CFR 5.1 by Radcliffe Cardiology

Cardiac Failure Review Volume 5 • Issue 1 • Spring 2019

©Radcliffe Cardiology

Volume 5 • Issue 1 • Spring 2019

www.CFRjournal.com

Treatment of Heart Failure with Sodium-Glucose Cotransporter 2 Inhibitors and Other Anti-diabetic Drugs Thomas A Zelniker and Eugene Braunwald

Focusing on Referral Rather than Selection for Advanced Heart Failure Therapies Tonje Thorvaldsen and Lars H Lund

Natriuretic Peptides in Chronic Heart Failure Hans-Peter Brunner-La Rocca and Sandra Sanders-van Wijk

Subclinical Left Ventricular Dysfunction During Chemotherapy Martin Nicol, Mathilde Baudet and Alain Cohen-Solal

Heart Failure and Problems with Frailty Syndrome

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Exercise Training and Heart Failure

Heart with Pain Centre

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ESC Congress Paris 2019 Together with

World Congress of Cardiology 31 August - 4 September

Spotlight Global Cardiovascular Health

Abstract submission: December - 14 February Clinical Case submission: Mid January - 1 March Late-Breaking Science submission: Mid March - 21 May Early registration deadline: 31 May Late registration deadline: 31 July

escardio.org/ESC2019

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Volume 5 • Issue 1 • Spring 2019

www.CFRjournal.com

Editor-in-Chief Andrew JS Coats Monash University, Melbourne, Australia and University of Warwick, Coventry, UK

Deputy Editor-in-Chief Giuseppe Rosano Department of Medical Sciences, IRCCS San Raffaele, Rome, Italy; Cardiology Clinical Academic Group, St George’s Hospitals NHS Trust, University of London, UK

Associate Editor Cristiana Vitale Department of Medical Sciences, IRCCS San Raffaele, Rome, Italy

Editorial Board William T Abraham

Michael B Fowler

Kian-Keong Poh

Ali Ahmed

Michael Fu

A Mark Richards

David L Hare

Giuseppe Rosano

Michael Henein

Jose Antonio Magaña Serrano

Adelino Leite-Moreira

Martin St John Sutton

Alexander Lyon

Allan D Struthers

Theresa A McDonagh

Michal Tendera

Kenneth McDonald

Maurizio Volterrani

Ileana L Piña

Cheuk Man Yu

The Ohio State University, US Washington DC VA Medical Center, US

Inder Anand

University of Minnesota, US

John Atherton

Royal Brisbane and Women’s Hospital, Australia

Michael Böhm

Saarland University, Germany

Alain Cohen-Solal

Paris Diderot University, France

Henry J Dargie

Western Infirmary, Glasgow

Carmine De Pasquale

Flinders University, Australia

Frank Edelmann

Cover image © stock.adobe.com.

Charité University Medicine, Germany

Stanford University, US

National University Heart Center, Singapore

Sahlgrenska University Hospital, Sweden University of Melbourne, Australia Heart Centre and Umea University, Sweden University of Porto, Portugal

Imperial College London, UK King’s College Hospital, UK

St Vincent’s Hospital, Ireland Montefiore Einstein Center for Heart & Vascular Care, US

University of Otago, New Zealand St George’s University of London, UK National Medical Centre, Mexico

Hospital of the University of Pennsylvania, US Ninewells Hospital & Medical School, UK University of Silesia, Poland IRCCS San Raffaele Pisana, Italy The Chinese University of Hong Kong, Hong Kong

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Managing Editor Rosie Scott | Production Editor Aashni Shah Publishing Director Leiah Norcott | Senior Designer Tatiana Losinska Contact rosie.scott@radcliffe-group.com

Key Account Directors Rob Barclay, David Bradbury, Gary Swanston Accounts Team William Cadden, Bradley Wilson Contact rob.barclay@radcliffe-group.com

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Chief Executive Officer David Ramsey Chief Operations Officer Liam O’Neill

Published by Radcliffe Cardiology. 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 © 2019 All rights reserved ISSN: 2057–7540 • eISSN: 2057–7559

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Established: March 2015 | Frequency: Quarterly | Current issue: Spring 2019

Aims and Scope

Submissions and Instructions to Authors

• Cardiac Failure Review aims to assist time-pressured physicians to stay abreast of key advances and opinion in heart failure. • Cardiac Failure Review comprises balanced and comprehensive articles written by leading authorities, addressing the most pertinent developments in the field. • Cardiac Failure Review provides comprehensive updates on a range of salient issues to support physicians in continuously developing their knowledge and effectiveness in day-to-day clinical practice.

• Contributors are identified by the Editor-in-Chief with the support of the Editorial Board and Managing Editor. • Following acceptance of an invitation, the author(s) and Managing Editor, in conjunction with the Editor-in-Chief, formalise the working title and scope of the article. • The ‘Instructions to Authors’ document and additional submission details are available at www.CFRjournal.com • Leading authorities wishing to discuss potential submissions should contact the Managing Editor, Rosie Scott rosie.scott@radcliffe-group.com

Structure and Format • Cardiac Failure Review is a quarterly journal comprising review articles, expert opinion articles and guest editorials. • The structure and degree of coverage assigned to each category of the journal is the decision of the Editor-in-Chief, with the support of the Editorial Board. • Articles are fully referenced, providing a comprehensive review of existing knowledge and opinion. • Each edition of Cardiac Failure Review is available in full online at www.CFRjournal.com

Reprints All articles included in Cardiac Failure Review are available as reprints. Please contact the Sales Director, Rob Barclay rob.barclay@radcliffe-group.com

Distribution and Readership Cardiac Failure Review is distributed quarterly through controlled circulation to senior healthcare professionals in the field in Europe.

Editorial Expertise

Abstracting and Indexing

Cardiac Failure Review is supported by various levels of expertise: • Overall direction from an Editor-in-Chief, supported by the Editorial Board comprising leading authorities from a variety of related disciplines. • Invited contributors who are recognised authorities in their respective fields. • Peer review – conducted by experts appointed for their experience and knowledge of a specific topic. • An experienced team of Editors and Technical Editors.

CFR is abstracted, indexed and listed in PubMed and Crossref. All articles are published in full on PubMed Central one month after publication.

Peer Review • On submission, all articles are assessed by the Editor-in-Chief to determine their suitability for inclusion. • The Managing Editor, following consultation with the Editor-in-Chief sends the manuscript to reviewers who are selected on the basis of their specialist knowledge in the relevant area. All peer review is conducted double-blind. • Following review, manuscripts are accepted without modification, accepted pending modification (in which case the manuscripts are returned to the author(s) to incorporate required changes), or rejected outright. The Editor-in-Chief reserves the right to accept or reject any proposed amendments. • Once the authors have amended a manuscript in accordance with the reviewers’ comments, the manuscript is assessed to ensure the revised version meets quality expectations. The manuscript is sent to the Editor-in-Chief for final approval prior to publication.

Open Access, Copyright and Permissions Articles published within this journal are open access, which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly. The author retains all non-commercial rights for articles published herein under the CC-BY-NC 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/ legalcode). Radcliffe Cardiology retain all commercial rights for articles published herein unless otherwise stated. Permission to reproduce an article for commercial purposes, either in full or in part, should be sought from the publication’s Managing Editor.

Online All manuscripts published in Cardiac Failure Review are available free to view at www.CFRjournal.com. Also available at www.radcliffecardiology.com are articles from other journals within Radcliffe Cardiology’s cardiovascular portfolio – including, Arrhythmia and Electrophysiology Review, Interventional Cardiology Review, European Cardiology Review and US Cardiology Review.

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Contents

Foreword Andrew JS Coats and Giuseppe Rosano

DOI: https://doi.org/10.15420/cfr.2019.4.1

Advanced Heart Failure The New Heart Failure Association Definition of Advanced Heart Failure

Marco Metra, Elisabetta Dinatolo and Nicolò Dasseni DOI: https://doi.org/10.15420/cfr.2018.43.1

Ultrafiltration in Acute Heart Failure

Maria Rosa Costanzo DOI: https://doi.org/10.15420/cfr.2018.29.2

Choosing Between Left Ventricular Assist Devices and Biventricular Assist Devices

Sajad Shehab and Christopher S Hayward DOI: https://doi.org/10.15420/cfr.2018.23.2

Focusing on Referral Rather than Selection for Advanced Heart Failure Therapies

Tonje Thorvaldsen and Lars H Lund DOI: https://doi.org/10.15420/cfr.2018.35.1

Co-morbidities Treatment of Heart Failure with Sodium-Glucose Cotransporter 2 Inhibitors and Other Anti-diabetic Drugs

Thomas A Zelniker and Eugene Braunwald DOI: https://doi.org/10.15420/cfr.2018.44.1

Subclinical Left Ventricular Dysfunction During Chemotherapy

Martin Nicol, Mathilde Baudet and Alain Cohen-Solal DOI: https://doi.org/10.15420/cfr.2018.25.1

Heart Failure and Problems with Frailty Syndrome: Why it is Time to Care About Frailty Syndrome in Heart Failure

Izabella Uchmanowicz, Agnieszka Młynarska, Magdalena Lisiak, Marta Kałuz·na-Oleksy, Marta Wleklik, Anna Chudiak, Magdalena Dudek, Jacek Migaj, Lynne Hinterbuchner and Robbert Gobbens DOI: https://doi.org/10.15420/cfr.2018.37.1

Biomarkers Natriuretic Peptides in Chronic Heart Failure

Hans-Peter Brunner-La Rocca and Sandra Sanders-van Wijk DOI: https://doi.org/10.15420/cfr.2018.26.1

Biomarkers in Routine Heart Failure Clinical Care

Sunil K Nadar and Muhammed Mujtaba Shaikh DOI: https://doi.org/10.15420/cfr.2018.27.2

Exercise Exercise Training and Heart Failure: A Review of the Literature

Jacqueline H Morris and Leway Chen DOI: https://doi.org/10.15420/cfr.2018.31.1

Erratum Erratum to: Foreword

Andrew JS Coats and Giuseppe Rosano DOI: https://doi.org/10.15420/cfr.2018.34.1

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Foreword

Andrew JS Coats is the inaugural Joint Academic Vice-President of Monash University, Australia and the University of Warwick, UK and Director of the Monash Warwick Alliance

Giuseppe Rosano is Professor of Pharmacology, Director of the Centre of Clinical and Experimental Medicine at the IRCCS San Raffaele, Italy and Professor of Cardiology and Consultant Cardiologist (Hon) at St George's University of London, UK

t is with great pleasure that we introduce to you, our readers, to the first issue of Cardiac Failure Review for 2019.

This issue features a range of articles on major areas of advance in heart failure from renowned experts. Some of the most topical areas in the management of heart failure are the effects and treatment of co-morbidities, and none more so than diabetes. In this issue, Thomas A Zelniker and Eugene Braunwald discuss the treatment of heart failure with sodium-glucose cotransporter 2 inhibitors (SGLT2i) and other anti-diabetic drugs following the three recent large trials that have demonstrated a reduction in heart failure hospitalisation and progressive renal failure, and including one, the EMPA-REG OUTCOME trial, that also showed a significant reduction in cardiovascular and total mortality. They conclude that the three tested drugs of the SGLT2i class cause robust reductions in heart failure hospitalisation rates but that only one, empagliflozin, was associated with a clear reduction in mortality. They also summarise another drug class, the GLP-1-RA agents, and suggest that some of this class may be beneficial in reducing atherosclerotic cardiac events in high-risk diabetic patients. In their article, Hans-Peter Brunner-La Rocca and Sandra Sanders-van Wijk review the use of natriuretic peptides diagnosis and monitoring of patients with established chronic heart failure, a less well-studied setting compared to their role in the evaluation of acutely breathless patients. They conclude that natriuretic peptides are strong prognostic markers also in the chronic setting, but that proving improved patient outcomes when the results of natriuretic peptides level monitoring is used in clinical care decisions has been inconsistent in the trials to date. Sunil K Nadar and Muhammed Mujtaba Shaikh also discuss other biomarkers and their role in routine heart failure clinical care. Tonje Thorvaldsen and Lars H Lund discuss referral rather than selection for advanced heart failure therapies, and propose strategies for optimising timely referral for advanced heart failure evaluation. Marco Metra et al. discuss the new Heart Failure Association definition of advanced heart failure, which was updated in 2018 and they stress that comorbidities, tachyarrhythmias and heart failure in the setting of preserved ejection fraction are all of increasing importance. Mechanical circulatory support, which continues to progress as a viable effective treatment option with technological advances, a development we all predict will speed up in the years to come. Sajad Shehab and Christopher S Hayward also extend this theme in their article by reviewing the options of left ventricular assist devices and biventricular assist devices in advanced heart failure, and Maria Rosa Costanzo looks at ultrafiltration in acute heart failure and summarises excellently the studies to date and what the future may hold, concluding finally that ultrafiltration remains an attractive alternative to diuretics because it more predictably lessens total body sodium load. She suggests that for future studies, ultrafiltration might be best adjusted according to the patientâ&#x20AC;&#x2122;s individual haemodynamic and renal profile, with a more precision target for the rate, duration and target fluid removal. Another setting we have seen considerably more effort in unravelling is the field of cardio-oncology. In this regard Martin Nicol et al. provide an excellent article on the detection and significance of subclinical left ventricular dysfunction seen during modern chemotherapeutic regimens. Lastly, but importantly, Jacqueline H Morris and Leway Chen review the literature on exercise training and heart failure, and Izabella Uchmanowicz et al. discuss heart failure and the associated problems when it coincides with the frailty syndrome, a feature we see much more of as the populations of the world progressively age. We hope you enjoy the reading this latest issue of Cardiac Failure Review.

DOI: https://doi.org/10.15420/cfr.2019.4.1

Access at: www.CFRjournal.com

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ÂŠ RADCLIFFE CARDIOLOGY 2019

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Advanced Heart Failure

The New Heart Failure Association Definition of Advanced Heart Failure Marco Metra, Elisabetta Dinatolo and Nicolò Dasseni Cardiology, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University and Civil Hospital of Brescia, Brescia, Italy

Abstract The clinical course of heart failure is characterised by progressive worsening of cardiac function and symptoms. Patients progress to a condition where traditional treatment is no longer effective and advanced therapies, such as mechanical circulatory support, heart transplantation and/or palliative care, are needed. This condition is called advanced chronic heart failure. The Heart Failure Association first defined it in 2007 and this definition was updated in 2018. The updated version emphasises the role of comorbidities, including tachyarrhythmias, and the role of heart failure with preserved ejection fraction. Improvements in mechanical circulatory support technology and better disease management programmes are major advances and are radically changing the management of these patients.

Keywords Heart failure, advanced heart failure, mechanical circulatory support, heart transplantation, prognosis Disclosure: MM has received honoraria as participant in clinical trials committees or to advisory boards from Amgen, Bayer, Fresenius, Novartis and Servier. The other authors have no conflict of interest to declare. Received: 3 December 2018 Accepted: 7 January 2019 Citation: Cardiac Failure Review 2019;5(1):5–8. DOI: https://doi.org/10.15420/cfr.2018.43.1 Correspondence: Marco Metra, Cardiology Unit, Department of Medical and Surgical Specialties, Radiologic Sciences and Public Health, University Cardio-Thoracic Department, Civil Hospitals, Piazza Spedali Civili 1, Brescia 25123, Italy. E: metramarco@libero.it 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.

Despite improvements in treatment, heart failure (HF) continues to have a progressive clinical course characterised by worsening of cardiac function and clinical condition, leading to a stage of advanced chronic HF. At this stage, the clinical picture is characterised by severe symptoms, frequent episodes of decompensation, poor quality of life and poor survival. Evidence-based medical treatments and devices are no longer effective in controlling symptoms and improving the clinical course and, in the case of neurohormonal antagonists, may not frequently be tolerated. The Heart Failure Association (HFA) of the European Society of Cardiology (ESC) first used the term advanced chronic HF to define this condition in 2007.1 The definition was updated in 2018 to include additional clinical aspects, such as outpatient treatment of episodes of decompensation and the role of comorbidities, and an update of treatment, namely with the new mechanical circulatory support (MCS) devices.2 After the first HFA position statement had been issued, and because the New York Heart Association (NYHA) classification of HF into four classes was felt to be inadequate, the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) classification was developed.3 This classification divides patients into seven clinical profiles to better describe the severity of their condition. These criteria stratify people into different risk profiles, and are associated with different outcomes once a patient has received an MCS.4 However, the INTERMACS criteria were developed to have a registry to classify patients undergoing MCS in the US. The aim was to identify different levels of HF severity but only for patients receiving this treatment. Because of this, they do not cover patients’ clinical history but only the severity of their symptoms at the time of treatment.

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In contrast, the HFA criteria were developed with the aim of identifying all patients with advanced chronic HF, independently of whether they could be treated with an MCS. The HFA classification included patients who may not have an indication for MCS, such as those with a preserved ejection fraction as well as those with significant comorbidities, such as severe renal and/or liver dysfunction. Such patients are commonly seen in clinical practice and the 2017 HFA position statement gives them due attention.

Updated Definition of Advanced Chronic Heart Failure The 2007 and 2018 criteria of advanced chronic HF are outlined in Table 1. Like the HF definition in the ESC guidelines, they adopt the criterion of having both HF signs and symptoms and an objective evidence of cardiac dysfunction to define advanced chronic HF.5 In both the 2007 and the 2018 definitions, the signs and symptoms are those of severe NYHA class III or IV HF. In respect to cardiac dysfunction, the 2007 statement included systolic dysfunction, shown by a left ventricular ejection fraction (LVEF) <30%, as well as LV diastolic dysfunction shown by echocardiographic abnormalities and/or signs of high intracardiac filling pressure by either invasive measurements or high brain natriuretic peptides (BNP) plasma levels.1 The 2018 statement adopts the same definition of systolic dysfunction (e.g. a LVEF <30%) and uses the 2016 ESC guidelines’ criteria for the definition of HF with preserved ejection fraction.2,5 In addition, it suggests isolated right ventricular (RV) failure, such as that resulting from arrhythmogenic right ventricular cardiomyopathy, or non-operable severe valve abnormalities and congenital abnormalities as possible causes of severe cardiac dysfunction.2

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Advanced Heart Failure Table 1: HFA Criteria for Advanced Chronic HF: Comparison of the 2007 and 2018 Definitions Criteria in the 2007 HFA position statement1

Criteria in the 2018 position statement2

Severe symptoms of HF with dyspnoea and/or fatigue at rest or with minimal exertion (NYHA functional class III or IV)

1. Severe and persistent symptoms of heart failure (NYHA class III [advanced] or IV)

Objective evidence of severe cardiac dysfunction, shown by at least one of the following: • low LVEF (<30%); • severe abnormality of cardiac function on Doppler echocardiography with a pseudonormal or restrictive mitral inflow pattern; or • high LV filling pressures (mean PCWP >16 mmHg, and/or mean RAP >12 mmHg by pulmonary artery catheterisation), and/or high BNP or NT-proBNP plasma levels, in the absence of non-cardiac causes.

2. Severe cardiac dysfunction, defined by: • reduced LVEF ≤30% • isolated RV failure (e.g. ARVC) • non-operable severe valve abnormalities • congenital abnormalities persistently high (or increasing) BNP or NT-proBNP values and data showing severe diastolic dysfunction or LV structural abnormalities, according to the ESC definition of HFpEF and HFmrEF

Episodes of fluid retention (pulmonary and/or systemic congestion, or peripheral oedema) and/or of reduced cardiac output at rest (peripheral hypoperfusion)

3. Episodes of pulmonary or systemic congestion requiring high-dose intravenous diuretics (or diuretic combinations) or episodes of low output requiring inotropes or vasoactive drugs or malignant arrhythmias causing >1 unplanned visit or hospitalisation in the past 12 months

History of ≥1 HF hospitalisation in the past 6 months Severe impairment of functional capacity shown by one of the following: • inability to exercise; • 6MWTD < 300 m or less in women and/or patients aged ≥75 years; or • pVO2 < 12–14 ml/kg/min

4. Severe impairment of exercise capacity with inability to exercise or low 6MWTD (<300 m) or pVO2 (<12–14 ml/kg/min), estimated to be of cardiac origin

Presence of all features above despite attempts to optimise therapy including diuretics, inhibitors of the renin–angiotensin–aldosterone system, and beta-blockers, unless these are poorly tolerated or contraindicated, and cardiac resynchronisation therapy, when indicated.

In addition to the above, extracardiac organ dysfunction resulting from heart failure (e.g. cardiac cachexia, or liver or kidney dysfunction) or type 2 pulmonary hypertension may be present, but are not required. Criteria 1 and 4 can be met in patients who have cardiac dysfunction (as described in criterion 2), but also have substantial limitation caused by other conditions (e.g. severe pulmonary disease, non-cardiac cirrhosis or, most commonly, renal disease with mixed aetiology). These patients have a limited quality of life and survival because of advanced disease and warrant the same intensity of evaluation as someone in whom the only disease is cardiac; however, the therapeutic options for these patients are usually more limited.

6MWTD = 6-minute walk test distance; ARVC = arrhythmogenic right ventricular cardiomyopathy; BNP = B-type natriuretic peptide; EF = ejection fraction; ESC = European Society of Cardiology; HF = heart failure; HFA = Heart Failure Association; HFmrEF = heart failure with mid-range ejection fraction; HFpEF = heart failure with preserved ejection fraction; LV = left ventricle; NT-proBNP = N-terminal pro-B-type natriuretic peptide; NYHA = New York Heart Association; PCWP = pulmonary capillary wedge pressure; pVO2 = peak exercise oxygen consumption; RAP = right atrial pressure; RV = right ventricular.

Both documents state the need to show severe limitation of exercise capacity, shown by a low <300 m, 6-minute walk test distance, or low peak oxygen consumption or inability to exercise. A poor clinical course, shown by episodes of HF decompensation in the past 6 or 12 months, is also required. 1,2 Because many patients with an acute HF decompensation are now treated in an outpatient setting or in emergency departments with short-term loop diuretics or, less often, inotropic drugs infusion,6–9 unplanned hospital visits are included in the more recent statement.2 Similarly, emergency department visits or hospitalisations for malignant tachyarrhythmias are now included.2

those hospitalised for acute HF. Relatively little data specific to patients with advanced chronic HF is available.

Finally, comorbidities, including pulmonary disease and liver and kidney dysfunction, are now included as possible major determinants of a poor clinical course and prognosis for patients with advanced chronic HF.10,11 It is also considered that, in some cases, such comorbidities may dominate the clinical course of HF itself (Table 1).2 Both documents clearly state that they must be present despite optimal evidence-based treatment that now includes ivabradine, sacubitril/valsartan, cardiac resynchronisation therapy and implantable cardioverter defibrillator implantation, under the most recent guidelines.2,5

Among biochemical parameters, markers of end-stage organ dysfunction and injury (such as myocardial, renal and liver dysfunction), as well as markers of iron deficiency, electrolyte abnormalities (hyponatremia, hypo- or hyper-kalaemia and hypochloraemia) have all been associated with poorer outcomes. The prognostic role of hypochloraemia has been demonstrated in recent studies.12–14

Prognostic Stratification Risk stratification is crucial for HF management. Several prognostic risk scores and numerous single risk markers have been identified. However, studies are generally based on ambulatory patients or on

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Several clinical features predict a worse overall prognosis patients with HF and in those with advanced HF. Among them, older age, longer QRS duration, tachycardia (especially when in sinus rhythm), a longer history of HF symptoms, higher NYHA functional class, recurrent hospitalisations for HF, and signs of systemic or pulmonary congestion and/or reduced cardiac output (often shown by a lower blood pressure), are associated with an increased incidence of cardiovascular hospitalisations and deaths.

Imaging and Functional Capacity Assessment Many parameters obtained by imaging, mainly by Doppler echocardiography and cardiac magnetic resonance imaging, have greater prognostic value than LVEF. These include LV dilatation and hypertrophy, mitral regurgitation, left atrial function, valve abnormalities, right ventricular function, pulmonary arterial pressure estimates and inferior vena cava diameter and dynamics. The accuracy of noninvasive measurements to estimate LV filling pressure is still controversial with

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Advanced Chronic Heart Failure the use of multiparametric approaches likely better than one single measurement such as the E/e’ ratio.15,16 Cardiopulmonary exercise testing (CPET) provides objective information about the exercise capacity of ambulatory patients with HF. It is indicated for the selection of candidates for heart transplantation. Peak exercise oxygen consumption (VO2), measured both as per cent of maximal predicted values and as an absolute value, as well as minute ventilation/carbon dioxide production (VE/VCO2) and an oscillatory pattern of ventilation during exercise have all been shown to have independent prognostic value.17 Based on prognostic studies, heart transplantation is indicated when peak VO2 is ≤14 ml/kg/min or ≤12 ml/kg/min in patients on beta-blockers. Achievement of a respiratory exchange rate >1.05 is important to define achievement of maximal aerobic capacity. Ventilatory response to exercise provides an objective assessment of exercise capacity, independently of patients’ motivation and, along with the presence of an oscillatory pattern of ventilation, may further stratify the patients.17 A low 6-minute walking test distance (6MWTD) may also be used in prognostic assessment.

patients with advanced HF. Resistance to loop diuretics remains a major hallmark of advanced HF and strategies to overcome it are of utmost value. Intravenous ultrafiltration, especially with new, simpler devices, might become a valid alternative to diuretic treatment.26 Alternatives to IV furosemide administration, such as subcutaneous furosemide, IV and oral torasemide, or a combination of acetazolamide or thiazides or metolazone, may show favourable results in future trials.27–31 Renal replacement therapy, for example, peritoneal dialysis, may also become necessary.5 Inotropic drugs are still an option as a palliative treatment. However, intermittent levosimendan administration has been associated with favourable effects on natriuretic peptides, quality of life and possibly hospitalisations.9

Multivariable Prognostic Scores

The use of short- or long-term MCS is warranted in patients with advanced HF when it is caused by LV systolic dysfunction and in the absence of major contraindications, such as comorbidities or severe right ventricular dysfunction.5,32,33 Better safety and survival of patients with permanent LV assist devices is widening their indication. Recent trial data support their indication also for people who have severe functional limitation although they are ambulatory and not dependent on inotropes.34

Several multiparametric risk scores have been developed. They include the Heart Failure Survival Score (HFSS), the Seattle Heart Failure Model (SHFM), the Metabolic Exercise test data combined with Cardiac and Kidney Indexes (MECKI) score and the Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC).18–21

Nonetheless, determining the best therapeutic strategy for individual patients with advanced HF remains challenging, and the use of MCS carries a high risk of adverse events, including device failure, infections, thromboembolic and haemorrhagic events.35–37

The HFSS was developed for the selection of candidates for heart transplantation among ambulatory patients with severe HF. Fully noninvasive models, including CPET, can be as accurate at predicting prognosis as those including invasive measurements.19 The SHFM has been fully validated. It has shown an adequate discrimination power though underestimated the absolute risk in patients with advanced HF, namely in those indicated for MCS.22 Its predictive value has also been shown in patients on MCS so it may be used to estimate outcomes compared with no intervention.23 MAGGIC, which is based on individual data of 39,372 patients with heart failure with reduced ejection fraction and preserved ejection fraction from 30 cohort studies and six clinical trials, is among the most comprehensive and consistent.18 The MECKI score includes CPET data, percent predicted pVO2 and VE/VCO2 slope, haemoglobin, serum sodium and renal function. It compares favourably with HFSS and SHFM, although the latter does not require CPET data.24

Heart transplantation remains the best option for most patients with advanced HF, including those with right ventricular dysfunction. The number of transplants seems, however, to have reached a plateau in recent years, because the number of donor hearts are limited. It may be hoped that improvements in MCS technology may allow for a greater use of these devices for the treatment of advanced HF. In the case of indications for both MCS and of heart transplantation, appropriate organisation and communication between different advanced HF centres is mandatory. Patient selection and treatment should be performed using hub and spoke models, as outlined in the recent advanced HF position statement.1 Palliative care remains an important option to be indicated not only when treatment has failed but also as concomitant treatment in patients with severe disease.2,38

Conclusion A comparative study showed a similar predictive accuracy of the four scores with a tendency to underestimate event rates with the SHFM and HFSS scores and a tendency to overestimate them with MAGGIC and MECKI scores.25

Treatment By definition, traditional treatment with drugs and devices is not effective in relieving symptoms and improving the clinical course of the

etra M, Ponikowski P, Dickstein K, et al. Advanced chronic M heart failure: a position statement from the Study Group on Advanced Heart Failure of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail 2007;9:684–94. https://doi.org/10.1016/j.ejheart.2007.04.003; PMID: 17481947. Crespo-Leiro MG, Metra M, Lund LH, et al. Advanced heart failure: a position statement of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail 2018;20:1505–35. https://doi.org/10.1002/ejhf.1236;

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Advanced chronic HF is the condition where HF has progressed to a stage where traditional, evidence-based, treatment has become ineffective and the patients have severe symptoms, frequent episodes of decompensation and poor survival. It is important to increase awareness of this condition, as new treatments are now available. They include palliative therapy, disease management programmes and MCS devices. The use of such treatments may improve quality of life and, at least in some cases, outcomes too. n

PMID: 29806100. Stevenson LW, Pagani FD, Young JB, et al. INTERMACS profiles of advanced heart failure: the current picture. J Heart Lung Transplant 2009;28:535–41. https://doi.org/10.1016/ j.healun.2009.02.015; PMID: 19481012. Jorde UP, Kushwaha SS, Tatooles AJ, et al. Results of the destination therapy post-food and drug administration approval study with a continuous flow left ventricular assist device: a prospective study using the INTERMACS registry (Interagency Registry for Mechanically Assisted Circulatory

Support). J Am Coll Cardiol 2014;63:1751–7. https://doi. org/10.1016/j.jacc.2014.01.053; PMID: 24613333. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail 2016;18:891–975. https://doi.org/10.1002/ejhf.592; PMID: 27207191.

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kali H, Dwyer EM, Goldstein R, et al. Prognosis and response S to therapy of first inpatient and outpatient heart failure event in a heart failure clinical trial: MADIT-CRT. Eur J Heart Fail 2014;16:560–5. https://doi.org/10.1002/ejhf.71; PMID: 24578164. Okumura N, Jhund PS, Gong J, et al. Importance of clinical worsening of heart failure treated in the outpatient setting: evidence from the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure trial (PARADIGM-HF). Circulation 2016;133:2254– 62. https://doi.org/10.1161/CIRCULATIONAHA.115.020729; PMID: 27143684. Ferreira JP, Metra M, Mordi I, et al. Heart failure in the outpatient versus inpatient setting: findings from the BIOSTAT-CHF study. Eur J Heart Fail 2019;21:112–20. https://doi. org/10.1002/ejhf.1323; PMID: 30338883. Comin-Colet J, Manito N, Segovia-Cubero J, et al. Efficacy and safety of intermittent intravenous outpatient administration of levosimendan in patients with advanced heart failure: the LIONHEART multicentre randomised trial. Eur J Heart Fail 2018;20:1128– 36. https://doi.org/10.1002/ejhf.1145; PMID: 29405611. Iorio A, Senni M, Barbati G, et al. Prevalence and prognostic impact of non-cardiac co-morbidities in heart failure outpatients with preserved and reduced ejection fraction: a community-based study. Eur J Heart Fail 2018;20:1257–66. https://doi.org/10.1002/ejhf.1202; PMID: 29917301. Canepa M, Straburzynska-Migaj E, Drozdz J, et al. Characteristics, treatments and 1–year prognosis of hospitalized and ambulatory heart failure patients with chronic obstructive pulmonary disease in the European Society of Cardiology Heart Failure Long-Term Registry. Eur J Heart Fail 2018;20:100–10. https://doi.org/10.1002/ejhf.964; PMID: 28949063. Ter Maaten JM, Damman K, Hanberg JS, et al. Hypochloremia, diuretic resistance, and outcome in patients with acute heart failure. Circ Heart Fail 2016;9:e003109. https://doi.org/10.1161/ CIRCHEARTFAILURE.116.003109; PMID: 27507112. Cuthbert JJ, Pellicori P, Rigby A, et al. Low serum chloride in patients with chronic heart failure: clinical associations and prognostic significance. Eur J Heart Fail 2018;20:1426–35. https://doi.org/10.1002/ejhf.1247; PMID: 29943886. Testani JM, Hanberg JS, Arroyo JP, et al. Hypochloraemia is strongly and independently associated with mortality in patients with chronic heart failure. Eur J Heart Fail 2016;18: 660–8. https://doi.org/10.1002/ejhf.477; PMID: 2676389. Nauta JF, Hummel YM, van der Meer P, et al. Correlation with invasive left ventricular filling pressures and prognostic relevance of the echocardiographic diastolic parameters used in the 2016 ESC heart failure guidelines and in the 2016 ASE/ EACVI recommendations: a systematic review in patients with heart failure with preserved ejection fraction. Eur J Heart Fail 2018;20:1303–11. https://doi.org/10.1002/ejhf.1220; PMID: 29877602. Nagueh SF. Non-invasive assessment of left ventricular filling

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pressure. Eur J Heart Fail 2018;20:38–48. https://doi.org/10.1002/ ejhf.971; PMID: 28990316. Corra U, Agostoni PG, Anker SD, et al. Role of cardiopulmonary exercise testing in clinical stratification in heart failure. A position paper from the Committee on Exercise Physiology and Training of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail 2018;20:3–15. https://doi. org/10.1002/ejhf.979; PMID: 28925073. Pocock SJ, Ariti CA, McMurray JJ, et al. Predicting survival in heart failure: a risk score based on 39 372 patients from 30 studies. Eur Heart J 2013;34:1404–13. https://doi.org/10.1093/ eurheartj/ehs337; PMID: 23095984. Aaronson KD, Schwartz JS, Chen TM, et al. Development and prospective validation of a clinical index to predict survival in ambulatory patients referred for cardiac transplant evaluation. Circulation 1997;95:2660–7. https://doi. org/10.1161/01.CIR.95.12.2660; PMID: 9193435. Agostoni P, Corra U, Cattadori G, et al. Metabolic exercise test data combined with cardiac and kidney indexes, the MECKI score: a multiparametric approach to heart failure prognosis. Int J Cardiol 2013;167:2710–8. https://doi.org/10.1016/j.ijcard. 2012.06.113; PMID: 22795401. Levy WC, Mozaffarian D, Linker DT, et al. The Seattle Heart Failure Model: prediction of survival in heart failure. Circulation 2006;113:1424–33. https://doi.org/10.1161/ CIRCULATIONAHA.105.584102; PMID: 16534009. Kalogeropoulos AP, Georgiopoulou VV, Giamouzis G, et al. Utility of the Seattle Heart Failure Model in patients with advanced heart failure. J Am Coll Cardiol 2009;53: 334–42. https://doi.org/10.1016/j.jacc.2008.10.023; PMID: 19161882. Ketchum ES, Moorman AJ, Fishbein DP, et al. Predictive value of the Seattle Heart Failure Model in patients undergoing left ventricular assist device placement. J Heart Lung Transplant 2010;29:1021–5. https://doi.org/10.1016/j.healun.2010.05.002; PMID: 20558086. Agostoni P, Paolillo S, Mapelli M, et al. Multiparametric prognostic scores in chronic heart failure with reduced ejection fraction: a long-term comparison. Eur J Heart Fail 2018;20:700–10. https://doi.org/10.1002/ejhf.989; PMID: 28949086. Freitas P, Aguiar C, Ferreira A, et al. Comparative analysis of four scores to stratify patients with heart failure and reduced ejection fraction. Am J Cardiol 2017;120:443–9. https://doi. org/10.1016/j.amjcard.2017.04.047; PMID: 28629552. Costanzo MR, Ronco C, Abraham WT, et al. Extracorporeal ultrafiltration for fluid overload in heart failure: current status and prospects for further research. J Am Coll Cardiol 2017;69:2428–45. https://doi.org/10.1016/j.jacc.2017.03.528; PMID: 28494980. Sica DA, Muntendam P, Myers RL, et al. Subcutaneous furosemide in heart failure: pharmacokinetic characteristics of a newly buffered solution. JACC Basic Transl Sci 2018;3: 25–34. https://doi.org/10.1016/j.jacbts.2017.10.001;

PMID: 30062191. 28. G ilotra NA, Princewill O, Marino B, et al. Efficacy of intravenous furosemide versus a Novel, pH-neutral furosemide formulation administered subcutaneously in outpatients with worsening heart failure. JACC Heart Fail 2018;6:65–70. https://doi.org/10.1016/j.jchf.2017.10.001; PMID: 29226816. 29. Greene SJ, Mentz RJ. Potential advantages of torsemide in patients with heart failure: more than just a ‘water pill’? Eur J Heart Fail 2018;20:471–3. https://doi.org/10.1002/ejhf.1024; PMID: 29082584. 30. Trippel TD, Van Linthout S, Westermann D, et al. Investigating a biomarker-driven approach to target collagen turnover in diabetic heart failure with preserved ejection fraction patients. Effect of torasemide versus furosemide on serum C-terminal propeptide of procollagen type I (DROP-PIP trial). Eur J Heart Fail 2018;20:460–70. https://doi.org/10.1002/ejhf.960; PMID: 28891228. 31. Mullens W, Verbrugge FH, Nijst P, et al. Rationale and design of the ADVOR (Acetazolamide in Decompensated Heart Failure with Volume Overload) trial. Eur J Heart Fail 2018;20:1591–600. https://doi.org/10.1002/ejhf.1307; PMID: 30238574. 32. Meani P, Gelsomino S, Natour E, et al. Modalities and effects of left ventricle unloading on extracorporeal life support: a review of the current literature. Eur J Heart Fail 2017;19(Suppl 2):84–91. https://doi.org/10.1002/ejhf.850; PMID: 28470925. 33. Gustafsson F, Rogers JG. Left ventricular assist device therapy in advanced heart failure: patient selection and outcomes. Eur J Heart Fail 2017;19:595–602. https://doi.org/10.1002/ejhf.779; PMID: 28198133. 34. Estep JD, Starling RC, Horstmanshof DA, et al. Risk assessment and comparative effectiveness of left ventricular assist device and medical management in ambulatory heart failure patients: results from the ROADMAP Study. J Am Coll Cardiol 2015;66:1747–61. https://doi.org/10.1016/ j.jacc.2015.07.075; PMID: 26483097. 35. Mehra MR, Naka Y, Uriel N, et al. A fully magnetically levitated circulatory pump for advanced heart failure. N Engl J Med 2017;376:440–50. https://doi.org/10.1056/NEJMoa1610426; PMID: 27959709. 36. Mehra MR, Goldstein DJ, Uriel N, et al. Two-year outcomes with a magnetically levitated cardiac pump in heart failure. N Engl J Med 2018;378:1386–95. https://doi.org/10.1056/ NEJMoa1800866; PMID: 29526139. 37. Starling RC, Moazami N, Silvestry SC, et al. Unexpected abrupt increase in left ventricular assist device thrombosis. N Engl J Med 2014;370:33–40. https://doi.org/10.1056/NEJMoa1313385; PMID: 24283197. 38. Campbell RT, Petrie MC, Jackson CE, et al. Which patients with heart failure should receive specialist palliative care? Eur J Heart Fail 2018;20:1338–47. https://doi.org/10.1002/ejhf.1240; PMID: 29952090.

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Advanced Heart Failure

Ultrafiltration in Acute Heart Failure Maria Rosa Costanzo Advocate Heart Institute, Naperville, Illinois, US

Abstract Congestion is the predominant cause of more than 1 million annual heart failure hospitalisations and recurrent fluid overload predicts poor outcomes. Unresolved congestion trumps serum creatinine increases in predicting adverse heart failure outcomes. No pharmacological approach for acute heart failure has reduced these deleterious consequences. Simplified ultrafiltration devices permit fluid removal in lower acuity hospital settings, but results regarding safety and efficacy have been variable. However, adjustment of ultrafiltration rates to patients’ vital signs and renal function has been associated with more effective decongestion and fewer heart failure events. Many aspects of ultrafiltration, including patient selection, fluid removal rates, venous access, prevention of therapyrelated complications and costs, require further investigation.

Keywords Diuretics, fluid overload, heart failure, ultrafiltration, venous congestion Disclosure: MRC served as the Principal Investigator of the Ultrafiltration Versus Intravenous Diuretics for Patients Hospitalized for Acute Decompensated Heart Failure (UNLOAD) and Aquapheresis Versus Intravenous Diuretics and Hospitalization for Heart Failure (AVOID-HF) clinical trials and her institution received a research grant related to the studies. MRC has also been a consultant for Axon Therapies, CHF-Solutions and Fresenius Medical Care. Received: 3 September 2018 Accepted: 10 January 2019 Citation: Cardiac Failure Review 2019;5(1):9–18. DOI: https://doi.org/10.15420/cfr.2018.29.2 Correspondence: Maria Rosa Costanzo, Advocate Medical Group Midwest Heart Specialists, Edward Heart Hospital, 4th Floor, 801 South Washington St, PO Box 3226, Naperville, IL 60566, US. E: mariarosa.costanzo@advocatehealth.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.

Approximately 90% of the more than 1 million yearly heart failure hospitalisations in the US and Europe are a result of symptoms and signs of fluid overload and are associated with readmission rates of 24% and 50% at 30 days and 6 months, respectively.1,2 Recurrent heart failure-related hospitalisations have uniformly been associated with worse outcomes, independent of age and renal function.3 Abnormal fluid handling begins in the asymptomatic stages of heart failure and leads to physiological abnormalities in multiple organ systems.4–9 Elevations of central venous pressure are rapidly transmitted to the renal veins, causing increased interstitial and tubular hydrostatic pressures, which decrease net glomerular filtration in both acute and chronic heart failure.8,10–12 The consistent finding that inadequate reduction of fluid excess in acute heart failure patients trumps increases in serum creatinine in predicting poor outcomes underscores the importance of effective decongestion. If a decrease in intravascular volume by fluid removal causes small transient increases in serum creatinine, achieving euvolaemia may still be essential to protect the kidneys in the long term.13,14

The clinical hallmarks of diuretic resistance are insufficient symptom relief, higher risk of in-hospital worsening of heart failure, increased mortality after discharge and a threefold increase in rehospitalisation rates.16 Among more than 50,000 patients enrolled in the Acute Decompensated Heart Failure National Registry (ADHERE) and treated with conventional diuretic therapy, only 33% lost 2.3 kg or more, 16% gained weight during hospitalisation and almost 50% were discharged with unresolved congestion.17 Irrespective of diuretic strategy, 42% of acute heart failure subjects in the Diuretic Optimization Strategies Evaluation (DOSE) trial reached the composite endpoint of death, rehospitalisation, or A&E visit at 60 days.18 All other pharmacological approaches studied as adjuncts or alternative therapies for acute heart failure have failed to improve long-term outcomes.19–21 Therefore, alternative and more effective methods of fluid removal are critically needed. One promising therapy is extracorporeal ultrafiltration (UF). 22 Greater access to UF has been facilitated by the development of simplified devices that do not require specialised technicians or acute care settings.22

Diuretic Resistance in Heart Failure

Process of Fluid Removal by Ultrafiltration, Haemofilters, Pumps and Vascular Access

Diuretics, the most widely used drugs to reduce fluid excess, become increasingly ineffective with heart failure progression as a result of impaired absorption, decreased renal blood flow, azotaemia and proteinuria, all resulting in reduced levels of active diuretics in the tubular lumen.15,16 Several definitions of diuretic resistance and responsiveness have been proposed.16

UF consists of the production of plasma water from whole blood across a semipermeable membrane (haemofilter) in response to a transmembrane pressure gradient.23 The newer, simplified UF devices afford the advantages of small size, portability, low blood flow rates and an extracorporeal blood volume below 50 ml.24 They can provide a wide range of UF rates (0–500 ml/h) and do not mandate admission to

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Acute Heart Failure Figure 1A: Ultrafiltration Circuit

Table 1: Comparative Characteristics of Loop Diuretics and Isolated Ultrafiltration

Venous pressure sensor Ultrafiltrate pressure sensor

Vascular access Air detector

Blood leak detector Haemofilter

Ultrafiltrate pump

Arterial pressure sensor

Blood pump Ultrafiltrate weight scale

Blood volume sensor

The console controls blood removal rates and extracts ultrafiltrate at a maximum rate set by the clinician. Blood is withdrawn from a vein through the withdrawal catheter (red), connected by tubing to the blood pump. Blood passes through the withdrawal pressure sensor before entering the blood pump tubing loop. After exiting the blood pump, blood passes through the air detector and enters the haemofilter (made of a bundle of hollow fibres) through a port on the bottom, exits through the port at the top of the filter, and passes through the infusion pressure sensor before returning to the patient (blue). Ultrafiltrate sequentially passes through the ultrafiltrate pressure sensor, pump, and collecting bag suspended from the weight scale. A haematocrit sensor is located on the withdrawal line. Source: Costanzo et al. 2017.63 Reproduced with permission from Elsevier.

Figure 1B: Ultrafiltration Circuit One-way Needle-free valve sampling

Air detector

Air free pressure dome

Blood leakage detector

Pump chamber

Single lumen SuperCath cannula with side holes Blood detector

Needle-free One-way Air sampling valve detector

Haematocrit

This ultrafiltration system requires only a single-lumen, multi-hole, small (18-gauge) cannula inserted in a peripheral vein of the arm. A syringe pump drives the blood inside the extracorporeal circuit, which includes two check valves that allow the blood to move from the vein to the filter and then return to the same vein through alternate flows that can be independent. The priming volume of 50 ml and the reduced contact surface between blood and tubing set ensures minimal blood loss if circuit clots and reduced heparin requirements. Source: Costanzo et al. 2017.63 Reproduced with permission from Elsevier.

intensive care units. Vascular access can be achieved through either a peripheral or a small central vein such as the internal jugular or subclavian veins. The characteristics of two of these devices are shown in Figure 1.

Differences in Fluid Removal with Ultrafiltration Versus Diuretics Loop diuretics selectively block the Na+/K+/2Cl− cotransporter in the luminal membrane of the medullary thick ascending loop of Henle. This builds a concentration gradient towards the renal papilla, which is essential to concentrate the urine. This is why loop diuretics lead to the production of hypotonic urine.23

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Isolated Ultrafiltration

Direct neurohormonal activation

No direct neurohormonal activation

Elimination of hypotonic urine

Removal of isotonic plasma water

Unpredictable elimination of sodium and water

Precise control of rate and amount of fluid removal

Development of diuretic resistance with prolonged administration

Restoration of diuretic responsiveness

Risk of hypokalemia and hypomagnaesemia

No effect on plasma concentration of potassium and magnesium

Peripheral venous access

Peripheral or central venous catheter

No need for anticoagulation

Need for anticoagulation

No extracorporeal circuit

Need for extracorporeal circuit

Source: Costanzo et al. 2017.63 Reproduced with permission from Elsevier.

In contrast, because the ultrafiltrate is almost isotonic with plasma, approximately 134–138 mmol of sodium are removed with each litre of ultrafiltrate.23 Thus, for any amount of fluid withdrawn, more sodium is likely to be removed with UF than with diuretics.24,25 Furthermore, changes in intravascular volume in response to diuretics are unpredictable.8,23,26 As opposed to loop diuretics-induced renin release by the afferent arteriole, neurohormonal activation only occurs with UF if fluid removal exceeds the plasma refilling rate, causing intravascular volume depletion (Table 1).25,27,28 Plasma water movement from the interstitium to the vasculature varies between patients according to serum albumin concentration, that is, serum oncotic pressure and capillary permeability. Although rates of UF ≤250 ml/h are less likely to exceed the plasma-refilling rate, the pace of fluid removal should be adjusted to patients’ vital signs, serum creatinine and urine output to preserve blood volume and haemodynamic stability (Figure 2).27,28

Randomised Controlled Trials of Ultrafiltration

Syringe pump

Ultrafiltration

Loop Diuretics

The fact that refill of the intravascular space from the oedematous interstitium decreases as fluid is removed led to the hypothesis of the Ultrafiltration Versus Intravenous Diuretics for Patients Hospitalised for Acute Decompensated Heart Failure (UNLOAD) trial that initiation of UF before diuretic administration might be superior to IV loop diuretics in fluid overloaded heart failure patients. 29 Compared with standard care, the UF group had greater weight loss and similar improvement in dyspnoea score (the co-primary endpoints) at 48 hours. The percentage of patients with increases in serum creatinine levels of 0.3 mg/dl or more was similar in the UF and control groups up to 90 days. 29 There was no between-group difference in the duration of the index hospitalisation. In UNLOAD, 90-day heart failure events were a pre-specified secondary endpoint, and the investigators determined whether these were related to worsening heart failure or not. Because UNLOAD did not have an independent clinical event committee to adjudicate whether an event was heart failure-related or not, the possibility of patient or investigator bias cannot be excluded. Nevertheless, compared with standard care, at 90 days patients treated with UF had 52% fewer unscheduled visits, 44% fewer heart failure-related rehospitalisations and a 63% reduction in rehospitalisation days. Limitations of the UNLOAD trial include lack of treatment targets, blood volume assessments, cost analysis and adjudication of events by an independent clinical event committee.

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Ultrafiltration in Acute Heart Failure Figure 2: Proposed Mechanisms of Benefit of Ultrafiltration Chronic heart failure

Decreased cardiac output

RAAS activation SNS activation Renal hypoperfusion Non-osmotic AVP release

Hypotonic urine Diuretics

Decrease water clearance + Increased sodium reabsorption

Volume overload

Diuretic resistance Braking phenomenon, DT adaptation, uraemic anions, proteinuria

Ultrafiltration Water flux contains sodium (nearly) isotonic to plasma water

Haemodynamically driven reduction in GFR (“pre-renal”)

Advantages of ultrafiltration

NGAL, cystatin-C, KIM-1 If sCr rises Ischaemic renal tubular injury +NGAL, +cystatin-C, +KIM-1

Predictable removal of sodium and fluids No direct neurohormonal activation No changes in electrolytes, particularly K and Mg

Plasma sodium ~140 mmol/l

1 litre of ultrafiltrate contains ~140 mmol sodium, equivalent to ~8 g of salt

Sodium removal from patient, no concentration changes

Shouldn’t this be redrawn?

Of more than 1 million heart failure hospitalisations in the US and Europe, >90% are a result of signs and symptoms of fluid overload. This healthcare burden is aggravated by the fact that recurrent congestion worsens patients’ outcomes regardless of age and renal function. Abnormal haemodynamics, neurohormonal activation, excessive tubular sodium reabsorption, inflammation, oxidative stress and nephrotoxic medications drive the complex interactions between heart and kidney (cardio-renal syndrome). Loop diuretics are used in most congested patients. As a result of their mechanism and site of action, loop diuretics lead to the production of hypotonic urine and may contribute to diuretic resistance (braking phenomenon, distal tubular adaptation and increased renin secretion in the macula densa). Increased uraemic anions and proteinuria also impair achievement of therapeutic concentrations at their tubular site of action. Ultrafiltration is the production of plasma water from whole blood across a haemofilter in response to a transmembrane pressure. Therefore, ultrafiltration removes isotonic fluid without direct activation of the renin-angiotensin-aldosterone system, provided that fluid removal rates do not exceed capillary refill. Any method of fluid removal may cause an increase in serum creatinine. However, in the absence of evidence of renal tubular injury, e.g. augmented urinary concentration of neutrophil gelatinase-associated lipocalin, this increase represents a physiological decrease in estimated glomerular filtration rate as a result of decreased intravascular volume from fluid removal. AVP = arginine vasopressin; DT adaptation = distal tubular adaptation; GFR = glomerular filtration rate; NGAL = neutrophil gelatinase-associated lipocalin; RAAS = renin-angiotensin-aldosterone system; SNS = sympathetic nervous system.

In the Effects of ULTRAfiltration vs DIureticS on clinical, biohumoral and haemodynamic variables in patients with deCOmpensated heart failure (ULTRADISCO) study, at 36 hours, UF patients had greater reduction in body weight, signs and symptoms of heart failure, aldosterone and N-terminal pro B-type natriuretic peptide levels, and systemic vascular resistance, as well as greater improvements in cardiac performance, compared with the diuretic group.30 The Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF) compared the effects of UF, intended to be delivered at a fixed rate of 200 ml/h, with those of stepped pharmacological therapy (consisting of adjustable doses of IV loop diuretics, thiazide diuretics, vasodilators and inotropes) in acute heart failure patients with pre-randomisation increases in serum creatinine. 31,32 The primary endpoint of CARRESS-HF was the bivariate change in serum creatinine and body weight from baseline to 96 hours after randomisation.31,32 According to the CARRESS-HF design manuscript, this primary endpoint assumes that weight loss is a measure of effective fluid removal and that an increase in serum creatinine represents acute tubular injury.30 In CARRESS-HF, both groups lost a similar amount of weight but increases in serum creatinine were greater with UF.32 In addition, a higher percentage of patients in the UF group experienced serious adverse events.32 However, the fact that 37 patients (39%) randomised to the UF group received only diuretics, or were given these drugs before the assessment of the primary endpoint at 96 hours, impairs adjudication of adverse events to one or the other therapy.32

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In heart failure, increases in serum creatinine (0.3 mg/dl or more) have been equated to actual renal tubular damage, which portend adverse long-term prognosis, but transient increases in serum creatinine can merely reflect a haemodynamically-driven decrease in estimated glomerular filtration rate (eGFR) similar to that occurring with angiotensin converting enzyme inhibitors. Notably, recent studies show that transient increases in serum creatinine may indicate more complete decongestion and are associated with better post-discharge outcomes.4,14,33 The per-protocol analysis of CARRESS-HF was recently published.34 With the inclusion of only subjects who received their randomised treatment, UF was associated with higher cumulative fluid loss, net fluid loss and relative reduction in weight compared with stepped pharmacological therapy. The UF group had higher serum creatinine and blood urea nitrogen by 72 hours.34 The per-protocol analysis of CARRESS-HF also confirms the astonishing finding of the primary publication that 90% of the study’s subjects had unresolved congestion at the time of evaluation of the primary endpoint.32 It remains difficult to discern whether the inability to achieve adequate decongestion was a result of intrinsic ineffectiveness of the CARRESSHF’s stepped pharmacological therapy strategy, or of inadequate adherence of the investigators to the study’s protocol. In contrast, causes for the poor performance of UF, which could be surmised in CARRESS-HF’s intention-to-treat analysis, are laid bare by the perprotocol analysis. At 96 hours – the time of evaluation of the primary endpoint – only 30 of 94 subjects (32%) were still undergoing UF,

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Advanced Heart Failure compared with the stepped pharmacological therapy arm, in which 76 of 94 (80%) remained on treatment. For 28 of 64 patients (43%) no longer on UF by 96 hours, the reason for therapy discontinuation is described as “MD decision”. Because such choice is separate from the other listed causes of therapy discontinuation, including achievement of optimal volume status, haemodynamic instability, evidence of volume depletion, increased serum creatinine, filter clotting and vascular access failure, the suspicion arises that UF was prematurely terminated either for convenience, lack of familiarity with the therapy, or both.34 The unprecedented incidence of filter clotting, which occurred in 23 of 64 patients (36%) no longer on UF at 96 hours is also disconcerting. The estimated UF rates were 83 (46–109) ml/h; 140 (83–178) ml/h; 107 (32–178) ml/h and 70 (21–115) ml/h for each sequential 24-hour period from baseline to 96 hours. Low UF rates should reduce, rather than increase, filter clotting by decreasing filtration fraction.35 Therefore, the most plausible culprit of filter clotting was the use of excessively low blood flows, which augment the risk of haemofilter clotting by increasing the filtration fraction. Notably, UF rates at 48 and 72 hours were higher than those used at 24 hours. This fact suggests disregard for the physiological principles of fluid shift between the interstitium and the vascular space described by Starling.36 In the UNLOAD trial UF, used at rates higher than those reported for CARRESS-HF, achieved better decongestion compared with pharmacological therapy, without greater increases in serum creatinine.29 This apparent paradox can be explained by considering that in CARRESS-HF, by protocol, UF rates were not tailored to individual patients baseline renal function, vital signs and urine output. The low average UF rates in CARRESS-HF may be misleading as they may not reflect either lingering congestion in the subjects who might have needed more fluid extraction or overzealous fluid removal in individuals at higher risk of hypovolaemia.32,34 With awareness of the inherent limitations of any per-protocol analysis, the results of the CARRESS-HF per-protocol analysis differ significantly from those of the intent-to-treat analysis and corroborate the key findings of UNLOAD, which demonstrated more effective decongestion with UF than with pharmacological therapies.29 However, in contrast to UNLOAD, which showed greater reductions in heart failure events in the UF arm compared with the diuretic arm, the per-protocol analysis of CARRESS-HF showed no differences in 60-day outcomes between the UF and pharmacological arms.29,32,34 This finding is hardly surprising because 90% of the CARRESS-HF population was not adequately decongested when the primary endpoint was evaluated. In the Continuous Ultrafiltration for Congestive Heart Failure (CUORE) trial, 27 UF-treated patients had fewer heart failure-related rehospitalisations during one-year follow up than the 29 standard care subjects, despite similar weight loss at discharge.37 In CUORE, diuretics were continued during UF because of the belief that this strategy may increase sensitivity to diuretics by augmenting urinary sodium excretion.37 The wisdom of removing the ‘diuretic holiday’, during which loop diuretic-induced neurohormonal activation does not occur, is controversial.29,38,39 The Aquapheresis versus Intravenous Diuretics and Hospitalization for Heart Failure (AVOID-HF) trial tested the hypothesis that patients hospitalised for heart failure treated with adjustable UF would have

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a longer time to first heart failure event within 90 days than those receiving adjustable IV loop diuretics.40 The AVOID-HF trial, designed as a multicentre, one-to-one randomised study of 810 hospitalised heart failure patients, was terminated unilaterally and prematurely by the sponsor (Baxter International) after enrolment of 224 patients (27.5%). Both therapies were adjusted according to patients’ vital signs, renal function and urine output (Figures 3 and 4).41 Patients in the adjustable UF group had a longer time to first heart failure event than patients in the adjustable diuretics group (62 versus 34 days; p=0.106), but this difference was not statistically significant. However, there was enough evidence to show that within 30 days after discharge patients in the adjustable UF group had fewer heart failure and cardiovascular events than the adjustable diuretics group.40 Importantly, these events were adjudicated by an independent committee blinded to randomised therapy.40 The finding of similar renal function changes in the two groups are consistent with that of UNLOAD.29,40 In AVOID-HF, the average UF rate of 138 ml/h and therapy was delivered over an average of 70 hours.40 Adjustments of UF rates to individual patients’ haemodynamics and renal function may explain the lack of difference in serum creatinine between groups, despite a larger net fluid loss with UF.40 Restoration of diuretic responsiveness may be a key mechanism by which UF delays recurrence of heart failure events.40 Significantly more patients in the UF group than in the diuretics group (31% versus 17%; p=0.018) experienced adverse events of special interest (infection requiring IV antibiotics, bleeding requiring transfusion, symptomatic hypotension requiring vasopressor agents or rapid fluid replacement, drop in haemoglobin greater than 3 g/ dl and acute coronary syndrome requiring intervention). Serious therapy-related adverse events occurred at higher rates in the UF group than in the diuretics group (14.6% versus 5.4%; p=0.026).40 In AVOID-HF, UF-related adverse events were fewer than in CARRESS-HF, but the excess of therapy-related complications with UF is a serious concern.32,40 Further study of the specifics of providing UF is needed to identify strategies aimed at minimising access-related and other potentially preventable complications.32,40

Knowledge Gaps in the Use of Ultrafiltration in Acute Heart Failure Selection of Potential Candidates Patient selection and fluid removal targets for UF remain incompletely understood.32,40 Current practice guidelines recommend the use of UF only for patients with a degree of diuretic resistance similar to that of CARRESS-HF subjects.32,42,43 In AVOID-HF, fine-tuning of UF rates in response to vital signs, renal function or urine output resulted in greater net fluid loss and was associated with fewer 30-day heart failure events, without a greater increase in serum creatinine levels, compared with the adjustable diuretic group.40 These observations underscore the critical need for additional investigation of UF as both first-line and rescue therapy, provided that UF rates are adjusted in each patient in response to changes in vital signs and renal function.32,40 As a result of the potential complications and cost of UF, it should not be used in all patients with acute heart failure. For example, patients with de novo heart failure or those not receiving daily diuretics are likely to respond to IV diuretics. The lingering question is, which

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Ultrafiltration in Acute Heart Failure Figure 3A: Adjustable Ultrafiltration Guidelines Employed by the AVOID-HF investigators: Guidelines for the Adjustment of Ultrafiltration Therapy Choose initial UF rate

SBP 100–120 mmHg: 200 cc/h

SBP <100 mmHg: 150 cc/h

SBP >120 mmHg: 250 cc/h

Decrease initial UF rate by 50 cc/hour if ANY of the following are present: • RV >LV dysfunction • sCr increase 0.3 mg/dl above recent baseline • Baseline sCr >2.0 mg/dl • History of instability with diuresis or UF in the past

Every 6 hours, evaluate recent BP, HR, UO, net intake/output, sCr

• sCr rise >30% or 0.4 mg/dl compared to prior measurement • Resting SBP decreases >20 mmHg compared to prior 6 hours, but remains >80 mmHg • UO <125 cc/h • Resting HR increase >30 BPM compared to prior 6 hours or >120 BPM

• sCr rise >15% or 0.2 mg/dl compared to prior measurement • Resting SBP decreases >10 mmHg compared to prior 6 hours, but remains >80 mmHg • UO drops >50% compared to prior 6 hours, but remains >125 cc/h • Resting HR increase >20 BPM compared to prior 6 hours but remains <120 BPM

Strongly consider holding UF and checking STAT sCr

Consider decreasing UF rate by 50 cc/hour and checking STAT sCr

If UF held, re-evaluate after laboratory values are available. If haemodynamics are stable and sCr has plateaued, then consider restarting UF at 50–100 cc/hour less than previous rate If persistent, volume overload present, then consider • IV inotropes in patients with LVEF <40% RV systolic dysfunction • Weaning vasodilators, especially in patients with HFpEF • RHC

Resolution of congestion (all of the following):

Best achievable ‘dry weight’ has been achieve

• JVP <8 cm H2O • No orthopnoea • Trace or no peripheral oedema

• Evidence of proof tolerance of fluid removal AND • UF rate <100 cc/h or net negative <1 l/24h Persistent elevation in sCr >1.0 mg/dl above baseline at start of IV diuretic treatment

Persistent haemodynamic instability

Any of these present None of these present

Consider completion of UF therapy

BP = blood pressure; HFpEF = heart failure with preserved ejection fraction; HR = heart rate; JVP = jugular venous pressure; LV = left ventricular; LVEF = left ventricular ejection fraction; RHC = right heart catheterisation; RV = right ventricular; SBP = systolic blood pressure ; sCr = serum creatinine; UF = ultrafiltration; UO = urine output. Source: Costanzo et al. 2017.63 Reproduced with permission from Elsevier.

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Advanced Heart Failure Figure 3B: Guidelines for the Completion of Ultrafiltration Therapy After completion of UF therapy

If satisfactory ‘dry weight’ has been reached AND sCr is stable: • Initiate oral loop diuretic therapy with goal to keep net even • GDMT

If sCr, haemodynamics or UO are NOT stable: • Hold diuretics until creatinine is stable for a minimum of 12 hours and then: • If ‘dry weight’/adequate decongestion has been reached then initiate oral diuretics with a goal to keep net even • If ‘dry weight’/adequate decongestion has NOT been reached then initiate IV diuretics • If elevated sCr or haemodynamic instability present, then consider a bolus of IV fluid

Guidelines for the completion of ultrafiltration therapy: 40 mg furosemide = 1 mg bumetanide or 10 mg torsemide. See also: Costanzo et al. 201541 and Costanzo et al. 2016.40 GDMT = guideline-directed medical therapy; Cr = serum creatinine; UF = ultrafiltration; UO = urine output. Source: Costanzo et al. 2017.63 Reproduced with permission from Elsevier.

patients who develop acute heart failure despite daily oral diuretics should receive UF instead of IV diuretics? To date, all studies of UF in heart failure patients have used only clinical signs and symptoms of congestion, both as inclusion criteria and fluid removal targets. This is challenging, given the poor correlation between clinical signs and objective measures of increased filling pressures.44 The hypothesis that UF may be especially effective in patients with urinary sodium concentrations <100 mEq after a specified dose of IV diuretics should be tested in randomised trials. A single nonrandomised prospective cohort study showed similar effects of UF in heart failure with reduced versus preserved left ventricular ejection fraction.45 However, because these two heart failure types are pathophysiologically and clinically different, response to UF in the two heart failure settings should be evaluated in controlled trials.

Fluid Removal Targets and Monitoring of Ultrafiltration Therapy An important general recommendation is that once an initial UF rate is decided it should be either maintained or reduced, because capillary refill from the interstitium decreases as fluid is removed.27 While optimal rate and duration of UF must be individualised, UF rates >250 ml/h are not typically recommended. 40,41 Patients with predominantly right sided, or preserved ejection fraction heart failure are more susceptible to intravascular volume depletion and may only tolerate UF rates ≤100 ml/h.46 Clinical experience suggests that UF is better tolerated when conducted with low fluid removal rates over prolonged periods of time.32,40 Typically, patients’ current weight is compared with the weight recorded in the absence of congestive signs and symptoms and this ‘dry weight’ is used as the target for fluid removal. Given the detrimental renal effects of increased central venous pressure,8,11,12,27,28,47 controlled studies may evaluate whether fluid removal by UF should be aimed at achieving certain central venous pressure targets, i.e. ≤10 mmHg. However, central venous pressure is poorly correlated with measured blood volume and, in the context of UF, fluid overload may still be present despite achievement of a low cardiac filling pressure.48 Instead of invasive haemodynamic measurements, ultrasonography can help estimate central venous pressure with evaluation of the respiratory excursions of the diameter of the inferior vena cava.49 However, the reliability of ultrasonography strictly depends on operator’s skill and patient’s respiratory effort.49

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Baseline pulmonary artery diastolic pressure consistently predicts heart failure events. Interventions aimed at reducing pulmonary artery pressures to pre-specified target ranges have effectively reduced heart failure events without significant renal function changes.50,51 The CardioMEMS™ HF System (Abbott) measures pulmonary artery pressures as frequently as clinically indicated. In patients implanted with the CardioMEMS device, it is conceivable that fluid can be removed by UF until achievement of the target range of pulmonary artery pressures that effectively reduced heart failure events.50,51

Blood Volume and Fluid Excess Assessment The haematocrit is the ratio of the volume occupied by red blood cells to that of the whole blood. Since red blood cell mass does not change in the short term, unless bleeding occurs, fluctuations in haematocrit reflect changes in intravascular volume.52 Online haematocrit sensors permit continuous estimation of blood volume changes during UF and can be programmed to stop fluid removal if the haematocrit exceeds a threshold set by the clinician; for example, 5–7%, and resume therapy when the haematocrit value falls below the pre-specified limit, indicating an adequate refilling of the intravascular volume from the interstitial space.52 However, because numerous factors, such as change in body position, can alter haematocrit values, physical, laboratory and haemodynamic variables should be concomitantly assessed to determine the appropriate UF rates and the amount of fluid that should be removed.52 Bioimpedance vector analysis is based on the principle that wholebody impedance to an alternating current reflects total body water (r=0.996).53 Measurements of bioimpedance vector analysis require two pairs of electrodes placed on the wrist and ankles and the application of a 50 kHz alternating microcurrent (CardioEFG, EFG Diagnostics).53 Bioimpedance vector analysis could be used to determine fluid status before treatment initiation and serially to guide the amount and rate of fluid removal. Diaphoresis, hirsutism, incorrect electrode placement, cutaneous alterations, or improper electrical grounding can affect the reliability of bioimpedance vector analysis measurements. Bioimpedance spectroscopy is also being investigated in patients with heart failure.54 Unfortunately, no existing bioimpedance-based method can differentiate intravascular from interstitial extracellular fluid volume, a distinction that is critical for safe and effective fluid removal.53,54

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Ultrafiltration in Acute Heart Failure Figure 4A: Adjustable Loop Diuretic Guidelines Employed by the AVOID-HF Investigators: Initiation of Loop Diuretics Initial diuretics regimen

UO >5 l/day

UO 3–5 l/day

Reduce current diuretic regimen if desired*

UO <3 l/day

Continue current diuretic regimen

See Figure 3A

At 24 hours if persistent volume overload present

UO >5 l/day

UO 3–5 l/day

Reduce current diuretic regimen if desired*

UO <3 l/day

Continue current diuretic regimen

See Figure 3A

At 48 hours if persistent volume overload present

UO >5 l/day

UO 3–5 l/day

Reduce current diuretic regimen if desired*

UO <3 l/day

Continue current diuretic regimen

See Figure 3A and consider: a. IV inotropes if SBP <110 mmHg and LVEF <40% or RV systolic dysfunction b. NTG or nesiritide if SBP >120 mmHg (any LVEF) and severe symptoms

At 72 hours if persistent volume overload present

UO >5 l/day

UO 3–5 l/day

Reduce current diuretic regimen if desired*

UO <3 l/day

Continue current diuretic regimen

See Figure 3A and consider: a. IV inotropes if SBP <110 mmHg and LVEF <40% or RV systolic dysfunction b. NTG or nesiritide if SBP >120 mmHg (any LVEF) and severe symptoms c. Right heart catheterisation

Repeat 72 hours step until treatment complete

Suggested dose

Current dose Timepoint

Loop (mg/day)

Thiazide

Loop

Thiazide

≤80

+ or –

40 mg IV bolus + 5 mg/h

81–160

+ or –

80 mg IV bolus + 10 mg/h

5 mg metolazone four times daily

161–240

+ or –

80 mg IV bolus + 20 mg/h

5 mg metolazone twice daily

>240

+ or –

80 mg IV bolus + 30 mg/h

5 mg metolazone twice daily

*Evaluation of blood pressure, heart rate, urine output and net intake/output is performed every 6 hours; evaluation of serum chemistries is performed every 12 hours. Consider decreasing or holding diuretic dose if: Serum creatinine rises by 30% or ≥0.4 mg/dl (whichever is less) versus prior measurement; resting systolic blood pressure decreases >20 mmHg compared with prior 6 hours or drops <80 mmHg; or resting heart rate >30 BPM, compared with prior 6 hours or >120 BPM. LVEF = left ventricular ejection fraction; NTG = nitroglycerin; RV = right ventricular; SBP = systolic blood pressure; UO = urine output. Source: Costanzo et al. 2017.63 Reproduced with permission from Elsevier.

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Advanced Heart Failure Figure 4B: Guidelines for the Completion of Adjustable Loop Diuretics Consider completion of therapy if ONE of the following occurs:

Resolution of congestion (all of the following): • JVP <8 cm H2O • No orthopnoea • Trace or no peripheral oedema

Best achievable ‘dry weight’ has been achieved • Haemodynamic evidence of poor tolerance of fluid removal by persistent haemodynamic changes AND • Net negative <1 l/ 24 h

Persistent haemodynamic instability

Persistent elevation in sCr >1.0 mg/dl above baseline at the start of IV diuretic treatment Source: Costanzo et al. 2017.63 Reproduced with permission from Elsevier. JVP = jugular venous pressure; sCr = serum creatinine.

Figure 4C: Guidelines for Management After Completion of Adjustable Loop Diuretics After completion of IV loop diuretic therapy

If satisfactory “dry weight” has been reached AND sCr is stable: • Initiate oral loop diuretic therapy with goal to keep net even • GDMT

If sCr, haemodynamics or UO are NOT stable: • Hold diuretics until sCr is stable for a minimum of 12 hours and then initiate oral diuretics as above • If elevated sCr or haemodynamic instability present, then consider a bolus of IV fluid

See also: Costanzo et al. 201541 and Costanzo et al. 2016.40 Source: Costanzo et al. 2017.63 Reproduced with permission from Elsevier. GDMT = guideline-directed medical therapy; sCr = serum creatinine; UO = urine output.

The measurement of blood volume using albumin labelled with iodine-131 is accurate, but the six to nine blood draws needed to create the dilution curve make it impractical for the serial assessments needed during fluid removal.55 The lack of optimal methods for the estimation of blood volume and fluid excess underscores the critical need for research in this area.

Biomarkers The use of natriuretic peptides to assess volume status and guide decongestive therapies cannot be recommended because fluid overload is not the sole cause of increases in the levels of these biomarkers.56 The removal of fluid to achieve pre-specified natriuretic peptide levels is untested in acute heart failure. Serum creatinine is used to guide fluid removal because of the assumption that its level indicates both renal filtration and tubular status. However, serum creatinine was established and validated as a measure of renal function only at the point of steady state. Therefore, it is puzzling that serum creatinine is considered an accurate measure of renal function in patients with acute heart failure, where the rates of creatinine production and excretion can be altered. Screening of 3.8 million patients revealed that 75% of serum creatinine elevations are a physiologically appropriate response to decreases in intravascular fluid volume and do not reflect acute renal damage.57 More importantly, serum creatinine can be normal with true tubular injury because measurable changes are delayed.58 Typically, haemodynamically-driven increases in serum creatinine can

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be reversed with treatment in 24 to 72 hours, whereas changes as a result of acute tubular damage may persist for weeks.59 As such, the duration of serum creatinine increase is more predictive of outcomes than the magnitude of this biomarker’s elevation.59 Indeed, the use of increases in serum creatinine as an endpoint for acute heart failure trials has been questioned. In DOSE, increase in subjects’ serum creatinine from baseline to 72 hours was associated with lower risk for the composite outcome of death or heart failure events. In contrast, there was a strong correlation between improved renal function during hospitalisation and poor 60-day outcomes.60 Neutrophil gelatinase-associated lipocalin (NGAL) is secreted in the urine and the plasma by a damaged kidney within 3 hours of pathogenic events such as sepsis, nephrotoxins, obstruction or ischaemia. Furthermore, the amount of secreted NGAL (from 20 ng/ml up to 5 μg/ml) was proportional to the severity and time to resolution of the causative event.58 Evidence suggests NGAL is not expressed when serum creatinine increases as a result of volume depletion.61 In future, urinary levels of NGAL and other biomarkers of tubular injury may help to distinguish a rise in serum creatinine as a result of a haemodynamically mediated decrease in eGFR versus true tubular injury.57

Suggestions for Future Studies of Ultrafiltration Priority should be given to mechanistic studies, including evaluation of diuretic responsiveness at baseline, during and after fluid removal using the measures described in this article.16 Haemodynamic measurements that reflect fluid status, for example central venous

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Ultrafiltration in Acute Heart Failure pressure and pulmonary artery diastolic pressure, should also be performed at baseline and throughout therapy. Specific haemodynamic targets indicative of optimal fluid status should be established in individual patients, similar to the strategies used to guide medication adjustment in studies of pulmonary artery pressure sensors.50,51 Different UF rates should be tested in terms of their ability to reach these haemodynamic targets without causing renal tubular damage, as detectable by increase in urine levels of biomarkers such as NGAL. 57,58,61,62 This will require simultaneous measurement of the selected haemodynamic values and biomarker levels capable of differentiating rises in serum creatinine as a result of decreases in eGFR produced by intravascular fluid removal, from those reflective of renal injury. Serial measurements of urine and ultrafiltrate sodium content (non-invasive, inexpensive and readily available) may also help to better characterise and compare the amount and pattern of sodium extraction during UF therapy and conventional diureticbased regimens. The results of mechanistic studies are essential to determine how fluid removal rates and amounts should be adjusted in individual subjects of future controlled trials, that is, ‘precision’ fluid removal. Development of vascular accesses and UF device components that increase the efficiency and safety of the therapy is also critical. The device- and therapy-related adverse events observed in previous trials should undergo careful re-evaluation to determine which were preventable or related to operator experience versus those that were inherent to how therapy was delivered or were unpredictable. 32,40

mbrosy AP, Fonarow GC, Butler J, et al. The global health A and economic burden of hospitalizations for heart failure: lessons learned from hospitalized heart failure registries. J Am Coll Cardiol 2014;63:1123–33. https://doi.org/10.1016/ j.jacc.2013.11.053; PMID: 24491689. 2. Crespo-Leiro MG, Anker SD, Maggioni AP, et al. European Society of Cardiology Heart Failure Long-Term Registry (ESCHF-LT): 1-year follow-up outcomes and differences across regions. Eur J Heart Fail 2016;18:613–25. https://doi.org/10.1002/ ejhf.566; PMID: 27324686. 3. Setoguchi S, Stevenson LW, Schneeweiss S. Repeated hospitalizations predict mortality in the community population with heart failure. Am Heart J 2007;154:260–6. https://doi.org/10.1016/j.ahj.2007.01.041; PMID: 17643574. 4. McKie PM, Schirger JA, Costello-Boerrigter LC, et al. Impaired natriuretic and renal endocrine response to acute volume expansion in pre-clinical systolic and diastolic dysfunction. J Am Coll Cardiol 2011;58:2095–103. https://doi.org/10.1016/ j.jacc.2011.07.042; PMID: 22051332. 5. Peacock WF, De MT, Fonarow GC, et al. Cardiac troponin and outcome in acute heart failure. N Engl J Med 2008;358: 2117–26. https://doi.org/10.1056/NEJMoa0706824; PMID: 18480204. 6. Verbrugge FH, Bertrand PB, Willems E, et al. Global myocardial oedema in advanced decompensated heart failure. Eur Heart J Cardiovasc Imaging 2017;18:787–94. https://doi.org/10.1093/ ehjci/jew131; PMID: 27378769. 7. Verbrugge FH, Dupont M, Steels P, et al. The kidney in congestive heart failure: ‘are natriuresis, sodium, and diuretics really the good, the bad and the ugly?’. Eur J Heart Fail 2014;16:133–42. https://doi.org/10.1002/ejhf.35; PMID: 24464967. 8. Braam B, Cupples WA, Joles JA, et al. Systemic arterial and venous determinants of renal hemodynamics in congestive heart failure. Heart Fail Rev 2012;17:161–75. https://doi. org/10.1007/s10741-011-9246-2; PMID: 21553212. 9. Ronco C, Haapio M, House AA et al. Cardiorenal syndrome. J Am Coll Cardiol 2008;52:1527–39. https://doi.org/10.1016/ j.jacc.2008.07.051; PMID: 19007588. 10. Firth JD, Raine AE, Ledingham JG. Raised venous pressure: a direct cause of renal sodium retention in oedema? Lancet 1988;1:1033–5. https://doi.org/10.1016/S01406736(88)91851-X; PMID: 2896877. 11. Damman K, van Deursen VM, Navis G, et al. Increased central venous pressure is associated with impaired renal

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Only after these issues have been satisfactorily addressed should a carefully designed, adequately powered study be considered to prospectively compare UF with pharmacological fluid removal therapies. All treatments should be tailored to individual patients’ haemodynamic and renal status. In addition, the study’s follow-up period should be long enough to permit the evaluation of morbidity (rehospitalisations) and mortality. Future trials should evaluate whether higher costs of mechanical fluid removal during the index hospitalisation are offset by the savings resulting from fewer heart failure events in UF-treated patients. As the cost of in-patient care is high, serious consideration should be given to studies in the out-patient setting to determine the relative safety and effectiveness of intermittent pharmacological and mechanical fluid removal therapies for the prevention of heart failure hospitalisations. Intermittent out-patient UF to restore responsiveness to oral diuretics is also a strategy that deserves investigation. Finally, technological advances may permit the development of wearable UF devices capable of delivering individualised UF therapy. UF is an attractive alternative therapy because it predictably removes total body sodium. Practice guidelines recommend extracorporeal fluid removal by UF only in diuretic-resistant fluid-overloaded heart failure patients. In future studies, UF should be adjusted according to the individual’s haemodynamic and renal profiles, and patient selection, fluid removal amount, duration and rate should be guided by objective, complementary and informative measures of fluid overload and kidney function. The urgency of these investigations is underscored by the alarming prognostic and economic implications of recurrent heart failure hospitalisations, which remain unacceptably high with conventional pharmacological therapies. n

function and mortality in a broad spectrum of patients with cardiovascular disease. J Am Coll Cardiol 2009;53:582–8. https:// doi.org/10.1016/j.jacc.2008.08.080; PMID: 19215832. Mullens W, Abrahams Z, Francis GS, et al. Importance of venous congestion for worsening of renal function in advanced decompensated heart failure. J Am Coll Cardiol 2009;53:589–96. https://doi.org/10.1016/j.jacc.2008.05.068; PMID: 19215833. Metra M, Davison B, Bettari L, et al. Is worsening renal function an ominous prognostic sign in patients with acute heart failure? The role of congestion and its interaction with renal function. Circ Heart Fail 2012;5:54–62. https://doi.org/10.1161/CIRCHEARTFAILURE.111.963413; PMID: 22167320. Testani JM, Chen J, McCauley BD, et al. Potential effects of aggressive decongestion during the treatment of decompensated heart failure on renal function and survival. Circulation 2010;122:265–72. https://doi.org/10.1161/ CIRCULATIONAHA.109.933275; PMID: 20606118. Singh D, Shrestha K, Testani JM, et al. Insufficient natriuretic response to continuous intravenous furosemide is associated with poor long-term outcomes in acute decompensated heart failure. J Card Fail 2014;20:392–9. https://doi.org/10.1016/ j.cardfail.2014.03.006; PMID: 24704538. ter Maaten JM, Valente MA, Damman K, et al. Diuretic response in acute heart failure-pathophysiology, evaluation, and therapy. Nat Rev Cardiol 2015;12:184–92. https://doi. org/10.1038/nrcardio.2014.215; PMID: 25560378. Gheorghiade M, Filippatos G. Reassessing treatment of acute heart failure syndromes: the ADHERE Registry. Eur Heart J Suppl 2005;7(Suppl B):B13–9. https://doi.org/10.1093/eurheartj/ sui008. Felker GM, Lee KL, Bull DA, et al. Diuretic strategies in patients with acute decompensated heart failure. N Engl J Med 2011;364:797–805. https://doi.org/10.1056/NEJMoa1005419; PMID: 21366472. Konstam MA, Gheorghiade M, Burnett JC Jr, et al. Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST Outcome Trial. JAMA 2007;297:1319–31. https://doi.org/10.1001/jama.297.12.1319; PMID: 17384437. Massie BM, O’Connor CM, Metra M, et al. Rolofylline, an adenosine A1-receptor antagonist, in acute heart failure. N Engl J Med 2010;363:1419–28. https://doi.org/10.1056/ NEJMoa0912613; PMID: 20925544. O’Connor CM, Starling RC, Hernandez AF et al. Effect of

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nesiritide in patients with acute decompensated heart failure. N Engl J Med 2011;365:32–43. https://doi.org/10.1056/ NEJMoa1100171; PMID: 21732835. Kazory A, Costanzo MR. Extracorporeal isolated ultrafiltration for management of congestion in heart failure and cardiorenal syndrome. Adv Chronic Kidney Dis 2018;25:434–42. https://doi. org/10.1053/j.ackd.2018.08.007; PMID: 30309461. Ronco C, Ricci Z, Bellomo R, et al. Extracorporeal ultrafiltration for the treatment of overhydration and congestive heart failure. Cardiology 2001;96:155–68. https://doi.org/10.1159/ 000047399; PMID: 11805382. Jaski BE, Ha J, Denys BG. Peripherally inserted veno-venous ultrafiltration for rapid treatment of volume overloaded patients. J Card Fail 2003;9:227–31. https://doi.org/10.1054/ jcaf.2003.28; PMID: 12815573. Agostoni P, Marenzi G, Lauri G, et al. Sustained improvement in functional capacity after removal of body fluid with isolated ultrafiltration in chronic cardiac insufficiency: failure of furosemide to provide the same result. Am J Med 1994;96:191–9. https://doi.org/10.1016/0002-9343(94)90142-2; PMID: 8154506. Miller WL, Mullan BP. Understanding the heterogeneity in volume overload and fluid distribution in decompensated heart failure is key to optimal volume management: role for blood volume quantitation. JACC Heart Fail 2014;2:298–305. https://doi.org/10.1016/j.jchf.2014.02.007; PMID: 24952698. Marenzi G, Grazi S, Giraldi F, et al. Interrelation of humoral factors, hemodynamics, and fluid and salt metabolism in congestive heart failure: effects of extracorporeal ultrafiltration. Am J Med 1993;94:49–56. https://doi. org/10.1016/0002-9343(93)90119-A; PMID: 8420299. Marenzi G, Lauri G, Grazi M, et al. Circulatory response to fluid overload removal by extracorporeal ultrafiltration in refractory congestive heart failure. J Am Coll Cardiol 2001;38:963–8. https://doi.org/10.1016/S0735-1097(01)01479-6; PMID: 11583865. Costanzo MR, Guglin ME, Saltzberg MT, et al. Ultrafiltration versus intravenous diuretics for patients hospitalized for acute decompensated heart failure. J Am Coll Cardiol 2007;49:675–83. https://doi.org/10.1016/j.jacc.2006.07.073; PMID: 17291932. Giglioli C, Landi D, Cecchi E, et al. Effects of ULTRAfiltration vs. DIureticS on clinical, biohumoral and haemodynamic variables in patients with deCOmpensated heart failure: the ULTRADISCO study. Eur J Heart Fail 2011;13:337–46.

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Advanced Heart Failure https://doi.org/10.1093/eurjhf/hfq207; PMID: 21131387. 31. B art BA, Goldsmith SR, Lee KL, et al. Cardiorenal rescue study in acute decompensated heart failure: rationale and design of CARRESS-HF, for the Heart Failure Clinical Research Network. J Card Fail 2012;18:176–82. https://doi.org/10.1016/ j.cardfail.2011.12.009; PMID: 22385937. 32. Bart BA, Goldsmith SR, Lee KL, et al. Ultrafiltration in decompensated heart failure with cardiorenal syndrome. N Engl J Med 2012;367:2296–304. https://doi.org/10.1056/ NEJMoa1210357; PMID: 23131078. 33. Testani JM, Brisco MA, Chen J, et al. Timing of hemoconcentration during treatment of acute decompensated heart failure and subsequent survival: importance of sustained decongestion. J Am Coll Cardiol 2013;62:516–24. https://doi.org/10.1016/j.jacc.2013.05.027; PMID: 23747773. 34. Grodin JL, Carter S, Bart BA, et al. Comparison of ultrafiltration to pharmacological decongestion in heart failure: a perprotocol analysis of CARRESS-HF. Eur J Heart Fail 2018;20: 1148–56. https://doi.org/10.1002/ejhf.1158; PMID: 29493059. 35. Brain M, Winson E, Roodenburg O, McNeil J. Non anticoagulant factors associated with filter life in continuous renal replacement therapy (CRRT): a systematic review and meta-analysis. BMC Nephrology 2017;18:69. https://doi. org/10.1186/s12882-017-0445-5; PMID: 28219324. 36. Starling EH. On the absorption of fluids from the connective tissue spaces. J Physiol 1896;19:312–26. https://doi.org/10.1113/jphysiol.1896.sp000596; PMID: 16992325. 37. Marenzi G, Muratori M, Cosentino ER, et al. Continuous ultrafiltration for congestive heart failure: the CUORE trial. J Card Fail 2014;20:9–17. https://doi.org/10.1016/ j.cardfail.2013.11.004; PMID: 24269855. 38. Lorenz JN, Weihprecht H, Schnermann J, et al. Renin release from isolated juxtaglomerular apparatus depends on macula densa chloride transport. Am J Physiol 1991;260:F486–93. https://doi.org/10.1152/ajprenal.1991.260.4.F486; PMID: 2012204. 39. Schlatter E, Salomonsson M, Persson AE, et al. Macula densa cells sense luminal NaCl concentration via furosemide sensitive Na+2Cl-K+ cotransport. Pflugers Arch 1989;414:286– 90. https://doi.org/10.1007/BF00584628; PMID: 2780213. 40. Costanzo MR, Negoianu D, Jaski BE, et al. Aquapheresis versus intravenous diuretics and hospitalizations for heart failure. JACC Heart Fail 2016;4:95–105. https://doi.org/10.1016/ j.jchf.2015.08.005; PMID: 26519995. 41. Costanzo MR, Negoianu D, Fonarow GC, et al. Rationale and design of the Aquapheresis Versus Intravenous Diuretics and Hospitalization for Heart Failure (AVOID-HF) trial. Am Heart J 2015;170:471–82. https://doi.org/10.1016/j.ahj.2015.05.019; PMID: 26385030.

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42. P onikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the task force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J 2016;37:2129–200. https://doi.org/10.1093/eurheartj/ehw128; PMID: 27206819. 43. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013;62:e147–239. https://doi.org/10.1016/ j.jacc.2013.05.019; PMID: 23747642. 44. Stevenson LW, Perloff JK. The limited reliability of physical signs for estimating hemodynamics in chronic heart failure. JAMA 1989;261:884–8. https://doi.org/10.1001/ jama.1989.03420060100040; PMID: 2913385. 45. Jefferies JL, Bartone C, Menon S, et al. Ultrafiltration in heart failure with preserved ejection fraction: comparison with systolic heart failure patients. Circ Heart Fail 2013;6:733–9. https://doi.org/10.1161/CIRCHEARTFAILURE.112.000309; PMID: 23735537. 46. Schrier RW, Bansal S. Pulmonary hypertension, right ventricular failure, and kidney: different from left ventricular failure? Clin J Am Soc Nephrol 2008;3:1232–7. https://doi. org/10.2215/CJN.01960408; PMID: 18614776. 47. Marik PE, Baram M, Vahid B. Does central venous pressure predict fluid responsiveness? A systematic review of the literature and the tale of seven mares. Chest 2008;134:172–8. https://doi.org/10.1378/chest.07-2331; PMID: 18628220. 48. Ross EA. Congestive renal failure: the pathophysiology and treatment of renal venous hypertension. J Card Fail 2012;18:930–8. https://doi.org/10.1016/j.cardfail.2012.10.010; PMID: 23207082. 49. Stawicki SP, Braslow BM, Panebianco NL, et al. Intensivist use of hand-carried ultrasonography to measure IVC collapsibility in estimating intravascular volume status: correlations with CVP. J Am Coll Surg 2009;209:55–61. https://doi.org/10.1016/ j.jamcollsurg.2009.02.062; PMID: 19651063. 50. Abraham WT, Adamson PB, Bourge RC, et al. Wireless pulmonary artery haemodynamic monitoring in chronic heart failure: a randomised controlled trial. Lancet 2011;377:658–66. https://doi.org/10.1016/S01406736(11)60101-3; PMID: 21315441. 51. Costanzo MR, Stevenson LW, Adamson PB, et al. Interventions linked to decreased heart failure hospitalizations during ambulatory pulmonary artery pressure monitoring. JACC Heart Fail 2016;4:333–44. https://doi.org/10.1016/j.jchf.2015.11.011; PMID: 26874388. 52. Ronco C, Brendolan A, Bellomo R. Online monitoring

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in continuous renal replacement therapies. Kidney Int 1999;56(Suppl 72):S8–14. https://doi. org/10.1046/j.1523-1755.56.s72.11.x; PMID: 10560797. Piccoli A. Whole body – single frequency bioimpedance. Contrib Nephrol 2005;149:150–61. https://doi. org/10.1159/000085478; PMID: 15876839. Ribas N, Nescolarde L, Domingo M, et al. Longitudinal and transversal bioimpedance measurements in addition to diagnosis of heart failure. Journal of Physics: Conference Series 2010;224:012099. https://doi.org/10.1088/17426596/224/1/012099. Margouleff D. Blood volume determination, a nuclear medicine test in evolution. Clin Nucl Med 2013;38:534–7. https://doi.org/10.1097/RLU.0b013e318292f370; PMID: 23657140. Bayes-Genis A, Lupon J, Jaffe AS. Can natriuretic peptides be used to guide therapy? EJIFCC 2016;27:208–16. PMID: 27683534. Parikh CR, Coca SG. Acute kidney injury: defining prerenal azotemia in clinical practice and research. Nat Rev Nephrol 2010;6:641–2. https://doi.org/10.1038/nrneph.2010.128; PMID: 20981121. Sise ME, Forster C, Singer E, et al. Urine neutrophil gelatinase-associated lipocalin identifies unilateral and bilateral urinary tract obstruction. Nephrol Dial Transplant 2011;26:4132–5. https://doi.org/10.1093/ndt/gfr569; PMID: 22049182. Brown JR, Kramer RS, Coca SG, et al. Duration of acute kidney injury impacts long-term survival after cardiac surgery. Ann Thorac Surg 2010;90:1142–8. https://doi.org/10.1016/ j.athoracsur.2010.04.039; PMID: 20868804. Brisco MA, Zile MR, Hanberg JS, et al. Relevance of changes in serum creatinine during a heart failure trial of decongestive strategies: insights from the DOSE trial. J Card Fail 2016;22:753–60. https://doi.org/10.1016/ j.cardfail.2016.06.423; PMID: 27374839. Xu K, Rosenstiel P, Paragas N, et al. Unique transcriptional programs identify subtypes of AKI. J Am Soc Nephrol 2016; 28:1729–40. https://doi.org/10.1681/ASN.2016090974; PMID: 28028135. Nickolas TL, O’Rourke MJ, Yang J, et al. Sensitivity and specificity of a single emergency department measurement of urinary neutrophil gelatinase-associated lipocalin for diagnosing acute kidney injury. Ann Intern Med 2008;148:810–9. https://doi.org/10.7326/0003-4819-148-11-200806030-00003; PMID: 18519927. Costanzo MR, Ronco C, Abraham WT, et al. Extracorporeal ultrafiltration for fluid overload in heart failure: current status and prospects for further research. J Am Coll Cardiol 2017;69:2428–45. https://doi.org/10.1016/j.jacc.2017.03.528; PMID: 28494980.

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Advanced Heart Failure

Choosing Between Left Ventricular Assist Devices and Biventricular Assist Devices Sajad Shehab and Christopher S Hayward Cardiology Department, St Vincent’s Hospital, Sydney, Australia

Abstract Right ventricular failure following left ventricular assist devices implantation is a serious complication associated with high mortality. In patients with or at high risk of developing right ventricular failure, biventricular support is recommended. Because univentricular support is associated with high survival rates, biventricular support is often undertaken as a last resort. With the advent of newer right ventricular and biventricular systems under design and testing, better differentiation is required to ensure optimal patients care. Clear guidelines on patient selection, time of intervention and device selection are required to improve patient outcomes.

Keywords Biventricular assist device, left ventricular assist device, right heart failure, patient selection, temporary mechanical support Disclosure: Christopher S Hayward has received research funds from HeartWare Inc unrelated to this article. There are no other conflicts of interest. Received: 27 June 2018 Accepted: 29 November 2018 Citation: Cardiac Failure Review 2019;5(1):19–23. DOI: https://doi.org/10.15420/cfr.2018.23.2 Correspondence: Christopher S Hayward, Cardiology Department, St Vincent’s Hospital, 390 Victoria Street, Darlinghurst, NSW 2010 Australia. E: cshayward@stvincents.com.au Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

The use of left ventricular assist devices (LVADs) in patients with advanced heart failure is well established; they make up 90% of all implanted continuous flow ventricular assist devices (VADs).1 In advanced heart failure, they are superior to medical therapy alone,1 with improvements demonstrated in survival, quality of life and functional status in carefully selected patients.2,3 Although initially designed as a bridge to cardiac transplantation, they have been reportedly used as destination therapy in 46% of cases, while 23% are implanted in anticipation of potential cardiac transplantation (bridge to candidacy).1 A significant limitation of LVADs is the lack of corresponding right heart support, which results in one-third of patients developing clinical right heart failure after LVAD implantation. 4,5 Because there was some early success in these very sick patients, studies have evaluated applicability of VADs in a biventricular configuration (dual LVAD therapy) – one to support the left ventricle (LV) and another to support the right ventricle (RV). 6–10 Compared with traditional pulsatile biventricular assist device (BiVAD) systems, dual VAD therapy has demonstrated improved survival rates and fewer adverse events, and enabled hospital discharge. 6–10 Despite this, better outcomes continue to be achieved with isolated LVADs, producing an environment where durable BiVAD are only undertaken in irretrievable cases. 1,12 To date, biventricular support has been offered to patients unsuitable for isolated LVAD therapy who have pre-existing, right heart failure or impairment and who are thought unlikely to improve after LVAD implantation.

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It is important to recognise that those requiring biventricular support are a different population from patients who undergo univentricular support. These patients are generally sicker, with more profound multiple organ dysfunction than those requiring LVAD. Implanting LVADs into a patient with concomitant right ventricular failure (RVF) or at risk of developing RVF is associated with high mortality.4 With many durable BiVAD systems under development and testing, establishing clear criteria for LVAD and BiVAD support is imperative in providing optimum patient care. Therefore, early intervention, effective patient selection and sound criteria for device selection are required for making the decision between univentricular versus biventricular support.

Patient Selection Patient selection involves identifying suitable candidates who have a minimum risk of developing adverse events while receiving the maximum benefits of VAD support. Ideally, a universal selection criterion based on validated research should be used to ensure a standardised process of identifying suitable candidates for VAD support. This would simplify the selection criteria and enable correlation between different studies and centres. However, to date, no such standard exists. While few clinical trials are available to determine the general requirements of mechanical support with LVADs, no such trials exist with continuous flow BiVADs, resulting in patients being selected depending on individualised institutional criteria, such as clinical status, inotrope dependence and invasive haemodynamic and echocardiographic parameters.

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Advanced Heart Failure Based on these variables, individual predictors of poor operative outcomes for both LVAD and BiVAD support have been derived, including age, female sex, RVF markers, respiratory failure, impaired renal or hepatic function, diabetes, prior cardiac surgery, preoperative extracorporeal membrane oxygenation use, infection and coagulation abnormalities such as a declining platelet count.13–20 With a few key exceptions, most of these predictors are common in patients suitable for both LVAD and BiVAD support, which makes deciding between univentricular and biventricular support all the more challenging.

Patient Selection for Biventricular Assist Devices The decision to implant BiVADs can be difficult and varies between institutions. The main indications for early biventricular support have been acute circulatory collapse due to fulminant myocarditis, acute decompensation of dilated biventricular cardiomyopathy, massive MI (involving the septum or RV) or acute deterioration following toxic cardiomyopathy. BiVAD support may be more suitable in the presence of other widespread cardiac pathologies such as infiltrative cardiomyopathy or RV cardiomyopathies with concomitant involvement of the LV.7,26

Patient Selection for Left Ventricular Assist Devices LVADs are used in patients with advanced heart failure who are at a high risk of cardiogenic shock and/or multiple organ failure. The objective is to improve circulation, alleviate symptoms, improve quality of life and bridge suitable candidates to transplantation. Additional benefits of LVAD support include stabilisation or reversal of left ventricular dysfunction or pulmonary vascular hypertension. Factors to consider when selecting patients for LVAD support include inotropic dependence, maximally tolerated medical therapy, low LV ejection fraction (<25%), declining renal function or low systolic blood pressure (<80 mmHg) or high pulmonary capillary wedge pressure (>20 mmHg).21 These variables are well-recognised clinical signs of LV failure. However, rather than a focus on individual predictors, a more holistic approach of the patient’s clinical condition should guide the decision. This includes identifying potential contraindications for support such as evidence of aortic regurgitation, severe comorbidities such as renal or liver failure that are unlikely to be salvageable, active infection and/or bleeding, low platelet count, existing LV thrombus, psychosocial limitations such as the inability to comply with medical regimen or device maintenance, and a pre-existing high risk of developing RVF. Recently, it has been increasingly recognised that physical and cognitive frailty are strong predictors of outcome after LVAD implantation, and efforts have been made to define and standardise the assessment of these more accurately.22

Impact of an Left Ventricular Assist Devices on the Right Ventricle The development of RVF is multifactorial and may not become apparent until after LVAD implantation. A healthy RV is responsible for delivering blood through the lungs and to the left ventricle. The inability to perform such an action can result in inadequate blood delivery to the left ventricle and therefore a decreased delivery of oxygenated blood to the tissue and organs.23 While the LVAD can improve left ventricular activity, it does not directly aid the RV to pump blood to the lungs. However, the LVAD can indirectly influence the RV by affecting factors such as venous return, septal motion and pulmonary artery pressure.24 In severe secondary pulmonary hypertension, the use of an LVAD has been shown to relieve pulmonary pressure and decrease right ventricular afterload.25 This is achieved by increasing forward flow to the body, thereby decreasing right ventricular afterload. However, the increased cardiac output created by the LVAD may overwhelm the load-sensitive RV. Moreover, by decreasing intraventricular LV pressure, the use of the LVAD forces the wall of the septum to shift towards the left, with altered RV geometry resulting in RVF because of decreased RV contractility and reduced RV compliance.24

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Predicting RVF can improve patient and device selection and significantly affect patient outcomes. As such, numerous studies have closely examined the performance and structural integrity of the RV to find potential predictors of RVF. Echocardiographic and haemodynamic markers of RVF include: severe tricuspid regurgitation; low RV ejection fraction <30%; right atrial (RA) diameter >50 mm; decreased right ventricular stroke work index; markers of elevated serum bilirubin and creatinine; pulmonary artery pressure or elevated central venous pressure, especially relative to LV filling pressures with systemic hypoperfusion.17,18,27–31 While cut-offs for these variables differ between studies, increased research in the area can gradually lead to standards being established that can be adapted in future studies. Unlike with LVADs, no clinical trials have been conducted to determine risk scores for patients in need of BiVAD support. Given the proven difficulty in assessing patients at risk for RVF clinically, attempts have been made to develop scoring systems, incorporating clinical, echocardiographic and haemodynamic markers.31–34 Despite the appeal of these apparently objective assessments, the predictive capacity of any one of them is limited outside its derivation cohort. The most recent appears to have some promise and represents the largest derivation and validation cohort to date.35

Time of Intervention In addition to selecting the correct patients for isolated LVAD or BiVAD support, great consideration must also be given to selecting patients with sufficient severity of illness to achieve a benefit while avoiding those who are too ill or too early in the disease course to derive any gain. VADs are often considered after all other therapeutic options such as lifestyle changes and pharmacological interventions have failed to restore a patient’s cardiac functional status. At the end-stage period of the disease, patients are often plagued with various comorbidities and have significant limitations because of poor circulation. Although VADs can restore circulation, their efficacy is limited by the patient’s comorbidity profile and clinical status. The timing of device intervention is therefore crucial in achieving optimum outcomes. There is a general consensus that patients receiving an implant earlier in the clinical course of their disease perform better in terms of survival than those having the procedure at the end stage. This can be seen in the seventh annual report of the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACs), where INTERMACs groups 3 and 4 have higher survival rates than INTERMACs groups 1 and 2.2 Similarly, there is clear evidence to associate early BiVAD support with superior outcomes compared to delayed RVAD support following LVAD implantation.36,37 The disadvantage of delayed RVAD support is that an already compromised patient must undergo an additional surgical procedure. Moreover, patients who require delayed RVAD support are

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Choosing between LVAD and BiVAD by definition failing isolated LVAD support and therefore have worse haemodynamic instability and circulatory flow than someone without a need for subsequent RVAD support. Takeda et al. assessed the impact of initial versus delayed RVAD support using the Levitronix CentriMag and showed that initial RVAD support resulted in significantly improved survival and transplantation rates compared to delayed RVAD support.37 These findings are also supported in recent durable BiVAD studies, which strongly favoured planned BiVAD support.7 While BiVAD recipients have greater mortality and morbidity than LVAD recipients, survival following cardiac transplantation does not appear to be associated with the type of configuration used (LVAD versus BiVAD).38 Therefore, as long as BiVAD recipients are successfully bridged to cardiac transplantation, they will have similar post-transplant survival rates as their LVAD counterparts. As the pathology of biventricular failure is largely associated with poor systemic blood circulation, it is logical to assume that early intervention with durable BiVADs can reduce mortality rates during the early postoperative period and therefore increase the number of successfully bridged candidates. The challenge then will be to determine the difference between early and too early.

Figure 1: Dual Ventricular Assist Device Therapy Right ventricular implant

Right atrial implant

X-ray image of dual VAD therapy using the HeartWare HVAD as a biventricular system using two different right heart support configurations. A: Right ventricle free wall and left ventricular apical implantation. B: Right atrial and left ventricular apical implantation.

Figure 2: Levitronix CentriMag Pump and Motor

Device Selection The type of device, its weight, size, flow dynamics (pulsatile versus continuous) and mode of support (extra- or para-corporeal or implantable) can all affect its suitability as a biventricular system. Continuous flow miniaturised devices have an advantage over larger extra/paracorporeal pulsatile flow models as they require less surgical invasiveness so a shorter procedural time. Continuous flow VADs are also mechanically simpler, with better device durability. The surgical procedure and implantation technique can also influence device selection. For example, despite successful implantation and RVAD support with the continuous flow Jarvik 2000 implantable LVAD system, the connection to the descending aorta has made its removal during subsequent heart transplantation difficult, extending both surgical and cardiopulmonary bypass time.39 Other devices, such as the HeartWare HVAD, can be used for RV support but require minor modifications to implantation technique.6,7,9 The HVAD inflow cannula is too long for the dimension of the RV and, if unaddressed, this may lead to interaction with the interventricular septum or other chambers of the heart, resulting in obstruction and reduced circulatory flow. To circumvent this, it has been suggested that spacers are placed between the RV wall and the HVAD to decrease the protrusion of the inflow cannula into the RV or RA cavity. This reduces the risk of RVAD flow obstruction and thrombus formation. In addition, to reduce the risk of pulmonary oedema caused by high RVAD flows to the lungs, banding of the outflow graft may be performed to increase resistance. However, in the event of RV recovery, the RV dramatically shrinks due to structural remodelling and draws the inflow cannula closer to the interventricular septum, increasing the risk of occlusion and potentially promoting thrombus formation. As a result, alternative implantation sites have been investigated such as the right atrium (Figure 1). 7 Right atrial implantation reduces the risk of occlusion from interactions with the interventricular septum. It also eliminates the need for additional surgical correction in the presence of severe tricuspid regurgitation and potentially increases right ventricular cardiac output in such patients. Additionally, the RA site enables implantation in smaller

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Published with permission from St Jude Medical.

patients without risk of VAD positional changes following sternum closure.7 Implantation of a second VAD into right heart chambers remains an unapproved indication by regulatory authorities. The HVAD is capable of providing long-term BiVAD support with favourable outcomes. Ideally, early planned BiVAD support should be considered in patients with concomitant RVF. However, in those with mild RVF who are likely to recover, long-term durable RVAD support may not be the optimum choice. To date, few options are available for short-term RV support. The Levitronix CentriMag is an extracorporeal, third generation, continuous flow system that has successfully provided short term RVAD support (Figure 2).37,40,41 RVAD support is commonly established with the RA as inflow and the pulmonary artery as outflow. The advantage of the Levitronix CentriMag are its lack of bearing and seals, which reduces thermal damage to blood component and haemolysis, as well as the risks of thrombus formation and mechanical failure. In addition, it can be implanted in smaller patients, such as women and children. Its application as a RVAD has yielded variable outcomes with 30-day survival rates in the 30â&#x20AC;&#x201C;75% range.40,42,43 Major complications associated with the CentriMag include bleeding, infection, respiratory failure, liver dysfunction and neurological complications.40,42,43 Short-term RVAD support has been successfully performed with various VAD models yielding similar results to long-term BiVAD outcomes.37,44 Technological advances in venopulmonary arterial

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Advanced Heart Failure Figure 3: Abiomed Impella RP System Repositioning unit

Motor Differential pressure sensor Inlet Cannula

Pump

Outlet Pigtail

Catheter shaft

Check valve Pressure reservoir

Published with permission from Abiomed.

extracorporeal life support (VPA–ECLS) have also made it a viable option for temporary RVAD support, warranting further investigation. These short-term devices can successfully unload the RV during the perioperative period, stabilise RV parameters, transition patients back on isolated LVAD support and eliminate the consequences of long-term BiVAD support. The greatest inherent advantage of VPA–ECLS devices compared to RVAD systems is that they can be implanted at the bedside, provide concomitant oxygenator support and can be removed without reoperation, reducing the risk of additional open heart surgery. Oxygenators can be useful in the event of severe lung oedema, hypoxia or in patients on ECLS support prior to receiving VAD support.45 While promising, survival rates with more durable RVAD support systems remain similar to those with BiVAD support.46,47 Nonetheless, owing to the novelty of these interventions, improvements in survival and wean rates can be expected with improved patient selection and postoperative management. Another short-term RVAD option is the Abiomed Impella RP Heart Pump (Impella RP), which uses a 22 Fr catheter-mounted microaxial flow pump (Figure 3). It is designed to be implanted percutaneously, using a standard catheterisation procedure via the femoral vein. Blood enters the microaxial pump via the inflow cannula positioned at the

ose EA, Gelijns A, Moskowitz A, et al. Randomized R Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) Study Group. Long-term mechanical left ventricular assistance for end-stage heart failure. N Engl J Med 2001;345:1435–43. https://doi.org/10.1056/ NEJMoa012175; PMID: 11794191. Kirklin JK, Naftel DC, Pagani FD, et al. Seventh INTERMACS annual report: 15,000 patients and counting. J Heart Lung Transplant 2015;34:1495–504. https://doi.org/10.1016/ j.healun.2015.10.003; PMID: 26520247. Eckman P, Rosenbaum A, Vongooru H, et al. Survival of INTERMACS profile 4–6 patients after left ventricular assist device implant is improved compared to Seattle heart failure model estimated survival. J Card Fail 2011;1:S38–9. https://doi. org/10.1016/j.cardfail.2011.06.129. Drakos SG, Janicki L, Horne BD, et al. Risk factors predictive of right ventricular failure after left ventricular assist device implantation. Am J Cardiol 2010;105:1030–5. https://doi. org/10.1016/j.amjcard.2009.11.026; PMID: 20346326. Baumwol J, Macdonald PS, Keogh AM, et al. Right heart failure and “failure to thrive” after left ventricular assist device: clinical predictors and outcomes. J Heart Lung Transplant 2011;30:888–95. https://doi.org/10.1016/j.healun.2011.03.006; PMID: 21530314. Krabatsch T, Hennig E, Stepanenko A, et al. Evaluation of the HeartWare HVAD centrifugal pump for right ventricular assistance in an in vitro model. ASAIO J 2011;57:183–7. https:// doi.org/10.1097/MAT.0b013e318211ba2b; PMID: 21336105. Shehab S, Macdonald PS, Keogh AM, et al. Chronic biventricular HVAD support-case series of right atrial and right ventricular implantation outcomes. J Heart Lung Transplant 2016;35:466–73. https://doi.org/10.1016/j.healun.2015.12.001;

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14.

inferior vena cava and is delivered directly to the pulmonary artery at a rate of up to 4 l/min, bypassing the RA and the tricuspid and pulmonary valves. The Impella RP is relatively new, and few single-centre studies have reported on outcomes. The prospective RECOVER RIGHT study assessed the safety and benefits of the Impella RP in RVF patients after LVAD implantation as well as after a cardiotomy.48 The 6-month survival rates were better in the post-LVAD group at approximately 80% compared to approximately 60% in those who had had a cardiotomy. Although the device is approved for 14 days of temporary RV support, patients required support for an average of only 4 days before successful RV haemodynamic stabilisation and subsequent weaning.48 The main advantage of the Impella RP is its simple implantation procedure, which allows rapid intervention before RV shock becomes irreversible. There are contraindications, however, which include a body surface area <1.5 m2, the presence of mechanical valves, severe valvular stenosis or valvular regurgitation of the tricuspid or pulmonary valve, and other disorders of the pulmonary artery wall that would preclude placement or correct positioning of the Impeller RP device. Although small studies and anecdotal cases have demonstrated positive outcomes, further investigation is warranted.48–50

Conclusion Deciding between univentricular and biventricular support remains complicated. This requires a holistic approach rather than considering isolated markers. Patients should be thoroughly screened and appropriately matched to the device that can yield optimum outcomes. Patients with evident RVF may be considered for long-term dual VAD therapy for biventricular support. Those with mild signs of RVF may benefit from right-sided temporary percutaneous implantable pumps in the early perioperative period to allow for RV haemodynamic stabilisation. Where weaning is impossible, temporary BiVADs can serve as a bridge to decision or potential cardiac transplantation in eligible patients. Early intervention, careful patient and device selection can further improve outcomes in patients in need of BiVAD support and may help bridge the disparity between uni- and biventricular outcomes. n

PMID: 26849954. Strueber M, Meyer AL, Malehsa D, Haverich A. Successful use of the HeartWare HVAD rotary blood pump for biventricular support. J Thorac Cardiovasc Surg 2010;140:936–7. https://doi. org/10.1016/j.jtcvs.2010.04.007; PMID: 20478575. Krabatsch T, Potapov E, Stepanenko A, et al. Biventricular circulatory support with two miniaturized implantable assist devices. Circulation 2011;124(Suppl 1):S179–86. https://doi. org/10.1161/CIRCULATIONAHA.110.011502; PMID: 21911810. Loforte A, Della Monica PL, Montalto A, Musumeci F. HeartWare third-generation implantable continuous flow pump as biventricular support: mid-term follow-up. Interact Cardiovasc Thorac Surg 2011;12:458–60. https://doi.org/10.1510/ icvts.2010.250654; PMID: 21172943, Kormos RL, Teuteberg JJ, Pagani FD, et al. Right ventricular failure in patients with the HeartMate II continuous-flow left ventricular assist device: incidence, risk factors, and effect on outcomes. J Thorac Cardiovasc Surg 2010;139:1316. https://doi. org/10.1016/j.jtcvs.2009.11.020; PMID: 20132950 Cleveland Jr JC, Naftel DC, Reece TB, et al. Survival after biventricular assist device implantation: an analysis of the Interagency Registry for Mechanically Assisted Circulatory Support database. J Heart Lung Transplant 2011;30:862–9. https://doi.org/10.1016/j.healun.2011.04.004 Deng MC, Edwards LB, Hertz MI, et al. Mechanical circulatory support device database of the International Society for Heart and Lung Transplantation: third annual report – 2005. J Heart Lung Transplant 2005;24:1182–7. https://doi.org/10.1016/ j.healun.2005.07.002; PMID: 16143231. Kirklin JK, Naftel DC, Kormos RL, et al. Fifth INTERMACS annual report: risk factor analysis from more than 6,000 mechanical circulatory support patients. J Heart Lung Transplant

15.

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18.

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21.

2013;32:141–56. https://doi.org/10.1016/j.healun.2012.12.004; PMID: 23352390 Stevenson LW, Pagani FD, Young JB, et al. INTERMACS profiles of advanced heart failure: the current picture. J Heart Lung Transplant 2009;28:535–41. https://doi.org/10.1016/j. healun.2009.02.015; PMID: 19481012. Ochiai Y, McCarthy PM, Smedira NG, et al. Predictors of severe right ventricular failure after implantable left ventricular assist device insertion: analysis of 245 patients. Circulation 2002;106(Suppl 1):I198–202. PMID: 12354733. Potapov EV, Stepanenko A, Dandel M, et al. Tricuspid incompetence and geometry of the right ventricle as predictors of right ventricular function after implantation of a left ventricular assist device. J Heart Lung Transplant 2008;27:1275–81. https://doi.org/10.1016/j.healun.2008. 08.012; PMID: 19059106. Kormos RL, Teuteberg JJ, Pagani FD, et al. Right ventricular failure in patients with the HeartMate II continuous-flow left ventricular assist device: incidence, risk factors, and effect on outcomes. J Thorac Cardiovasc Surg 2010;139:1316–24. https://doi.org/10.1016/j.jtcvs.2009.11.020; PMID: 20132950. Holek M, Kettner J. Pre-operative renal parameters in patients indicated to long-term ventricular assist device implantation – when we should be afraid of acute renal failure requiring renal replacement therapy? Eur J Heart Fail 2013;12:S31–2. Sandner SE, Zimpfer D, Zrunek P, et al. Renal function and outcome after continuous flow left ventricular assist device implantation. Ann Thorac Surg 2009;87:1072–8. https://doi. org/10.1016/j.athoracsur.2009.01.022; PMID: 19324130. Lund LH, Matthews J, Aaronson K. Patient selection for left ventricular assist devices. Eur J Heart Fail 2010;12:434–43. https://doi.org/10.1093/eurjhf/hfq006; PMID: 20172939.

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Choosing between LVAD and BiVAD

22. J ha SR, Hannu MK, Gore K, et al. Cognitive impairment improves the predictive validity of physical frailty for mortality in patients with advanced heart failure referred for heart transplantation. J Heart Lung Transplant 2016;35:1092–100. https://doi.org/10.1016/j. healun.2016.04.008; PMID: 27282417. 23. Puhlman M. Continuous-flow left ventricular assist device and the right ventricle. AACN Adv Crit Care 2012;23:86. https://doi. org/10.1097/NCI.0b013e31823ef240; PMID: 22290094. 24. Furukawa K, Motomura T, Nosé Y. Right ventricular failure after left ventricular assist device implantation: the need for an implantable right ventricular assist device. Artif Organs 2005;29:369–77. https://doi.org/10.1111/j.15251594.2005.29063.x; PMID: 15854212. 25. Kumarasinghe G, Jain P, Jabbour A, et al. Comparison of continuous-flow ventricular assist device therapy with intensive medical therapy in fixed pulmonary hypertension secondary to advanced left heart failure. ESC Heart Fail 2018;5:695–702. https://doi.org/10.1002/ehf2.12284; PMID: 29573567. 26. Shehab S, Newton PJ, Allida SM, et al. Biventricular mechanical support devices–clinical perspectives. Expert Rev Med Devices 2016;13:353–65. https://doi.org/10.1586/17434440. 2016.1154454; PMID: 26894825. 27. Morgan JA, John R, Lee BJ, et al. Is severe right ventricular failure in left ventricular assist device recipients a risk factor for unsuccessful bridging to transplant and post-transplant mortality. Ann Thorac Surg 2004;77:859–63. https://doi. org/10.1016/j.athoracsur.2003.09.048; PMID: 14992887. 28. Dang NC, Topkara VK, Mercando M, et al. Right heart failure after left ventricular assist device implantation in patients with chronic congestive heart failure. J Heart Lung Transplant 2006;25:1–6. https://doi.org/10.1016/j.healun.2005.07.008; PMID: 16399523. 29. Kang G, Ha R, Banerjee D. Pulmonary artery pulsatility index predicts right ventricular failure after left ventricular assist device implantation. J Heart Lung Transplant 2016;35:67–73. https://doi.org/10.1016/j.healun.2015.06.009; PMID: 26212656. 30. Puhlman M. Continuous-flow left ventricular assist device and the right ventricle. AACN Adv Crit Care 2012;23:86–90. https:// doi.org/10.1097/NCI.0b013e31823ef240; PMID: 22290094. 31. Matthews JC, Koelling TM, Pagani FD, Aaronson KD. The right ventricular failure risk score: a pre-operative tool for assessing the risk of right ventricular failure in left ventricular assist device candidates. J Am Coll Cardiol 2008;51:2163–72. https://doi.org/10.1016/j.jacc.2008.03.009; PMID: 18510965.

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32. J oly JM, El-Dabh A, Marshell R, et al. Performance of noninvasive assessment in the diagnosis of right heart failure after left ventricular assist device. ASAIO J 2018. https://doi. org/10.1097/MAT.0000000000000830; PMID: 29877889; epub ahead of press. 33. Fitzpatrick JR, Frederick JR, Hsu VM, et al. Risk score derived from pre-operative data analysis predicts the need for biventricular mechanical circulatory support. J Heart Lung Transplant 2008;27:1286–92. https://doi.org/10.1016/ j.healun.2008.09.006; PMID: 19059108. 34. Drakos SG, Janicki L, Horne BD, et al. Risk factors predictive of right ventricular failure after left ventricular assist device implantation. Am J Cardiol 2010;105:1030–5. https://doi. org/10.1016/j.amjcard.2009.11.026; PMID: 20346326. 35. Soliman OII, Akin S, Muslem R, et al. Derivation and validation of a novel right-sided heart failure model after implantation of continuous flow left ventricular assist devices: the EUROMACS (European Registry for Patients with Mechanical Circulatory Support) right-sided heart failure risk score. Circulation 2018;137:891–906. https://doi.org/10.1161/ CIRCULATIONAHA.117.030543; PMID: 28847897. 36. Fitzpatrick JR 3rd, Frederick JR, Hiesinger W, et al. Early planned institution of biventricular mechanical circulatory support results in improved outcomes compared with delayed conversion of a left ventricular assist device to a biventricular assist device. J Thorac Cardiovasc Surg 2009;137:971–7. https://doi.org/10.1016/j.jtcvs.2008.09.021; PMID: 19327526. 37. Takeda K, Naka Y, Yang JA, et al. Outcome of unplanned right ventricular assist device support for severe right heart failure after implantable left ventricular assist device insertion. J Heart Lung Transplant 2014;33:141–8. https://doi.org/10.1016/ j.healun.2013.06.025; PMID: 23932442. 38. Pavie A, Leger P. Physiology of univentricular versus biventricular support. Ann Thorac Surg 1996;61:347–9. https:// doi.org/10.1016/0003-4975(95)01026-2; PMID: 8561603. 39. Frazier O, Myers TJ, Gregoric I. Biventricular assistance with the Jarvik FlowMaker: a case report. J Thorac Cardiovasc Surg 2004;128:625–6. https://doi.org/10.1016/j.jtcvs.2004.02.023; PMID: 15457169. 40. Shuhaiber JH, Jenkins D, Berman M, et al. The Papworth experience with the Levitronix CentriMag ventricular assist device. J Heart Lung Transplant 2008;27:158–64. https://doi. org/10.1016/j.healun.2007.10.015; PMID: 18267221. 41. John R, Long JW, Massey HT, et al. Outcomes of a multicenter trial of the Levitronix CentriMag ventricular assist system

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for short-term circulatory support. J Thorac Cardiovasc Surg 2011;141:932–9. https://doi.org/10.1016/j.jtcvs.2010.03.046; PMID: 20605026. Mohamedali B, Bhat G, Yost G, Tatooles A. Survival on biventricular mechanical support with the Centrimag® as a bridge to decision: a single-center risk stratification. Perfusion 2015;30:201–8. https://doi.org/10.1177/0267659114563947; PMID: 25524992. Mohite PN, Zych B, Popov AF, et al. CentriMag® short-term ventricular assist as a bridge to solution in patients with advanced heart failure: use beyond 30 days. Eur J Cardiothorac Surg 2013;44:e310–5. https://doi.org/10.1093/ejcts/ezt415; PMID: 23990618. Samuels LE, Shemanski KA, Casanova-Ghosh E, et al. Hybrid ventricular assist device: Heartmate XVE LVAD and Abiomed AB5000 RVAD. ASAIO J 2008;54:332–4. https://doi.org/10.1097/ MAT.0b013e318172eeb8; PMID: 18496285. Boulate D, Luyt C-E, Pozzi M, et al. Acute lung injury after mechanical circulatory support implantation in patients on extracorporeal life support: an unrecognized problem. Eu J Cardiothorac Surg 2013;44:544–50. https://doi.org/10.1093/ejcts/ ezt125; PMID: 23477925. Noly P-E, Kirsch M, Quessard A, et al. Temporary right ventricular support following left ventricle assist device implantation: a comparison of two techniques. Interact Cardiovasc Thorac Surg 2014;19:49–55. https://doi.org/10.1093/ icvts/ivu072; PMID: 24659551. Shehab S, Rao S, Macdonald P, et al. Outcomes of venopulmonary arterial extracorporeal life support as temporary right ventricular support after left ventricular assist implantation. J Thorac Cardiovasc Surg 2018;156:2143–52. https://doi.org/10.1016/j.jtcvs.2018.05.077; PMID: 30025607. Anderson MB, Goldstein J, Milano C, et al. Benefits of a novel percutaneous ventricular assist device for right heart failure: the prospective RECOVER RIGHT study of the Impella RP device. J Heart Lung Transplant 2015;34:1549–60. https://doi. org/10.1016/j.healun.2015.08.018; PMID: 26681124. Morgan JA, O’Neill WW. Percutaneous right ventricular assist device support in a patient supported by an LVAD. ASAIO J 2016;62:e41–2. https://doi.org/10.1097/ MAT.0000000000000344; PMID: 26771398. Cheung AW, White CW, Davis MK, Freed DH. Short-term mechanical circulatory support for recovery from acute right ventricular failure: clinical outcomes. J Heart Lung Transplant 2014;33:794–9. https://doi.org/10.1016/j.healun.2014.02.028; PMID: 24726682.

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Advanced Heart Failure

Focusing on Referral Rather than Selection for Advanced Heart Failure Therapies Tonje Thorvaldsen and Lars H Lund Karolinska Institutet, Department of Medicine, Stockholm, Sweden; Karolinska University Hospital, Heart and Vascular Theme, Stockholm, Sweden

Abstract Despite advances in heart failure treatment, advanced heart failure affects 5–10% of people with the condition and is associated with poor prognosis. Selection for heart transplantation and left ventricular assist device implantation is a rigorous and validated process performed by specialised heart failure teams. This entails comprehensive assessment of complex diagnostic tests and risk scores, and selecting patients with the optimal benefit-risk profile. In contrast, referral for advanced heart failure evaluation is an arbitrary and poorly studied process, performed by generalists, and patients are often referred too late or not at all. The study elaborates on the differences between selection and referral and proposes some simple strategies for optimising timely referral for advanced heart failure evaluation.

Keywords Advanced heart failure, selection, referral, heart transplantation, left ventricular assist device, palliative care Disclosure: TT: The author has no conflict of interest to declare. LHL: There are no conflicts of interest related to the work submitted. Outside this, there are the following potential conflicts of interest: research grants to author’s institution, speaker’s and/or consulting fees: AstraZeneca, Novartis, Bayer, Vifor Pharma, Relypsa, Abbott and Sanofi Received: 15 November 2018 Accepted: 4 January 2019 Citation: Cardiac Failure Review 2019;5(1):24–6. DOI: https://doi.org/10.15420/cfr.2018.35.1 Correspondence: Lars H Lund, Karolinska Institutet, Department of Medicine, Karolinska University Hospital, Norrbacka, S1:02, 171 76 Stockholm, Sweden. E: Lars.Lund@alumni.duke.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.

Heart failure (HF) is associated with poor quality of life, high risk of death and is the leading cause of hospitalisation.1 With an ageing population and improved care for cardiovascular diseases, the prevalence of HF is increasing. Despite advances in HF therapies, 1–10% of the population with HF progress to an advanced stage of the disease.2,3 In the US, an estimated 250,000–300,000 patients younger than 75 years suffer from advanced HF; extrapolated, this would yield approximately 500,000 patients in the EU. 4 Prognosis in advanced heart failure is poor, with 1-year mortality rates of 25–50%5,6 Heart transplantation (HTx) remains the gold standard treatment for severe HF refractory to medical and device therapy, with a 1-year survival of almost 90%.7,8 However, since access to organs is limited, durable left ventricular assist devices (LVADs) are increasingly being implanted in these patients either as bridge to transplantation or destination therapy.9 There have been remarkable advances in mechanical assist device therapy over the past decade and current data indicate a survival after LVAD implantation of around 80% at 1 year and 70% at 2 years.10,11 Patients are, however, believed to be underserved regarding advanced HF therapies.12,13 While the main explanation for HTx is organ shortage, important reasons for underuse of LVADs are most likely a lack of awareness among clinicians caring for patients with HF and difficulty in assessing the need for advanced therapy.

Access at: www.CFRjournal.com

CFR_Lund_FINAL.indd 24

Accurate prognostication in HF is challenging. The transition from stable, chronic HF to advanced HF is often gradual and no single test or imaging modality is capable of identifying this change in severity. For general practitioners or cardiologists who do not deal with advanced HF on a daily basis, it is difficult to identify patients who may benefit from HTx or LVAD therapy. Patients are often referred too late, when end-stage organ failure that disqualifies them for advanced treatment is already present.14 While HF teams and advanced HF referral centres follow rigorous selection criteria and guidelines when selecting patients for HTx and LVAD implantation, there are no guidelines or criteria to serve the GP or cardiologist in deciding when to refer patients for advanced HF assessment and potential selection for advanced therapy.15–17

Referral to an Advanced Heart Failure Centre Before advanced therapy is considered, evidence-based HF therapy should be optimised. Medication must be uptitrated to maximum tolerated doses and patients should receive cardiac resynchronisation therapy and/or implantable defibrillation therapy (ICD) as indicated according to current guidelines.18 No validated criteria or cut-off values for referral to an advanced HF clinic or HF specialist exist. The Heart Failure Association of the European Society of Cardiology position statement lists triggers for referral (Table 1).19 The variables listed include clinical, laboratory, imaging and risk score data; they are all relevant prognostic variables,

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Referral and Selection in Advanced Heart Failure Table 1: Triggers for Referral for Advanced Therapy Clinical

Laboratory

Imaging

• >1 HF hospitalisation in past year • NYHA class III–IV • Intolerant of optimal dose of any GDMT HF drug • Increasing diuretic requirement • SBP ≤90 mmHg • Inability to perform CPET • 6MWT • CRT non‐responder clinically • Cachexia, unintentional weight loss • KCCQ • MLHFQ

• • • • • • • •

• LVEF ≤30% • MAGGIC predicted survival ≤80% at • Large area of akinesis/dyskinesis or 1 year aneurysm • SHFM predicted survival ≤80% at • Moderate–severe mitral regurgitation 1 year • RV dysfunction • PA pressure ≥50 mmHg • Moderate‐severe tricuspid regurgitation • Difficult to grade aortic stenosis • IVC dilated or without respiratory variation

eGFR <45 ml/min SCr ≥160 mmol/ K >5.2 or <3.5 mmol/ Hyponatraemia Hb ≤120 g/l NT‐proBNP ≥1000 pg/ml Abnormal liver function test Low albumin

Risk Score Data

6MWT = 6‐min walk test; CPET = cardiopulmonary exercise test; CRT = cardiac resynchronization therapy; eGFR = estimated glomerular filtration rate; GDMT = guideline‐directed medical therapy; Hb = haemoglobin; HF = heart failure; IVC = inferior vena cava; K = potassium; KCCQ = Kansas City Cardiomyopathy Questionnaire; LVEF = left ventricular ejection fraction; MAGGIC = Meta‐Analysis Global Group in Chronic Heart Failure; MLHFQ = Minnesota Living with Heart Failure Questionnaire; Na = sodium; NT‐proBNP = N‐terminal pro‐B‐type natriuretic peptide; NYHA = New York Heart Association; PA = pulmonary artery; RV = right ventricular; SBP = systolic blood pressure; SCr = serum creatinine; SHFM = Seattle Heart Failure Model. Source: Crespo-Leiro et al. 2018.19 Reproduced with permission from John Wiley and Sons.

Figure 1: Survival by Number of Risk Factors for New York Heart Association Class III–IV, with Ejection Fraction <40% 100

1-year survival post-heart transplantation 1-year survival post-LVAD implantation

Survival rates (%)

isk

fac

isk

3–5

risk

Systolic BP <90mmHg

tor

Creatinine ≥160μmol/l

fac

tor

fac

Pre-specified risk factors

Hemoglobin ≤120g/Ll No ACE inhibitors or ARB

tor

ors 4

Years ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BP, blood pressure; LVAD, left ventricular assist device. Source: Adapted from Thorvaldsen, et al. 2014,24 with permission from Elsevier.

but many are non-specific and/or subjective. The variables should perhaps be seen as general markers of deterioration rather than distinct referral criteria. Articles in which referral for advanced HF therapy is discussed tend to focus on selection criteria for HTx or LVAD implantation rather than referral criteria.14 Cardiopulmonary exercise testing, 6-minutewalk test, assessment of prognosis using comprehensive risk scores, evaluation of end-stage organ failure, assessment of cardiac index and intracardiac pressures measured by right heart catheterisation are all part of a complete patient eligibility assessment performed by the interdisciplinary HF team at specialised HF centres when evaluating potential candidates for advanced HF treatment.20 It should be noted that, for referral to a HF centre, a complete assessment of the patient is not required. The general cardiologist or primary care physician does need, however, to identify that the disease is progressing toward a stage of advanced HF, and this may be challenging. Systematic screening of certain patient categories has been suggested as a way of improving referral for advanced therapy. A pilot study suggested that screening patients receiving cardiac resynchronisation therapy for possible HTx or LVAD indication identified otherwise neglected candidates.21. The Screening for Advanced Heart Failure Treatment (SEE-HF) study showed that actively screening patients

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Assessment of Eligibility for

Indications for Referral to a

Advanced Heart Failure Therapy

Specialised Heart Failure Centre

• • • • •

• • • • • •

No beta-blocker

fact

0 0

Table 2: Assessment of Eligibility for Advanced Heart Failure Treatment Versus Indications for Referral to a Specialised Heart Failure Centre

• •

• • •

• • • • •

NYHA class INTERMACS level NT-proBNP levels Electrolytes, bilirubin Echocardiography parameters, including ejection fraction, measures of right heart function, valve function Peak VO2 consumption Right heart catheterisation with assessment of cardiac index, right and left heart pressures Heart Failure Survival Score Seattle Heart Failure Model Comorbidity profile, including respiratory status, liver and kidney function Current or prior diagnosis of cancer Current psychological status and prior psychological problems Current HF treatment Inotrope dependency Repeated hospitalisations for congestion

NYHA class III–IV and Intolerance to HF medication or Hypotension or Anaemia or Deterioration of renal function or Repeated HF hospitalisations

EF = ejection fraction; HF = heart failure; INTERMACS = Interagency Registry for Mechanically Assisted Circulatory Support; NT-proBNP = N-Terminal-pro brain natriuretic peptide; NYHA = New York Heart Association; VO2 = volume oxygen.

with cardiac resynchronisation therapy and/or an ICD in an outpatient setting found few patients were candidates for advanced therapy. However, when selecting patients with an ejection fraction (EF) <40% and New York Heart Association (NYHA) class III–IV, 26% were found to have an unrecognised need for advanced therapy (HTx and/or LVAD).22 More studies are needed to evaluate the effectiveness of screening to identify candidates for advanced therapy. Clinical decision supports (CDS) may be of value in identifying patients eligible for advanced therapies. Evans, et al. developed a computer application that, by automatically extracting information from the patient’s integrated electronic health record, could monitor their HF

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Advanced Heart Failure status and alert the treating physician if the criteria for advanced HF were met.23 More patients were referred to specialised heart facilities when CDS were used than in the year before CDS were introduced. However, if information cannot be abstracted automatically – which is the case in many healthcare systems – it would be time consuming to use the application and possibly of less help in busy daily practice. Most likely, simpler tools are needed to ensure timely referral. In a study by the Swedish Heart Failure Registry, five risk factors were suggested as triggers for referral to an advanced HF centre.24 For patients with NYHA class III–IV HF and EF <40% with one or more of the defined risk factors present, 1-year survival was worse than for HF patients post-HTx or post-LVAD implantation (Figure 1). One or more risk factors is therefore reason to refer to a HF centre. The five risk factors were: systolic blood pressure <90 mmHg; creatinine >160 µmol/l, haemoglobin <120 g/l; no renin-angiotensin system antagonist and no beta-blocker. These risk factors are easily identified in daily clinical practice and reflect disease severity. The focus of the study was not on optimal biological discrimination (in which glomerular filtration rate rather than creatinine would be used, and discrimination would be formally assessed with e.g. areas under the receiver operating characteristic curves), but rather on simple, memorable and distinct criteria suitable for busy clinicians. In a recent review article, it was suggested that if a patient was highly symptomatic (NYHA III–IV) despite optimal HF treatment, this should prompt for referral to a HF centre.4 More than one hospitalisation despite good medical therapy indicates disease is severe, as do intolerance to HF medication and hyponatremia.12,25 A pragmatic approach, such as using the five risk factors or a patient being highly symptomatic despite the best care as referral criteria could increase the number of referrals. By no means does this imply that the majority of these patients would benefit from or be eligible

mbrosy AP, Fonarow GC, Butler J, et al. The global health A and economic burden of hospitalizations for heart failure: lessons learned from hospitalized heart failure registries. J Am Coll Cardiol 2014;63:1123–33. https://doi.org/10.1016/ j.jacc.2013.11.053; PMID: 24491689. 2. Xanthakis V, Enserro DM, Larson MG, et al. Prevalence, neurohormonal correlates, and prognosis of heart failure stages in the community. JACC Heart Fail 2016;4:808–15. https:// doi.org/10.1016/j.jchf.2016.05.001; PMID: 27395350. 3. Bjork JB, Alton KK, Georgiopoulou VV, et al. Defining advanced heart failure: a systematic review of criteria used in clinical trials. J Card Fail 2016;22:569–77. https://doi.org/10.1016/ j.cardfail.2016.03.003; PMID: 26975942. 4. Gustafsson F, Rogers JG. Left ventricular assist device therapy in advanced heart failure: patient selection and outcomes. Eur J Heart Fail 2017;19:595–602. https://doi.org/10.1002/ejhf.779; PMID: 28198133. 5. Metra M, Eichhorn E, Abraham WT, et al. Effects of low-dose oral enoximone administration on mortality, morbidity, and exercise capacity in patients with advanced heart failure: the randomized, double-blind, placebo-controlled, parallel group ESSENTIAL trials. Eur Heart J 2009;30:3015–26. https://doi. org/10.1093/eurheartj/ehp338; PMID: 19700774. 6. Lindenfeld J, Feldman AM, Saxon L, et al. Effects of cardiac resynchronization therapy with or without a defibrillator on survival and hospitalizations in patients with New York Heart Association class IV heart failure. Circulation 2007;115:204–12. https://doi.org/10.1161/CIRCULATIONAHA.106.629261; PMID: 17190867. 7. Lund LH, Edwards LB, Dipchand AI, et al. The registry of the International Society for Heart and Lung Transplantation: thirty-third adult heart transplantation report – 2016; focus theme: primary diagnostic indications for transplant. J Heart Lung Transplant 2016;35:1158–69. https://doi.org/10.1016/ j.healun.2016.08.017; PMID: 27772668. 8. Lund LH. Optimizing outcomes after heart transplantation. Eur J Heart Fail 2018;20:395–7. https://doi.org/10.1002/ejhf.1026; PMID: 29034592. 9. Ciarka A, Edwards L, Nilsson J, et al. Trends in the use of mechanical circulatory support as a bridge to heart transplantation across different age groups. Int J Cardiol 2017;231:225–7. https://doi.org/10.1016/j.ijcard.2016.10.049; PMID: 27776746. 10. Kirklin JK, Pagani FD, Kormos RL, et al. Eighth annual INTERMACS report: special focus on framing the impact of adverse events. J Heart Lung Transplant 2017;36:1080–6. https:// doi.org/10.1016/j.healun.2017.07.005; PMID: 28942782.

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for HTx or LVAD implantation; it means only that they deserve at least one expert assessment by a HF specialist. Additionally, underuse of intermediate-level HF interventions such as cardiac resynchronisation and ICD therapy has been reported previously, so a more liberal referral to a HF specialist seems motivated by a wish to optimise evidencebased treatments.26–28 Palliative programmes have been shown to reduce readmissions and improve symptoms in patients with end-stage HF.29 However, palliative care is substantially less implemented for patients with HF than in those with cancer, and is often initiated too late.30,31 The benefits of palliative care have been recognised by the American Heart Association and the body of literature focusing on the integration of palliative care in HF management is increasing.32 Therefore, even for patients with a heavy comorbidity burden or those who are presumed to be too old for advanced HF therapy, a referral to an advanced HF centre is justified for considering different treatment options and initiating palliative care if appropriate. Table 2 shows the important differences between the comprehensive assessment of a potential candidate for LVAD and/or HTx and suggested criteria for referring a patient to an advanced HF centre discussed in this article.

Conclusion Mortality in advanced HF remains high. Identifying patients in need of advanced therapy starts with referral to a heart failure centre. Timely referral for evaluation for HTx and LVAD therapy is crucial for the success of these treatments. In contrast to the complex criteria for selection for LVAD and HTx therapy, indication for evaluation to a HF specialist should simply be deterioration despite optimal HF care. n

11. K irklin JK, Cantor R, Mohacsi P, et al. First annual IMACS report: a global international society for heart and lung transplantation registry for mechanical circulatory support. J Heart Lung Transplant 2016;35:407–12. https://doi.org/10.1016/ j.healun.2016.01.002; PMID: 26922275. 12. Miller LW. Left ventricular assist devices are underutilized. Circulation 2011;123(14):1552–8. https://doi.org/10.1161/ CIRCULATIONAHA.110.958991; PMID: 21482973. 13. Miller LW, Guglin M. Patient selection for ventricular assist devices: a moving target. J Am Coll Cardiol 2013;61:1209–21. https://doi.org/10.1016/j.jacc.2012.08.1029; PMID: 23290542. 14. Fanaroff AC, DeVore AD, Mentz RJ, et al. Patient selection for advanced heart failure therapy referral. Crit Pathw Cardiol 2014;13:1–5. https://doi.org/10.1097/HPC.0000000000000004; PMID: 24526143. 15. Mehra MR, Canter CE, Hannan MM, et al. The 2016 International Society for Heart Lung Transplantation listing criteria for heart transplantation: a 10–year update. J Heart Lung Transplant 2016;35:1–23. https://doi.org/10.1016/ j.healun.2015.10.023; PMID: 26776864. 16. Sartipy U, Goda A, Yuzefpolskaya M, et al. Utility of the Seattle Heart Failure Model in patients with cardiac resynchronization therapy and implantable cardioverter defibrillator referred for heart transplantation. Am Heart J 2014;168:325–31. https://doi. org/10.1016/j.ahj.2014.03.025; PMID: 25173544. 17. Lund LH, Matthews J, Aaronson K. Patient selection for left ventricular assist devices. Eur J Heart Fail 2010;12: 434–43. https://doi.org/10.1093/eurjhf/hfq006; PMID: 20172939. 18. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2016;37:2129–200. https://doi.org/10.1093/ eurheartj/ehw128; PMID: 27206819. 19. Crespo-Leiro MG, Metra M, Lund LH, et al. Advanced heart failure: a position statement of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail 2018;20:1505– 35. https://doi.org/10.1002/ejhf.1236; PMID: 29806100. 20. Goda A, Williams P, Mancini D, Lund LH. Selecting patients for heart transplantation: comparison of the Heart Failure Survival Score (HFSS) and the Seattle heart failure model (SHFM). J Heart Lung Transplant 2011;30:1236–43. https://doi. org/10.1016/j.healun.2011.05.012; PMID: 21764604. 21. Zabarovskaja S, Gadler F, Gabrielsen A, et al. Identifying patients for advanced heart failure therapy by screening patients with cardiac resynchronization therapy or implantable cardioverter-defibrillator: a pilot study. J Heart Lung Transplant 2013;32:651–4. https://doi.org/10.1016/

j.healun.2013.02.008; PMID: 23701855. 22. L und LH, Trochu JN, Meyns B, et al. Screening for heart transplantation and left ventricular assist system: results from the ScrEEning for advanced Heart Failure treatment (SEE-HF) study. Eur J Heart Fail 2018;20: 152–60. https://doi.org/10.1002/ejhf.975; PMID: 28960673. 23. Evans RS, Kfoury AG, Horne BD, et al. Clinical decision support to efficiently identify patients eligible for advanced heart failure Therapies. J Card Fail 2017;23:719–26. https://doi. org/10.1016/j.cardfail.2017.08.449; PMID: 28821391. 24. Thorvaldsen T, Benson L, Stahlberg M, et al. Triage of patients with moderate to severe heart failure: who should be referred to a heart failure center? J Am Coll Cardiol 2014;63:661–71. https://doi.org/10.1016/j.jacc.2013.10.017; PMID: 24161453. 25. Trochu JN, Leprince P, Bielefeld-Gomez M, et al. Left ventricle assist device: when and which patients should we refer? Arch Cardiovasc Dis 2012;105:114–21. https://doi.org/10.1016/ j.acvd.2011.11.004; PMID: 22424329. 26. Thorvaldsen T, Benson L, Dahlstrom U et al. Use of evidencebased therapy and survival in heart failure in Sweden 2003– 2012. Eur J Heart Fail 2016;18:503–11. https://doi.org/10.1002/ ejhf.496; PMID: 26869252. 27. Bank AJ, Gage RM, Olshansky B. On the underutilization of cardiac resynchronization therapy. J Card Fail 2014;20:696–705. https://doi.org/10.1016/j.cardfail.2014.06.005; PMID: 24948569. 28. Bradfield J, Warner A, Bersohn MM. Low referral rate for prophylactic implantation of cardioverter-defibrillators in a tertiary care medical center. Pacing Clin Electrophysiol 2009;32 Suppl 1:S194–7. https://doi.org/10.1111/j.15408159.2008.02281.x; PMID: 19250092. 29. Wong FK, Ng AY, Lee PH, et al. Effects of a transitional palliative care model on patients with end-stage heart failure: a randomised controlled trial. Heart 2016;102:1100–8. https://doi.org/10.1136/heartjnl-2015-308638; PMID: 26969631. 30. Setoguchi S, Glynn RJ, Stedman M, et al. Hospice, opiates, and acute care service use among the elderly before death from heart failure or cancer. Am Heart J 2010;160:139–44. https://doi. org/10.1016/j.ahj.2010.03.038; PMID: 20598984. 31. Bakitas M, Macmartin M, Trzepkowski K, et al. Palliative care consultations for heart failure patients: how many, when, and why? J Card Fail 2013;19:193–201. https://doi.org/10.1016/ j.cardfail.2013.01.011; PMID: 23482081. 32. Diop MS, Rudolph JL, Zimmerman KM, et al. Palliative care interventions for patients with heart failure: a systematic review and meta-analysis. J Palliat Med 2017;20:84–92. https:// doi.org/10.1089/jpm.2016.0330; PMID: 27912043.

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Co-morbidities

Treatment of Heart Failure with Sodium-Glucose Cotransporter 2 Inhibitors and Other Anti-diabetic Drugs Thomas A Zelniker and Eugene Braunwald TIMI Study Group, Cardiovascular Division, Brigham and Women’s Hospital, and Department of Medicine, Harvard Medical School, Boston, MA, USA

Abstract Patients with type 2 diabetes are at increased risk of developing heart failure, cardiovascular death and renal failure. The recent results of three large sodium-glucose cotransporter 2 inhibitor cardiovascular outcomes trials have demonstrated a reduction in heart failure hospitalisation and progressive renal failure. One trial also showed a fall in cardiovascular and total death. A broad spectrum of patients with diabetes benefit from these salutary effects in cardiac and renal function and so these trials have important implications for the management of patients with type 2 diabetes. Selected glucagon-like peptide 1 receptor agonists have also been shown to reduce adverse cardiovascular outcomes.

Keywords Diabetes, heart failure, renal function, sodium-glucose cotransporter 2 inhibitors Disclosure: TAZ is supported by the German Research Foundation (Deutsche Forschungsgemeinschaft ZE 1109/1-1 to TAZ). EB has no conflicts of interest to declare. Received: 6 December 2018 Accepted: 7 January 2019 Citation: Cardiac Failure Review 2019;5(1):27–30. DOI: https://doi.org/10.15420/cfr.2018.44.1 Correspondence: Eugene Braunwald, TIMI Study Group, 60 Fenwood Road, 7th floor, Boston, MA 02115, USA. E: ebraunwald@partners.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.

With progressive ageing and the growing incidence of obesity in the population, the prevalence of type 2 diabetes (T2D) has been rising rapidly and has become a major cause of death and disability worldwide.1 It is well established that atherosclerotic cardiovascular disease (ASCVD) and renal failure are responsible for a large majority of deaths in patients with T2D.2-4 Over the past decade, the management of T2D has been undergoing an important transformation from simply targeting abnormally elevated glucose concentration to preventing complications of ASCVD, including heart failure (HF) and the progression of diabetic renal disease.5,6 Several pathophysiological mechanisms may explain the relationship between T2D and HF: T2D is associated with accelerated atherogenesis, which is responsible for macrovascular coronary atherosclerosis leading to MI and impairment of cardiovascular function. Arterial hypertension, which is common in T2D, and the ensuing left ventricular hypertrophy and increased wall stiffness also contribute to the development of HF. Some observations have suggested that T2D may be associated with a specific form of cardiomyopathy, termed diabetic cardiomyopathy, which can lead first to HF with preserved ejection fraction then progressing to HF with reduced ejection fraction.7,8 T2D can also cause microvascular obstruction, which can play an important role in the development and progression of diabetic nephropathy, which is now the leading cause of end-stage renal disease in Europe and North America.9 Disorders of the coronary microcirculation may also contribute to the development of HF with preserved ejection fraction. In addition, the

CFR_Braunwald_FINAL.indd 27

importance of the cardiorenal axis is well established with disorders of either cardiac or renal function causing malfunction in the other organ, leading to a vicious circle.10–13 In addition, HF intensifies the impairment of glucose control in patients with T2D, with the resultant glucotoxicity setting the stage for a second vicious circle.14,15 In a recent cohort study, the Swedish National Diabetes Register, >270,000 patients with T2D were matched with >1,300,000 nondiabetic controls. It showed that T2D patients in whom all five risk factors (HbA1c, LDL cholesterol, albuminuria, smoking and blood pressure) were within the target ranges exhibited similar risks of MI, stroke and death as people who do not have diabetes, but they remained at increased risk for the development of HF.16 From such studies, it has become apparent that the treatment of T2D must not only include control of glucose metabolism and of the well-established risk factors for atherosclerosis but must also reduce the risk of HF and advanced kidney disease.

Recent Developments in Type 2 Diabetes Concerns about the cardiovascular safety of the widely-used thiazolidinedione rosiglitazone in the first decade of this century prompted the US Food and Drug Administration in 2008 and the European Medicines Agency in 2009 to issue new requirements for approval of antidiabetic drugs.17–19 Specifically, these agencies required the safety of antidiabetic drugs to be demonstrated in wellpowered, non-inferiority trials. The resultant trials have both enhanced understanding of the pathobiology of T2D and confirmed that the reduction of HbA1c does not necessarily translate into a reduction of major adverse cardiovascular events.5,6,20

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Co-morbidities Figure 1: SGLT2i Treatment Effects Outcome

No of Events

MACE

HR (95% CI)

3,342

0.89 (0.83–0.96)

HHF

962

0.69 (0.61–0.79)

Composite renal endpoint

766

0.55 (0.48–0.64) 0.45 0.50

0.75 1.0 1.25 Favours Favours ← ← SGLT2i placebo

Overall treatment effects of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in three large cardiovascular outcomes trials comprising 34,322 patients. SGLT2i reduced the risk of major adverse cardiovascular events (MACE, the composite of cardiovascular death, MI and stroke), hospitalisation for heart failure (HHF) and a renal composite endpoint of worsening of eGFR, end-stage renal disease and renal death. Source: Modified from Zelniker, et al. 2019.27

Figure 2: Differential Treatment Effects of SGLT2i MACE

No of Events

Established ASCVD MRF for ASCVD

Subsequently, the results of large trials involving two other SGLT2i drugs in patients with T2D were reported: the CANagliflozin cardioVascular Assessment Study (CANVAS) Program with canagliflozin; and the Dapagliflozin Effect on Cardiovascular Events (DECLARE-TIMI) 58 trial, which studied dapagliflozin.25,26 A recent meta-analysis of the three published CV outcomes trials included a total of 34,322 patients with T2D, with 20,650 patients having established ASCVD, and 13,672 patients with multiple risk factors but no clinically apparent ASCVD. 27 Overall, SGLT2i reduced the risk of hospitalization for HF and the progression of renal disease in these patients by 31% and 45%, respectively (Figure 1). However, the benefit in reducing atherosclerotic MACE was modest and confined to those with known ASCVD (Figure 2). Caption caption caption

HR (95% CI)

2,588

0.86 (0.80–0.93)

754

1.00 (0.87–1.16) 1.0 1.25 0.75 Favours SGLT2i ← ← Favours placebo

Treatment effects of sodium-glucose cotransporter 2 inhibitor (SGLT2i) in cardiovascular outcomes trials on MACE, stratified by presence of established atherosclerotic cardiovascular disease (ASCVD) and patients with multiple risk factors (MRF) for but no clinical evidence of ASCVD. There was a significant interaction between these groups (p=0.05). Source: Modified from Zelniker, et al. 2019.27

Figure 3: Overview of Unfavourable and Favourable Effects of SGLT2i in Patients with Type 2 Diabetes

Sodium-Glucose Cotransporter 2 Inhibitor Mechanisms of Action Although the precise molecular mechanisms mediating the reduction in adverse cardiovascular and renal outcomes of SGLT2i have not been fully defined (Figure 3), their principal beneficial action appears to result from blockade of the reabsorption of glucose and sodium from the glomerular filtrate by the proximal tubule, leading to their excretion into the urine. This action reduces extracellular fluid volume, which in turn increases hematocrit and lowers cardiac preload, afterload, arterial stiffness, blood pressure and left ventricular mass.28 There is a reduction in epicardial adipose tissue and with it, a number of noxious stimuli.29,30 It has also been suggested that SGLT2i drugs improve myocardial performance by increasing the metabolism of beta-hydroxybutyrate, a preferential fuel.31,32 They may also inhibit the Na+/H+ exchanger, resulting in a lowering of cytosolic Na+ and Ca2+ which may be cardioprotective.33 It has also been suggested that SGLT2i may inhibit cardiac fibrosis.34

Unfavourable effects 1. Genital infections 2. Diabetic ketoacidosis 3. Amputations 3. Fractures

Favourable effects 1. Prevention of heart failure 2. Preservation of renal function 3. Reduction in major adverse cardiovascular events 4. Reduction in blood pressure 5. Weight loss 6. Improvement in glycaemia

Sodium-Glucose Cotransporter 2 Inhibitors: an Advance in Type 2 Diabetes Treatment A number of large cardiovascular outcomes trials showed that these agents reduce HbA1c levels and are generally safe.20–23 In contrast, the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) trial of empagliflozin, a sodium-glucose cotransporter 2 inhibitor (SGLT2i), lowered major adverse cardiovascular events (MACE), the composite of cardiovascular (CV) death, MI and stroke, by a modest, albeit statistically significant 14%, a finding that was, of course, welcomed.24 Unexpectedly, this trial also demonstrated a significant 38% reduction (HR 0.62; 95% CI [0.49– 0.77]) in CV death and a 32% fall in all-cause death. A significant 35% lowering in hospitalisation for HF was also observed, indicating that the improvement in cardiac pump function was primarily responsible for these reductions of CV and all-cause death.

CFR_Braunwald_FINAL.indd 28

SGLT2i drugs cause vasoconstriction of the afferent glomerular arterioles and dilatation of the efferent arterioles. These changes in the nephrons’ microcirculation lower the intraglomerular pressure, thereby reducing albuminuria and glomerular fibrosis and delaying the decline in renal function.28,35 However, in two of the three large trials in the SGLT2i metaanalysis, patients with estimated glomerular filtration rates (eGFR) lower than 30 ml/min/1.73m2 body surface area (BSA) were excluded and, in the third, patients with a creatinine clearance <60 ml/min/1.73m2 BSA were excluded. Given the frequency of reductions of eGFR below these values in people with T2D, it is important to determine the efficacy and safety of these drugs in such patients.

Adverse Effects SGLT2i drugs are generally well tolerated and safe. However, their glucosuric effect increases the risk of genital infections. An increased risk of fractures and lower limb amputations (predominantly of the toes and metatarsal bones) have been reported with canagliflozin, but not with empagliflozin or dapagliflozin.25 A near doubling of an uncommon complication, diabetic ketoacidosis, has also been observed.27 Initial concerns about an increased risk of bladder cancer have not been borne out.26,27 The salutary effects of SGLT2i on HF in patients with T2D have raised the intriguing question of whether these agents can also be effective in the treatment and/or the prevention of HF in patients with HF without

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Treatment of Heart Failure with Anti-diabetic Drugs T2D; this question is being addressed by ongoing trials. The form of HF affected in the SGLT2i trials – with reduced and/or preserved ejection fraction – was not defined in the above-mentioned trials and this issue is receiving attention.

Glucagon-like Peptide 1 Receptor Agonists In addition to the SGLT2i, three glucagon-like peptide 1 receptor agonists (GLP1-RA) have been shown to be of clinical benefit in T2D cardiovascular outcomes trials. This class of drugs has been used for a number of years to reduce HbA1c. Liraglutide, semaglutide and albiglutide have been demonstrated to reduce the risk of MACE significantly, with liraglutide also lowering the incidence of CV death.36–38 In addition, a recent press release has stated that the Researching Cardiovascular Events With a Weekly Incretin in Diabetes (REWIND) trial (NCT01394952) studying the CV safety of dulaglutide in a predominantly primary prevention cohort reduced the risk of MACE significantly.39 A press release about the trial Investigating the Cardiovascular Safety of Oral Semaglutide in Subjects With Type 2 Diabetes (PIONEER 6; NCT02692716) reported that oral semaglutide had been proven to be safe and reduced the risk of CV death significantly but it did not meet statistical significance for MACE.40 No significant reduction in hospitalisation for HF or a slowing in the decline of eGFR have been reported for any GLP1-RA to date, although numerical reductions in HF have been seen for both liraglutide and albiglutide.36,38 The most recent guidelines for the treatment of T2D released by the American Diabetes Association and the European Association for the

10.

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12.

13.

regg EW, Li Y, Wang J, Burrows NR, et al. Changes in G diabetes-related complications in the United States, 1990– 2010. N Engl J Med 2014;370:1514–23. https://doi.org/10.1056/ NEJMoa1310799; PMID: 24738668. Ahmad FS, Ning H, Rich JD, et al. Hypertension, obesity, diabetes, and heart failure-free survival: the Cardiovascular Disease Lifetime Risk Pooling Project. JACC Heart Fail 2016;4:911–9. https://doi.org/10.1016/j.jchf.2016.08.001; PMID: 27908389. Benjamin EJ, Virani SS, Callaway CW, et al. Heart disease and stroke statistics – 2018 update: a report from the American Heart Association. Circulation 2018;137:e67–e492. https://doi.org/10.1161/CIR.0000000000000558; PMID: 29386200. American Diabetes Association. 10. Microvascular complications and foot care: Standards of Medical Care in Diabetes – 2018. Diabetes Care 2018;41(Suppl 1):S105–S18. https://doi.org/10.2337/dc18-S010; PMID: 29222381. Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein HC, Miller ME, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:2545–59. https://doi.org/10.1056/NEJMoa0802743; PMID: 18539917. Advance Collaborative Group, Patel A, MacMahon S, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008;358:2560–72. https://doi.org/10.1056/NEJMoa0802987; PMID: 18539916 Boudina S, Abel ED. Diabetic cardiomyopathy revisited. Circulation 2007;115:3213–23. https://doi.org/10.1161/ CIRCULATIONAHA.106.679597; PMID: 17592090. Schilling JD, Mann DL. Diabetic cardiomyopathy: bench to bedside. Heart Fail Clin 2012;8:619–31. https://doi.org/10.1016/ j.hfc.2012.06.007; PMID: 22999244. Umanath K, Lewis JB. Update on diabetic nephropathy: core curriculum 2018. Am J Kidney Dis 2018;71:884–95. https://doi. org/10.1053/j.ajkd.2017.10.026; PMID: 29398179. Sattar N, McGuire DK. Pathways to cardiorenal complications in type 2 diabetes mellitus: a need to rethink. Circulation 2018;138:7–9. https://doi.org/10.1161/ CIRCULATIONAHA.118.035083; PMID: 29967228. Bock JS, Gottlieb SS. Cardiorenal syndrome: new perspectives. Circulation 2010;121:2592–600. https://doi.org/10.1161/ CIRCULATIONAHA.109.886473; PMID: 20547939. Hatamizadeh P, Fonarow GC, Budoff MJ, et al. Cardiorenal syndrome: pathophysiology and potential targets for clinical management. Nat Rev Nephrol 2013;9:99–111. https://doi. org/10.1038/nrneph.2012.279; PMID: 23247571. Braam B, Joles JA, Danishwar AH, Gaillard CA. Cardiorenal syndrome –current understanding and future perspectives. Nat Rev Nephrol 2014;10:48–55. https://doi.org/10.1038/

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Study of Diabetes begin with a recommendation for lifestyle changes for all patients.41 Metformin remains the primary pharmaceutical agent for reducing HbA1c. This drug is efficacious, well tolerated and inexpensive. If HbA1c remains above target levels despite the abovecited therapy, either an SGLT2i or one of the aforementioned GLP1-RAs with proven benefit should be added. Based on the finding in the meta-analysis summarised above, which was published after the release of the most recent practice guidelines, the authors of this review recommend the administration of an SGLT2i first, especially in patients with T2D and ASCVD, HF, chronic kidney disease and/or kidney disease and/or multiple risk factors.27 When SGLT2i drugs are not tolerated, contraindicated or do not bring the HbA1c to target levels, the addition or substitution of a GLP1-RA with proven CV benefit should be considered. Thiazolidinediones have been reported to increase fluid retention and cardiac decompensation and should not be used in patients with HF.42 Caution should also be applied when using certain DPP-4 inhibitors.20

Conclusion After many neutral findings in CV outcomes trials in patients with T2D, the results of the trials with SGLT2i have shown that drugs in this class cause robust reductions in HF and delay the development of renal failure. Selected GLP-1-RA agents also appear beneficial in reducing atherosclerotic cardiac events in these patients. These two classes of agents are meeting important needs in the management of the growing number of people with T2D.

nrneph.2013.250; PMID: 24247284. 14. M amas MA, Deaton C, Rutter MK, et al. Impaired glucose tolerance and insulin resistance in heart failure: underrecognized and undertreated? J Card Fail 2010;16:761–8. https://doi.org/10.1016/j.cardfail.2010.05.027. PMID: 20797600. 15. Maack C, Lehrke M, Backs J, et al. Heart failure and diabetes: metabolic alterations and therapeutic interventions: a state-of-the-art review from the Translational Research Committee of the Heart Failure Association-European Society of Cardiology. Eur Heart J 2018;39:4243–54. https://doi. org/10.1093/eurheartj/ehy596; PMID: 30295797. 16. Rawshani A, Rawshani A, Franzen S, et al. Risk factors, mortality, and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2018;379:633–44. https://doi. org/10.1056/NEJMoa1800256; PMID: 30110583. 17. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007;356:2457–71. https://doi.org/10.1056/ NEJMoa072761; PMID: 17517853. 18. US Food and Drug Administration. Guidance for industry: diabetes mellitus evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. 2008. Available at: www.fda.gov/downloads/Drugs/ GuidanceComplianceRegulatoryInformation/Guidances/ ucm071627.pdf (accessed 7 January 2019). 19. European Medicines Agency. Guideline on clinical investigation of medicinal products in the treatment or prevention of diabetes mellitus. 2018. Available at: https:// www.ema.europa.eu/documents/scientific-guideline/draftguideline-clinical-investigation-medicinal-products-treatmentprevention-diabetes-mellitus_en.pdf (accessed 16 January 2019). 20. Scirica BM, Bhatt DL, Braunwald E, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 2013;369:1317–26. https://doi. org/10.1056/NEJMoa1307684; PMID: 23992601. 21. Green JB, Bethel MA, Armstrong PW, et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med 2015;373:232–42. https://doi.org/10.1056/NEJMoa1501352; PMID: 26052984. 22. Rosenstock J, Perkovic V, Johansen OE, et al. Effect of linagliptin vs placebo on major cardiovascular events in adults with type 2 diabetes and high cardiovascular and renal risk: the CARMELINA randomized clinical trial. JAMA 2018. https://doi.org/10.1001/jama.2018.18269; PMID: 30418475; epub ahead of press. 23. White WB, Cannon CP, Heller SR, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med 2013;369:1327–35. https://doi.org/10.1056/

NEJMoa1305889; PMID: 23992602. 24. Z inman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117–28. https://doi.org/10.1056/ NEJMoa1504720; PMID: 26378978. 25. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017;377:644–57. https://doi.org/10.1056/NEJMoa1611925; PMID: 28605608. 26. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2018. https://doi.org/10.1056/NEJMoa1812389; PMID: 30415602; epub ahead of press. 27. Zelniker TA, Wiviott SD, Raz I, et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet 2019;393:31–9. https://doi.org/10.1016/S01406736(18)32590-X; PMID: 30424892. 28. Zelniker TA, Braunwald E. Cardiac and renal effects of sodium-glucose co-transporter 2 inhibitors in diabetes. J Am Coll Cardiol 2018;72:1845–55. https://doi.org/10.1016/ j.jacc.2018.06.040; PMID: 30075873. 29. Sato T, Aizawa Y, Yuasa S, et al. The effect of dapagliflozin treatment on epicardial adipose tissue volume. Cardiovasc Diabetol 2018;17:6. https://doi.org/10.1186/s12933-017-0658-8; PMID: 29301516. 30. Packer M. Leptin-aldosterone-neprilysin axis: identification of its distinctive role in the pathogenesis of the three phenotypes of heart failure in people with obesity. Circulation 2018;137:1614–31. https://doi.org/10.1161/ CIRCULATIONAHA.117.032474; PMID: 29632154. 31. Ferrannini G, Hach T, Crowe S, et al. Energy balance after sodium-glucose cotransporter 2 inhibition. Diabetes Care 2015;38:1730–5. https://doi.org/10.2337/dc15-0355; PMID: 26180105. 32. Ferrannini E, Baldi S, Frascerra S, et al. Shift to fatty substrate utilization in response to sodium-glucose cotransporter 2 inhibition in subjects without diabetes and patients with type 2 diabetes. Diabetes 2016;65:1190–5. https://doi.org/10.2337/ db15-1356; PMID: 26861783. 33. Uthman L, Baartscheer A, Bleijlevens B, et al. Class effects of SGLT2 inhibitors in mouse cardiomyocytes and hearts: inhibition of Na+/H+ exchanger, lowering of cytosolic Na+ and vasodilation. Diabetologia 2018;61:722–6. https://doi. org/10.1007/s00125-017-4509-7; PMID: 29197997. 34. Verma S, McMurray JJV. SGLT2 inhibitors and mechanisms of cardiovascular benefit: a state-of-the-art review. Diabetologia 2018;61:2108–17. https://doi.org/10.1007/s00125-018-4670-7. PMID: 30132036.

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Co-morbidities 35. H eerspink HJ, Perkins BA, Fitchett DH, et al. Sodium glucose cotransporter 2 inhibitors in the treatment of diabetes mellitus: cardiovascular and kidney effects, potential mechanisms, and clinical applications. Circulation 2016;134:752–72. https://doi.org/10.1161/ CIRCULATIONAHA.116.021887; PMID: 27470878. 36. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016;375:311–22. https://doi.org/10.1056/NEJMoa1603827; PMID: 27295427. 37. Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2016;375:1834–44. https://doi.org/10.1056/ NEJMoa1607141; PMID: 27633186. 38. Hernandez AF, Green JB, Janmohamed S, et al. Albiglutide

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and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial. Lancet 2018;392:1519–29. https://doi.org/10.1016/S01406736(18)32261-X; PMID: 30291013. 39. Eli Lilly. Trulicity® (dulaglutide) demonstrates superiority in reduction of cardiovascular events for broad range of people with type 2 diabetes. Press release. 11 May 2018. Available at: https://investor.lilly.com/news-releases/news-release-details/ trulicityr-dulaglutide-demonstrates-superiority-reduction (accessed 15 January 2019). 40. Novo Nordisk. Oral semaglutide demonstrates favourable cardiovascular safety profile and significant reduction in cardiovascular death and all-cause mortality in people with type 2 diabetes in the PIONEER 6 trial. Press release.

23 November 2018. Available at: www.novonordisk.com/ content/Denmark/HQ/www-novonordisk-com/en_gb/home/ media/news-details.2226789.html (accessed 15 January 2019). 41. Davies MJ, D’Alessio DA, Fradkin J, et al. Management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 2018;41:2669–701. https://doi.org/10.2337/ dci18-0033; PMID: 30291106. 42. Nesto RW, Bell D, Bonow RO, et al. Thiazolidinedione use, fluid retention, and congestive heart failure: a consensus statement from the American Heart Association and American Diabetes Association. Diabetes Care 2004;27:256–63. https://doi.org/10.2337/diacare.27.1.256; PMID: 14693998.

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Co-morbidities

Subclinical Left Ventricular Dysfunction During Chemotherapy Martin Nicol, 1 Mathilde Baudet 1 and Alain Cohen-Solal 1,2 1. Lariboisiere/Saint Louis Hospital, Cardiology Department, Paris, France; 2. UMR-S942 (BioCANVAS), Paris Diderot University, Paris, France

Abstract Subclinical left ventricular dysfunction is the most common cardiac complication after chemotherapy administration. Detection and early treatment are major issues for better cardiac outcomes in this cancer population. The most common definition of cardiotoxicity is a 10-percentage point decrease of left ventricular ejection fraction (LVEF) to a value <53%. The myocardial injury induced by chemotherapies is probably a continuum starting with cardiac biomarkers increase before the occurence of a structural myocardial deformation leading to a LVEF decline. An individualised risk profile (depending on age, cardiovascular risk factors, type of chemotherapy, baseline troponin, baseline global longitudinal strain and baseline LVEF) has to be determined before starting chemotherapy to consider cardioprotective treatment. To date, there is no proof of a systematic cardioprotective treatment (angiotensin-converting enzyme inhibitor and/or betablocker) in all cancer patients. However, early cardioprotective treatment in case of subclinical left ventricular dysfunction seems to be promising in the prevention of cardiac events.

Keywords Left ventricular dysfunction, cardio-oncology, cardiotoxicity Disclosure: The authors have no conflicts of interest to declare Received: 22 July 2018 Accepted: 29 November 2018 Citation: Cardiac Failure Review 2019;5(1):31–6. DOI: https://doi.org/10.15420/cfr.2018.25.1 Correspondence: Alain Cohen-Solal, 2 Rue Ambroise-Paré, Lariboisière Hospital, 75010 Paris, France. E: alain.cohen-solal@aphp.fr 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.

Advances in the early detection and treatment of cancer have improved overall survival in cancer patients. Nevertheless, cardiovascular diseases appear as the major cause of morbidity and mortality among cancer survivors.1 Left ventricular (LV) dysfunction and/or heart failure are the most common cardiovascular complications after administration of chemotherapies. The term ‘cardiotoxicity’ is generally used to refer to LV dysfunction. The two main anticancer agents responsible for LV dysfunction are anthracyclines and targeted therapies (tyrosine kinase inhibitor, anti-human epidermal growth factor receptor 2, anti-vascular endothelial growth factor, proteasome inhibitors). Recently, immune fulminant myocarditis was reported with the use of checkpoint immune inhibitors (anti-programmed cell death protein 1, anti-programmed cell death ligand 1, anti-cytotoxic T lymphocyte-associated protein 4), suggesting new cardiotoxicity pathways.2 LV dysfunction remains asymptomatic for a long time, but once symptomatic, the prognosis is one of the poorest in the heart failure population.3 The challenge is then to detect myocardial toxicity before symptomatic heart failure. The aim of this review was to define subclinical LV dysfunction during chemotherapy, to identify the best early strategy for cardiodetection, and to summarise the studies’ results about a cardioprotective treatment for cancer patients with subclinical LV dysfunction.

Definition of Left Ventricular Dysfunction Induced by Cardiotoxic Chemotherapies LV dysfunction induced by cardiotoxic chemotherapies is defined by a decrease in left ventricular ejection fraction (LVEF) of >10 percentage points to a value <53%.4 To detect early myocardial damage before a

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change in LVEF, an increase in biomarkers levels (mainly troponin I; TnI) and a decrease of >15% of the global longitudinal strain are useful tools. According to the European Society of Cardiology, LVEF assessment can be performed by echocardiography (attempting to favour 3D LVEF), cardiac nuclear imaging and cardiac MRI.2,5

Detecting Subclinical Left Ventricular Dysfunction Before LVEF Decrease Identifying High-risk Patients The paediatric population (aged <18 years) or older patients (aged >65 years) have an increased risk of cardiotoxicity. Moreover, cardiovascular risk factors (arterial hypertension, diabetes, hypercholesterolaemia or family history of cardiovascular disease), current myocardial disease, previous cardiotoxic cancer therapies or lifestyle risk factors (smoking, alcohol, sedentary habits, obesity) are associated with LV dysfunction related to cancer therapy. A careful baseline evaluation and cardiac monitoring during and after treatment of these patients is recommended.5

Monitoring Using Cardiac Biomarkers Troponins (Troponin I and Troponin T) Cardinale et al. measured TnI in 703 breast cancer patients before chemotherapy, 3 days after and 1 month after chemotherapy, and showed that elevated TnI was able to predict cardiovascular events (cardiovascular mortality, pulmonary oedema, LVEF <25%, arrhythmias).6 Patients with an early or persistent increase of TnI ≥0.08 ng/ml had a higher incidence of cardiac events (37% and 84% respectively; p<0.001).

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Co-morbidities In a cohort of 204 patients, including 133 with breast cancer, the same authors studied TnI changes in those receiving high-dose chemotherapy, measured before the start of the chemotherapy and at 12, 24, 36 and 72 hours after. In 53% of cases, an increase in TnI occurred within 72 hours after chemotherapy. At the end of chemotherapy, a decrease of LVEF was observed in the TnI+ and TnI− groups, but LVEF decline was significantly lower in the TnI− group. At 10 months, LVEF was still impaired in the TnI+ group, whereas it remained at the baseline level in the TnI− group. TnI levels were negatively correlated with the LVEF changes (r = –0.87, p<0.0001).7 In 2010, Cardinale et al. measured TnI in 251 breast cancer patients treated with targeted anti-human epidermal growth factor receptor 2 therapy.8 They observed a TnI increase in 36 patients (14%), most of the time after the first cycle of trastuzumab. In patients developing cardiotoxicity (defined by LVEF decrease >10 units and <50%), plasmatic TnI was 32 pg/ml versus 17 pg/ml in patients without cardiotoxicity (p<0.05). A total of 62% of patients with TnI increase developed LV dysfunction (versus 5% of patients without TnI increase; p<0.001). In addition, those patients were less likely to recover from LV dysfunction and had more cardiovascular events. More recently, a study of patients receiving trastuzumab and lapatinib (tyrosine kinase inhibitor) after anthracycline chemotherapy also showed that an increase in TnI preceded the maximal LVEF decrease.9 In metastatic kidney cancer patients treated with sunitinib (tyrosine kinase inhibitor), a prospective study revealed an increase of troponin T in 10% of cases. Almost all the patients (8/9) with troponin increase had a LV dysfunction.10 Ederhy et al. reported that in metastatic solid tumours of patients treated with anti-vascular endothelial growth factor and tyrosine kinase inhibitors, TnI elevation occurred in 11%, but this was not due to myocarditis or acute coronary syndrome.11 TnI elevation was not associated with a decrease in LVEF at the time of the patients’ inclusion. The lack of prospective follow-up prevented the authors from knowing if these patients with a TnI increase had a LVEF decline. Several studies failed to prove the troponin value to detect cardiotoxicity.12,13 These different results may be explained by different troponin assay (T or I, hypersensitive or not), different definitions of cardiotoxicity, and different populations and treatments (type, doses).

Natriuretic Peptides Lenihan et al. performed a study of 109 patients receiving anthracyclines, in which 10% had a cardiac event (LV dysfunction, arrhythmias, sudden death, sudden cardiac arrest).14 All of these patients had at least one brain natriuretic peptide (BNP) level >100 μg/ml. The biomarkers were assayed before each cycle of chemotherapy and 24 hours later.

In a study of 159 metastatic renal cell carcinomas in patients treated with tyrosine kinase inhibitors, 43 developed cardiotoxicity (defined by elevated NT-proBNP and LVEF drop). Of note, 12 of 38 patients with increased NT-proBNP developed a LV dysfunction.18 In a prospective study of metastatic renal cell carcinoma treated with sunitinib, a LVEF decline of 1.9% was found after the first cycle of chemotherapy, but was not associated with any changes in BNP level.19 It should be noted, however, that many studies have shown no correlation between an increase of NT-proBNP or BNP and cardiac dysfunction.20,21 Indeed, Daugaart et al. showed no correlation between baseline BNP or BNP changes with LVEF after chemotherapy.22 The main reasons for the negative results are the lack of a standardised range. Elderly cancer patients often have worse renal function and also higher natriuretic peptide levels.

Other Proposed Biomarkers Myeloperoxidase is a marker of oxidative stress, one of the key elements in the pathophysiology of anthracycline cardiotoxicity. In a cohort of 78 patients with breast cancer undergoing doxorubicin and trastuzumab therapy, an increase of plasmatic myeloperoxidase was associated with a greater risk of cardiotoxicity (defined by an asymptomatic reduction of LVEF of >10% to <55%; HR 1.34, p=0.04).23 The subgroup of patients with myeloperoxidase and troponin increases developed higher cardiotoxicity. MicroRNAs (miRNAs) are small, non-coding RNA molecules that play an important role in the regulation of gene expression. They can be associated with cardiovascular diseases. In 24 children treated with anthracyclines compared with nine children treated with non-cardiotoxic chemotherapies, plasma miRs-29b and -499 levels were upregulated 6–24 hours after anthracycline administration. The authors found a correlation between miRs expression, anthracycline doses and troponin T increase.24 In a breast cancer population treated with doxorubucin, the circulating level of miR-1 was associated with LVEF decrease and was better than TnI to discriminate patients who develop cardiotoxicity.25 Some biomarkers of inflammation have been studied. Mercuro et al. showed an interesting correlation between interleukin-6 increase and systolic function decrease in a epirubicin-treated population.26 Somehow, Ky et al. did not find any correlation between C-reactive protein rise and cardiotoxicity in a breast cancer population treated with doxorubicin and trastuzumab.23 Beer et al. also reported through proteomic profiling that high baseline immunoglobulin E levels were associated with a lower risk of cardiotoxicity in doxorubicin- and trastuzumab-treated cancer patients.27

In a study conducted by Pichon et al. of 79 women treated for breast cancer with anthracyclines, a BNP level >51.3 ng/l predicted cardiotoxicity (defined by a LVEF decrease in ventriculography) with a sensitivity of 83% and specificity of 90%.15

Monitoring Using Cardiac Imaging

Sandri et al. reported that a persistently elevated N-terminal pro BNP (NT-proBNP) after anthracycline administration predicts LV dysfunction.16 In breast cancer patients treated with anthracyclines and trastuzumab, De Iulius et al. found elevated NT-proBNP levels at each cycle of chemotherapy, whereas LVEF was not modified. This correlated with the 1-year mortality.17

For years, LVEF was the only parameter monitoring method that detected cardiotoxicity, and multigated acquisition was the most common method used by oncologists. In the past 10 years, 2D and 3D echocardiography has become the standard for myocardial function assessment. Diastolic dysfunction or Doppler imaging have been promising parameters to detect subclinical cardiotoxicity, but current research is focusing on myocardial deformation analysis.4

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Subclinical Left Ventricular Dysfunction During Chemotherapy Deformation Imaging by 2D Echocardiography Global longitudinal strain (GLS) is a strong predictor of cardiovascular morbidity and mortality in several cardiac diseases, and seems to be a consistent marker of cardiotoxicity. Negishi et al. showed that GLS was significantly decreased in 24 patients developing cardiotoxicity (defined as a >10% decline from baseline LVEF). They also observed that an 11% decrease of GLS predicts cardiotoxicity (sensitivity 65% and specificity 94%).28 At 12-month follow-up, longitudinal strain was still associated with LVEF decline.29 Recently, in a population of patients with haematological diseases (lymphoma, leukaemia) treated with anthracyclines, GLS <–17.45% after 150 mg/m² of doxorubicin had a sensitivity of 67% and a specificity of 97% for the detection of cardiotoxicity at 1 year (defined as a decrease of >10% of the LVEF with a LVEF <53%).30 The expert consensus of the American Society of Echocardiography and the European Association of Cardiovascular Imaging considered a 15% reduction of GLS as a significant change to detect cardiotoxicity.4

An Integrated Approach In a small study of 44 patients treated with anthracycline and trastuzumab, Sawaya et al. showed that a 10% decrease of GLS combined with an increase of TnI from baseline to 3 months had an 83% positive predictive value and an 89% negative predictive value to detect cardiotoxicity (as defined as a symptomatic decrease >5% of LVEF with LVEF <55% or an asymptomatic decrease >10% with LVEF <55%).41 The same team showed, in a breast cancer population treated with anthracycline and trastuzumab, that a GLS >–19% and a TnI >30 pg/ml have less sensitivity, but a 93% specificity to detect cardiotoxicity.31 Integrated biomarkers and cardiac imaging appears as a promising approach to precisely detect and predict cardiotoxicity.

3D Echocardiography 3D LVEF was shown to have the lowest temporal variability.32 A recent study of breast cancer patients has suggested that nadir LVEF values were identified by 3D echocardiography earlier than 2D echocardiography, suggesting that 3D measured LVEF might be a useful method to identify early cardiac injury.33 3D LVEF and myocardial strain were associated with concurrent and subsequent changes in 2D LVEF, and concurrent change in diastolic function (E/e’). When adjusted for the respective 2D parameters, post-anthracycline 3D LVEF and global circumferential strain predicted subsequent 2D LVEF.

Cardiac Magnetic Resonance Cardiac magnetic resonance (CMR) is particularly interesting in the cancer population, because of its spatial and temporal resolution, its reproducibility and accuracy for LVEF assessment. Recent evidence suggests that LV global circumferential strain and GLS measured with feature-tracking CMR may also identify early LV dysfunction.34 CMR also helps us to better understand that the decrease in LVEF and strain in cancer patients receiving chemotherapy is partly explained by the decrease in LV end diastolic volume due to a decrease in preload (vomiting, diarrhoea, sepsis leading to dehydration); therefore, LV end diastolic volume and LV end systolic volume should always be taken into account.35 Increased LV afterload represents a condition

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that may promote an increase in LV end systolic volume related to a factor extrinsic to the LV myocardium; for example, increased vascular resistance resulting from administration of tyrosine kinase inhibitors or endothelium receptors antagonists.36 In cancer patients receiving trastuzumab, a decrease of global circumferential strain and GLS with an increase of LV end diastolic volume seems to predict LV dysfunction.37 CMR may facilitate our understanding for cardiotoxicity pathogenesis. Myocardial tissue changes, such as intracellular and interstitial oedema, and fibrosis, may precede the alterations in LV volumes, reduction in LVEF, or changes in myocardial strain. and may represent early markers of myocardial injury. Also, there is accumulating evidence of the presence of diffuse interstitial fibrosis (assessed by increased T1 mapping and extracellular volume fraction in anthracycline-induced cardiomyopathy), independent of cardiovascular comorbidities and associated with impaired diastolic function.38 There are also many aetiologies of myocellular dysfunction that lead to LV dysfunction in patients receiving cardiotoxic chemotherapies that CMR can diagnose: myocarditis, stress-induced cardiomyopathy, myocellular injury and interstitial fibrosis.39

Should We Treat Subclinical LV Dysfunction In Primary Prevention? There is currently no evidence showing that a cardioprotective treatment, such as angiotensin-converting enzyme (ACE) inhibitor and/or beta-blocker, should be given to all cancer patients undergoing potential cardiotoxic chemotherapy. Table 1 provides a summary of ACE inhibitors and beta-blockers in primary prevention of cardiotoxicity before chemotherapy. Regarding patients treated with anthracycline for haematological malignancies, Bosch et al. showed a preventive effect of enalapril associated with carvedilol.40 The Adjuvant Breast Cancer Therapy (PRADA) trial more recently showed a benefit of angiotensin 2 receptor antagonists (candesartan) to prevent LVEF decrease, but metoprolol had no protective effect.41 Akpek et al. showed a beneficial effect of spironolactone on the prevention of myocardial dysfunction (defined by a 10% decrease of LVEF), but only 80 patients were randomised.42 Recently, the Carvedilol Effect for Prevention of Chemotherapy-Related CardiotoxicitY (CECCY) study, which tested the cardioprotective effect of systemic carvedilol preventive therapy, did not find any benefit in LV dysfunction prevention, but showed a TnI decrease at 6 months compared with a placebo.43 Boekhout et al. did not find any benefit of candesartan in the prevention of trastuzumab-induced cardiotoxicity.44 However, Pituskin et al. showed that perindopril and bisoprolol prevented the LVEF decrease, but had no effect on cardiac remodelling at 1 year compared with a placebo.45 More recently, Cardinale et al. compared the initiation of treatment with enalapril either systematically in prevention or during a troponin increase after receiving an anthracycline-based regimen in a low cardiovascular risk population (4% hypertension, 4% diabetes). The incidence of troponin elevation was 23% in the prevention group (treated with enalapril) and 26% in the non-treated group, respectively; p=0.50. Only three (1.1%) patients developed cardiotoxicity (defined as a LVEF decrease <10 percentage points from baseline to a value <50%), and there was no difference in terms of cardiac dysfunction in the two groups. This study suggests that in a low cardiovascular risk population, systematic treatment does not bring any benefit compared to a strategy guided on cardiac biomarkers increase.46

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Co-morbidities Table 1: Summary of Angiotensin-converting Enzyme Inhibitor and/or Beta-blocker in the Primary Prevention of Cardiotoxicity Before Chemotherapy Author and year

Medication

Chemotherapy

Patients (n)

Follow-up (months)

Results

Kalay et al. 200652

Carvedilol versus placebo

Anthracycline

Placebo: LVEF ∆ –16% Carvedilol: LVEF ∆ –1.5%

Georgakapoulos et al.

Metoprolol versus enalapril versus placebo

Anthracycline

125

201053

Metoprolol: LVEF ∆ −3.7%* Enalapril: LVEF ∆ −2% Placebo: LVEF ∆ −1.4%

Bosch et al. 201340

Enalapril + carvedilol versus placebo

Anthracycline

ACEI + BB: LVEF ∆ 0% Placebo: LVEF ∆ –11%

Akpek et al. 201442

Spironolactone versus placebo

Anthracycline

Spironolactone: LVEF ∆ −1.5%* Placebo: LVEF ∆ −11%*

Gulati et al. 201641

Candesartan versus metoprolol versus placebo

Anthracycline

130

3–12

Candesartan: LVEF ∆ −0.8%* Metoprolol: LVEF ∆ −0.6% Placebo: LVEF −2.6%

Boekhout et al. 201644

Candesartan versus placebo

Trastuzumab

206

Candesartan : LVEF ∆ −0% Placebo : LVEF ∆ −1.5%

Pituskin et al. 201745

Perindopril versus bisoprolol versus placebo

Trastuzumab

Perindopril: LVEF ∆ −3% Bisoprolol: LVEF ∆ −1%* Placebo: LVEF ∆ −5% No effect on remodelling

Avila et al. 201843

Carvedilol versus placebo

Anthracycline

200

Carvedilol : LVEF ∆ −1.4% Placebo : LVEF ∆ −2%

*p<0.05. ∆: change from baseline LVEF; ACEI = angiotensin-converting enzyme inhibitor; BB = beta-blocker; LVEF = left ventricular ejection fraction.

As reviewed in Table 1, the systematic use of heart failure therapy in the primary setting remains controversial. However, a high cardiotoxicity risk population seems to benefit from an early introduction of heart failure therapy. In contrast, low-risk patients may not benefit from a cardioprotective treatment and be unnecessarily exposed to adverse events, such as hypotension and renal failure.

Should We Treat Subclinical LV Dysfunction If Troponin Increases? The potential value of a troponin-guided cardioprotective treatment was investigated by Cardinale in 2006 in a prospective randomised study enrolling 473 patients treated with anthracycline. TnI was measured at each chemotherapy administration, and 114 patients showed an increase of TnI. In this population, 1 month after the end of anthracycline treatment, patients were randomised to receive a 1-year enalapril treatment or placebo. At 12 months, no cardiotoxicity (defined as LVEF decrease <10 percentage points from baseline to a value <50%), was noted in the enalapril group, whereas 43% of patients developed a LV dysfunction in the placebo group (p<0.001). Moreover, the incidence of cardiotoxicity was higher in the persistent troponin increase group than those who showed an increase of troponin only during the anthracycline regimen. The placebo group exhibited a higher risk of cardiac events.47

Should We Treat Subclinical LV Dysfunction If Global Longitudinal Strain Decreases? GLS-guided heart failure therapy is less studied. A small, observational, non-randomised study enrolled 159 patients receiving anthracycline, trastuzumab or both. Fifty-two patients showed a decrease of GLS >–11% at 6 months after baseline evaluation. Of 52 patients, 24 were treated with beta-blockers and 28 with a placebo. After 6 months of treatment, GLS and LVEF significantly improved in the beta-blockers group, but not in the placebo group.48 The Strain SUrveillance During Chemotherapy for Improving Cardiovascular OUtcomes (SUCCOUR) study will give

CFR_Cohen Solal_FINAL.indd 34

some answers. Indeed, in this study in progress, patients with a relative reduction of GLS by ≥12% are treated with cardioprotective therapy.49

Should We Treat Subclinical LV Dysfunction If LVEF is <53%? According to the position paper of the Working Group on Cardiooncology of the European Society of Cardiology, ACE inhibitors and beta-blockers are recommended in patients with asymptomatic cardiac dysfunction to prevent the development of symptomatic heart failure or further dysfunction. This recommendation is based on an observational study, enrolling 2625 patients treated with anthracycline. In the population developing cardiotoxicity (n=226; defined by a decrease of 10 percentage points to a value <50%), ACE inhibitors +/– beta-blockers were initiated early. Among these 226 patients, 82% recovered from cardiotoxicity at least partially with heart failure therapy. Nevertheless, those who failed to improve LVEF had a significantly higher risk of major cardiovascular events.50 The same results have been observed regarding the effect of heart failure therapy in cancer patients receiving anthracycline treatment when LVEF <45% (201 patients).51 Although there was no control group, full LVEF recovery occurred in 42% of patients treated with enalapril and carvedilol. Responders showed a lower rate of cumulative cardiac events than partial and non-responders (5%, 31% and 29%, respectively; p<0.001). These findings support the fact that early detection of subclinical cardiac dysfunction by LVEF decrease could lead to an early start of heart failure therapy, thus preventing cardiac outcomes.

Conclusion The early detection of myocardial dysfunction during chemotherapy is a major issue. The currently used tools are cardiac biomarkers (especially TnI), global longitudinal strain, and LVEF. According to the

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Subclinical Left Ventricular Dysfunction During Chemotherapy Figure 1: Diagnosing Subclinical Left Ventricular Dysfunction During Chemotherapy Before Heart Failure Occurrence Subclinical Left Ventricular Dysfunction

LVEF Decrease and Heart Failure Symptomatic LV dysfunction Asymptomatic LV dysfunction

Myocardial structural deformation Myocardial cell aggression LVEF <53% with 10% LVEF drop LVEF

LVEF <53% Heart failure symptoms

>53%

Biomarkers – TnI++/TnT – NT-proBNP/BNP – Oxidative stress: myeloperoxidase, GDF-15 – Inflammation: IL-6, CRP – Immunity: IgE – MiRNAs: miR-1, miR-29b, miR-499 – Fibrosis: sT2, galectin-3

Echocardiography – Tissue Doppler imaging – GLS 2D (change >15%) and 3D – LVEF 2D and 3D

Echocardiography Cardiac magnetic resonance MUGA

Cardiac magnetic resonance – LVEF, GLS, GCS – T1 and T2 mapping, ECV – LGE

BNP = brain natriuretic peptide; CRP = C-reactive protein; ECV = extracellular volume; GCS = global circumferential strain; GLS = global longitudinal strain; IgE = immunoglobulin E; IL-6 = interleukin-6; LGE = late gadolinium enhancement; LV = left ventricular; LVEF = left ventricular ejection fraction; MiRNA = microRNA; MUGA = multigated acquisition scan; NT-proBNP = N-terminal pro brain natriuretic peptide; TnI = troponin I; TnT = troponin T.

above-mentioned studies, systematic preventive treatment with betablocker and/or ACE inhibitor has not shown a reduction in cardiac outcomes. However, individualised management of patients with careful evaluation and treatment of cardiovascular risk factors should be performed before the start of chemotherapy. An increase of TnI during chemotherapy should lead to administering cardioprotective ACE antagonist-based treatment. In the case of asymptomatic LVEF

ooning MJ, Botma A, Aleman BM, et al. Long-term risk of H cardiovascular disease in 10-year survivors of breast cancer. J Natl Cancer Inst 2007;99:365–75. https://doi.org/10.1093/jnci/ djk064; PMID: 17341728. Johnson DB, Balko JM, Compton ML, et al. Fulminant myocarditis with combination immune checkpoint blockade. N Engl J Med 2016;375:1749–55. https://doi.org/10.1056/ NEJMoa1609214; PMID: 27806233. Felker GM, Thompson RE, Hare JM, et al. Underlying causes and long-term survival in patients with initially unexplained cardiomyopathy. N Engl J Med 2000;342:1077–84. https://doi. org/10.1056/NEJM200004133421502; PMID: 10760308. Plana JC, Galderisi M, Barac A, et al. Expert consensus for multimodality imaging evaluation of adult patients during and after cancer therapy: a report from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Eur Heart J Cardiovasc Imaging 2014;15:1063–93. https://doi.org/10.1093/ehjci/jeu192; PMID: 25239940. Zamorano JL, Lancellotti P, Rodriguez Muñoz D, et al. 2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines: The Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC). Eur Heart J 2016;37:2768–801. https://doi. org/10.1093/eurheartj/ehw211; PMID: 27567406. Cardinale D, Sandri MT, Colombo A, et al. Prognostic value of troponin I in cardiac risk stratification of cancer patients undergoing high-dose chemotherapy. Circulation 2004;109:2749–54. https://doi.org/10.1161/01. CIR.0000130926.51766.CC; PMID: 15148277. Cardinale D, Sandri MT, Martinoni A, et al. Left ventricular dysfunction predicted by early troponin I release after highdose chemotherapy. J Am Coll Cardiol 2000;36:517–22. https:// doi.org/10.1016/S0735-1097(00)00748-8; PMID: 10933366. Cardinale D, Colombo A, Torrisi R, et al. Trastuzumab-induced cardiotoxicity: clinical and prognostic implications of troponin I evaluation. J Clin Oncol 2010;28:3910–6. https://doi. org/10.1200/JCO.2009.27.3615; PMID: 20679614. Morris PG, Chen C, Steingart R, et al. Troponin I and C-reactive protein are commonly detected in patients with

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decrease, beta-blocker and ACE antagonist should be given. There is no specific management of symptomatic heart failure therapy during chemotherapy. The current definition of cardiotoxicity, which is still based on heart failure symptoms onset or LVEF drop, has to be changed, moving from a clinical to a subclinical definition, based on earlier, more sensitive and specific biomarkers, and new imaging tools based on echocardiography and CMR (Figure 1). n

breast cancer treated with dose-dense chemotherapy incorporating trastuzumab and lapatinib. Clin Cancer Res 2011;17:3490–9. https://doi.org/10.1158/1078-0432.CCR-101359; PMID: 21372222. Schmidinger M, Zielinski CC, Vogl UM, et al. Cardiac toxicity of sunitinib and sorafenib in patients with metastatic renal cell carcinoma. J Clin Oncol 2008;26:5204–12. https://doi. org/10.1200/JCO.2007.15.6331; PMID: 18838713. Ederhy S, Massard C, Dufaitre G, et al. Frequency and management of troponin I elevation in patients treated with molecular targeted therapies in phase I trials. Invest New Drugs 2012;30:611–5. https://doi.org/10.1007/s10637-010-9546-8; PMID: 20924643. Dodos F, Halbsguth T, Erdmann E, Hoppe UC. Usefulness of myocardial performance index and biochemical markers for early detection of anthracycline-induced cardiotoxicity in adults. Clin Res Cardiol 2008;97:318–26. https://doi.org/10.1007/ s00392-007-0633-6; PMID: 18193371. Fallah-Rad N, Walker JR, Wassef A, et al. The utility of cardiac biomarkers, tissue velocity and strain imaging, and cardiac magnetic resonance imaging in predicting early left ventricular dysfunction in patients with human epidermal growth factor receptor II-positive breast cancer treated with adjuvant trastuzumab therapy. J Am Coll Cardiol 2011;57:2263–70. https://doi.org/10.1016/j.jacc.2010.11.063; PMID: 21616287. Lenihan DJ, Stevens PL, Massey M, et al. The utility of point-of-care biomarkers to detect cardiotoxicity during anthracycline chemotherapy: a feasibility study. J Card Fail 2016;22:433–8. https://doi.org/10.1016/j.cardfail.2016.04.003; PMID: 27079675. Pichon MF, Cvitkovic F, Hacene K, et al. Drug-induced cardiotoxicity studied by longitudinal B-type natriuretic peptide assays and radionuclide ventriculography. In Vivo 2005;19:567–76. PMID: 15875778. Sandri MT, Salvatici M, Cardinale D, et al. N-terminal proB-type natriuretic peptide after high-dose chemotherapy: a marker predictive of cardiac dysfunction? Clin Chem 2005;51:1405–10. https://doi.org/10.1373/ clinchem.2005.050153; PMID: 15932966. De Iuliis F, Salerno G, Taglieri L, et al. Serum biomarkers evaluation to predict chemotherapy-induced cardiotoxicity in

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breast cancer patients. Tumour Biol 2016;37:3379–87. https:// doi.org/10.1007/s13277-015-4183-7; PMID: 26449821. Hall PS, Harshman LC, Srinivas S, Witteles RM. The frequency and severity of cardiovascular toxicity from targeted therapy in advanced renal cell carcinoma patients. JACC Heart Fail 2013;1:72–8. https://doi.org/10.1016/j.jchf.2012.09.001; PMID: 24621801. Narayan V, Keefe S, Haas N, et al. Prospective evaluation of sunitinib-induced cardiotoxicity in patients with metastatic renal cell carcinoma. Clin Cancer Res 2017;23:3601–9. https:// doi.org/10.1158/1078-0432.CCR-16-2869; PMID: 28196874. Sawaya H, Sebag IA, Plana JC, et al. Early detection and prediction of cardiotoxicity in chemotherapy-treated patients. Am J Cardiol 2011;107:1375–80. https://doi.org/10.1016/j. amjcard.2011.01.006; PMID: 21371685. Drafts BC, Twomley KM, D’Agostino R, et al. Low to moderate dose anthracycline-based chemotherapy is associated with early noninvasive imaging evidence of subclinical cardiovascular disease. JACC Cardiovasc Imaging 2013;6:877–85. https://doi.org/10.1016/j.jcmg.2012.11.017; PMID: 23643285. Daugaard G, Lassen U, Bie P, et al. Natriuretic peptides in the monitoring of anthracycline induced reduction in left ventricular ejection fraction. Eur J Heart Fail 2005;7:87–93. https://doi.org/10.1016/j.ejheart.2004.03.009; PMID: 15642537. Ky B, Putt M, Sawaya H, et al. Early increases in multiple biomarkers predict subsequent cardiotoxicity in patients with breast cancer treated with doxorubicin, taxanes, and trastuzumab. J Am Coll Cardiol 2014;63:809–16. https://doi. org/10.1016/j.jacc.2013.10.061; PMID: 24291281. Leger KJ, Leonard D, Nielson D, et al. Circulating microRNAs: potential markers of cardiotoxicity in children and young adults treated with anthracycline chemotherapy. J Am Heart Assoc 2017;6. https://doi.org/10.1161/JAHA.116.004653; PMID: 28377429. Rigaud VO, Ferreira LRP, Ayub-Ferreira SM, et al. Circulating miR-1 as a potential biomarker of doxorubicin-induced cardiotoxicity in breast cancer patients. Oncotarget 2017; 8:6994–7002. https://doi.org/10.18632/oncotarget.14355; PMID: 28052002. Mercuro G, Cadeddu C, Piras A, et al. Early epirubicin-induced myocardial dysfunction revealed by serial tissue Doppler

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echocardiography: correlation with inflammatory and oxidative stress markers. Oncologist 2007;12:1124–33. https:// doi.org/10.1634/theoncologist.12-9-1124; PMID: 17914082. Beer LA, Kossenkov AV, Liu Q, et al. Baseline immunoglobulin E levels as a marker of doxorubicin- and trastuzumabassociated cardiac dysfunction. Circ Res 2016;119:1135–44. https://doi.org/10.1161/CIRCRESAHA.116.309004; PMID: 27582370. Negishi K, Negishi T, Hare JL, et al. Independent and incremental value of deformation indices for prediction of trastuzumab-induced cardiotoxicity. J Am Soc Echocardiogr 2013;26:493–8. https://doi.org/10.1016/j.echo.2013.02.008; PMID: 23562088. Narayan HK, Finkelman B, French B, et al. Detailed echocardiographic phenotyping in breast cancer patients: associations with ejection fraction decline, recovery, and heart failure symptoms over 3 years of follow-up. Circulation 2017;135:1397–412. https://doi.org/10.1161/ CIRCULATIONAHA.116.023463; PMID: 28104715. Charbonnel C, Convers-Domart R, Rigaudeau S, et al. Assessment of global longitudinal strain at low-dose anthracycline-based chemotherapy, for the prediction of subsequent cardiotoxicity. Eur Heart J Cardiovasc Imaging 2017;18:392–401. https://doi.org/10.1093/ehjci/jew223; PMID: 28064155. Sawaya H, Sebag IA, Plana JC, et al. Assessment of echocardiography and biomarkers for the extended prediction of cardiotoxicity in patients treated with anthracyclines, taxanes, and trastuzumab. Circ Cardiovasc Imaging 2012;5:596–603. https://doi.org/10.1161/ CIRCIMAGING.112.973321; PMID: 22744937. Thavendiranathan P, Grant AD, Negishi T, et al. Reproducibility of echocardiographic techniques for sequential assessment of left ventricular ejection fraction and volumes: application to patients undergoing cancer chemotherapy. J Am Coll Cardiol 2013;61:77–84. https://doi.org/10.1016/j.jacc.2012.09.035; PMID: 23199515. Zhang KW, Finkelman BS, Gulati G, et al. Abnormalities in 3-dimensional left ventricular mechanics with anthracycline chemotherapy are associated with systolic and diastolic dysfunction. JACC Cardiovasc Imaging 2018;11:1059–68. https:// doi.org/10.1016/j.jcmg.2018.01.015; PMID: 29550306. Jolly MP, Jordan JH, Meléndez GC, et al. Automated assessments of circumferential strain from cine CMR correlate with LVEF declines in cancer patients early after receipt of cardio-toxic chemotherapy. J Cardiovasc Magn Reson 2017;19:59. https://doi.org/10.1186/s12968-017-0373-3; PMID: 28768517. Jordan JH, Sukpraphrute B, Meléndez GC, et al. Early

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myocardial strain changes during potentially cardiotoxic chemotherapy may occur as a result of reductions in left ventricular end-diastolic volume: the need to interpret left ventricular strain with volumes. Circulation 2017;135:2575–7. https://doi.org/10.1161/CIRCULATIONAHA.117.027930; PMID: 28630272. Li W, Croce K, Steensma DP, et al. Vascular and metabolic implications of novel targeted cancer therapies: focus on kinase inhibitors. J Am Coll Cardiol 2015;66:1160–78. https://doi. org/10.1016/j.jacc.2015.07.025; PMID: 26337996. Ong G, Brezden-Masley C, Dhir V, et al. Myocardial strain imaging by cardiac magnetic resonance for detection of subclinical myocardial dysfunction in breast cancer patients receiving trastuzumab and chemotherapy. Int J Cardiol 2018; 261:228–33. https://doi.org/10.1016/j.ijcard.2018.03.041; PMID: 29555336. Neilan TG, Coelho-Filho OR, Shah RV, et al. Myocardial extracellular volume by cardiac magnetic resonance imaging in patients treated with anthracycline-based chemotherapy. Am J Cardiol 2013;111:717–22. https://doi.org/10.1016/ j.amjcard.2012.11.022; PMID: 23228924. Jordan JH, Todd RM, Vasu S, Hundley WG. Cardiovascular magnetic resonance in the oncology patient. JACC Cardiovasc Imaging 2018;11:1150–72. https://doi.org/10.1016/j. jcmg.2018.06.004; PMID: 30092971. Wadhwa D, Fallah-Rad N, Grenier D, et al. Trastuzumab mediated cardiotoxicity in the setting of adjuvant chemotherapy for breast cancer: a retrospective study. Breast Cancer Res Treat 2009;117:357–64. https://doi.org/10.1007/ s10549-008-0260-6; PMID: 19082707. Gulati G, Heck SL, Ree AH, et al. Prevention of cardiac dysfunction during adjuvant breast cancer therapy (PRADA): a 2 × 2 factorial, randomized, placebo-controlled, doubleblind clinical trial of candesartan and metoprolol. Eur Heart J 2016;37:1671–80. https://doi.org/10.1093/eurheartj/ehw022; PMID: 26903532. Akpek M, Ozdogru I, Sahin O, et al. Protective effects of spironolactone against anthracycline-induced cardiomyopathy. Eur J Heart Fail 2015;17:81–9. https://doi. org/10.1002/ejhf.196; PMID: 25410653. Avila MS, Ayub-Ferreira SM, de Barros Wanderley MR, et al. Carvedilol for prevention of chemotherapy-related cardiotoxicity: the CECCY Trial. J Am Coll Cardiol 2018;71: 2281–90. https://doi.org/10.1016/j.jacc.2018.02.049; PMID: 29540327. Boekhout AH, Gietema JA, Milojkovic Kerklaan B, et al. Angiotensin II-receptor inhibition with candesartan to prevent trastuzumab-related cardiotoxic effects in patients with early breast cancer: a randomized clinical trial. JAMA Oncol

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Heart Failure and Problems with Frailty Syndrome: Why it is Time to Care About Frailty Syndrome in Heart Failure Izabella Uchmanowicz, 1 Agnieszka Młynarska, 2 Magdalena Lisiak, 1 Marta Kałuz·na-Oleksy, 3 Marta Wleklik, 1 Anna Chudiak, 1 Magdalena Dudek, 3 Jacek Migaj, 3 Lynne Hinterbuchner 4 and Robbert Gobbens 5,6,7 1. Department of Clinical Nursing, Faculty of Health Science, Wroclaw Medical University, Poland; 2. Department of Gerontology and Geriatric Nursing, School of Health Sciences, Medical University of Silesia, Poland; 3. Department of Cardiology, Poznan University of Medical Sciences, Poland; 4. Department for Internal Medicine and Cardiology, Salzburg University Hospital, Austria; 5. Faculty of Health, Sports and Social Work, Inholland University of Applied Sciences, Amsterdam, the Netherlands; 6. Zonnehuisgroep Amstelland, Amstelveen, the Netherlands 7. Department of Primary and Interdisciplinary Care, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium

Abstract Frailty syndrome (FS) is an independent predictor of mortality in cardiovascular disease and is found in 15–74% of patients with heart failure (HF). The syndrome has a complex, multidimensional aetiology and contributes to adverse outcomes. Proper FS diagnosis and treatment determine prognosis and support the evaluation of treatment outcomes. Routine FS assessment for HF patients should be included in daily clinical practice as an important prognostic factor within a holistic process of diagnosis and treatment. Multidisciplinary team members, particularly nurses, play an important role in FS assessment in hospital and primary care settings, and in the home care environment. Raising awareness of concurrent FS in patients with HF patients and promoting targeted interventions may contribute to a decreased risk of adverse events, and a better prognosis and quality of life.

Keywords Frailty, heart failure, older people, multidisciplinary care, assessment instruments, prognostic factors Disclosure: The authors have no conflicts of interest to declare Received: 16 November 2018 Accepted: 7 January 2019 Citation: Cardiac Failure Review 2019;5(1):37–43. DOI: https://doi.org/10.15420/cfr.2018.37.1 Correspondence: Izabella Uchmanowicz, Department of Clinical Nursing, Faculty of Health Science, Wroclaw Medical University, Poland. E: izabella.uchmanowicz@umed.wroc.pl Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

The first paper that referred to the problem of ‘frail elderly patients’ was published in 1953, and frailty syndrome (FS) was first described in the 1990s.1,2 Although it has long been recognised and diagnosed, no consensus definition of this clinical syndrome has been established. The Second International Working Meeting on Frailty and Aging in 2006 concluded that FS involves increased vulnerability to external and internal stressors due to impairments in multiple interrelated physiological systems.3,4 FS involves a lowering in reserves and decreased resistance to stressors. A simplified definition of FS concerns a loss of the body’s adaptive capabilities. From this perspective, FS is understood to be a process that dynamically accelerates ageing, but with no disability in its early stages. It is generally agreed that FS should be perceived as a multidimensional physical and psychological process associated with ageing.5,6,7 In geriatric medicine, FS is defined as a state of increased vulnerability to endogenous and exogenous stress factors, resulting from decreased physiological reserves and dysfunction and dysregulation of multiple systems, which interfere with homeostasis and response to stress.8,9

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FS results in a higher risk of adverse events, including falls, disability and mortality. In this understanding, FS corresponds to an intermediate period between a state of unimpaired psychophysical functioning with full recovery capacity and a state of disability, impaired recovery, and transition from an anabolic to a more catabolic state.10 FS may be defined in two main ways: rule based or indicator based. Rule-based definitions include components used to evaluate individual patients. The best-known definition is that by Fried et al.; this comprises five frailty components: unintended body weight loss of 4.5 kg or more within the past year, low physical activity, slow walking speed, muscle weakness and subjectively reported exhaustion. However, it is not considered a gold standard as it may not reflect the multidimensional nature of frailty.1,2 Another method for defining and diagnosing FS involves ‘frailty indicators’, which are calculated by adding the number of deficits defined or by comparing the number of deficits found in a patient to the number of all deficits considered as part of frailty (diseases; cognitive, physical and functional dysfunctions; and abnormal laboratory results). This is associated with the notion of FS as an accumulation of deficits that impair one’s reserves and ability to respond to stressors.2

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Co-morbidities Potential definitions of FS are often synonymous with disability, multimorbidity or advanced old age.1,11 In geriatric medicine, FS is characterised as a biological syndrome associated with decreased reserves and resistance to stressors, resulting from an accumulation of deficits in multiple physiological systems, and causing vulnerability to adverse outcomes. FS is also likely to be associated with impairment of physiological processes or reserves in other systems, leading to a reduced capacity to maintain homeostasis when stressors are present, causing weaknesses.1,2,11,12 Nonetheless, 30% of the normal physiological reserves is considered a level sufficient to maintain adequate function of basic organs.13 With regard to homeostatic reserve decrease, three stages of frailty can be described: the initial process, the state of frailty and frailtyrelated complications. The initial process is clinically silent. In this state, sufficient physiological reserves are maintained, the body reacts adequately to changes – such as acute disease, trauma or stress – and full recovery is possible. The state of frailty can easily be diagnosed clinically. It includes slow and incomplete recovery after each subsequent incidence of acute disease, trauma or stress, which indicates that available reserves are insufficient for full recovery. Progression of FS is associated with a high risk of frailty-associated complications, including falls, functional deficits leading to disability, polypharmacy, hospitalisation, cross-infection, institutionalisation and mortality.2,13 FS corresponds to an intermediate period between unimpaired psychophysical functioning with full recovery capacity and a state of disability with impaired ability to recover.12

Frailty Syndrome Pathophysiology Most available scientific reports agree that FS involves increased vulnerability to biological stressors and its diagnosis should be based on an assessment of five criteria: slowness, weakness, physical activity, exhaustion and muscle mass.14 Unfortunately, it is often not easy to make a distinction between the clinical symptoms and signs related to ageing, chronic illness or frailty. It is even unclear whether frailty is an independent syndrome or a result of chronic illness or developing multiple comorbidities with ageing.15 Some authors show that frailty syndrome can be diagnosed in people who do not demonstrate any chronic illness.1 Others argue that chronic illnesses and frailty share many characteristics, the most commonly cited example being heart failure (HF). Therefore, there is a link between FS and HF. HF is becoming a major challenge in cardiology, primarily owing to the rising prevalence because of ageing populations in developed countries. According to current estimates, by 2050, more than 40% of the population of western Europe will be 60 or older.16 A similar trend applies in Poland, where people aged 60 and above are expected to account for 35% of the population by the middle of this century.17 The incidence of FS increases with age, so the number of patients with concurrent FS and HF is anticipated to rise. Frailty is considered one of the most important issues associated with human ageing, and this has significant implications for patients and the healthcare system.1 The relationship between frailty and a higher risk of falling, loss of functional independence, reduced quality of life, institutionalisation and mortality has been clearly demonstrated.18,19

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Both frail patients and those with HF may demonstrate poor tolerance of exertion, exhaustion and loss of body weight (muscle mass). Distinguishing frailty syndrome from heart failure may be particularly difficult in the elderly, who tend to show HF with preserved ejection fraction.14 Up to 25% of elderly patients with heart failure show frailty, and frail patients have an increased risk of developing heart failure.20–22 Frailty in chronic HF has been reported as possibly reversible in a study of patients undergoing heart transplantation or implantation of ventricular assist devices.23 There seems to be a clear relationship between HF, ageing and frailty; however, this is poorly understood. All of the above-mentioned conditions are associated with elevated inflammatory markers, so a common inflammatory background has been proposed.15 This can be attributed to several mechanisms. A model of sterile inflammation has been proposed, where the breakdown of tissue (sterile cell necrosis without microbial invasion) connected with conditions such as ageing, MI and HF frees cellular substances, which in turn provokes a degree of immune response.24 Such a mechanism seems to explain some of the common features of HF, ageing and frailty, because most of the signs and symptoms common in these conditions can be attributed to sarcopenia (loss of muscle mass). In this model, degradation of muscular tissue causes chronic, sterile inflammation.15 A chronic mild elevation of inflammatory markers in these conditions can be attributed to other mechanisms as well. It has been proposed that HF may lead to bacterial translocation as a result of intestinal hypoperfusion, and elevation of inflammatory markers in older patients may be caused by latent viral infections or the breaking down of both fatty and muscular tissue.15 Quality of life (QoL) is low in both the HF and the frail populations. Multimorbidity and physical, psychological and social frailty problems have been demonstrated to correlate negatively with QoL.25–27 It is generally accepted that almost half of the total population in Europe has at least one long-term condition. Among the most common chronic conditions in the European population are arthritis, diabetes, heart disease, cancer and stroke.28 Many patients have two or more concurrent chronic diseases, especially those aged 65 years or older. Multimorbidity is associated with hospitalisation, emergency department visits and a reduction in QoL.12,13 It is more common in women than men.28

Frailty Syndrome Epidemiology Both frailty and HF are common in the elderly population. It is estimated that HF affects at least 26 million people worldwide.29 The incidence of HF is associated with age – at 65 years, the estimated incidence of HF is 1% and this percentage approximately doubles with each decade of age thereafter.30 Moreover, people aged 65 years or older constitute more than 80% of those with HF, and 25% of these patients are aged 80 years or older.31 Prevalence figures of frailty are highly dependent on the measurement instrument used. Roughly speaking, these instruments are based on the physical approach to frailty (physical frailty) or on the multidimensional approach to frailty (multidimensional frailty). Physical frailty instruments assess exclusively physical limitations that older people may have. An example is the phenotype of frailty by Fried, which includes unintentional weight loss, weakness, poor self-reported endurance, slow gait speed and low physical activity.1

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Heart Failure and Frailty Syndrome Multidimensional frailty instruments also include psychological and/ or social components in their assessment. Examples include the Comprehensive Geriatric Assessment, the Frailty Index (FI) and the Tilburg Frailty Indicator (TFI).32–34 If frailty concerns only physical limitations that older people may have, its prevalence is generally lower than if it also covers psychological and social limitations. In community-dwelling older people aged 65 years or older, the prevalence of frailty varies enormously, and has been found to range from 4.0% to 59.1%.35 Currently, no frailty instrument has been validated specifically for people with HF.36 The most commonly used instrument is the phenotype of frailty, followed by the Comprehensive Geriatric Assessment and the FI.1,32,33 The use of these different instruments in people with HF explains why the prevalence figures of frailty in this target group also differ.

therapeutic decision-making in elderly patients. Identification of frailty or early identification of pre-frailty may be significant in the prevention of FS consequences. FS diagnosis remains a challenge. Health and social care professionals have to choose the most suitable assessment instrument.45 These are outlined below.

Edmonton Frail Scale The Edmonton Frail Scale (EFS) comprises 10 domains evaluating cognitive function, balance, mobility, mood, independent daily functioning, medication, eating, health attitudes, social support and QoL. It should take less than 15 minutes to administer. The ‘clock test’ is used to assess cognitive function, and a walking test to evaluate balance and mobility. The maximum score is 17; scores of 0–3 indicate no frailty, and scores above 9 indicate the highest level of frailty.46

Cardiovascular Health Study Scale Denfeld et al. conducted a systematic review and meta-analysis that aimed to quantitatively synthesise studies about the prevalence of frailty in people with HF.37 The overall prevalence of frailty in people with HF was found to be 44.5%. The authors also demonstrated that the prevalence of frailty was lower in studies using physical frailty than in those that also included psychological and/or social components of frailty, also called multidimensional frailty (42.9% versus 47.4%).37 Many studies have shown that frailty is associated with older age.1,38,39 Altimir et al. found frailty occurred more often in people with HF aged 70 years or older, but even younger people with HF demonstrated a high prevalence of frailty (53.3% versus 33.3%).40 Moreover, the prevalence of frailty was higher among women than among men (62.6% versus 33.7%). These findings were supported by Lupón et al.41 From the prevalence figures, it can be deduced that frailty and HF are closely linked. This is also evident from the results of two studies.22,42 The Longitudinal Aging Study Amsterdam (LASA) revealed that community-dwelling elderly people with HF had an increased risk of frailty, independent of potential confounders such as sex, age and multimorbidity.42 The Health ABC Study, which had a follow-up of 11.4 years and included 2,825 people with a mean age of 74 years at baseline, demonstrated that frailty is independently associated with risk of HF in older people.22 Frailty is common in people with HF because the pathophysiology of HF contributes to frailty by reducing both skeletal muscle function and exercise capacity.43 Frailty and HF are probably the result of similar pathways involving inflammatory processes as well as metabolic and autonomic disturbances.44 In addition, the development of frailty in people with HF may be accelerated because they are more susceptible to falls and are more likely to have cognitive impairment because of reduced cerebral perfusion.43 More major longitudinal studies are necessary to create clarity regarding the cause and effect relationship between frailty and HF.

Assessment Instruments for Frailty Syndrome FS, rather than chronological age, is considered a significant risk factor for cardiovascular disease, and a significant predictor of outcomes. One important issue related to identifying frail patients is distinguishing between multimorbidity and/or disability and concurrent FS. Early FS identification offers an opportunity to provide individualised, targeted healthcare. Prevention of complications is a strategic health-related issue and should be prioritised in the process of evidence-based

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The Cardiovascular Health Study Scale (CHS) is one of the most commonly used frailty scales, and assesses its most important criteria.1 These include: • unintentional weight loss (>5 kg in 12 months); • decreased grip strength, as measured using a dynamometer, taking the patient’s age and body mass index (BMI) into consideration; • exhaustion, as measured using a depression scale (CES–D, Center for Epidemiologic Studies Depression Scale);47 • slow walking, that is, taking ≥20 seconds per 15 ft (approximately 4.6 m) in the walking test, considering the patient’s age and sex;48 • decreased physical activity, based on criteria from the short version of the Minnesota Leisure Time Activity Questionnaire (MLTAQ).49 A positive result for three or more criteria corresponds to an FS diagnosis, while a score of 1 or 2 criteria indicates a predisposition to developing FS.1

Tilburg Frailty Indicator The TFI was developed by Gobbens et al.34 Part A covers health-related determinants of frailty, while part B comprises 15 questions regarding the main FS components. The TFI includes three subscales, with eight physical, four psychological and three social components. There are no criteria for identifying high or low scores on each subscale, so results must be interpreted by comparing a patient’s score with the maximum for each subscale. Moreover, each subscale includes a different number of questions, which also affects the interpretation. The maximum score for the entire scale is 15 points. Frailty is identified when a patient scores 5 or more.50

Canadian Study of Health and Aging Frailty Index The Canadian Study of Health and Aging Frailty Index (CSHA-FI) was developed on the basis of a 5–year cohort study called the Canadian Study of Health and Aging. It included 10,262 respondents aged 65 and above. The questionnaire covers deficits that interfere with daily functioning in elderly individuals, including: • alarming symptoms: sleep disorders, memory impairment, low mood; • physical signs, such as tremors and weakened pulse;

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Co-morbidities • l aboratory results, including in particular abnormal creatinine and calcium levels; • comorbidities, e.g. diabetes or Parkinson’s disease; • disability components, including limitations in activities of daily living such as washing, dressing, using the toilet and eating. Depending on the results, each patient is categorised as: very fit, fit, managing well, vulnerable, mildly frail, moderately frail or severely frail.51–53

including psychological and social care. The difference between the two main approaches to FS is that one defines frailty as a physical phenotype, and the other considers frailty as a more multidimensional concept, concerning physical as well as psychological and social functioning.1 These two different approaches are also reflected in the instruments developed for assessing frailty, and in the multidisciplinary approach, in which the therapeutic options considered do not include only medical interventions. Psychological and social support seems key in patients who are frail.

FRAIL Scale The FRAIL scale is a simple instrument recommended by the International Association of Nutrition and Aging. It is named for the five components it covers: Fatigue, Resistance, mobility (Aerobic), Illnesses, and Loss of weight. Notably, the score largely depends on the selfreported experience of the patient with regard to these components.54

As FS very often affects elderly, cognitively impaired patients with multimorbidities who experience difficulties in self-care, management may be challenging. Patients with HF and concurrent FS require more attention than those without FS. As FS is estimated to affect as many as 70% or more of patients with HF aged 80 and above, the problem seems significant.62

Groningen Frailty Indicator The Groningen Frailty Indicator (GFI) questionnaire comprises 15 items concerning the severity of frailty symptoms, as well as limitations in daily functioning. Four main domains are identified: physical (mobility, health issues, fatigue, eyesight and hearing); psychological (mood disorders and depression symptoms); social (emotional isolation); and cognitive (cognitive functioning). FS is identified when a patient scores 4 or more.55,56

MacArthur Study of Successful Aging Scale This MacArthur Study of Successful Aging Scale (MSSA) is a modification of the CHS, with five added components. Besides the criteria covered by the CHS, it includes raised C-reactive protein (CRP) levels; increased interleukin 6 (IL-6) levels; decreased appetite identified using the Hopkins Symptom Checklist (HSCL); self-reported weakness identified using the same questionnaire; and cognitive impairment identified using tests for language skills, executive functions, spatial functions, and verbal and non-verbal memory. A positive result for at least 4 out of 10 components warrants a diagnosis of FS.57

Calgary Cardiac and Cognition Scale The questionnaire covers five key frailty indicators: cognitive impairment assessed using the Trail-Making Test; mood disorders identified using the Geriatric Depression Scale developed by Yesavage et al.; maintaining balance for less than 10 seconds in the Tandem Balance Test; a BMI <21 or >30 kg/m2; and living alone.58–61 A positive result for three or more criteria is indicative of FS.58–59

Prognostic Role of Frailty in Heart Failure The clinical consequences of concurrent frailty in patients with HF can vary, depending on the severity of both FS and HF. FS is often associated with limiting physical activity to the basic activities of daily living, such as washing or dressing, which may mask HF symptoms, as the latter are typically exacerbated by effort. The distortion of HF symptom severity by FS results in later diagnosis, and late (often too late) implementation of treatment. Problems in self-care and difficulties in leaving home may reduce a patient’s access to healthcare, which also contributes to insufficient treatment surveillance, delayed responses and untimely treatment modifications. Patients with concurrent FS and HF require an individualised management approach, with particular focus on non-pharmaceutical treatment,

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Weight loss is a major component of FS.63–65 Calorie supplementation helps weight gain and reduces complications and mortality in undernourished older individuals.66 HF is often associated with eating disorders and a reduction in skeletal muscle, which may result in cachexia. Under its current definition, cachexia involves an unintended body weight loss (without changes in volaemia) greater than 5% within 12 months (or a BMI <20 kg/m2), with at least three of the following criteria: decreased muscle strength; fatigue; anorexia; low fat-free mass index; and abnormal blood test results, including increased inflammatory markers (C-reactive protein, interleukin 6), anaemia (red blood cells <12 g/dl) or low albumin (<3.2 g/dl).67 Cachexia is a generalised process affecting most tissues, including lean tissue such as skeletal muscle, fat tissue (energy reserves) and bone tissue (leading to osteoporosis). It may occur in 5–15% of patients with HF, especially those at more advanced stages of HF with reduced ejection fraction.68 HF is also often associated with calcium–phosphorus imbalances resulting from secondary hyperparathyroidism and vitamin D deficiency, primarily caused by kidney dysfunction. Additionally, increased TNFalpha in patients with HF suppresses calcitriol and vitamin D synthesis, and the resulting decrease in vitamin D concentration leads to a greater release of renin, which may accelerate the development of cachexia. Therefore, vitamin D supplementation is increasingly promoted in HF treatment. Research demonstrates that, besides increasing vitamin D concentration, the supplementation also decreases excess aldosterone in patients with HF.69–71 Planned exercise should be a part of daily routine in all patients with HF and FS. The importance of physical activity in the management of a number of chronic diseases, including chronic HF or cancers, is currently under discussion.72 Exercise is a crucial part of FS management. It has been demonstrated that a year of resistance exercise in frail patients following hip fracture decreases hospitalisations and nursing home placement, and that 45–60 minutes of exercise three times a week seems to have positive effects on frail older adults and may be used for the management of frailty.73,74 Exercise in frail individuals increases their functional performance, walking speed, sit-to-stand test, stair climbing and balance, and decreases depression and fear of falling.75 Individualisation seems essential in care for HF and FS patients. This means that healthcare professionals should focus their interventions on all three domains of human functioning – physical, psychological and social. The focus should on characteristics such as poor physical

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Heart Failure and Frailty Syndrome health, a lack of social relations, a lack of social support, feeling down and being unable to cope with problems, as these issues – as well as frailty components and HF – have the biggest impact on QoL in the elderly.74

Directions for Future Research It is well known that frailty has many adverse outcomes in the general population of older people, including disability, institutionalisation, hospitalisation, lower QoL and premature death.1,52,76,77 Logically, frailty also has several negative consequences for people with heart failure. A recent systematic review and meta-analysis based on 20 studies showed that frailty, measured with a wide variety of scales (e.g. the phenotype of frailty by Fried et al., FI, Canadian Study of Health and Aging Clinical Frailty Scale) is a significant predictor of all-cause mortality and hospital readmissions in people with heart failure.1,33,52,78 In addition, in people with advanced HF, the risk of all-cause mortality after undergoing a ventricular assist device (VAD) implantation was significantly higher in those with frailty than in non-frail people.78 According to Jha et al., in people with advanced HF undergoing a left ventricular assist device (LVAD) implantation, a preoperative measurement of frailty can identify people with increased postoperative risk of death, prolonged length of hospitalisation and longer use of intensive care.79 Moayedi et al. showed that, adjusted for B-type natriuretic peptide or peak oxygen consumption (VO2), frailty identified using the phenotype of frailty was not associated with increased mortality in people with advanced HF.80 However, Moayedi et al. also found that when peak VO2 was stratified into two categories (≥12 ml/kg/min versus <12 ml/kg/min), frailty was associated with a 72% higher risk of death in this group.80 Of the individual phenotype of frailty components, low physical activity assessed with the Duke Activity Status Index was associated with the highest risk of death.81,82 A study by Martin-Sánchez et al. showed that the presence of physical frailty in people with moderate disability has an impact on 30–day mortality in people ≥65 years with acute decompensated HF attending an emergency department.83 Besides premature death and hospital (re)admission, studies have also shown that frailty in people with HF is significantly associated with other adverse outcomes such as disability and poorer quality of life.84,85 Vidan et al. demonstrated in a sample of 450 non-dependent people aged 70 years or older hospitalised for HF that frailty is a strong predictor of disability; among the five frailty phenotype components, low physical activity, low gait speed and weakness were predictive for early disability.85 Furthermore, frailty has a negative impact on healthrelated QoL in older people with a diagnosis of HF; this is reflected by strong negative correlations between the TFI and both the physical and mental component scales of the Short Form Medical Outcomes Study Survey.84,86 Many of the aforementioned studies used a measure of physical frailty, but studies have also examined a multidimensional measurement of frailty, providing evidence for using a multidimensional measurement of frailty in people with HF. Jha et al. concluded that adding cognitive impairment to the assessment of physical frailty improved the identification of people with advanced HF referred for heart transplantation who are at high risk of premature death.87 Moreover, the Observational study to assess and Predict the in-patient course, risk of Re-Admission and mortality for patients hospitalised for or with

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Heart Failure (OPERA-HF) study of 671 patients hospitalised for HF with a mean age of 76 years, showed that psychosocial factors are strongly associated with unplanned recurrent readmissions as well as mortality.88 In another study, Uchmanowicz et al. demonstrated that the social frailty components of the TFI (living alone, loneliness and a lack of social support) were associated with hospital readmissions in people with HF.89 Pulignano et al. found that an intensive, hospital-based disease management programme (DMP) for people with HF attending an HF outpatient clinic was more effective for those with mild-to-moderate frailty.90 The DMP improved outcomes (death, heart failure admissions and all-cause admissions) and decreased costs. According to this research group, a multidimensional measurement of frailty could be useful for an appropriate selection of a model of care. Tjam et al. made a similar recommendation based on a study of longterm residents with HF using the Resident Assessment Instrument (RAI) 2.0, a comprehensive assessment system developed particularly for frail older people.91 This study showed that the RAI 2.0 is superior to the New York Heart Association functional classification in predicting mortality in frail older people with HF. Moreover, Lee et al. provided evidence that physical and psychological symptom profiles appear to be useful in identifying adults (mean age 57 years) with HF who are at the highest risk of adverse clinical outcomes (worse 1-year event-free survival, independent of prognosis based on objective clinical data concerning HF).92 Among a sample of 192,327 adult hospitalisations for HF, four distinct comorbidity profiles – common, lifestyle, renal and neurovascular – were associated with differences in the length of stay, the risk of death and cost.93 Together with frailty profiles, these comorbidity profiles could be helpful in identifying people with HF who are at a high risk of adverse outcomes while in hospital. Despite the poor prognosis of people with both HF and frailty, it is important to note that frailty can be reversed or improved in people with HF. For example, Maurer et al. showed that implantation of a LVAD decreased frailty, defined as having three or more of the frailty components identified by Fried et al., and these positive changes in frailty were associated with improvement in quality of life, using the Kansas City Cardiomyopathy Questionnaire.1,94,95 The current literature consistently demonstrates the added prognostic value of frailty in people with HF, for mortality and hospitalisation in particular. According to Jermyn and Patel, the inclusion of frailty into HF algorithms is possibly the next advancement in the management of HF by allowing healthcare providers to make better-founded decisions as well as make efficient use of healthcare resources.96

Conclusion FS is a complex clinical syndrome commonly associated with both older age and chronic illness. The significance and characteristics of FS in HF are increasingly recognised. Elderly patients with HF are a distinct population, and are characterised by a large number of comorbidities. Old age is a significant predictor of FS. Other determinants of FS include strength, mobility, energy/fatigue, physical activity, nutrition, polypharmacy and cognitive function. Elderly HF patients are at a higher risk of developing FS, but a converse relationship also exists in that patients aged above 65 years

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Co-morbidities with multimorbidity are at a higher risk of developing HF.97 Thus, FS and HF have a bidirectional association, believed to be caused by proinflammatory factor activation, metabolic dysfunction and hormone dysregulation. Moreover, FS symptoms are found in nearly half of all patients with HF.98 A variety of unidimensional and multidimensional instruments are used in FS diagnosis.99 Regardless of the model used, a diagnosis of FS is associated with adverse outcomes.82,85,97,100–102 Consequences of concurrent FS in HF patients include an increase in hospital admission, poorer prognosis, higher risk of disability and falls, cognitive impairment and decreased QoL. In addition, increased severity of FS symptoms is associated with a fourfold increase of rehospitalisation risk and an increase in 1-year mortality in HF patients.100 Considering FS and its implications may be a decisive factor in the diagnosis and treatment process for patients with HF.22,103 For multidisciplinary healthcare teams, managing frail patients with HF remains a challenge. The overall objective of any intervention should be to improve outcomes, decrease hospitalisation, improve QoL and provide continued care.104

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Clinical Implications Accurate evaluation in patients with FS and HF allows for the implementation of an individualised healthcare programme to prevent the adverse consequences of FS. Therefore, a consistent, multidimensional evaluation is necessary. Multidisciplinary teams should focus on rapid diagnosis to identify the high-risk group of patients with HF and concurrent FS, as this may be a decisive factor in improving prognosis and QoL in these patients. HF treatment remains a challenge, especially in patients with concurrent FS. Providing comprehensive specialist care to patients with HF and FS should be a priority, and diagnosis and treatment optimised. Implementation of strategies for identifying FS in patients with HF may be decisive with regard to individualisation of treatment and care plans. There is an urgent need for accurate risk estimation, including factors associated with FS, in patients with HF. Management of HF should include the implementation of interventions to prevent frailty, alleviate its symptoms and prevent or limit its consequences. This objective may be achieved only through skilful collaboration between all team members, with a multidimensional consideration of frail HF patients. n

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Heart Failure and Frailty Syndrome tb01616.x; PMID: 1991946. 49. T aylor HL, Jacobs DR Jr, Schucker BA, et al. A questionnaire for the assessment of leisure time physical activities. J Chronic Dis 1978;31:741–55. J Chronic Dis 1978;31:741–55. https://doi. org/10.1016/0021-9681(78)90058-9; PMID: 748370. 50. Gobbens RJ1, Luijkx KG, Wijnen-Sponselee MT, Schols JM. Towards an integral conceptual model of frailty. J Nutr Health Aging 2010;14:175–81. https://doi.org/10.1007/s12603-0100045-6; PMID: 20191249. 51. Mitnitski AB, Mogilner AJ, Rockwood K. Accumulation of deficits as a proxy measure of aging. ScientificWorldJournal 2001;1:323–36. https://doi.org/10.1100/tsw.2001.58; PMID: 12806071. 52. Rockwood K, Song X, MacKnight C, et al. A global clinical measure of fitness and frailty in elderly people. CMAJ 2005;173:489–95. https://doi.org/10.1503/cmaj.050051; PMID: 16129869. 53. Koller K, Rockwood K. Frailty in older adults: implications for endoflife care. Cleve Clin J Med 2013;80:168–74. https://doi. org/10.3949/ccjm.80a.12100; PMID: 23456467. 54. Abellan van Kan G, Rolland YM, Morley JE, Vellas B. Frailty: toward a clinical definition. J Am Med Dir Assoc 2008;9:71–2. https://doi.org/10.1016/j.jamda.2007.11.005; PMID: 18261696. 55. Stevernik N, Slaets JPL, Schuurmans H, van Lis M. Measuring frailty: development and testing the GFI (Groningen Frailty Indicator). Gerontologist 2001;41:236–7. 56. Slaets JP. Vulnerability in the elderly: frailty. Med Clin North Am 2006;90:593–601. https://doi.org/10.1016/j.mcna.2006.05.008; PMID: 16843764. 57. Sarkisian CA, Gruenewald TL, John Boscardin W, Seeman TE. Preliminary evidence for subdimensions of geriatric frailty: the MacArthur Study of Successful Aging. J Am Geriatr Soc 2008;56:2292–7. https://doi.org/10.1111/ j.1532-5415.2008.02041.x; PMID: 19016933. 58. Sánchez-Cubillo I, Periáñez JA, Adrover-Roig D, et al. Construct validity of the Trail Making Test: role of task switching, working memory, inhibition/interference control, and visuomotor abilities. J Int Neuropsychol Soc 2009;15:438–50. https://doi.org/10.1017/S1355617709090626; PMID: 19402930. 59. Talarowska M, Zboralski K, Mossakowska-Wójcik J, Gałecki P. [Results of the Trail Making Test among patients suffering from depressive disorders and organic depressive disorders.] Psychiatr Pol 2012;XLVI:273–82 [in Polish]. 60. Yesavage JA, Brink TL, Rose TL, et al. Development and validation of a geriatric depression screening scale: a preliminary report. J Psychiatr Res 19821983;17:37–49. PMID: 7183759. 61. Freiheit EA, Hogan DB, Eliasziw M, et al. Development of a frailty index for patients with coronary artery disease. J Am Geriatr Soc 2010;58:1526–31. https://doi.org/10.1111/j.15325415.2010.02961.x; PMID: 20633198. 62. Butrous H, Hummel SL. Heart failure in older adults. Can J Cardiol 2016;32:1140-7. https://doi.org/10.1249/ MSS.0000000000001274. PMID: 27476982. 63. Landi F, Laviano A, Cruz-Jentoft AJ. The anorexia of aging: is it a geriatric syndrome? J Am Med Dir Assoc 2010;11:53–6. https:// doi.org/10.1016/j.jamda.2009.09.003; PMID: 20188310. 64. Morley JE. Undernutrition: a major problem in nursing homes. J Am Med Dir Assoc 2011;12:243–6. https://doi.org/10.1016/j. jamda.2011.02.013; PMID: 21527163. 65. Morley JE. Weight loss in older persons: New therapeutic approaches. Curr Pharm Des 2007;13:3637–47. https://doi. org/10.2174/138161207782794149; PMID: 18220800. 66. Milne AC, Potter J, Vivanti A, Avenell A. Protein and energy supplementation in elderly people at risk from malnutrition. Cochrane Database Syst Rev 2009;CD003288. https://doi. org/10.1002/14651858.CD003288.pub3; PMID: 19370584. 67. Okoshi MP, Capalbo RV, Romeiro FG, Okoshi K. Cardiac cachexia: perspectives for prevention and treatment. Arq Bras Cardiol 2017;108:74–80. https://doi.org/10.5935/abc.20160142; PMID: 27812676. 68. Von Haehling S, Anker SD. Prevalence, incidence and clinical impact of cachexia: facts and numbers – update 2014. J Cachexia Sarcopenia Muscle 2014;5:261–3. https://doi. org/10.1007/s13539-014-0164-8; PMID: 25384990. 69. Witham MD, Crighton LJ, Gillespie ND, et al. The effects of vitamin D supplementation on physical function and quality of life in older patients with heart failure: A randomized controlled trial. Circ Heart Fail 2010;3:195–201. https://doi.

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org/10.1161/CIRCHEARTFAILURE.109.907899; PMID: 20103775. 70. B oxer RS, Kenny AM, Schmotzer BJ, et al. A randomized controlled trial of high dose vitamin D3 in patients with heart failure. JACC Heart Fail 2013;1:84–90. https://doi.org/10.1016/j. jchf.2012.11.003; PMID: 24614995. 71. Sciatti E, Lombardi C, Ravera A, et al. Nutritional deficiency in patients with heart failure. Nutrients 2016;8:E442. https://doi. org/10.3390/nu8070442; PMID: 27455314. 72. Kubota Y, Evenson KR, Maclehose RF, et al. Physical activity and lifetime risk of cardiovascular disease and cancer. Med Sci Sports Exerc 2017;49:1599-605. https://doi.org/10.1249/ MSS.0000000000001274; PMID: 28350711. 73. Singh NA, Quine S, Clemson LM, et al. Effects of high-intensity progressive resistance training and targeted multidisciplinary treatment of frailty on mortality and nursing home admissions after hip fracture: a randomized controlled trial. J Am Med Dir Assoc 2012;13:24–30. https://doi.org/10.1016/j. jamda.2011.08.005; PMID: 21944168. 74. Theou O, Stathokostas L, Roland KP, et al. The effectiveness of exercise interventions for the management of frailty: a systematic review. J Aging Res 2011;2011:569194. https://doi. org/10.4061/2011/569194; PMID: 21584244. 75. Morley JE, Vellas B, van Kan GA, et al. Frailty consensus: a call to action. J Am Med Dir Assoc 2013;14:392–7. https://doi. org/10.1016/j.jamda.2013.03.022; PMID: 23764209. 76. Gobbens RJ, van Assen MA. The prediction of ADL and IADL disability using six physical indicators of frailty: a longitudinal study in the Netherlands. Curr Gerontol Geriatr Res 2014;2014:358137. https://doi.org/10.1155/2014/358137; PMID: 24782894. 77. Kojima G1, Iliffe S1, Jivraj S2, Walters K. Association between frailty and quality of life among community-dwelling older people: a systematic review and meta-analysis. J Epidemiol Community Health 2016;70:716–21. https://doi.org/10.1136/jech2015-206717; PMID: 26783304. 78. Zhang Y, Yuan M, Gong M, et al. Frailty and clinical outcomes in heart failure: a systematic review and meta-analysis. J Am Med Dir Assoc 2018;19:1003–8.e1. https://doi.org/10.1016/j. jamda.2018.06.009; PMID: 30076123. 79. Jha SR1, Hannu MK, Newton PJ, et al. Reversibility of frailty after bridge-to-transplant ventricular assist device implantation or heart transplantation. Transplant Direct 2017;3:e167. https://doi.org/10.1097/TXD.0000000000000690; PMID: 28706970. 80. Moayedi Y, Duero Posada JG, Foroutan F, et al. The prognostic significance of frailty compared to peak oxygen consumption and B-type natriuretic peptide in patients with advanced heart failure. Clin Transplant 2018;32:e13158. https://doi. org/10.1111/ctr.13158; PMID: 29168222. 81. Hlatky MA, Boineau RE, Higginbotham MB, et al. A brief selfadministered questionnaire to determine functional capacity (the Duke Activity Status Index). Am J Cardiol 1989;64:651–4. https://doi.org/10.1016/0002-9149(89)90496-7; PMID: 2782256. 82. Butrous H, Hummel SL. Heart failure in older adults. Can J Cardiol 2016;32:1140–7. https://doi.org/10.1016/j. cjca.2016.05.005; PMID: 27476982. 83. Martín-Sánchez FJ, Rodríguez-Adrada E, Vidan MT, et al. Impact of frailty and disability on 30–day mortality in older patients with acute heart failure. Am J Cardiol 2017;120:1151–7. https://doi.org/10.1016/j.amjcard.2017.06.059; PMID: 28826899. 84. Uchmanowicz I, Gobbens RJ. The relationship between frailty, anxiety and depression, and health-related quality of life in elderly patients with heart failure. Clin Interv Aging 2015;10:1595–600. https://doi.org/10.2147/CIA.S90077; PMID: 26491276. 85. Vidán MT, Blaya-Novakova V, Sánchez E, et al. Prevalence and prognostic impact of frailty and its components in non-dependent elderly patients with heart failure. Eur J Heart Fail 2016;18:869–75. https://doi.org/10.1002/ejhf.518; PMID: 27072307. 86. McHorney CA, Ware JE Jr, Raczek AE. The MOS 36–Item Short-Form Health Survey (SF–36): II. Psychometric and clinical tests of validity in measuring physical and mental health constructs. Med Care 1993;31:247–63. https://doi. org/10.1097/00005650-199303000-00006; PMID: 8450681. 87. Jha SR, Hannu MK, Gore K. Cognitive impairment improves the predictive validity of physical frailty for mortality in patients with advanced heart failure referred for heart

transplantation. J Heart Lung Transplant 2016;35:1092-100. https://doi.org/10.1016/j.healun.2016.04.008; PMID: 27282417. 88. Sokoreli I, Pauws SC, Steyerberg EW. Prognostic value of psychosocial factors for first and recurrent hospitalizations and mortality in heart failure patients: insights from the OPERA-HF study. Eur J Heart Fail 2018;20:689–96. https://doi. org/10.1002/ejhf.1112; PMID: 29314447. 89. Uchmanowicz I, Kuśnierz M, Wleklik M, et al. Frailty syndrome and rehospitalizations in elderly heart failure patients. Aging Clin Exp Res 2018;30:617–23. https://doi.org/10.1007/s40520017-0824-6; PMID: 28849550. 90. Pulignano G, Del Sindaco D, Di Lenarda A, et al. Usefulness of frailty profile for targeting older heart failure patients in disease management programs: a cost-effectiveness, pilot study. J Cardiovasc Med (Hagerstown) 2010;11:739–47. https://doi.org/10.2459/JCM.0b013e328339d981; PMID: 20736784. 91. Tjam EY, Heckman GA, Smith S. Predicting heart failure mortality in frail seniors: comparing the NYHA functional classification with the Resident Assessment Instrument (RAI) 2.0. Int J Cardiol 2012;155:75–80. https://doi.org/10.1016/j. ijcard.2011.01.031; PMID: 21292334. 92. Lee CS, Gelow JM, Denfeld QE. Physical and psychological symptom profiling and event-free survival in adults with moderate to advanced heart failure. J Cardiovasc Nurs 2014;29:315–23. https://doi.org/10.1097/ JCN.0b013e318285968a; PMID: 23416942. 93. Lee CS, Chien CV, Bidwell JT. Comorbidity profiles and inpatient outcomes during hospitalization for heart failure: an analysis of the US Nationwide inpatient sample. BMC Cardiovasc Disord 2014;14:73. https://doi.org/10.1186/1471-2261-14-73; PMID: 24898986. 94. Maurer MS, Horn E, Reyentovich A. Can a left ventricular assist device in individuals with advanced systolic heart failure improve or reverse frailty? J Am Geriatr Soc 2017;65:2383–90. https://doi.org/10.1111/jgs.15124; PMID: 28940248. 95. Green CP, Porter CB, Bresnahan DR, Spertus JA. Development and evaluation of the Kansas City Cardiomyopathy Questionnaire: a new health status measure for heart failure. J Am Coll Cardiol 2000;35:12–55. https://doi.org/10.1016/S07351097(00)00531-3; PMID: 10758967. 96. Jermyn R, Patel S. The biologic syndrome of frailty in heart failure. Clin Med Insights Cardiol 2015;8(Suppl 1):87–92. https:// doi.org/10.4137/CMC.S15720; PMID: 25861225. 97. Goldwater DS, Pinney SP. Frailty in advanced heart failure: a consequence of aging or a separate entity? Clin Med Insights Cardiol 2015;9:39–46. https://doi.org/10.4137/CMC.S19698; PMID: 26244037. 98. Afilalo J, Alexander KP, Mack MJ, et al. Frailty assessment in the cardiovascular care of older adults. J Am Coll Cardiol 2014;63:747–62. https://doi.org/10.1016/j.jacc.2013.09.070; PMID: 24291279. 99. Goldfarb M, Sheppard R, Afilalo J. Prognostic and therapeutic implications of frailty in older adults with heart failure. Curr Cardiol Rep 2015;17:651. https://doi.org/10.1007/s11886-0150651-3; PMID: 26346250. 100. McNallan SM, Singh M, Chamberlain AM, et al. Frailty and healthcare utilization among patients with heart failure in the community. JACC Heart Fail 2013;1:135–41. https://doi. org/10.1016/j.jchf.2013.01.002; PMID: 2395695. 101. Vidan MT, Sanchez E, Fernandez-Aviles F, et al. Frail–Hf, a study to evaluate the clinical complexity of heart failure in nondependent older patients: rationale, methods and baseline characteristics. Clin Cardiol 2014;37:725–32. https://doi.org/10.1002/clc.22345; PMID: 25516357. 102. Afilalo J, Karunananthan S, Eisenberg MJ, et al. Role of frailty in patients with cardiovascular disease. Am J Cardiol 2009;103:1616–21. https://doi.org/10.1016/j. amjcard.2009.01.375; PMID: 19463525. 103. Kalogeropoulos A, Georgiopoulou V, Psaty BM, et al. Inflammatory markers and incident heart failure risk in older adults: the Health ABC (Health, Aging, and Body Composition) Study. J Am Coll Cardiol 2010;55:2129–37. https://doi.org/10.1016/j.jacc.2009.12.045; PMID: 20447537. 104. Piepoli MF, Davos C, Francis DP, et al. Exercise training metaanalysis of trials in patients with chronic heart failure (ExTraMATCH). BMJ 2004;328:189. https://doi.org/10.1136/ bmj.328.7441.711-b; PMID: 14729656.

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Biomarkers

Natriuretic Peptides in Chronic Heart Failure Hans-Peter Brunner-La Rocca and Sandra Sanders-van Wijk Department of Cardiology, Maastricht University Medical Center, Maastricht, the Netherlands

Abstract Normal brain natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) levels are helpful in excluding chronic heart failure in the ambulatory setting, although they have been studied less well and possibly less accurately than in acute care. They may also be of help in screening patients at risk to intervene and reduce the development of heart failure. Natriuretic peptides are also excellent prognostic markers of chronic heart failure, but the clinical value of such prognostic information is less clear. One possible application for this information is guiding medical therapy in chronic heart failure. Many studies have investigated this approach, but results are mixed and do not clearly show improvement in outcome. Still, it may be that in patients with reduced ejection fraction and few comorbidities, measuring NT-proBNP to uptitrate medication improves prognosis.

Keywords Natriuretic peptides, chronic heart failure, therapy guidance, prognosis, diagnosis, BNP, NT-proBNP Disclosure: Both authors receive unrestricted research grants from Roche Diagnostics. Received: 31 July 2018 Accepted: 4 January 2019 Citation: Cardiac Failure Review 2019;5(1):44–9. DOI: https://doi.org/10.15420/cfr.2018.26.1 Correspondence: HP Brunner-La Rocca, Department of Cardiology, Maastricht University Medical Center, PO Box 5800, 6202 AZ Maastricht, the Netherlands. E: hp.brunnerlarocca@mumc.nl 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.

Natriuretic peptides (NPs) are well established in the diagnostic process of heart failure (HF). Low levels of NPs are particularly useful to exclude heart failure (HF). Numerous studies, predominantly in patients presenting with acute onset of symptoms suspected of HF, have convincingly shown the value of NPs in this regard. A meta-analysis published in 2015 clearly summarised the value of brain (B-type) NP (BNP), N-terminal proBNP (NT-proBNP) and midregional pro-atrial NP (MR-proANP) in the acute setting, uniformly showing a very high negative predictive value when using low cutoff levels (i.e. BNP <100 pg/ml; NT-proBNP <300 pg/ml, MR-proANP <120 pmol/l).1

Outpatient cut-off values are less investigated than cut-off values in the acute setting, particularly with respect to BNP. The best cut-off values found in these studies are not as uniform as various guidelines may recommend; only some are in this range, with many of them being higher and more in the range of the values recommended in the acute setting, as well as some being lower.4–9

These cut-off values, recommended by the European Society of Cardiology (ESC) guidelines, have an excellent ability to exclude acute HF, missing only a few cases. They help to distinguish HF from noncardiac causes of dyspnoea.2,3 However, the specificity is modest and variable, indicating that confirmatory diagnostic testing by cardiac imaging is required if the result is positive. In addition, the negative predictive value varies quite significantly between studies if higher cut-off values are used.1

In addition, the negative predictive value may be less than it is in the acute setting, which possibly relates to diagnostic accuracy reducing with increasing age (i.e. c-statistics decreasing from 0.95 in patients aged <50 years to 0.82 in patients aged >75 years), as shown in a meta-analysis including >5,500 patients from 10 studies to test the diagnostic value of NT-proBNP to detect LVEF≤40%.10 These authors suggested using an age-specific cut-off value to rule out HF in primary care settings, which would be lower than recommendations in the current US and ESC guidelines for young (<50 years, cut-off value 50 pg/ml) and middle-aged people (50–75 years, 75 pg/ml), but higher for elderly patients (>75 years, 250 pg/ml).10 Still, this analysis has not been considered by the guidelines and the suggested cut-off values differ between European, US and UK guidelines.2,11,12

For patients in the outpatient setting not presenting with acute symptoms, the recommended cut-off values are lower, at 35 pg/ml for BNP and 125 pg/ml for NT-proBNP.2 Levels above these values are also required as part of the diagnosis of patients with HF and preserved ejection fraction (HFpEF; LVEF ≥50%) or mildly reduced (mid-range; HFmrEF; LVEF 40–49%) left-ventricular ejection fraction (LVEF).2 No recommendation is given for MR-proANP as no larger studies in the outpatient setting have been published.

While the majority of these studies did not distinguish between HF with reduced ejection fraction (HFrEF; LVEF <40%) and HFpEF, some studies focused on diastolic dysfunction only.13 Although NP levels are lower in HFpEF in general, the established thresholds for diagnosing acute HF remain useful in patients with preserved ejection fraction, with only minor loss of diagnostic performance (NPV 90% at a BNP of 100 pg/ml).14 The distinction may be less relevant in the acute setting, where therapy is largely similar regardless of LVEF. In chronic

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Natriuretic Peptides in Chronic Heart Failure HF however, treatment of chronic HFrEF is well defined, in contrast to that for HFpEF.2 In addition and especially in the elderly, NPs have a much poorer diagnostic performance for HFpEF.15

Table 1: Factors Influencing Natriuretic Peptide Levels Independent of Heart Failure Increase in natriuretic peptides

Another study showed the added value of NT-proBNP in diagnosing HF, with increasing levels being added to a score including nine clinical features (age, coronary artery disease, loop diuretics use, pulse rate and regularity, displaced apex beat, rales, heart murmur and elevated jugular vein pressure) to diagnose HF.16 This score had high c-statistics of 0.86 in the derivation set and higher c-statistics of 0.88 and 0.95 in two external validation sets.16 The problems with such a score are that it is not easily applicable in clinics and there is a significant zone of uncertainty. A recent meta-analysis investigated cut-off values using point-ofcare devices in both the acute and ambulatory outpatient settings.17 This analysis may provide the currently most accurate overview of the diagnostic accuracy of NPs in the ambulatory setting. Data from primary care were scarce and ranges of cut-off values varied widely, particularly for BNP. The ESC recommended cut-off level for the non-acute setting (35 pg/ml) was not used in any of the included studies, whereas the value for NT-proBNP (125 pg/ml) was used in four studies.17 However, results depend on the patient population included and may vary, depending on the prevalence of HF. Additional studies are needed to identify the best cut-off values in the non-acute setting to diagnose HF. In addition, many factors independent of HF may influence NP levels (Table 1). Although there is an obvious overlap of the cardiac causes and HF itself, interpretation of NP levels in individual patients must be done against the background of additional factors influencing these values. For example, in a young patient with no comorbidities, expected NP levels are very low, whereas in elderly patients with reduced renal function and atrial fibrillation levels clearly above the cut-off value are common even in the absence of HF. Recent data support the application of different thresholds of NT-proBNP for the diagnosis of HFpEF in patients with AF versus those in sinus rhythm.18 Importantly, obese patients with HF can have normal values of NPs, even if they are volume overloaded; the Breathing-NotProperly study found that the best cut-off value in severely obese subjects is much lower than in lean patients.19 However, prospective validation of these types of individualised cut-offs is lacking and so is not yet supported by HF guidelines. Measurement of NPs may also help as screening tool in primary care to stratify patients and reduce risk. The Irish Screening To Prevent Heart Failure (STOP-HF) study randomised patients at risk for developing HF into either usual care or additional measurement of BNP levels.20 If BNP was 50 pg/ml or higher, patients were referred for echocardiography. This resulted in more cardiovascular investigations and more treatment, but less HF and left ventricular dysfunction.20 The measurement of BNP in this setting was likely to be cost effective.21 Although these results are promising, confirmation in other populations and healthcare systems is still absent. The finding that intensifying medical therapy may result in less chronic HF in high-risk patients with elevated NP levels is supported by the Austrian NT-proBNP Selected PreventiOn of cardiac eveNts in a populaTion of dIabetic patients without A history of Cardiac disease

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Cardiac • Acute coronary syndromes • Atrial fibrillation • Valvular heart disease • Cardiomyopathies • Myocarditis • Cardioversion • Left ventricular hypertrophy Noncardiac • Age • Female gender • Renal impairment • Pulmonary embolism • Systemic bacterial infections (e.g. pneumonia, sepsis) • Obstructive sleep apnea • Critical Illness • Severe burns • Cancer chemotherapy • Toxic and metabolic insults Decrease in natriuretic peptides • Obesity

(PONTIAC) trial in people with diabetes with NTproBNP levels >125 pg/ml but free from any cardiac diseases.22 MR-proANP has not been studied in this regard but was shown to stratify risk for the development of cardiovascular mortality and incident HF in patients with coronary artery disease. In addition, only patients with at least two of three biomarkers elevated – MR-proANP, MR-proADM and CT-proET-1 – showed an improvement in outcome with ACE-inhibition.23 Obviously, this is no proof that interventions based on MR-proANP levels would result in better outcome, which needs to be prospectively investigated. Taken together, BNP and NT-proBNP levels are diagnostically useful not only in the acute setting but also in the diagnostic process of chronic HF and possibly in the identification of patients at risk of developing HF. Still, more research is needed in the ambulatory setting. Therefore, cutoff values to exclude HF are not yet clearly defined and their diagnostic value might be less than in the acute setting. In addition, the value of MR-proANP has not yet been tested in this setting. Confirmatory studies are required to define the role of NPs in identifying patients at risk who need advance diagnostics and more aggressive medical therapy.

Prognostic Value of Natriuretic Peptides in Chronic Heart Failure Without doubt, NPs are strong prognostic markers in patients with chronic HF. This is true for all NPs for which tests are commercially available. However, although NPs may be considered as the most robust prognostic markers in chronic HF, individual studies indicate some variety, showing some other biomarkers having a better prognostic value. Despite this, no single biomarker is clearly prognostically superior to NPs. In many instances, other biomarkers representing different pathophysiological pathways provide additional prognostic information to NPs.24 A 2005 systematic review showed the prognostic value of BNP, including identifying changes over time, in a large number of studies and this number has increased considerably since then.25 It is beyond the scope of this review to discuss these studies and recent reviews discussing the prognostic value of NPs in detail.26,27

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Biomarkers Table 2: Some Criteria of Natriuretic Peptide Guided Trials Including Patients with Heart Failure with Reduced Ejection Fraction Troughton Beck-da-

STARS-

TIME-

BATTLE-

et al.33

BNP35

CHF36

SCARRED39

Silva et

PRIMA38

SIGNAL-

Berger

HF40

et al.37

UPSTEP42

STARBRITE43 PROTECT41 GUIDE-IT29

al.34 n

220

499 (622)

134 (364)

229 (345)

252

177 (278)

279

137

151

894

Blinded

Single

Double

Single

Marker

NT-proBNP BNP

Target (pg/ml) 1,692

BNP

NT-proBNP NT-proBNP

NT-proBNP NT-proBNP NT-proBNP BNP

BNP

NT-proBNP NT-proBNP

Not stated

100

400/800

Discharge 50% reduction

Discharge

1.000

Usual care ≤ NYHA class II

1,270

Two groups Usual care HF spec

2,200

150/300

Two groups Usual care HF spec

1.000

Control

HF score

HF spec

Usual care HF spec

Primary endpoint

Death, CV hosp HF

Mean beta- HF death, Death, all- All-cause blocker doseHF hosp cause hosp mortality achieved

Days alive Days alive HF hosp, outside outside CV death hospital hospital

Death, HF Days alive hosp/worse outside hospital

CV events

CV death, HF hosp

Age (mean)

NT-BNP/BNP 1,981 at baseline (pg/ml)

~600

350

4,328

2,008

2,940

~2,500

~2,350

851

450

2,118

2,650

Study duration

90 days

450 days

18 months

3 years

2 years

9 months

18 months

At least 1 year

90 days

1 year

24 months

12 months

The total number of patients included if different is shown in parentheses; differences concern patients with heart failure with preserved ejection fraction or undetermined left ventricular ejection fraction, or two control groups. BNP = B-type natriuretic peptide; CV = cardiovascular; HF = heart failure; HF spec = heart failure specialists; hosp = hospitalisation; NT-proBNP = N-terminal pro–B-type natriuretic peptide.

Table 3: Medication Intensification Troughton Beck-da- STARSet al.33

Silva et

TIME-CHF36 BATTLE-

BNP35

PRIMA38 SIGNAL-

SCARRED39

Berger

HF40

et al.37

~90%

89%

UPSTEP42 STARBRITE43 PROTECT41 GUIDE-IT29

al.34 ACE/ARB

100%

99%

95%

82%

79%

98%

86%

81%

77%

Beta-blocker

100%

98%

79%

68%

77%

97%

77%

94%

96%

93%

Diuretics

100%

93%

95%

96%

68%

81%

90%

94%

91%

49%

ACE/ARB

Yes

(Yes)

Yes

No/Yes

Yes

Beta-blocker

Yes

Spironolac

Yes

Diuretics

Yes

Decrease

More adverse events

Trend

Primary endpoint Positive

Negative Positive

Mortality

2/4

p=0.06

Negative

7/11, ns p=0.06

Negative

Negative Negative

Positive

Negative

Positive

Negative

Identical

p=0.21

Identical

1/3

Identical

p=0.37

Identical

Rows 1–3 show medication at baseline. Rows 4–7 show medication intensification in the natriuretic peptide guided groups as compared to the control group. Rows 8-9 show if more adverse events were present, the primary endpoint was reached and if mortality was changed. ACE = angiotensin-converting-enzyme-inhibitor; ARB = angiotensin receptor blocker; NR = not reported. Mortality: p-value if positive trend; numbers indicate number of deaths in natriuretic peptide group and control group.

More important are the clinical consequences of knowing the prognosis of an individual patient. Guidelines recommend risk assessment by using risk scores to inform management decisions on advanced therapy such as ventricular assist devices and cardiac transplantation, despite no studies showing the clinical value of this recommendation. One may argue that patients at high risk should be monitored more closely. To the best of the authors’ knowledge, it has not yet been investigated whether basing frequency of consultations on prognostic markers results in better outcomes and if such an approach would be cost-effective. However, more specialised treatment with scheduled follow-ups does not seem to improve outcome as the NorthStar trial shows.28 Also, the number of visits per se also does not seem to influence outcome.29 Nevertheless, NPs are increasingly used in clinical trials, based on their prognostic value to better predict event rate and to increase the study

CFR_BrunnerLa Rocca_FINAL.indd 46

power by including patients at higher risk. A prominent recent example is the Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial, which investigated the effect of sacubitril/valsartan compared to enalapril in chronic HFrEF.30 To meet the inclusion criteria, patients had to have a BNP level of ≥150 pg/ml or NT-proBNP level of ≥600 pg/ ml or 100 pg/ml and 400 pg/ml, respectively, if hospitalised within the previous 12 months. Such inclusion criteria based on NPs are not the result of specific underlying pathophysiology but related purely to the strong prognostic value of NPs. In addition, NPs may predict sudden cardiac death and, therefore, might be helpful for indication of ICD implantation.31 However, such an approach needs to be prospectively tested before NPs can be recommended as selection criterion. Combining the strong prognostic value of NPs, together with the fact that NP levels change with altered therapy, make them an interesting guide for therapy in HF.32

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Natriuretic Peptides in Chronic Heart Failure Therapy guidance using natriuretic peptides in chronic heart failure Due to the prognostic power of NPs and because many patients with HF do not meet the target doses of HF drugs as recommended by guidelines, many studies have been conducted to test the hypothesis that therapy guided by repeated measurements of NPs improves outcome compared to usual care. The first study investigating this hypothesis was published in 2000 but, 19 years and more than a dozen trials later, it has not been established whether this hypothesis is true or not.33 This is in part related to the fact that none of the NP-guided trials was large enough to convincingly show the effects of this approach. This may be true even for the GUIDE-IT trial, which is the latest and largest study investigating this topic, which was stopped early so did not meet the predefined sample size and follow-up.29 Even more importantly, there is a large variation between the trials29, 33–43 with regard to several aspects, including that: the included populations differed significantly; the interventions were not uniform; and follow-up length and the number of time-points to adjust therapy varied (Tables 2 and 3). A recent meta-analysis came to conclusion that NP-guided therapy does not result in any benefit.44 However, this meta-analysis did not properly account for the large diversity between the trials, nor did it perform sufficient sensitivity analyses despite including different kind of studies that are not directly comparable. Strikingly, the use of NPs both in the acute setting and in chronic HF was combined in this investigation and studies were included regardless of whether they included patients with HFrEF, HFpEF or both. It is well known that HFpEF does not respond to classic HF therapy, and a previous metaanalysis based on individual patient data showed a different response to NP-guided therapy in HFrEF and HFpEF.2,45 In addition, one study (NorthStar) included in this meta-analysis suggested action should be taken only if NT-proBNP levels significantly increased but not if they remained elevated and it included both HFrEF and HFpEF. Not surprisingly, adjustments in therapy were limited and identical in the two treatment arms and, consequently, NT-proBNP hardly changed.46 Most other NP-guided trials showed a significant reduction in NP levels in both treatment arms (e.g. Felker, et al, 2017; Pfisterer, et al, 2009).29, 36 The only genuinely relevant group of patients in whom NP guidance in chronic HF should be investigated are those with HFrEF. When only results in chronic HFrEF from the previous trials (1,507 in the NP-guided group and 1,516 in the control group) are included, NP-guided therapy – mostly using NT-proBNP, some using BNP – resulted in a significant reduction in mortality (Figure 1).29,33–43 Overall, 222 (14.7%) patients died in the NP-guided group and 275 (18.1%) in the control group. As far as we can say, NP-guided therapy seems to be safe, even in elderly patients with significant comorbidities, and may be costeffective as well.47–49 However, further evidence from more trials on NP-guided therapy is required. Trials where adjustment in therapy did not differ between the NP-guided versus the clinical guided group, or where increasing loop diuretics was the main difference, usually showed a neutral outcome. In contrast, trials where the focus was mainly on intensifying guideline-recommended medication (e.g. angiotensin-converting enzyme [ACE] inhibition or angiotensin-receptor blockers, betablockers or mineralocorticoid receptor antagonists) showed some

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positive results although, because of a lack of statistical power, the primary endpoint of the trials was not always reached (Table 3). This shows that applying guidelines when managing patients with HFrEF is crucial to improve outcome. The fact that NP guidance in TIME-CHF resulted in significantly larger uptitration of evidence-based treatment even in patients aged >75 years indicates that, in many patients with HFrEF, the maximum tolerated has not been reached and forced uptitration is feasible.36 Unfortunately, this is often not done in reality and the question arises over what may encourage physicians to do more for these patients. Measuring NPs to indicate the importance of uptitration may help in this regard.

Sacubitril: A Problem for Measuring Natriuretic Peptides? Among the bioactive peptides, sacubitril reduces the breakdown of the biologically active NPs by inhibiting the enzyme neprilysin, a circulating neutral endopeptidase involved in the degradation of NPs.50 This is true for both ANP and BNP, but BNP is a poorer substrate for neprilysin than ANP. Therefore, the increase of BNP may be less.51 The increase in BNP was only small although significant whereas the increase in urinary cGMP was much larger with sacubitril/valsartan in the PARADIGM-HF study.52 Sacubitril has no direct influence on NT-proBNP because neprilysin has no effect on cleavage of NT-proBNP. However, it might be speculated that an increasing level of BNP results in a negative feedback regarding production of proBNP, thereby reducing NT-proBNP. To the best of our knowledge, this has not been properly tested. In clinical trials, sacubitril/valsartan resulted in a reduction of NT-proBNP, as well as a small increase in BNP as mentioned above.52,53 This reduction was accompanied by a better outcome. Therefore, it is likely that the decrease in NT-proBNP is, at least in part, related to more effective treatment of HF. To what extent NT-proBNP levels are influenced by a negative feedback mechanism remains to be determined. With the more widespread clinical use of sacubitril/valsartan, the measurement of serum NP levels in patients taking this drug may change and a rethinking of their interpretation is required. In patients taking sacubitril/valsartan, levels of BNP may rise because of decreased serum breakdown rather than because of a change in underlying disease state (such as volume overload in AHF), which potentially interferes with the prognostic and diagnostic utility of BNP.27 However, this does not impair the clinical utility of BNP testing to rule out HF rapidly. Also, the clinical interpretation of NT-proBNP levels in patients with HF is probably not affected in a clinically meaningful way by neprilysin inhibition, based on published data.

When to Measure Natriuretic Peptides in Chronic Heart Failure First, NPs are useful in the initial diagnosis or exclusion of HF. They may also help to identify patients at risk of developing HF where early intervention may reduce risk. Second, NPs should be used in the outpatient management of HFrEF when deciding whether to start a patient on eplerenone (BNP >250 pg/ml or NT-proBNP >500 pg/ml in men or >750 pg/ml in women, unless they have been hospitalised within the previous 6 months because of HF) or sacubitril/valsartan (BNP >150 pg/ml or NT-proBNP

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Biomarkers Figure 1: Mortality in Natriuretic Peptide Guided Trials in Chronic Heart Failure with Reduced Ejection Fraction Hazard ratio Study or subgroup

Weight

Hazard ratio

Exp ([O – E]/V), fixed 95% Cl

Beck-da-Silva34

0.6%

0.48 (0.05–4.85)

STARBRITE43

0.6%

0.33 (0.03–3.18)

Troughton et al.33

0.7%

0.15 (0.02–1.20)

SIGNAL-HF40

2.4%

0.87 (0.27–2.80)

PROTECT

2.9%

1.28 (0.44–3.68)

STARS-BNP35

3.3%

0.61 (0.23–1.64)

BATTLESCARRED39

6.2%

0.82 (0.40–1.69)

Berger et al.37

7.8%

1.04 (0.55–1.99)

12.6%

1.03 (0.62–1. 71)

UP STEP42 PRIMA38

13.7%

0.71 (0.44–1.15)

TIME-CHF36

20.1%

0.67 (0.45–1.00)

GUIDE-IT29

29.1%

0.86 (0.62–1.20)

100.0%

0.81 (0.67–0.97)

Total (95% Cl)

Total events Heterogeneity: chi-squared = 7.07; df = 11 (p=0.79); I2 = 0% Test for overall effect: Z = 2.34 (p=0.02)

Exp ([O – E]/V), fixed 95% Cl

0.1

0.2

0.5 Favours NP-guided

Favours control

Forest plot of mortality among participants in natriuretic peptide (NP) guided trials in chronic HFrEF, showing unadjusted individual and mean hazard ratios with 95% confidence intervals (CIs) for 12 studies (individual patient data in eight studies – Troughton, et al. 2000;33, Pfisterer, et al. 2009;36 Berger et al. 2010;37 Eurlings, et al. 2010;38 Lainchbury, et al. 2010;39 Persson, et al. 2010;40 Januzzi, et al. 2011;41 Karlstrom, et al. 2011;42) and aggregate data in four studies (Felker, et al. 2017;29 Beck-da-Silva, et al. 2005;34 Jourdain, et al. 2007;35 Shah, et al. 201133).

>600 pg/ml; in case of a HF, hospitalisation within the previous 12 months, BNP >100 pg/ml or NT-proBNP >400 pg/ml), in line with the ESC HF guidelines, which are based on the inclusion criteria of the respective drug trials.2 Third, despite a lack of sufficient evidence for the superiority of natriuretic guided-therapy overall, NPs can help to decide whether a patient is being treated optimally. This is supported by the American College of Cardiology/American Heart Association guidelines (class IIA level of evidence), although this recommendation might change after the recent GUIDE-IT trial, and is not mentioned in the ESC HF guideline.2,11 Based on (pre-stratified) subgroup analyses, we would recommend this approach mainly in patients who have HFrEF and few comorbidities.45 Based on trials, it seems best to use a target around normal values, meaning ~125 pg/ml for BNP and ~1,000 pg/ml for NT-proBNP (Table 2).

oberts E, Ludman AJ, Dworzynski K, et al. The diagnostic R accuracy of the natriuretic peptides in heart failure: systematic review and diagnostic meta-analysis in the acute care setting. BMJ 2015;350:h910. https://doi.org/10.1136/bmj. h910; PMID: 25740799. P onikowski P, Voors AA, Anker SD, et al. 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J 2016;37:2129–200. https://doi.org/10.1093/eurheartj/ehw128; PMID: 27206819. Morrison LK, Harrison A, Krishnaswamy P, et al. Utility of a rapid B-natriuretic peptide assay in differentiating congestive heart failure from lung disease in patients presenting with dyspnea. J Am Coll Cardiol 2002;39:202–9. https://doi. org/10.1016/S0735-1097(01)01744-2; PMID: 11788208. F uat A, Murphy JJ, Hungin AP, et al. The diagnostic accuracy and utility of a B-type natriuretic peptide test in a community population of patients with suspected heart failure. Br J Gen Pract 2006;56:327–33. PMID: 16638247. Tang WH, Girod JP, Lee MJ, et al. Plasma B-type natriuretic peptide levels in ambulatory patients with established chronic symptomatic systolic heart failure. Circulation 2003;108:2964–6. https://doi.org/10.1161/01.CIR.0000106903.98196.B6; PMID: 14662703.

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The focus should be on improving and intensifying drugs that improve outcomes, such as renin–angiotensin system blockers, beta-blockers and mineralocorticoid receptor antagonists in patients whose (NT-pro)BNP levels remain elevated, not on the use of intensified diuretic therapy. This could be done merely to convince patients or their caregivers that (further) uptitration of evidence-based medicine is crucial. As to whether a lack of elevated NPs means that further uptitration of medication is not required remains to be prospectively tested in a randomised trial. This may be relevant in patients who are most susceptible of side effects (e.g. frail elderly people). Fourth, NPs may help to distinguish whether an increase in symptoms is related to worsening HF or deterioration of another condition (e.g. chronic obstructive pulmonary disease). When patients are using sacubitril/valsartan, the preferred NP is definitely NT-proBNP.

owie MR, Struthers AD, Wood DA, et al. Value of natriuretic C peptides in assessment of patients with possible new heart failure in primary care. Lancet 1997;350:1349–53. https://doi. org/10.1016/S0140-6736(97)06031-5; PMID: 1 19365448. 7. H obbs FD, Davis RC, Roalfe AK, et al. Reliability of N-terminal pro-brain natriuretic peptide assay in diagnosis of heart failure: cohort study in representative and high risk community populations. BMJ 2002;324:1498. https://doi. org/10.1136/bmj.324.7352.1498; PMID: 12077039. 8. Wright SP, Doughty RN, Pearl A, et al. Plasma amino-terminal pro-brain natriuretic peptide and accuracy of heart-failure diagnosis in primary care. A randomized, controlled trial. J Am Coll Cardiol 2003;42:1793–800. https://doi.org/10.1016/ j.jacc.2003.05.011; PMID: 14642690. 9. Landray MJ, Lehman R, Arnold I. Measuring brain natriuretic peptide in suspected left ventricular systolic dysfunction in general practice: cross-sectional study. BMJ 2000;320:985–6. https://doi.org/10.1136/bmj.320.7240.985; PMID: 1 110753153 10. H ildebrandt P, Collinson PO, Doughty RN, et al. Age-dependent values of N-terminal pro-B-type natriuretic peptide are superior to a single cut-point for ruling out suspected systolic dysfunction in primary care. Eur Heart J 2010;31:1881–9. https:// doi.org/10.1093/eurheartj/ehq163; PMID: 20519241. 11. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA Guideline for the Management of Heart Failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am

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Natriuretic Peptides in Chronic Heart Failure

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PMID: 28829876. 30. M cMurray JJ, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014;371:993–1004. https://doi.org/10.1056/NEJMoa1409077; PMID: 25176015. 31. B erger R, Huelsman M, Strecker K, et al. B-type natriuretic peptide predicts sudden death in patients with chronic heart failure. Circulation 2002;105:2392–7. https://doi. org/10.1161/01.CIR.0000016642.15031.34; PMID: 12021226. 32. Brunner-La Rocca HP, Weilenmann D, Kiowski W, et al. Within-patient comparison of effects of different dosages of enalapril on functional capacity and neurohormone levels in patients with chronic heart failure. Am Heart J 1999;138:654– 62. https://doi.org/10.1016/S0002-8703(99)70179-1; PMID: 10502210. 33. Troughton RW, Frampton CM, Yandle TG, et al. Treatment of heart failure guided by plasma aminoterminal brain natriuretic peptide (N-BNP) concentrations. Lancet 2000;355:1126–30. https://doi.org/10.1016/S01406736(00)02060-2; PMID: 1 110791374. 34. B eck-da-Silva L, de Bold A, Fraser M, et al. BNP-guided therapy not better than expert’s clinical assessment for beta-blocker titration in patients with heart failure. Congest Heart Fail 2005;11:248–53. https://doi.org/10.1111/j.15275299.2005.04239.x; PMID: 16230866. 35. Jourdain P, Jondeau G, Funck F, et al. Plasma brain natriuretic peptide-guided therapy to improve outcome in heart failure: the STARS-BNP Multicenter Study. J Am Coll Cardiol 2007;49:1733–9. https://doi.org/10.1016/j.jacc.2006.10.081; PMID: 17448376. 36. Pfisterer M, Buser P, Rickli H, et al. BNP-guided vs symptomguided heart failure therapy: the Trial of Intensified vs Standard Medical Therapy in Elderly Patients With Congestive Heart Failure (TIME-CHF) randomized trial. JAMA 2009;301: 383–92. https://doi.org/10.1001/jama.2009.2; PMID: 19176440. 37. Berger R, Moertl D, Peter S, et al. N-terminal pro-B-type natriuretic peptide-guided, intensive patient management in addition to multidisciplinary care in chronic heart failure a 3–arm, prospective, randomized pilot study. J Am Coll Cardiol 2010;55:645–53. https://doi.org/10.1016/j.jacc.2009.08.078; PMID: 20170790. 38. Eurlings LW, van Pol PE, Kok WE, et al. Management of chronic heart failure guided by individual N-terminal pro-Btype natriuretic peptide targets: results of the PRIMA (Can PRo-brain-natriuretic peptide guided therapy of chronic heart failure IMprove heart fAilure morbidity and mortality?) study. J Am Coll Cardiol 2010;56:2090–100. https://doi.org/10.1016/ j.jacc.2010.07.030; PMID: 21144969. 39. L ainchbury JG, Troughton RW, Strangman KM, et al. N-terminal pro-B-type natriuretic peptide-guided treatment for chronic heart failure: results from the BATTLESCARRED (NT-proBNPAssisted Treatment To Lessen Serial Cardiac Readmissions and Death) trial. J Am Coll Cardiol 2010;55:53–60. https://doi. org/10.1016/j.jacc.2009.02.095; PMID: 20117364. 40. Persson H, Erntell H, Eriksson B, et al. Improved pharmacological therapy of chronic heart failure in primary care: a randomized Study of NT-proBNP Guided Management of Heart Failure – SIGNAL-HF (Swedish Intervention study – Guidelines and NT-proBNP AnaLysis in Heart Failure). Eur J Heart Fail 2010;12:1300–8. https://doi.org/10.1093/eurjhf/ hfq169; PMID: 20876734. 41. J anuzzi JL Jr, Rehman SU, Mohammed AA, et al. Use of amino-terminal pro-B-type natriuretic peptide to guide outpatient therapy of patients with chronic left ventricular systolic dysfunction. J Am Coll Cardiol 2011;58:1881–9. https://

doi.org/10.1016/j.jacc.2011.03.072; PMID: 22018299. 42. K arlstrom P, Alehagen U, Boman K, et al. Brain natriuretic peptide-guided treatment does not improve morbidity and mortality in extensively treated patients with chronic heart failure: responders to treatment have a significantly better outcome. Eur J Heart Fail 2011;13:1096–103. https://doi. org/10.1093/eurjhf/hfr078; PMID: 21715446. 43. Shah MR, Califf RM, Nohria A, et al. The STARBRITE trial: a randomized, pilot study of B-type natriuretic peptideguided therapy in patients with advanced heart failure. J Card Fail 2011;17:613–21. https://doi.org/10.1016/j. cardfail.2011.04.012; PMID: 21807321. 44. Khan MS, Siddiqi TJ, Usman MS, et al. Does natriuretic peptide monitoring improve outcomes in heart failure patients? A systematic review and meta-analysis. Int J Cardiol 2018;263:80–7. https://doi.org/10.1016/j.ijcard.2018.04.049; PMID: 29685696. 45. Brunner-La Rocca HP, Eurlings L, Richards AM, et al. Which heart failure patients profit from natriuretic peptide guided therapy? A meta-analysis from individual patient data of randomized trials. Eur J Heart Fail 2015;17:1252–61. https://doi. org/10.1002/ejhf.401; PMID: 26419999. 46. Schou M, Gustafsson F, Videbaek L, et al. Adding serial N-terminal pro brain natriuretic peptide measurements to optimal clinical management in outpatients with systolic heart failure: a multicentre randomized clinical trial (NorthStar monitoring study). Eur J Heart Fail 2013;15:818–27. https://doi.org/10.1093/eurjhf/hft037; PMID: 23507787. 47. Sanders-van Wijk S, Muzzarelli S, Neuhaus M, et al. Safety and tolerability of intensified, N-terminal pro brain natriuretic peptide-guided compared with standard medical therapy in elderly patients with congestive heart failure: results from TIME-CHF. Eur J Heart Fail 2013;15:910–18. https://doi. org/10.1093/eurjhf/hft079; PMID: 23666681. 48. Sanders-van Wijk S, van Asselt AD, Rickli H, et al. Costeffectiveness of N-terminal pro-B-type natriuretic-guided therapy in elderly heart failure patients: results from TIMECHF (Trial of Intensified versus Standard Medical Therapy in Elderly Patients with Congestive Heart Failure). JACC Heart Fail 2013;1:64–71. https://doi.org/10.1016/j.jchf.2012.08.002; PMID: 24621800. 49. Adlbrecht C, Huelsmann M, Berger R, et al. Cost analysis and cost-effectiveness of NT-proBNP-guided heart failure specialist care in addition to home-based nurse care. Eur J Clin Invest 2011;41:315–22. https://doi.org/10.1111/j.13652362.2010.02412.x; PMID: 21070222. 50. Mangiafico S, Costello-Boerrigter LC, Andersen IA, et al. Neutral endopeptidase inhibition and the natriuretic peptide system: an evolving strategy in cardiovascular therapeutics. Eur Heart J 2013;34:886–93c. https://doi.org/10.1093/eurheartj/ ehs262; PMID: 22942338. 51. Mair J, Lindahl B, Giannitsis E, et al. Will sacubitril-valsartan diminish the clinical utility of B-type natriuretic peptide testing in acute cardiac care? Eur Heart J Acute Cardiovasc Care 2017;6:321–8. https://doi.org/10.1177/2048872615626355; PMID: 26758541. 52. Packer M, McMurray JJ, Desai AS, et al. Angiotensin receptor neprilysin inhibition compared with enalapril on the risk of clinical progression in surviving patients with heart failure. Circulation 2015;131:54–61. https://doi.org/10.1161/ CIRCULATIONAHA.114.013748; PMID: 25403646. 53. Solomon SD, Zile M, Pieske B, et al. The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: a phase 2 double-blind randomised controlled trial. Lancet 2012;380:1387–95. https://doi. org/10.1016/S0140-6736(12)61227-6. PMID: 122932717.

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Biomarkers

Biomarkers in Routine Heart Failure Clinical Care Sunil K Nadar and Muhammed Mujtaba Shaikh Department of Medicine, Sultan Qaboos University Hospital, Muscat, Oman

Abstract Heart failure is a clinical condition with complex pathophysiology that involves many different processes. Diagnosis is often difficult in patients presenting for the first time with breathlessness. Many biomarkers have been identified that are elevated in heart failure and their role in assessing prognosis has also been investigated. However, at present the natriuretic peptides appear to be the gold standard biomarker against which the other biomarkers are compared. In this review we will examine the evidence behind the other biomarkers for use in heart failure patients and the current guidelines for their use.

Keywords Acute heart failure, chronic heart failure, biomarkers, natriuretic peptides, troponin, prognosis, diagnosis Disclosure: The authors have no conflicts of interest to declare Received: 3 August 2018 Accepted: 25 October 2018 Citation: Cardiac Failure Review 2019;5(1):50–6. DOI: https://doi.org/10.15420/cfr.2018.27.2 Correspondence: Sunil Nadar, Department of Medicine, Sultan Qaboos University Hospital, Muscat, Oman. E: sunilnadar@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.

The National Institutes of Health Biomarkers Definitions Working Group define a biomarker as “a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention”.1 Biomarkers have become increasingly important in current medical practice as they offer an easy way to either diagnose an illness or to monitor progress. Tijsen et al. have suggested that an ideal biomarker ought to be easy to collect non-invasively, should have a high degree of sensitivity and specificity, should be cheap, easily reproducible and should have a rapid measurement system that assists in prompt clinical management.2 For patients presenting with breathlessness, there is a need for a reliable biomarker for the early diagnosis of heart failure. Previous studies have demonstrated a high degree of uncertainty when patients present with breathlessness.3 Heart failure and chronic obstructive airway disease often coexist in approximately 30% of patients, making diagnosis confusing. The Breathing Not Properly study reported clinical confusion in approximately half of cases presenting to the emergency department with breathlessness.4 Echocardiography can detect abnormal left ventricular (LV) function, but that may not be the cause of breathlessness because almost 50% of the communitydwelling population with decreased LV function have been shown to be asymptomatic.5 Hence there is a need for a biomarker that could assist in diagnosis. Similarly, there is also a need for better monitoring of patients receiving treatment for heart failure. It has been demonstrated that physiological changes often precede clinical deterioration that would lead to a patient attending hospital.6 Invasive mechanisms such as pacemaker devices with physiological monitoring mechanisms can alert the physician to clinical deterioration.7 However, these are invasive and not

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all patients with heart failure have a pacemaker. Non-invasive means such as a biomarker have therefore become useful. There are many potential biomarkers for heart failure (Figure 1). In this article, we discuss the biomarkers that are available for clinical use in patients with heart failure – both for diagnosis and prognosis – reviewing the evidence and the recommendations of various guidelines. Furthermore, we will highlight some of the emerging biomarkers in this field, along with the evidence for their use.

Biomarkers for Diagnosis The diagnosis of heart failure in a patient presenting with breathlessness for the first time is often difficult, and biomarkers – along with other investigations – can contribute to diagnosis. Traditionally, clinical presentation along with chest X-ray has been used to make a diagnosis of heart failure. However, studies have repeatedly shown a low sensitivity and specificity for making a clinical diagnosis of heart failure. Echocardiography is a useful component of diagnosis, but in the acute setting it may not always be possible to obtain an echocardiogram, particularly out of hours. Additionally, the echocardiogram may be normal in heart failure with preserved ejection fraction (HFpEF). The natriuretic peptides are the most extensively studied and used biomarkers in heart failure.8 As a result of myocardial stretch, the B-type natriuretic peptide (BNP) gene is activated and prohormone proBNP1–108 is produced. This is cleaved to the biologically active BNP and the biologically inert but stable NT-proBNP1–76. They downregulate the sympathetic system, cause diuresis, decrease peripheral resistance and increase smooth muscle relaxation (Figure 2). Atrial natriuretic peptide (ANP) as rapid clearance and is less consistent as a diagnostic marker and hence is not used routinely. However, newer assays have been developed that measure the precursor hormone of

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Biomarkers in Routine Heart Failure Clinical Care Figure 1: Different Potential Biomarkers in the Diagnosis and Management of Heart Failure

Uric acid Myeloperoxidase

Oxidative stress

Neuroendocrine

MR proADM Copeptin Endothelin-1

Activation of BNP gene

Troponin Creatinine kinase H-type FABP

Myocardial injury

Heart failure

Chamber dilatation/ myocardial stretch

Natriuretic peptides

Creatinine Cystatin C Electrolytes NGAL

Fibrosis, matrix remodelling

Inflammation

Pro BNP (108 AA)

ST2 Galectin 2 MMP

hsCRP IL-6 ST2 TNF-alpha Procalcitonin

ANP, mid-regional proANP (MR-proANP). MR-proANP is more stable, giving more reliable results, and has therefore been identified as a reliable marker. The pharmacokinetics of these molecules is shown in Table 1.9 The Breathing Not Properly Study was one of the first major trials studying the role of natriuretic peptides in the emergency department for the diagnosis of heart failure.10 Here the authors measured BNP levels in 1,586 patients presenting to the emergency department with acute breathlessness. Patients with clinically diagnosed heart failure had higher BNP levels compared with those without heart failure (mean 675 ± 450 pg/ml versus 110 ± 225 pg/ml; p=0.001). Increasing severity of heart failure, as measured by New York Heart Association (NYHA) functional class, correlated directly with increasing concentrations of BNP (p<0.001). BNP was the best single predictor of a final diagnosis of heart failure compared with all individual history, physical examination, chest x-ray and laboratory findings. A cut-off BNP value of 100 pg/ml had a sensitivity of 90% and a specificity of 76%. In addition, BNP was more accurate (83%) than either the National Health and Nutrition Examination Survey criteria (67%) or the Framingham criteria (73%), two established criteria for heart failure diagnosis. Importantly, the best method of diagnosis of heart failure was seen when BNP and clinical findings were combined. The use of NT-proBNP in the diagnosis of acutely decompensated heart failure was first demonstrated in the ProBNP Investigation of Dyspnea in the Emergency Department (PRIDE) study.11 Here, NT-proBNP had a high sensitivity for the diagnosis of heart failure, again supplementing clinical judgment as BNP did in the Breathing Not Properly study. Subsequently, the International Collaborative Of NT-proBNP (ICON) study examined optimal applications of NT-proBNP in 1256 acutely dyspnoeic patients.12 Patients with acutely decompensated heart failure had considerably higher NT-proBNP concentrations compared with those without heart failure (4,639 pg/ml versus 108 pg/ml; p<0.001) and symptom severity correlated with NT-proBNP concentrations (p=0.008). As natriuretic peptide concentrations rise with increasing age, the ICON investigators found the best approach for use of NT-proBNP in heart failure diagnosis was through use of age-stratified cut-off points; this approach improved the positive predictive value of the assay considerably.

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Myocardial stretch

Renal injury

FABP = fatty acid binding protein; hsCRP = high sensitivity C-reactive protein; IL = interleukin; MMP = matrix metalloproteinase; NGAL = neutrophil gelatinase associated lipocalin; ST2 = suppression of tumourigenicity-2; TNF = tumour necrosis factor.

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Figure 2: Activation of the B-type Natriuretic Peptide

NT-proBNP (AA 1–76) Biologically inactive

Pre-proBNP (134 AA) Signal peptide (26 AA) BNP (AA 77–108)

Active metabolite

Intra-myocardial Counteracts the renin angiotensin system, causing natriuresis and diuresis

AA = amino acid; BNP = B-type natriuretic peptide; NT-proBNP = N-terminal-proBNP.

The utility of MR-proANP in the diagnosis of heart failure was demonstrated in the Biomarkers In Acute Heart Failure (BACH) study.13 In the diagnosis of acute heart failure in those presenting to the emergency department with dyspnoea, a MR-proANP level greater than the predefined cut point of 120 pmol/l was found to be noninferior to BNP at the 100 pg/ml cut point. Combining MR-proANP and BNP increased diagnostic accuracy from 73.6% with BNP alone to 76.6%. It was also found that in cases where BNP and NT-proBNP could be less informative (obesity, old age, renal dysfunction or ‘grey zone’ values), MR-proANP added value when used in combination with each biomarker. Thus it has been suggested that the addition of MR-proANP with other natriuretic peptides adds to diagnostic accuracy. It should be remembered that there are many other causes of raised natriuretic peptides besides heart failure.14 These include cardiac causes such as acute coronary syndrome, myocarditis, cardioversion etc., along with non-cardiac causes such as age, anaemia and renal failure. Conversely, obesity has been shown to decrease natriuretic peptide levels.14 Kim and Januzzi have suggested cut-off points for different scenarios.14 For BNP, they have suggested a ‘grey zone’ approach. A value of <100 pg/ ml would exclude heart failure and >400 pg/ml would confirm heart failure. For those in the ‘grey zone’ of 100–400 pg/ml, further tests would be required. For NT proBNP, an age-stratified approach is suggested. Values <450 pg/ml would be used as a cut-off for patients aged <50 years, <900 pg/ml for those aged 50–75 years and <1,800 pg/ml for those aged >75 years. In patients with renal dysfunction, (glomerular filtration rate <60 ml/min/1.73 m2), a BNP cut-off value of 200 pg/ml or NT-proBNP of <1,200 pg/ml should be used. Similarly, different cut-off values for BNP have been suggested based on BMI. A cut-off of 170 pg/ ml is recommended for BMI <25 kg/m2, 110 pg/ml for BMI 25–35 kg/m2 and 54 pg/ml for BMI >35 kg/m2. No correction is required for NT-proBNP based on BMI. All these values have a high sensitivity and specificity. Among the other non-natriuretic-peptide biomarkers, the troponins are often elevated in patients with heart failure.15 However they only represent myocardial injury and are therefore not specific for making a diagnosis of heart failure. They could also be increased in any condition that puts increased stress on the heart muscle. They may also be useful in diagnosing concomitant acute coronary syndromes in the presence of heart failure.16 Similarly, biomarkers, such as soluble suppression of tumourigenicity-2 (ST2), galectin-3 and pro-adrenomedullin, are also increased in patients

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Biomarkers Table 1: Pharmacokinetics of the Natriuretic Peptides Natriuretic Peptide

Production

Half-life

Clearance

B-type natriuretic peptide (BNP)

Produced from pre-proBNP, which is released from myocytes under stress.

20 min

Endocytosis, renal filtration or passive excretion

N-terminal-proBNP

Produced from proBNP, formed mainly in the left ventricle.

60–90 min

Renal excretion

Atrial natriuretic peptide

Produced by muscle cells in the atrial wall as a result of stretch.

1 min

Renal clearance of its metabolites

Table 2: Characteristics of Other Biomarkers for Heart Failure Biomarker Galectin-369

Physiological Actions Mediator of tumour growth and metastasis

Produced by neutrophils and Neutrophil endothelial cells as an acute gelatinase phase protein associated lipocalin (NGAL)70 mid-regional proadrenomedullin (MR-ProADM)71

Conditions Where it is

Management Diagnostic capability = no

Earliest marker of nephrotoxic or ischaemic renal injury

Action on the heart unknown, but levels increase in acute heart failure even in the presence of normal renal function

Diagnostic capability = yes

Increases myocardial contractility via a cyclic AMP-independent mechanism. Also causes vasodilatation and increases cardiac index

Diagnostic capability = no

First found in pheochromocytoma cells. They have vasodilatory effects and increase nitric oxide synthesis

The American and European guidelines on the management of heart failure both give measuring natriuretic peptides for the diagnosis of heart failure a class 1A recommendation.19,20 The European guidelines recommended that the upper limit of normal in a non-acute setting is 35 pg/ml for BNP and 125 pg/ml for NT-proBNP. In the acute setting, the cut-off values are higher at 100 pg/ml for BNP and 300 pg/ml for NT-proBNP. At these cut-off values the negative predictive values are similar and high at 0.94–0.98 in both the acute and non-acute settings but the positive predictive values are low. Therefore it has been suggested that the use of the natriuretic peptides are mainly for ruling out a diagnosis of heart failure rather than establishing it, when there is clinical uncertainty. However, at higher natriuretic peptide values, the positive predictive value is high. The American guidelines do not specify any cut-off values. Both sets of guidelines mention that other biomarkers are elevated in acute or stable heart failure, but they do not recommend their routine use for the diagnosis of heart failure.

Biomarkers for Prognosis The natriuretic peptides again are the most extensively investigated biomarker for assessing prognosis of patients with heart failure – both in the acute setting as well as for patients with chronic heart failure seen in the office setting. It has been shown that at baseline, the higher the BNP, the worse the prognosis, with patients having almost a fivefold greater mortality between the highest and lowest tertiles.21 In patients admitted with heart failure, the risk of readmission and death is high if the discharge BNP is not lower than the admission value.22 Many of the large heart failure studies have also examined

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Role in Heart Failure

Increasing age, diabetic Promotes cardiac fibroblast nephropathy, fibrotic conditions of proliferation, collagen deposition liver and lung, chronic pancreatitis and ventricular dysfunction

with heart failure.17 However, they are not useful for the diagnosis of heart failure as they are not specific for these patients and are increased in other conditions as well.18 Their characteristics are summarised in Table 2 and are discussed in detail in the prognosis section.

Cardiac Actions

Increased

Prognostic capability = yes

the role of biomarkers in prognosis. In the Valsartan Heart Failure Trial (Val-HEFT), patients with the greatest fall in BNP with treatment had the best prognosis.3 Similarly, in the Organized Program To Initiate Lifesaving Treatment In Hospitalized Patients With Heart Failure (OPTIMIZE-HF) study, discharge BNP was shown to affect prognosis.24 A meta analysis by Doust et al. found that for every 100 pg/ml increase in BNP there was a 35% increase in the risk of death.25 In the Framingham study, it was shown that even in asymptomatic patients without overt heart failure, every standard deviation of the log BNP value was associated with a 27% increase in the risk of death, 28% increase in first cardiovascular event, 77% increase in the risk of heart failure, 66% increase in AF and a 53% increase in stroke/transient ischaemic attack.26 However there was no relation with coronary artery events. Similar results were also obtained from community-dwelling populations in the Omsted county study.27 In a comparison of NT-proBNP and MR-proANP using a sample of 525 chronic heart failure patients of all NYHA classes, MR-proANP was found to be positively correlated with NYHA class, and – after correction for NT-proBNP, age, ejection fraction, NYHA class, creatinine, and BMI – MR-proANP was found to be a predictor of poor survival.28 In the PRIDE study, elevated MR-proANP was independently prognostic and reclassified mortality risk at 1 year (HR 2.00; p<0.001) and at 4 years (HR 3.12; p=0.001).29 MR-proANP was also associated with death up to 4 years, both alone and with other biomarkers. In chronic heart failure, the Gruppo Italiano Perlo Stuio Della Sopravvivenza Nell’insufficienza Cardiaca Heart Failure (GISSI-HF) study,30 showed that the prognostic accuracy for MR-proANP for mortality was best with an area under the curve (AUC) of 0.74 (95% CI [0.71–0.77]) with an optimal cut-off point of 278 pmol/l, followed by NT-proBNP with an AUC of 0.73 (95% CI [0.70– 0.76]) and an optimal cut-off of 1,181 pg/mol. Changes in MR-proANP over 3 months also appeared to be predictive of future mortality.

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Biomarkers in Routine Heart Failure Clinical Care Table 3: Studies Involving the Biomarker ST2 Study

Number of Patients

Patient Group

Findings

PRIDE17

593

Patients admitted to the ER with breathlessness

Inferior to NPs for the diagnosis of heart failure, but higher ST2 values associated with worse NYHA class and symptoms. Values also correlate with risk of death at 1 year

Rehman et al.72

346

Acute heart failure

Patients with higher values were more likely to die in one year, with a two fold increased risk of mortality compared with those with normal values. When ST2 values were low, NPs did not predict mortality

Boisot et al.73

150

Acute decompensated heart failure

Values decrease with treatment and patients with a rapid decrease had better outcomes. Percentage change with treatment was predictive of 90-day mortality

MERLIN-TIMI 3674

4426

NSTE-ACS

Weak correlation with NPs and troponins but strongly predictive of the risk of heart failure after NSTE-ACS

TIME-CHF57

458 (HFrEF) 112 (HFpEF)

Acute heart failure

ST2 levels significantly higher in HFpEF than in HFrEF patients. Similar effect on predicting prognosis in both groups

HFpEF = heart failure with preserved ejection fraction; HFrEF = heart failure with reduced ejection fraction; MERLIN-TIMI = Metabolic Efficiency With Ranolazine For Less Ischemia In Non-ST Elevation Acute Coronary Syndromes - Thrombolysis In Myocardial Infarction; NP = natriuretic peptide; NSTE-ACS = non ST segment elevation acute coronary syndrome; NYHA = New York Heart Association; PRIDE = ProBNP Investigation Of Dyspnea In The Emergency Department; ST2 = soluble suppression of tumourigenicity-2; TIME-CHF = Trial of Intensified Versus Standard Medical Therapy In Elderly Patients With Congestive Heart Failure.

Among the other non-natriuretic-peptide biomarkers, high baseline troponin corresponded to a worse prognosis with an OR of 2.5 for death within a year.31 Serial measurements of high sensitivity troponins (hsTn) during a hospitalisation for acute heart failure can risk stratify patients for 90-day mortality and readmission.15 It has been shown that patients whose discharge troponin value rose compared with the admission value had the greatest risk.32 Another study showed that an elevated hsTn as well as a >20% increase in the value was associated with increased mortality.33 The prognostic value is enhanced when combined with natriuretic peptides.34 Here the troponins are likely to reflect the level of myocardial strain and stress secondary to the heart failure rather than a coexisting acute coronary syndrome. Adrenomedullin (ADM) is a 52-amino acid peptide thought to be upregulated as a result of increased volume overload and is mediated by vasoactive hormones. However, because of its rapid clearance from the circulation and short half-life (22 minutes), using ADM as a routine biomarker is impractical. MR-proADM, the mid-regional segment of ADMâ&#x20AC;&#x2122;s precursor pre-proADM, is released in equimolar concentrations as ADM and thus is an effective substitute, and because of its inactivity and longer half-life, MR-proADM is a better surrogate marker. The BACH trial13 ADM appeared to predict 90-day mortality or rehospitalisation due to cardiovascular causes better than BNP/proBNP. Similar results were also reported by Klip et al.35 ADM was also found to be predictive of mortality in a cohort of community-dwelling patients.36 Other biomarkers, including ST2, have been shown to be associated with adverse outcomes in heart failure and predict mortality risk in these patients. It is also known as interleukin-1 receptor-like 1, and is a member of the interleukin-1 receptor family.37 In the PRIDE study17 ST2 values >0.20 ng/ml had an increased risk of death at 1 year. It was better than other biomarkers in both acute and chronic heart failure in predicting prognosis and works synergistically with the natriuretic peptides to enhance mortality prediction in acute and chronic heart failure. Similarly, in the Val-HEFT study, change in ST2 values over time was significantly and independently associated with mortality.38 It has also been shown to be predictive of mortality and cardiovascular events in non-ischaemic dilated cardiomyopathy.39 Some of the important trials highlighting the usefulness of ST2 are summarised in Table 3.

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Galectin-3 is secreted by activated macrophages and causes cardiac fibrosis by proliferation of cardiac fibroblasts. 40 It also regulates inflammation, immunity and cancer, and can act as a surrogate marker of cardiac remodelling and the fibrosis that is seen in heart failure. It has not been shown to be useful in diagnosis, but has strong prognostic value. In the Pravastatin Or Atorvastatin Evaluation And Infection Therapy â&#x20AC;&#x201C; Thrombolysis In MI 22 (PROVE-ITTIMI 22) study, 41 higher galectin-3 levels correlated with the development of heart failure. Similarly, in the Coordinating Study Evaluating Outcomes Of Advising And Counselling In Heart Failure (COACH) trial,higher levels increased the risk of death or rehospitalisation over 18 months.42 Its value also correlated with inflammatory markers such as C-reactive protein, vascular endothelial growth factor and interleukin-6. It has also been shown to predict mortality in non-ischaemic dilated cardiomyopathy.39,43 Numerous studies however have shown that when more than one biomarker is studied, they predict prognosis much better than the individual markers alone. For example, Gaggin et al. demonstrated that a model that contains clinical data, NT-proBNP, hsTn1 and ST2 along with endothelin-1, had a very good predictive value.44 This is understandable because each of these markers studies the impact of heart failure on various different pathophysiological processes that comprise heart failure. The American heart failure guidelines recommend the use of natriuretic peptides and troponins for risk stratification and for determining prognosis in both acute and ambulatory patients with heart failure.19 The European guidelines mention the role of biomarkers in determining prognosis, but do not issue any specific recommendations.20

Biomarkers as a Guide For Therapy Studies have consistently shown that patients whose BNP or NT-proBNP values show greater reductions tend to have better prognosis.23 It would therefore appear logical that we could use BNP values to guide therapy with frequent monitoring of the values to assess whether patients need more intense heart failure treatment.45 However, results have been conflicting and not entirely as expected. Early studies were promising. In the Systolic Heart Failure Treatment Supported By BNP (STARS-BNP) trial,Jourdain et al. randomised 220

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Biomarkers patients with NYHA functional class II and III to either routine medical therapy or to a natriuretic-peptide-guided therapy where the aim was to reduce BNP to <100 pg/ml.46 At 15 months, there were far fewer clinical end points (heart-failure-related death or hospitalisation) in the BNP-guided group (24% versus 52%; p<0.001). However those in the BNP-guided arm had significantly higher physician visits and drug changes although only around a third of patients reached the target BNP value of <100 pg/ml. Similarly the Pro-BNP Outpatient Tailored CHF Therapy (PROTECT) trial by Januzzi et al. with 151 subjects also showed a benefit for patients who had NT-proBNP-guided therapy for heart failure.47 Despite the initial positive trials, later larger trials were not so convincing. The NT-proBNPâ&#x20AC;&#x201C;Assisted Treatment To Lessen Serial Cardiac Readmissions and Death (BATTLESCARRED) trial randomised 364 patients with heart failure to either natriuretic-peptide-guided therapy, clinical-guided therapy or usual care.48 They found that intensive heart failure management that was guided by NT-proBNP monitoring was associated with improved mortality compared with usual care. However, when compared to clinical guided therapy, natriuretic-peptide-guided therapy improved long term mortality only in patients aged <75 years. The Trial of Intensified versus Standard Medical Therapy In Elderly Patients With Congestive Heart Failure (TIME-CHF) randomised trial on the other hand did not find any benefit either in terms of quality of life or cardiovascular outcomes with intensive management guided by NT-proBNP.49 Similarly, the Can Pro-Brain-Natriuretic Peptide Guided Therapy Of Chronic Heart Failure Improve Heart Failure Morbidity And Mortality? (PRIMA) study also failed to show any benefit with natriuretic-peptide-guided therapy.50 Troughton et al. performed an individual patient data meta-analysis of the various trials that studied the effect of natriuretic peptide monitoring during heart failure therapy.51 They identified 11 eligible studies, of which eight had individual patient data (n=2,000). Pooling the data, they found that there was a survival benefit in the group that had natriuretic peptide monitoring. However, when classified according to age, this benefit was seen only in those aged <75 years and not in those >75 years of age. The authors explain that perhaps in the elderly, due to intolerance, optimal drug dosages would not have been achieved and hence explain why monitoring natriuretic peptide values did not improve mortality. The superior mortality benefit in the younger group could conversely be explained by the fact that these patients tolerated the higher dosages of the drugs and were able to achieve maximal dosages of guideline-directed medical therapeutic agents. The meta-analysis also noted significant benefit in terms of hospital readmission rates in those where treatment was guided by natriuretic peptide monitoring. Similarly, a recent Cochrane review of the subject concluded that there was low-quality evidence to suggest that natriuretic peptide-guided therapy could lead to a reduction in heart failure admissions, but there was uncertainty regarding the effect of natriuretic-peptide-guided therapy on mortality and all cause admission and quality of life.52 Other biomarkers such as ST2 have also been shown to change with therapy.53 The use of beta-blockers and mineralocorticoid receptor blockers have been shown to reduce elevated ST2 levels. However, data are lacking in large trials studying specifically

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the utility of other markers besides the natriuretic peptides in guiding therapy. The American guidelines give a Class IIa (level of evidence B) recommendation for the use of BNP or NT-pro BNP to achieve optimal dosing for guideline-directed medical therapy in select euvolaemic patients (in the outpatient setting) who are followed up in a wellstructured heart failure management programme.19 However, they suggest that using serial natriuretic peptide monitoring during therapy does not help in reducing hospitalisation or mortality in either the ambulatory outpatient setting or in the acute decompensated setting. The European guidelines do not advocate the use of natriuretic peptides in monitoring the progress of patients being treated for heart failure, stating there is insufficient data to recommend it.20

Heart Failure with Preserved Ejection Fraction Most of the studies of biomarkers in heart failure are confined to patients with heart failure with reduced ejection fraction (HFrEF). This could be due to the fact that HFpEF has been defined as a separate and distinct entity much more recently compared with the traditional HFrEF subgroup, and also because HFpEF is generally more difficult to diagnose clinically. Studies have shown that the natriuretic peptides are moderately increased in HFpEF and that values fall to normal during symptom-free periods.54,55 Although the sensitivity of these biomarkers is slightly lower for patients with HFpEF compared with HFrEF, it still has a high diagnostic accuracy. Markers of inflammation such as ST2 have been shown to be increased in HFpEF patients and correlated well with pro-inflammatory comorbidities.56 In a study of 458 patients with HFrEF and 112 patients with HFpEF, ST2, high sensitivity C-reactive protein and cystatin C levels have been shown to be higher in HFpEF than HFrEF, while NT-ProBNP and troponin values were higher in HFrEF. 57 However, although they predicted prognosis to a similar level in both types, ManzanoFernandez et al. showed that ST2 values were lower in HfpEF than HFrEF, while maintaining their prognostic predictability.58 Similarly, markers of myocardial fibrosis like galectin-3 have been shown to be elevated in HFpEF. In the COACH study, higher levels of galectin-3 were associated with higher rates of rehospitalisation and death in HFpEF but not HFrEF patients.42 Despite this, studies have failed to show any correlation between levels of galectin-3 and measures of cardiac structure and function including left ventricular geometry.59 The role of biomarkers in the diagnosis of HFpEF has recently been reviewed by Michalska-Kasiczak et al.60 They conclude that one single biomarker may not be sufficient for the correct diagnosis of HFpEF as it is a very heterogeneous group of patients. They suggest that a panel of biomarkers including mRNAs may be required. Because of the paucity of data, neither the American nor the European guidelines differentiate between the two subgroups with regards to the biomarkers.19,20

Newer Biomarkers and Future Prospects Many new biomarkers that have been studied in heart failure. However most of these have limited data and often fall short when compared to the NPs. These biomarkers target different aspects of the pathogenesis

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Biomarkers in Routine Heart Failure Clinical Care of heart failure, such as myocardial injury, inflammatory response, renal injury and volume status. Some of the novel ones, for example ST2, galectin 3 and pro-ADM, have been discussed earlier. Neutrophil gelatinase-associated lipocalin is expressed by neutrophils and epithelial cells.61 It is a marker of renal injury. The values are also high in heart failure, even when the reductions in renal function or minimal. Studies such as Optimal Trial In Myocardial Infarction With The Angiotensin II Antagonist Losartan (OPTIMAAL)and NGAL Evaluation Along With B-type Natriuretic Peptide (BNP) In Acutely Decompensated Heart Failure (GALLANT) have demonstrated a role for this marker in the diagnosis and prognostic prediction in patients with heart failure.62,63 Another exciting prospect is the role of circulating microRNA (miRNA) in heart failure. It has been shown that these are differentially expressed in the failing heart.64 Different miRNAs, such as miR423-5p, miR320a and miR22, have been shown to be increased in patients with heart failure.65 A recent meta-analysis of the role of miRNAs in the management of heart failure suggested that miR423-5p offered the best potential as a biomarker.66 However, large-scale trials are required to validate their utility. Many other molecules, such as procalcitonin, matrix metalloproteinases, interleukins and tumour necrosis factor alpha, have been studied in heart failure. However none of them are specific and have variable findings. It is most likely that future heart failure biomarker studies would involve a panel of markers, including natriuretic peptides, ST2 and hsTn1, which study the different pathophysiological processes that

iomarkers Definitions Working Group. Biomarkers and B surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther 2001;69:89–95. https://doi. org/10.1067/mcp.2001.113989; PMID: 11240971. 2. Tijsen AJ, Pinto YM, Creemers EE. Circulating microRNAs as diagnostic biomarkers for cardiovascular diseases. Am J Physiol Heart Circ Physiol 2012;303:H1085–H95. https://doi.org/10.1152/ ajpheart.00191.2012; PMID: 22942181. 3. Fonseca C. Diagnosis of heart failure in primary care. Heart Fail Rev 2006;11:95–107. https://doi.org/10.1007/s10741-006-94810; PMID: 16937029. 4. McCullough PA, Nowak RM, McCord J, et al. B-type natriuretic peptide and clinical judgment in emergency diagnosis of heart failure: analysis from Breathing Not Properly (BNP) Multinational Study. Circulation 2002;106:416–22. https://doi. org/10.1161/01.CIR.0000025242.79963.4C; PMID: 12135939. 5. McDonagh TA, Morrison CE, Lawrence A, et al. Symptomatic and asymptomatic left-ventricular systolic dysfunction in an urban population. Lancet 1997;350:829–33. https://doi. org/10.1016/S0140-6736(97)03033-X; PMID: 9310600. 6. Zhang J, Goode KM, Cuddihy PE, Cleland JG. Predicting hospitalization due to worsening heart failure using daily weight measurement: analysis of the Trans-European Network-Home-Care Management System (TEN-HMS) study. Eur J Heart Fail 2009;11:420–7. https://doi.org/10.1093/eurjhf/ hfp033; PMID: 19252210. 7. Yu CM, Wang L, Chau E, Chan RH, Kong SL, Tang MO, et al. Intrathoracic impedance monitoring in patients with heart failure: correlation with fluid status and feasibility of early warning preceding hospitalization. Circulation 2005;112:841–8. https://doi.org/10.1161/CIRCULATIONAHA.104.492207; PMID: 16061743. 8. Lin DC, Diamandis EP, Januzzi JL, Jr., et al. Natriuretic peptides in heart failure. Clin Chem 2014;60:1040–6. https://doi. org/10.1373/clinchem.2014.223057; PMID: 24700774. 9. Curry FR. Atrial natriuretic peptide: an essential physiological regulator of transvascular fluid, protein transport, and plasma volume. J Clin Invest 2005;115:1458–61. https://doi.org/10.1172/ JCI25417; PMID: 15931381. 10. Maisel AS, Krishnaswamy P, Nowak RM, McCord J, Hollander JE, Duc P, et al. Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure. N Engl J Med 2002;347:161–7. https://doi.org/10.1056/NEJMoa020233; PMID: 12124404. 11. Januzzi JL, Jr., Camargo CA, Anwaruddin S, Baggish AL, Chen AA, Krauser DG, et al. The N-terminal Pro-BNP investigation of dyspnea in the emergency department (PRIDE) study. Am J Cardiol 2005;95:948–54. https://doi.org/10.1016/j. amjcard.2004.12.032; PMID: 15820160. 12. Januzzi JL, van Kimmenade R, Lainchbury J, et al. NT-proBNP

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are involved in heart failure. The use of genetic testing including miRNA could become more widespread. Metabolomic profiling (study of the byproducts of metabolism) and transcriptomics (the study of complete sets of RNA transcripts produced by the genome) are another two areas that are undergoing extensive research in the field of heart failure. Initial studies have been promising but more research is required to see if these become standard of care for patients with heart failure in the future.67,68

Conclusion The use of biomarkers in the management of patients with heart failure has increased tremendously over the past few years. Currently the natriuretic peptides are the most commonly used biomarker and help in the diagnosis and prognostication of patients with heart failure. Their role in the monitoring of treatment is still debatable, although it seems reasonable that patients have their natriuretic peptide values checked at discharge. There are many new biomarkers currently under investigation. The results are promising and they evaluate different aspects of the heart failure spectrum. At present they appear to have a synergistic role along with the natriuretic peptides – both in terms of diagnosis and determination of prognosis. However, on their own, none of them are specific for heart failure and none are recommended for routine clinical use at present. Further research is required to see which of the newer agents can be used as a reliable biomarker for the diagnosis and monitoring of patients with heart failure.

testing for diagnosis and short-term prognosis in acute destabilized heart failure: an international pooled analysis of 1256 patients: the International Collaborative of NT-proBNP Study. Eur Heart J 2006;27:330–7. https://doi.org/10.1093/ eurheartj/ehi631; PMID: 16293638. Maisel A, Mueller C, Nowak R, et al. Mid-region pro-hormone markers for diagnosis and prognosis in acute dyspnea: results from the BACH (Biomarkers in Acute Heart Failure) trial. J Am Coll Cardiol 2010;55:2062–76. https://doi.org/10.1016/j. jacc.2010.02.025; PMID: 20447528. Kim HN, Januzzi JL, Jr. Natriuretic peptide testing in heart failure. Circulation 2011;123:2015–9. https://doi.org/10.1161/ CIRCULATIONAHA.110.979500; PMID: 21555724. Xue Y, Clopton P, Peacock WF, Maisel AS. Serial changes in high-sensitive troponin I predict outcome in patients with decompensated heart failure. Eur J Heart Fail 2011;13:37–42. https://doi.org/10.1093/eurjhf/hfq210; PMID: 21149316. Daubert MA, Jeremias A. The utility of troponin measurement to detect myocardial infarction: review of the current findings. Vasc Health Risk Manag 2010;6:691–9. https://doi.org/10.2147/ VHRM.S5306; PMID: 20859540. Januzzi JL, Jr., Peacock WF, Maisel AS, et al. Measurement of the interleukin family member ST2 in patients with acute dyspnea: results from the PRIDE (Pro-Brain Natriuretic Peptide Investigation of Dyspnea in the Emergency Department) study. J Am Coll Cardiol 2007;50:607–13. https://doi. org/10.1016/j.jacc.2007.05.014; PMID: 17692745. Schmitz J, Owyang A, Oldham E, Song Y, Murphy E, McClanahan TK, et al. IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity 2005;23:479–90. https://doi.org/10.1016/j.immuni.2005.09.015; PMID: 16286016. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013;62:e147–e239. https://doi.org/10.1016/j. jacc.2013.05.019; PMID: 23747642. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J 2016;37:2129–200. https://doi.org/10.1093/eurheartj/ehw128; PMID: 27206819. Tsutamoto T, Wada A, Maeda K, et al. Attenuation of compensation of endogenous cardiac natriuretic peptide system in chronic heart failure: prognostic role of plasma

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brain natriuretic peptide concentration in patients with chronic symptomatic left ventricular dysfunction. Circulation 1997;96:509–16. https://doi.org/10.1161/01.CIR.96.2.509; PMID: 9244219. Logeart D, Thabut G, Jourdain P, et al. Predischarge B-type natriuretic peptide assay for identifying patients at high risk of re-admission after decompensated heart failure. J Am Coll Cardiol 2004;43:635–41. https://doi.org/10.1016/j. jacc.2003.09.044; PMID: 14975475. Masson S, Latini R, Anand IS, et al. Prognostic value of changes in N-terminal pro-brain natriuretic peptide in Val-HeFT (Valsartan Heart Failure Trial). J Am Coll Cardiol 2008;52:997–1003. https://doi.org/10.1016/j.jacc.2008.04.069; PMID: 18786480. Kociol RD, Horton JR, Fonarow GC, et al. Admission, discharge, or change in B-type natriuretic peptide and long-term outcomes: data from Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF) linked to Medicare claims. Circ Heart Fail 2011;4:628–36. https://doi.org/10.1161/ CIRCHEARTFAILURE.111.962290; PMID: 21743005. Doust JA, Glasziou PP, Pietrzak E, Dobson AJ. A systematic review of the diagnostic accuracy of natriuretic peptides for heart failure. Arch Intern Med 2004;164:1978–84. https://doi. org/10.1001/archinte.164.18.1978; PMID: 15477431. Wang TJ, Larson MG, Levy D, et al. Plasma natriuretic peptide levels and the risk of cardiovascular events and death. N Engl J Med 2004;350:655–63. https://doi.org/10.1056/NEJMoa031994; PMID: 14960742. McKie PM, Rodeheffer RJ, Cataliotti A, et al. Amino-terminal pro-B-type natriuretic peptide and B-type natriuretic peptide: biomarkers for mortality in a large community-based cohort free of heart failure. Hypertension 2006;47:874–80. https://doi. org/10.1161/01.HYP.0000216794.24161.8c; PMID: 16585413. von Haehling S, Jankowska EA, Morgenthaler NG, et al. Comparison of midregional pro-atrial natriuretic peptide with N-terminal pro-B-type natriuretic peptide in predicting survival in patients with chronic heart failure. J Am Coll Cardiol 2007;50:1973–80. https://doi.org/10.1016/j.jacc.2007.08.012; PMID: 17996563. Shah RV, Truong QA, Gaggin HK, et al. Mid-regional proatrial natriuretic peptide and pro-adrenomedullin testing for the diagnostic and prognostic evaluation of patients with acute dyspnoea. Eur Heart J 2012;33:2197–205. https://doi. org/10.1093/eurheartj/ehs136; PMID: 22645194. Masson S, Latini R, Carbonieri E, et al. The predictive value of stable precursor fragments of vasoactive peptides in patients with chronic heart failure: data from the GISSI-heart failure (GISSI-HF) trial. Eur J Heart Fail 2010;12:338–47. https://doi. org/10.1093/eurjhf/hfp206; PMID: 20097683.

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Biomarkers 31. P eacock WF, De MT, Fonarow GC, et al. Cardiac troponin and outcome in acute heart failure. N Engl J Med 2008;358:2117–26. https://doi.org/10.1056/NEJMoa0706824; PMID: 18480204. 32. Pascual-Figal DA, Manzano-Fernandez S, Boronat M, et al. Soluble ST2, high-sensitivity troponin T- and N-terminal pro-B-type natriuretic peptide: complementary role for risk stratification in acutely decompensated heart failure. Eur J Heart Fail 2011;13:718–25. https://doi.org/10.1093/eurjhf/ hfr047; PMID: 21551163. 33. Felker GM, Mentz RJ, Teerlink JR, et al. Serial high sensitivity cardiac troponin T measurement in acute heart failure: insights from the RELAX-AHF study. Eur J Heart Fail 2015;17:1262–70. https://doi.org/10.1002/ejhf.341; PMID: 26333655. 34. Tsutamoto T, Kawahara C, Nishiyama K, et al. Prognostic role of highly sensitive cardiac troponin I in patients with systolic heart failure. Am Heart J 2010;159:63–7. https://doi. org/10.1016/j.ahj.2009.10.022; PMID: 20102868. 35. Klip IT, Voors AA, Anker SD, et al. Prognostic value of midregional pro-adrenomedullin in patients with heart failure after an acute myocardial infarction. Heart 2011;97:892–8. https://doi.org/10.1136/hrt.2010.210948; PMID: 21415071. 36. Odermatt J, Meili M, Hersberger L, et al. Pro-Adrenomedullin predicts 10-year all-cause mortality in community-dwelling patients: a prospective cohort study. BMC Cardiovasc Disord 2017;17:178. https://doi.org/10.1186/s12872-017-0605-3; PMID: 28676115. 37. Dattagupta A, Immaneni S. ST2: Current status. Indian Heart J 2018;70 Suppl 1:S96–S101. https://doi.org/10.1016/j. ihj.2018.03.001; PMID: 30122246. 38. Anand IS, Rector TS, Kuskowski M, et al. Prognostic value of soluble ST2 in the Valsartan Heart Failure Trial. Circ Heart Fail 2014;7:418–26. https://doi.org/10.1161/ CIRCHEARTFAILURE.113.001036; PMID:24622243. 39. Binas D, Daniel H, Richter A, et al. The prognostic value of sST2 and galectin-3 considering different aetiologies in nonischaemic heart failure. Open Heart 2018;5:e000750. http:// dx.doi.org/10.1136/openhrt-2017-000750; PMID: 29531765. 40. McCullough PA, Olobatoke A, Vanhecke TE. Galectin-3: a novel blood test for the evaluation and management of patients with heart failure. Rev Cardiovasc Med 2011;12:200–10. http:// doi.org/10.3909/ricm0624; PMID: 22249510. 41. Grandin EW, Jarolim P, Murphy SA, et al. Galectin-3 and the development of heart failure after acute coronary syndrome: pilot experience from PROVE IT-TIMI 22. Clin Chem 2012;58:267–73. https://doi.org/10.1373/ clinchem.2011.174359; PMID: 22110019. 42. de Boer RA, Lok DJ, Jaarsma T, et al. Predictive value of plasma galectin-3 levels in heart failure with reduced and preserved ejection fraction. Ann Med 2011;43:60–8. https://doi. org/10.3109/07853890.2010.538080; PMID: 21189092. 43. Karatolios K, Chatzis G, Holzendorf V, et al. Galectin-3 as a Predictor of Left Ventricular Reverse Remodeling in RecentOnset Dilated Cardiomyopathy. Dis Markers 2018;2018:2958219. https://doi.org/10.1155/2018/2958219; PMID: 30018673. 44. Gaggin HK, Truong QA, Gandhi PU, et al. Systematic evaluation of endothelin 1 measurement relative to traditional and modern biomarkers for clinical assessment and prognosis in patients with chronic systolic heart failure: serial measurement and multimarker testing. Am J Clin Pathol 2017;147:461–72. https://doi.org/10.1093/ajcp/aqx014; PMID: 28398455. 45. Januzzi JL, Troughton R. Are serial BNP measurements useful in heart failure management? Serial natriuretic peptide measurements are useful in heart failure management. Circulation 2013;127:500–7. https://doi.org/10.1161/ CIRCULATIONAHA.112.120485; PMID: 23357662. 46. Jourdain P, Jondeau G, Funck F, et al. Plasma brain natriuretic peptide-guided therapy to improve outcome in heart failure: the STARS-BNP Multicenter Study. J Am Coll Cardiol 2007;49:1733–9.

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https://doi.org/10.1016/j.jacc.2006.10.081; PMID: 17448376. 47. J anuzzi JL, Jr., Rehman SU, Mohammed AA, et al. Use of amino-terminal pro-B-type natriuretic peptide to guide outpatient therapy of patients with chronic left ventricular systolic dysfunction. J Am Coll Cardiol 2011;58:1881–9. https:// doi.org/10.1016/j.jacc.2011.03.072; PMID: 22018299. 48. Lainchbury JG, Troughton RW, Strangman KM, et al. N-terminal pro-B-type natriuretic peptide-guided treatment for chronic heart failure: results from the BATTLESCARRED (NT-proBNPAssisted Treatment To Lessen Serial Cardiac Readmissions and Death) trial. J Am Coll Cardiol 2009;55:53–60. https://doi. org/10.1016/j.jacc.2009.02.095; PMID: 20117364. 49. Pfisterer M, Buser P, Rickli H, et al. BNP-guided vs symptomguided heart failure therapy: the Trial of Intensified vs Standard Medical Therapy in Elderly Patients With Congestive Heart Failure (TIME-CHF) randomized trial. JAMA 2009;301:383– 92. https://doi.org/10.1001/jama.2009.2; PMID: 19176440. 50. Eurlings LW, van Pol PE, Kok WE, et al. Management of chronic heart failure guided by individual N-terminal pro-Btype natriuretic peptide targets: results of the PRIMA (Can PRo-brain-natriuretic peptide guided therapy of chronic heart failure IMprove heart fAilure morbidity and mortality?) study. J Am Coll Cardiol 2010;56:2090–100. https://doi.org/10.1016/j. jacc.2010.07.030; PMID: 21144969. 51. Troughton RW, Frampton CM, Brunner-La Rocca HP, et al. Effect of B-type natriuretic peptide-guided treatment of chronic heart failure on total mortality and hospitalization: an individual patient meta-analysis. Eur Heart J 2014;35:1559–67. https://doi.org/10.1093/eurheartj/ehu090; PMID: 24603309. 52. McLellan J, Heneghan CJ, Perera R, et al. B-type natriuretic peptide-guided treatment for heart failure. Cochrane Database Syst Rev 2016;12:CD008966. https://www.cochranelibrary. com/cdsr/doi/10.1002/14651858.CD008966.pub2/full; PMID: 28102899. 53. Januzzi JL, Jr. ST2 as a cardiovascular risk biomarker: from the bench to the bedside. J Cardiovasc Transl Res 2013;6:493–500. https://doi.org/10.1007/s12265-013-9459-y; PMID: 23558647. 54. Lubien E, DeMaria A, Krishnaswamy P, et al. Utility of B-natriuretic peptide in detecting diastolic dysfunction: comparison with Doppler velocity recordings. Circulation 2002;105:595–601. https://doi.org/10.1161/hc0502.103010; PMID: 11827925. 55. Tschope C, Kasner M, Westermann D, et al. The role of NT-proBNP in the diagnostics of isolated diastolic dysfunction: correlation with echocardiographic and invasive measurements. Eur Heart J 2005;26:2277–84. https://doi. org/10.1093/eurheartj/ehi406; PMID: 16014646. 56. AbouEzzeddine OF, McKie PM, Dunlay SM, et al. Suppression of tumorigenicity 2 in heart failure with preserved ejection fraction. J Am Heart Assoc 2017;6: e004382. https://doi.org/ 10.1161/JAHA.116.004382; PMID: 28214792. 57. Sanders-van Wijk S, van Empel V, Davarzani N, et al. Circulating biomarkers of distinct pathophysiological pathways in heart failure with preserved vs. reduced left ventricular ejection fraction. Eur J Heart Fail 2015;17:1006–14. https://doi.org/10.1002/ejhf.414; PMID: 26472682. 58. Manzano-Fernandez S, Mueller T, Pascual-Figal D, et al. Usefulness of soluble concentrations of interleukin family member ST2 as predictor of mortality in patients with acutely decompensated heart failure relative to left ventricular ejection fraction. Am J Cardiol 2011;107:259–67. https://doi. org/10.1016/j.amjcard.2010.09.011; PMID: 21211603. 59. AbouEzzeddine OF, Haines P, Stevens S, et al. Galectin-3 in heart failure with preserved ejection fraction. A RELAX trial substudy (Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart Failure). JACC Heart Fail 2015;3:245–52. https://doi.org/10.1016/j.

jchf.2014.10.009; PMID: 25742762. 60. M ichalska-Kasiczak M, Bielecka-Dabrowa A, von Haehling S, et al. Biomarkers, myocardial fibrosis and co-morbidities in heart failure with preserved ejection fraction: an overview. Arch Med Sci 2018;14:890–909. https://doi.org/10.5114/ aoms.2018.76279; PMID: 30002709. 61. Friedl A, Stoesz SP, Buckley P, Gould MN. Neutrophil gelatinase-associated lipocalin in normal and neoplastic human tissues. Cell type-specific pattern of expression. Histochem J 1999;31:433–41. https://doi. org/10.1023/A:1003708808934; PMID: 10475571. 62. Dickstein K, Kjekshus J. Effects of losartan and captopril on mortality and morbidity in high-risk patients after acute myocardial infarction: the OPTIMAAL randomised trial. Lancet 2002;360:752–60. https://doi.org/10.1016/S01406736(02)09895-1; PMID: 12241832. 63. Maisel AS, Mueller C, Fitzgerald R, et al. Prognostic utility of plasma neutrophil gelatinase-associated lipocalin in patients with acute heart failure: the NGAL EvaLuation Along with B-type NaTriuretic Peptide in acutely decompensated heart failure (GALLANT) trial. Eur J Heart Fail 2011;13:846–51. https://doi.org/10.1093/eurjhf/hfr087; PMID: 21791540. 64. van Rooij E, Sutherland LB, Liu N, et al. A signature pattern of stress-responsive microRNAs that can evoke cardiac hypertrophy and heart failure. Proc Natl Acad Sci USA 2006;103:18255–60. https://doi.org/10.1073/pnas.0608791103; PMID: 17108080. 65. Corsten MF, Dennert R, Jochems S, et al. Circulating MicroRNA-208b and MicroRNA-499 reflect myocardial damage in cardiovascular disease. Circ Cardiovasc Genet 2010;3:499–506. https://doi.org/10.1161/ CIRCGENETICS.110.957415; PMID: 20921333. 66. Yan H, Ma F, Zhang Y, et al. miRNAs as biomarkers for diagnosis of heart failure: A systematic review and metaanalysis. Medicine (Baltimore) 2017;96:e6825. https://doi. org/10.1097/MD.0000000000006825; PMID: 28562533. 67. Lanfear DE, Gibbs JJ, Li J, et al. Targeted metabolomic profiling of plasma and survival in heart failure patients. JACC Heart Fail 2017;5:823–32. https://doi.org/10.1016/j.jchf.2017.07.009; PMID: 29096792. 68. Toma M, Mak GJ, Chen V, et al. Differentiating heart failure phenotypes using sex-specific transcriptomic and proteomic biomarker panels. ESC Heart Fail 2017;4:301–11. https://doi. org/10.1002/ehf2.12136; PMID: 28772032. 69. Suarez G, Meyerrose G. Heart failure and galectin 3. Ann Transl Med 2014;2:86. https://doi.org/10.3978/j.issn.23055839.2014.09.10; PMID: 25405161. 70. Soni SS, Cruz D, Bobek I, et al. NGAL: a biomarker of acute kidney injury and other systemic conditions. Int Urol Nephrol 2010;42:141–50. https://doi.org/10.1007/s11255-009-9608-z; PMID: 19582588. 71. Potocki M, Ziller R, Mueller C. Mid-regional proadrenomedullin in acute heart failure: a better biomarker or just another biomarker? Curr Heart Fail Rep 2012;9:244–51. https://doi.org/10.1007/s11897-012-0096-6; PMID: 22733501. 72. Rehman SU, Mueller T, Januzzi JL, Jr. Characteristics of the novel interleukin family biomarker ST2 in patients with acute heart failure. J Am Coll Cardiol 2008;52:1458–65. https://doi. org/10.1016/j.jacc.2008.07.042; PMID: 19017513. 73. Boisot S, Beede J, Isakson S, et al. Serial sampling of ST2 predicts 90-day mortality following destabilized heart failure. J Card Fail 2008;14:732–8. https://doi.org/10.1016/j. cardfail.2008.06.415; PMID: 18995177. 74. Morrow DA1, Scirica BM, Karwatowska-Prokopczuk E, et al.; MERLIN-TIMI 36 Trial Investigators. Effects of ranolazine on recurrent cardiovascular events in patients with nonST-elevation acute coronary syndromes: the MERLIN-TIMI 36 randomized trial. JAMA 2007;297(16):1775-83. ttps://doi. org/10.1001/jama.297.16.1775; PMID: 17456819.

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Exercise

Exercise Training and Heart Failure: A Review of the Literature Jacqueline H Morris and Leway Chen University of Rochester Medical Center, Rochester, New York, USA

Abstract Exercise and cardiac rehabilitation have been underused therapy options for patients with congestive heart failure despite being recommended in international guidelines and being covered by Medicare in the US. This article reviews the evidence behind this treatment strategy and details current trials that will contribute to the evidence base.

Keywords Exercise training, cardiac rehabilitation, congestive heart failure, transplantation, quality of life Disclosure: The authors have no conflicts of interest to declare Received: 21 August 2018 Accepted: 29 November 2018 Citation: Cardiac Failure Review 2019;5(1):57–61. DOI: https://doi.org/10.15420/cfr.2018.31.1 Correspondence: Leway Chen, University of Rochester Medical Center, 601 Elmwood Ave, Box 679-T, Rochester, NY 14642-8679, USA. E: leway_chen@urmc.rochester.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.

Congestive heart failure (CHF) is a progressive cardiovascular disease with significant morbidity and mortality that affects an increasing amount of people worldwide. There are approximately 6.5 million people in the US, more than 14 million people in Europe, and 26 million people worldwide who are living with heart failure, and the prevalence continues to grow.1–3 In the US alone, there were 960,000 new cases of CHF diagnosed in 2017, and this is expected to continue to increase year on year in the ageing population. It has been estimated that by 2030, the prevalence in the US will exceed 8 million people.4 Along with the high disease prevalence, there is also a significant cost burden related to CHF. The annual worldwide cost of heart failure has been estimated to be US$108 billion, which is about 1–2% of the global healthcare budget.5 The US is responsible for about 28% of the global expenditure, while Europe accounts for about 7%.5,6 In an evaluation of US costs published in 2014, the direct and indirect costs of heart failure were calculated from publicly available resources to be about US$60.2 billion and US$115.4 billion, respectively, significantly higher than previous estimates.7 Given the significant disease prevalence and cost burden, it is essential that healthcare providers investigate multiple therapies to improve clinical outcomes for people with CHF. Despite there being many evidence-based therapies that are endorsed by guidelines and have shown to reduce mortality rates and hospitalisations and improve quality of life (QoL) and symptoms, many patients with CHF remain dyspnoeic and fatigued with recurrent hospitalisations, a diminished exercise tolerance and a poor QoL.8 Many studies have shown numerous benefits of cardiac rehabilitation (CR) and exercise training in patients with heart failure, including a reduction in morbidity and mortality.9–11 Guidelines from the American College of Cardiology/American Heart Association, European Society of Cardiology and Canadian Cardiovascular Society have included

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evidence-based recommendations for the use of exercise in the management of CHF (Table 1).12–14 Additionally, given the data supporting the use of exercise in heart failure as well as the revised guidelines, the US Centers for Medicare & Medicaid Services (CMS) extended coverage for CR for patients with heart failure with a reduced ejection fraction (HFrEF) in 2014.15 Despite inclusion in guidelines and CMS coverage and numerous studies showing clinical benefit from exercise therapy and its safety, it has been underused by people with CHF. It is essential that healthcare providers understand the available literature regarding the safety and clinical benefits related to exercise in this population, as well as the barriers to participation and adherence to CR. It is important that patients are referred to CR programmes and they are encouraged to participate. Safety of exercise has been consistently demonstrated in patients with numerous types of clinical HF (Table 2). The Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION) trial, which was the largest trial of exercise training in patients with HF with a reduced ejection fraction (HFrEF), investigated the efficacy and safety of exercise for these patients. This was a multicentre, randomised controlled trial that included 2,331 medically stable patients with HF with left ventricular ejection fraction (LVEF) ≤35% and New York Heart Association (NYHA) Class II–VI symptoms despite optimal medical therapy for 6 weeks. Exercise training was demonstrated to be well tolerated and safe for these patients.10 A meta-analysis of 33 trials (including HF-ACTION), involving 4,740 patients with HFrEF with an LVEF <40% and NYHA Class II or III, demonstrated no significant adverse effects of exercise in patients with HF. 16 In an evaluation of outcomes for HF with preserved ejection fraction (HFpEF), a meta-analysis that included 276 patients with well-compensated heart failure in six randomised controlled trials demonstrated no major adverse effects of exercise training.17 A study of rehabilitation with 27 patients and another

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Exercise Table 1: Guideline Recommendations for Exercise for People with Heart Failure Class

demonstrated a decrease in hospitalisations, but failed to show significant reductions in mortality.8,28

Guideline Recommendations

American College of Cardiology/American Heart Association, 2013

Class I

Exercise training (or regular physical activity) is recommended as safe and effective for patients with HF who are able to participate to improve functional status (level of evidence: A)

Class IIa

Cardiac rehabilitation can be used in clinically stable patients with HF to improve functional capacity, exercise duration, health-related quality of life, and mortality (level of evidence: B)

Canadian Cardiovascular Society, 201714 Regular exercise to improve exercise capacity, symptoms and quality of life in all HF patients (strong recommendation; moderate quality evidence) Regular exercise in HF patients with reduced EF to decrease hospital admissions (strong recommendations; moderate-quality evidence) European Society of Cardiology, 201613 Class I

It is recommended that regular aerobic exercise is encouraged in patients with HF to improve symptoms and functional capacity (level of evidence: A)

Class I

It is recommended that regular aerobic exercise is encouraged in stable patients with HFrEF to reduce the risk of hospitalisation from HF (level of evidence: A)

HF = heart failure; HFrEF = heart failure with a reduced ejection fraction.

including 278 patients both demonstrated that exercise was safe for patients with acute decompensated HF (ADHF).18,19 The Rehabilitation ventricular assist device (Rehab-VAD) trial and the 2017 Cochrane review of exercise-based cardiac rehabilitation in heart transplant recipients demonstrated the safety of exercising with a LV assist device (LVAD) and orthotropic heart transplant (OHT), respectively.20,21 There has been investigation into the pathophysiology of exercise intolerance in patients with HF and the beneficial effects of exercise training. Mechanisms that may lead to decreased exercise capacity in this patient population include cardiac dysfunction, abnormalities in peripheral flow, endothelial dysfunction, skeletal muscle dysfunction, ventilatory deficits and abnormalities of autonomic nervous system function.22 Exercise capacity is best quantified by peak oxygen consumption (peak VO2) and many studies have demonstrated improvements in peak VO2 with exercise training. 9,11,22–24 Additionally, exercise with moderate aerobic training has led to favourable effects on central haemodynamic function, sympathetic tone, peripheral vascular and skeletal muscle function, ventilatory efficiency with decreased dyspnoea and improved QoL.22,25,26

Heart Failure with Reduced Ejection Fraction The majority of studies investigating the effects of exercise on HF have been related to chronic HFrEF and have demonstrated beneficial clinical outcomes (Table 2). Exercise Training Meta-Analysis of Trials in Patients with Chronic Heart Failure (ExTraMATCH) was a 2004 metaanalysis of nine prospective randomised controlled trials comparing exercise training and usual care in patients with CHF related to LV dysfunction. Significant reductions in mortality and hospitalisations were demonstrated.27 Subsequent systematic reviews have also

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An updated Cochrane review in 2017, which examined 33 randomised controlled trials including 4,740 participants, predominantly with HFrEF and NYHA Class II and III, demonstrated a reduction in all-cause hospital admissions and HF-specific admissions in up to 12 months of follow-up. Additionally, there was an improved health-related QoL in the exercise training programme group compared with the control.16 There is also evidence to support cost–effectiveness of exercisebased rehabilitation based on two trials included in the review that was attributed to a reduction in hospital bed days.16 The HF-ACTION trial was included in this Cochrane review; it demonstrated safety and an improved QoL among CHF patients randomised to the exercise therapy group.10 Although there was a non-significant reduction in the risk of all-cause mortality and all-cause hospitalisation in this group of patients with chronic HFrEF, there was a risk reduction in the primary endpoint of death or hospitalisation of any cause when adjusted for highly prognostic predictors, including duration of the cardiopulmonary exercise test, LVEF, Beck Depression Inventory II score and a history of atrial fibrillation or flutter. Further substudy analysis demonstrated that the volume of exercise was a logarithmic predictor of the primary outcome of all-cause mortality or hospitalisation and that there was significant benefit demonstrated from moderate exercise.29

Heart Failure with Preserved Ejection Fraction Multiple studies have demonstrated safety and effectiveness of exercise for people with HFrEF to improve symptoms, aerobic capacity/endurance and QoL, although people with HFpEF have been under-represented in the studies. Given that HFpEF leads to about 50% of hospital admission for HF and that there is a lack of demonstrated benefit from pharmacotherapies in this patient population, investigation of other potential beneficial interventions for people with HFpEF is essential.16,17 In addition to demonstrating the safety of exercise with no major adverse effects reported in the 276 patients with well-compensated HFpEF in a meta-analysis that included six randomised controlled trials, it was suggested that exercise training improved cardiorespiratory fitness by an increase in peak VO2 and QoL.17 These improvements were noted to be unrelated to a significant change in the diastolic LV function. The Exercise Training in Diastolic Heart Failure (Ex-DHF) pilot study was a randomised study involving 64 patients that compared supervised exercise or usual care and it demonstrated improvements in exercise capacity and health-related QoL.30 There have been no studies evaluating the effect of exercise on hospitalisations or mortality in the HFpEF population, and HFpEF was excluded from CMS coverage for CR in the most recent decision memo in 2014.15 The Ex-DHF trial, which is currently enrolling participants, is the first multicentre trial to evaluate the long-term effects of exercise on a composite outcome of all-cause mortality, hospitalisations, NYHA functional class, global self-rated heath, maximal exercise capacity, and diastolic function in HFpEF patients.31

Acute Decompensated Heart Failure There is extremely limited data on the safety and clinical outcomes related to exercise therapy in people with ADHF, which is a leading cause of hospitalisation and is associated with significant morbidity, mortality, and healthcare costs, especially in older patients. These

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Exercise Training and Heart Failure Table 2: Clinical Outcomes and CMS Coverage in Congestive Heart Failure Clinical Outcome

Mortality Reduction

Rehospitalisation Reduction

Safety

CMS Coverage

HFrEF

ExTraMATCH 2004: yes; HF ACTion and Cochrane 2017: no mortality benefit

Yes

HFpEF

Awaiting results from Ex-DHF trial

Yes

ADHF

Lack of data

Yes, based on a study in Australia (n=278). Awaiting results from REHAB-HF trial

LVAD

Lack of data

Yes

Yes*

OHT

Lack of data

Yes

*Many LVAD patients are eligible for CR under HFrEF indication or for medical criteria for disability with LVEF ≤30% with symptoms affecting daily life.27 ADHF = acute decompensated heart failure; CMS = Centre for Medicare & Medicaid Services; HFpEF = heart failure with preserved ejection fraction; HFrEF = heart failure with reduced ejection fraction; LVAD = ventricular assist decice; OHT = orthotopic heart transplant.

patients have been excluded from previous exercise training trials and the updated CMS memo for CR coverage from 2014.15 The Rehabilitation Therapy in Older Acute Heart Failure Patients (REHAB-HF) pilot study provided feasibility of an ongoing multicentre, randomised, attention-controlled trial funded by the National Institute of Health to evaluate the use of rehabilitation to improve physical function and reduce rehospitalisations for patients ≥60 years beginning in the hospital during an admission for ADHF (including HFrEF and HFpEF) and continuing for 12 weeks after discharge.18 This pilot study included 27 patients with admissions for ADHF that were randomised into a novel rehabilitation intervention group, focusing on improved balance, strength, mobility and endurance, an attention control group or usual care, and demonstrated feasibility, safety and a trend toward improved physical function and decreased hospitalisations in the intervention group. Given that this is a pilot study with a small sample size of the larger and randomised controlled trial (REHAB-HF) that is currently enrolling participants, the authors recommend caution in instituting immediate rehabilitation in older patients with ADHF. The Exercise Joins Education: Combined Therapy to Improve Outcomes in Newly-discharged Heart Failure (EJECTION-HF) trial was a multicentre randomised controlled trial in Australia that included 278 recently discharged CHF patients who were randomised to 24 weeks of supervised centre-based exercise therapy commencing within 6 weeks of discharge or standard care.19 Average time to initiation of CR in these patients was 43 days and there were no adverse events associated with the therapy, suggesting that exercise therapy in patients recently hospitalised with acute HF is safe and feasible. Adherence in the home exercise group was 75% at 3 months and 68% at 6 months, while the centre-based exercise group had poor adherence with only 43% of patients participating in ≥50% of the sessions. There was no difference in the primary outcome of all-cause death or readmissions, although there was a significant reduction in all-cause mortality in the exercise group (based on a small number of events), which should be interpreted with caution. The results of the REHAB-HF trial will provide additional insight into the benefit of early rehabilitation for patients with ADHF.

Left Ventricular Assist Devices Patients that have been implanted with LVADs are reported to have improved survival, functional capacity and health status, although many continue to report exercise intolerance and heart failure symptoms. The Rehab-VAD trial is the largest prospective randomised

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Figure 1: Patients Exercising

A: An LVAD patient. B. A cardiac transplant patient exercising. Source: Submitted photos.

trial of the beneficial effects of exercise on LVAD patients. It included 26 patients randomised to CR or usual care after implantation of an LVAD. It demonstrated that exercise was safe in the CR group with only one event (syncope) in more than 300 sessions, and showed an improved total treadmill time, muscle strength and improved health status (evaluated by the Kansas City Cardiomyopathy Questionnaire) with continuous flow LVADs compared with usual care.20 There was no difference in the peak VO2, which has been a marker of exercise capacity in people with CHF, although additional studies have suggested an improvement in VO2 with exercise therapy after VAD implantation.32 A recent study of 1,164 Medicare beneficiaries receiving LVADs demonstrated low participation in CR (30%). Of those who participated in CR, there was a decreased risk of hospitalisation and mortality at 1 year after multivariate adjustment with a 23% and 47% reduction, respectively, compared with those who did not participate in CR.33 This was not the primary outcome of this study and there were likely additional confounding variables, although it suggests potential clinical benefits and identifies a need for further studies to evaluate the value of exercise in people with LVADs (Figure 1A).

Cardiac Transplantation Although there have been significant improvements in OHTs over the past 40 years, long-term survival remains limited. Exercise capacity and health-related QoL in transplant recipients have been noted to be inferior compared with age-matched healthy people.34 In the past, transplant patients were advised not to exercise due to concerns of chronotropic incompetence in the denervated heart, although further

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Exercise Table 3: Indications for CMS Cardiac Rehabilitation Coverage Coverage Decision Memorandum, 200640

Coverage Decision Memorandum, 201415

• • • • •

Acute MI Coronary artery bypass graft Stable angina pectoris Heart valve repair or replacement Percutaneous transluminal coronary angioplasty or coronary stenting • Heart transplant • Heart and lung transplant Stable chronic heart failure (LVEF ≤35%) and NYHA class II–IV symptoms despite optimal medical therapy for at least 6 weeks without recent (≤6 weeks) or planned (≤6 months) major cardiovascular hospitalisations or procedures.

CMS = Centers for Medicare & Medicaid Services; LVEF = left ventricular ejection fraction; NYHA = New York Heart Association.

studies have shown evidence of sympathetic reinnervation, which is associated with improved exercise capacity and may be improved by physical training.35 An updated Cochrane review in 2017 included ten randomised controlled trials with 300 patients who had OHTs demonstrated the safety of exercise therapy in transplant patients with only one reported adverse event. Nine studies compared exercising to control and one study compared high-intensity to moderate-intensity training.21 CR participation was associated with an improvement in peak VO2 and exercise capacity, although there was no significant improvement in health-related QoL in a 12-week period. There was no data to report hospitalisations or mortality benefit in these studies. Additional studies have demonstrated improvement of peak heart rate, ventilatory capacity, autonomic function and QoL with exercise training.36 In an evaluation of CR and readmission rates for 595 Medicare beneficiaries that received heart transplants in the US in 2013, 55% of patients were enrolled in CR. Participation in CR was associated with a 29% lower readmission risk at 1 year.36 Younger patients (aged 35–49 years) were significantly less likely to enrol in CR, and those that enrolled were likely to attend fewer sessions that patients older then 65 years. There have been no published studies investigating the effects on mortality of OHT patients who have participated in exercise training or CR. Given the significant benefits of CR and the CMS coverage of CR in orthotopic heart transplant patients that was approved in 2006, there should be a significant effort to improve uptake of CR in this patient population (Figure 1B).37

CMS Coverage In 2006, CMS published a decision that there was adequate evidence to approve coverage of CR for patients with an acute MI, coronary artery bypass graft, stable angina, heart valve repair or replacement, percutaneous transluminal coronary angioplasty or coronary stenting, and heart or heart and lung transplant (Table 3).37 At that time, there was insufficient evidence to approve CR coverage for CHF patients. After numerous studies were published demonstrating benefit of exercise training for patients with HFrEF, the largest of which being HF-ACTION, CMS expanded coverage for stable, chronic HF defined as patient with an LVEF ≤35% with NYHA II–IV symptoms despite optimal medical therapy for at least 6 weeks without recent or planned hospitalisation or procedure.15 Specific CR coverage is not available for patients with HFpEF, ADHF or LVAD, although many LVAD patients are eligible for CR under the HFrEF indication, or by medical criteria for disability with LVEF ≤30% with symptoms affecting daily living.33

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Although HFpEF patients represent a significant number of CHF patients and hospital admissions, and ADHF is a significant cause of morbidity, mortality and is a component of healthcare expenditures, there is currently no CMS coverage for CR for these patients. Additional studies, including the Ex-DHF trial for HFpEF and REHAB-HF trial for ADHF, are necessary to demonstrate safety and clinical benefit to encourage CMS coverage for CR.18,30,31

Uptake and Adherence Despite numerous benefits and CMS coverage for many patients, there has been significant underuse of CR for people with CHF. An earlier study demonstrated that only 10.4% (12.2% HFrEF, 8.8% HFpEF) of 105,619 eligible patients with HF (48% with HFrEF, 52% with HFpEF) received a CR referral after hospitalisation for CHF.38 In the HF-ACTION trial with HFrEF patients, despite numerous methods to reinforce adherence, about 30% of those enrolled in the exercise arm exercised at or above the target goal.10 A retrospective study using the CMS and the Veterans Health Administration (VA) national data between 2007 and 2011 evaluated CHF patient enrolment in one or more sessions of CR. Of the 66,710 veterans and 243,208 Medicare beneficiaries hospitalised for HF, 2.3% and 2.6% respectively, attended one or more sessions of outpatient CR.39 The investigators noted that they were unable to determine the prevalence of HFrEF that would be eligible for CR in these populations by using the ICD-9 codes. Much of the US data was collected before CMS coverage expansion of HFrEF in 2014. For LVAD and OHT recipients with Medicare coverage, uptake of CR was 30% (of 1,164 LVAD patients) and 55% (of 595 OHT patients).33,36 In a 2010 European survey, it was reported that <20% of HF patients were participating in CR.40 There are many potential barriers involving either the healthcare system or patient adherence that influence the use of CR. The healthcare provider should understand that current guidelines, consensus statements and high-impact studies demonstrate the value of exercise training, in addition to confirming available CR sites with educated CR teams. Additionally, many patient factors, including socioeconomic factors, work conflicts, inadequate transportation, lack of reimbursement, significant symptoms, as well as patient attitude, beliefs and motivations, affect enrolment and adherence to CR.43 In many cases, there are multiple barriers that need to be addressed to significantly improve CR use in people with CHF.

Conclusion CHF is an increasingly prevalent disease with significant morbidity and mortality despite optimal drug and device therapies. Exercise training and cardiac rehabilitation have demonstrated numerous benefits for people with CHF, including improved exercise capacity and QoL, in addition to improved clinical outcomes. Exercise has also been established as safe and feasible with HF and, in some studies, exercise therapy has demonstrated improved cost-efficiency in HF management. The majority of current studies and subsequent guidelines have been established based on the benefits of exercise in HFrEF patients, although further studies are necessary to evaluate clinical outcomes with exercise in different HF populations to drive expansion of the guidelines to include HFpEF, VAD and OHT patients. Despite numerous benefits in multiple HF groups, there is significant underuse of CR due to many barriers that need to be overcome. Healthcare providers should strongly consider referring their patients with CHF to CR and encouraging participation in and adherence to exercise training programmes.

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Erratum

Erratum to: Foreword Andrew JS Coats and Giuseppe Rosano

Citation: Cardiac Failure Review 2018;5(1):62. DOI: https://doi.org/10.15420/cfr.2018.34.1 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 Foreword by Andrew JS Coats and Giuseppe Rosano in Cardiac Failure Review 2018;4(2), the DOI was incorrectly presented as: DOI: https://doi.org/10.15420/cfr.2018.4.1.FO1 The correct DOI should be: DOI: https://doi.org/10.15420/cfr.2018.33.1 The editors would like to sincerely apologise for any inconvenience caused.

Access at: www.CFRjournal.com

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Supporting lifelong learning for cardiovascular professionals Led by Editor-in-Chief Andrew JS Coats and underpinned by an editorial board of world-renowned physicians, Cardiac Failure Review is a peer-reviewed journal publishing comprehensive articles. Available in print and online, Cardiac Failure Reviewâ&#x20AC;&#x2122;s articles are free to access, and aim to support continuous learning for physicians within the field.

Call for Submissions Cardiac Failure Review publishes invited contributions from prominent experts, but also welcomes speculative submissions of a superior quality. For further information on submitting an article, or for free access to the journal, please visit: www.CFRjournal.com

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