support as a function of the extent of revascularization.53 More extensive revascularization was associated with improved 90-day MAE compared to limited revascularization. Among patients undergoing extensive revascularization, Impella support was associated with lower 90-day MAE than IABP (32% versus 50%; p<0.05).

Alaswad et al. compared the effects of Impella 2.5/CP support during HR-PCI in 661 patients with LVEF ≤35% versus 230 with LVEF >35% from the cVAD study.61 Notably, patients with LVEF >35% had severe comorbidities and complex angiographic features necessitating Impella support. Despite several high-risk features among those with LVEF >35%, the observed in-hospital mortality was 1.7%, lower than the predicted Society of Thoracic Surgeons (STS) mortality rate of 4.9%. This study suggested that elective Impella use during HR-PCI is safe, feasible, and beneficial among those with complex CAD and LVEF >35% in addition to those with LVEF ≤35%.

Impella Protects Against Acute Kidney Injury Periprocedural acute kidney injury (AKI) is observed in 4–28% of patients undergoing HR-PCI, depending on the definition of AKI used.45,49,54 Flaherty et al. compared the in-hospital incidence of AKI among 115 patients with LVEF <35% undergoing Impella 2.5 supported PCI versus 115 unsupported matched controls.55 Despite the presence of pre-existing chronic kidney disease and lower LVEF, only 5.2% of Impella-supported patients developed in-hospital AKI versus 27.8% of unsupported controls (p<0.001). Also, postprocedure hemodialysis was needed in only 0.9% of Impella patients versus 6.1% of controls. Consistent results of a lower incidence of AKI than expected based on the Mehran risk score were obtained among 223 patients undergoing HR-PCI supported with Impella 2.5/CP in the global cVAD study (a prospective, multicenter, FDA post-market study).56 The putative mechanism of action includes the maintenance of continuous blood flow during Impella-supported PCI, thus reducing renal hypoperfusion and preventing stagnation of contrast material in the renal tubules.

Long-term Clinical Outcomes With Impella Support After High-risk Percutaneous Coronary Intervention

Guidelines The role of hemodynamic support in HR-PCI is only minimally addressed in the guidelines because of the lack of evidence from randomized trials.

Currently, the role of Impella in HR-PCI has been addressed in expert consensus documents.62–64 The 2011 guidelines state that elective insertion of an appropriate hemodynamic support device as an adjunct to PCI may be reasonable in carefully selected high-risk patients (Class IIB, level of evidence C).65 The 2010 European Society of Cardiology guidelines suggest that circulatory support should be considered in non-emergent HR-PCI procedures such as left main disease, single remaining patent coronary artery, and complex chronic total occlusions performed by adequately experienced operators at centers that have access to circulatory support and on-site cardiovascular surgery.66 However, no recommendations for specific devices are provided.

Improvement in Survival and Ejection Fraction

Ongoing and Future Studies

Multiple registries have reported long-term clinical outcomes following Impella-supported PCI, including the German Impella registry (n=157, 6 months follow-up), IMP-IT registry (n=177, 1-year follow-up), and the Roma-Verona Registry (n=86, mean 14 months follow-up).57–59 A common limitation of all these retrospective analyses includes the lack of a control group (no hemodynamic support or other devices) and ascertainment bias. Also, the comparison of mortality and adverse event rates across these studies is challenging given the variable baseline patient characteristics and the threshold for device usage. Nonetheless, the allcause mortality at 1-year among patients supported with Impella during HR-PCI were similar at 15.6% in the IMP-IT registry58 and 15.3% in the analysis by Azzalini et al.21

Restore EF is an ongoing real-world quality metric study investigating the effects of Impella-protected HR-PCI on the improvement in LVEF at 60– 180 days in over 500 patients.67 This multicenter, prospective, single-arm, observational study was initiated in 2019 to capture the intermediateterm clinical outcomes from electronic health records of patients who underwent Impella-supported HR-PCI at up to 30 centers globally.

Burzotta et al. investigated the effect of extent of revascularization on LVEF and survival in 86 patients undergoing Impella-supported PCI in the Roma-Verona registry.59 At a mean follow-up of 14 months, the all-cause mortality rate was 10%. In addition, reassessment of LV function at 6 months after HR-PCI demonstrated a 3-fold increase in the number of patients with ejection fraction ≥35% (67% of patients had ejection fraction ≥35% at 6-month follow-up compared to 22% at baseline). Notably, the extent of revascularization was associated with significant improvement in LVEF and survival. These results are consistent with the observations of Daubert et al.60 In the PROTECT II trial, suggesting reverse LV remodeling and an associated improvement in LVEF following hemodynamically supported extensive revascularization in addition to the immediate reversal of the ischemic and hibernating myocardium.

PROTECT IV is a recently announced on-label randomized trial comparing HR-PCI with Impella CP versus standard of care in patients with LVEF ≤40% and prohibitive risk for CABG.68 The study is currently being designed. It aims to begin enrolling patients in 2021 and will be based on validated best practices with Impella use.

Conclusion Patients with LV dysfunction, complex CAD, and multiple comorbidities are a growing population often deemed ineligible for surgical revascularization.

Hemodynamic support devices act as an adjunct to HR-PCI maintaining hemodynamics, ensuring end-organ perfusion while decreasing myocardial oxygen consumption. While the use of IABP is on the decline based on the failure to show benefit in the BCIS-1 trial, centrifugal pumps such as TandemHeart and VA-ECMO are sparingly used due to increased complications. The safety and efficacy of Impella 2.5 and Impella CP in HRPCI has been demonstrated in the PROTECT-II trial and multiple real-world studies over the past 12 years. Future randomized controlled trials, such as PROTECT IV, will provide more definitive answers on the role of hemodynamic support during HR-PCI and strengthen guideline recommendations.

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US CARDIOLOGY REVIEW

Complex Coronary Intervention

Type and Duration of Dual Antiplatelet Therapy in Complex Percutaneous Coronary Intervention Dimitrios Alexopoulos, MD, Charalampos Varlamos, MD, and Despoina-Rafailia Benetou, MD Second Department of Cardiology, Attikon University Hospital, National and Kapodistrian University of Athens Medical School, Athens, Greece

Abstract Complex percutaneous coronary intervention (PCI) patients are a high-risk population for ischemic complications. Antiplatelet therapy in such patients remains controversial, as the beneficial effects of the use of more potent agents or prolonged dual antiplatelet treatment (DAPT) on atherothrombotic complications are hindered by a concomitant increase in bleeding rates. The aim of this article is to describe ischemic and bleeding outcomes associated with complex PCI procedures and to compare different types and durations of DAPT regimens in terms of safety and efficacy outcomes.

Issues concerning special patient groups, such as those with left main, chronic total occlusion, or bifurcation lesions, are discussed.

Keywords Complex percutaneous coronary intervention, antiplatelet therapy, dual antiplatelet treatment, bifurcation, chronic total occlusion, left main occlusion Disclosure: DA has received lecturing honoraria/advisory board fees from AstraZeneca, Bayer, Boehringer Ingelheim, Pfizer, Medtronic, Biotronik, and Chiesi Hellas. All other authors have no conflicts of interest to declare.

Received: March 22, 2020 Accepted: August 11, 2020 Citation: US Cardiology Review 2020;14:e14. DOI: https://doi.org/10.15420/usc.2020.13 Correspondence: Dimitrios Alexopoulos, Second Department of Cardiology, Attikon University Hospital, Rimini 1, Chaidari, Athens 12462, Greece.

E: dalex@med.uoa.gr 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.

Complex percutaneous coronary intervention (PCI) usually refers to procedures that include bifurcation with two stents implanted, the treatment of three or more lesions, the implantation of three or more stents, total stent length >60 mm, or a chronic total occlusion (CTO).1 However, as there is no universal definition, other features, such as left main (LM) or proximal left anterior descending (LAD) lesions, bifurcation, vein bypass graft PCI, lesion length ≥30 mm, rotational atherectomy use for severely calcified lesions, or thrombus-containing lesions, have also been considered as additional components of complex PCI in various studies.2–4 The presence of complex PCI features, which have become increasingly frequent during the past decade, has been associated with a higher rate of major adverse cardiovascular events (MACE).5–9 However, the type and duration of dual antiplatelet therapy (DAPT) in patients undergoing PCI vary, as clinical settings, patient characteristics, as well as various risk factors, can affect decision-making.1 Although a prolonged DAPT regimen may be beneficial for reducing ischemic risk associated with complex PCI, the fact that these patients may be at an increased risk of bleeding raises concerns about associated bleeding complications.2 In this article, we focus on antiplatelet use in a high-risk subset of patients with complex PCI.

Antiplatelet Therapy with Drug-Eluting Stents (ADAPT-DES) study evaluated the outcomes of patients undergoing PCI according to disease extent and complexity, and concluded that patients had a higher 2-year risk of MACE (adjusted HR 1.56, 95% CI [1.29–1.89], p<0.0001), which was progressively greater as the number of complex PCI features increased. A higher risk of stent thrombosis (ST), MI, ischemia-driven revascularization, as well as major bleeding, has been described in complex PCI patients.2 A core laboratory analysis of 10,854 patients in the Cangrelor versus standard therapy to AcHieve optimal Management of Platelet InhibitiON PHOENIX (CHAMPION-PHOENIX) trial reported a MACE rate (composite of death, MI, ischemia-driven revascularization, or ST) of 2.5%, 4.1%, 6.5%, and 7.5% at 48 hours in patients with no, one, two, or three or more complex PCI features, respectively (p<0.0001), whereas the presence of complex PCI features was not associated with major bleeding events. Notably, a 21% reduction in the MACE rate at 48 hours was noted with the use of potent intravenous P2Y12 inhibitor, cangrelor, compared to clopidogrel, irrespective of target lesion complexity (p=0.46 for interaction), whereas the absolute reduction in the ST rate at 48 hours was particularly higher in patients with three or more complex PCI features (OR 0.43, 95% CI [0.23–0.82]).10

Complex PCI: A High-Risk Cohort

Duration of DAPT Regimens

Several studies support the notion that patients with complex PCI features are at a high risk for ischemic complications.7–9 The Assessment of Dual

Identifying the optimal duration of DAPT after complex PCI is important, although controversial (Table 1).1,11 A total of 3,730 patients with complex

© RADCLIFFE CARDIOLOGY 2020

Access at: www.USCjournal.com

Complex Coronary Intervention Table 1: Studies of Different Dual Antiplatelet Therapy Regimens in Complex Percutaneous Coronary Intervention Patients Study

Size (n)

Stent Type

P2Y12 Inhibitor

Results

Yeh et al. 20173

3,730

DES (82.8%) BMS (17.2%)

Clopidogrel (65.6%) Prasugrel (34.4%)

30-month versus 12-month DAPT HR 0.55, 95% CI [0.38–0.79], p=0.001 for MI or ST HR 0.72, 95% CI [0.55–0.96], p=0.02 for MACCE HR 1.41, 95% CI [0.87–2.28], p=0.16 for moderate or severe bleeding

Costa et al. 20194

3,118

Second-generation DES (81.3%) First-generation DES (8%) BMS (10.6%)

Clopidogrel (79.5%) Prasugrel (10%) Ticagrelor (8.5%)

Long-term (12 or 24 months) versus short-term (3 or 6 months) DAPT in patients with and without HBR ARD: −3.86%, p=0.05 for non-HBR and +1.30%, p=0.76 for HBR patients for the composite of MI, definite ST, stroke, or target vessel revascularization ARD: +0.28%, p=0.57 for non-HBR and +3.04%, p=0.30 for HBR patients for TIMI major or minor bleeding ARD: −4.05%, p=0.04 for non-HBR and +1.68%, p=0.73 for HBR patients for net clinical benefit

Giustino et al. 20169

1,680

DES

Clopidogrel

Long-term (≥12 months) versus short-term (3 or 6 months) DAPT HR 0.56, 95% CI [0.35–0.89] for MACE HR 1.81, 95% CI [0.67–4.91] for major bleeding

Serruys et al. 201912

4,570

Biolimus A9-eluting stents

Ticagrelor

23-month ticagrelor monotherapy following 1-month DAPT (experimental strategy) versus 12-month aspirin monotherapy following 12-month DAPT (reference strategy) HR 0.64, 95% CI [0.48–0.85], p=0.002 for the composite of all-cause death or new Q wave MI HR 0.80, 95% CI [0.69–0.93], p=0.003 for POCE (all-cause death, stroke, MI, or revascularization) HR 0.97, 95% CI [0.67–1.40], p=0.856 for BARC type 3 or 5 bleeding HR 0.80, 95% CI [0.69–0.92], p=0.002 for net adverse clinical events

Dangas et al. 202014

2,324

DES

Ticagrelor

Ticagrelor monotherapy versus DAPT with ticagrelor plus aspirin following 3 months of uneventful DAPT HR 0.77, 95% CI [0.52–1.15] for composite of all-cause death, MI, or stroke HR 0.59, 95% CI [0.27–1.29] for all-cause death HR 0.56, 95% CI [0.19–1.67] for ST HR 0.54, 95% CI [0.38–0.76] for BARC type 3 or 5 bleeding

ARD = absolute risk difference; BARC = Bleeding Academic Research Consortium; BMS = bare metal stent; DAPT = dual antiplatelet therapy; DES = drug-eluting stent; HBR = high bleeding risk; MACCE = major adverse cardiovascular and cerebrovascular events; MACE = major adverse cardiovascular events; PCI = percutaneous coronary intervention; POCE = patient-oriented composite endpoint; ST = stent thrombosis; TIMI = thrombolysis in myocardial infarction.

lesions and 7,824 patients without were enrolled in the DAPT study, which evaluated the effect of DAPT duration on both safety and efficacy outcomes. Regarding the type of P2Y12 inhibitor used, 65.6% of complex PCI patients were treated with clopidogrel, whereas the remaining 34.4% received prasugrel plus aspirin. The majority of patients (82.8%) received a drug-eluting stent (DES), and only 17.2% had a bare metal stent (BMS) implanted. Patients with complex target lesions had higher rates of MI and ST during the first year (3.9% versus 2.4%, p<0.001), whereas there was no significant difference between these rates at 12–30 months (3.5% versus 2.9%, p=0.07). Complex PCI patients randomized to prolonged (30 months) DAPT had a reduced risk of major adverse cardiovascular and cerebrovascular events (MACCE), as well as MI and ST, compared to standard (12 months) DAPT (HR 0.72, 95% CI [0.55–0.96], p=0.02 for MACCE; HR 0.55, 95% CI [0.38–0.79], p=0.001 for MI and ST), a trend that was also observed in non-complex-PCI patients (p=0.88 [for interaction] for MACCE; p=0.81 for MI and ST). Prolonged DAPT was found to increase moderate/severe bleeding events in non-complex PCI patients (HR 1.78, 95% CI [1.27–2.50], p<0.001); the difference was not found to be statistically significant in complex PCI patients (HR 1.41, 95% CI [0.87– 2.28], p=0.16, p=0.44 for interaction).3 Through a pooled analysis of patient-level data from six randomized controlled trials, complex PCI patients, who were treated with clopidogrel and had a DES implantation, were found to have an increased risk of

MACE (HR 1.98, 95% CI [1.50–2.60], p<0.0001) and coronary thrombotic events (CTEs); the composite of MI or definite or probable ST (HR 2.36, 95% CI [1.70–3.22], p<0.0001). Long-term (≥12 months) DAPT was associated with a reduction in both MACE and CTE rate in complex PCI patients (adjusted HR: 0.56, 95% CI [0.35–0.89] for MACE; adjusted HR 0.57, 95% CI [0.33–0.97] for CTEs) compared to short-term (3 or 6 months) DAPT, a beneficial impact that was progressively greater with an increase in procedural complexity. Long-term DAPT was also associated with higher rates of major bleeding (1.03% versus 0.52%, incidence rate difference 0.51%), although statistical significance was not evident (HR 1.81, 95% CI [0.67–4.91].9 In their study of 14,963 patients from eight randomized trials, Costa et al. incorporated both angiographic and clinical high-risk features, such as high bleeding risk (HBR) status (PREdicting bleeding Complications in patients undergoing stent Implantation and SubsequEnt DAPT [PRECISEDAPT] score ≥25), and concluded that complex PCI patients had a greater risk of the composite endpoint of MI, definite ST, stroke, or target vessel revascularization compared to non-complex PCI patients (p<0.0001), irrespective of HBR status.4 The majority of patients (79.5%) received clopidogrel, whereas 10% and 8.5% received prasugrel and ticagrelor, respectively. Most patients (81.3%) had a second-generation DES implanted, 8% had a first-generation DES implanted, and 10.6% had a BMS implanted. Prolonged DAPT (12 or 24 months) reduced ischemic events

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DAPT in Complex PCI without increasing the rate of bleeding in non-HBR complex PCI patients, whereas complex PCI was not found to significantly increase bleeding events. The co-existence of complex PCI features and acute coronary syndrome (ACS) among non-HBR patients identified a cohort obtaining particular benefit with prolonged DAPT.4 Interestingly, a post-hoc analysis of the Global Leaders: A Clinical Study Comparing Two Forms of Anti-platelet Therapy After Stent Implantation trial, which investigated the role of an experimental regimen (23 months of ticagrelor monotherapy after 1 month of DAPT) versus a reference regimen (12 months of aspirin monotherapy after 12 months of DAPT) in 15,450 patients, found that complex PCI patients had a higher risk of a patient-oriented composite endpoint (POCE) of allcause death, stroke, MI, or revascularization (HR: 1.29, 95% CI [1.18– 1.41], p<0.001), as well as Bleeding Academic Research Consortium (BARC) type 3 or 5 bleeding (HR 1.28, 95% CI [1.02–1.61], p=0.034) compared to the non-complex PCI group, leading to an increased risk of net adverse clinical events (NACE; HR 1.29, 95% CI [1.18–1.40], p<0.001). All patients were treated with Biolimus A9-eluting stents.

Complex PCI patients on the experimental regimen had a significant lower risk of POCE (HR 0.80, 95% CI [0.69–0.93], p=0.003) with a similar risk of bleeding (HR 0.97, 95% CI [0.67–1.40], p=0.856), resulting in a significantly reduced risk of NACE (HR 0.80, 95% CI [0.69–0.92, p=0.002).

Of importance, the beneficial effects of the experimental strategy seemed to be mainly confined to ACS patients (p<0.05 [for interaction] for POCE and NACE between ACS and elective PCI patients).12 This finding was also supported by Takahashi et al.’s post-hoc analysis of patients with multivessel PCI, in which ACS patients following the experimental strategy were shown to have a lower risk for all-cause death or new Q wave MI (HR 0.55, 95% CI [0.35–0.89], p=0.014, p=0.032 for interaction), as well as a reduced risk of bleeding (HR: 0.58, 95% CI [0.33–1.01], p=0.053, p=0.334 for interaction). 13 The recently published Ticagrelor With aspIrin or aLone In hiGH-risk paTients after COMPLEX percutaneous coronary intervention (TWILIGHTCOMPLEX) study is a post-hoc analysis of the TWILIGHT trial, which included 2,342 patients undergoing complex PCI. It evaluated the effects of ticagrelor monotherapy compared to ticagrelor plus aspirin in patients who had completed 3 months of uneventful DAPT treatment. The results showed that, following the ticagrelor monotherapy regimen, patients were less likely to have a clinically relevant bleeding BARC type 2, 3, or 5 during the follow-up period of 1 year (4.2% versus 7.7%, absolute risk difference: –3.5%, HR 0.54, 95% CI [0.38–0.76]), whereas severe or fatal bleeding (i.e. BARC types 3 and 5) rates were also significantly reduced in the ticagrelor monotherapy compared to ticagrelor plus aspirin arm (1.1% versus 2.6%, absolute risk difference: −1.5%, HR 0.41, 95% CI [0.21– 0.80]). There were no statistically significant differences in ischemic endpoints, such as the composite of death, MI, stroke (3.8% versus 4.9%, absolute risk difference −1.1%, HR 0.77, 95% CI [0.52–1.15]), or ST (0.4% versus 0.8%, absolute risk difference −0.4%, HR: 0.56, 95% CI [0.19–1.67]) between the two groups. The sensitivity analysis found that the benefit of bleeding risk reduction associated with ticagrelor monotherapy regimen was consistent across all individual subgroups of complex PCI (three or more lesions treated, three vessels treated, stent length >60 mm, bifurcation with two stents implanted, use of atherectomy device, LM PCI, surgical bypass graft, or chronic total occlusion).14

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A recent meta-analysis with a total of 8340 complex PCI patients evaluated the safety and efficacy of prolonged (>12 months) DAPT. In most studies, clopidogrel was the P2Y12 inhibitor of choice, whereas the majority of patients had a DES implanted. Compared to DAPT <12 months, a prolonged DAPT duration (>12 months) was associated with a reduced rate of cardiac mortality (OR 0.57, 95% CI: [0.35–0.92], p=0.02) and MACE (OR 0.76, 95% CI [0.59–0.96], p=0.02). Additionally, although the bleeding rate was significantly increased with prolonged DAPT (OR 1.75, 95% CI [1.20–2.20], p=0.004), rate of all-cause mortality was similar (p=0.41).15 In brief, prolonged DAPT is beneficial for the prevention of ischemic events, but has a potentially higher bleeding risk in patients undergoing complex PCI. Nevertheless, in cases where bleeding prevention is essential, early de-escalation of DAPT to long-term ticagrelor monotherapy could be an alternative strategy, and has been shown to reduce bleeding events without significantly compromising efficacy.

Antiplatelet Use in Bifurcation, LM, and CTO PCI Bifurcation and LM lesions, as well as CTO interventions, are of particular interest (Table 2). In the COronary BIfurcation Stenting II registry, which included 2,082 patients with bifurcation PCI, prolonged DAPT (≥12 months) was associated with lower rates of all-cause death or MI compared to standard DAPT (<12 months) at 4 years post-PCI (adjusted HR 0.22, 95% CI [0.12–0.38], p<0.001). All patients were treated with a DES although, interestingly, patients in the prolonged DAPT group were more likely to have a second-generation DES implanted compared to patients in the standard DAPT group (14.4% versus 7.2%). Of note, the treatment effect of prolonged DAPT duration did not differ significantly based on the type of stent used.16 Of the 1,754 patients randomized to 6 or 24 months of DAPT with clopidogrel in the PRODIGY (PROlonging Dual antiplatelet treatment after Grading stent-induced Intimal hyperplasia) study, who were analyzed by LM or proximal LAD (pLAD) PCI, the rate of definite, probable, or possible ST in the 24-month DAPT group was significantly lower in patients with LM/pLAD lumen narrowing (HR 0.45, 95% CI [0.23–0.89], p=0.02), whereas it was higher in patients without LM/pLAD lumen narrowing (HR 2.15, 95% CI [1.01–4.58], p=0.046, p=0.002 for interaction), rendering the presence of LM/pLAD lumen narrowing as a possible treatment duration modifier.

Of note, 26.8% and 26.2% of patients in the 24-month and 6-month DAPT groups, respectively, received a BMS; the remaining patients in each group were treated with a zotarolimus-, everolimus- or paclitaxel-eluting stent. However, although separate analysis regarding the effect of DAPT on ischemic outcomes for each stent subgroup was not performed, after excluding first-generation DES, the results remained similar with those observed in the overall population.17 In the Evaluation of XIENCE versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization (EXCEL) trial, prolongation of DAPT beyond 12 months after PCI with everolimus-eluting stents in patients with LM disease did not result in improved event-free survival, with similar 1–3 year rates of death, MI, or stroke composite compared to standard DAPT duration (p=0.28). Of note, 72.9%, 18.5%, and 7% of patients in the EXCEL trial were discharged on clopidogrel, prasugrel, or ticagrelor, respectively, with corresponding rates of 67.8%, 17.8%, and 5.4% at 1 year, and 54.7%, 10%, and 2.9% at 3 years post-PCI.18

Complex Coronary Intervention Table 2: Dual Antiplatelet Therapy in Specific Anatomical Subsets of Complex Percutaneous Coronary Intervention Study

Size (n)

Stent Type

P2Y12 Inhibitor

Results

Jang et al. 201816

2,082

DES

Clopidogrel

≥12-month versus <12-month DAPT in patients with bifurcation stenting HR 0.22, 95% CI [0.12–0.38], p<0.001 for all-cause death or MI HR 0.13, 95% CI [0.02–0.71], p=0.02 for cardiac death HR 0.06, 95% CI [0.02–0.17], p<0.001 for MI HR 0.51, 95% CI [0.23–1.13], p=0.09 for all-cause death

Costa et al. 201617

953

BMS (26.5%) DES (73.5%)

Clopidogrel

24- versus 6-month DAPT in patients with LM/pLAD lumen narrowing HR 0.96, 95% CI [0.65–1.41], p=0.84 for MACE HR 0.45, 95% CI [0.23–0.89], p=0.02 for ST HR 2.51, 95% CI [1.43–4.42], p=0.003 for BARC type 2, 3, or 5 bleeding

Brener et al. 201818

633

Everolimus-eluting stents

Clopidogrel (72.9%) Prasugrel (18.5%) Ticagrelor (7%)

3-year versus 1-year DAPT in patients with LM stenting HR 1.59, 95% CI [0.69–3.48], p=0.28 for death, MI, or stroke HR 2.69, 95% CI [0.82–8.84], p=0.10 for all-cause death

Rhee et al. 201819

700

DES (biolimus-, everolimus-, or zotarolimus-eluting stent)

Clopidogrel

<12-month versus ≥12-month DAPT in patients with one- or two-stent bifurcation lesions HR 3.81; 95% CI [1.56–9.28], p=0.003 for 3-year TLF in the two-stent group 17.2% versus 1.9% (p=0.006) for 3-year net adverse cardiovascular events in the two-stent group

Lee et al. 201720

512

DES Clopidogrel (paclitaxel-, sirolimus-, zotarolimus-, biolimus-, or everolimus-eluting stent)

≤12-month versus >12-month DAPT in patients with chronic total occlusion PCI HR 0.95, 95% CI [0.52–1.76], p=0.88 for MACCE HR 1.00, 95% CI [0.20–4.96], p=0.99 for BARC type 2, 3, or 5 bleeding

BARC =Bleeding Academic Research Consortium; BMS = bare metal stent; DAPT = dual antiplatelet therapy; DES = drug-eluting stent; LM = left main; MACCE = major adverse cardiovascular and cerebrovascular events; MACE = major adverse cardiovascular events; pLAD = proximal left anterior descending; ST = stent thrombosis; TLF = target lesion failure.

Table 3: Complex Percutaneous Coronary Intervention Definition Components Complex PCI Features

Valgimigli et al.1 Giustino et al.9 Yeh et al.3 Généreux et al.2 Serruys et al.12 Costa et al.4 Dangas et al.14

Bifurcation

√

√

≥3 stents

√

√

≥3 lesions

√

√

>2 lesions/vessels

√

√ √

√

√

√

√

√

√

√

√ √

√ √ √

√

√

√

√

√

√

Rotational atherectomy Vein graft PCI

√

√

LM PCI Unprotected LM

√ √

√

Lesion ≥30 mm

Thrombus

√ √

√

√

3 vessels

CTO

√

√

Multivessel PCI

Stent >60 mm

√

√

CTO = chronic total occlusion; LM = left main; PCI = percutaneous coronary intervention.

Prolonged DAPT with clopidogrel has been reported to be beneficial for patients following a two-stent strategy for LM bifurcation, as DAPT <12 months was associated with higher target lesion failure and thrombotic adverse cardiovascular events (TACE) rates in patients with a two-stent versus one-stent implantation strategy (p=0.001 and p=0.002, respectively), with no differences in bleeding outcomes between subgroups, indicating a positive net clinical benefit of prolonged DAPT in this subset of patients. Of note, patients were treated with biodegradable

polymer-coated biolimus-, durable polymer-coated everolimus-, and durable polymer-coated zotarolimus-eluting stents, with similar rates between the different DAPT duration subgroups (p=0.633).19 Of the 512 retrospectively analyzed patients treated with PCI and DES implantation for CTO lesions, the rates of MACCE, as well as BARC type 2, 3, or 5 bleeding, were similar between the ≤12-month and >12-month DAPT groups (p=0.26 and p=0.72, respectively), whereas there were no

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DAPT in Complex PCI significant interactions between baseline lesion or procedural characteristics and DAPT duration for MACCE. Interestingly, although in the prolonged DAPT group the rates of newer-generation stents were higher (25.6% versus 11.6% for everolimus-, 19.8% versus 14.6% for zotarolimus-, and 8.3% versus 7.5% for biolimus-eluting stents), there were no significant interactions between DAPT duration effect on MACCE and stent generation (p=0.41 for interaction).20

Current and Future Considerations Heterogeneity in features used to define a complex PCI procedure significantly hinders comparison between studies and the DAPT regimens used (Table 3).1–4,9,12 This is further complicated by the fact that, apart from complex coronary anatomical features, comorbidities and/or hemodynamic compromise may co-exist and characterize a ‘complex PCI patient’ (Figure 1). Of importance, patients with complex coronary artery disease (CAD) are at an increased risk of adverse outcomes, even after the completion of a complex PCI procedure, depending on the residual ischemia burden, a factor that should be taken into consideration during the evaluation and comparison of trials’ efficacy outcomes.21 The American College of Cardiology/American Heart Association guidelines consider features, such as greater stent length or bifurcation lesions, as factors that elevate ischemic and ST risk, potentially advocating for a prolonged duration of DAPT,11 whereas the European Society of Cardiology (ESC) guidelines propose that prolonged DAPT (>6 months) may be considered (class IIb recommendation) for patients undergoing complex PCI.1 DAPT beyond 1 year is also discussed in the Canadian guidelines (weak recommendation, moderate-quality evidence), and concerns stable CAD patients with a low risk of bleeding undergoing complex PCI.22 Of note, the use of a potent P2Y12 inhibitor in complex PCI patients, which could provide an alternative strategy for ischemic risk reduction, has not been studied extensively, as most published studies have mainly used clopidogrel as part of DAPT.4,9,16–20 An analysis of the PROMETHEUS (a multicenter observational study comparing outcomes with prasugrel versus clopidogrel in ACS PCI patients) study, which compared prasugrel versus clopidogrel in 9,735 ACS patients undergoing complex PCI, showed that physicians hesitated to use potent P2Y12 inhibitors in high-risk situations; as procedural complexity increased, the prescription of prasugrel decreased.23 The

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Valgimigli M, Bueno H, Byrne RA, et al. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: The Task Force for Dual Antiplatelet Therapy in Coronary Artery Disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J 2018;39:213–60. https://doi.org/10.1093/eurheartj/ehx419; PMID: 28886622.

Généreux P, Giustino G, Redfors B, et al. Impact of percutaneous coronary intervention extent, complexity and platelet reactivity on outcomes after drug eluting stent implantation. Int J Cardiol 2018;268:61–7. https://doi.org/10.1016/j.ijcard.2018.03.103; PMID: 30041804.

Yeh RW, Kereiakes DJ, Steg PG, et al. Lesion complexity and outcomes of extended dual antiplatelet therapy after percutaneous coronary intervention. J Am Coll Cardiol 2017;70:2213–23. https://doi.org/10.1016/j.jacc.2017.09.011; PMID: 29073947.

Costa F, Van Klaveren D, Feres F, et al. Dual antiplatelet therapy duration based on ischemic and bleeding risks after coronary stenting. J Am Coll Cardiol 2019;73:741–54. https://doi. org/10.1016/j.jacc.2018.11.048; PMID: 30784667.

Bortnick AE, Epps KC, Selzer F, et al. Five-year follow-up of

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6.

7.

8.

9.

Figure 1: Definition of a Complex PCI Patient Patient comorbidities

Complex CAD

Heart failure Diabetes Advanced age Peripheral vascular disease Unstable angina/NSTEMI Prior surgery

Operator experience

Complex PCI patients

Elderly patients >80 years old, often surgical turn-downs

Individual skills Personal experience

Multivessel disease Left main disease Calcification Long lesion Venous bypass grafts

Hemodynamic compromise Low ejection fraction Low cardiac output

CAD = coronary artery disease; NSTEMI = non-ST-elevation MI; PCI = percutaneous coronary intervention. Source: Werner et al. 2018.6 Reproduced with permission from Springer Nature.

recent 2018 ESC/European Association for Cardio-Thoracic Surgery guidelines on myocardial revascularization propose prasugrel or ticagrelor in high-risk elective PCI, such as LM stenting and CTO procedures (class IIb recommendation).24 Potent P2Y12 use in patients undergoing elective complex PCI is currently under evaluation in the ongoing SMART-ATTEMPT (Aspirin and a PoTent P2Y12 inhibitor versus aspirin and clopidogrel Therapy in Patients Undergoing Elective percutaneous coronary intervention for coMPlex lesion Treatment) trial (NCT04014803).

Conclusion Complex PCI cases, as well as their associated risks, represent a common clinical scenario, indicating a need to identify optimal antiplatelet therapy that would benefit these high-risk patients. With the exception of the increased ischemic risks associated with procedural complexity, it is evident that the risk of bleeding plays an important role in tailoring both the type and the duration of antithrombotic regimen, and should guide treatment decision-making. The adoption of a universal definition of complex PCI and widely-used ischemic and bleeding scores may facilitate a comparison of study outcomes and the conduction of large randomized controlled trials investigating different DAPT strategies, as well as the use of alternative agents, such as potent P2Y12 inhibitors, in such patients.

patients treated for coronary artery disease in the face of an increasing burden of co-morbidity and disease complexity (from the NHLBI Dynamic Registry). Am J Cardiol 2014;113:573–9. https://doi.org/10.1016/j.amjcard.2013.10.039; PMID: 24388624.

Werner N, Nickenig G, Sinning JM. Complex PCI procedures: challenges for the interventional cardiologist. Clin Res Cardiol 2018;107(Suppl 2):64–73. https://doi.org/10.1007/s00392-0181316-1; PMID: 29978353.

Stefanini GG, Serruys PW, Silber S, et al. The impact of patient and lesion complexity on clinical and angiographic outcomes after revascularization with zotarolimus- and everolimus-eluting stents: a substudy of the RESOLUTE All Comers Trial (a randomized comparison of a zotarolimus-eluting stent with an everolimus-eluting stent for percutaneous coronary intervention). J Am Coll Cardiol 2011;57:2221–32. https://doi. org/10.1016/j.jacc.2011.01.036; PMID: 21616282.

Wilensky RL, Selzer F, Johnston J, et al. Relation of percutaneous coronary intervention of complex lesions to clinical outcomes (from the NHLBI Dynamic Registry). Am J Cardiol 2002;90:216–21. https://doi.org/10.1016/s00029149(02)02457-8; PMID: 12127606.

Giustino G, Chieffo A, Palmerini T, et al. Efficacy and safety of

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Stone GW, Généreux P, Harrington RA, et al. Impact of lesion complexity on peri-procedural adverse events and the benefit of potent intravenous platelet adenosine diphosphate receptor inhibition after percutaneous coronary intervention: core laboratory analysis from 10 854 patients from the CHAMPION PHOENIX trial. Eur Heart J 2018;39:4112–21. https://doi. org/10.1093/eurheartj/ehy562; PMID:30203006.

Levine GN, Bates ER, Bittl JA, et al. 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease. J Am Coll Cardiol 2016;68:1082–115. https://doi.org/10.1161/ CIR.0000000000000404; PMID: 27026020.

Serruys PW, Takahashi K, Chichareon P, et al. Impact of long-term ticagrelor monotherapy following 1-month dual antiplatelet therapy in patients who underwent complex percutaneous coronary intervention: insights from the Global Leaders trial. Eur Heart J 2019;40:2595–604. https://doi.org/10.1093/eurheartj/ ehz453; PMID: 31397487.

Takahashi K, Serruys PW, Chichareon P, et al. Efficacy and safety

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Dangas G, Baber U, Sharma S, et al. Ticagrelor with or without aspirin after complex PCI. J Am Coll Cardiol 2020;75:2414–24. https://doi.org/10.1016/j.jacc.2020.03.011; PMID: 32240761.

Subhaharan D, Mridha N, Singh K. Clinical benefits of prolonged dual antiplatelet therapy following complex percutaneous coronary intervention. Coron Artery Dis 2020;31:273–8. https://doi. org/10.1097/MCA.0000000000000827; PMID: 31658148.

Jang WJ, Ahn SG, Song YB, et al. Benefit of prolonged dual antiplatelet therapy after implantation of drug-eluting stent for coronary bifurcation lesions: results from the Coronary Bifurcation Stenting Registry II. Circ Cardiovasc Interv 2018;11:e005849. https://doi.org/10.1161/ CIRCINTERVENTIONS.117.005849; PMID: 30006330.

Costa F, Adamo M, Ariotti S, et al. Left main or proximal left anterior descending coronary artery disease location identifies high-risk patients deriving potentially greater benefit from

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Brener SJ, Serruys PW, Morice MC, et al. Optimal duration of dual antiplatelet therapy after left main coronary stenting. J Am Coll Cardiol 2018;72:2086–7. https://doi.org/10.1016/j. jacc.2018.07.084; PMID: 30336833.

Rhee TM, Park KW, Kim CH, et al. Dual antiplatelet therapy duration determines outcome after 2- but not 1-stent strategy in left main bifurcation percutaneous coronary intervention. JACC Cardiovasc Interv 2018;11:2453–63. https://doi.org/10.1016/j. jcin.2018.09.020; PMID: 30573055.

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Farooq V, Serruys PW, Bourantas CV, et al. Quantification of incomplete revascularization and its association with five-year

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22. Mehta SR, Bainey KR, Cantor WJ, et al. 2018 Canadian Cardiovascular Society/Canadian Association of Interventional Cardiology Focused Update of the Guidelines for the Use of Antiplatelet Therapy. Can J Cardiol 2018;34:214–33. https://doi. org/10.1016/j.cjca.2017.12.012; PMID: 29475527.

23. Chandrasekhar J, Baber U, Sartori S, et al. Associations between complex PCI and prasugrel or clopidogrel use in patients with acute coronary syndrome who undergo PCI: from the PROMETHEUS study. Can J Cardiol 2018;34:319–29. https://doi. org/10.1016/j.cjca.2017.12.023; PMID: 29475531.

24. Neumann FJ, Sousa-Uva M, Ahlsson A, et al. 2018 ESC/EACTS guidelines on myocardial revascularization. Eur Heart J 2019;40:87–165. https://doi.org/10.1093/eurheartj/ehy394; PMID: 30165437.

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