Cardiac Failure Review Vol 3 No 1 2017 by Radcliffe Cardiology

©Radcliffe Cardiology

Volume 3 • Issue 1 • Spring 2017

www.CFRjournal.com

Neurohormonal Blockade in Heart Failure Thomas G von Lueder, Dipak Kotecha, Dan Atar and Ingrid Hopper

Is Medication Titration in Heart Failure too Complex? John J Atherton and Annabel Hickey

Heart Failure in Patients with Diabetes Mellitus Giuseppe MC Rosano, Cristiana Vitale and Petar Seferovic

Practical Applications for Single Pill Combinations in the Cardiovascular Continuum Ferdinando Iellamo, Karl Werdan, Krzysztof Narkiewicz, Giuseppe Rosano and Maurizio Volterrani

Dietary potassium B.

Patiromer H+/K+ ATPase

Decrease extracellular potassium Extracellular potassium

ZS-9 6

Potassium absorption

Mechanisms of Action of ZS-9 and Patiromer D.

Potassium excretion Flow velocity [cm/s]

4 Time [s]

60 40 20

Increase Native T1 ma Medication titration Measurements of extracellular in heart failure Central Pressure andpotassium Flow Data pping

Urinary loss of potassium

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Volume 3 • Issue 1 • Spring 2017

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Editor-in-Chief Andrew JS Coats

William T Abraham

Alexander Lyon

Ali Ahmed

Theresa A McDonagh

The Ohio State University, USA

Imperial College London, UK

Washington DC VA Medical Center, USA

King’s College Hospital, UK

Inder Anand

Kenneth McDonald

John Atherton

Ileana L Piña

University of Minnesota, USA

St Vincent’s Hospital, Ireland

Royal Brisbane and Women’s Hospital, Australia

Montefiore Einstein Center for Heart & Vascular Care, USA

Michael Böhm

Saarland University, Germany

Kian-Keong Poh

National University Heart Center, Singapore

Alain Cohen Solal

Paris Diderot University, France

A Mark Richards

Henry J Dargie

University of Otago, New Zealand

Western Infirmary, Glasgow

Giuseppe Rosano

Carmine De Pasquale

St George’s University of London, UK

Flinders University, Australia

Jose Antonio Magaña Serrano

Frank Edelmann

National Medical Centre, Mexico

Charité University Medicine, Germany

Martin St John Sutton

Michael B Fowler

Hospital of the University of Pennsylvania, USA

Stanford University, USA

Allan D Struthers

Michael Fu

Ninewells Hospital & Medical School, UK

Sahlgrenska University Hospital, Sweden

Michal Tendera

David L Hare

University of Silesia, Poland

University of Melbourne, Australia

Michael Henein

Maurizio Volterrani

Adelino Leite-Moreira

Cheuk Man Yu

IRCCS San Raffaele Pisana, Italy

Heart Centre and Umea University, Sweden University of Porto, Portugal

The Chinese University of Hong Kong, Hong Kong

Managing Editor Lindsey Mathews • Production Jennifer Lucy • Senior Designer Tatiana Losinska Digital Commercial Manager Ben Sullivan • New Business & Partnership Director Rob Barclay Publishing Director Liam O’Neill • Managing Director David Ramsey • Commercial Director Mark Watson •

Editorial Contact Lindsey Mathews commeditor@radcliffecardiology.com Circulation & Commercial Contact David Ramsey david.ramsey@radcliffecardiology.com •

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credit: 7activestudio © www.istockphoto.com / Box 3 credit: nathan4847 © www.istockphoto.com

•

Design Tatiana Losinska

Radcliffe Cardiology

Lifelong Learning for Cardiovascular Professionals

Radcliffe Cardiology

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 there of. Where opinion is expressed, it is that of the authors and does not necessarily coincide with the editorial views of Radcliffe Cardiology. Statistical and financial data in this publication have been compiled on the basis of factual information and do not constitute any investment advertisement or investment advice. Radcliffe Cardiology, Unit F, First Floor, Bourne End Business Park, Cores End Road, Bourne End, Buckinghamshire, SL8 5AS © 2017 All rights reserved ISSN: 2057–7540 • eISSN: 2057–7559

Established: March 2015 Frequency: Bi-annual Current issue: Spring 2017

Aims and Scope • 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.

Structure and Format • Cardiac Failure Review is a bi-annual 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

Editorial Expertise 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.

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.

Submissions and Instructions to Authors • 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, Lindsey Mathews commeditor@radcliffecardiology.com

Reprints All articles included in Cardiac Failure Review are available as reprints. Please contact the Publishing Director, Liam O’Neill liam.oneill@radcliffecardiology.com

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

Copyright and Permission Radcliffe Cardiology is the sole owner of all articles and other materials that appear in Cardiac Failure Review unless otherwise stated. Permission to reproduce an article, 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 manuscripts from other journals within Radcliffe Cardiology’s cardiovascular portfolio – including, Arrhythmia and Electrophysiology Review, Interventional Cardiology Review, European Cardiology Review and US Cardiology Review. n

Contents

www.CFRjournal.com

Foreword

Andrew JS Coats and Giuseppe Rosano

Epidemiology

Global Public Health Burden of Heart Failure Gianluigi Savarese and Lars H Lund

Pathophysiology

Ventricular–Arterial Coupling in Chronic Heart Failure Julio A Chirino and Nancy Sweitzer

Pharmacotherapy

Neurohormonal Blockade in Heart Failure

Is Medication Titration in Heart Failure too Complex?

How to Improve Adherence to Life-saving Heart Failure Treatments with Potassium Binders

Thomas G von Lueder, Dipak Kotecha, Dan Atar and Ingrid Hopper

John J Atherton and Annabel Hickey

Mitja Lainscak

Practical Applications for Single Pill Combinations in the Cardiovascular Continuum Ferdinando Iellamo, Karl Werdan, Krzysztof Narkiewicz, Giuseppe Rosano and Maurizio Volterrani

Clinical Care

Chronic Heart Failure Care Planning: Considerations in Older Patients Eilidh Hill and Jackie Taylor

Comorbidities

Heart Failure in Patients with Diabetes Mellitus

Challenges of Treating Acute Heart Failure in Patients with Chronic Obstructive Pulmonary Disease

Giuseppe MC Rosano, Cristiana Vitale and Petar Seferovic

Jelena Cˇelutkiene˙, Mindaugas Balcˇ iuˉnas, Denis Kablucˇ ko, Liucija Vaitkevicˇ iuˉte˙, Jelena Blašcˇ iuk and Edvardas Danila

Cardiac Atrophy and Heart Failure In Cancer

Cancer and Heart Failure: Understanding the Intersection

Mark Sweeney, Angela Yiu and Alexander R Lyon

Carine E Hamo and Michelle W Bloom

CARDIAC FAILURE REVIEW

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 Georges University of London, UK

e have great pleasure in introducing the latest issue of Cardiac Failure Review. As we gear up for the annual heart failure congress of the European Heart Failure Association (29 April–2 May 2017), we reflect on the successes and failures since the influential European guidelines were published in Florence a year ago.

In this 12-month period we have seen the promotion of a new category of chronic heart failure; the so-called heart failure with mid-range ejection fraction (HFmrEF). A major driver for this no category was the desire for more clinical trials in a group of patients that includes both those with minor systolic dysfunction and some who have improved from more severe heart failure with reduced ejection fraction-type dysfunction and no longer fall into that category. Our major clinical trials, on which almost all treatment recommendations are based, have variably included some of the patients but not enough to be confident we know how to treat this group. As we all know, major clinical trials take many years to complete so we will not see answers for some time, but it is encouraging to see observational studies on HFmrEF already coming out. When it comes to major trials in heart failure, the only major mortality and morbidity trial to report recently (RELAX-AHF-2) was disappointingly neutral, with no added benefit of serelaxin in the setting of acute heart failure. Comorbidities are attracting increasing attention as we struggle to evaluate and treat our ever-ageing population of heart failure patients. Foremost of these in terms of rapidly accumulating evidence is diabetes. Following a run of newer agents that have sometimes lead to an increased risk of heart failure at least we have an hypoglycemic agent with major cardiovascular benefit in high-risk diabetic patients with cardiovascular disease. The SGLT2 inhibitor (“gliflozin”), empagliflozin, was studied in patients with high cardiovascular risk in the EMPA-REG OUTCOME trial and this demonstrated reduced cardiovascular death and a significant reduction in new-onset heart failure. These findings will now be further explored in specific heart failure populations by the up-coming two EMPEROR HF clinical trials: EMPEROR HF-Preserved [NCT03057951] in heart failure with preserved ejection fraction, and EMPEROR HF-Reduced [NCT03057977] in heart failure with reduced ejection fraction. Another agent of a different class, the GLP1 receptor agonist liraglutide, showed an overall benefit on cardiovascular mortality in the recent LEADER study. Who better to review the complex and rapidly changing area of the management of the diabetic patient with heart failure for our readers this issue than Rosano and Seferovic? We also cover vital topics such as how and when to get the best from neurohormonal blockade, how to up-titrate (and not overdo the complexity of our treatments), the role of combination pills to ease patient compliance, and how to manage the hyperkalaemia that can lead to premature discontinuation of potentially life-saving therapies. These are masterfully covered by von Lueder et al, Atherton and Hickey, Werdan et al, and Lainscak, in turn. Savarese and Lund review the increasing global burden of heart failure as the West ages, the East adopts poorer Western diets and the developing world rapidly grows economically stronger, but sadly weaker in terms of healthy diets and lifestyles. There are two very informative articles on the emerging field of cardio-oncology, where both some of the newer anti-cancer

Foreword drugs can be bedevilled by cardiac damage side-effects, and even cancer itself has been implicated in causing an new form of cardiomyopathy. Lastly we review the impact of abnormal ventriculo-aortic haemodynamic coupling putting additional stress on the already damaged ventricle. We review the care of the older chronic heart failure patient and we look at the complexity of managing acute heart failure in the presence of active lung disease that can so confuse the clinical picture. We hope you enjoy reading our latest issue of Cardiac Failure Review. n

C A R D I A C FA I L U R E R E V I E W

Epidemiology

Global Public Health Burden of Heart Failure Gianluigi Savarese 1,2 and Lars H Lund 1,2 1. Division of Cardiology, Department of Medicine, Karolinska Insitutet, Stockholm, Sweden; 2. Department of Cardiology, Karolinska University Hospital, Stockholm, Sweden

Abstract Heart failure (HF) is a global pandemic affecting at least 26 million people worldwide and is increasing in prevalence. HF health expenditures are considerable and will increase dramatically with an ageing population. Despite the significant advances in therapies and prevention, mortality and morbidity are still high and quality of life poor. The prevalence, incidence, mortality and morbidity rates reported show geographic variations, depending on the different aetiologies and clinical characteristics observed among patients with HF. In this review we focus on the global epidemiology of HF, providing data about prevalence, incidence, mortality and morbidity worldwide.

Keywords Heart failure, heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, heart failure with mid-range ejection fraction, prevalence, incidence, mortality, morbidity, clinical characteristics, geographic differences Disclosure: The authors have no conflicts of interest to declare. Received: 31 October 2016 Accepted: 2 March 2017 Citation: Cardiac Failure Review 2017;3(1):7–11. DOI: 10.15420/cfr.2016:25:2 Correspondence: Lars H Lund, Department of Medicine, Cardiology Unit, Karolinska Institutet, FoU Tema Hjarta och Karl, S1:02, 17176 Stockholm, Sweden. E: Lars.Lund@karolinska.se

Heart failure (HF) is a complex clinical syndrome characterised by the reduced ability of the heart to pump and/or fill with blood.1,2 From a physiological point of view, HF can be defined as an inadequate cardiac output to meet metabolic demands or adequate cardiac output secondary to compensatory neurohormonal activation (generally manifesting as increased left ventricular filling pressure).2 HF has recently been classified into three subtypes, namely HF with reduced ejection fraction (HFrEF), HF with preserved ejection fraction (HFpEF) and HF mid-range ejection fraction (HFmrEF), according to the ejection fraction, natriuretic peptide levels and the presence of structural heart disease and diastolic dysfunction.3 HF has been defined as global pandemic, since it affects around 26 million people worldwide.4 In 2012 it was responsible for an estimated health expenditure of around $31 billion (£22.5 billion), equivalent to more than 10 % of the total health expenditure for cardiovascular diseases in the United States (US).5 Projections are even more alarming, however, with total costs expected to increase by 127 % between 2012 and 2030.5 In this review we describe the epidemiology of HF, providing data about the prevalence, incidence, mortality and morbidity worldwide.

Prevalence and Incidence Currently 5.7 million people in the US have HF, but the projections are worrisome since it is expected that by 2030 more than 8 million people will have this condition, accounting for a 46 % increase in prevalence (see Figure 1).5 In Europe, the EPidemiologia da Insuficiencia Cardiaca e Aprendizagem (Epidemiology of Heart Failure and Learning – EPICA) study performed in the late 1990s in Portugal reported HF prevalence of 1.36 % in the 25–49-year-old group, 2.93 % in the 50–59-yearold group, 7.63 % in the 60–69-year-old group, 12.67 % in the

70–79-year-old group, and 16.14 % in patients >80 years.6 Another analysis in Spain showed HF prevalence steadily increasing from 895 per 100,000 population per year in 2000 to 2,126 cases in 2007, with higher rates in men than women. The prevalence of HFpEF was higher than that of HFrEF; in the former rates were higher in women, while in the latter they were higher in men. The overall HF prevalence significantly increased with ageing, particularly among patients >64 years and with HFpEF.7 In Germany in 2006 the prevalence of HF was 1.6 % in women and 1.8 % in men, with numbers increasing considerably with advancing age.8 In Sweden in 2010 the crude prevalence of HF was 1.8 % and was similar in men and women, but after adjustment for demographic composition the estimated rate was 2.2 %, with a weak decrease in temporal trend in women but not men between 2006 and 2010.9 A recent survey reported HF prevalence of 1.44 % in Italy, with rates increasing with the ageing of the population.10 HF is also an important health problem in Asia, and its prevalence seems to be even higher compared to Western countries, ranging between 1.3 % and 6.7 %.11 Currently in China there are 4.2 million people with HF, with an estimated prevalence of 1.3 %.12,13 In Japan around 1 million people have the condition, accounting for 1 % of the population.14–16 In India the estimates range between 1.3 and 4.6 million, which translates to a prevalence of 0.12–0.44 %, although this may be underestimated.17 In Southeast Asia 9 million people have HF; with a prevalence of 6.7 % in Malaysia and 4.5 % in Singapore.4,18 In South America the HF prevalence is 1 % and in Australia it ranges between 1 % and 2 %, similar to Western countries (see Figure 2).19,20 Although aetiologies and clinical characteristics have been studied in Sub-Saharan Africa,21 there are actually no population studies providing insight into prevalence or incidence .22 Few studies have evaluated the different trends in HFrEF and HFpEF prevalence and there are currently no data on the emerging HFmrEF

Access at: www.CFRjournal.com

Epidemiology

Number of people (×10,000)

Figure 1: Burden of Heart Failure Actual burden

100

77.2

80 60 40 16.6

670,000 new HF cases in 2007 348,000 new HF 34.8 cases in 2000 25.5

53.7 772,000 projected new HF cases in 2040

Projected burden assuming stable incidence of 10/1,000 person-years in persons ≥65 years

0 1960

1980

2020

2000 Year

2040

The actual annual incidence of heart failure (HF) reported in the US (squares and dotted line) exceeded the projected annual incidence (triangles and solid line) calculated based on a stable incidence of 10 per 1,000 person-years in persons aged ≥65 years. Source: Lam et al., 2011.69 Reproduced with permission, © 2011 John Wiley & Sons.

Figure 2: Prevalence and Incidence of Heart Failure Worldwide Incidence (%) 0.5 0.4 0.3 0.2 0.1 0.1–0.2 0.39 0.27 0.31–0.39 0.39–0.44 0.38 0.1–0.2 0.9 0.05–0.17

0.2

1 Portugal Spain Germany Sweden Italy UK Netherlands USA China Japan India Malaysia Singapore South America Australia

5 Prevalence (%)

1–2 2.1 1.6–1.8 1.8–2.2 1.44

1.5–1.9 1.3 1 0.12–0.44 6.7 4.5 1 1–2

category. Data are heterogeneous and also depend on the definition used for HFpEF and HFrEF, but it might be that about half of HF patients have HFrEF and half HFpEF, with the proportion of individuals with HFpEF increasing, particularly if more unselected populations are considered (see Figure 3).23–26 HFpEF could be dominant in driving the overall HF prevalence, since in the past 20 years secular trends have reported an increasing proportion of patients with HFpEF but relatively stable or even decreasing rates with HFrEF (see Figure 4); thus it is expected that by 2020 65 % of patients hospitalised for HF will have HFpEF.27

Currently every year in US there are still 915,000 new cases of HF, accounting for an incidence approaching 10 per 1,000 population after 65 years of age. At 40 years of age the lifetime risk of developing HF is one in five and at 80 the remaining lifetime risk of developing HF remains at 20 %, despite the shorter life expectancy.5 In Portugal the EPICA study reported an incidence of 1.3 cases per 1,000 population per year for those aged ≥25 years, increasing to 8.8 per 1,000 population at >65 years and 11.6 per 1,000 population at >85 years, with 1.75-fold higher rates in males versus females.6 In UK, however, the overall incidence rate was 4.4 per 1,000 population per year in men and 3.9 per 1,000 in women, with rates doubling every 5 years after the age of 55.33 In Spain between 2000 and 2007 the overall incidence of HF increased from 2.96 to 3.90 cases per 1,000 population per year, with a higher incidence among men (0.2 cases per 1,000 population per year). Notably, the incidence of HFrEF surpassed that of HFpEF by 0.24 cases per 1,000 population per year. There were 0.32 more HFrEF cases per 1,000 population per year in men; whereas HFpEF was 0.17 cases per 1,000 population per year higher in women.7 However, when observing the trends over time, in 2007 the rise in overall incidence of HF plateaued, with HFrEF rates starting to slowly decrease in 2005 while HFpEF was still increasing.7 In Germany in 2006 the age- and genderstandardised incidence of HF was 2.7 cases per 1,000 population per year, with rates being higher in men than women (2.3 versus 3.1 cases per 1,000 population per year). These incidences more than doubled in each of the higher age categories in both genders.8 The Prevention of Renal and Vascular End-stage Disease (PREVEND) study that enrolled all 28–75-year-old inhabitants of Groningen (85,421 subjects) in the Netherlands in 1997–8 and followed them until the end of 2009 reported an overall HF incidence of 4.4 %, with 34 % of new-onset cases classified as HFpEF and 66 % as HFrEF.34 In Sweden in 2010 the incidence of HF was 3.1 cases per 1,000 population per year, and was similar in women and men; however, after adjustment for demographic composition the estimated incidences were revised to 3.7 in women and 3.9 in men, with a decreasing temporal trend of 0.9 cases per 1,000 population per year in absolute terms between 2006 and 2010.9 In Asia there are fewer data about the incidence of HF. In China every year 500,000 new HF cases are diagnosed, accounting for an incidence of 0.9 %,12 whereas in India there are 0.5–1.8 million new cases per year (an incidence of 0.05–0.17 %), which again may be underrestimated.17 In South America the incidence of HF, according to a single population study, is 199 cases per 100,000 person-years (see Figure 2).19

Demographic and Clinical Characteristics Notably, the increase in HF prevalence observed worldwide may not necessarily be linked with an increase in HF incidence, which has been reported to be stable or even decreasing in several studies, particularly in women.28,29 The ageing of the population, together with improved HF survival due to the advancement in treatments and diagnostic technology could explain the increase in prevalence, whereas the reduction in incidence (due to prevention programmes) may be determined by lower severity and better treatment of acute coronary syndromes.29–32 In addition to this, the risk factors for HFpEF are multifactorial and complex and there is no known prevention other than treatment of the risk factors, such as hypertension, diabetes and obesity; whereas prevention and early treatment strategies (i.e. early revascularisation) appear to be effective in reducing the risk and severity of acute myocardial infarction. These observations may explain a reduction in the incidence of HFrEF but increasing incidence of HFpEF and HFmrEF.

The demographic and clinical characteristics of HF have been widely described in Europe and the US, and have been shown to differ considerably between HFpEF and HFrEF, with further variation according to the populations enrolled and the definitions of HFpEF and HFrEF adopted. In particular, it has emerged that HFpEF patients are more likely to be women and older, obese, with a higher New York Heart Association (NYHA) class and cardiovascular comorbidities (such as hypertension, diabetes, atrial fibrillation, valvular disease) and non-cardiovascular comorbidities (such as a anaemia, chronic kidney disease, chronic pulmonary disease, hypothyroidism, cancer, peptic ulcer and psychiatric disorders); whereas coronary artery disease is the main determinant of HFrEF.23–27,35–38 Recently, HFmrEF has been recognised as a potentially distinct entity and the few observations available suggest that its characteristics are generally intermediate between those of HFpEF and HFrEF: a high prevalence of comorbidities as in HFpEF (i.e. hypertension, diabetes, atrial fibrillation, chronic

C A R D I A C FA I L U R E R E V I E W

Public Health

Most studies describing HF characteristics have been performed in North America and Europe; however the phenotypes of HF patients could be different in other regions due to different aetiologies, comorbidities, economic and health care systems. One study showed that in Africa HF patients are younger than in other regions, with most being NYHA class III/IV and having valve disease.41 Half of these HF patients are male and 29 % have HFpEF. The leading causes of HF in Africa are hypertensive heart disease and dilated cardiomyopathy.41–43 In Asia the proportion of patients in NYHA class III/IV is similar to that in NYHA class II.17,41,44 Coronary artery disease is the leading HF aetiology. More than the half of the HF population is male and has hypertension, and HFpEF is present in 41 % of patients.17,41,44 It is notable that in Japan ischaemic aetiology is still lower than in Western countries. It has, however, increased over time, and the HFpEF prevalence ranges between 34 % and 68 %.16 Middle Eastern HF patients are also young, and are more likely to be male. There is a high prevalence of several comorbidities as such obesity, diabetes, hypertension, hyperlipidaemia and valve disease, but only 10–30 % of the population has HFpEF. Coronary artery disease is the main cause of HF in the Middle East.41,45 In South America the most common cause of HF is coronary artery disease. More than half of HF patients are male and have hypertension, and around half have dyslipidaemia and valve disease.41,46,47 In Australia

Figure 3: Distribution of Left Ventricular Ejection Fraction in Heart Failure Hospital-based sample (n=4,910) 20 Male Female 15 Patients (%)

pulmonary and kidney disease); and a high prevalence of coronary artery disease as in HFrEF, particularly in males and older patients.36,39,40

0 0

C A R D I A C FA I L U R E R E V I E W

100

Bimodal distribution of left ventricular ejection fraction in Olmsted County heart failure population. Source: Borlaug and Redfield, 2011.70 Reproduced with permission, © 2011 Wolters Kluwer Health, Inc.

Figure 4: Temporal Trends in Heart Failure with Preserved Ejection Fraction and Heart Failure with Reduced Ejection Fraction

250

Outcomes

In Europe, the EuroHeart Failure Survey compared prognosis in 3,148 patients with HFpEF and 3,658 with HFrEF, reporting higher 90-day mortality in those with HFrEF (12 %) compared with HFpEF (10 %), but similar readmission rates (21 % versus 22 %, respectively).23 In the

Ejection Fraction (%)

HF patients are more likely to be male and the leading HF aetiology is coronary artery disease; HFpEF is present in 25 % of cases.48

Preserved ejection fraction r=0.81, P<0.001

Reduced ejection fraction r=–0.33, P=0.23

200 Admissions (n)

HF outcomes have been extensively investigated in the US. The Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients With Heart Failure (OPTIMIZE-HF) study enrolling 20,118 patients with HFrEF and 21,149 with HFpEF (EF ≥40 %) reported no differences between HFrEF and HFpEF in 60–90-day mortality (9.8 % versus 9.5 %) and rehospitalisation (29.9 % versus 29.2 %), but higher in-hospital mortality in those with HFrEF (3.9 %) versus HFpEF (2.9 %). When the comparison between HFpEF (EF >50 %) and HFmrEF (EF 40–50 %) was performed, no differences in outcomes were observed.36 Similarly, the Get With The Guidelines (GWTG) registry that enrolled 15,716 patients with HFrEF, 5,626 with HFmrEF and 18,897 with HFpEF observed 37.5 %, 35.1 % and 35.6 % mortality at 1 yearm respectively, with no differences in risk after several adjustments. The 1-year HF hospital readmission rates were 30.9 %, 28.4 % and 24.3 % in HFrEF, HFmrEF and HFpEF, respectively, but there was a higher risk in HFrEF and HFmrEF compared with HFpEF.49 The Management Predischarge Process for Assessment of Carvedilol Therapy for Heart Failure (IMPACT-HF) study reported that >50 % of patients were discharged with unresolved symptoms, and within 60 days half had worsening symptoms, a quarter were re-hospitalised and >10 % died.50 The Canadian Enhanced Feedback for Effective Cardiac Treatment (EFFECT) study enrolling 1,570 patients with HFrEF and 880 with HFpEF reported no differences in mortality at 30 days (7.1 % and 5.3 %, respectively) and 1 year (25.5 % and 22.2 %, respectively). Similarly, for HFrEF and HFpEF there were no differences between HF readmissions at 30 days (4.9 % and 4.5 %, respectively) and at 1-year (16.1 % and 13.5 %, respectively).51

150

100

0 1986

1990

1994

1998

2002

Year The solid lines represent the regression lines for the relation between the year of admission and the percentage of patients with HF. The dashed lines indicate 95 % confidence intervals. Source: Owan et al., 2006.27 Reproduced with permission, Copyright © 2006, Massachusetts Medical Society.

EuroHeart Failure Survey II, which enrolled 3,580 patients hospitalised for HF, overall in-hospital mortality was 6.4 %.52,53 Recently, in the European Society of Cardiology Heart Failure Long-Term (ESC-HF-LT) registry that enrolled 12,440 patients with acute and chronic HF from 21 European and/or Mediterranean countries, the 1-year mortality rate was estimated to be 23.6 % for acute HF and 6.4 for chronic HF; whereas the rates for the combined endpoint of mortality or HF hospitalisation within 1 year were 36 % for acute HF and 14.5 % for chronic HF. Mortality rates ranged across the different regions from 21.6 % to 36.5 % for acute HF and from 6.9 % to 15.6 % for chronic HF.54 Fewer studies have evaluated outcomes in other world regions. Thirtyday mortality reported in China was 5.3 %, while it was 3.9 % in Taiwan.55 In Singapore, in a cohort of 15,774 HF patients followed from 1991 to

Epidemiology 1998, total mortality was 2.5 %.56 In a more recent study with 2-year follow-up, however, there was a trend towards a higher mortality among Malays compared with Indians or Chinese (27.0 % versus 14.3 % versus 18.6 %, respectively) living in Singapore.57 In Korea an analysis of 1,527 patients with HFrEF showed 3.8 % mortality at 60 days and 9.2 % at 1 year, whereas hospitalisation rates were 3.1 % at 60 days and 9.8 % at 1 year.58 In Japan, an analysis from the Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD) reported an 8.9 % 1-year mortality rate in HFrEF versus 11.6 % in HFpEF, with higher in-hospital mortality in HFpEF (6.5 %) versus HFrEF (3.9 %).59 Similar 1-year mortality (17 %) was found in the Acute Decompensated Heart Failure Syndromes (ATTEND) registry, which enrolled 4,842 Japanese patients hospitalised for HF.60 Rates were lower (4.2 %), however, in the more recent Chronic Heart failure Analysis and Registry in Tohoku district (CHART)-2 study.11,16 In Australia mortality of 20.5–20.7 % at 1 year has been reported in HF patients,61 with a trend towards reduction over time.62 In South America, reported hospital readmission rates were 33 %, 28 %, 31 % and 35 % at follow up of 3, 6, 12 and 24–60 months, respectively; whereas the 1-year mortality was 24.5 % and the in-hospital mortality was 11.7 %, with rates being higher in patients with HFrEF.19

selective.64 A report from the nationwide and generalisable Swedish Heart Failure Registry suggests poor treatment utilisation, particularly of mineralocorticoid receptor antagonists and device therapy.65 Quality of life in HF is worse than in many other chronic diseases.66 Indeed, a national registry in Sweden has reported that 66,318 and 59,535 premature life-years are lost due to HF compared to 55,364 and 64,533 due to cancer in men and women, respectively.67 In the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) trial, health-related quality of life was similarly impaired in patients with HFpEF and HFrEF (41.1 versus 40.8) and independent factors were associated with worse health-related quality of life in both populations (female gender, younger age, higher body mass index, lower systolic blood pressure, greater symptom burden and worse functional status).68

Limitation The current review reports data from studies with different designs and settings, thus the prevalence, incidence and outcome rates might not be fully comparable.

Conclusion Since many episodes of worsening of HF are treated by modifying oral therapy or by temporary intravenous treatments in community departments without hospital admission, ambulatory care has a role in HF management. The Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial recently showed that episodes of outpatient treatment-intensification could significantly contribute to accrue a target number of endpoints in an event-driven trial.63 According the most recent US reports, in 2011 there were 553,000 emergency department visits and 257,000 outpatient department visits for HF; whereas in 2012 there were 1,774,000 physician office visits with a primary diagnosis of HF.5 No similar estimates are available in Europe, but the quality of outpatient care has been evaluated by the ESC-HF-LT registry, which reported only 3.2–5.4 % non-adherence to guidelinesuggested drugs, although enrolment in this registry was highly

1. 2.

Coronel R, de Groot JR, van Lieshout JJ. Defining heart failure. Cardiovasc Res 2001;50:419–22. PMID: 11376615 Tan LB, Williams SG, Tan DK, et al. So many definitions of heart failure: are they all universally valid? A critical appraisal. Expert Rev Cardiovasc Ther 2010;8:217–28. DOI: 10.1586/erc.09.187; PMID: 20136608 Ponikowski P, Voors AA, Anker SD, et al; Authors/Task Force Members. 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. DOI: 10.1093/ eurheartj/ehw128; PMID: 27206819 Ponikowski P, Anker SD, AlHabib KF, et al. Heart failure: preventing disease and death worldwide. ESC Heart Failure 2014;1:4–25. DOI: 10.1002/ehf2.12005 Mozaffarian D, Benjamin EJ, Go AS, et al; American Heart Association Statistics Committee; Stroke Statistics Subcommittee. Heart Disease and Stroke Statistics-2016 Update: A report from the American Heart Association. Circulation 2016;133:e38–e360. DOI: 10.1161/ CIR.0000000000000350; PMID: 26673558 Ceia F, Fonseca C, Mota T, et al; EPICA Investigators. Prevalence of chronic heart failure in Southwestern Europe: the EPICA study. Eur J Heart Fail 2002;4:531–9. PMID: 12167394 Gomez-Soto FM, Andrey JL, Garcia-Egido AA, et al. Incidence and mortality of heart failure: a community-based study. Int J Cardiol 2011;151:40–5. DOI: 10.1016/j.ijcard.2010.04.055; PMID: 20471122 Ohlmeier C, Mikolajczyk R, Frick J, et al. Incidence, prevalence and 1-year all-cause mortality of heart failure in Germany: a study based on electronic healthcare data of more than six million persons. Clin Res Cardiol 2015;104:688–96. DOI: 10.1007/ s00392-015-0841-4; PMID: 25777937

10.

11. 12.

13.

14. 15.

16.

17.

18. 19.

Dataindicate that HF is a major and growing public health problem worldwide. Even though the incidence of HF is stable, the prevalence is going to rise because of the ageing population and improvements in treatment. This will cause further increases in hospitalisation rates and, consequently, in health care costs. HF is a common disease not only in Europe and the US, but worldwide. The switch toward a Western lifestyle in developing countries may be contributing to a real HF pandemic. Phenotyping of HFpEF and HFmrEF, testing existing drugs and developing novel interventions for these categories represents an important future challenge. Currently HFpEF and HFmrEF are poorly investigated, particularly in developing countries, and there are no effective therapies. In order to reduce the number of hospitalisations and related costs, appropriate treatments are needed and further epidemiological studies are required to better characterise the HF population and improve trial design. n

Z arrinkoub R, Wettermark B, Wandell P, et al. The epidemiology of heart failure, based on data for 2.1 million inhabitants in Sweden. Eur J Heart Fail 2013;15:995–1002. DOI: 10.1093/eurjhf/hft064; PMID: 23645498 Buja A, Solinas G, Visca M, et al. Prevalence of heart failure and adherence to process indicators: which sociodemographic determinants are involved? Int J Environ Res Public Health 2016;13:238. DOI: 10.3390/ijerph13020238; PMID: 26907316 Sakata Y, Shimokawa H. Epidemiology of heart failure in Asia. Circ J 2013;77:2209–17. PMID: 23955345 Hu SS, Kong LZ, Gao RL, et al. Outline of the report on cardiovascular disease in China, 2010. Biomed Environ Sci 2012;25:251–6. DOI: 10.3967/0895-3988.2012.03.001; PMID: 22840574 Yang YN, Ma YT, Liu F, et al. [Incidence and distributing feature of chronic heart failure in adult population of Xinjiang]. Zhonghua Xin Xue Guan Bing Za Zhi 2010;38:460–4. PMID: 20654109 Okamoto H, Kitabatake A. [The epidemiology of heart failure in Japan]. Nihon Rinsho 2003;61:709–14. PMID: 12754992 Okura Y, Ramadan MM, Ohno Y, et al. Impending epidemic: future projection of heart failure in Japan to the year 2055. Circ J 2008;72:489–91. PMID: 18296852 Konishi M, Ishida J, Springer J, et al. Heart failure epidemiology and novel treatments in Japan: facts and numbers. ESC Heart Failure 2016;3:145–51. DOI: 10.1002/ehf2.12103; Huffman MD, Prabhakaran D. Heart failure: epidemiology and prevention in India. Natl Med J India 2010;23:283–8. PMID: 21250584 Lam CSP. Heart failure in Southeast Asia: facts and numbers. ESC Heart Failure 2015;2:46–9. DOI: 10.1002/ehf2.12036 Ciapponi A, Alcaraz A, Calderon M, et al. Burden of heart failure in Latin America: a systematic review and metaanalysis. Rev Esp Cardiol (Engl Ed) 2016;69:1051–60. DOI: 10.1016/j.rec.2016.04.054; PMID: 27553287

20. S ahle BW, Owen AJ, Mutowo MP, et al. Prevalence of heart failure in Australia: a systematic review. BMC Cardiovasc Disord 2016;16:32. DOI: 10.1186/s12872-016-0208-4; PMID: 26852410 21. Makubi A, Hage C, Lwakatare J, et al. Contemporary aetiology, clinical characteristics and prognosis of adults with heart failure observed in a tertiary hospital in Tanzania: the prospective Tanzania Heart Failure (TaHeF) study. Heart 2014;100:1235–41. DOI: 10.1136/heartjnl-2014-305599; PMID: 24743164 22. Ntusi NB, Mayosi BM. Epidemiology of heart failure in subSaharan Africa. Expert Rev Cardiovasc Ther 2009;7:169–80. DOI: 10.1586/14779072.7.2.169; PMID: 19210213 23. Lenzen MJ, Scholte op Reimer WJ, Boersma E, et al. Differences between patients with a preserved and a depressed left ventricular function: a report from the EuroHeart Failure Survey. Eur Heart J 2004;25:1214–20. DOI: 10.1016/j.ehj.2004.06.006; PMID: 15246639 24. Bursi F, Weston SA, Redfield MM, et al. Systolic and diastolic heart failure in the community. JAMA 2006;296:2209–16. DOI: 10.1001/jama.296.18.2209; PMID: 17090767 25. Goyal P, Almarzooq ZI, Horn EM, et al. Characteristics of hospitalizations for heart failure with preserved ejection fraction. Am J Med 2016;129:635 e15–26. DOI: 10.1016/ j.amjmed.2016.02.007; PMID: 27215991 26. Lee DS, Gona P, Vasan RS, et al. Relation of disease pathogenesis and risk factors to heart failure with preserved or reduced ejection fraction: insights from the Framingham Heart Study of the National Heart, Lung, and Blood Institute. Circulation 2009;119:3070–7. DOI: 10.1161/ CIRCULATIONAHA.108.815944; PMID:19506115 27. Owan TE, Hodge DO, Herges RM, et al. Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med 2006;355:251–9. DOI: 10.1056/NEJMoa052256; PMID: 16855265 28. Levy D, Kenchaiah S, Larson MG, et al. Long-term trends in

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j.ijcard.2015.11.183; PMID: 26657608 42. S liwa K, Damasceno A, Mayosi BM. Epidemiology and etiology of cardiomyopathy in Africa. Circulation 2005;112:3577–83. DOI: 10.1161/CIRCULATIONAHA.105.542894; PMID: 16330699 43. Sliwa K, Wilkinson D, Hansen C, et al. Spectrum of heart disease and risk factors in a black urban population in South Africa (the Heart of Soweto Study): a cohort study. Lancet 2008;371:915–22. DOI: 10.1016/S0140-6736(08)60417-1; PMID: 18342686 44. Harikrishnan S, Sanjay G, Anees T, et al; Trivandrum Heart Failure Registry. Clinical presentation, management, in-hospital and 90-day outcomes of heart failure patients in Trivandrum, Kerala, India: the Trivandrum Heart Failure Registry. Eur J Heart Fail 2015;17:794–800. DOI: 10.1002/ejhf.283; PMID: 26011246 45. Sulaiman K, Panduranga P, Al-Zakwani I, et al. Clinical characteristics, management, and outcomes of acute heart failure patients: observations from the Gulf acute heart failure registry (Gulf CARE). Eur J Heart Fail 2015;17:374–84. DOI: 10.1002/ejhf.245; PMID: 25739882 46. Bocchi EA. Heart failure in South America. Curr Cardiol Rev 2013;9:147–56. PMID: 23597301 47. Bocchi EA, Guimaraes G, Tarasoutshi F, et al. Cardiomyopathy, adult valve disease and heart failure in South America. Heart 2009;95:181–9. DOI: 10.1136/hrt.2008.151225; PMID: 18977804 48. Clark RA, McLennan S, Dawson A, et al. Uncovering a hidden epidemic: a study of the current burden of heart failure in Australia. Heart Lung Circ 2004;13:266–73. DOI: 10.1016/ j.hlc.2004.06.007; PMID: 16352206 49. Cheng RK, Cox M, Neely ML, et al. Outcomes in patients with heart failure with preserved, borderline, and reduced ejection fraction in the Medicare population. Am Heart J 2014;168: 721–30. DOI: 10.1016/j.ahj.2014.07.008; PMID: 25440801 50. Gheorghiade M, Filippatos G, De Luca L, et al. Congestion in acute heart failure syndromes: an essential target of evaluation and treatment. Am J Med 2006;119:S3–S10. DOI: 10.1016/j.amjmed.2006.09.011; PMID: 17113398 51. Bhatia RS, Tu JV, Lee DS, et al. Outcome of heart failure with preserved ejection fraction in a population-based study. N Engl J Med 2006;355:260–9. DOI: 10.1056/NEJMoa051530; PMID: 16855266 52. Nieminen MS, Brutsaert D, Dickstein K, et al; EuroHeart Survey Investigators; Heart Failure Association; European Society of Cardiology. EuroHeart Failure Survey II (EHFS II): a survey on hospitalized acute heart failure patients: description of population. Eur Heart J 2006;27:2725–36. DOI: 10.1093/ eurheartj/ehl193; PMID: 17000631 53. Lund LH, Benson L, Dahlström U, et al. Association between use of beta-blockers and outcomes in patients with heart failure and preserved ejection fraction. JAMA 2014;312: 2008–18. DOI: 10.1001/jama.2014.15241; PMID: 25399276 54. Crespo-Leiro MG, Anker SD, Maggioni AP, et al; Heart Failure Association (HFA) of the European Society of Cardiology (ESC). European Society of Cardiology Heart Failure LongTerm Registry (ESC-HF-LT): 1-year follow-up outcomes and differences across regions. Eur J Heart Fail 2016;18:613–25. DOI: 10.1002/ejhf.566; PMID: 27324686 55. Guo Y, Lip GY, Banerjee A. Heart failure in East Asia. Curr Cardiol Rev. 2013 May;9(2):112–22. 56. Ng TP, Niti M. Trends and ethnic differences in hospital admissions and mortality for congestive heart failure in the elderly in Singapore, 1991 to 1998. Heart 2003;89:865–70. PMID: 12860859 57. Lee R, Chan SP, Chan YH, et al. Impact of race on morbidity and mortality in patients with congestive heart failure: a study of the multiracial population in Singapore. Int J Cardiol 2009;134:

422–5. DOI: 10.1016/j.ijcard.2007.12.107; PMID: 18372060 58. Y oun YJ, Yoo BS, Lee JW, et al. Treatment performance measures affect clinical outcomes in patients with acute systolic heart failure: report from the Korean Heart Failure Registry. Circ J 2012;76:1151–8. PMID: 22343195 59. Tsuchihashi-Makaya M, Hamaguchi S, Kinugawa S, et al; JCARE-CARD Investigators. Characteristics and outcomes of hospitalized patients with heart failure and reduced vs preserved ejection fraction. Report from the Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD). Circ J 2009;73:1893–900. PMID: 19644216 60. Kajimoto K, Sato N, Takano T; Investigators of the Acute Decompensated Heart Failure Syndromes (ATTEND) Registry. Association of age and baseline systolic blood pressure with outcomes in patients hospitalized for acute heart failure syndromes. Int J Cardiol 2015;191:100–6. DOI: 10.1016/ j.ijcard.2015.04.258; PMID: 25965613 61. Teng TH, Katzenellenbogen JM, Hung J, et al. Rural-urban differentials in 30-day and 1-year mortality following first-ever heart failure hospitalisation in Western Australia: a populationbased study using data linkage. BMJ Open 2014;4:e004724. DOI: 10.1136/bmjopen-2013-004724; PMID: 24793254 62. McLean AS, Eslick GD, Coats AJ. The epidemiology of heart failure in Australia. Int J Cardiol 2007;118:370–4. DOI: 10.1016/ j.ijcard.2006.07.050; PMID: 17046084 63. Okumura N, Jhund PS, Gong J, et al; PARADIGM-HF Investigators and Committees. 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. DOI: 10.1161/CIRCULATIONAHA.115.020729; PMID: 27143684 64. Maggioni AP, Anker SD, Dahlstrom U, et al; Heart Failure Association of the ESC. Are hospitalized or ambulatory patients with heart failure treated in accordance with European Society of Cardiology guidelines? Evidence from 12,440 patients of the ESC Heart Failure Long-Term Registry. Eur J Heart Fail 2013;15:1173–84. DOI: 10.1093/eurjhf/hft134; PMID: 23978433 65. 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. DOI: 10.1002/ejhf.496; PMID: 26869252 66. Hobbs FD, Kenkre JE, Roalfe AK, et al. Impact of heart failure and left ventricular systolic dysfunction on quality of life: a cross-sectional study comparing common chronic cardiac and medical disorders and a representative adult population. Eur Heart J 2002;23:1867–76. PMID: 12445536 67. Stewart S, Ekman I, Ekman T, et al. Population impact of heart failure and the most common forms of cancer: a study of 1 162 309 hospital cases in Sweden (1988 to 2004). Circ Cardiovasc Qual Outcomes 2010;3:573–80. DOI: 10.1161/ CIRCOUTCOMES.110.957571; PMID: 20923990 68. Lewis EF, Lamas GA, O’Meara E, et al; CHARM Investigators. Characterization of health-related quality of life in heart failure patients with preserved versus low ejection fraction in CHARM. Eur J Heart Fail 2007;9:83–91. DOI: 10.1016/j. ejheart.2006.10.012; PMID: 17188020 69. Lam CS, Donal E, Kraigher-Krainer E, et al. Epidemiology and clinical course of heart failure with preserved ejection fraction. Eur J Heart Fail 2011;13:18–28. DOI: 10.1093/eurjhf/ hfq121; PMID: 20685685 70. Borlaug BA, Redfield MM. Diastolic and systolic heart failure are distinct phenotypes within the heart failure spectrum. Circulation 2011;123:2006–13. DOI: 10.1161/ CIRCULATIONAHA.110.954388; PMID: 21555723

Pathophysiology

Ventricular–Arterial Coupling in Chronic Heart Failure Julio A Chirinos 1 and Nancy Sweitzer 2 1. University of Pennsylvania Perelman School of Medicine and Hospital of the University of Pennsylvania, Philadelphia, PA, USA; 2. Tucson and Arizona Sarver Heart Center, University of Arizona College of Medicine, Tucson, AZ, USA

Abstract Measures of interaction between the left ventricle (LV) and arterial system (ventricular–arterial coupling) are important but underrecognised cardiovascular phenotypes in heart failure. Ventriculo-arterial coupling is commonly assessed in the pressure–volume plane, using the ratio of effective arterial elastance (EA) to LV end-systolic elastance (EES) to provide information on ventricular–arterial system mechanical efficiency and performance when LV ejection fraction is abnormal. These analyses have significant limitations, such as neglecting systolic loading sequence, and are less informative in heart failure with preserved ejection fraction (HFpEF). EA is almost entirely dependent on vascular resistance and heart rate. Assessment of pulsatile arterial haemodynamics and time-resolved myocardial wall stress provide critical incremental physiological information and should be more widely utilised. Pulsatile arterial load represents a promising therapeutic target in HFpEF. Here, we review various approaches to assess ventricular–arterial interactions, and their pathophysiological and clinical implications in heart failure.

Keywords Ventricular–arterial coupling, heart failure, heart failure with preserved ejection fraction, arterial haemodynamics, wave reflections, afterload, pulsatile load Disclosure: JAC has received consulting honoraria from Bristol-Myers Squibb, OPKO Healthcare, Fukuda Denshi, Microsoft, Vital Labs and Merck. He has received research grants from the National Institutes of Health, American College of Radiology Network, American Heart Association, Fukuda Denshi, Bristol-Myers Squibb, Microsoft and CVRx Inc., and device loans from AtCor Medical. He is named as inventor in a University of Pennsylvania patent application for the use of inorganic nitrates/nitrites for the treatment of heart failure and preserved ejection fraction. NKS has research grants from the National Institutes of Health, American Heart Association, Novartis, Merck and Corvia Medical. This work was supported by NIH grants R01 HL 121510-01A1 (J.A.C) and R56HL-124073-01A1 (J.A.C). Received: 12 February 2017 Accepted: 29 March 2017 Citation: Cardiac Failure Review 2017;3(1):12–8. DOI: 10.15420/cfr.2017:4:2 Correspondence: Julio A Chirinos, South Tower, Room 11-138, Perelman Center for Advanced Medicine, 3400 Civic Center Boulevard, Philadelphia, PA 19104, USA; E: Julio.chirinos@uphs.upenn.edu

Detailed phenotyping of ventricular–arterial coupling (VAC) and systemic arterial haemodynamics provide important insights into the pathophysiology of left ventricular (LV) energetics, remodelling and fibrosis, and systolic and diastolic dysfunction in various disease states including heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF).1 Interactions between the left ventricle, the proximal aorta and the systemic arterial tree encompass a broad and complex set of haemodynamic phenomena. VAC, defined narrowly to encompass the determinants of stroke volume and the energetic coupling of the left ventricle and arterial system, has most frequently been assessed in the pressure–volume plane. This approach provides useful information regarding the mechanical efficiency and performance of the ventricular–arterial system when the LV ejection fraction (LVEF) is frankly abnormal. Analyses in the pressure–volume plane have significant limitations, however, and are less informative in HFpEF. More importantly, analyses in the pressure–volume plane do not characterise broader aspects of ventricular–arterial cross talk, which are clinically relevant among patients at risk for heart failure and for patients with established HFrEF or HFpEF. Assessment of arterial load and VAC via analysis of pressure–flow relations and time-resolved myocardial wall stress provide important incremental physiological information about the cardiovascular system. In particular the systolic loading sequence (early versus late systolic load), an important aspect

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of VAC, is neglected by pressure–volume analyses, and can profoundly impact LV function, remodelling and progression to heart failure. This review provides a critical analysis and details of a number of approaches used to assess ventricular–arterial interactions and coupling, with a focus on underlying physiological principles and the interpretation of various indices obtained using non-invasive methods.

The pressure–volume plane Physiological considerations As formulated by Suga and Sagawa several decades ago,2–5 when a ‘family’ of LV pressure–volume loops are obtained from the same subject during acute preload or afterload alterations at a constant inotropic state, the left upper loop corners (end-systolic pressure– volume points) describe the end-systolic pressure–volume relation (ESPVR). The LV end-systolic elastance (EES) is the slope of the ESPVR (Figure 1), which is generally considered to be linear within physiological ranges. In this paradigm, V0 is the volume–axis intercept of the linearly projected ESPVR. V0 represents a purely theoretical LV volume at zero intracavitary pressure, under the assumption of a linear ESPVR. This is, in reality, a false assumption because the ESPVR is markedly non-linear at lower and higher ranges of end-systolic pressure. V0, therefore, can be negative (a physical impossibility) when the ESPVR is projected linearly toward the volume–axis intercept.

Ventriculo-arterial Coupling

For a given beat, the pressure–volume area (PVA) is the area circumscribed by: the end-diastolic pressure–volume relation curve; the end-systolic pressure–volume relation line; and the systolic portion of the pressure–volume loop trajectory (Figure 1).3,10 The PVA in an ejecting contraction that can be divided into two parts: the area within the pressure–volume loop trajectory, which equals LV stroke work (or external work; blue area in Figure 1); and the approximately triangular area enclosed by the end-systolic pressure–volume relation, the left border of a single pressure–volume loop and the end-diastolic pressure–volume relation (grey area in Figure 1), which has been proposed to represent the end-systolic elastic potential energy built up and stored in the left ventricle wall during systole. However, as mentioned above, the left-hand side of this area, corresponding to a linear ESPVR down to its volume axis intercept, is not realistic and substantially differs from the non-linear ESPRV measured at lower pressure ranges. According to the time-varying elastance paradigm, the PVA represents the total mechanical energy generated by LV contraction until the end of systole. In a single heart operating at a stable contractile state under various preload and afterload conditions, the PVA correlates strongly with myocardial oxygen consumption (MVO2) per beat. Therefore, when studying a single heart operating at a stable contractile state and heart rate, changes in the ratio of stroke work to PVA (which strictly in this context is a good surrogate of MVO2 per beat) are representative of changes in the mechanical efficiency of that heart. Unfortunately, both the slope and the MVO2 axis intercept of the PVA–MVO2 relation vary greatly between individuals.3,10–12 Given the widely varying function that relates MVO2 to the PVA, the ratio of stroke work to PVA is much less informative when comparing the underlying mechanical efficiency between individuals or disease populations. Great caution should therefore be undertaken when interpreting studies in which analyses derived from the pressure–volume plane are used for this purpose. Given the usefulness of the pressure–volume plane to assess LV function and energetics, an extension of this approach to assess arterial load and VAC was subsequently developed, primarily to study the determinants of stroke volume.13–15 In this paradigm, arterial load is quantified as an ‘effective arterial elastance’, which is defined as the ratio of end-systolic pressure to stroke volume. When arterial load is defined is this manner, the arterial elastance (EA)/EES ratio can be computed as an index of VAC. Due to simple geometric principles, the EA/EES ratio correlates well with the degree to which stroke work and potential energy contribute to the PVA (which, in turn, correlates strongly with the operating mechanical efficiency of a given heart operating at a given heart rate and contractile state). Importantly, the EA/EES ratio is intimately related to ejection fraction (EF=1/[1+EA/EES]); consequently, markedly inefficient ratios are closely associated with

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Figure 1: Analysis of Ventricular–Arterial Coupling in the Pressure–Volume Plane 100

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E ES is an index of the contractility and systolic stiffness of the left ventricle. As such, it is affected by the inotropic state of the myocardium and, in the long-term, by geometric remodelling and biophysical myocyte and interstitial properties. 6,7 Although E ES is ideally assessed invasively using data from a family of pressure– volume loops obtained during an acute preload or afterload alterations, ‘single-beat’ methods have also been developed 8,9 that allow for non-invasive E ES estimations using simple echocardiographic measurements. Single-beat methods have undergone limited validation, but are nevertheless broadly used in epidemiological and clinical research due to their ease of use.

PVA

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Volume, mL A pressure–volume loop is shown, along with the end-systolic pressure–volume relation (black dashed line). The blue area represents stroke work (SW); the grey area represents potential energy (PE). EES is the slope of the end-systolic pressure–volume relation. EA (orange dashed line) is plotted on top of the pressure–volume loop. V0 is the volume–axis intercept of the end-systolic pressure–volume relation. The pressure–volume area (PVA) is the sum of potential energy and stroke (i.e. external) work. The PVA represents the total mechanical energy generated by left ventricle contraction until the end of systole.

the presence of important reductions in LVEF. Abnormal EA/EES has been shown to denote poor operating energetic and mechanical efficiency of the left ventricle, particularly when the LVEF is frankly reduced.1,12–17 This approach is less useful when we want to compare energetic VAC between individuals or to characterise the operating energetic efficiency of the system when the ejection fraction is preserved.

The Pressure–Volume Plane in HFrEF and HFpEF A reduction of LV chamber pump function (with a reduction of EES), with or without increases in effective EA, results in a high EA/EES ratio, which is accompanied by an increased proportion of the PVA corresponding to potential energy (grey area in Figure 1) rather than external work (blue area in Figure 1), denoting an unfavourable energetic efficiency state. This situation is associated with a reduction in ejection fraction, given the intimate relationship between the EA/EES ratio and ejection fraction. When EES is primarily reduced, therapeutic reductions in EA have the potential to improve the EA/EES ratio (and thus the mechanical efficiency of a given LV–arterial system), but this approach is limited by the minimum mean arterial pressure required for the perfusion of peripheral organs. In hearts with markedly decreased EES, an optimal mechanical efficiency is only achievable at lower mean (and endsystolic) pressures than those required to maintain adequate systemic circulation; operating efficiency is thus substantially decreased relative to the maximally attainable efficiency in order to maintain systemic perfusion. This pathophysiology is characteristic of patients with heart failure with severely reduced LVEF. Interestingly, it has been shown experimentally that both stroke work and efficiency operate at ≥90 % of their optimal values over a broad range of EA/EES ratios (0.3–1.3),17 which corresponds to a wide range of ejection fractions (~40–80 %). Therefore, precise optimisation of the stroke work of the PVA or stroke work relation appears to be of little consequence for energetics in the absence of severe abnormalities in EES/EA (or pronounced reductions in LVEF).17 In severely abnormal coupling states, however, this homeostasis may be lost. For example, in patients with heart failure with severely reduced LVEF these ratios may rise to as high as 4.0 due to the relative

Pathophysiology Figure 2: Example of Measurements of Central Pressure and Flow Data

Pressure [mmHg]

load and broader aspects of ventricular–arterial interactions. With each heart beat the left ventricle ejects blood against the hydraulic load imposed by the systemic arterial tree. Given the pulsatile nature of the left ventricle as a pump, arterial load varies over time, is complex and cannot be expressed as a single number.12,22 The EA/EES ratio does not account for time-varying phenomena during ejection,12 thus intrinsically neglecting the LV loading sequence (late versus early systolic load), an important determinant of maladaptive remodelling, hypertrophy, diastolic dysfunction and heart failure risk.22,24–29

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decline in ventricular contractile function (lower EES) and often the accompanying high EA. This is clearly suboptimal from the standpoint of ventricular performance and energetic efficiency. A small study of patients with HFpEF suggested increases in both EA and EES beyond those associated with ageing and/or hypertension.18 However, subsequent studies with larger sample sizes demonstrated that EA and EES were similarly increased in hypertensive controls and HFpEF patients.19,20 Furthermore, patients with HFpEF demonstrate normal energetic ‘coupling’ of the LV (EES) and the arterial load (EA), as assessed in the pressure–volume plane, suggesting that this approach fails to capture key features of the abnormal ventricular–arterial crosstalk in this condition. However, as previously described in great detail,1 pressure–volume analyses can help us understand some aspects of the pathophysiology of HFpEF, including the limited stroke volume reserve, increased blood pressure lability and pre-load sensitivity in this population.1,12,21,22 In particular, subjects with HFpEF have been shown to exhibit a reduced contractile and vasodilatory reserve during exercise, which reduces the “coupling” reserve, as manifested by a less pronounced reduction in the Ea/Ees ratio and a less pronounced increase in EF and cardiac index during exercise.23

Limitations of the Pressure–Volume Plane Despite its popularity, the pressure–volume plane has important limitations for the comprehensive characterisation of pulsatile arterial

Importantly, the commonly made assumption that EA is a lumped parameter of resistive and pulsatile arterial load is incorrect.12,30–32 EA is not a true elastance (i.e. the inverse of a compliance) and is almost entirely dependent on vascular resistance (a microvascular, rather than a conduit artery, property) and heart rate.31,33 EA has been shown to be minimally sensitive to (and in some cases to vary inversely with) parameters of pulsatile arterial load.12,30–32 The poor performance of EA in capturing pulsatile arterial load is readily explained by the many simplifying assumptions made during its derivation,12,31,32 which are untenable in the presence of prominent wave reflections.22,34

The analysis of time-varying pressure and flow represents a powerful approach for the assessment of ventricular–arterial interactions that overcomes the limitations of the pressure–volume plane. Noninvasive assessment of pressure–flow relations can be accomplished in humans using carotid or radial arterial tonometry35 to measure pressure in conjunction with either Doppler echocardiography or phase-contrast magnetic resonance imaging to measure flow. The central pressure–flow relationship can be studied in detail and allows for a comprehensive assessment of LV afterload and VAC. 22,36,37 An example of non-invasively obtained central pressure and flow waveforms obtained using carotid arterial tonometry is given in Figure 2A and an example using Doppler echocardiography in Figure 2A. An example of how a pressure–flow pair can be used to assess arterial load and various parameters of VAC in the frequency domain is shown in Figure 3A and how to quantify the effects of wave reflection on the central pressure–flow relation is given in Figure 3B and C.

The Early Systolic Pressure–Flow Relation In the arterial tree of older adults, a nearly reflectionless state occurs only in very early systole, before the arrival of the bulk of backwardtravelling waves. The slope of the pressure–flow relation during this period is governed by proximal aortic characteristic impedance (Zc). Zc is a local (aortic root) property dependent on the size and stiffness of the aortic root, and is proportional to the product of aortic root crosssectional area and pulse wave velocity. The slope of the pressure–flow relation in early systole closely approximates Zc and can be estimated as the ratio of pressure increase versus flow increase in early systole. Given that wave reflections cancel at high frequencies, aortic Zc can also be measured as the average modulus of input impedance in the frequency domain (dashed line in Figure 3A).

Effects of Wave Reflections The antegrade pulse wave generated by LV contraction travels in the arteries and is partially reflected at sites of impedance mismatch, such as points of branching, change in wall diameter or change in material properties along the arterial tree. Innumerable reflections merge as they travel back to the left ventricle, where a discrete reflected wave can be observed.22,36,37 The time of arrival of the reflected wave in the

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Ventriculo-arterial Coupling

Net pressure and flow measured at the aortic root result from the sum of the forward wave, which affects pressure and flow in the same direction, and the backward-travelling wave, which has opposing effects on pressure and flow. Since the backward wave increases pressure relative to flow, its effects are readily apparent from visual inspection of the pressure–flow pair, when pressure and flow are scaled according to the aortic root Zc (Figure 2, bottom panel). Alternatively, the product of flow and aortic Zc (QZc) can be computed and displayed in units of pressure to demonstrate the effects of wave reflections (green area, Figure 3C). When wave reflections are absent in systole, measured systolic pressure equals the QZc product; whereas in the presence of wave reflections, systolic measured pressure is greater than the QZc product (red area, Figure 3C). We hereby refer to the difference between measured pressure and the QZc product as ‘wasted LV effort’, which is analogous to the concept originally proposed using pressure-only approaches.42,43 As will be further discussed below, this difference is proportional to the net effects of wave reflection on the systolic pressure profile (being equal to twice the systolic portion of the backward pressure wave; Figure 3B and C).

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Such early wave reflections are a feature of middle and older age in humans. In young adults, wave reflections return to the left ventricle predominantly in diastole, thus augmenting coronary blood flow, with minimal adverse impact on LV systolic workload. It is worth noting that early wave reflections tend to sustain systolic pressure in mid-to-late systole, which may occur with or without pronounced increases in peak systolic pressure. Central systolic pressure, pulse pressure and pressure augmentation, although influenced by wave reflections, are therefore not adequate measurements of the magnitude of wave reflections or their effects on LV workload. Furthermore, aortic pressure augmentation is confounded by multiple factors, including the LV contractility, temporal pattern of LV contraction and preload.41 Wave reflections and their physiological effects are best assessed via analyses of pressure–flow relations.

Figure 3: Assessment of Arterial Load and Ventricular– Arterial Interactions with Pressure–Flow Relations

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proximal aorta depends on the location of reflection sites and on the pulse wave velocity of conduit vessels, particularly the aorta, which transmits both forward- and backward-travelling waves from and towards the left ventricle, respectively.22,38,39 Stiffer aortas (with greater pulse wave velocity) conduct the forward- and backward-travelling waves at greater velocities and therefore promote shorter reflected wave transit times (i.e. earlier arrival of wave reflections to the left ventricle).22,40 In older adults, wave reflections travel quickly, arriving back in the proximal aorta while the ventricle is still ejecting blood in systole. This early arrival of wave reflections increases the mid-to-late systolic workload of the left ventricle and profoundly impacts the LV loading sequence (late relative to early systolic load).

Wasted LV effort

An important but commonly unrecognised fact is that the heart itself is also a reflector.44,45 Backward-travelling reflected waves can re-reflect at the left ventricle during systole, becoming part of the forward wave. The forward wave is therefore influenced by wave reflections, just like the backward wave is a function of the forward wave. Re-reflections are also present in diastole, because backward-travelling waves re-reflect and rectify at the aortic valve. This is why a forward wave is always present in diastole, despite the cessation of LV ejection. When stroke volume is normal, the QZc product can be interpreted clinically as an indicator of the degree of mismatch between aortic root properties (size and stiffness) and systemic flow requirements.

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Time [ms] (A) Modulus (top) and phase (bottom) of aortic input impedance. The dashed line in the modulus plot represents aortic Zc. (B) Wave separation analysis showing forward (green dashed line) and backward (red dotted line) waves. (C) Time-domain analysis of the timeintegral of the QZc product (green area, which represents the pressure generated as a result of the pulse flow interacting with the aortic root Zc) versus the additional systolic pressure related to wave reflections (represented by the red area). LV = left ventricular; QZc = product of flow and aortic characteristic impedance; Zc = aortic characteristic impedance.

Mismatch may be due to an abnormally increased Zc (which may contribute to increased pulse pressure with ageing and various

Pathophysiology Figure 4: Time-Resolved Myocardial Wall Stress of a Normal Aged Left Ventricle B

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(A) The ejection-phase aortic pressure profile. (B) The time-resolved ejection-phase myocardial wall stress (MWS). (C) The pressure–MWS relation. In all plots, the 1st, 2nd and 3rd thirds of ejection are plotted in solid blue, dotted orange, and solid black, respectively. It can be seen that MWS peaks in early systole and subsequently decreases, even in the context of increasing pressure. This is due to a mid-systolic shift in the pressure-stress relation (black arrow) that favours lower MWS for any given pressure. This shift is due to the geometric reconfiguration of the left ventricle (decreased cavity volume relative to left ventricular wall volume), and is impaired in the presence of reductions in left ventricular ejection fraction, concentric geometric remodelling and reduced early systolic ejection (reduced early-phase ejection fraction).

disease states) or increased flow requirements (i.e. thyrotoxicosis). However, an abnormal QZc product may also be a consequence of a reduced (e.g. HFrEF) or increased (e.g. aortic insufficiency) stroke volume (and pulse volume flow) in the absence of changes in systemic flow requirements or in aortic Zc. It is important to recognise that the forward pressure wave exceeds the QZc product by an amount equal to the backward wave. Forward pressure wave amplitude, therefore, cannot be interpreted purely as an index of mismatch flow needs and aortic root properties, because it also contains contributions from wave re-reflections.44

and are therefore more ‘pure’ indices of arterial load. The reader is referred to previous publications for more detailed descriptions of pressure–flow relations in the frequency domain.22,37,46 Frequencydomain analyses tend to be considered complex for intuitive clinical assessments, but remain extremely valuable for mechanistic clinical research studies.

Effect of Wave Reflections and Late Systolic LV Load on LV Remodelling, Hypertrophy and Heart Failure Risk

The difference between measured pressure and the QZc product can be interpreted as the pulsatile pressure that is not primarily required to promote pulsatile systolic flow through the aortic root Zc, but is necessary to overcome the effect of wave reflection. An analogous concept was originally proposed by Hashimoto, Nichols and O’Rourke and called ‘wasted LV effort’, using pressure-only approaches.42,43 This principle can be extended to the pressure–flow pair, as shown in Figure 3C (red area).

For any given level of systolic blood pressure, prominent latesystolic loading has been shown to exert deleterious effects on LV structure and function in animal and human studies (Figure 4).22,26,28 Late systolic load from wave reflections has been shown to induce LV hypertrophy and fibrosis in rats.26 Accordingly, a relationship between reflection magnitude and LV mass measured with cardiac magnetic resonance imaging has been reported in community-based studies,47,48 and changes in wave reflection magnitude occurring during antihypertensive therapy are associated with the regression of LV mass independently of the reduction in blood pressure.27

A popular approach to characterise wave reflections is to compute reflection magnitude as the ratio of the amplitude of the backward wave over the forward wave (Pb/Pf). This computation, however, can underestimate the effects of reflections on pressure (and LV load) because, as stated above, peripheral reflections that re-reflect at the heart become part of the forward wave, adding to the denominator rather than solely the numerator of reflection magnitude. Similarly, reflection magnitude does not contain information about the timing of the reflected wave and its net effect on aortic (and LV) pressure in systole. Furthermore, this ratio can be impacted by the time pattern of LV contraction for any given input impedance of the systemic circulation. In many instances it therefore becomes particularly important to pay attention to indices such as QZc and the difference between total pressure and QZc during systole, in addition to more detailed analyses of pressure–flow relations (and the effects of wave reflections) in the frequency domain. In particular, reflection coefficients computed in the frequency domain are entirely derived from the input impedance spectrum,

Wave reflection also plays a role in diastolic dysfunction. Canine studies have shown that for any given increase in LV pressure, late systolic LV loading induces greater impairment of LV relaxation than early systolic loading.28 In support of these experimental findings demonstrating a cause and effect relationship between late systolic load and impaired relaxation, human studies demonstrate that indices of late systolic load are independently associated with diastolic dysfunction, 23,25,49–51 left atrial remodelling 50,52,53 and longitudinal systolic dysfunction. 54 A more direct quantification of the myocardial loading sequence can be accomplished by measurements of time-resolved ejection-phase myocardial wall stress (Figure 4). Time-resolved wall stress integrates the impact of prevalent arterial load, including chronic changes in LV structure and function, and the LV contraction pattern, on the myocardial load. Wave reflections selectively increase late systolic wall stress, which is in turn associated with impaired relaxation. 29,55 Interestingly, the LV contraction pattern can modulate the influence of wave reflections on late systolic myocardial load. Normally, a marked mid-systolic

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Ventriculo-arterial Coupling

Consistent with the effects of wave reflections on LV remodelling, fibrosis and dysfunction, wave reflection magnitude (the ratio of backward to forward wave amplitude) and late systolic hypertension have been shown to strongly predict incident heart failure in the general population.56,58,59 These studies did not distinguish between incident HFpEF and HFrEF.

Wave Reflections and Pressure–Flow Relations in Established HFrEF and HFpEF

Figure 5: The Impact of Wave Reflections on Late Systolic Load

LVH/remodeling Late systolic load Wave reflections

shift in the relationship between LV pressure and myocardial wall stress (pressure–stress relation) occurs as a result of LV contraction (Figure 5). This shift effectively protects LV cardiomyocytes against excessive wall stress in late systole, a period of increased vulnerability to the ill effects of load. During late systole, several cellular processes may operate to mediate myocardial dysfunction and remodelling. Abnormalities such as reduced early-phase ejection, a lower LVEF, and concentric hypertrophy/remodelling, can impair the mid-systolic shift in the pressure–myocardial wall stress relation, making the left ventricle more susceptible to the effects of wave reflections on the myocardium. 56,57

Fibrosis Myocardial dysfunction

Wave reflections increase late systolic left ventricular load, which favours left ventricle remodelling and myocardial dysfunction. However, the effect of wave reflection on myocardial load is modulated by contraction pattern and the time course of myocardial wall stress. Left ventricles in which mid-systolic shift in the pressure–stress relation is impaired (due to a reduced ejection fraction, concentric geometric remodelling, and/or reduced early systolic ejection) fail to protect cardiomyocytes against the load induced by wave reflections in late systole, a period of vulnerability to load. This may represent a vicious cycle that favours the development and furthers progression of heart failure. LVH = left ventricular hypertrophy.

When LV pump function is preserved, the reflected wave typically induces a late systolic pressure peak in the pressure waveform, augmenting aortic pressure in mid-to-late systole.22 These features are prominent in patients with HFpEF.25,60,61 When LV pump function is reduced, however, wave reflection may exert more pronounced effects to decrease flow, with no apparent alteration in the appearance of the pressure waveform (when the latter is analysed in isolation). It is therefore important to measure both pressure and flow in order to properly measure and interpret wave reflections (particularly in patients with impaired LV systolic function). In patients with severe LV systolic dysfunction (LVEF ≤30 %), wave reflections truncate flow, reduce stroke volume and induce a shortening of ejection duration.62 In addition, the magnitude of wave reflection, which is normally reduced during exercise, may exhibit abnormalities in heart failure. Patients with HFrEF secondary to idiopathic dilated cardiomyopathy have been shown to demonstrate an impairment in the reduction in wave reflections during exercise, with a smaller reduction in wave reflections for any given reduction in systemic vascular resistance, compared to normal controls.63 This could increase myocardial work during exercise and contribute to exercise intolerance. Changes in wave reflection during exercise have not been studied in HFpEF.

Consistent with newly-described normoxic activation of nitrite in conduit arteries,67 inorganic nitrate has recently been shown to reduce wave reflections in patients with HFpEF,61 and has demonstrated promising effects on exercise capacity and quality of life in phase IIa studies in this population.61,68,69 Larger phase IIb trials are currently being performed.70 Organic nitrate, in contrast to inorganic nitrate, has been shown to exert deleterious effects in this patient population. In the Nitrate’s Effect on Activity Tolerance in Heart Failure with Preserved Ejection Fraction (NEAT-HFpEF) trial, isosorbide mononitrate caused a dose-dependent reduction in physical activity.71 In another recent trial, isosorbide dinitrate, with or without hydralazine, did not exert beneficial effects on wave reflections, LV remodelling or submaximal exercise in HFpEF and was poorly tolerated. Furthermore, combination therapy with isosorbide dinitrate and hydralazine actually increased wave reflections, reduced submaximal exercise capacity and increased the native myocardial T1, suggesting deleterious effects on myocardial remodelling.72 Effects of systemic nitrates or B-type natriuretic peptide to improve reflected waves may be countered by the effects of these compounds on preload, leading to a net reduction in stroke volume and an overall unfavourable haemodynamic response.41

Therapeutic Approaches

Conclusion

In HFrEF, nitroprusside has been shown to reduce wave reflections at rest and during exercise. 64 Interestingly, inotropic therapy with dobutamine, but not dopamine, can simultaneously increase inotropy and reduce arterial load in HFrEF. 65 In advanced HFrEF, reduced blood pressure and vasodilation by current standard pharmacological therapy may substantially reduce arterial load and wave reflections, leading to improved VAC. Interestingly, in post-transplant patients, these effects of standard heart failure therapy are eliminated over a short time period. In this setting, heart transplant recipients with antecedent ischaemic cardiomyopathy demonstrated increased markers of wave reflections compared with non-ischaemic heart transplant recipients. 66 It is unclear, however, whether this is due to differences in ‘residual’ (post-transplant) therapy (such as vasodilators for hypertension) and/or to the presence of atherosclerotic plaques in conduit arteries that may serve as sources of wave reflection.

Although the pressure–volume plane remains the gold standard to assess left ventricle chamber pump function in a load-independent manner, it has serious limitations for the assessment of pulsatile arterial load and VAC, particularly in HFpEF. Comprehensive assessment of pulsatile arterial load and ventricular–arterial interactions can be achieved with analyses of pressure–flow relations. Despite the apparent complexity of pressure–flow analyses, this approach can be implemented at the bedside and can be highly informative in clinical research and potentially in clinical practice. Wider application of methods to characterise ventricular–arterial interaction should be incorporated into the design of clinical trials. Such mechanistic heart failure studies are critical, particularly in HFpEF, and may ultimately lead to effective therapy for this condition. Eventually, assessments of individual patients may facilitate the application of tailored (personalised) therapeutic approaches in the era of precision medicine. n

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DOI: 10.1152/ ajpheart.00764.2001; PMID: 11834502 Chirinos JA, Rietzschel ER, Shiva-Kumar P, et al. Effective arterial elastance is insensitive to pulsatile arterial load. Hypertension 2014;64:1022–31. DOI: 10.1161/ HYPERTENSIONAHA.114.03696; PMID: 25069668 Chemla D, Antony I, Lecarpentier Y, et al. Contribution of systemic vascular resistance and total arterial compliance to effective arterial elastance in humans. Am J Physiol Heart Circ Physiol 2003;285:H614–20. DOI: 10.1152/ajpheart.00823.2002; PMID: 12689857 Sunagawa K, Maughan WL, Burkhoff D, et al. Left ventricular interaction with arterial load studied in isolated canine ventricle. Am J Physiol 1983;245:H773–80. PMID: 6638199 Colan SD, Borow KM, Neumann A. Use of the calibrated carotid pulse tracing for calculation of left ventricular pressure and wall stress throughout ejection. Am Heart J 1985;109:1306–10. PMID: 4003241 Chirinos JA, Segers P. Noninvasive evaluation of left ventricular afterload: part 1: pressure and flow measurements and basic principles of wave conduction and reflection. Hypertension 2010;56:555–62. DOI: 10.1161/ HYPERTENSIONAHA.110.157321; PMID: 20733089 Chirinos JA, Segers P. Noninvasive evaluation of left ventricular afterload: part 2: arterial pressure-flow and pressure-volume relations in humans. Hypertension 2010;56:563–70. DOI: 10.1161/HYPERTENSIONAHA.110.157339; PMID: 20733088 Mitchell GF. Arterial stiffness and wave reflection in hypertension: pathophysiologic and therapeutic implications. Curr Hypertens Rep 2004;6:436–41. PMID: 15527687 Mitchell GF. Clinical achievements of impedance analysis. Med Biol Eng Comput 2009;47:153–63. DOI: 10.1007/s11517-0080402-3; PMID: 18853214. Phan TS, Li JK, Segers P, et al. Aging is associated with an earlier arrival of reflected waves without a distal shift in reflection sites. J Am Heart Assoc 2016;5:e003733. DOI: 10.1161/ JAHA.116.003733; PMID: 27572821 Sweitzer NK, Hetzel SJ, Skalski J, et al. Left ventricular responses to acute changes in late systolic pressure augmentation in older adults. Am J Hypertens 2013;26:866–71. DOI: 10.1093/ajh/hpt043 Hashimoto J, Nichols WW, O’Rourke MF, et al. Association between wasted pressure effort and left ventricular hypertrophy in hypertension: influence of arterial wave reflection. Am J Hypertens 2008;21:329–33. DOI: 10.1038/ ajh.2007.49; PMID: 18202668 Westerhof BE. Wave reflection: wasted effort in left ventricular hypertrophy. Am J Hypertens 2008;21:243. DOI: 10.1038/ajh.2007.76; PMID: 18311120 Phan TS, Li JK, Segers P, et al. Misinterpretation of the determinants of elevated forward wave amplitude inflates the role of the proximal aorta. J Am Heart Assoc 2016;5:e003069. DOI: 10.1161/JAHA.115.003069; PMID: 2689647 Westerhof N, Segers P, Westerhof BE. Wave separation, wave intensity, the reservoir-wave concept, and the instantaneous wave-free ratio: presumptions and principles. Hypertension 2015;66:93–8. DOI: 10.1161/HYPERTENSIONAHA.115.05567; PMID: 26015448 Segers P, Rietzschel ER, De Buyzere ML, et al; Asklepios Investigators. Noninvasive (input) impedance, pulse wave velocity, and wave reflection in healthy middle-aged men and women. Hypertension 2007;49:1248–55. DOI: 10.1161/ HYPERTENSIONAHA.106.085480; PMID: 17404183 Zamani P, Bluemke DA, Jacobs DR, Jr., et al. Resistive and pulsatile arterial load as predictors of left ventricular mass and geometry: the multi-ethnic study of atherosclerosis. Hypertension 2015;65:85–92. DOI: 10.1161/ HYPERTENSIONAHA.114.04333; PMID: 25287396 Booysen HL, Woodiwiss AJ, Sibiya MJ, et al. Indexes of aortic pressure augmentation markedly underestimate the contribution of reflected waves toward variations in aortic pressure and left ventricular mass. Hypertension 2015;65: 540–6. DOI: 10.1161/HYPERTENSIONAHA.114.04582; PMID: 25510830 Borlaug BA, Melenovsky V, Redfield MM, et al. Impact of arterial load and loading sequence on left ventricular tissue velocities in humans. J Am Coll Cardiol 2007;50:1570–7. DOI: 10.1016/j.jacc.2007.07.032; PMID: 17936156 Peterson VR, Woodiwiss AJ, Libhaber CD, et al. Cardiac diastolic dysfunction is associated with aortic wave reflection, but not stiffness in a predominantly young-to-middle-aged

community sample. Am J Hypertens 2016;29:1148–57. DOI: 10.1093/ajh/hpw052; PMID: 27209442 51. G oto T, Ohte N, Fukuta H, et al. Relationship between effective arterial elastance, total vascular resistance, and augmentation index at the ascending aorta and left ventricular diastolic function in older women. Circ J 2013;77:123–9. PMID: 23037325 52. Jaroch J, Rzyczkowska B, Bociaga Z, et al. Arterial-atrial coupling in untreated hypertension. Blood Press 2015;24:72–8. DOI: 10.3109/08037051.2014.986929; PMID: 25545339 53. Jaroch J, Rzyczkowska B, Bocia˛ ga Z, et al. Relationship of carotid arterial functional and structural changes to left atrial volume in untreated hypertension. Acta Cardiol 2016;71:227–33. DOI:10.2143/AC.71.2.3141854; PMID: 27090046 54. Russo C, Jin Z, Takei Y, et al. Arterial wave reflection and subclinical left ventricular systolic dysfunction. J Hypertens 2011;29:574–82. DOI: 10.1097/HJH.0b013e328342ca56; PMID: 21169863 55. Chirinos JA, Segers P, Gillebert TC, et al; Asklepios Investigators. Arterial properties as determinants of timevarying myocardial stress in humans. Hypertension 2012;60: 64–70. DOI: 10.1161/HYPERTENSIONAHA.112.190710; PMID: 22665121 56. Shah SJ, Wasserstrom JA. Increased arterial wave reflection magnitude: a novel form of stage B heart failure? J Am Coll Cardiol 2012;60:2178–81. DOI: 0.1016/j.jacc.2012.07.055 57. Chirinos JA, Segers P, Gupta AK, et al. Time-varying myocardial stress and systolic pressure-stress relationship: role in myocardial-arterial coupling in hypertension. Circulation 2009;119:2798–807. DOI: 10.1161/ CIRCULATIONAHA.108.829366; PMID: 19451350 58. Chirinos JA, Segers P, Duprez DA, et al. Late systolic central hypertension as a predictor of incident heart failure: the Multi-ethnic Study of Atherosclerosis. J Am Heart Assoc 2015;4:e001335. DOI: 10.1161/JAHA.114.001335; PMID: 25736440 59. Chirinos JA, Kips JG, Jacobs DR, Jr., et al. Arterial wave reflections and incident cardiovascular events and heart failure: MESA (Multiethnic Study of Atherosclerosis). J Am Coll Cardiol 2012;60:2170–7. DOI: 10.1016/j.jacc.2012.07.054; PMID: 23103044 60. Weber T, Wassertheurer S, O’Rourke MF, et al. Pulsatile hemodynamics in patients with exertional dyspnea: potentially of value in the diagnostic evaluation of suspected heart failure with preserved ejection fraction. J Am Coll Cardiol 2013;61:1874–83. DOI: 10.1016/j.jacc.2013.02.013; PMID: 23500307 61. Zamani P, Rawat D, Shiva-Kumar P, et al. Effect of inorganic nitrate on exercise capacity in heart failure with preserved ejection fraction. Circulation 2015;131:371–80; discussion 380. DOI: 10.1161/CIRCULATIONAHA.114.012957; PMID: 25533966 62. Paglia A, Sasso L, Pirozzi F, et al. Arterial wave reflections and ventricular–vascular interaction in patients with left ventricular systolic dysfunction. Int Heart J 2014;55:526–32. PMID: 25318554 63. Laskey WK, Kussmaul WG. Arterial wave reflection in heart failure. Circulation 1987;75:711–22. PMID: 3829333 64. Brin KP, Yin FC. Effect of nitroprusside on wave reflections in patients with heart failure. Ann Biomed Eng 1984;12:135–50. PMID: 6507963 65. Binkley PF, Van Fossen DB, Haas GJ, et al. Increased ventricular contractility is not sufficient for effective positive inotropic intervention. Am J Physiol 1996;271:H1635–42. PMID: 8897961 66. Pierce GL, Schofield RS, Nichols WW, et al. Role of heart failure etiology on arterial wave reflection in heart transplant recipients: relation with C-reactive protein. J Hypertens 2007;25:2273–9. DOI: 10.1097/HJH.0b013e3282efec70; PMID: 17921822 67. Omar SA, Fok H, Tilgner KD, et al. Paradoxical normoxiadependent selective actions of inorganic nitrite in human muscular conduit arteries and related selective actions on central blood pressures. Circulation 2015;131:381–9; discussion 389. DOI: 10.1161/CIRCULATIONAHA.114.009554; PMID: 25533964 68. Zamani P, Tan VX, Soto-Calderon H, et al. Pharmacokinetics and pharmacodynamics of inorganic nitrate in heart failure with preserved ejection fraction. Circ Res 2016;120:1151–61. DOI: 10.1161/CIRCRESAHA.116.309832; PMID: 27927683 69. Eggebeen J, Kim-Shapiro DB, Haykowsky M, et al. One week of daily dosing with beetroot juice improves submaximal endurance and blood pressure in older patients with heart failure and preserved ejection fraction. JACC Heart Fail 2016;4:428–37. DOI: 10.1016/j.jchf.2015.12.013; PMID: 26874390 70. Chirinos JA, Zamani P. The nitrate-nitrite-NO pathway and its implications for heart failure and preserved ejection fraction. Curr Heart Fail Rep 2016;13:47–59. DOI: 10.1007/s11897-0160277-9; PMID: 26792295 71. Redfield MM, Anstrom KJ, Levine JA, et al; NHLBI Heart Failure Clinical Research Network. Isosorbide mononitrate in heart failure with preserved ejection fraction. N Engl J Med 2015;373:2314–24. PMID: 26549714; DOI: 10.1056/ NEJMoa1510774 72. Zamani P AS, Soto-Calderon H, Beraun M, et al. Isosorbide dinitrate, with or without hydralazine, does not reduce wave reflections, LV hypertrophy, or myocardial fibrosis in HFpEF. J Am Heart Assoc 2017;6:e004262. DOI: 10.1161/ JAHA.116.004262; PMID: 28219917

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Pharmacotherapy

Neurohormonal Blockade in Heart Failure T homa s G v on Lueder, 1 , 2 D i p a k Ko t e c h a , 2 ,3 D a n A t a r 1 a n d I n g r i d H o p p e r 2 1. Department of Cardiology, Oslo University Hospital Ullevål, Oslo, Norway; 2. Monash Centre of Cardiovascular Research and Education in Therapeutics, Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia and Alfred Hospital, Melbourne, Australia; 3. University of Birmingham Institute of Cardiovascular Sciences, Birmingham, UK

Abstract A key feature of chronic heart failure (HF) is the sustained activation of endogenous neurohormonal systems in response to impaired cardiac pumping and/or filling properties. The clinical use of neurohormonal blockers has revolutionised the care of HF patients over the past three decades. Drug therapy that is active against imbalance in both the autonomic and renin–angiotensin–aldosterone systems consistently reduces morbidity and mortality in chronic HF with reduced left ventricular ejection fraction and in sinus rhythm. This article provides an assessment of the major neurohormonal systems and their therapeutic blockade in patients with chronic HF.

Keywords Heart failure, chronic heart failure, neurohormone, neurohormonal blockade, renin–angiotensin–aldosterone, left ventricular ejection fraction, sinus rhythm Disclosure: TGvL has consulted for Novartis, St Jude Medical and Vifor Pharma, and is a member of the Beta-blockers in Heart Failure (BB-meta-HF) Collaborative Group. DK has received grants from Menarini, non-financial support from Daiichi Sankyo and personal fees from AtriCure, outside the submitted work; and is Chief Investigator for the RAte control Therapy Evaluation in Atrial Fibrillation (RATE-AF) Trial and Steering Committee Lead for the BB-meta-HF Collaborative Group. DA has received speaker honoraria from Novartis, MSD and Vifor Pharma. IH has no conflicts of interest to declare. Acknowledgements: Supported by National Health Medical Research Council of Australia Program Grant ID 546272. DK is funded by a National Institute for Health Research (NIHR) Career Development Fellowship (CDF-2015-08-074). The opinions expressed are those of the authors and do not represent the NIHR or the UK Department of Health. Received: 26 September 2016 Accepted: 30 November 2016 Citation: Cardiac Failure Review 2017;3(1):19–24. DOI: 10.15420/cfr.2016:22:2 Correspondence: Dr Thomas G von Lueder, Department of Cardiology, Oslo University Hospital Ullevål, 0407 Oslo, Norway. E: tomvonoslo@yahoo.com

Heart Failure (HF) constitutes a major global health problem, evidenced by substantial morbidity and mortality, requiring enormous healthcare-related expenditure. HF is associated with high symptomatic burden, and with a relentless and progressive clinical course towards end-stage disease. A large body of epidemiological data suggests that the prognosis in HF is as poor as in advanced cancer.1 Survival after first hospitalisation for HF is very poor, and less than 50 % of patients are alive after 5 years.2,3 By contrast, cardiac transplantation has very favorable 1- and 10-year survival rates of approximately 90 % and 50 %, respectively, but is restricted to an extremely select group of patients. Medical therapy therefore remains the treatment of choice for most patients with HF. HF is divided clinically according to left ventricular ejection fraction (LVEF) into reduced (<40 %), preserved (>50 %) and the newlyintroduced category of intermediate or “midrange” ejection fraction (40–49 %).4 A key feature of chronic HF is the sustained activation of endogenous neurohormonal systems in response to impaired cardiac pumping and/or filling properties. It is widely believed that neurohormonal systems are essential survival and “injury response” mechanisms that have evolved over thousands of years in order to cope with hostile environments and variable climates.5,6 Neurohormonal systems provide survival benefits through actions such as water and salt conservation or vasoconstriction (for example minimising the impact of haemorrhage). In addition, many neurohormonal systems are essential for normal embryonic development.7,8

While these neurohormonal systems may have compensatory haemodynamic effects in the initial stages of HF, chronic stimulation and dysregulation occurs that exerts profound deleterious actions on a broad range of cardiovascular (CV) tissues. When LVEF is in the midrange or preserved categories, guidelines require additional evidence of elevated natriuretic peptide levels for a diagnosis of HF.4 Based on the above considerations, and following scrutiny of randomised clinical trials (RCTs), pharmacological agents that counteract adverse neurohormonal actions have been introduced into clinical practice over the past three decades. The sympathetic nervous system (SNS) and the renin–angiotensin–aldosterone system (RAAS) are major neurohormonal systems that exert potentially maladaptive actions in HF.9 In patients with HF with reduced ejection fraction (HFrEF) in sinus rhythm, pharmacological blockade of these systems has been shown to markedly reduce mortality and morbidity (see Table 1).4,10–15 As yet, no medical therapy has been shown to improve the prognosis of patients with HF with preserved ejection fraction (HFpEF), despite evidence that both systolic and diastolic dysfunction affect the sympatho–vagal balance.16 This article provides an assessment of the major neurohormonal systems and their therapeutic blockade in patients with chronic HF.

The Sympathetic Nervous System and Pharmacological Blockade Activation of the SNS increases stroke volume and induces peripheral vasoconstriction in order to maintain arterial perfusion pressure.

Access at: www.CFRjournal.com

Pharmacotherapy Table 1: Important Neurohormonal Systems and their Blockade in Heart Failure Neurohormonal system

Maladaptive effects

Drug class

Efficacy of blockade

Notes

Sympathetic nervous

Cardiovascular hypertrophy and

Beta-blocker

Reduced morbidity and

Class I indication

system

fibrosis, apoptosis, arrhythmia

mortality (only patients in sinus rhythm)

Alpha-blocker

No morbidity or mortality

No indication

benefit Renin–angiotensin–

Cardiovascular and renal fibrosis,

aldosterone system

hypertrophy, salt and water retention

Endothelin system

Sympatholytic

No benefit; possible harm

No indication

ACE inhibitor

Reduced morbidity and

Class I indication

mortality Angiotensin receptor

Reduced morbidity and

Class I indication if intolerant to

blocker

mortality

ACE inhibitor

Mineralocorticoid receptor

Reduced morbidity and

Class I indication

antagonist

mortality

Vasoconstriction, cardiovascular

Endothelin receptor

No morbidity or mortality

Useful in some forms of

fibrosis, hypertrophy

antagonist

benefit

pulmonary hypertension

Endothelin-converting

No data available

Not evaluated in randomised trials

enzyme inhibitor Natriuretic peptides

Counteracts the renin–angiotensin–

Neprilysin inhibitor (single-

No morbidity or mortality

Not evaluated in large

aldosterone system in heart failure:

acting) pressure-lowering

benefit

randomised-controlled trials

Vasopeptidase inhibitor

Uncertain morbidity

Abandoned due to safety

(dual-acting)

and mortality benefit

concerns

Angiotensin receptor

Greater reduction in

Class I indication if

neprilysin inhibitor

morbidity and mortality

symptomatic despite

(dual-acting)

than ACE inhibitor

ACE inhibitor, beta-

natriuresis, diuresis, antifibrotic, antihypertrophic, blood

blocker and mineralocorticoid receptor antagonist ACE = angiotensin-converting enzyme.

The interface between the sympathetic nerve fibres and the CV system is formed by the adrenergic receptors. In HF, sustained sympathetic stimulation through elevated catecholamine levels (noradrenaline and others) leads to reductions in cardiac beta-1adrenergic receptor density and function over time, contributing to disease progression.17–20 Initially thought to be contraindicated in HF, beta-adrenergic receptor antagonists (beta-blockers) represent a cornerstone of the current medical management of HF based on a well-documented reduction in clinical event rates.4,21,22 The beneficial actions of beta-blockers are believed to occur through mechanisms including reduced heart rate and myocardial oxygen demand, to reduce the incidence of arrhythmia and sudden cardiac death, and to provide protection from ischaemia. These adaptations to the pathophysiology of HF and their resultant effects on autonomic and neurohormonal balance translate into tangible patient benefits: in HFrEF with sinus rhythm, beta-blockers lead to a 24 % relative reduction (4 % absolute reduction) in all-cause mortality, and a similar reduction in hospital admissions.15 The beta-blockers with proven survival benefit in HF recommended by the European Society of Cardiology and Heart Failure Association guidelines are bisoprolol, metoprolol, carvedilol and nebivolol. 4 While bisoprolol and metoprolol are highly selective for the beta1-adrenergic receptor, carvedilol possesses broader substrate specifities, having alpha-adrenergic and proposed pleiotropic and antioxidant properties.23

Recent data suggest that the survival benefit of beta-blockers in patients with HFrEF does not extend to those with concomitant atrial fibrillation (AF).21,24 The role of the autonomic nervous system in the (patho)physiology of AF is complex and is related to the modulation of both sympathetic and parasympathetic responses. 25 When AF develops in patients with HFrEF, central sympathetic activity is augmented, but the appropriate sympathetic response to exercise is diminished.26,27 These observations raise the possibility that lack of beta-blocker efficacy in AF may be related to differences in autonomic function (and, consequently, the neurohormonal axis), a likelihood supported by the observation that heart rate is associated with mortality in HFrEF with sinus rhythm, but not in HFrEF with AF. 28 Blockade of other adrenergic signalling pathways, such as alphaadrenergic receptors, has been ineffective in HF. In patients with hypertension in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) the alpha receptor-blocker doxazosin doubled the incidence of HF, although overall mortality was similar. 29 Some sympatholytics, such as hydralazine and clonidine, have been used in resistant hypertension.30 In African Americans hydralazine has been reported to be of benefit.30 Other centrally-acting sympatholytics have shown signs of harm in HF.31 Non-pharmacological strategies to block the SNS in HF, such as catheter-based renal sympathetic denervation and vagal nerve stimulation, are currently undergoing evaluation in clinical trials.32–34

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Neurohormonal Blockade in Heart Failure

The Renin–Angiotensin–Aldosterone System and Pharmacological Blockade The RAAS is a vastly complex neurohormonal system including the protagonist hormones angiotensin-II and aldosterone. AngiotensinII and aldosterone mediate a range of maladaptive actions upon chronic activation, including renal water and sodium retention, peripheral vasoconstriction leading to hypertension, and cellular effects such as hypertrophy and fibrosis of the heart, kidney and vasculature. The first RAAS blockers were introduced in the late 1980s, with angiotensin-converting enzyme (ACE) inhibitor use being supported by a number of clinical trials in HFrEF that demonstrated substantial reductions in mortality and morbidity.35 Angiotensin receptor blockers (ARBs) are recommended only as an alternative in patients intolerant of an ACE inhibitor.4 Renin is located upstream of ACE in the pathway and constitutes a rate-limiting step in the generation of biologically-active angiotensin-II. Therapeutic inhibition of this first specific step in the cascade using direct renin inhibitors was thought to potentially offer therapeutic advantages over ACE inhibition.36 The recent Aliskiren Trial to Minimize OutcomeS in Patients with HEart failuRE (ATMOSPHERE) trial, however, showed that the addition of aliskiren to enalapril increased adverse events without providing any clinical benefit. In addition, statistical non-inferiority could not be demonstrated for monotherapy with aliskiren as compared with enalapril.37 A number of trials have investigated the potential utility of blocking RAAS at multiple levels – not only in HF but also in other CV diseases – and have failed to demonstrate a consistent benefit for dual-acting RAAS blockade.38–42 It therefore seems that adequate RAAS blockade with a single agent (i.e. the maximum tolerated dose of an ACE inhibitor) ensures adequate blockade of angiotensin-II signalling that cannot be enhanced by the addition of an ARB or a direct renin inhibitor. Beyond angiotensin-II, the mineralocorticoid hormone aldosterone exerts potent cardiorenal fibrosis and hypertrophy and often escapes RAAS blockade with stand-alone ACE inhibition.43–45 Clinical trials have demonstrated that mineralocorticoid receptor antagonists (MRAs) can improve prognosis in addition to standard therapy with ACE inhibitors and beta-blockers.46,47 MRAs likely promote antifibrotic actions in a broad range of organs such as the heart, kidney, vasculature and lungs, all of which are affected in HF. Despite their class I indication, however, they remain markedly underutilised in daily HF practice, probably due to their real and perceived potential off-target effects on renal function and serum potassium levels.4,48,49 Following encouraging preclinical studies, non-steroidal MRAs are currently being investigated in clinical trials such as the MinerAlocorticoid Receptor antagonist Tolerability Study – Heart Failure (ARTS-HF).14,50–53 These novel compounds appear to induce less hyperkalaemia and less worsening of renal function in HF.

Dual-acting Neprilysin/RAAS Blockers: From Omapatrilat to Sacubitril/Valsartan The natriuretic peptide (NP) system promotes natriuresis and diuresis and lowers blood pressure. In HF patients, the NP system also counteracts the RAAS and SNS, thereby attenuating the hypertrophy and fibrosis of CV and renal tissues as well as inflammation and neo-angiogenesis.54–56 Hydrolysis by the metallopeptidase neprilysin constitutes the primary breakdown mechanism of NPs; therefore pharmacological targeting of neprilysin has been proposed as a strategy to restore or augment the beneficial actions of NP.57 Single-

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acting neprilysin inhibitors produce essentially neutral effects in humans, perhaps due to the fact that neprilysin broadly interacts with other vasoactive peptides such as adrenomedullin, bradykinin, endothelin-1, substance P, encephalin and others.58–60 Apart from the membrane-bound fraction of neprilysin, a soluble form exists that is measurable and retains activity in the plasma of patients with HF.61 Better understanding of the molecular mechanisms underlying HF has led to the recognition that in order to exploit the benefits of neprilysin inhibition, RAAS needs to be inhibited concomitantly.62 The vasopeptidase inhibitors were the first class of drugs to inhibit both ACE and neural endopeptidase.63,64 Omapatrilat underwent extensive clinical testing in the treatment of hypertension and HF.65,66 Omapatrilat showed superior antihypertensive effects to stand-alone RAAS blockade in the large Omapatrilat Cardiovascular Treatment versus Enalapril (OCTAVE) trial (n=25,302).67 In the phase-II Inhibition of Metallo Protease by BMS-186716 in a Randomized Exercise and Symptoms Study in Subjects With Heart Failure (IMPRESS) trial, omapatrilat reduced the composite endpoint of all-cause mortality or HF hospitalisation compared to lisinopril.68 In the subsequent phase-III Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events (OVERTURE), however, the primary endpoint was not significantly reduced and the trial failed to meet the pre-specified superiority criterion. 69 Important off-target effects, most notably a substantially higher rate of angioedema ascribed to bradykinin accumulation, halted further development of omapatrilat and other vasopeptidase inhibitors.70 A logical extension of research efforts into combined neprilysin and RAAS blockade are the angiotensin receptor neprilysin inhibitors (ARNIs).62,71,72 Utilising an ARB rather than ACE inhibitor as the RAAS blocker, ARNIs circumvent the issue of bradykinin accumulation.70 In an experimental angioedema model, vasopeptidase inhibition – but not ARB or neural endopeptidase inhibition or their combination (replicating ARNIs) – induced bradykinin-mediated tracheal plasma extravasation.73 Sacubitril/valsartan, the first-in-class ARNI, has undergone broad clinical testing in HF and hypertension.74,75 The Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial evaluated sacubitril/valsartan as an alternative to enalapril in patients with HFrEF (i.e. current best therapy based on the Studies Of Left Ventricular Dysfunction (SOLVD) study).76,77 The trial was terminated prematurely due to overwhelming benefit: compared to enalapril, sacubitril/valsartan reduced the risk of the primary composite endpoint of CV mortality or hospitalisation for HF by 20 %. Sacubitril/valsartan was also superior in reducing a number of other pre-specified endpoints, such as time to clinical deterioration and 30-day readmission rates, and was more efficacious regardless of age, LVEF or the presence of AF.78–82 Experimental work suggests that sacubitril/valsartan better protects against angiotensin-II-stimulated myocardial cellular injury, hypertrophy and fibrosis than single-acting RAAS blockade.83,84 Such dual-acting neurohormonal inhibition was also recently reported to offer better renal protection compared to single RAAS blockade.85–87 Based on encouraging results from the phase II Prospective comparison of ARNI with ARB on Management Of heart failUre with preserved ejectioN fracTion (PARAMOUNT-HF) study, sacubitril/valsartan is currently being tested in Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction (PARAGON-HF), a large clinical outcome trial scheduled to enrol 4,300 patients with HFpEF (www.clinicaltrials.gov, NCT01920711).75

Pharmacotherapy Other Neurohormonal Systems with Possible Relevance to HF Endothelin-1, the major isoform of the endothelin peptide family in the CV system, is an extremely potent vasoconstrictor with additional pro-hypertrophic, pro-fibrotic and mitogenic effects on myocardium and vasculature.88 Endothelin activation in HF disturbs salt and water homeostasis, stimulates the RAAS and SNS, mediates vasoconstriction, and directly contributes to progressive CV and renal dysfunction and remodelling in HF.89,90 Endothelin-1 plasma levels are strongly correlated with mortality and morbidity.91 Fuelled by encouraging experimental and early clinical evidence, several RCTs have explored the putative utility of blocking the endothelin system in acute and chronic HF settings.90,92–96 With the exception of some forms of pulmonary arterial hypertension, the vast majority of large RCTs of endothelin antagonism have failed to show reduced clinical event rates (see Table 1). Unfortunately, some trials (with neutral or negative outcomes presented at scientific meetings) have not been published, or only in abstract form.97–100 In HF, the only current application of endothelin antagonists seems to be to lower pulmonary vascular resistance in high-risk patients on the heart transplant list, although even this indication has been subject of debate.101–103 Among numerous other neurohormones with putative implications in HF pathophysiology are adrenomedullin, bradykinin, serotonin, and urotensin-II.104–107 Their role in HF remains incompletely understood, and no specific pharmacological modulator has advanced into clinical testing. Since several of these neurohormones are substrates of neprilysin, their metabolism could conceivably be altered by neprilysin inhibition.58–60

Remaining Challenges for Neurohormonal Blockade in HF Concomitant blockade of multiple neurohormonal systems, built on a strong scientific foundation, is the current gold standard of pharmacotherapy in HFrEF. Current treatment recommendations are based on trials that showed clinical benefits for target doses of RAAS and SNS blockers.4 Guideline-adherent treatment is frequently not achieved in practice, however.108 There are various reasons for this, such as the lenient attitude of some caregivers (sometimes termed “therapeutic inertia”) towards patients who appear euvolemic and asymptomatic, and the real or perceived side effects of medical therapy such as hypotension, bradycardia, hyperkalaemia and worsening renal function.109 There is a considerable knowledge gap regarding neurohormonal blockade in various HF entities: renal dysfunction affects at least one in five HF patients and is a major adverse prognostic factor.110 Traditionally these patients have been excluded from RCTs, although there is accumulating evidence for the particular value of neurohormonal blockade in these patients, as discussed above. HF commonly coexists with AF and represents a clinical dilemma.111,112 In patients with HFrEF and AF, the mortality and morbidity benefits of beta-blockers for neurohormonal blockade appear to be absent,15,21 and the data for RAAS antagonists and MRAs are limited.111 Patterns of autonomic activation have not yet been sufficiently studied in

patients with concomitant HF and AF, limiting our understanding of the impact of pharmacotherapy. Some authors have argued that the therapeutic blockade of neurohormonal systems may have been exhausted, and that a ceiling may have been reached. In particular, a discrepancy between promising early-phase and frequently disappointing clinical endpoint trial results of neurohormonal blockade has been noted.113 Recent examples of neurohormonal blockers with promising scientific underpinnings that failed to lower event rates in clinical early-phase or outcome trials include endothelin receptor blockers, adenosine receptor antagonists, tumour necrosis factor antagonists and phosphodiesterase inhibitors.98,114–116 Of note, very recent insights from the PARADIGM-HF study using valsartan/sacubitril support the notion that combination therapy with neurohormonal modulators may be superior to singleacting therapy, even at subtarget doses.117 Such a strategy may better exploit the benefits of abrogating multiple specific maladaptive signalling pathways while circumventing the adverse effects of neurohormonal blocker monotherapy. For instance, renal failure frequently occurs in HF patients, and experimental as well as clinical studies have demonstrated that dual-acting RAAS blockade and neprilysin inhibition offers superior nephroprotection to single-acting therapy.85,86 Finally, no single effective therapy has been identified for patients with HFpEF,118 although this category includes a very heterogeneous population defined by an arbitrary cut-off in LVEF. The limited benefit of neurohormonal blockers in HFpEF may also be explained by older age, more advanced comorbidities and a higher likelihood of death from non-CV causes.119–121 Rates of AF are also higher in patients with HFpEF, leading to additional neurohormonal activation.111,112 In addition, a substantial proportion of patients with HFpEF show evidence of impaired or resolving systolic function.122 The recently-introduced category of HF with midrange ejection fraction has little evidence-base as yet, but will likely increase clinical awareness of these patients.

Conclusion Sustained activation of neurohormonal systems is a hallmark feature of HF. The clinical use of neurohormonal blockers has revolutionised the care of patients over the past four decades. Drug therapy that is active against imbalance in both the autonomic and renin– angiotensin–aldosterone systems consistently reduces morbidity and mortality in chronic HF with reduced LVEF and sinus rhythm. HF is an extraordinarily complex and multi-faceted chronic syndrome, and current knowledge of the interface between the epidemiological, clinical, pathophysiological and molecular features remains limited. Initiation and up-titration of effective neurohormonal therapies remains challenging in patient subcohorts. In addition, optimal medical therapy is frequently not achieved or even attempted despite HF having a similar overall prognosis to cancer. The recent introduction of the novel ARNI drug class attests to superior efficacy of multiple-acting neurohormonal blockade in chronic HF. HFpEF and HF with coexisting AF represent major remaining clinical challenges that appear to be less susceptible to conventional pharmacotherapy. Novel neurohormonal blockers and the refined use of existing therapeutic agents, as well as up-titration to recommended target doses, are needed to reduce adverse clinical events and to improve outcomes in HF. ■

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renal function in heart failure. Int J Cardiol 2015;179 : 329–30. DOI: 10.1016/j.ijcard.2014.11.059; PMID: 25464479 86. Wang BH, von Lueder TG, Kompa AR, et al. Combined angiotensin receptor blockade and neprilysin inhibition attenuates angiotensin-II mediated renal cellular collagen synthesis. Int J Cardiol 2015;186 :104–5. DOI: 10.1016/j. ijcard.2015.03.116; PMID: 25828104 87. Voors AA, Gori M, Liu LC, et al.; PARAMOUNT Investigators. Renal effects of the angiotensin receptor neprilysin inhibitor LCZ696 in patients with heart failure and preserved ejection fraction. Eur J Heart Fail 2015;17 :510–7. DOI: 10.1002/ejhf.232; PMID: 25657064 88. Yanagisawa M, Kurihara H, Kimura S, et al. A novel peptide vasoconstrictor, endothelin, is produced by vascular endothelium and modulates smooth muscle Ca2+ channels. J Hypertens Suppl 1988;6 :S188–91. PMID: 2853725 89. Davenport AP, Hyndman KA, Dhaun N, et al. Endothelin. Pharmacol Rev 2016;68 :357–418. DOI: 10.1124/pr.115.011833; PMID: 26956245 90. Kiowski W, Sutsch G, Hunziker P, et al. Evidence for endothelin-1-mediated vasoconstriction in severe chronic heart failure. Lancet 1995;346 :732–6. PMID: 7658874 91. Lerman A, Kubo SH, Tschumperlin LK, et al. Plasma endothelin concentrations in humans with end-stage heart failure and after heart transplantation. J Am Coll Cardiol 1992;20 :849–53. PMID: 1527295 92. Sakai S, Miyauchi T, Kobayashi M, et al. Inhibition of myocardial endothelin pathway improves longterm survival in heart failure. Nature 1996;384 :353–5. DOI: 10.1038/384353a0; PMID: 8934519 93. Fraccarollo D, Hu K, Galuppo P, et al. Chronic endothelin receptor blockade attenuates progressive ventricular dilation and improves cardiac function in rats with myocardial infarction: possible involvement of myocardial endothelin system in ventricular remodeling. Circulation 1997;96 :3963-73. PMID: 9403621 94. Mulder P, Richard V, Derumeaux G, et al. Role of endogenous endothelin in chronic heart failure: effect of long- term treatment with an endothelin antagonist on survival, hemodynamics, and cardiac remodeling. Circulation 1997;96 :1976–82. PMID: 9323089 95. Sutsch G, Kiowski W, Yan XW, et al. Short-term oral endothelin-receptor antagonist therapy in conventionally treated patients with symptomatic severe chronic heart failure. Circulation 1998;98 :2262–8. PMID: 9826312 96. Love MP, Haynes WG, Gray GA, et al. Vasodilator effects of endothelin-converting enzyme inhibition and endothelin ETA receptor blockade in chronic heart failure patients treated with ACE inhibitors. Circulation 1996;94 :2131–7. PMID: 8901663 97. Kelland NF, Webb DJ. Clinical trials of endothelin antagonists in heart failure: publication is good for the public health. Heart 2007;93 :2–4. DOI: 10.1136/hrt.2006.089250 98. Kelland NF, Webb DJ. Clinical trials of endothelin antagonists in heart failure: a question of dose? Exp Biol Med (Maywood) 2006;231 :696–9. PMID: 16740982 99. Teerlink JR. Endothelins: pathophysiology and treatment implications in chronic heart failure. Curr Heart Fail Res 2005;2 :191–7. PMID: 16332312 100. Gottlieb SS. The impact of finally publishing a negative study: new conclusions about endothelin antagonists. J Card Fail 2005;11 :21–2. PMID: 15704059 101. Hefke T, Zittermann A, Fuchs U, et al. Bosentan effects on hemodynamics and clinical outcome in heart failure patients with pulmonary hypertension awaiting cardiac transplantation. Thorac Cardiovasc Surg 2012;60 :26–34. DOI: 10.1055/s-0030-1250726; PMID: 21432755 102. Padeletti M, Caputo M, Zaca V, et al. Effect of bosentan on pulmonary hypertension secondary to systolic heart failure. Pharmacology 2013;92 :281–5. DOI: 10.1159/000355875; PMID: 24296902 103. Perez-Villa F, Farrero M, Cardona M, et al. Bosentan in heart transplantation candidates with severe pulmonary hypertension: efficacy, safety and outcome after transplantation. Clin Transplant 2013;27 :25–31. DOI: 10.1111/j.1399-0012.2012.01689.x; PMID: 22861120 104. Nagaya N, Satoh T, Nishikimi T, et al. Hemodynamic, renal, and hormonal effects of adrenomedullin infusion in patients with congestive heart failure. Circulation 2000;101 :498–503. PMID: 10662746

105. Ames RS, Sarau HM, Chambers JK, et al. Human urotensin-II is a potent vasoconstrictor and agonist for the orphan receptor GPR14. Nature 1999;401 :282–6. DOI: 10.1038/45809; PMID: 10499587 106. Douglas SA, Tayara L, Ohlstein EH, et al. Congestive heart failure and expression of myocardial urotensin II. Lancet 2002;359 :1990–7. DOI: 10.1016/S0140-6736(02)08831-1; PMID: 12076554 107. Jougasaki M, Wei CM, McKinley LJ, et al. Elevation of circulating and ventricular adrenomedullin in human congestive heart failure. Circulation 1995;92 :286–9. PMID: 7634439 108. Chin KL, Skiba M, Tonkin A, et al. The treatment gap in patients with chronic systolic heart failure: a systematic review of evidence-based prescribing in practice. Heart Fail Rev 2016;21 :675–97. DOI: 10.1007/s10741-016-9575-2; PMID: 27465132 109. Packer M. Heart failure’s dark secret: Does anyone really care about optimal medical therapy? Circulation 2016; 134 :629–31. DOI: 10.1161/CIRCULATIONAHA.116.024498; PMID: 27572876 110. Cohen-Solal A, Kotecha D, van Veldhuisen DJ, et al.; SENIORS Investigators. Efficacy and safety of nebivolol in elderly heart failure patients with impaired renal function: insights from the SENIORS trial. Eur J Heart Fail 2009;11 :872–80. DOI: 10.1093/eurjhf/hfp104; PMID: 19648605 111. Kotecha D, Piccini JP. Atrial fibrillation in heart failure: what should we do? Eur Heart J 2015;36 :3250–7. DOI: 10.1093/ eurheartj/ehv513 112. Kotecha D, Lam CS, Van Veldhuisen DJ, et al. Vicious twins heart failure with preserved ejection fraction and atrial fibrillation. J Am Coll Cardiol 2016:68 :2217–28. DOI: 10.1016/j. jacc.2016.08.048; PMID: 27855811 113. Gheorghiade M, Larson CJ, Shah SJ, et al. Developing new treatments for heart failure: focus on the heart. Circ Heart Fail 2016;9 :e002727. DOI: 10.1161/ CIRCHEARTFAILURE.115.002727; PMID: 27166246 114. Mann DL, McMurray JJ, Packer M, et al. Targeted anticytokine therapy in patients with chronic heart failure: results of the Randomized Etanercept Worldwide Evaluation (RENEWAL). Circulation . 2004;109 :1594–602. DOI: 10.1161/01. CIR.0000124490.27666.B2; PMID: 15023878 115. Anand I, McMurray J, Cohn JN, et al.; EARTH Investigators. Long-term effects of darusentan on left-ventricular remodelling and clinical outcomes in the Endothelin: A Receptor Antagonist Trial in Heart Failure (EARTH): randomised, double-blind, placebo-controlled trial. Lancet 2004;364 :347–54. DOI: 10.1016/S0140-6736(04)16723-8; PMID: 15276394 116. Borlaug BA, Lewis GD, McNulty SE, et al. Effects of sildenafil on ventricular and vascular function in heart failure with preserved ejection fraction. Circ Heart Fail 2015;8 :533–41. DOI: 10.1161/CIRCHEARTFAILURE.114.001915; PMID: 25782985 117. Packer M. Kicking the tyres of a heart failure trial: physician response to the approval of sacubitril/valsartan in the USA. Eur J Heart Fail 2016;18 :1211–9. DOI: 10.1002/ejhf.623; PMID: 27510447 118. Campbell RT, Jhund PS, Castagno D, et al. What have we learned about patients with heart failure and preserved ejection fraction from DIG-PEF, CHARM-preserved, and I-PRESERVE? J Am Coll Cardiol 2012;60 :2349–56. DOI: 10.1016/j. jacc.2012.04.064; PMID: 23141494 119. Mentz RJ, Kelly JP, von Lueder TG, et al. Noncardiac Comorbidities in heart failure with reduced versus preserved ejection fraction. J Am Coll Cardiol 2014;64 :2281–93. DOI: 10.1016/j.jacc.2014.08.036; PMID: 25456761 120. Chamberlain AM, St Sauver JL, Gerber Y, et al. Multimorbidity in heart failure: a community perspective. Am J Med 2015;128 :38–45. DOI: 10.1016/j.amjmed.2014.08.024; PMID: 25220613 121. Gerber Y, Weston SA, Redfield MM, et al. A contemporary appraisal of the heart failure epidemic in Olmsted County, Minnesota, 2000 to 2010. JAMA Intern Med 2015;175 :996–1004. DOI: 10.1001/jamainternmed.2015.0924; PMID: 25895156 122. Shah AM, Claggett B, Sweitzer NK, et al. Prognostic importance of impaired systolic function in heart failure with preserved ejection fraction and the impact of spironolactone. Circulation 2015;132 :402–14. DOI: 10.1161/ CIRCULATIONAHA.115.015884; PMID: 26130119

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Pharmacotherapy

Expert Comment Is Medication Titration in Heart Failure too Complex? John J Atherton 1,2 and Annabel Hickey 3 1. Department of Cardiology, Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia; 2. School of Medicine, University of Queensland, Brisbane, Queensland, Australia; 3. Advanced Heart Failure and Cardiac Transplant Unit, The Prince Charles Hospital, Brisbane, Queensland, Australia

Abstract Large-scale randomised controlled trials (RCTs) have demonstrated that angiotensin-converting enzyme inhibitors, angiotensin receptor blockers and beta-blockers decrease mortality and hospitalisation in patients with heart failure (HF) associated with a reduced left ventricular ejection fraction. This has led to high prescription rates; however, these drugs are generally prescribed at much lower doses than the doses achieved in the RCTs. A number of strategies have been evaluated to improve medication titration in HF, including forced medication up-titration protocols, point-of-care decision support and extended scope of clinical practice for nurses and pharmacists. Most successful strategies have been multifaceted and have adapted existing multidisciplinary models of care. Furthermore, given the central role of general practitioners in long-term monitoring and care coordination in HF patients, these strategies should engage with primary care to facilitate the transition between the acute and primary healthcare sectors.

Keywords Heart failure, angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, beta-blocker, titration Disclosure: JJA has received honoraria, consultancy fees and/or sponsorship to attend conferences from Alphapharm, AstraZeneca, CSL, Menarini, Novartis and Servier. AH has no conflict of interest to declare. Received: 27 December 2016 Accepted: 18 February 2017 Citation: Cardiac Failure Review 2017;3(1):25–32. DOI: 10.15420/cfr.2017:1:2 Correspondence: John J Atherton, Director of Cardiology, Royal Brisbane and Women’s Hospital, Butterfield Street, Herston, Brisbane, 4029 Queensland, Australia. E: john.atherton@health.qld.gov.au

The prevalence of heart failure (HF) continues to rise, driven by an ageing population, increasing rates of obesity and diabetes, and better survival in patients with cardiovascular disease.1 While HF is associated with substantial morbidity and mortality, a number of treatments have been shown to improve outcomes in large-scale randomised controlled trials (RCT), including pharmacological inhibition of the renin–angiotensin system (with or without neprilysin inhibition), betablockers, mineralocorticoid receptor antagonists, sinus node inhibition, cardiac resynchronisation therapy with biventricular pacing, implantable cardioverter defibrillators and multidisciplinary models of care.2–4 In order to realise the benefits of these treatments, however, we need to consider how patients were selected for these RCT and how the treatments were delivered. The adoption of innovative models of care and the delivery of device therapies can be particularly challenging, given that they are highly dependent on the individual operators and rely on substantial infrastructure and staffing support. At first glance, it would appear that the administration of pharmacological therapies for HF should be relatively straightforward, but such therapies are also highly dependent on the individual prescribers, rely on substantial infrastructure and staffing support, and involve real complexities around medication persistence and patient adherence. In this review, we will discuss medication titration in HF and consider whether or not it is too complex in the real-world setting.

We conducted a literature search in November and December 2016 using PubMed. Keywords included ‘heart failure’, which was used in combination with ‘medication’ or ‘therapy’ and ‘titration’ or ‘up-titration’, ‘dose’ or ‘target dose’. We also searched reference lists of relevant primary studies and systematic reviews. We used no language or date restrictions. All types of study design were included where medication titration was a primary endpoint.

Clinical Trials Evaluating Medications in Heart Failure Large-scale randomised controlled trials (RCTs) have demonstrated that angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), beta-blockers and mineralocorticoid receptor antagonists all improve clinical outcomes in patients with HF associated with a reduced left ventricular ejection fraction (HFrEF).5–12 Indeed, such studies suggest that the combination of an ACEI, betablocker and mineralocorticoid receptor antagonist should translate to a 60–70 % relative risk reduction in all-cause mortality.13 Nevertheless, it is likely that the balance between benefit and harm varies according to patient age, disease severity, associated comorbidities and approaches to monitoring and medication titration. An example of the impact of comorbidities was demonstrated by an individual patient data meta-analysis of the beta-blocker RCTs, in which the benefits were only observed in patients in sinus rhythm, there was no reduction in hospitalisation or mortality in patients who were in atrial fibrillation when they were enrolled in the studies.14

Access at: www.CFRjournal.com

Pharmacotherapy Clinical Trial Evidence for Target Doses In the absence of an easily measurable and accepted HF physiological surrogate endpoint, the large HF RCTs evaluating the efficacy of ACEIs, ARBs and beta-blockers used forced up-titration at pre-specified intervals, unless there were adverse events or intolerance, aiming for target doses largely guided by those used to treat hypertension. Early studies reported conflicting results as to whether ACEIs have a dose–response effect on haemodynamic measures in HF patients.15,16 The NETWORK investigators compared three doses of enalapril in 1,532 HF patients and failed to demonstrate a dose-related difference in the combined endpoint of death, HF-related hospitalisation or worsening HF.17 A reduced left ventricular ejection fraction was not a prerequisite for patient selection, however, and patients were only followed for 24 weeks. The Assessment of Treatment with Lisinopril and Survival (ATLAS) study is the largest to address the question of whether we should aim for higher doses of ACEIs. In this study, 3,164 HFrEF patients were randomised to receive either low-dose (2.5–5.0 mg/day) or very-high-dose (32.5–35.0 mg/day) lisinopril.18 While there was no significant difference in the primary endpoint of all-cause mortality, there was a significant 12 % relative risk reduction in the combined endpoint of all-cause mortality or hospitalisation, which was driven by a 24 % relative risk reduction in HF hospitalisation. This study was originally powered based on the assumption that low-dose lisinopril would have no effect on mortality. Indirect comparisons, however, suggest that the low dose achieved approximately half the reduction in mortality and HF hospitalisation observed with the doses of enalapril used in the Studies of Left Ventricular Dysfunction (SOLVD)–Treatment research.10 The authors concluded that patients should be titrated beyond low doses of ACEIs unless the dose is limited by side effects.18 While it was unclear whether patients should be titrated to the very high dose of ACEI used in the ATLAS study, the difference between intermediate and high doses seemed to be small. Indirect comparison of the initial Cardiac Insufficiency Bisoprolol Study (CIBIS) and CIBIS-II provides some support for the use of higher doses of beta-blockers.5,19 CIBIS (up to 5 mg/day bisoprolol without forced up-titration) failed to achieve its primary endpoint, with a non-significant 20 % relative risk reduction in mortality; however, CIBIS-II (forced up-titration to 10 mg/day bisoprolol) demonstrated an impressive 34 % relative risk reduction in mortality in HFrEF patients. Subsequent post-hoc analyses from the Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart failure (MERIT-HF) study and CIBISII reported similar placebo-corrected benefits regardless of the dose of beta-blocker achieved.20,21 These were non-randomised comparisons, however, and are therefore subject to selection bias. Furthermore, based upon the trial design, all patients had been exposed to forced up-titration to the pre-specified target dose and were therefore on maximal tolerated doses. The Multicenter Oral Carvedilol Heart Failure Assessment (MOCHA) study reported dose-related, placebo-corrected improvements in left ventricular ejection fraction and survival in patients who were randomised to receive 25 mg twice daily carvedilol compared with lower doses; however, this analysis was based upon 25 deaths.22 While this was a small study, it nonetheless provided further support for maximal tolerated doses of beta-blockers. In summary, the majority of studies or analyses that have been undertaken to address the question of whether lower doses of ACEIs and beta-blockers achieve similar benefits were either underpowered for major clinical outcomes or based on post-hoc, nonrandomised comparisons. Nonetheless, the major efficacy studies

were all based upon forced up-titration aiming for specified target doses. For this reason, clinical guidelines recommend up titrating to maximal tolerated doses.2–4

Target Dose Achievement in Clinical Practice HF prescription rates for both ACEIs/ARBs and beta-blockers have increased substantially over the past two decades,23–26 such that 92 % of patients were on ACEI or ARB therapy and 93 % were on beta-blockers in the recent European Society of Cardiology Heart Failure Longterm Registry, with most of those patients not on treatment having a documented contraindication or previous medication intolerance.26 Despite this, only 29 % of patients were on target doses of ACEIs and 18 % were on target doses of beta-blockers, with approximately onethird having no reason documented for the failure to up-titrate.26 This contrasts with the RCTs, where at least 50–60 % of patients achieved target doses.5,6,10–12 Clinicians have generally paid greater attention to the up-titration of beta-blockers, given the impressive benefits achieved in clinical trials that involved the forced up-titration of these drugs to target doses on top of background therapy (which included an ACEI or ARB in >90 % of patients).5,6,11,14 Furthermore, while ACEIs can be safely up-titrated in a relatively short time period,27 a ‘start low and go slow’ approach is generally taken with beta-blockers, given their short-term, negative inotropic effects. Despite the benefits, however, only 10–30 % of patients achieve target doses of beta-blockers in most real-world studies (see Table 1). One reason for the low titration rates achieved in clinical practice may be that the patients are not selected in the same way as those enrolled in clinical trials; in practice, patients are generally over a decade older with numerous comorbidities. Indeed, after applying all the RCT inclusion and exclusion criteria to the Euro Heart Survey on Heart Failure population,28 only 9 % of patients would have been eligible for enrolment in the SOLVD–Treatment study and 5 % in the MERIT-HF study.29 Even in the patients who satisfied all the eligibility criteria for those studies, only 46 % achieved target doses of ACEIs and just 6 % achieved target doses of beta-blockers.29 This outcome suggests that the systems available to support clinical trials (including the availability of dedicated research nurses applying forced medication up-titration under the supervision of a principal investigator) may not be readily available in routine clinical practice.

Medication Titration Intervention Studies Barriers to medication titration include health-provider knowledge, self-efficacy and attitudes; patient-related factors, including age, body mass index, comorbidities and polypharmacy; and limited time and support structures to facilitate regular monitoring.30–32 Patients also frequently transition between the acute and community healthcare sectors, which further complicates care coordination, as there is unclear role delineation for healthcare providers. This was clearly demonstrated in the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients With Heart Failure, where there was no attempt to up-titrate beta-blocker therapy in over two-thirds of patients in the initial 60–90 days following hospital discharge.33 A number of strategies have been evaluated to improve medication prescribing in HF, including case management, educational initiatives, decision support, telephone-based monitoring, clinical audit and feedback, strategies to improve communication between healthcare

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Expert Opinion Table 1: Beta-blocker Titration Achievement in Clinical Practice Study

Design

Description

Target Dose Achievement

Tandon et al., 200453

Prospective observational

• n=479

• 1989–2001: 18 % on beta-blockers

• Median age 69 years

• 1998–2001: 24 % on beta-blockers

• 75 % with systolic dysfunction

• Contraindications excluded

• On beta-blockers

• Multidisciplinary heart function clinic

Franciosa et al., 200454

Prospective observational

• n=4,280

• Primary care physicians: 27 %

• Mean age 67 years

• Cardiologists: 49 %

• Mean LVEF 31 % (including normal EF)

• Contraindications excluded

• Community-based registry

• Patients initiated on carvedilol

Mehta et al., 200455

Prospective audit

• n=62

6.6 %

• Mean age 67 years

• Eligible patients

• Contraindications excluded

• District hospital

• Patients initiated on carvedilol

Moyer-Knox et al., 200442 Prospective observational

• n=70

• Mean age 65 years

• Eligible patients

• Contraindications excluded

• HF clinic with protocol-driven titration by

71 %

advanced practice nurse with telephone monitoring Jain et al., 200534

Prospective audit

• Patients initiated on carvedilol • n=234

<25 %

• Mean age 64 years

• Eligible patients

• Contraindications included

• Protocol-driven HF clinics staffed by nurse

and pharmacist and supervised by cardiologist Lenzen et al., 200529

Retrospective audit

• n=272

• Eligible patients

• Contraindications excluded

• On beta-blockers

• Euro Heart Survey on HF

Gustafsson et al., 200730

Prospective audit

• n=1,533

• Eligible patients (LVEF ≤45 %) • Contraindications included

• Nurse-led HF clinic

Prospective observational

• n=3,721

• Eligible patients • Contraindications excluded

• Physician managed outpatients

Prospective survey

• n=1,100

18 % on ESC-recommended beta-blockers

• Mean age 70 years (whole group)

• Eligible patients

• Contraindications excluded

• On beta-blockers

• Cardiologist-managed outpatients

Fonarow et al., 200833

Prospective observational

26 %

• Median age 65 years

de Groote et al., 200757

21 %

• Mean age 69 years

Lainscak et al., 200756

6 % on beta-blockers

• Mean age 67 years

• n=1,863

• 8 % on carvedilol

• Mean age 70 years (whole group)

• 18 % on metoprolol succinate

• Eligible patients

• Contraindications excluded

• On beta-blockers

• Post-HF hospitalisation

C A R D I A C FA I L U R E R E V I E W

Pharmacotherapy Table 1: Cont. Study Rector et al., 200858

Design Retrospective cohort

Description • n=26,112

Target Dose Achievement • 22 % on carvedilol • 4 % on metoprolol succinate

• Median age 74/75 years

• On beta-blockers (>1 script)

• Veteran Health Administrative nationwide dataset

Calvert et al., 200959

• n=2,315

Retrospective cohort

17 % on ESC-recommended beta-blockers

• Mean age 78 years (whole group)

• Contraindications excluded

• On beta-blockers

• General practice dataset

Maggioni et al., 201025

• n=2,774

• 37 % on carvedilol

• Mean age 68 years (whole group)

• 21 % on bisoprolol

• Contraindications excluded

• 21 % on metoprolol succinate

• On beta-blockers

• Hospital cardiology departments

Bosch et al., 201060

Prospective, observational

Retrospective, observational • n=195

12 % on beta-blockers

• Mean age 76 years (whole group)

• Contraindications excluded

• On beta-blockers

• Primary care

Driscoll et al., 201136

Prospective, observational

• n=389

• Usual care: 36 % on beta-blockers

• Mean age 67 years (whole group)

• Nurse-led: 48 % on beta-blockers

• Contraindications excluded

• On beta-blockers

• Community-based HF programmes

Steckler et al., 201143

• n=64

Prospective, observational

41 %

• Mean age 67 years

• Eligible patients (HFrEF)

• Noncompliant patients excluded

• HF clinic with nurse-led titration and telephone support

Maggioni et al., 201326

• n=6,468

Prospective, observational

17.5 % on beta-blockers

• Median age 68 years (whole group)

• Contraindications excluded

• On beta-blockers

• Hospital cardiology departments

Martinez et al., 201337

Retrospective chart review

• n=144

• Baseline: 25 %

• Mean age 69 years

• Pharmacist-managed with telephone

• Eligible patients (HFrEF) support: 49 %

• HF clinic with telemonitoring for weight, HR and BP

Hickey et al., 201648

Retrospective and

• n=280

Baseline cohort A: 38 %

prospective audits

• Mean age 69 years

Intervention cohort B: 33 %

• Eligible patients (HFrEF)

Intervention cohort C: 51 %

• Contraindications excluded

• Hospital-based HF services

BP = blood pressure; EF = ejection fraction; ESC = European Society of Cardiology; HF = heart failure; HFrEF = heart failure associated with a reduced left ventricular ejection fraction; HR = heart rate; LEVF = left ventricular ejection fraction.

Table 2: S trategies to Improve Medication Titration in Heart Failure • C are coordination with timely, written communication between healthcare providers in the acute and primary care sectors. • D ata collection built into the clinical workflow with regular audit and timely feedback of benchmarked clinical indicators. • C lear role delineation, e.g. specify the clinician primarily responsible for medication titration. • ‘ Forced’ medication up-titration protocols supported by regular monitoring of symptoms, signs and biochemistry. • Point-of-care decision support. • E xtended scope of clinical practice for nurses and pharmacists to prescribe/ up-titrate medical therapy.

providers and extended scope of clinical practice.30,34–44 While education, decision support and clinical audit and feedback have been successfully applied to improve prescribing behaviour, these approaches alone appear to be insufficient to improve medication titration.39,40 Successful strategies have generally involved multifaceted interventions and are likely to be context-specific (see Table 2). On the basis of clinical studies demonstrating the efficacy of multidisciplinary HF disease management, these programmes are becoming more widely available.45,46 Indeed, those strategies used in the larger HF RCTs that have demonstrated the efficacy of pharmacological therapies are replicated in many HF disease-management services. These include the availability of dedicated nursing staff that undertake

C A R D I A C FA I L U R E R E V I E W

Expert Opinion regular follow-up and monitoring of their patients and also provide a convenient point of contact. Such staff members could also be engaged to undertake ‘forced medication up-titration’. Recent studies have therefore evaluated the role of expanding the scope of nurses’ and pharmacists’ clinical practice for medication prescribing and titration, with favourable results reported in a number of prospective, observational studies.30,34,36,42,43 Ansari et al. undertook a single-centre, three-arm RCT in the United States comparing nurse-facilitated medication titration, provider and patient notification, and standard care in 169 HFrEF patients.39 All three groups received copies of HF treatment guidelines and group education. The nurse-facilitated medication titration group was much more likely to achieve target doses of beta-blockers at 12 months (43 %), compared with both the provider/patient notification group (2 %) and standard care (10 %). These findings are largely consistent with an evaluation of Australian community-based HF services that reported a higher proportion of patients achieving target doses of beta-blockers if they were enrolled in programmes undertaking nurseled medication titration.36 Similar improvement was reported in a RCT involving a multifaceted intervention including nurse-coordinated case management, education and telephone-based structured monitoring.44 A recent Cochrane review encompassing seven RCTs performed in 1,684 HFrEF patients reported that nurse-led medication titration resulted in a two-fold increase in the number of participants achieving target doses of beta-blockers, a 20 % relative risk reduction in all-cause hospitalisation and a 34 % relative risk reduction in all-cause mortality. These findings need to be tempered, however, by the lack of reporting of harm, with only two studies reporting on adverse events.47 Studies have also evaluated pharmacist-managed medication titration in HF.37,38 Recognising the key role that general practitioners (GPs) play in HF management, Lowrie et al. undertook a cluster-RCT of nonspecialist, pharmacist-managed medication titration in 1,090 HFrEF patients attending 87 practices in United Kingdom. While this study did not achieve its primary clinical endpoint, a higher proportion of patients who enrolled in practices with pharmacist-assisted titration achieved target doses of ACEI therapy. There were favourable trends for beta-blocker titration, however these did not achieve statistical significance.38 In a before–after, retrospective design study targeting 51 higher-risk HFrEF patients conducted in the United States, Martinez et al. demonstrated that a multifaceted intervention, which included pharmacist-managed titration guided by telephone monitoring, resulted in a higher proportion of patients achieving target doses of ACEI/ARB and beta-blockers.37 We recently undertook a quality improvement study that aimed to embed a pre-designed medication titration plan into standard clinical practice for patients newly referred to the HF services in three

Bui AL, Horwich TB, Fonarow GC. Epidemiology and risk profile of heart failure. Nat Rev Cardiol 2011;8:30–41. DOI: 10.1038/nrcardio.2010.165; PMID: 21060326 Ponikowski P, Voors AA, Anker SD, et al; Authors/Task Force Members. 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. DOI: 10.1093/eurheartj/ehw128; PMID: 27206819 Yancy CW, Jessup M, Bozkurt B, et al; American College of Cardiology Foundation; American Heart Association Task Force of Practice Guidelines. 2013 ACCF/AHA guideline for the management of heart failure: a report of the

C A R D I A C FA I L U R E R E V I E W

hospitals.48 This study involved completing and faxing a customised medication titration form to the patient’s GP on the day of hospital discharge that clearly defined which healthcare provider was primarily responsible for medication titration. This intervention was designed to facilitate point-of-care decision support, including specifying the order and extent of medication titration and providing trouble-shooting guidelines (see Appendix I). We discovered that patients who were not on target doses of ACEI/ARB or beta-blocker therapy were more likely to achieve target doses if the medication titration form was used. In the final cohort, 55 % of patients achieved target doses of ACEIs/ ARBs and 51 % achieved target doses of beta-blockers 6 months after hospital discharge.48 This medication titration form is now available online (http://www.health.qld.gov.au/heart_failure) and is used by all public hospitals with HF services in Queensland, with similar ACEI/ARB and beta-blocker titration rates observed in a recent analysis of an independent HFrEF cohort.32 A major limitation of strategies that are either coupled with established HF disease management programmes or that require additional staffing is their sustainability and limited external validity, since access to multidisciplinary HF services varies across jurisdictions.49 Given the central role played by the GP, processes that engage primary care are more likely to be successful in the broader HF population. Some studies, however, have reported a reluctance on the part of GPs to up-titrate HF therapy.50 Despite this, we observed increasing primary care involvement in our quality improvement study, with the patient’s GP being the designated healthcare provider responsible for medication titration in half the patients in the final cohort, when the highest titration rates were achieved.48 This suggests that, in addition to long-term monitoring and care coordination,51,52 GPs could play a more active role in medication titration.

Conclusion There have been marked improvements in ACEI and beta-blocker prescription rates for HFrEF over the past two decades; however, the doses prescribed in clinical practice are generally much lower than those achieved in the RCTs. While the clinical trials were generally not designed to determine whether the benefits were dose related, the successful studies were nonetheless based on forced up-titration to pre-specified target doses. Clinical audit and feedback have been shown to improve prescribing behaviour; however, additional contextspecific measures are required to support medication titration. The scope of clinical practice for nurses and pharmacists has successfully been extended to medication titration and builds on the recognised benefits of multidisciplinary HF disease management. However, strategies that engage primary care with timely communication, clear role delineation and point-of-care decision support may have wider applicability to allow the impressive gains demonstrated in the clinical trials to be applied to the broader HF population. ■

American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013;62:e147–239. DOI: 10.1016/j.jacc.2013.05.019; PMID: 23747642 Krum H, Jelinek MV, Stewart S, et al. 2011 update to National Heart Foundation of Australia and Cardiac Society of Australia and New Zealand guidelines for the prevention, detection and management of chronic heart failure in Australia, 2006. Med J Aust 2011;194:405–9. PMID: 21495941 CIBIS-II Investigators and Committees. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet 1999;353:9–13. PMID: 10023943 MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 1999;353:

2001–7. PMID: 10376614 Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 1999;341:709–17. DOI: 10.1056/ NEJM199909023411001; PMID: 10471456 8. Swedberg K, Kjekshus J. Effects of enalapril on mortality in severe congestive heart failure: results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). Am J Cardiol 1988;62:60A–66A. DOI: 10.1056/ NEJM198706043162301; PMID: 2883575 9. Zannad F, McMurray JJ, Krum H, et al; EMPHASIS-HF Study Group. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med 2011;364:11–21. DOI: 10.1056/ NEJMoa1009492; PMID: 21073363 10. SOLVD Investigators. Effect of enalapril on survival in

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24.

25.

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20805094 26. M aggioni AP, Anker SD, Dahlstrom U, et al; Heart Failure Association of the ESC. Are hospitalized or ambulatory patients with heart failure treated in accordance with European Society of Cardiology guidelines? Evidence from 12,440 patients of the ESC Heart Failure Long-Term Registry. Eur J Heart Fail 2013;15:1173–84. DOI: 10.1093/eurjhf/hft134; PMID: 23978433 27. Ryder M, Travers B, Timmons L, et al. Specialist nurse supervised in-hospital titration to target dose ACE inhibitor – is it safe and feasible in a community heart failure population? Eur J Cardiovasc Nurs 2003;2:183–8. DOI: 10.1016/ S1474-5151(03)00063-X; PMID: 14622625 28. Cleland JG, Swedberg K, Follath F, et al; Study Group on Diagnosis of the Working Group on Heart Failure of the European Society of Cardiology. The EuroHeart Failure survey programme – a survey on the quality of care among patients with heart failure in Europe. Part 1: patient characteristics and diagnosis. Eur Heart J 2003;24:442–63. PMID: 12633546 29. Lenzen MJ, Boersma E, Reimer WJ, et al. Under-utilization of evidence-based drug treatment in patients with heart failure is only partially explained by dissimilarity to patients enrolled in landmark trials: a report from the Euro Heart Survey on Heart Failure. Eur Heart J 2005;26:2706–13. DOI: 10.1093/ eurheartj/ehi499; PMID: 16183692 30. Gustafsson F, Schou M, Videbaek L, et al. Treatment with betablockers in nurse-led heart failure clinics: titration efficacy and predictors of failure. Eur J Heart Fail 2007;9:910–6. DOI: 10.1016/j.ejheart.2007.05.008; PMID: 17572146 31. Cabana MD, Rand CS, Powe NR, et al. Why don’t physicians follow clinical practice guidelines? A framework for improvement. JAMA 1999;282:1458–65. PMID: 10535437 32. Carroll R, Mudge A, Suna J, et al. Prescribing and up-titration in recently hospitalized heart failure patients attending a disease management program. Int J Cardiol 2016;216:121–7. DOI: 10.1016/j.ijcard.2016.04.084; PMID: 27153136 33. Fonarow GC, Abraham WT, Albert NM, et al. Dosing of betablocker therapy before, during, and after hospitalization for heart failure (from Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure). Am J Cardiol 2008;102:1524–9. DOI: 10.1016/j.amjcard.2008.07.045; PMID: 19026308 34. Jain A, Mills P, Nunn LM, et al. Success of a multidisciplinary heart failure clinic for initiation and up-titration of key therapeutic agents. Eur J Heart Fail 2005;7:405–10. DOI: 10.1016/j.ejheart.2004.09.009; PMID: 15718181 35. Driscoll A, Srivastava P, Toia D, et al. A nurse-led up-titration clinic improves chronic heart failure optimization of betaadrenergic receptor blocking therapy – a randomized controlled trial. BMC Res Notes 2014;7:668. DOI: 10.1186/17560500-7-668; sPMID: 25248944 36. Driscoll A, Krum H, Wolfe R, et al; BENCH Study Group. Nurseled titration of β-adrenoreceptor blocking agents in chronic heart failure patients in the community. Journal of Cardiac Failure 2011;17:224–30. DOI: 10.1016/j.cardfail.2010.10.010 37. Martinez AS, Saef J, Paszczuk A, et al. Implementation of a pharmacist-managed heart failure medication titration clinic. Am J Health Syst Pharm 2013;70:1070–6. DOI: 10.2146/ajhp120267; PMID: 23719886 38. Lowrie R, Mair FS, Greenlaw N, et al; Heart Failure Optimal Outcomes from Pharmacy Study (HOOPS) Investigators. Pharmacist intervention in primary care to improve outcomes in patients with left ventricular systolic dysfunction. Eur Heart J 2012;33:314–24. DOI: 10.1093/eurheartj/ehr433; PMID: 22083873 39. Ansari M, Shlipak MG, Heidenreich PA, et al. Improving guideline adherence: a randomized trial evaluating strategies to increase beta-blocker use in heart failure. Circulation 2003;107:2799–804. DOI: 10.1161/01. CIR.0000070952.08969.5B; PMID: 12756157 40. Scott IA, Denaro CP, Bennett CJ, et al. Achieving better in-hospital and after-hospital care of patients with acute cardiac disease. Med J Aust 2004;180:S83–8. PMID: 15139843 41. Laramee AS, Levinsky SK, Sargent J, et al. Case management in a heterogeneous congestive heart failure population: a randomized controlled trial. Arch Intern Med 2003;163:809–17. DOI: 10.1001/archinte.163.7.809; PMID: 12695272

42. M oyer-Knox D, Mueller TM, Vuckovic K, et al. Remote titration of carvedilol for heart failure patients by advanced practice nurses. Journal of Cardiac Failure 2004;10:219–24 PMID: 15190531 43. Steckler AE, Bishu K, Wassif H, et al. Telephone titration of heart failure medications. J Cardiovasc Nurs 2011;26:29–36. DOI: 10.1097/JCN.0b013e3181ec1223; PMID: 21127425 44. Guder G, Stork S, Gelbrich G, et al. Nurse-coordinated collaborative disease management improves the quality of guideline-recommended heart failure therapy, patientreported outcomes, and left ventricular remodelling. Eur J Heart Fail 2015;17:442–52. DOI: 10.1002/ejhf.252; PMID: 25727879 45. Whellan DJ, Hasselblad V, Peterson E, et al. Metaanalysis and review of heart failure disease management randomized controlled clinical trials. Am Heart J 2005;149:722–9. DOI: 10.1016/j.ahj.2004.09.023; PMID: 15990759 46. Takeda A, Taylor SJ, Taylor RS, et al. Clinical service organisation for heart failure. Cochrane Database Syst Rev 2012;9:CD002752. DOI: 10.1002/14651858.CD002752.pub3; PMID: 22972058 47. Driscoll A, Currey J, Tonkin A, et al. Nurse-led titration of angiotensin converting enzyme inhibitors, beta-adrenergic blocking agents, and angiotensin receptor blockers for people with heart failure with reduced ejection fraction. Cochrane Database Syst Rev 2015;(12):CD009889. DOI: 10.1002/14651858. CD009889.pub2; PMID: 26689943 48. Hickey A, Suna J, Marquart L, et al. Improving medication titration in heart failure by embedding a structured medication titration plan. Int J Cardiol 2016;224:99–106. DOI: 10.1016/j.ijcard.2016.09.001; PMID: 27643473 49. Clark RA, Driscoll A. Access and quality of heart failure management programs in Australia. Aust Crit Care 2009; 22:111–6. DOI: 10.1016/j.aucc.2009.06.003; PMID: 19586780 50. Swennen MH, Rutten FH, Kalkman CJ, et al. Do general practitioners follow treatment recommendations from guidelines in their decisions on heart failure management? A cross-sectional study. BMJ Open 2013;3:e002982. DOI: 10.1136/ bmjopen-2013-002982 51. Luttik ML, Jaarsma T, van Geel PP, et al. Long-term follow-up in optimally treated and stable heart failure patients: primary care vs. heart failure clinic. Results of the COACH-2 study. Eur J Heart Fail 2014;16:1241–8. DOI: 10.1002/ejhf.173; PMID: 25302753 52. Gjesing A, Schou M, Torp-Pedersen C, et al. Patient adherence to evidence-based pharmacotherapy in systolic heart failure and the transition of follow-up from specialized heart failure outpatient clinics to primary care. Eur J Heart Fail 2013;15:671–8. DOI: 10.1093/eurjhf/hft011; PMID: 23397577 53. Tandon P, McAlister FA, Tsuyuki RT, et al. The use of betablockers in a tertiary care heart failure clinic: dosing, tolerance, and outcomes. Arch Intern Med 2004;164:769–74. DOI: 10.1001/archinte.164.7.769; PMID: 15078647 54. Franciosa JM, Massie BM, Lukas MA, et al; COHERE Participant Physicians. B-blocker therapy for heart failure outside the clinical trial setting: Findings of a communitybased registry. Am Heart J 2004;148:718–26. DOI: 10.1016/j. ahj.2004.04.006; PMID: 15459606 55. Mehta PA, McDonagh S, Poole-Wilson PA, et al. Heart failure in a district general hospital: are target doses of betablockers realistic? QJM 2004;97:133–9. PMID: 14976270 56. Lainscak M, Moullet C, Schön N, et al. Treatment of chronic heart failure with carvedilol in daily practice: the SATELLITE survey experience. Int J Cardiol 2007;122:149–55. DOI: 10.1016/j. ijcard.2007.08.001; PMID: 17804098 57. de Groote P, Isnard R, Assyag P, et al. Is the gap between guidelines and clinical practice in heart failure treatment being filled? Insights from the IMPACT RECO survey. Eur J Heart Fail 2007;9:1205–11. DOI: 10.1016/j.ejheart.2007.09.008; PMID: 18023249 58. Rector TS, Anand IS, Nelson DB, et al. Carvedilol versus controlled-release metoprolol for elderly veterans with heart failure. J Am Geriatr Soc 2008;56:1021–7. DOI: 10.1111/j.15325415.2008.01682.x; PMID: 18384583 59. Calvert MJ, Shankar A, McManus RJ, et al. Evaluation of the management of heart failure in primary care. Fam Pract 2009;26:145–53. DOI: 10.1093/fampra/cmn105 60. Bosch M, Wensing M, Bakx JC, et al. Current treatment of chronic heart failure in primary care; still room for improvement. J Eval Clin Pract 2010;16:644–50. DOI: 10.1111/j.1365-2753.2010.01455.x; PMID: 20438610

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Expert Opinion

Appendix I: Heart Failure Medication Titration Plan © 2017 Queensland Government. This form specifies the healthcare provider primarily responsible for medication titration, the order and extent of medication titration, and provides trouble-shooting guidelines. Form available at https://www.health.qld.gov.au/__data/assets/pdf_file/0018/428121/medn_titration.pdf

label here) URN: Family name:

[Insert facility name]

Heart Failure Medication Titration Plan

Given name(s): Address: Date of birth:

Sex:

- Titration to maximum tolerated doses of ACE inhibitor, beta-blocker and mineralocorticoid receptor antagonist (MRA) reduce morbidity and mortality in left ventricular systolic heart failure. - Check BP and pulse each visit and clinically review the patient prior to each dose adjustment. - Patients over 75 years old with co-morbidities are more likely to experience adverse effects. 1. Heart Failure Medications to be Titrated by (nominate person responsible): 2. Titrate First: (tick one only) MRA (Spironolactone/Eplerenone)

ACE inhibitor or Angiotensin II receptor antagonist (ARB)

Beta-blocker

3. Observations eGFR:

BP:

EF:

Target weight: kg

4. ACE Inhibitor or ARB (check electrolyte, creatinine and urea 1 week after commencing or titrating)

Weight:

5. Beta Blocker

Medication:

Current dose:

Target dose:

Increase dose by:

every

week(s)

Increase dose by:

every

week(s)

6. MRA (appropriate drug and dose) a Start if patients remain symptomatic (NYHA II–IV) despite appropriate doses of ACE inhibitor and Beta-Blocker. Ensure that baseline serum potassium is less than 5mmol/L and eGFR is greater than 30mL/min b Check electrolytes (especially serum potassium); creatinine and urea 1 week after commencing or titrating dose. Continue monitoring monthly for 6 months and then 6 monthly thereafter once stable dosing. c Medication Spironolactone Eplerenone

Starting dose

Target dose

12.5mg daily (eGFR 30–49mL/min) 25–50mg daily 25mg daily (eGFR greater than or equal to 50mL/min) 25mg daily

50mg daily

d Increase dose by:

every

week(s)

Caution: (i) eGFR may over estimate renal function in low body weight individuals. (ii) eGFR does not accurate renal function in individuals with

creatinine levels.

SW066

ÌSW066ÇÎ

v4.00 - 05/2016

7. Variable Dose Diuretic Action Plan An increased diuretic dose beyond 3 days requires medical review and blood chemistry. status and blood chemistry 3–7 days post reduction. A decreased diuretic dose requires assessment of Current diuretic:

Current dose:

Fluid overload: If weight increases by more than 2kg above stable weight for 2 days:

Increase dose to:

Dehydration: If weight decreases by more than 2kg below stable weight for 2 days and there are signs of dehydration (dizziness, postural hypotension, dry mucosa):

Decrease dose to:

Prescribed by (name): Consultant (name):

Signature:

HEART FAILURE MEDICATION TITRATION PLAN

DO NOT WRITE IN THIS BINDING MARGIN

Heart rate:

mL/min

[Insert Service Name] Date: Phone:

Fax:

Page 1 of 2 C A R D I A C FA I L U R E R E V I E W

Pharmacotherapy label here) URN: Family name:

Heart Failure Medication Titration Plan

Given name(s): Address: Date of birth:

Sex:

Heart Failure Medication Titration Problem Solving Guidelines NSAIDs or COX-2 inhibitors are contraindicated in patients with heart failure. Avoid negatively inotropic calcium-channel blockers (verapamil, diltiazem) in systolic heart failure.

worsening. No action is necessary if the change is small and patient is asymptomatic.

Hypotension •

Asymptomatic Hypotension does not usually require any change in therapy (systolic BP 90–100 mmHg).

•

Symptomatic Hypotension (dizziness, lightheadedness and/or confusion): i.

Stop or reduce calcium-channel blockers and/or other vasodilators unless essential e.g. for angina.

An eGFR decrease of up to 30% is acceptable provided it stabilises within 2 weeks, however, repeat electrolytes, creatinine and urea within 48 hours if required.

•

If the eGFR declines further than 30%, the patient should be reviewed urgently for clinical assessment of volume status and review of nephrotoxic medications. Seek specialist advice regarding the safety of continuing therapy.

•

Careful potassium monitoring is required:

ii. Consider reducing diuretic dose if there are no signs or symptoms of congestion. iii. Temporarily reduce ACE inhibitor or beta-blocker dose if above measures do not work. •

Severe symptomatic hypotension or shock requires immediate referral to an emergency department. Review patient as clinically appropriate (daily to weekly review) and seek specialist advice if the above measures do not work.

ii. If potassium rises greater than 5.6–5.9 mmol/L, cease all potassium supplements / retaining agents.

ACE inhibitors in heart failure •

•

iii. If potassium rises greater than 6 mmol/L, seek immediate specialist advice.

Angioedema, although rare, can occur at any time when using ACE inhibitors. Stop ACE inhibitor immediately and seek specialist advice. Trial of an Angiotensin II antagonist should only occur on specialist advice due to possible cross-sensitivity.

MRA in heart failure (Spironolactone/ Eplerenone)

Cough is common in patients with heart failure. Pulmonary oedema should be excluded as a cause if cough is new or worsening. If the patient develops a drug cough, that is likely to be caused by the ACE inhibitor, it is not always necessary to discontinue the drug. If the cough is troublesome and/or interferes with sleep, consider substituting ACE inhibitor with an angiotensin II receptor antagonist.

Worsening renal function •

•

If potassium rises greater than 5.0–5.5 mmol/L, review and reduce potassium supplements or potassium retaining agents (eg. amiloride, spironolactone, eplerenone).

ACE inhibitors are generally well tolerated even in renal impairment (creatinine patients with greater than 200 micromol/L or eGFR less than 30mL/ min). These patients are more vulnerable to acute renal failure following a destabilising event such as a dehydrating illness (sepsis, diarrhoea/vomiting), dehydration from over-diuresis or addition of nephrotoxic medications. NB. Advise patients experiencing such an event to seek urgent medical attention and to stop the ACE inhibitor until they are clinically reviewed and blood chemistry is checked. Some rise in urea, creatinine and potassium is expected after commencing an ACE inhibitor due to a decrease in eGFR. Blood chemistry must be checked several days after initiation of therapy and monitored closely thereafter to ensure kidney function is not

•

Stop the therapy if serum potassium is greater than 5.5 mmol/L or serum creatinine greater than 220 micromol/L.

•

Urgently check electrolytes (especially potassium) creatinine and urea if patient is dehydrated or septic.

DO NOT WRITE IN THIS BINDING MARGIN

•

Beta-blockers in heart failure Worsening symptoms / signs •

Worsening Congestion: increase the diuretic dose and if this does not work halve the dose of beta-blocker and liaise with the heart failure service.

•

Marked fatigue and/or bradycardia (see below) halve dose of beta-blocker (rarely necessary).

•

Bradycardia (less than 50 beats/min): review the need for other drugs that slow heart rate (e.g. digoxin, amiodarone) in consultation with specialist; and arrange ECG to exclude heart block.

•

If symptoms are worsening, review the patient as clinically appropriate (daily to weekly review); seek specialist advice if symptoms do not improve; and, if there is severe deterioration, stop beta-blocker and refer patient to an emergency department immediately.

This form is not intended to replace clinical judgement. Endorsed by Queensland Heart Failure Steering Committee. Date 9/12/2011. Copies of form can be obtained from: http://www.health.qld.gov.au/heart_failure Page 2 of 2

C A R D I A C FA I L U R E R E V I E W

Pharmacotherapy

How to Improve Adherence to Life-saving Heart Failure Treatments with Potassium Binders Mitja Lainscak Faculty of Medicine, University of Ljubljana and Department of Internal Medicine, General Hospital Murska Sobota, Ljubljana, Slovenia

Abstract Medications that affect the renin–angiotensin–aldosterone system (RAAS) form the mainstay of current heart failure (HF) therapy in patients with reduced ejection fraction. Concerns about the risk of hyperkalaemia have created a significant barrier to optimal RAAS inhibitor therapy in patients with HF, however, and many patients are discontinuing or receiving suboptimal doses of these lifesaving therapies. This has serious health and economic implications due to adverse renal and cardiovascular events. There is therefore an important unmet need for novel therapeutic options for the long-term management of patients with, and at risk for, hyperkalaemia. Two new potassium-binding agents, patiromer and ZS-9, have been shown to be effective and safe for the treatment of hyperkalaemia, as well as the maintenance of normokalaemia, without dose reduction or discontinuation of RAAS inhibitors. In addition, the fast onset of ZS-9 action suggests that it may be useful in the treatment of acute hyperkalaemia. These agents may allow for dose optimisation of RAAS inhibitors for the long-term maintenance and protection of the renal and cardiovascular system.

Keywords Heart failure, hyperkalaemia, renin–angiotensin–aldosterone inhibitors, patiromer, ZS-9 Disclosure: The author has no conflicts of interest to declare. Received: 12 December 2016 Accepted: 4 April 2017 Citation: Cardiac Failure Review 2017;3(1):33–9. DOI: 10.15420/cfr. 2017.2.1 Correspondence: Mitja Lainscak, General Hospital Murska Sobota, Dr. Vrbnjaka 6, SI-9000 Murska Sobota, Slovenia. E: mitja.lainscak@guest.arnes.si

The renin–angiotensin–aldosterone system (RAAS) is an essential regulatory component of cardiovascular homeostasis that exerts its actions through hormones, angiotensin II and aldosterone, which regulate vascular tone and blood pressure by causing vasoconstriction and renal sodium and water retention.1 Abnormalities in cardiac function in heart failure (HF) activate the RAAS and sympathetic nervous system in order to maintain perfusion of vital organs.2 Prolonged activation of these systems causes myocardial hypertrophy, fibrosis and apoptosis, increased systemic vascular resistance, increased sodium and water retention, and potassium excretion. This has led to the therapeutic use of RAAS inhibitors in HF,3,4 including angiotensin-converting enzyme inhibitors (ACEIs),5 angiotensin receptor blockers (ARBs)6 and mineralocorticoid receptor antagonists (MRAs).7 These drugs have become the mainstay of current therapy in heart failure with reduced ejection fraction (HFrEF). While RAAS inhibitors have substantial clinical benefit in patients with HFrEF, they interfere with the stimulatory effect of angiotensin II on aldosterone secretion in the adrenal gland,8 resulting in decreased aldosterone concentrations, decreased delivery of sodium to the distal nephron, abnormal collecting tubule function and impaired renal excretion of potassium, leading to hyperkalaemia.9 This is particularly common in patients with hypovolemia and worsening of renal function. Furthermore, physiological changes associated with HF progression may influence the pharmacokinetics and pharmacodynamics of all drugs used in patients with HF.10 As a result of the risk of hyperkalaemia, many patients are maintained on suboptimal RAAS inhibitor therapy (both in terms of individual drug classes and daily dose) or even discontinuing therapy. Clinical data suggest that higher

doses of RAAS inhibitors than those currently in use might be most effective11,12 but at present this cannot be tested because of the risk of inducing hyperkalaemia. This article aims to discuss the management of HF patients who require RAAS blockade but are at risk of worsening renal function and hyperkalaemia, as well as describing two new potassium binders that have the potential to allow more HF patients to receive optimal doses of guideline-recommended therapies.

Hyperkalaemia: Prevalence and Risk Factors Hyperkalaemia is defined as serum potassium concentration >5.0 mEq/l and may result from extracellular shifts of potassium, excessive ingestion of potassium and/or impaired elimination of potassium by the kidneys.13 The European Society of Cardiology guidelines advise caution in the initiation of ACEIs or ARBs if potassium levels exceed 5.0 mEq/l and state that if during therapy potassium rises to >5.5 mEq/l, the ACEI or ARB should be adjusted or stopped and specialist advice sought.14 Laboratory monitoring of potassium levels after MRA initiation frequently does not meet guideline recommendations, even in patients at higher risk for complications or in a specialised setting, placing patients at risk of hyperkalaemia that goes unnoticed.15 In clinical trials evaluating RAAS inhibitor therapy in patients with HFrEF, such as the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF) and Randomized Aldactone Evaluation Study (RALES), severe hyperkalaemia (defined as serum potassium concentration ≥6.0 mEq/l) has been reported

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Pharmacotherapy in around 2.0–2.5 % of participants.7,16 Hyperkalaemia of any degree has been reported in 10 % of patients within a year of initiating RAAS blockade and is severe in approximately 1 % of patients with diabetes.17–19 However, patients with baseline renal dysfunction or hyperkalaemia were excluded from these clinical trials and there are strict protocols in place to minimise risk of significant side effects in such trials. In more advanced stages of chronic HF, as renal function begins to decline the risk of hyperkalaemia increases significantly; an incidence of between 5 and 10 % has been reported in patients with chronic kidney disease (CKD), and this increases with disease stage. 20,21 Hypokalaemia is also highly prevalent in older HF patients. In the Trial of Intensified versus Standard Medical Therapy in Elderly Patients with Congestive Heart Failure (TIME-CHF), in which patients ≥60 years of age (n=586) were randomised to a standard versus an intensified N-terminal brain natriuretic peptide-guided HF therapy, during 18-month follow up hyperkalaemia (≥5.5 mEq/l) was reported in 13.4 % of patients, with severe hyperkalaemia (≥6.0 mEq/l) in 4.9 %. 22 Renal dysfunction is a common comorbidity in HF patients.23 A study of 552 hospitalised HF patients reported a mean estimated glomerular filtration rate (eGFR) of 66.9±30.4 ml/min/m², severe kidney failure (eGFR<30 ml/min/1.73 m²) in 8.0 %, moderate kidney failure (eGFR 30–60 ml/min/1.73 m²) in 35.5 %, and an eGFR of >60 ml/min/1.73 m² (no/mild kidney failure) in 56.5 %.24 In the European Society of Cardiology HF Pilot study, a prospective, multicentre, observational survey conducted in 136 cardiology centres in 12 European countries (n=5,118), severe kidney failure was reported in 9.9 % of patients with acute HF and 5.1 % with chronic HF; eGFR of >60 ml/min/1.73 m² was reported in 49.3 % and 40.6 % of acute and chronic HF patients, respectively.25 In the EuroHeart Failure Survey of 3,658 patients with HF due to left ventricular systolic dysfunction, eGFR <60 ml/min/1.73 m² was reported in 52.6 % of participants. Renal dysfunction was associated with lower prescription of ACEIs at discharge (74 % versus 83 %, p<0.001).26 The difference between controlled clinical studies and routine clinical practice was illustrated by RALES, which investigated the MRA spironolactone in patients with HF and serum creatinine <2.5 mg/dl. This study reported only a 2 % incidence of hyperkalaemia,7 but following its publication abrupt increases were seen in the rate of prescriptions for spironolactone and in hyperkalaemia-associated morbidity and mortality.27 There is also a dose-dependent increase in the risk of hyperkalaemia with escalation in RAAS inhibitor therapy. In the RALES dose-finding study, the incidence of hyperkalaemia was 5 % with 12.5 mg spironolactone but was 24 % with a 75 mg dose.28 The EMPHASIS-HF study investigated the safety and efficacy of the MRA eplerenone in patients with systolic HF and mild symptoms (New York Heart Association functional class II). Eplerenone reduced cardiovascular death or HF hospitalisation when added to evidencebased therapy (including RAAS inhibitors and beta-blockers), although hyperkalaemia was reported as an adverse effect (8 % in the eplerenone group versus 3.7 % in the placebo group; p<0.001).16 In an analysis of high-risk subgroups, patients treated with eplerenone had an increased risk of potassium >5.5 mEq/l, but not of potassium >6.0 mEq/l, and of hospitalisation for hyperkalaemia.29 Despite this, the incidence of hyperkalaemia did not eliminate the survival benefit of eplerenone.30 Serum potassium levels and renal function should be assessed prior to initiating eplerenone therapy and periodic

monitoring should be undertaken, especially in patients at high risk of developing hyperkalaemia.31 In a recent secondary analysis of the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure (PARADIGM-HF) study, severe hyperkalaemia (potassium >6.0 mEq/l) was more common in patients randomly assigned to enalapril than to sacubitril/valsartan (3.1 versus 2.2 per 100 patientyears; hazard ratio: 1.37, 95 % CI [1.06–1.76]; p=0.02).32 These data suggest that neprilysin inhibition attenuates the risk of hyperkalaemia when MRAs are combined with other RAAS inhibitors in patients with HF. The exclusion from clinical trials of patients who are at the greatest risk for hyperkalaemia means that its true incidence may have been underestimated: in a study at an outpatient centre of 1,818 patients using ACEIs, 11 % of patients developed hyperkalaemia.33 In addition to this, patients in clinical trials are closely monitored, including frequent blood tests and clinical visits. As a result, rising serum potassium levels are more likely to be addressed at an early stage. Risk factors for hyperkalaemia in patients with HF include: age >65 years; comorbidities that impair kidney function and decrease eGFR, including diabetes (in which a prevalence of 15 % has been reported)34 and kidney disease (e.g. acute or chronic tubulointerstitial renal disease, diabetic nephropathy, renal transplants, urinary tract obstruction, systemic lupus erythematosus and sickle cell disease); current use of potassium-sparing diuretics, excessive potassium ingestion and the use of several concomitant medications including non-steroidal anti-inflammatory drugs (NSAIDs), antimicrobial drugs and beta-blockers.17,35–37 NSAIDs may also impair renal function in patients with HF.38 Since diabetes, CKD and HF occur together in many patients, hyperkalaemia presents a significant clinical challenge and an unfortunate paradox: while RAAS inhibitor therapy reduces morbidity and mortality in patients with HF, it increases the risk of hyperkalaemia in these already high-risk patients. The clinical consequences of hyperkalaemia are severe: arrhythmias and asystole that may lead to cardiac arrest and sudden death.39,40 Hyperkalaemia is responsible for increased morbidity, mortality and hospitalisations in patients with HF, particularly in older patients with comorbidities.27,36,41 Severe hyperkalaemia has a mortality rate of up to 30 % if not treated rapidly.42 Interestingly, one study found that the association between hyperkalaemia and mortality was no longer significant if the plasma potassium decreased by ≥1 mEq/l within 48 h of admission to the critical care unit.43 In addition to the direct risk imposed by increased serum potassium, intermittent hyperkalaemia has a more serious negative impact on clinical outcomes because its treatment usually involves discontinuation or dose reductions of lifesaving drugs.44 Although clinical data show that up-titrating RAAS inhibitors confers significant clinical benefit,11,12 the dosage of RAAS inhibitors is often suboptimal in everyday clinical practice,45,46 with one study reporting that less than one-third of eligible patients hospitalised for HF received guideline-recommended aldosterone antagonist therapy.47 Underutilisation of RAAS inhibitors results largely from clinician fears of adverse effects including hyperkalaemia.48 There is therefore a need for effective treatment options for hyperkalaemia.

Treatment Options for Hyperkalaemia Therapeutic goals for patients with acute hyperkalaemia are to reverse adverse cardiac effects, shift potassium into the cells, eliminate

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Potassium Binders potassium from the body and normalise serum potassium levels. Acute treatments include 25–50 % intravenous glucose, calcium gluconate or chloride, insulin, sodium bicarbonate, beta-2-agonists, diuretics, cationexchange salts and haemodialysis.49 However, these treatments are temporary and often inadequate; costly and invasive haemodialysis is usually needed for patients with severe hyperkalaemia.50 For >50 years, sodium polystyrene sulfonate (SPS), a cation-exchange resin that binds potassium in the colon, has been used in the longterm lowering of serum potassium levels.51 It is, however, intolerable to many, has never been tested in a randomised controlled trial and there are questions regarding its efficacy and safety.52 The administration of SPS alone can lead to severe constipation and impaction, which have led to its co-administration with sorbitol. Treatment with SPS and sorbitol, however, has been shown to cause potentially fatal colonic necrosis.52,53 SDS has a boxed warning for colonic necrosis and its use is contraindicated in patients who do not have normal bowel function.54 Despite concerns related to colonic necrosis, this serious complication appears to be rare: a retrospective cohort study found an incidence of 0.14 % in 2,194 patients prescribed SPS versus 0.07 % in those not prescribed SPS (p=0.2). Other strategies for the control of intermittent hyperkalaemia include the restriction of dietary potassium, but this leads to poor dietary adherence and limits healthy food choices that are associated with beneficial cardiovascular outcomes.55 Patients with HF are advised to restrict sodium intake, which leads to them using salt substitutes that are rich in potassium – a case was reported in The Lancet in 2013.56 For many years there remained an unmet need for a hyperkalaemia therapy that was effective, safe and well tolerated. In October 2015 the US Food and Drug administration approved the first new potassium binder for the treatment of hyperkalaemia in >50 years.57 Patiromer is an organic, high-capacity cation-exchange polymer in the form of its calcium salt complexed with sorbitol (ratio 2:1), and exchanges calcium for potassium as it moves through the colon, preventing the reabsorption of potassium and facilitating its elimination in the faeces (see Figure 1).58,59 It is a dry, odourless, tasteless powder that has a low viscosity, consisting of small (100 µm) uniform beads that swell minimally when suspended in water, and is typically administered in 40 ml of water with a meal.58 It does not require co-administration with a laxative and is more palatable than SPS. Four clinical studies have demonstrated the efficacy of patiromer in decreasing serum potassium, preventing the recurrence of hyperkalaemia and reducing RAAS inhibitor discontinuation (see Table 1). RLY5016 in the Treatment of Hyperkalemia in Patients With Hypertension and Diabetic Nephropathy (AMETHYST-DN), was a phase II, multicentre, randomised, open-label, dose-ranging study of patients (n=304) with type 2 diabetes and CKD stage 3 or above (eGFR 15 ml to <60 ml/min/1.73 m2) and serum potassium >5.0 mEq/l in the setting of RAAS inhibitor dose optimisation for blood pressure control, or who were on a RAAS inhibitor and had serum potassium >5.0 mEq/l at the time of screening. After 4 weeks, patients in the patiromer group showed statistically significant decreases in serum potassium levels, which were maintained throughout the 52-week treatment period.60 The Two-Part, Single-Blind, Phase III Study Evaluating the Efficacy and Safety of Patiromer for the Treatment of Hyperkalemia (OPAL-HK) trial was a phase III study that evaluated the efficacy and safety of

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Figure 1: Mechanisms of Action of ZS-9 and Patiromer Dietary potassium

Patiromer H+/K+ ATPase

Decrease extracellular potassium Extracellular potassium

ZS-9 Potassium absorption

Potassium excretion

Increase extracellular potassium Urinary loss of potassium

Source: Adapted from van der Meer et al. 2011.59

patiromer for the treatment of hyperkalaemia in patients with stage 3 or 4 CKD on ≥1 RAAS inhibitor. By week 4 of the initial treatment phase, three-quarters of patients taking patiromer achieved normal potassium levels.58 Finally, a multicentre, open-label 52-week trial evaluated patiromer in patients with HF and CKD, type 2 diabetes and hypertension. Patiromer reduced and maintained mean serum potassium ≤5.0 mEq/l for up to 1 year in HF and was well tolerated.61 Patiromer has also been evaluated for the prevention of hyperkalaemia in patients. The Evaluation of RLY5016 in Heart Failure Patients (PEARLHF) was a multicentre, randomised, double-blind, placebo-controlled parallel group multiple-dose study in patients receiving standard therapy and spironolactone (n=105). Spironolactone was given to both groups at 25 mg/day and increased to 50 mg/day if serum potassium was ≤5.1 mEq/l. From day 3, the patiromer group had significantly lower serum potassium levels than the placebo group, and at the end of the treatment period (week 4) the patiromer group had a significantly lower incidence of hyperkalaemia. In addition, the administration of patiromer enabled the dosage of spironolactone to be up-titrated while still maintaining normokalaemia.62 Another agent in clinical development, sodium zirconium cyclosilicate (ZS-9), is an orally-administered, insoluble, non-absorbed inorganic sodium–potassium cation exchange agent that is >125 times more selective for potassium ions than SDS in vitro.13 The potassium-lowering action of ZS-9 is based on size-selective micropores in the zirconium silicate crystalline lattice structure that trap potassium in the intestinal tract (Figure 2).13 It has been hypothesised that the hydronium sites are responsible for the majority of potassium binding, exchanging protons for potassium ions, leaving most of the sodium ions bound to ZS-9 in a less exchangeable site. The exact mechanism of how the exchange occurs, however, has not been determined.13 Preclinical studies suggest that ZS-9 acts throughout the entire gastrointestinal tract.13 ZS-9 has demonstrated excellent efficacy in three large clinical trials (see Table 1). In a two-phase dose-finding phase III study, patients with hyperkalaemia (n=753) were randomised to receive either ZS-9 or placebo three times daily for 48 h. Patients who achieved normokalaemia (serum potassium 3.5–4.9 mEq/l) at 48 h were randomly assigned to receive either ZS-9 or placebo once daily on days 3–14 (maintenance phase).63 The Hyperkalemia Randomized Intervention Multidose ZS-9 Maintenance (HARMONIZE) study was a randomised, double-blind, placebo-controlled phase III trial with

Pharmacotherapy Table 1: Key Clinical Studies Involving ZS-9 and Patiromer Treatment

Trial Design

ZS-9 0.3 g (n=12), 3 g (n=24), Phase II randomised, double-blind, 10 g (n=24), or placebo (n=30) placebo-controlled, dose-escalation for 2 days with meals study of 90 patients with stable stage 3 CKD and HK66

Key Efficacy Findings

Key Safety Findings

Mean s-K+ decreased by 0.92±0.52 mEq/l at 38 h. Urinary K+ excretion decreased with 10 g ZS-9 versus placebo at day 2 (+15.8±21.8 versus +8.9±22.9 mEq/l per 24 h) from placebo at day 2

No serious AEs reported; only mild constipation in the 3 g dose group was possibly related to treatment

ZS-9 (10 g) three times daily in HARMONIZE phase III randomised, s-K+ significantly lower on days 8–29 in all 258 patients in initial 48-h double-blind, placebo-controlled trial ZS-9 groups versus placebo (4.8 mEq/l, 4.5 mEq/l, and 4.4 mEq/l for 5 g, 10 g, and 15 g, respectively, open-label phase; patients in 237 outpatients with HK64 with normokalaemia at 48 h versus 5.1 mEq/l for placebo; p<0.001 for all received ZS-9 5 g (n=45), 10 g comparisons). Proportion of patients with mean (n=51), 15 g (n=56), or placebo s-K+ <5.1 mEq/l on days 8–29 was significantly (n=85) daily for 28 days in higher in all ZS-9 groups compared with placebo randomised phase (80 %, 90 %, and 94 % for 5 g, 10 g, and 15 g versus 46 % for placebo; p<0.001 for each dose versus placebo)

AEs were comparable between zirconium cyclosilicate and placebo, although oedema was more common in the 15 g group (oedema incidence: 2 %, 2 %, 6 % and 14 % in the placebo, 5 g, 10 g, and 15 g groups). HK developed in 10 % and 11 % in the 10 g and 15 g zirconium cyclosilicate groups versus none in the 5 g or placebo groups

ZS-9 (10 g) three times daily Substudy of HARMONIZE phase III trial in 94 patients in initial 48-h in patients with a history of HF65 open-label phase; patients with normokalaemia at 48 h received ZS-9 5 g (n=18), 10 g (n=18), 15 g (n=18), or placebo (n=25) daily for 28 days in randomised phase

Safety profile similar to that of HARMONIZE

Patients on 5 g, 10 g, and 15 g ZS-9 maintained a lower potassium level (4.7 mEq/l, 4.5 mEq/l, and 4.4 mEq/l, respectively) than the placebo group (5.2 mEq/l; p<0.01 versus each ZS-9 group); greater proportions of ZS-9 patients (83 %, 89 %, and 92 %, respectively) maintained normokalaemia than placebo (40 %; p<0.01 versus each ZS-9 group)

ZS-9 1.25 g (n=145), 2.5 g (n=141), Two-stage phase III double-blind, Initial phase: mean exponential reduction Rates of AEs were similar in the 5 g (n=158), 10 g (n=143) or placebo-controlled trial in patients from baseline per hour in s-K+ at 48 h: ZS-9 ZS-9 group and the placebo 1.25 g, 0.11 % (p>0.05); 2.5 g, 0.16 % (p<0.001); group (12.9 % and 10.8 %, placebo (n=158) three times with HK63 daily for 48 h in 753 patients 5 g, 0.21 % (p<0.001); and 10 g, 0.30 % (p<0.001) respectively, in the initial phase; (initial phase); 543 patients versus placebo, 0.09 %. Maintenance phase: 25.1 % and 24.5 %, respectively, with normokalaemia at 48 h ZS-9 5 g and 10 g significantly superior to in the maintenance phase). received ZS-9 or placebo once placebo in maintaining normokalaemia Diarrhoea was the most daily on days 3–14 (maintenance (p=0.008 and p<0.001, respectively) common complication in the phase) two study groups Patiromer 4.2 g or 8.4 g twice Single-group, single-blind study of daily in patients with mild or 237 patients with CKD and HK moderate HK, respectively, for receiving RAAS inhibitors in the 4 weeks (initial phase); patients initial treatment phase; placebo- continued with patiromer (n=55) controlled, single-blind, randomised or switched to placebo (n=52) withdrawal phase (n=107)58 for an additional 8 weeks (withdrawal phase)

Initial phase: mean change in s-K+ level: −1.01 mEq/l (p<0.001). At week 4, 76 % of patients had reached the target potassium level (3.8–<5.1 mEq/l). Estimated median change in s-K+ to week 4 of withdrawal phase: 0 mEq/l for patiromer versus 0.72 mEq/l for placebo (p<0.001)

Mild-to-moderate constipation was the most common AE (11 %); HK occurred in 3 %

For mild HK, patiromer 4.2 g Phase II, open-label, dose-ranging, Mean reductions in s-K+ in patients with (n=74), 8.4 g (n=74), or 12.6 g randomised study in outpatients mild HK: 4.2 g, 0.35 mEq/l; 8.4 g, (n=74) twice daily; for moderate with type-2 diabetes and mild 0.51 mEq/l; 12.6 g, 0.55 mEq/l Mean reductions in s-K+ in patients with HK, patiromer 8.4 g (n=26), (n=222) or moderate (n=84) HK60 12.6 g (n=28), or 16.8 g (n=30) moderate HK: 8.4 g, 0.87 mEq/l; 12.6 g, twice daily; all patients received 0.97 mEq/l; 16.8 g, 0.92 mEq/l RAAS inhibitors

Hypomagnesemia (7.2 %) was the most common treatmentrelated AE, mild-to-moderate constipation (6.3 %) was the most common gastrointestinal AE, and hypokalaemia (<3.5 mEq/l) occurred in 5.6 % of patients

Patiromer 15 g twice daily Double-blind, randomised, placebo- Significantly reduced mean s-K+ with or placebo twice daily for controlled, parallel-group study of patiromer versus placebo at week 4 4 weeks. Spironolactone, patients with HF and a history of (−45 mEq/l, p<0.001) initiated at 25 mg/day, was HK or CKD (n=105)62 increased to 50 mg/day on day 15 if K+ was ≤5.1 mEq/l

AEs were mainly gastrointestinal, and mild or moderate in severity. AEs resulting in study withdrawal were similar (7 % RLY5016, 6 % placebo). There were no drugrelated serious AEs. HK (K+ <3.5 mEq/l) occurred in 6 % of RLY5016 patients versus 0 % of placebo patients (p=0.094)

Patiromer starting doses by Multicentre open-label trial patients baseline s-K+: >5.0–5.5 mEq/l with HF and CKD, diabetes mellitus, (4.2, 8.4 or 12.6 g twice daily), hypertension and s-K+ >5.0 mEq/l, mild HK (n=220); and >5.5– 52 weeks61 <6.0 mEq/l (8.4, 12.6 or 16.8 g twice daily), moderate HK (n=84); then titrated to achieve-maintain s-K+ ≤5.0 mEq/l

AE in 7 %; diarrhoea was the most common gastrointestinal AE (4.8 %, none severe)

Reductions in s-K+ (p<0.001) at 48 h in HF (n=105) and non-HF (n=199) patients with mild and moderate HK, from respective baseline means of 5.1 and 5.6 mEq/l (HF) and 5.2 and 5.7 mEq/l (non-HF), with similar effects across dose groups. In HF patients, mean s-K+ was controlled (≤5.0 mEq/l) at 48 h (mild HK) and week 1 (moderate HK) and maintained for 52 weeks. Similar results in non-HF patients

AE = adverse event; CKD = chronic kidney disease; GI = gastrointestinal; HARMONIZE = The Hyperkalemia Randomized Intervention Multidose ZS-9 Maintenance; HF = heart failure; HK = hyperkalaemia; RAAS = renin–angiotensin–aldosterone system; s-K+ = serum potassium.

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Potassium Binders Figure 2: ZS-9 Pore Detail A

B zr

zr o

K+

Na+

Ca2+

si si

si o

o zr

o si

o zr

(A) Potassium ion; (B) sodium ion; and (C) calcium ion pore structure. Source: Stavros et al, 201413. Reproduced under Creative Commons, © The Authors 2014.

an open-label phase (n=258) and a randomised phase (n=257). The use of ZS-9 normalised serum potassium within a median of 2.2 h and normal potassium levels were maintained for up to 28 days in a high proportion of patients on all ZS-9 doses. Patients with higher baseline serum potassium levels experienced greater reductions. All doses of ZS-9 reduced serum aldosterone, and the efficacy was not affected by the use of RAAS inhibitors.64 In a substudy of HARMONIZE, HF patients with evidence of hyperkalaemia (serum potassium ≥5.1 mEq/l, n=94) were treated with open-label ZS-9 for 48 h. Patients (n=87; 60 receiving RAAS inhibitors) who achieved normokalaemia were randomly assigned to daily ZS-9 or placebo for 28 days. The majority of patients (69 %) in this study received RAAS inhibitors while taking ZS-9 and maintained normal serum potassium levels without adjustment of their RAAS inhibitor dose.65 In addition, a phase II randomised, double-blind, placebo-controlled, dose-escalation study evaluated ZS-9 in HF patients with stable stage 3 CKD and hyperkalaemia (n=90). ZS-9 caused a rapid, sustained reduction in serum potassium and was well tolerated.66 The long-term safety and efficacy of ZS-9 are being evaluated in an ongoing open-label phase III study, ZS-005. Patients (n=751) with hyperkalaemia (defined as serum potassium ≥5.1 mEq/l) received an induction regimen of ZS-9 10 g three times daily for 24–72 h. Those whose potassium reached normal levels on the study drug – a serum potassium level of 3.5–5.0 mEq/l – received a maintenance regimen of ZS-9 5 g/day for a maximum of 12 months. Interim results for 436 patients who had completed at least 6 months of treatment were presented recently. The mean serum potassium was 4.7 mEq/l, and almost 90 % of patients had a mean serum potassium ≤5.1 mEq/l over months 3–12.67 The US Food and Drug Administration issued a Complete Response Letter regarding the New Drug Application for ZS-9 in May 2016 due to observations arising from a pre-approval manufacturing inspection;68 however, resubmission is expected.

Comparison of Potassium-binding Agents A comparison of the available potassium-binding agents is given in Table 2. Of the three, ZS-9 and patiromer offer greater potassiumbinding selectivity than SDS and are unaffected by the presence

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Table 2: Comparison of Therapies for Intermittent Hyperkalaemia Property

Sodium

Patiromer

ZS-9

Chemical Cation-exchange properties polymer resin

Non-absorbed organic resin and sorbitol complex; preferentially binds K+ in the colon

Inorganic crystalline polymer; enables cation exchange

Sorbitol content

2 g in each 4.2 g

None

polystyrene sulfonate

20 g in each 15 g

Site of action Colon Colon

Entire gastrointestinal tract

Means of Daily; oral suspension Twice daily; oral administration or enema suspension in water with meals

Three times daily (acute); daily (long-term); oral suspension or tablet

Time to onset 12 h of action

7 h

of calcium or magnesium ions.13,58 ZS-9 has the fastest onset of action: within 1 h 64 compared to within 12 h for SPS 69 and within 7 h for patiromer.70 A combined analysis of both phase III trials of ZS-9 focused on the short-term changes in serum potassium of receiving an initial 10 g dose of ZS-9 in a subpopulation of patients with severe hyperkalaemia (defined as serum potassium 6.1–7.2 mEq/l). The mean serum potassium was reduced by 0.4 mEq/l at 1 h, 0.6 mEq/l at 2 h and 0.7 mEq/l at 4 h. The median time to serum potassium levels <6 and 5.5 mEq/l were 1.07 and 4 h, respectively. No cases of hypokalaemia or adverse effects were reported during the first 48 h of ZS-9 therapy.71 ZS-9 may therefore be useful in the acute setting. All three agents are available as oral suspensions, although SPS can also be used as an enema.72 SPS may be administered one to four times daily, depending on the desired total dose. In clinical trials, patiromer was administered twice daily for maintenance therapy,58,60–62 whereas ZS-9 was administered once daily.63,64 However, in acute use for initial lowering of potassium over 48 h, ZS-9 was typically given three times daily.64,66

Pharmacotherapy SDS when administered alone is associated with severe gastrointestinal side effects, making it unsuitable for routine use. Adverse effects with patiromer include mild-to-moderate constipation (up to 11 %), hypokalaemia (5–6 %) and hypomagnesemia (3–24 %), but these have not been reported to be serious. For ZS-9, mild constipation/ diarrhoea (2–8.7 %), hypokalaemia (around 10 % depending on dose) and oedema (2–4 %) have been reported. The latter was not serious in the clinical studies but, given the relationship between oedema and HF, patients should be monitored.

Practical Aspects of Treatment with Potassiumbinding Agents It is essential that the use of these therapies does not result in less stringent monitoring of patients’ potassium levels. Patients with HF and renal failure and at risk for hyperkalaemia need very close clinical follow-up, including laboratory testing, even if they are taking potassium binders. In addition, ZS-9 and patiromer require close monitoring for hypokalaemia, and ZS-9 requires monitoring for oedema. It is important to educate patients in the importance of adherence to these therapies; the once-daily dosing of ZS-9 may be advantageous in this respect. Although clinical studies to date have not identified significant drug– drug interactions, one potential complication of these agents is their ability to bind other drugs. Patiromer binds furosemide, metoprolol and amlodipine, which are among the most common drugs prescribed to CKD patients. Patiromer carries a boxed warning stating that there should be a 6-h window between taking any orally-administered medication and patiromer.57

Summary and Concluding Remarks The management of hyperkalaemia in patients taking RAAS inhibitors in HF is challenging, and often leads to suboptimal use of these lifesaving drugs, resulting in increased morbidity and mortality. Clinical trial data indicate that patiromer and ZS-9 are effective, safe and predictable options for the treatment of hyperkalaemia, as well as the maintenance of normokalaemia, without the dose reduction or discontinuation of RAAS inhibitors. In addition, ZS-9 offers the potential for acute therapy in conscious patients instead of insulin and glucose. Acute dialysis for the sole indication of hyperkalaemia may also be eliminated. It must be stressed that patiromer has been shown to demonstrate safety and efficacy over 52 weeks, but long-term safety data for

v on Lueder TG, Sangaralingham SJ, Wang BH, et al. Reninangiotensin blockade combined with natriuretic peptide system augmentation: novel therapeutic concepts to combat heart failure. Circ Heart Fail 2013;6:594–605. DOI: 10.1161/ CIRCHEARTFAILURE.112.000289; PMID: 23694773 Schrier RW, Abdallah JG, Weinberger HH, et al. Therapy of heart failure. Kidney Int 2000;57:1418–25. DOI: 10.1046 /j.1523-1755.2000.00986.x Brewster UC, Setaro JF, Perazella MA. The renin-angiotensinaldosterone system: cardiorenal effects and implications for renal and cardiovascular disease states. Am J Med Sci 2003;326:15–24. PMID: 12861121 McMurray JJ, Adamopoulos S, Anker SD, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J 2012;33:1787–847. DOI: 10.1093/eurheartj/ehs104; PMID: 22611136 Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. The SOLVD Investigators. N Engl J Med 1991;325:293–302. DOI: 10.1056/NEJM199108013250501; PMID: 2057034 Pfeffer MA, Swedberg K, Granger CB, et al. CHARM Investigators and Committees. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme. Lancet 2003;362:759–66. PMID: 13678868

ZS-9 are still not available; studies are currently ongoing. Further long-term, randomised-controlled trials will be needed to determine whether patiromer and ZS-9 can increase the use of optimum doses of RAAS inhibitors and improve outcomes in patients with HF. Future studies should include specific patient cohorts, including patients with severe hyperkalaemia, more advanced HF, those with a preserved ejection fraction and with severe CKD. Since hyperkalaemia is often diagnosed in the hospital setting, hospitalised patients should also be observed in future trials. Hyperkalaemia can develop during transient worsening of renal function, a relatively common occurrence during RAAS initiation/up-titration, and this warrants further investigation. There is a need for studies to determine whether there are any issues such as fluid and electrolyte or acid–base changes, drug–drug interactions or longterm tolerability that might influence the choice of patiromer or ZS-9 in specific patient populations or indications. There is also a need for more information on the long-term efficacy and safety of both drugs in real-world settings in patients with other comorbidities and taking multiple drugs. To date, ZS-9 and patiromer have only been evaluated in the treatment of hyperkalaemia, but they may find a more important role in the prevention of hyperkalaemia. At present, many patients with moderate CKD who have high serum potassium levels, around 4.8 or 4.9 mEq/l, are not given RAAS inhibitors because of the fear of causing hyperkalaemia. These agents may be beneficial in patients who have previously taken RAAS inhibitors but discontinued them after experiencing a single hyperkaliaemic event. They may also enable the use of RAAS inhibitors in patients with risk factors for hyperkalaemia. There is a need for further study investigating the optimisation of RAAS inhibitors in such patients. The fast onset of ZS-9 suggests that it may be an effective treatment option for acute hyperkalaemia. Again, further investigation is required. However, caution should be exercised in prescribing potassium binders; they should be given only to selected patients. In conclusion, the use of patiromer and ZS-9 represents an important development in HF therapy, potentially enabling patients with HF to optimise the use and dose of RAAS inhibitors, improve dietary choices, improve quality of life and possibly reduce morbidity and mortality in these high-risk populations. n

itt B, Zannad F, Remme WJ, et al. The effect of spironolactone P on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med 1999;341:709–17. DOI: 10.1056/ NEJM199909023411001; PMID: 10471456 8. Shier DN, Kusano E, Stoner GD, et al. Production of renin, angiotensin II, and aldosterone by adrenal explant cultures: response to potassium and converting enzyme inhibition. Endocrinology 1989;125:486–91. DOI: 10.1210/endo-125-1-486; PMID: 2544410 9. Ramirez E, Rossignoli T, Campos AJ, et al. Drug-induced life-threatening potassium disturbances detected by a pharmacovigilance program from laboratory signals. Eur J Clin Pharmacol 2013;69:97–110. DOI: 10.1007/s00228-012-1303-9; PMID: 22648277 10. Lainscak M, Vitale C, Seferovic P, et al. Pharmacokinetics and pharmacodynamics of cardiovascular drugs in chronic heart failure. Int J Cardiol 2016;224:191–8. DOI: 10.1016/j. ijcard.2016.09.015; PMID: 27657473 11. Konstam MA, Neaton JD, Dickstein K, et al. HEAAL Investigators. Effects of high-dose versus low-dose losartan on clinical outcomes in patients with heart failure (HEAAL study): a randomised, double-blind trial. Lancet 2009;374:1840– 8. DOI: 10.1016/S0140-6736(09)61913-9; PMID: 19922995 12. Packer M, Poole-Wilson PA, Armstrong PW, et al. Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure. ATLAS Study Group. Circulation 1999;100:2312–8. PMID: 10587334

13. S tavros F, Yang A, Leon A, et al. Characterization of structure and function of ZS-9, a K+ selective ion trap. PLoS One 2014;9:e114686. DOI: 10.1371/journal.pone.0114686; PMID: 25531770 14. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure – Web Addenda. Eur Heart J 2016:1–17. DOI: 10.1093/ eurheartj/ehw128 15. Allen LA, Shetterly SM, Peterson PN, et al. Guideline concordance of testing for hyperkalemia and kidney dysfunction during initiation of mineralocorticoid receptor antagonist therapy in patients with heart failure. Circ Heart Fail 2014;7:43–50. DOI: 10.1161/CIRCHEARTFAILURE.113.000709; PMID: 24281136 16. Zannad F, McMurray JJ, Krum H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med 2011;364:11–21. DOI: 10.1056/NEJMoa1009492; PMID: 21073363 17. Palmer BF. Managing hyperkalemia caused by inhibitors of the renin-angiotensin-aldosterone system. N Engl J Med 2004;351:585–92. DOI: 10.1056/NEJMra035279; PMID: 15295051 18. Weir MR, Rolfe M. Potassium homeostasis and renin– angiotensin–aldosterone system inhibitors. Clin J Am Soc Nephrol 2010;5:531–48. DOI: 10.2215/CJN.07821109; PMID: 20150448 19. Raebel MA. Hyperkalemia associated with use of angiotensinconverting enzyme inhibitors and angiotensin receptor blockers. Cardiovasc Ther 2012;30:e156–66. DOI: 10.1111/

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36. J ain N, Kotla S, Little BB, et al. Predictors of hyperkalemia and death in patients with cardiac and renal disease. Am J Cardiol 2012;109:1510–3. DOI: 10.1016/j.amjcard.2012.01.367; PMID: 22342847 37. Michel A, Martin-Perez M, Ruigomez A, et al. Risk factors for hyperkalaemia in a cohort of patients with newly diagnosed heart failure: a nested case-control study in UK general practice. Eur J Heart Fail 2015;17:205–13. DOI: 10.1002/ejhf.226; PMID: 25581138 38. Bleumink GS, Feenstra J, Sturkenboom MC, et al. Nonsteroidal anti-inflammatory drugs and heart failure. Drugs 2003;63: 525–34. PMID: 12656651 39. Alfonzo AV, Isles C, Geddes C, et al. Potassium disorders-clinical spectrum and emergency management. Resuscitation 2006;70:10–25. DOI: 10.1016/j.resuscitation.2005.11.002; PMID: 16600469 40. Genovesi S, Valsecchi MG, Rossi E, et al. Sudden death and associated factors in a historical cohort of chronic haemodialysis patients. Nephrol Dial Transplant 2009;24:2529–36. DOI: 10.1093/ndt/gfp104 41. Korgaonkar S, Tilea A, Gillespie BW, et al. Serum potassium and outcomes in CKD: insights from the RRI-CKD cohort study. Clin J Am Soc Nephrol 2010;5:762–9. DOI: 10.2215/ CJN.05850809; PMID: 20203167 42. An JN, Lee JP, Jeon HJ, et al. Severe hyperkalemia requiring hospitalization: predictors of mortality. Crit Care 2012;16:R225. DOI: 10.1186/cc11872; PMID: 23171442 43. McMahon GM, Mendu ML, Gibbons FK, et al. Association between hyperkalemia at critical care initiation and mortality. Intensive Care Med 2012;38:1834–42. DOI: 10.1007/s00134-0122636-7; PMID: 22806439 44. Houghton AR, Cowley AJ. Why are angiotensin converting enzyme inhibitors underutilised in the treatment of heart failure by general practitioners? Int J Cardiol 1997;59:7–10. PMID: 9080020 45. Lenzen MJ, Boersma E, Reimer WJ, et al. Under-utilization of evidence-based drug treatment in patients with heart failure is only partially explained by dissimilarity to patients enrolled in landmark trials: a report from the Euro Heart Survey on Heart Failure. Eur Heart J 2005;26:2706–13. DOI: 10.1093/ eurheartj/ehi499; PMID: 16183692 46. Bungard TJ, McAlister FA, Johnson JA, et al. Underutilisation of ACE inhibitors in patients with congestive heart failure. Drugs 2001;61:2021–33. PMID: 11735631 47. Albert NM, Yancy CW, Liang L, et al. Use of aldosterone antagonists in heart failure. JAMA 2009;302:1658–65. DOI: 10.1001/jama.2009.1493; PMID: 19843900 48. Hickling JA, Nazareth I, Rogers S. The barriers to effective management of heart failure in general practice. Br J Gen Pract 2001;51:615–8. PMID: 11510388 49. Alfonzo A, Soar, J. MacTier, R. et al. UK Renal Association Clinical Practice Guidelines: Treatment of Acute Hyperkalemia in Adults. Final version – March 2014. www.renal.org/docs/ default-source/default-document-library/hyperkalaemiaguideline.pdf (accessed 7 April 2017) 50. Weisberg LS. Management of severe hyperkalemia. Crit Care Med 2008;36:3246–51. DOI: 10.1097/CCM.0b013e31818f222b; PMID: 18936701 51. Kessler C, Ng J, Valdez K, et al. The use of sodium polystyrene sulfonate in the inpatient management of hyperkalemia. J Hosp Med 2011;6:136–40. DOI: 10.1002/jhm.834; PMID: 21387549 52. Sterns RH, Rojas M, Bernstein P, et al. Ion-exchange resins for the treatment of hyperkalemia: are they safe and effective? J Am Soc Nephrol 2010;21:733–5. DOI: 10.1681/ASN.2010010079; PMID: 20167700 53. Harel Z, Harel S, Shah PS, et al. Gastrointestinal adverse events with sodium polystyrene sulfonate (Kayexalate) use: a systematic review. Am J Med 2013;126:264 e9–24. DOI: 10.1016/j.amjmed.2012.08.016; PMID: 23321430 54. US Food and Drug Administration. Kayexalate (sodium polystyrene sulfonate) powder. www.fda.gov/Safety/ MedWatch/SafetyInformation/ucm186845.htm (accessed 23 August 2016) 55. Aburto NJ, Hanson S, Gutierrez H, et al. Effect of increased potassium intake on cardiovascular risk factors and disease:

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Pharmacology

Practical Applications for Single Pill Combinations in the Cardiovascular Continuum Ferdinando Iellamo, 1,2 Karl Werdan, 3 Krzysztof Narkiewicz, 4 Giuseppe Rosano 1,5 and Maurizio Volterrani 1 1. Dipartimento di Scienze Mediche, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele Pisana, Rome, Italy; 2. Department of Clinical Science and Translational Medicine, University Tor Vergata, Rome, Italy; 3. Department of Medicine III, University Hospital Halle (Saale), Martin Luther University Halle-Wittenberg, Halle, Germany. 4. Department of Hypertension and Diabetology Medical University of Gdansk, Gdansk, Poland; 5. St George’s University of London, London, UK

Abstract Despite the availability of new drugs and devices, the treatment of cardiovascular disease remains suboptimal. Single-pill combination therapy offers a number of potential advantages. It can combine different classes of drugs to increase efficacy while mitigating the risks of treatment-related adverse events, reduce pill burden, lower medical cost, and improve patient adherence. Furthermore, in hypertension, single pill combinations include lower doses of each drug than would be necessary to achieve goals with monotherapy, which may explain their better tolerability compared with higher dose monotherapy. Combination therapy is now established in the treatment of hypertension. In ischaemic heart disease, the concept of a preventative polypill has been studied, but its benefits have not been established conclusively. However, the combination of ivabradine and beta-blockers has proven efficacy in patients with stable angina pectoris. This combination has also demonstrated benefits in patients with chronic heart failure.

Keywords Angina, heart failure, hypertension, ischaemic heart disease, single pill combination Disclosure: FI, GR and MV have no conflicts of interest to declare. KN has received honoraria from Adamed, Berlin-Chemie/Menarini, Gedeon-Richter, Krka, Sandoz, Polpharma, Servier, Recordati. KW has received honoraria from Novartis and Servier. Acknowledgement: Katrina Mountfort of Medical Media Communications (Scientific) Ltd provided medical writing and editing support to the authors. Received: 6 April 2017 Accepted: 11 April 2017 Citation: Cardiac Failure Review 2017;3(1):40–5 DOI: 10.15420/cfr.2017:5:1 Correspondence: Dr Maurizio Volterrani, Dipartimento di Scienze Mediche, IRCCS San Raffaele Pisana, Via della Pisana 235, 00163 Roma, Italy. E: maurizio.volterrani@sanraffaele.it

Cardiovascular disease (CVD) is the leading cause of death worldwide and it is predicted that its incidence will increase markedly, particularly in developed countries, despite the introduction of new drugs and devices. One of the factors accounting for the limited effectiveness of pharmacological therapy is poor adherence to treatment, particularly in elderly patients. The use of combinations of multiple agents in a single pill formulation could be of value in improving adherence to treatment and disease control, as well as conferring other favourable actions. In an aging population, patients with CVD will inevitably present with multiple comorbidities requiring a number of different drugs. By choosing drugs with compatible pharmacokinetic properties, the use of single pill combinations can substantially reduce the pill burden for such patients. This article aims to briefly review the practical applications of single pill combinations in three important conditions in the cardiovascular continuum: hypertension, ischaemic heart disease (IHD) and chronic heart failure (CHF).

Hypertension It is well established that adequate blood pressure (BP) control is essential to reduce cardiovascular risk. Hypertension is the main cardiovascular risk factor due to its high incidence, and a linear relationship exists between BP and cardiovascular events.1,2 Overall, the prevalence of hypertension is around 30–45 % in the general

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population, with a marked increase in the elderly.3 Despite its importance in terms of public health and socio-economics, the prevalence of hypertension has remained essentially unchanged over the last 20 years. This is due, to a large extent, to the fact that the use of BP-lowering drugs is suboptimal and a substantial proportion of patients fails to achieve BP levels recommended by current guidelines.4–7 The multinational Prospective Urban Rural Epidemiology (PURE) study found that only a third of participants achieved BP control.8 Non-adherence to antihypertensive treatments is common, and is much higher in patients with resistant hypertension than in the general hypertensive population.9 In addition, non-adherence is difficult to monitor because most objective measures do not confirm ingestion of the medication.9 Therapeutic interventions that increase adherence are therefore of great value. Single pill combinations in hypertension have been associated with increased patient adherence.10–12 Therapeutic approaches for hypertension should consider not only BP values but also overall cardiovascular risk, which includes the presence of other risk factors and/or co-morbidities, in order to maximise costeffectiveness. Current guidelines suggest initiating antihypertensive therapy using a single drug or a pharmacological association on the basis of BP values and presence of concomitant risk factors.3 In general, monotherapy is effective in achieving normal BP values in 30–40 % of patients with mild hypertension who represent the majority of patients with arterial hypertension.3 However, combination therapies involving

Single pill combinations two classes of drugs result in a significant greater reduction of global cardiovascular, coronary and cerebrovascular events compared to monotherapy,13 and should therefore considered as initial therapy in essential hypertension.3 A meta-analysis of 40 studies concluded that combination therapy results in a greater reduction in blood pressure compared with increasing the dose of a single drug, regardless of the class of drugs used in combination.14 Potential advantages of using a single pill combination therapy as firstline treatment include: a faster reduction of BP and a greater possibility of achieving target BP, opposition to the counterregulatory pathways activated by monotherapies, improving tolerability and decreasing the adverse effects arising from up-titrating single agents. For example, angiotensin II receptor blockers (ARB) such as valsartan can minimise the peripheral oedema caused by a calcium channel blocker such as amlodipine,15 and the combination of perindopril/amlodipine has a reduced incidence of peripheral oedema compared with amlodipine monotherapy.16 In addition, a simplified administration favours a greater therapeutic adherence compared to that expected from frequent therapeutic changes in the attempt to find the most effective drug.10,17 The availability of single pill formulations with different doses of each single drug in the same combination should reduce the problem of changing the dose of a single drug independently from the other.

the combinations of ACE inhibitor/diuretic and beta-blocker/diuretic in reducing total and cardiovascular mortality and cardiovascular events. The results of the ACCOMPLISH study appear to be of particular clinical significance as an ACE inhibitor (benazepril) was used both in the arm receiving a calcium antagonist (amlodipine) and in the arm receiving a diuretic (hydrochlorothiazide). The study enrolled more than 11,000 patients with hypertension at high cardiovascular risk and the study was discontinued early after 36 months, when the pre-specified limits were exceeded. At that point, the benazepril/amlodipine therapy group had a relative risk reduction in primary outcome events of 19.6 % compared with the group taking benazapril/hydrochlorothiazide. The choice of pharmacological combinations is a crucial factor in the achievement of optimal BP values and in the prevention of cardiovascular events without impacting on tolerability. A 2015 editorial highlighted the fact that some combinations (e.g. calcium antagonists plus diuretics) have no additive effects, while other combinations (e.g. clonidine plus alpha-1 receptor blockers) can have a negative interaction.28 In the 2008 Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET), the combination of an ACE inhibitor with an ARB resulted in cases of severe renal failure,29 and in the Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE) study, in which a direct renin inhibitor was added to pre-existing therapy with an ACE inhibitor or an ARB, a high incidence of stroke and severe renal failure resulted in the discontinuation of the study.30

The combination of two (or even three) drugs in low doses also has the advantage of reducing side-effects compared with increasing the dose of a single drug administered as monotherapy.18 The Assessment of combination Therapy of Amlodipine/Ramipril (ATAR) study examined a combination of a calcium-antagonist (amlodipine) and an angiotensin converting enzyme (ACE) inhibitor (ramipril) in patients with grade 1 and 2 hypertension, and reported that combination therapy resulted in a significantly lower incidence of peripheral oedema (7.6 %) compared with the calcium-antagonist as monotherapy (18.7 %, p=0.011), and was associated with a significantly greater reduction in systolic-diastolic BP, measured using 24-hour ambulatory BP monitoring.19 In a cohort study, the use of a single pill combination therapy, prescribed on the basis of a simplified algorithm treatment, resulted in a decrease in BP in a significantly higher percentage of patients with mild hypertension compared to the therapy prescribed on the basis of current guidelines.20 Numerous studies support the increased use of single pill combinations in hypertension,21 including Perindopril pROtection aGainst REcurrent Stroke Study (PROGRESS),22 Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), 23 Avoiding Cardiovascular events through COMbination therapy in Patients LIving with Systolic Hypertension (ACCOMPLISH),24 HYpertension in the Very Elderly Trial (HYVET)25 and Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation (ADVANCE).26

It has also been argued that single pill combinations should be used in the early stages of hypertension; a matched cohort study found that initial combination therapy was associated with a significant risk reduction of 23 % for cardiovascular events or death compared with delayed therapy.33 A meta-analysis also supported the use of anti-hypertensive therapies even in grade 1 hypertension at low-tomoderate risk.34

The rationale for a combination therapy relies on utilising drugs with complementary mechanisms of action that lead to a more effective reduction in BP without increasing the risk of side-effects related to increasing the dose of a single drug. The choice of drug must therefore take into account the different mechanisms that sustain the rise in BP. Although various drug combinations have proved to be effective in improving BP control, some trials based on principles of clinical pharmacology have demonstrated that certain combination therapies are more effective than others in reducing cardiovascular risk in addition to decreasing BP. Both the ACCOMPLISH24 and the ASCOT BP lowering arm (ASCOT-BPLA)27 studies have shown that a calcium antagonist/ACE inhibitor combination is more effective than

In summary, increasing evidence indicates that a combination therapy of two different classes of drugs in a single pill is equally or more effective than monotherapy, even in mild-to-moderate hypertension, with an improved tolerability and safety profile. Current European guidelines recommend single pill combinations as firstline treatment for hypertension in patients with a systolic pressure higher than 20 mmHg and/or a diastolic pressure higher than 10 mmHg above the targeted goal, as well as in patients with multiple cardiovascular risk factors such as metabolic syndrome, diabetes, and heart and renal disease.3 Combination therapy is recommended in uncontrolled hypertension and should be prescribed in patients at high risk, because it offers a greater chance of achieving optimal

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Currently available single pill combinations include ACE inhibitor/ thiazide diuretic, ARB/thiazide diuretic, beta-blocker/thiazide diuretic, ACE inhibitor/calcium channel blocker (CCB), ARB/CCB, beta-blocker/ ACE inhibitor, and beta-blocker/CCB. Triple single pill combinations such as perindopril/indapamide/amlodipine,31 are also available for patients who fail to meet blood pressure goals with the combination of two drugs (see Table 1). Recently, a small clinical trial has demonstrated the efficacy and safety of a single pill combination containing four antihypertensive drugs each at quarter-dose (irbesartan 37.5 mg, amlodipine 1.25 mg, hydrochlorothiazide 6.25 mg, and atenolol 12.5 mg) and suggested that the benefits of quarter-dose therapy could be additive across classes.32

Pharmacology Table 1: Selected Fixed Dose Combinations Approved in Europe for the Treatment of Hypertension

Name

Active substances

Year approved

Amlodipine/valsartan Mylan (Mylan)

Amlodipine besylate/valsartan

2016

Copalia (Novartis)

Amlodipine besylate/valsartan

2007

Dafiro (Novartis)

Amlodipine/valsartan

2007

Exforge (Novartis)

Amlodipine/valsartan

2007

Imprida (Novartis)

Amlodipine besylate/valsartan

2007

Twynsta (Boehringer Ingelheim)

Amlodipine/telmisartan

2010

Coveram (Servier)

Amlodipine/perindopril arginine

2008

Viacoram (Servier)

Amlodipine/perindopril arginine

2015

Copalia HCT (Novartis)

Amlodipine besylate/valsartan/hydrochlorothiazide

2009

Dafiro HCT (Novartis)

Amlodipine besylate/valsartan/hydrochlorothiazide

2009

Exforge HCT (Novartis

Amlodipine besylate/valsartan/hydrochlorothiazide

2009

Imprida HCT (Novartis)

Amlodipine besylate/valsartan/ hydrochlorothiazide

2009

Triplixam (Servier)

Amlodipine/perindopril arginine/indapamide

2014

Amiodipine/indapamide

2013

CoAprovel (Sanofi)

Irbesartan/hydrochlorothiazide

1998

Ifirmacombi (Krka)

Irbesartan/hydrochlorothiazide

2011

Irbesartan hydrochlorothiazide (generic)

Irbesartan/hydrochlorothiazide

2007, 2009

Karvezide (Sanofi)

Irbesartan/hydrochlorothiazide

1998

Kinzalkomb (Bayer)

Telmisartan/hydrochlorothiazide

2002

MicardisPlus (Boehringer Ingelheim)

Telmisartan/hydrochlorothiazide

2002

PritorPlus (Bayer)

Telmisartan/hydrochlorothiazide

2002

Bisoprolol/perindopril

2015

Perindopril/amlodipine/atorvastatin

2015

Preterax/Noliterax (Servier)

Perindopril arginine/indapamide

2010

Preterax/Bipreterax (Servier)

Perindopril/indapamide

1997

CCB/ACEI

CCB/ACEI/diuretic

CCB/diuretic Natrixam (Servier) ARB/diuretic

ACEI/beta-blocker Cosyrel (Servier) ACEI/CCB/statin Triveram (Servier) ACEI/diuretic

ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin II receptor blocker; CCB = calcium channel blocker.

BP control.3 In prescribing a combination therapy, the drugs should have complementary mechanisms of action. Using fixed-dose drug combinations in a single tablet should ensure better adherence to therapy, as a result of a reduction in the number of pills to be taken daily. In turn, better adherence should result in improved BP control and fewer cardiovascular events.

Ischaemic Heart Disease Hypertension is also a major risk factor for ischaemic heart disease (IHD) and often coexists with dyslipidemia, the other main determinant of IHD.35,36 Coexistence of the two conditions results in an increase in coronary heart disease-related events that is more than additive for the anticipated event rates with each disease.37 Current treatment goals in IHD include delaying atherosclerotic progression by the use of statins and antianginal drugs to improve the imbalance between myocardial oxygen supply and demand. However, as in hypertension, therapeutic goals are rarely attained.38 The National

Cholesterol Education Program Adult Treatment Panel 3 guideline recommends aggressive management of patients with concomitant hypertension and dyslipidaemia.39 The European Society of Cardiology (ESC) guidelines for the management of stable coronary artery disease involve an algorithm containing two components: event prevention, typically comprising statins, aspirin, ACE inhibitors or ARBs, and treatment of symptoms, usually involving beta-blockers.40 Therefore single pill combinations are a logical means of simplifying treatment regimes. In addition, a substantial proportion of patients remain symptomatic despite optimal doses of first-line treatment. Combined therapeutic regimens offer a potential way to address this unmet need. As a result of the pill burden, adherence to cardiovascular drugs is low among patients with IHD, even lower than in hypertension. Adherence to concomitant antihypertensive and lipid lowering therapy is particularly poor, with only one in three patients adherent with both medications at 6 months.41 These findings emphasise the likely relevance of using single pill combinations drugs in IHD.

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Single pill combinations A preventive therapeutic strategy consisting of a single pill combination of low doses of statin, two antihypertensive drugs, aspirin and folate was first proposed by Wald and Law who suggested that such a polypill might reduce CVD by 80 % and might be prescribed to everyone over the age of 55 without the need for screening.42 The polypill approach has been studied in several clinical trials of patients with low to moderate CVD risk. A meta-analysis by Elley et al indicated that, compared with placebo, polypills reduced blood pressure and lipids, whereas tolerability was lower.43 The Use of a Multidrug Pill in Reducing Cardiovascular Events (UMPIRE)44 and IMProving Adherence using Combination Therapy (IMPACT)45 trials found that the use of such a strategy in patients with or at high risk of CVD resulted in significantly improved adherence at 15 months compared with usual care and a modest, yet significant, improvement in systolic BP and LDL-cholesterol, although no significant differences in cardiovascular events were detected. Similarly, a 2014 Cochrane review of trials from higher risk populations concluded that the effects of single pill combination therapy on all-cause mortality or CVD events are uncertain since few trials reported on the above outcomes, although single pill combinations were associated with improved adherence, reductions in BP and improved lipid parameters.46 Improving quality of life and symptom control are primary goals of angina treatment, whereas many studies using a single pill combination therapy have focused only on secondary prevention. Indeed, the recent Angina Prevalence and Provider Evaluation of Angina Relief (APPEAR) study found that many patients with angina are symptomatic but this is underacknowledged and undertreated by physicians.47 In particular, the effect on quality of life is often neglected in angina treatment. Living with angina is associated with functional limitations in terms of physical activity, social and emotional health status, and angina is associated with both an adverse health-related quality of life and higher levels of depression.48 The beneficial effect of beta-blockers, the most often used antianginal drugs, on quality of life is only small, but can be considerably improved by the addition of ivabradine. Ivabradine and beta-blockers have complementary and synergistic mechanisms of action, improving the balance between oxygen supply and demand to the ischemic myocardium.49 The combination of ivabradine and beta-blockers has been shown to reduce the number of angina attacks, nitrate consumption and improve quality of life, in addition to slowing heart rate, in patients with stable angina pectoris.50,51 In particular, the combination of ivabradine and metoprolol has proven effective and safe in patients with angina.52–54 A study evaluating combination therapy with non-maximum dose of beta-blockers and ivabradine compared with up-titration of beta-blockers in patients with stable angina found that the up-titration group experienced twice as many adverse reactions as the ivabradine group.55 A single pill combination of ivabradine plus metoprolol at different fixed doses (Implicor, Servier) has been approved recently in Europe as substitution therapy (see Table 2),56 and might prove beneficial in terms of adherence to treatment, which could further improve the antianginal effects of this combination therapy. Recent data from a large prospective, multicentre, observational cohort study of 610 patients with chronic stable angina, showed that an ivabradine/metoprolol single pill combination reduced heart rate, angina symptoms and nitrate consumption, as well as improving exercise capacity. Tolerability of the combination was rated as very good in 74 % of cases and good in 25 %.57 A systematic review concluded that the use of single pill

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Table 2: Fixed Dose Combinations Approved in Europe for the Treatment of Ischemic Heart Disease Name

Active substances

Year approved

Angina Implicor (Servier)

Metoprolol tartrate/ivabradine

2015

Cosyrel (Servier)

Bisoprolol/perindopril

2015

Clopidogrel/acetylsalicylic

Clopidogrel/acetylsalicylic acid

2014

Clopidogrel/acetylsalicylic acid

2010

Clopidogrel/acetylsalicylic acid

2010

Acute coronary syndrome/MI

acid (generic) Clopidogrel/acetylsalicylic acid (Zentiva) DuoPlavin (Sanofi/BristolMyers Squibb)

combinations increases adherence in the secondary prevention of recurrent cardiovascular events in individuals with established CVD.58 At present, a potential disadvantage for single pill combination therapy in angina patients is the relative lack of dosing flexibility for its individual components. Availability of multiple forms of fixed dose combinations incorporating different dosages will ensure dosing flexibility for its individual components. However, the advantages of single pill combinations, such as beta-blocker/ACE inhibitor or betablocker/ivabradine, outweigh the limitations and offer substantial benefits in terms of improved efficacy and reduced pill burden.

Heart Failure Chronic heart failure is at the end of the continuum of CVD and despite recent clinical advances, the prognosis for this condition remains poor,59,60 while its prevalence is expected to increase markedly. In patients with CHF, an add-on therapy approach is typically used, beginning with diuretics, then adding ACE inhibitors (or ARBs) and beta-blockers, followed by mineralocorticoid receptor antagonists. The complexity of drug regimens for CHF has led to suboptimal therapeutic adherence,61,62 which is associated with worse clinical outcomes.63 In CHF patients the altered haemodynamic homeostasis is associated with an increased heart rate (HR), associated with a negative prognosis, whereas the beneficial effect of beta-blockers has been linked to their HR-lowering effect.64–66 However, beta-blockers are often underused in clinical practice, are seldom prescribed at the doses proven to reduce events,67–69 and their up-titration in response to persistently elevated HR can be associated with an increased risk of adverse reactions.70 A number of studies have demonstrated the efficacy and safety of ivabradine in combination with beta-blockers, particularly carvedilol.71–75 Ivabradine selectively and specifically inhibits the If current in the sinoatrial node, thus reducing HR without affecting the autonomic nervous system.76,77 The effectiveness of ivabradine in CHF has been evaluated in the Systolic Heart Failure Treatment with the If inhibitor Ivabradine (SHIFT) study, in which 6,558 patients with CHF on stable background therapy, including beta-blockers, and a HR >70 BPM with sinus rhythm, were randomised to ivabradine (up to 7.5 mg twice daily) or placebo.71 At the median follow-up of 22.9 months, the results indicated an improved clinical outcomes: 18 % reduction in the primary composite endpoint of cardiovascular death or hospitalisation for worsening HF, a 26 % reduction in hospitalisation for worsening HF and a 26 %

Pharmacology Table 3: Fixed Dose Combinations Approved in Europe for the Treatment of Heart Failure Name

Active substances

Year approved

Carivalan (Servier)

Carvedilol/ivabradine

2016

Cosyrel (Servier)

Bisoprolol/perindopril

2015

reduction in pump failure death in the ivabradine group. Since the majority of patients in the SHIFT study were taking beta-blockers, it was hypothesised that the combination of beta-blockers plus ivabradine per se rather than the dose of beta-blocker was relevant to these findings. A subanalysis of the SHIFT study appeared to confirm this hypothesis, by showing that combination of drugs rather than the dose of beta-blockers were important in improving the primary endpoints of cardiovascular death and hospitalisation.78 A further study concluded that the combination of beta-blockers plus ivabradine resulted in improved outcomes regardless of the individual beta-blocker prescribed.73 Studies to date indicate that the combination of ivabradine and beta-blockers is safe and well tolerated, and as a result the combination is recommended in the 2016 ESC guidelines.79 At present, dozens of countries market the combination of ivabradine and carvedilol (Carivalan, Servier; see Table 3). A subanalysis of the SHIFT study found increased cardiovascular improvements with all co-prescription of ivabradine and beta-blockers, particularly carvedilol.73

Ezzati M, Lopez AD, Rodgers A, et al. Selected major risk factors and global and regional burden of disease. Lancet 2002;360:1347–60. DOI: 10.1016/S0140-6736(02)11403-6; PMID: 12423980. 2. Lewington S, Clarke R, Qizilbash N, et al. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 2002;360:1903–13. DOI: 10.1016/ S0140-6736(02)11911-8; PMID: 12493255. 3. Mancia G, Fagard R, Narkiewicz K, et al. 2013 ESH/ESC guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J 2013;34:2159–219. DOI: 10.3109/08037051.2014.868629; PMID: 24359485. 4. Prugger C, Keil U, Wellmann J, et al. Blood pressure control and knowledge of target blood pressure in coronary patients across Europe: results from the EUROASPIRE III survey. J Hypertens 2011;29:1641–8. DOI: 10.1097/ HJH.0b013e328348efa7; PMID: 21720270 5. Egan BM, Zhao Y, Axon RN. US trends in prevalence, awareness, treatment, and control of hypertension, 19882008. JAMA 2010;303:2043–50. DOI: 10.1001/jama.2010.650; PMID: 20501926. 6. Meng XJ, Dong GH, Wang D, et al. Prevalence, awareness, treatment, control, and risk factors associated with hypertension in urban adults from 33 communities of China: the CHPSNE study. J Hypertens 2011;29:1303–10. DOI: 10.1097/ HJH.0b013e328347f79e; PMID: 21558952. 7. Heeley EL, Peiris DP, Patel AA, et al. Cardiovascular risk perception and evidence–practice gaps in Australian general practice (the AusHEART study). Med J Aust 2010;192:254–9. PMID: 20201758. 8. Chow CK, Teo KK, Rangarajan S, et al. Prevalence, awareness, treatment, and control of hypertension in rural and urban communities in high-, middle-, and low-income countries. JAMA 2013;310:959–68. DOI: 10.1001/jama.2013.184182; PMID: 24002282. 9. Gupta P, Patel P, Horne R, et al. How to screen for nonadherence to antihypertensive therapy. Curr Hypertens Rep 2016;18:89. DOI: 10.1007/s11906-016-0697-7; PMID: 27889904. 10. Bangalore S, Kamalakkannan G, Parkar S, et al. Fixeddose combinations improve medication compliance: a meta-analysis. Am J Med 2007;120:713–9. DOI: 10.1016/j. amjmed.2006.08.033; PMID: 17679131. 11. Chrysant SG. Using fixed-dose combination therapies to achieve blood pressure goals. Clin Drug Investig 2008;28:713–34. PMID: 18840014. 12. Gupta AK, Arshad S, Poulter NR. Compliance, safety, and effectiveness of fixed-dose combinations of antihypertensive agents: a meta-analysis. Hypertension 2010;55:399–407. DOI:

Conclusion There is growing evidence to support the use of single pill combination drugs in the continuum of CVD from arterial hypertension to ischaemic heart disease and chronic heart failure. There is a need to improve efficacy, acceptability, tolerability and adherence in cardiovascular medicine. Fixed-dose combination formulations offer many of these potential advantages. Furthermore, single pill combinations offer advantages in terms of cost effectiveness, making them an attractive option in low-income countries. However, single pill combinations may also have disadvantages, such as less flexibility in altering doses and differences in the duration of action of the combined drugs. Single pill combinations are recommended by regulatory bodies as first-line treatment in arterial hypertension.3 Current ESC recommendations state that the benefits of combination use may outweigh the risks in a selected group of people with HF for whom other treatments are unsuitable.79 At present, however, there is a lack of single pills for many combinations of drugs. In summary, there is a need for single pill combinations in cardiovascular medicine. However there is a need for further data to establish the long-term safety and efficacy of such combinations. The results of ongoing clinical trials in several countries in primary and secondary CVD settings will evaluate the clinical implications of the routine use of single pill combinations. n

10.1161/HYPERTENSIONAHA.109.139816; PMID: 20026768. 13. Corrao G, Nicotra F, Parodi A, et al. Cardiovascular protection by initial and subsequent combination of antihypertensive drugs in daily life practice. Hypertension 2011;58:566–72. DOI: 10.1161/HYPERTENSIONAHA.111.177592; PMID: 21825231. 14. Wald DS, Law M, Morris JK, et al. Combination therapy versus monotherapy in reducing blood pressure: meta-analysis on 11,000 participants from 42 trials. Am J Med 2009;122:290–300. DOI: 10.1016/j.amjmed.2008.09.038; PMID: 19272490. 15. Waeber B, Ruilope LM. Amlodipine and valsartan as components of a rational and effective fixed-dose combination. Vasc Health Risk Manag 2009;5:165–74. DOI: 10.2147/VHRM.S3134; PMID: 19436661. 16. Shirley M, McCormack PL. Perindopril/amlodipine (Prestalia®): a review in hypertension. Am J Cardiovasc Drugs 2015;15:363–70. DOI: 10.1007/s40256-015-0144-1; PMID: 26341621. 17. Corrao G, Parodi A, Zambon A, et al. Reduced discontinuation of antihypertensive treatment by two-drug combination as first step. Evidence from daily life practice. J Hypertens 2010;28:1584–90. DOI: 10.1097/HJH.0b013e328339f9fa; PMID: 20543716. 18. Law MR, Wald NJ, Morris JK, Jordan RE. Value of low dose combination treatment with blood pressure lowering drugs: analysis of 354 randomised trials. BMJ 2003;326:1427. DOI: 10.1136/bmj.326.7404.1427; PMID: 12829555. 19. Miranda RD, Mion D Jr, Rocha JC, et al. An 18-week, prospective, randomized, double-blind, multicenter study of amlodipine/ramipril combination versus amlodipine monotherapy in the treatment of hypertension: the assessment of combination therapy of amlodipine/ramipril (ATAR) study. Clin Ther 2008;30:1618–28. DOI: 10.1016/j. clinthera.2008.09.008; PMID: 18840367. 20. Feldman RD, Zou GY, Vandervoort MK, et al. A simplified approach to the treatment of uncomplicated hypertension: a cluster randomized, controlled trial. Hypertension 2009;53:646– 53. DOI: 10.1161/HYPERTENSIONAHA.108.123455; PMID: 19237683. 21. Neutel JM. Prescribing patterns in hypertension: the emerging role of fixed-dose combinations for attaining BP goals in hypertensive patients. Curr Med Res Opin 2008;24:2389–401. DOI: 10.1185/03007990802262457; PMID: 18616863. 22. PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack. Lancet 2001;358:1033–41. DOI: 10.1016/S01406736(01)06178-5; PMID: 11589932. 23. Messerli FH, Oparil S, Feng Z. Comparison of efficacy and side effects of combination therapy of angiotensin-converting enzyme inhibitor (benazepril) with calcium antagonist (either nifedipine or amlodipine) versus high-dose calcium antagonist monotherapy for systemic hypertension. Am J Cardiol 2000;86:1182–7. DOI: 10.1016/S0002-9149(00)01199-1;

PMID: 11090788. 24. Jamerson K, Weber MA, Bakris GL, et al. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in highrisk patients. N Engl J Med 2008;359:2417–28. DOI: 10.1056/ NEJMoa0806182; PMID: 19052124. 25. Beckett NS, Peters R, Fletcher AE, et al. Treatment of hypertension in patients 80 years of age or older. N Engl J Med 2008;358:1887–98. DOI: 10.1056/NEJMoa0801369; PMID: 18378519. 26. Patel A, MacMahon S, Chalmers J, et al. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet 2007;370:829–40. DOI: 10.1016/S0140-6736(07)61303-8; PMID: 17765963. 27. Dahlöf B, Sever PS, Poulter NR, et al. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet 2005;366:895–906. DOI: 10.1016/S01406736(05)67185-1; PMID: 16154016. 28. Taddei S. Combination therapy in hypertension: what are the best options according to clinical pharmacology principles and controlled clinical trial evidence? Am J Cardiovasc Drugs 2015;15:185–94. doi: 10.1007/s40256-015-0116-5; PMID: 25850749. 29. Yusuf S, Teo KK, Pogue J, et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008;358:1547–59. DOI: 10.1056/NEJMoa0801317; PMID: 18378520. 30. Parving HH, Brenner BM, McMurray JJ, et al. Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N Engl J Med 2012;367:2204–13. 10.1056/NEJMoa1208799; PMID: 23121378. 31. Toth K. Antihypertensive efficacy of triple combination perindopril/indapamide plus amlodipine in high-risk hypertensives: results of the PIANIST study (PerindoprilIndapamide plus AmlodipiNe in high rISk hyperTensive patients). Am J Cardiovasc Drugs 2014;14:137–45. DOI: 10.1007/ s40256-014-0067-2; PMID: 24590580. 32. Chow CK, Thakkar J, Bennett A, et al. Quarter-dose quadruple combination therapy for initial treatment of hypertension: placebo-controlled, crossover, randomised trial and systematic review. Lancet 2017;389:1035-42. DOI: 10.1016/ S0140-6736(17)30260-X; PMID:28190578 33. Gradman AH, Parise H, Lefebvre P, et al. Initial combination therapy reduces the risk of cardiovascular events in hypertensive patients: a matched cohort study. Hypertension 2013;61:309–18. DOI: 10.1161/ HYPERTENSIONAHA.112.201566; PMID: 23184383. 34. Thomopoulos C, Parati G, Zanchetti A. Effects of blood

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Single pill combinations

35.

36.

37.

38.

39.

40.

41.

42.

43.

44.

45.

46.

47.

48.

pressure lowering on outcome incidence in hypertension: 2. Effects at different baseline and achieved blood pressure levels – overview and meta-analyses of randomized trials. J Hypertens 2014;32:2296–304. DOI: 10.1097/ HJH.0000000000000379; PMID: 25259547. Johnson ML, Pietz K, Battleman DS, et al. Prevalence of comorbid hypertension and dyslipidemia and associated cardiovascular disease. Am J Manag Care 2004;10:926–32. PMID: 15617368. Petrella RJ, Merikle E. A retrospective analysis of the prevalence and treatment of hypertension and dyslipidemia in Southwestern Ontario, Canada. Clin Ther 2008;30:1145–54. DOI; 10.1016/j.clinthera.2008.06.004; PMID: 18640470. Stamler J, Wentworth D, Neaton JD. Prevalence and prognostic significance of hypercholesterolemia in men with hypertension. Prospective data on the primary screenees of the Multiple Risk Factor Intervention Trial. Am J Med 1986;80:33–9. PMID: 3946459. Chopra I, Kamal KM. Factors associated with therapeutic goal attainment in patients with concomitant hypertension and dyslipidemia. Hosp Pract 2014;42:77–88. DOI: 10.3810/ hp.2014.04.1106; PMID: 24769787. Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285:2486–97. DOI: 10.1001/jama.285.19.2486; PMID: 11368702. Montalescot G, Sechtem U, Achenbach S, et al. 2013 ESC guidelines on the management of stable coronary artery disease: the Task Force on the management of stable coronary artery disease of the European Society of Cardiology. Eur Heart J 2013;34:2949–3003. DOI: 10.1093/ eurheartj/eht296; PMID: 23996286. Chapman RH, Benner JS, Petrilla AA, et al. Predictors of adherence with antihypertensive and lipid-lowering therapy. Arch Intern Med 2005;165:1147–52. DOI: 10.1001/ archinte.165.10.1147; PMID: 15911728. Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80%. BMJ 2003;326:1419. DOI: 10.1136/ bmj.326.7404.1419; PMID: 12829553. Elley CR, Gupta AK, Webster R, et al. The efficacy and tolerability of ‘polypills’: meta-analysis of randomised controlled trials. PLoS One 2012;7:e52145. DOI: 10.1371/journal. pone.0052145; PMID: 23284906. Thom S, Poulter N, Field J, et al. Effects of a fixed-dose combination strategy on adherence and risk factors in patients with or at high risk of CVD: the UMPIRE randomized clinical trial. JAMA 2013;310:918–29. DOI: 10.1001/ jama.2013.277064; PMID: 24002278. Selak V, Elley CR, Bullen C, et al. Effect of fixed dose combination treatment on adherence and risk factor control among patients at high risk of cardiovascular disease: randomised controlled trial in primary care. BMJ 2014;348:g3318. 10.1136/bmj.g3318; PMID: 24868083. de Cates AN, Farr MR, Wright N, et al. Fixed-dose combination therapy for the prevention of cardiovascular disease. Cochrane Database Syst Rev 2014;CD009868. DOI: 10.1002/14651858. CD009868.pub2; PMID: 24737108. Shafiq A, Arnold SV, Gosch K, et al. Patient and physician discordance in reporting symptoms of angina among stable coronary artery disease patients: Insights from the Angina Prevalence and Provider Evaluation of Angina Relief (APPEAR) study. Am Heart J 2016;175:94–100. DOI: 10.1016/j. ahj.2016.02.015; PMID: 27179728. Gravely-Witte S, De Gucht V, Heiser W, et al. The impact of angina and cardiac history on health-related quality of life and depression in coronary heart disease patients. Chronic Illn 2007;3:66–76. DOI: 10.1177/1742395307079192; PMID: 18072698.

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49. Heusch G, Skyschally A, Gres P, et al. Improvement of regional myocardial blood flow and function and reduction of infarct size with ivabradine: protection beyond heart rate reduction. Eur Heart J 2008;29:2265–75. DOI: 10.1093/eurheartj/ehn337; PMID: 18621770. 50. Werdan K, Ebelt H, Nuding S, et al. Ivabradine in combination with beta-blocker improves symptoms and quality of life in patients with stable angina pectoris: results from the ADDITIONS study. Clin Res Cardiol 2012;101:365–73. DOI: 10.1007/s00392-011-0402-4; PMID: 22231643. 51. Fox K, Ford I, Steg PG, et al. Relationship between ivabradine treatment and cardiovascular outcomes in patients with stable coronary artery disease and left ventricular systolic dysfunction with limiting angina: a subgroup analysis of the randomized, controlled BEAUTIFUL trial. Eur Heart J 2009;30:2337–45. DOI: 10.1093/eurheartj/ehp358; PMID: 19720635. 52. Werdan K, Perings S, Koster R, et al. Effectiveness of ivabradine treatment in different subpopulations with stable angina in clinical practice: a pooled analysis of observational studies. Cardiology 2016;135:141–50. DOI: 10.1159/000447443; PMID: 27333284. 53. Werdan K, Ebelt H, Nuding S, et al. Ivabradine in combination with metoprolol improves symptoms and quality of life in patients with stable angina pectoris: a post hoc analysis from the ADDITIONS Trial. Cardiology 2016;133:83–90. DOI: 10.1159/000439584; PMID: 26501486. 54. Zarifis J, Kallistratos M, Katsivas A. Antianginal efficacy of ivabradine/metoprolol combination in patients with stable angina. Clin Cardiol 2016;39:697–702. DOI: 10.1002/clc.22585; PMID: 27880009. 55. Karpov YA, Glezer MG, Vasyuk YA, et al. Ivabradine in combination with beta-blocker is more effective than up-titration of beta-blockers in patients with stable angina. Eur Heart J 2012;13(Suppl 1):777. P4439. 56. EMEA. Implicor 25 mg/5 mg, 50 mg/5 mg, 25 mg/7.5 mg and 50 mg/7.5 mg, film-coated tablets NL/H/3037/001004/DC. Available at: http://mri.cts-mrp.eu/download/ NL_H_3037_001_PAR.pdf (accessed 12 April 2017). 57. Divchev D, Stöckl G. Treatment of stable angina with a fixeddose combination of ivabradine and metoprolol: first data from clinical practice. Presented at the 83rd Annual Meeting of the German Cardiac Society, 19–22 April 2017, Mannheim, Germany. Abstract P1694. 58. Banerjee A, Khandelwal S, Nambiar L, et al. Health system barriers and facilitators to medication adherence for the secondary prevention of cardiovascular disease: a systematic review. Open Heart 2016;3:e000438. DOI: 10.1136/ openhrt-2016-000438; PMID: 27738515. 59. Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics – 2015 update: a report from the American Heart Association. Circulation 2015;131:e29–322. DOI: 10.1161/ CIR.0000000000000152; PMID: 25520374. 60. Stewart S, MacIntyre K, Hole DJ, et al. More ‘malignant’ than cancer? Five-year survival following a first admission for heart failure. Eur J Heart Fail 2001;3:315–22. DOI: 10.1016/ S1388-9842(00)00141-0; PMID: 11378002. 61. Hauptman PJ. Medication adherence in heart failure. Heart Fail Rev 2008;13:99–106. DOI: 10.1007/s10741-007-9020-7; PMID: 17479364. 62. van der Wal MH, Jaarsma T. Adherence in heart failure in the elderly: problem and possible solutions. Int J Cardiol 2008;125:203–8. DOI: 10.1016/j.ijcard.2007.10.011; PMID: 18031843. 63. Wu JR, Moser DK, De Jong MJ, et al. Defining an evidencebased cutpoint for medication adherence in heart failure. Am Heart J 2009;157:285–91. DOI: 10.1016/j.ahj.2008.10.001; PMID: 19185635. 64. Fox K, Borer JS, Camm AJ, et al. Resting heart rate in cardiovascular disease. J Am Coll Cardiol 2007;50:823–30. DOI:

10.1016/j.jacc.2007.04.079; PMID: 17719466. 65. Pocock SJ, Wang D, Pfeffer MA, et al. Predictors of mortality and morbidity in patients with chronic heart failure. Eur Heart J 2006;27:65–75. DOI: 10.1093/eurheartj/ehi555; PMID: 16219658. 66. Kjekshus J, Gullestad L. Heart rate as a therapeutic target in heart failure. Eur Heart J 1999;1:H64–9. 67. Vitale C, Iellamo F, Volterrani M, et al. Heart rate control in an unselected consecutive population of outpatients with stable coronary artery disease: Analysis of the CARDIf Study Cohort. Angiology 2010;61:763–7. DOI: 10.1177/0003319710369102; PMID: 20462892. 68. Butler J, Arbogast PG, BeLue R, et al. Outpatient adherence to beta-blocker therapy after acute myocardial infarction. J Am Coll Cardiol 2002;40:1589–95. DOI: 10.1016/S07351097(02)02379-3; PMID: 12427410. 69. de Groote P, Isnard R, Assyag P, et al. Is the gap between guidelines and clinical practice in heart failure treatment being filled? Insights from the IMPACT RECO survey. Eur J Heart Fail 2007;9:1205–11. DOI: 10.1016/j.ejheart.2007.09.008; PMID: 18023249. 70. Erdmann E. Safety and tolerability of beta-blockers: prejudices and reality. Indian Heart J 2010;62:132–5. PMID: 21180303. 71. Swedberg K, Komajda M, Böhm M, et al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet 2010;376:875–85. DOI: 10.1016/S0140-6736(10)61198-1; PMID: 20801500. 72. Volterrani M, Cice G, Caminiti G, et al. Effect of Carvedilol, Ivabradine or their combination on exercise capacity in patients with Heart Failure (the CARVIVA HF trial). Int J Cardiol 2011;151:218–24. DOI: 10.1016/j.ijcard.2011.06.098; PMID: 21764469. 73. Bocchi EA, Böhm M, Borer JS, et al. Effect of combining ivabradine and beta-blockers: focus on the use of carvedilol in the SHIFT population. Cardiology 2015;131:218–24. DOI: 10.1159/000380812; PMID: 25968495. 74. Hidalgo FJ, Anguita M, Castillo JC, et al. Effect of early treatment with ivabradine combined with beta-blockers versus beta-blockers alone in patients hospitalised with heart failure and reduced left ventricular ejection fraction (ETHICAHF): A randomised study. Int J Cardiol 2016;217:7-11. DOI: 10.1016/j.ijcard.2016.04.136; PMID: 27167103. 75. Bagriy AE, Schukina EV, Samoilova OV, et al. Addition of ivabradine to beta-blocker improves exercise capacity in systolic heart failure patients in a prospective, open-label study. Adv Ther 2015;32:108–19. DOI: 10.1007/s12325-0150185-5; PMID: 25700807. 76. Deedwania P. Selective and specific inhibition of If with ivabradine for the treatment of coronary artery disease or heart failure. Drugs 2013;73:1569–86. DOI: 10.1007/s40265013-0117-0; PMID: 24065301. 77. Pereira-Barretto AC. Cardiac and hemodynamic benefits: mode of action of ivabradine in heart failure. Adv Ther 2015;32:906–19. DOI: 10.1007/s12325-015-0257-6; PMID: 26521191. 78. Swedberg K, Komajda M, Böhm M, et al. Effects on outcomes of heart rate reduction by ivabradine in patients with congestive heart failure: is there an influence of betablocker dose?: findings from the SHIFT (Systolic Heart failure treatment with the I(f) inhibitor ivabradine Trial) study. J Am Coll Cardiol 2012;59:1938–45. DOI: 10.1016/j.jacc.2012.01.020; PMID: 22617188. 79. 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. DOI: 10.1093/eurheartj/ehw128; PMID: 27206819.

Clincial Care

Chronic Heart Failure Care Planning: Considerations in Older Patients Eilidh H i l l a n d J a c k i e Ta y l o r Department of Geriatric Medicine, Glasgow Royal Infirmary, Glasgow, UK

Abstract In developed countries, it is estimated that more than 10 % of adults aged over 70 years have heart failure (HF). Despite therapeutic advances, it remains a condition associated with significant morbidity and mortality. It is one of the commonest causes of unscheduled hospital admissions in older adults and data consistently show a lower uptake of evidence-based investigations and therapies as well as higher rates of HF hospitalisations and mortality than in younger adults. These rates are highest amongst patients discharged to ‘skilled nursing facilities’, where comorbidities, frailty and cognitive impairment are common and have a significant impact on outcomes. In this review, we examine current guidance and its limitations and offer a pragmatic approach to management of HF in this elderly population.

Keywords Older patient, heart failure, comorbidity, frailty, cognitive impairment, long-term care, comprehensive geriatric assessment Disclosure: The authors have no conflicts of interest to declare. Received: 02 September 2016 Accepted: 18 October 2016 Citation: Cardiac Failure Review 2017;3(1):46–51. DOI: 10.15420/cfr.2016:15:2 Correspondence: Dr Eilidh Hill, Department of Geriatric Medicine, Glasgow Royal Infirmary, 84 Castle Street, Glasgow, G4 0SF, UK. E: eilidh.hill@nhs.net

In developed countries, it is estimated that 1–2 % of the adult population has heart failure (HF), with the prevalence increasing to more than 10 % in those aged >70 years.1 Despite advances in therapies for heart failure with reduced ejection fraction (HFrEF), it remains a condition associated with significant morbidity and mortality, punctuated by episodes of unplanned hospitalisation.2 HF is one of the commonest causes of unscheduled hospital admissions3 and data consistently show a lower uptake of evidencebased investigations and therapies in adults >75 years as well as higher HF-related mortality.4 Mortality and rehospitalisation rates are higher amongst patients discharged to skilled nursing facilities than those going home.5 Older patients more frequently experience comorbidities, frailty, polypharmacy and cognitive impairment and these factors have a significant impact on outcomes. These aspects require proper evaluation to best assess and plan patients’ long-termcare needs. In this review, we examine HF-care planning in relation to older patients. While current guidance has its limitations, we offer here a pragmatic approach to care planning in this patient population.

Care Planning in Skilled Nursing Facilities While the majority of older people live at home alone, or with carers, in the UK 16 % of people aged >85 years live in care homes.6 The spectrum of care ranges from sheltered housing to a variety of assisted living facilities, residential and nursing homes. The reported prevalence of HF in nursing homes ranges from 20.0 to 37.4 %.7 The Heart Failure in Care Homes (HFinCH) study8 found a higher prevalence of HF in UK care-facility residents aged 65–100 years than in community populations. Most cases were previously undiagnosed and three-quarters of previously recorded cases were unconfirmed using the latest European Society of Cardiology (ESC) guidelines, echocardiogram and brain natriuretic peptide measurements.

Access at: www.CFRjournal.com

Furthermore, they found that the common symptoms and signs appeared to have little clinical utility in this population. A study of Canadian long-term-care residents >65 years found the use of evidence-based therapies appeared to be low, and not adequately explained by drug contraindications or advance directives.9 Monitoring of weight was performed infrequently and echocardiogram evaluation of left ventricle function under-utilised.10 That evidence-based medical therapies can improve outcomes (including incidence of hospitalisations) is the cornerstone of modern medicine, but the benefits of evidence-based care for institutionalised older people are less well understood. It is clear that HF patients discharged to long-term-care facilities are at higher risk of adverse events than those discharged home (whether with home health services or self-caring). Higher rates of rehospitalisation and 1-year mortality rates >50 % have been reported in this group.5 Given the reported under-utilisation of therapies and poor monitoring of volume overload, such poor outcomes require attention. Accordingly, the American Heart Association and the Heart Failure Society of America (AHA/HFSA) have issued a scientific statement with the aim of improving HF management in Skilled Nursing Facilities.7 This is a detailed document and Table 1 summarises some of the key recommendations related to care planning. With the exception of the recommendation on pharmacotherapy, most of the AHA/HFSA recommendations have a class I treatment effect (i.e. should be performed because benefit clearly outweighs risk) but only reach level C evidence (i.e. very limited population evaluated and recommendations reached by consensus opinion of experts). The level C evidence rating is understandable given that frailer, functionally and cognitively impaired patients are often excluded from large randomised controlled trials, which provide much of the evidence base. Injudicious application of treatment guidelines may

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not result in better outcomes for these patients in whom competing comorbidity may have a large impact on prognosis. A tailored and individualised approach to goal setting and care planning is necessary. This requires an understanding of how HF presents in older people, as well as an awareness of how comorbidities impact on standard management. After reviewing these issues, we will then discuss strategies for managing them, including an overview of multidisciplinary team work, comprehensive geriatric assessment and palliative, supportive and end-of-life care.

Non-specific Presentation Firstly, like many conditions in the elderly, HF may present with atypical features, for example, loss of appetite or decrease in body mass index, whilst traditional HF symptoms such as dyspnoea or oedema may be absent and lack specificity.11 This can result in delayed investigation and diagnosis.

Table 1: Summary of Recommendations for Improving Heart Failure (HF) Management in Skilled Nursing Facilities Clarify goals for their admission (i.e. rehabilitation, uncertain prognosis/interim, long-term care/palliation) as this will determine goals of HF therapy including how to deal with acute decompensations (i.e. admit to hospital or to transition to end-of-life care) Ensure clear documentation of clinical data (e.g. left ventricular ejection fraction, medications, renal function, weight) and maintain clear bidirectional communication at the transitions of care (i.e. goals for care, plans for follow-up) Regular monitoring for volume overload through symptoms/signs and weights to allow for early intervention to avoid symptomatic congestion Individualise management and incorporate shared decision-making either with capable informed patient or a power of attorney Individualise pharmacotherapy by consideration of prognosis, goals of care, comorbidities, potential adverse effects, etc. Otherwise therapies should broadly be similar to community dwelling older adults and should be reviewed

Another difference is the increased prevalence of heart failure with preserved ejection fraction (HFpEF), especially in elderly women.12 This compounds some of the challenges in managing elderly patients because, to date, this is a condition with no treatment proven to alter outcomes.

periodically to ensure appropriateness, effectiveness and minimise adverse effects (class I; Level of Evidence B) Immunisations: yearly influenza, pneumococcal one-off (unless prior dose given before age 65 and 5 years have elapsed since this dose). Education of healthcare providers (family and nursing) about HF self-care/ monitoring/management

Comorbidities

Identify cardiac implantable electronic devices and discuss patient’s

It is important to bear in mind that most randomised controlled trials in HF specifically exclude patients with significant comorbidities or HFpEF, yet this group constitutes a significant proportion of older people with HF.4 Up to 75 % of >65 year olds will have multiple chronic conditions that will impact HF management;13 comorbidity is one of the strongest independent predictors of rehospitalisation and mortality.14 Comorbidites can also confound early detection of HF; for example, osteoarthritis and difficulties mobilising may limit the patient before exertional dyspnoea is reported.15

wishes for deactivation as part of ACP*. Skilled Nursing Facilities should

Renal impairment, anaemia, atrial fibrillation, malignancy, cerebrovascular disease and orthostatic hypotension are all more common in older patients than younger patients and impact management and outcomes. These comorbidities increase the likelihood of polypharmacy as well as making drug-related side-effects more common. Polypharmacy itself, whilst often a result of well-intentioned and appropriate treatment of multiple comorbidites, is independently associated with poor outcomes; for example >4 different medications per day increases the risk of falling as well as the risk of recurrent falls.16 This is particularly important to consider given the relatively poor evidence base specifically applicable to this older comorbid population. Two key factors less frequently considered as comorbidities in patients with HF are cognitive impairment and frailty. In clinical practice, they are significant players and worthy of more in depth consideration.

Cognitive Impairment A recent review of cognitive impairment in HF reported an estimated prevalence between 30 and 80 %, with the wide range due to differences in study design, case mix and the types of cognitive assessments used.17 An independent association with increasing severity of disease (whether quantified by ejection fraction or symptom burden) and poorer cognition was also described. From our own experience, the authors also recognise a high prevalence of delirium among older HF patients. One study

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have deactivation policy and means to deactivate in emergency if required (doughnut magnet). ACP on admission (include goals of care and preferences for end-of-life) Nearing the end-of-life, medications should continue until limited by decreased oral intake, inability to swallow or hypotension Source: Adapted from Jurgens et al.7 ACP = Advance Care Planning.

estimated delirium was present in 17 % of patients with unscheduled HF hospitalisations.18 What is clear is that both dementia and delirium are associated with poorer clinical outcomes, with longer duration of hospitalisation and increased inpatient and 1-year mortality.19,20 Impaired cognitive function is associated with poor levels of selfcare and functional decline21 and predicts non-engagement in HF management programmes. Patients may not recognise or understand a change in symptoms or function, with negative consequences for overall care. Identifying cognitive impairment allows patient, carers and clinicians to plan bespoke management strategies and clinicians should be vigilant for its presence. Observational data suggest that informal assessment of cognition by cardiologists is insensitive, with approximately three in four HF patients with important cognitive problems not recognised as such during their routine consultations.22 National Institute for Health and Care Excellence (NICE) published guidance for chronic heart failure management in which they advise all patients have a clinical assessment of cognitive status.23 Although not a formal recommendation, the ESC suggest that cognitive function be assessed using the Mini-Mental State Examination (MMSE) or Montreal Cognitive Assessment (MOCA).1 However, their recommendation of these assessments are not specific to HF and a recent systematic review concluded that the accuracy of normative values for these tests in HF need to be established,24 work that is currently underway by

Clincial Care the Cochrane Dementia and Cognitive Improvement Group (http:// dementia.cochrane.org/). Locally, the authors use the 4AT (see www. the4AT.com) as a quick screening tool for cognitive impairment and delirium.25 This is a validated tool routinely used in clinical practice internationally to detect delirium with good sensitivity and specificity. Its benefits are that it takes only 2 minutes to administer and no special training is required. As yet, there are no specific medical treatments or approaches to care that have been shown to prevent cognitive decline in those with early dementia or pre-dementia syndromes; this includes interventions that aim to minimise the vascular component of cognitive decline26 and treatments targeting underlying neurochemical abnormalities of Alzheimer’s disease, such as acetylcholinestase inhibitors.27 Modifiable lifestyle risk-factors for dementia (such as smoking, excessive alcohol, sedentary lifestyle and diet) should be reviewed in patients with early dementia and, if appropriate, actively managed to prevent cognitive decline.28 In practice, regular review by a multidisciplinary HF team is required to evaluate clinical condition and medication tolerance. Collaboration with specialist dementia support teams is helpful because some patients do benefit from cognitive enhancers; however, acetylcholinestase inhibitors must be used with caution owing to the risk of bradycardia, sick sinus syndrome or other arrhythmias resulting from QT prolongation. Medication compliance aids, tailored self-care advice and involvement of family and/or caregivers can all improve adherence with complex HF medication and self-care regimens.1 We can find no good data to suggest standard HF therapy is harmful in patients with cognitive impairment and, given clear evidence of benefit in ‘fitter’ older patients, the best approach is to consider evidence-based treatments for all HF patients but individualise to take account of comorbidites or goals; for example, using digoxin sparingly to limit its potential for toxicity owing to decreased renal clearance with ageing. Another example from clinical practice is compromising on ‘study targets’ of beta blockers to accommodate the cognitive enhancer donepezil where the latter agent had produced benefits in cognition and function that a patient or caregiver valued more highly than potential life prolongation.

Frailty The concept of frailty is an important one for all professionals engaged in HF care to grasp. Frailty is a multidimensional syndrome characterised by increased vulnerability to stressors, occurring as a result of a cumulative decline in different physiological systems occurring during a lifetime.29 It is associated with increased risk of falls, hospitalisation, nursing home admission and mortality, with poorer outcomes seen for increasing severity of frailty.30,31 High prevalence of frailty has been reported in older patients with HF, with one study documenting its presence in >70 % patients >80 years old.32 Identifying which HF patients are frail is important for improving outcomes and avoiding unnecessary harm. Non-specific symptoms of fatigue that can signify progressive HF in older people must be differentiated from frailty because the former may be reversible with treatment. The use of objective tools to measure frailty can help with this (discussed in more detail below). In addition,

frailty should be factored into decision-making about procedural therapies (e.g. how well a patient might tolerate surgery and the likely benefit of the intervention). Finally, upon identification, frailty should indicate those patients who need closer contact with the HF specialist team and who would benefit from comprehensive geriatric assessment. There are two broad models of frailty: the Frailty Phenotype records multiple components of the syndrome (unintentional weight loss, weak grip strength, slow gait speed, physical inactivity and self-reported exhaustion), with frailty present in patients with three or more of these characteristics.33 The second model is the cumulative health deficit model first described by Rockwood.34 Both are too cumbersome for routine clinical practice. Following a review of the diagnostic accuracy of simple screening tests for frailty35, the British Geriatric Society recommends the use the timed-up-and-go test (with a cut off score of 10 seconds to get up from a chair, walk 3 metres, turn round and sit down) or gait speed (taking more than 5 seconds to walk 4 metres using usual walking aids if appropriate).36 Several HF trials have confirmed gait speed as a strong predictor of mortality, morbidity and re-hospitalisation in HF patients.37–39 The ESC have specific recommendations regarding monitoring and follow-up of the older adult with HF, including the monitoring of frailty along with addressing its reversible causes (both cardiovascular and non-cardiovascular).1 In many frail older patients, poor symptom control results in reduced exercise tolerance, which in turn leads to underused skeletal muscle and sarcopenia, thus accelerating a functional decline.40 The key to preventing advancing frailty in this patient group is to optimise symptom control, reduce frequency of HF exacerbations and maintain activity as best as able in each patient. Level 1 guideline supports the benefits of exercise training to improve functional capacity, quality of life, hospitalisations and survival in HF patients.13 In a Cochrane review of exercise interventions for long-term-care residents (a group who are likely to include the frailest elderly), strength and balance training successfully increased muscle strength and functional abilities.41 The most effective intensity (duration and frequency) of exercise intervention remains uncertain but it is encouraging that even small gains in strength can translate into important functional gains. Other than correcting vitamin D insufficiency and optimising protein intake, there is limited evidence for specific nutritional interventions.36 As we will discuss later, comprehensive geriatric assessment provides a robust method of managing these types of patients.42

Strategies for Management Understanding these comorbidities is important for planning care for older patients. As discussed earlier, the scientific statement on HF management in skilled nursing facilities provides details on specific clinical areas to be reviewed (see Table 1) but we also feel it is important to review the systems of care planning that are known to improve outcomes for older adults, notably multidisciplinary team work and comprehensive geriatric assessment.

Multidisciplinary Team Work Up to 25 % of patients hospitalised with HF are readmitted again within 30 days of discharge; only 35 % of these readmissions are for HF, with the remainder for diverse indications (renal impairment, pneumonia

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Care of Older Patients with CHF

and arrhythmias).43 Failure to understand and follow often complex plans of care are thought to contribute to these high rehospitalisation rates. As such, recent guidelines all emphasise the importance of developing a comprehensive plan of care using a multidisciplinary care team approach.

Increased attention is also being given to the transitions of care. A recent scientific statement from the AHA describes how integrated, interdisciplinary transition of care programs can help patients along the continuum of care.47

Comprehensive Geriatric Assessment McAlister et al. were one of the first groups to systematically review the evidence for systems of care for HF patients. Their work showed that follow-up by a specialist multidisciplinary team reduced mortality, HF hospitalisation and all-cause hospitalisations, suggesting the intervention helped manage more than just the patient’s HF.44 More recently, and to clarify which specific aspects of multidisciplinary care provide the most benefit, the Cochrane group performed a systematic review of disease management programs after hospital discharge.45 They identified programs as having eight common components: telephone follow-up, education, self-management, weight monitoring, sodium restriction, exercise recommendations, medication review and social and psychological support. When compared with usual care, clinic care models did not reduce either rehospitalisation or mortality but case management with its early, intense post-discharge monitoring reduced late mortality (>6 months after discharge). HF and all-cause rehospitalisation was reduced in both case management and multidisciplinary care programs. Another study found that reductions in hospitalisation rates were greatest among moderately frail HF patients.46 This study also found that applying a multidimensional assessment was useful to exclude severely frail patients, who require follow-up with intensive, home-based programs. In other words, identifying high-risk patients allows us to target the right treatment. The importance of multidisciplinary follow-up in HF management has been highlighted by both the American College of Cardiology Foundation and AHA13 and, more recently, the ESC1, who recommend that HF patients be enrolled in multidisciplinary-care management programs to reduce HF hospitalisation and mortality (class I recommendation, evidence level A). Different HF management programs exist in different countries and healthcare settings but the following list outlines some of the key components (adapted from ESC guidelines1). HF management programmes should: • employ a multidisciplinary team (cardiologists, primary care physicians, nurses, pharmacists, physiotherapists, occupational therapists, dieticians, social workers, psychologists, surgeons, geriatricians etc.) • target high-risk symptomatic patients • provide regular assessment of (and appropriate intervention in response to) weight changes , nutritional and functional status or laboratory findings. • facilitate patient education with special emphasis on symptom monitoring to enable self-care and the option of flexible diuretic dosing • provide follow-up after discharge (either in clinic, home-based visits, telephone support, remote monitoring or a combination thereof) • have easy access to care during episodes of decompensation • have access to advance treatment options including device management • provide psychosocial support to patients and family and/or caregivers

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Geriatricians use Comprehensive Geriatric Assessment (CGA) as a robust method for identifying high-risk patients. High CGA scores predict 2-year mortality in HF patients >75 years of age. 48 Rodriguez-Pascual et al. calculated participants’ CGA scores based on limitation in activities of daily living, mobility, comorbidities, cognitive impairment and pre-admission number of medications; all components showed a consistent association, with increased riskof death at 2 years. Though used in HF research mainly as a prognostic tool, CGA is a diagnostic process at the core of a geriatrician’s daily clinical practice. Much like the use of a frailty assessment tool, a CGA should identify which patients need closer contact with the HF specialist team and those who would benefit from assessment by a geriatrician. Using coordinated multidisciplinary assessment and geriatric medicine expertise, a CGA determines the medical, psychological and functional capabilities of an older person to develop an integrated plan for treatment and long-term follow-up.42 Targeted interventions may involve enlisting social support services, discontinuing non-essential medications, adapting the home environment and providing mobility aids, to name but a few. The Cochrane group reviewed 22 trials that compared CGA to usual care and evaluated 10,315 participants in six countries. Patients admitted to hospital in an emergency who were assessed with CGA were more likely to be alive and in their own homes at 6-months (odds ratio [OR] 1.25; 95 % CI [1.11–1.42]; p<0.001) and 12-month follow-up (OR 1.16; 95 % CI [1.05–1.28]; p=0.003) compared with general medical care. They were less likely to be institutionalised (OR 0.79), die or experience deterioration in their condition (OR 0.76) and more likely to have improved cognition (OR 1.11). Models of CGA have evolved in different healthcare settings to meet differing needs. While none of these trials specifically examined HF patients, we know that HF is one of the commonest reasons for unscheduled medical admission 3 , so we feel these processes are relevant to our patients. However, subgroup analysis of primary outcomes in the Cochrane review showed the positive outcomes were primarily the result of CGA wards and the effect was not as clearly seen where patients remained in a general ward receiving assessment from a visiting specialist multidisciplinary team. This requires research specifically for HF patients but certainly raises an interesting debate for where these complex patients are most optimally managed.

Applying the Guidelines in Frail Older Adults with Multimorbidity There is increasing recognition that disease-specific guidelines have traditionally failed to meet the complex needs of physically frail individuals with multimorbidity. Distinct therapeutic strategies that carefully balance the characteristics of frailty against the potential for benefit and harm from treatment need to be developed as well as consideration given to how services can be reorganised to facilitate such an approach. The recent ESC guidelines on heart failure have helpfully highlighted some of these issues, with a

Clincial Care Table 2: Summary of Recommendations for Delivering Patient Care that Takes Account of Multimorbidity Discuss the purpose of an approach to care that takes account of multimorbidity (i.e. whether quality of life could be improved by modifying treatments or follow-up arrangements) Establish disease and treatment burden: e.g. discussing the impact of health problems on wellbeing; discussing number of healthcare appointments; degree of polypharmacy; and whether they are experiencing anticipated symptom relief or conversely any side-effects from medications Establish patient goals, values and priorities e.g. maintaining independence, preventing specific adverse outcome, lengthening life, reducing treatment burden etc. Review medicines and other treatments e.g. using database of treatment effects (accessible online from resources in NICE guideline NG56) to find information on effectiveness of treatments based on trial evidence and applicability to individual patients. A discussion about stopping preventative chronic disease medication should include the potential impact on the

The majority of HF patients value quality of life over longevity.51 However, the transition from solely focusing on disease modification to prioritising quality of life will be at a different point for each patient. Advance care planning allows for open discussion of patients’ preferences in treatment and preferred place of care.Key aspects of the clinician’s role in advance care planning havebeen highlighted in the ESC’s 2016 guidelines1 and can be summarised as follows. • Discuss when to stop medication that does not have an immediate effect on symptom management or health-related quality-of-life, e.g. statins or osteoporosis treatment • Document patient’s decision regarding resuscitation attempts • Discuss deactivation of an implantable cardioverter defibrillator at end-of-life • Discuss preferred place for care and death • Offer emotional support to the patient and family and/or caregiver with appropriate referral for psychological or spiritual support

hoped for long term outcomes for the individual. Validated medication appropriateness checklists such as STOPP/START guidelines can help with this (see NICE guideline NG553)

As symptoms and quality of life change over time, regular re-assessment is needed.

Agree on an individualised management plan: e.g. record any medication changes, which healthcare appointments they want to prioritise, and try to anticipate possible changes to health/wellbeing. Communicate this plan to their involved healthcare professionals and arrange follow-up to review these decisions Source: Adapted from NICE Guideline 56.49

specific chapter devoted to comorbidities. More recently, the NICE have published excellent guidance for assessing and managing multimorbidity49 and Table 2 summarises their recommendations.

Palliative, Supportive and End-of-life Care Care planning for HF patients should incorporate anticipatory care planning and end-of-life care. Patients with severe HF symptoms despite optimal treatment, who are having repeated hospitalisations or experiencing progressive functional decline and dependence, have much to gain from supportive and palliative care services. In our own clinical practice, we find asking ourselves the ‘surprise’ question (“would you be surprised if this patient died in the next year?”) valuable. This is known to be a reliable and valid tool to identify patients who have a greatly increased risk of mortality in the coming year. 50

6. 7.

Ponikowski P, Voors AA, Anker SF, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2016;37 :2129–200. DOI: 10.1093/eurheartj/ ehw128 Maggioni AP, Dahlstrom U, Filippatos G, et al. EURObservational Research Programme: regional differences and 1-year follow-up results of the Heart Failure Pilot Survey (ESC-HF Pilot). Eur J Heart Fail 2013;15 :808–17. DOI: 10.1093/ eurjhf/hft050; PMID: 23537547 Krumholz HM, Normand SL, Wang Y. Trends in hospitalizations and outcomes for acute cardiovascular disease and stroke, 1999–2011. Circulation 2014;130 :966–75. DOI: 10.1161/CIRCULATIONAHA.113.007787 Donkor A, Cleland J, McDonagh T, et al. National Heart Failure Audit. April 2014–March 2015. Available at: www.ucl. ac.uk/nicor/audits/heartfailure/documents/annualreports/ heartfailurepublication14_15 Allen LA, Hernandez AF, Peterson ED, et al. Discharge to a skilled nursing facility and subsequent clinical outcomes among older patients hospitalized for heart failure. Circ Heart Fail 2011;4 :293–300 DOI: 10.1161/ CIRCHEARTFAILURE.110.959171; PMID: 21447803 Care of Elderly People Market Survey 2013/14, Laing and Buisson, 2014 Jurgens CY Goodline S, Dolansky M, et al. AHA/HFSA Scientific Statement. Heart Failure Management in Skilled Nursing Facilities. Circ Heart Fail 2015;8 :655–87 DOI: 10.1161/

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Assessing the level of cognitive impairment will determine how much advance care planning occurs with the patient directly; if there a concerns about cognitive abilities, it is important to check what powers of attorney are in place. For a more detailed review of the management of HF in patients nearing the end of life see LeMond and Goodlin.52

Conclusion Given demographic changes, improved survival from coronary artery disease and an anticipated doubling in prevalence of HF over the next few decades, it is important that clinicians develop a better understanding of the complex interactions between heart failure and old age. More research is required to evaluate the effectiveness of standard HF management among older adults, and also in the subgroup that requires nursing home care. Clinicians managing HF need to have an increased understanding of the complex interplay of multimorbidity, frailty and cognitive impairment because these domains are significant determinants of a patient’s place and level of care. We hope that by highlighting some of these special considerations, we can start to think practically about the best ways to tailor individual patient care. ■

HHF.0000000000000005 Hancock HC, Close H, Mason JM, et al. High prevalence of undetected heart failure in long-term care residents: finding from the Heart Failure in Care Homes (HFinCH) study. Eur J Heart Fail 2013:15 ;158–65. DOI: 10.1093/eurjhf/hfs165; PMID: 23112002 Shibata MC, Soneff CM, Tsuyuki RT. Utilisation of evidencebased therapies for heart failure in the institutionalised elderly. Eur J Heart Fail 2005:7 ;1122–5. DOI: 10.1016/j. ejheart.2005.03.005 Ahmed A, Weaver MT, Allman RM, et al. Quality of care of nursing home residents hospitalised with heart failure. J Am Geriatr Soc 2002:50 :1831–6. DOI: 10.1046/j.15325415.2002.50512.x Oudejans I, Mosterd A, Bloemen JA, et al. Clinical evaluation of geriatric outpatients with suspected heart failure: value of symptoms, signs, and additional tests. Eur J Heart Fail 2011;13 :518–27. DOI: 10.1093/eurjhf/hfr021; PMID: 21422000 Owen TE, Hodge DO Herges RM, et al. Trends in prevalence and outcome of HF with preserved ejection fraction. N Engl J Med 2006;355 :251–9. DOI: 10.1056/NEJMoa052256; PMID: 16855265 Yancy CQ, Jessup M, Bozhurt B, et al. 2013 ACCF/AHA Guideline for the management of heart failure. J Am Coll Cardiol 2013;62 :e147–239. DOI: 10.1016/j.jacc.2013.05.019 Oudejans I, Mosterd A, Zuithoff NP, et al. Comorbidity drives

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mortality in newly diagnosed HF: a study among geriatric outpatients. J Card Fail 2012;18 :47–52. DOI: 10.1016/j. cardfail.2011.10.009; PMID: 22196841 Chaudhry SI Wang Y, Gill TM, et al. Geriatric conditions and subsequent mortality in older patients with heart failure. J Am Coll Cardiol 2010;55 :309–16. DOI: 10.1016/j.jacc.2009.07.066; PMID: 20117435; PMCID: PMC2832791 Tromp AM, Plujim SM, Smit JH, et al. Fall-risk screening test: a positive study of predictors for falls in community-dwelling elderly. J Clin Epidemiol 2001;54 :837–44. PMID: 11470394 Cannon JA, McMurray JJ, Quinn TJ ‘Hearts and minds’: association, causation and implication of cognitive impairment in heart failure. Alzheimers Res Ther 2015:7 ;22. DOI: 10.1186/s13195-015-0106-5 Uthamalingham S, Gurm GS, Daley M, et al. Usefulness of acute delirium as a predictor of adverse outcomes in patients >65 years of age with acute decompensated heart failure. Am J Cardiol 2011;108 :402–8. DOI: 10.1016/j.amjcard.2011.03.059; PMID: 21757045 Zuccalà G, Pedone C, Cesari M, et al. The effects of cognitive impairment on mortality among hospitalized patients with heart failure. Am J Med 2003;115 :97–103. PMID: 12893394 Alosco ML, Spitznagel MB, Cohen R, et al. Reduced cognitive function predicts functional decline in patients with heart failure over 12 months. Eur J Cardiovasc Nurs 2013;13 :304–10. DOI: 10.1177/1474515113494026; PMID: 23754840 Harkness K, Heckman GA, Akhtar-Danesh N, et al. Cognitive

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function and self-care management in older patients with heart failure. Eur J Cardiovasc Nurs 2013;13 :277–84. DOI: 10.1177/1474515113492603; PMID: 23733350 Hanon O, Vidal JS, de Groote P, et al. Prevalence of memory disorders in ambulatory patients aged >/=70 years with chronic heart failure (from the EFICARE Study). Am J Cardiol 2014;113 :1205–10. DOI: 10.1016/j.amjcard.2013.12.032; PMID: 24507171 National Clinical Guideline Centre. (2010) Chronic heart failure: the management of chronic heart failure in adults in primary and secondary care. London: National Clinical Guideline Centre. Available at: www.guidance.nice.org.uk/ CG108/Guidance/pdf/English Davis KK, Allen JK. Identifying cognitive impairment in heart failure: a review of screening measures. Heart Lung 2013;42 :92–7. DOI: 10.1016/j.hrtlng.2012.11.003; PMID: 23260324 Bellelli G, Morandi A, Davis DH, et al. Validation of the 4AT, a new instrument for rapid delirium screening: a study in 234 hospitalised older people. Age Ageing 2014;43 :496–502. DOI: 10.1093/ageing/afu021; PMID: 24590568; PMCID: PMC4066613 Rands G, Orrell M. Aspirin for vascular dementia. Cochrane Database Systematic Rev 2000;4 :CD001296. DOI: 10.1002/14651858.CD001296 Russ TC, Morling JR. Cholinesterase inhibitors for mild cognitive impairment. Cochrane Database Syst Rev 2012;9 :CD009132. DOI: 10.1002/14651858.CD009132.pub2 National Collaborating Centre for Mental Health. National Clinical Practice Guidelines Number 42. Dementia. A NICESCIE Guideline on supporting people with dementia and their carers in health and social care. November 2006 (amended March 2011). The British Psychological Society and Gaskell. Available at: www.nice.org.uk/guidance/cg42/evidence/fullguideline-including-appendices-17-7020840317 Clegg A, Young J, Iliffe S, et al. Frailty in elderly people. Lancet 2013;381 :752–62. DOI: 10.1016/S0140-6736(12) 62167-9 Song X, Mitnitski A, Rockwood K. Prevalence and 10-year outcomes of frailty in older adults in relation to deficit accumulation. J Am Geriatr Soc 2010;58 :681–7. DOI: 10.1111/j.1532-5415.2010.02764.x; PMID: 20345864 Clegg A, Bates C, Young J, et al. Development and validation of an electronic frailty index using routine primary care electronic health record data. Age Ageing 2016;45 :353–60.

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DOI: 10.1093/ageing/afw039 32. Vidán MT, Sánchez E, Fernández-Avilés 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. DOI: 10.1002/clc.22345; PMID: 25516357 33. Fried LP, Tangen CM, Walston J, et al. Cardiovascular Health Study Collaborative Research Group. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci 2001;56 :M146–56 PMID: 11253156 34. Rockwood K, Song X, MacKnight C, et al. A global clinical measure of fitness and frailty in elderly people. CMAJ 2005;17 :489–95. DOI: 10.1503/cmaj.050051; PMID: 16129869; PMCID: PMC1188185 35. Clegg A, Rogers L, Young J. Diagnostic test accuracy of simple instruments for identifying frailty in communitydwelling older people: a systematic review. Age Ageing 2015;44 :148–52. DOI: 10.1093/ageing/afu157 36. Fit for Frailty – consensus best practice guidance for the care of older people living in community and outpatient settings – a report from the British Geriatrics Society 2014. Available at: www.bgs.org.uk/campaigns/fff/fff_ full.pdf 37. Chaudhry SI, McAvay G, Chen S, et al. Risk factors for hospital admission among older persons with newly diagnosed heart failure: findings from the cardiovascular health study. J Am Coll Cardiol 2013;61 :635–42. DOI: 10.1016/ j.jacc.2012.11.027; PMID: 23391194; PMCID: PMC3576871 38. Bittner V, Weiner DH, Yusuf S, et al. Prediction of mortality and morbidity with a 6-min walk test in patients with left ventricular dysfunction. SOLVD investigators. JAMA 1993;270 :1702–7. PMID: 8411500 39. Rostagno C, Olivo G, Comeglio M, et al. Prognostic value of 6-min walk corridor test in patients with mild to moderate heart failure: comparison with other methods of functional evaluation. Eur J Heart Fail 2003;5 :247–52. PMID: 12798821 40. Boxer RS, Shah KB, Kenny AM. Frailty and prognosis in advanced heart failure. Curr Opin Support Palliat Care 2014; 8 :25–9. DOI: 10.1097/SPC.0000000000000027; PMID: 24346236 41. Forster A, Lambley R Hardy J, et al. Rehabilitation for older people in long-term care. Cochrane Database Syst Rev 2009;1 :CD004294. PMID: 19160233 42. Ellis G, Whitehead MA, O’Neill D, et al. Comprehensive geriatric assessment for older adults admitted to hospital.

Cochrane Database Syst Rev 2011;7 :CD006211. 43. Dharmarajan K, Hsieh AF, Zhenqiu L, et al. Diagnoses and timing of 30-day readmissions after hospitalisation for heart failure, acute myocardial infarction, or pneumonia. JAMA 2013;309 :355–63. DOI: 10.1001/ jama.2012.216476 44. McAlister FA, Stewart S, Ferrua S, et al. Multidisciplinary strategies for the management of heart failure patients at high risk for admission: a systematic review of randomised trials. J Am Coll Cardiol 2004:44 :810–9. DOI: 10.1016/ j.jacc.2004.05.055; PMID: 15312864 45. Takeda A, Taylor SJ, Taylor RS, et al. Clinical service organisation for heart failure. Cochrane Database Syst Rev 2012;9 :CD002752. DOI: 10.1002/14651858.CD002752.pub3; PMID: 22972058 46. 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 2010;11 :739–47. DOI: 10.2459/ JCM.0b013e328339d981; PMID: 20736784 47. Albert, NM, Barnason S, Deswal A, et al. Transitions of care in heart failure. Circ Heart Fail 2015;8 :384–409. DOI: 10.1161/ HHF.0000000000000006 48. Rodriguez-Pascual C, Paredes-Galan E, Vilches-Moraga A, et al. Comprehensive geriatric assessment and 2-year mortality in elderly patients hospitalized for heart failure. Circ Cardiovasc Qual Outcomes 2014;7 :251–8. DOI: 10.1161/ CIRCOUTCOMES.113.000551 49. NICE. Multimorbidity: clinical assessment and management. 2016. Available at: www.nice.org.uk/guidance/ng56 50. Murray SA, Boyd K. Using the ‘surprise question’ can identify people with advanced heart failure and COPD who would benefit from a palliative care approach. Palliat Med 2011;25 :382. DOI: 10.1177/0269216311401949; PMID: 21610113 51. Kraai IH, Vermeulen KM, Luttik ML, et al. Preferences of heart failure patients in daily clinical practice: quality of life or longevity? Eur J Heart Fail 2013;15 :1113–21. DOI: 10.1093/ eurjhf/hft071; PMID: 23650130 52. LeMond L, Goodlin SJ. Management of heart failure in patients nearing the end of life. Cardiac Failure Rev 2015;1 : 31–4. DOI: 10.15420/cfr.2015.01.01.31 53. NICE. Medicines optimisation: the safe and effective use of medicines to enable the best possible outcomes. 2015. Available at: www.nice.org.uk/guidance/ng5

Comorbidities

Heart Failure in Patients with Diabetes Mellitus Giuseppe MC R osa no , 1 Cr i s t i a n a V i t a l e 2 a n d Pe t a r S e f e r o v i c 3 1. Clinical Academic Group Cardiovascular, St George’s Hospital NHS Trust Medical School, London, UK; 2. Department of Medical Sciences, IRCCS San Raffaele, Rome, Italy; 3. Department of Cardiology, University of Belgrade, Belgrade, Serbia

Abstract Diabetes and heart failure are closely related: patients with diabetes have an increased risk of developing heart failure and those with heart failure are at higher risk of developing diabetes. Furthermore, antidiabetic medications increase the risk of mortality and hospitalisation for heart failure in patients with and without pre-existing heart failure. When the two diseases are considered individually, heart failure has a much poorer prognosis than diabetes mellitus; therefore heart failure has to be a priority for treatment in patients presenting with the two conditions, and the diabetic patient with heart failure should be managed by the heart failure team. No specific randomised clinical trials have been conducted to test the effect of cardiovascular drugs in diabetic patients with heart failure, but a wealth of evidence suggests that all interventions effective at improving prognosis in patients with heart failure are equally beneficial in patients with and without diabetes. The negative effect of glucose-lowering agents in patients with heart failure or at increased risk of heart failure has become evident after the withdrawal of rosiglitazone, a thiazolidinedione, from the EU market due to evidence of increased risk of cardiovascular events and hospitalisations for heart failure. An important issue that remains unresolved is the optimal target level of glycated haemoglobin, as recent studies have demonstrated significant reductions in total mortality, morbidity and risk of heart failure despite achieving HbA1c levels similar to those observed in the UKPDS study conducted some decades ago. Meta-analyses showed that intensive glucose lowering is not associated with any significant reduction in cardiovascular risk but conversely results in a significant increase in heart failure risk. Different medications have different risk: benefit ratios in diabetic patients with heart failure; therefore, the heart failure team must judge the required intensity of glycaemic control, the type and dose of glucose lowering agents and any change in glucose-lowering therapy, according to the clinical conditions present.

Keywords Heart failure, diabetes, mortality, glucose lowering agents, glycated haemoglobin Disclosure: The authors have no conflicts of interest to declare. Received: 28 September 2016 Accepted: 27 October 2016 Citation: Cardiac Failure Review 2017;3(1):52–5. DOI: 10.15420/cfr.2016:20:2 Correspondence: Giuseppe MC Rosano, Clinical Academic Group Cardiovascular, St George’s Hospital NHS Trust Medical School, Cranmer Terrace, London, UK. E: grosano@sgul.ac.uk

Diabetes mellitus is highly prevalent amongst patients with heart failure, especially those with heart failure and preserved ejection fraction (HFpEF), and patients with the two conditions have a higher risk of mortality compared with patients without diabetes or heart failure.1–3 Diabetic patients have an increased risk of developing heart failure because of the abnormal cardiac handling of glucose and free fatty acids (FFAs), and because of the effect of the metabolic derangements of diabetes on the cardiovascular system. Furthermore, the metabolic risk of diabetes in heart failure is heightened by the effect of most anti-diabetic medications, as the use of certain anti-diabetic agents increase the risk of mortality and hospitalisation for heart failure both in patients with and without heart failure.4 This effect may be related to a direct effect of the glucose-lowering molecules on the cardiovascular system and/or to a negative effect of excessive glucose lowering, since lenient glycaemic control with newer therapeutic agents has shown to reduce significantly mortality, morbidity and risk of developing heart failure in diabeticpatients with proven cardiovascular disease.5 A wealth of epidemiological evidence demonstrates that diabetes mellitus is independently associated with the risk of developing heart

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failure, with the risk increasing by more than twofold in men and by more than fivefold in women.1-3,6 Heart failure is highly prevalent (25 % in chronic heart failure and up to 40 % in acute heart failure) in patients with diabetes mellitus. Its prevalence is four-times higher than that of the general population, suggesting a pathogenetic role of diabetes in heart failure. This pathogenetic role is also suggested by the fact that patients with diabetes and without heart failure have an increased risk of developing heart failure compared with a matched population (29 versus 18 %, respectively). In patients with diabetes mellitus, advanced age, duration of the disease, insulin use, presence of coronary artery disease and elevated serum creatinine are all independent risk factors for the development of heart failure.7 When the two diseases are considered individually, heart failure has a much poorer prognosis than diabetes mellitus, therefore heart failure has to be a priority for treatment in patients presenting with the two conditions, and the diabetic patient with heart failure should be managed by the heart failure team. This review will focus on the relationship between heart failure and type 2 diabetes mellitus.

Heart Failure in Diabetes Mellitus

Mechanisms of Cardiac Dysfunction in Diabetes Mellitus The altered systemic and cardiac glucose metabolism of patients with the range of disease that go from impaired glucose control to diabetes mellitus contribute to the structural and functional abnormalities of the heart that culminate in cardiac dysfunction. In diabetic patients, heart failure develops not only because of the underlying coronary artery disease, but also because of the multiple pathophysiological and metabolic abnormalities induced by altered glucose metabolism.8 The impaired cardiac glucose metabolism and the switch of glucose to FFA oxidation that occurs in the diabetic heart has a significant negative effect on cardiac contractility and functioning thereby inducing left ventricular systolic and diastolic dysfunction even in the absence of coronary artery disease (CAD) or structured heart disease.9,10 The alteration of cardiac function in diabetics occurs through several different mechanisms, such as decreased glucose transport and carbohydrate oxidation, increase in FFA utilisation, decrease in sarcolemmal calcium transport, and alterations in myofibrillar regulatory contractile proteins. Cardiac glucose metabolism is compromised at several points in patients with diabetes mellitus: glucose uptake, glycolysis and intramitochondrial pyruvate oxidation. The reduction in the glucose uptake is due to the slow rate of glucose transport across the sarcolemmal membrane into the myocardium, secondary to a reduction in the myocardial concentration of glucose transporter type 1 (GLUT 1) and glucose transporter type 4 (GLUT 4). Patients with diabetes mellitus have higher plasma levels and myocardial uptake of FFA. High levels of circulating FFAs and their increased oxidation are primarily responsible for the inhibition of both glycolysis and glucose oxidation in the heart. Although the shift of cardiac energy substrate utilisation from glucose to FFA oxidation, occurring in the diabetic heart, is essential to ensure continuous adenosine triphosphate (ATP) generation to maintain heart function, this chronically maladaptation leads to decreased energetic reserves and cardiac efficiency. Indeed, diabetic hearts are characterised by a diminished production of high-energy phosphate, since the betaoxidation of FFA is less efficient than the glycolysis in generating energy (in relation to oxygen consumption) and may increase the risk of cardiac dysfunction during increased metabolic demands or ischaemia.9,10 Hyperglycaemia and insulin resistance also contribute to the development of heart failure through several different mechanisms acting independently and synergistically; such as impaired microvascular endothelial function, abnormal cardiac metabolism (shift myocardial utilisation of glucose toward less efficient fatty acid oxidation), increased myocardial fibrosis, increased oxidative stress and local activation of the renin-angiotensin system and sympathetic nervous system.9,10

Diabetes in Patients with Heart Failure Both population studies and clinical trials have demonstrated that diabetes mellitus significantly increases the risk of recurrent hospitalisations for heart failure and the duration of hospital stay in patients with heart failure, and it is associated with a significantly higher mortality compared with those without diabetes.11 In the Candesartan in Heart failure â&#x20AC;&#x201C; Assessment of Reduction in Mortality and Morbidity (CHARM) programme the presence of diabetes mellitus was associated with a twofold increase of either death or the composite outcome of cardiovascular death or hospitalisation for heart failure in insulin users, and a 50Â % increase risk in non-insulintreated diabetics.3

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Diabetic patients with both reduced and preserved left ventricular ejection fraction show increased mortality and morbidity rates compared with patients without diabetes. This increased risk is also observed in those diabetic patients of either ischaemic or nonischaemic origin. Of interest, the prognostic importance of diabetes mellitus becomes weaker in hospitalised patients for acute heart failure; suggesting that in these patients the prognosis depends more on the severity of cardiac decompensation rather than on metabolic abnormalities.

The Treatment of Heart Failure in Diabetics No randomised clinical trials have been conducted to test the effect of cardiovascular interventions (drugs and/or devices) in diabetic patients with heart failure. However, abundant evidence suggests that all interventions effective at improving prognosis in patients with heart failure are equally beneficial in patients with and without diabetes.12 Beta-blockers and angiotensin-converting enzyme inhibitors are beneficial in patients with diabetes mellitus and their use is associated with reduced mortality and hospitalisations. Angiotensin II receptor blockers have shown similar efficacy in heart failure patients with and without diabetes. Although non-selective beta-blockers may have a negative effect on glycaemic control and increase the risk of future diabetes, and these effects may be less frequent with the more selective agents like bisoprolol, carvedilol and nebivolol, there is no reason to suggest a preferential use of a beta-blocker over another on the basis of the possible negative effect on glucose control. Despite a clear benefit of beta-blockers in heart failure patients with diabetes, these patients are still less likely to be discharged from hospital on a beta-blocker than non-diabetic patients with heart failure.12 Mineralocorticoid receptor antagonists are equally effective in patients with heart failure with and without diabetes mellitus. However, because of the frequent coexistence of diabetic nephropathy, a close surveillance of electrolyte and renal function is recommended in order to exclude hyperkalaemia. The two most recent drugs introduced in heart failure treatment, LCZ696 and ivabradine, are similarly effective in heart failure patients with and without diabetes, and should be implemented as suggested by the guidelines of the European Society of Cardiology/Heart Failure Association.12

Anti-diabetic Treatment in Patients with Diabetes and Heart Failure Glucose-lowering agents are known to increase the risk of cardiovascular events especially when a tight glycaemic control is pursued. Although initially linked to ischaemic heart disease, the negative effect of glucose-lowering agents in patients with heart failure or at increased risk of heart failure has become evident after rosiglitazone, a thiazolidinedione, was withdrawn from the EU market because of the evidence of increased risk of cardiovascular events.13 Despite the focus being mainly put on the risk of coronary events, it was evident even from the rosiglitazone saga that the most significant risk with the use of this drug(s) was related to heart failure. Glucose-lowering agents may favour the development of heart failure through several pathophysiological mechanisms related to the increased insulin levels, water retention and low glucose availability for the heart and muscles. The potential detrimental

Comorbidities effect of the glucose-lowering drugs cannot be dissected by the negative effect of excessive glucose lowering in diabetics. After the United Kingdom Prospective Diabetes Study (UKPDS) the majority of studies in diabetic patients aimed at glycated haemoglobin 1c (HbA1c) <7.5 % or even <7 %, and invariably reported an increased risk of cardiovascular events most often related to heart failure.1,14–18 Therefore, an important issue that is still unsolved is the target level of glycated haemoglobin that should be regarded as optimal – the recent Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG) showed a significant reduction in total mortality, morbidity and risk of heart failure despite the achieved HbA1c which was 7.8 %.5 A meta-analysis of 13 studies including 34,533 patients showed that intensive glucose lowering is not associated with any significant reduction in cardiovascular risk but conversely results in a 47 % increase in risk of heart failure (P<0.001).19 A study conducted in a large cohort of heart failure patients with diabetes mellitus showed a U-shaped relationship between HbA1c and mortality, with the lowest risk in patients with moderate glycaemic control (HbA1c 7.1–8.0 %).14 These results are in agreement with the findings of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study, which demonstrated an increase of 21 % in the risk of death from all causes and of 35 % in the occurrence of cardiovascular death with tight control of glucose in patients with diabetes mellitus.20 The importance of hypoglycaemia has also been highlighted by the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) that found a 38 % increased risk of a poorer outcome among patients with hypoglycaemia complicating heart failure post-myocardial infarction (MI).21 The glucose-lowering treatment should be carefully evaluated and gradually implemented in diabetic patients with heart failure. Preference in the treatment of diabetic patients with heart failure should be given to metformin and empagliflozin that have shown to be safe and effective.5,22,23 Metformin is excreted though the kidney, therefore caution should be exerted in patients with impaired renal function and its use is contraindicated only in patients with severe renal or hepatic impairment. Sulphonylureas may frequently cause hypoglycaemia, although this risk is minimised by the slow release formulations. An increased risk of worsening heart failure has been reported with sulphanylureas in cohort studies including diabetic patients but has never been reported by randomised clinical trials.4 These drugs should be used with caution in diabetic patients with heart failure.12

Dipeptidyl peptidase-4 inhibitors (DPP4is; gliptins) are trendy drugs for the control of glycaemia in patients with diabetes despite their small effect on HbA1c. Large randomised studies with DPP4i have cast doubts about their safety in heart failure showing an increased risk of heart failure hospitalisations, and despite recent data, suggest that they may be safe to use; given their limited clinical benefit and given that there is a lack of data on their effect in patients with heart failure their use is not recommended except under strict cardiology supervision.24,25,12,26 There are no data on the long term safety of glucagon-like peptide-1 (GLP-1) receptor agonists in patients with heart failure. Recently, liraglutide was tested against placebo in the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial and showed a significant reduction in the composite primary outcome of the first occurrence of cardiovascular death, nonfatal MI or non-fatal stroke, but no effect on heart failure endpoints. Given the absence of detailed data in patients with heart failure, the use of GLP-1 receptor agonists should be implemented only under strict cardiology supervision. The sodium-glucose cotransporter 2 inhibitors (SGLT2i) enhance glucose control by increasing the urinary excretion of glucose. Recently, the SGLT2i empagliflozin showed a significant and relevant effect on cardiovascular protection. 5 The EMPA-REG OUTCOME study conducted in 7,020 patients with type 2 diabetes (glycated haemoglobin level, 7.0–10.0 %) at high risk for cardiovascular events followed for a median of 3.1 years has shown that empagliflozin use led to a significant reduction in the rates of death from cardiovascular causes (38 % relative risk reduction), hospitalisation for heart failure (35 % relative risk reduction) and death from any cause (32 % relative reduction). Empagliflozin reduced by 39 % the hospitalisations for or death from heart failure (2.8 versus 4.5 %; HR 0.61 [0.47–0.79]; P<0.001) and was associated with a reduction in all-cause hospitalisation (36.8 versus 39.6 %; HR 0.89 [0.82–0.96]; P=0.003). The mechanisms responsible for the effects of empagliflozin on cardiovascular endpoints and heart failure are largely unknown. Potential mechanisms to be proven include effect on sodium retention and plasma volume, osmotic diuresis, reduction of insulin levels and insulin response to food intake, modulation of the renin-angiotensin aldosterone system, reduction weight and blood pressure without increases in sympathetic nervous activity.

Mitiglinides may induce water retention and should be used with caution in patients with heart failure. Alpha-glucosidase inhibitors like acarbose lack any effect on insulin, water and sodium retention, and are safe to use in patients with increased cardiovascular risk and in those with heart failure.

Insulin is often required for the glucose control of diabetic patients with type 1 diabetes, and of some patients with type 2 diabetes and pancreatic islet beta cell exhaustion. Since insulin induces significant sodium retention precipitating worsening of heart failure, the change in dose, schedule of administration and type of insulin used must be constantly supervised by a cardiologist in patients with chronic heart failure.

Thiazolidinediones are associated with increased sodium and fluid retention, and increase sympathetic nervous system activity. Randomised clinical trials and meta-analyses have shown that thiazolidinediones increase the risk of heart failure worsening and hospitalisations from heart failure, and they are contraindicated in patients with heart failure.13

Therefore, the heart failure team according to the clinical conditions should make the judgement on the intensity of glycaemic control, the type and dose of glucose-lowering agents, and any change in the glucose-lowering therapy should be closely monitored. ■

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Heart Failure in Diabetes Mellitus

Stratton IM, Adler AI, Neil HA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 2000;321 :405–12. DOI: http://dx.doi.org/10.1136/ bmj.321.7258.405 Metra M, Zacà V, Parati G, et al. Cardiovascular and noncardiovascular comorbidities in patients with chronic heart failure. J Cardiovasc Med (Hagerstown) 2011;12 :76–84. DOI:10.2459/JCM.0b013e32834058d1; PMID: 20962666 MacDonald MR, Petrie MC, Varyani F, et al. Impact of diabetes on outcomes in patients with low and preserved ejection fraction heart failure: an analysis of the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) programme. Eur Heart J 2008;29 :1377–85. DOI:10.1093/eurheartj/ehn153; PMID: 18413309 Fadini GP, Avogaro A, Degli Esposti L, et al. Risk of hospitalization for heart failure in patients with type 2 diabetes newly treated with DPP-4 inhibitors or other oral glucose-lowering medications: a retrospective registry study on 127,555 patients from the Nationwide OsMed Health-DB Database. Eur Heart J 2015;36 :2454–62. DOI:10.1093/eurheartj/ ehv301; PMID: 26112890 Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373 :2117–28. DOI: 10.1056/ NEJMoa1504720 Ryden L, Grant PJ, Anker SD, et al. ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD: the Task Force on diabetes,pre-diabetes, and cardiovascular diseases of the European Society of Cardiology (ESC) and developed in collaboration with the EuropeanAssociation for the Study of Diabetes (EASD). Eur Heart J 2013;34 :3035–87. DOI:10.1093/ eurheartj/eht108; PMID: 23996285 Wang Y, Negishi T, Negishi K, Marwick TH. Prediction of heart failure in patients with type 2 diabetes mellitus- a systematic review and meta-analysis. Diabetes Res Clin Pract 2015;108 : 55–66. DOI:10.1016/j.diabres.2015.01.011; PMID: 25686509 Rosano GM, Vitale C, Fragasso G. Metabolic therapy for patients with diabetes mellitus and coronary artery disease. Am J Cardiol 2006;98 (5A):14J–18J. DOI:10.1016/j.

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amjcard.2006.07.004; PMID: 16931201: Epub ahead of press. Nagoshi T, Yoshimura M, Rosano GM, et al. Optimization of cardiac metabolism in heart failure. Curr Pharm Des 2011;17 (35):3846–53. PMID: 21933140; PMCID:PMC3271354 Rosano GM, Fini M, Caminiti G, Barbaro G. Cardiac metabolism in myocardial ischemia. Curr Pharm Des 2008;14 :2551–62. PMID: 18991672 Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. The SOLVD Investigators. N Engl J Med 1991;325 :293–302. DOI:10.1056/NEJM199108013250501; PMID: 2057034 Ponikowski P, Voors A, Anker S, 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). Eur J Heart Fail 2016;37 :2129–200. Home PD, Pocock SJ, Beck-Nielsen H, et al. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial. Lancet 2009;373 :2125–35. DOI:10.1016/S0140-6736(09)60953-3; PMID: 19501900 Elder DH, Singh JS, Levin D, et al. Mean HbA1c and mortality in diabetic individuals with heart failure: a population cohort study. Eur J Heart Fail 2016;18 :94–102. DOI:10.1002/ejhf.455; PMID: 26663216 Goode KM, John J, Rigby AS, et al. Elevated glycated haemoglobin is a strong predictor of mortality in patients with left ventricular systolic dysfunction who are not receiving treatment for diabetes mellitus. Heart 2009;95 : 917–23. DOI:10.1136/hrt.2008.156646; PMID: 19233773 Aguilar D, Bozkurt B, Ramasubbu K, Deswal A. Relationship of haemoglobin A1C and mortality in heart failure patients with diabetes. J Am Coll Cardiol 2009;54 :422–8. DOI:10.1016/ j.jacc.2009.04.049; PMID: 19628117; PMCID:PMC2753214 Jeffcoate SL. Diabetes control and complications: the role of glycated haemoglobin, 25 years on. Diabet Med 2004;21 : 657–65. DOI:10.1046/j.1464-5491.2003.01065.x; PMID: 15209755 Lind M, Odén A, Fahlén M, Eliasson B. A systematic review of HbA1c variables used in the study of diabetic complications.

Diabetes Metab Synd: Clin Res Rev 2008;2 :282–93. 19. Boussageon R, Bejan-Angoulvant T, Saadatian-Elahi M, et al. Effect of intensive glucose lowering treatment on all cause mortality, cardiovascular death, and microvascular events in type 2 diabetes: meta-analysis of randomised controlled trials. BMJ 2011;343 :d4169. PMCID:PMC3144314; PMID: 21791495 20. ACCORD Study Group, Gerstein HC, Miller ME, Genuth S, et al. Long-term effects of intensive glucose lowering on cardiovascular outcomes. N Engl J Med 2011;364 :818–28. DOI:10.1056/NEJMoa1006524; PMID: 21366473; PMCID:PMC4083508 21. Ukena C, Dobre D, Mahfoud F, et al. Hypo- and hyperglycemia predict outcome in patients with left ventricular dysfunction after acute myocardial infarction: data from EPHESUS. J Card Fail 2012;18 : 439–45. DOI:10.1016/j.cardfail.2012.03.002; PMID: 22633301 22. MacDonald MR, Eurich DT, Majumdar SR, et al. Treatment of type 2 diabetes and outcomes in patients with heart failure: a nested case-control study from the U.K. General Practice Research Database. Diabetes Care 2010;33:1213–8. DOI:10.2337/dc09-2227; PMID: 20299488; PMCID:PMC2875425 23. Boussageon R, Supper I, Bejan-Angoulvant T, et al. Reappraisal of metformin efficacy in the treatment of type 2 diabetes: a meta-analysis of randomised controlled trials. PLoS Med 2012;9 :e1001204. DOI:10.1371/journal. pmed.1001204; PMID: 22509138; PMCID:PMC3323508 24. Monami M, Dicembrini I, Mannucci E. Dipeptidyl peptidase-4 inhibitors and heart failure: a meta-analysis of randomized clinical trials. Nutr Metab Cardiovasc Dis 2014;24 :689–97. DOI:10.1016/j.numecd.2014.01.017; PMID: 24793580 25. Savarese G, Perrone-Filardi P, D’Amore C, et al. Cardiovascular effects of dipeptidyl peptidase-4 inhibitors in diabetic patients: a meta-analysis. Int J Cardiol 2015;181 : 239–44. DOI:10.1016/j.ijcard.2014.12.017; PMID: 25528528 26. Green JB, Bethel MA, Armstrong PW, et al. Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 2015;373 (3):232–42. DOI:10.1056/NEJMoa1501352; PMID: 26052984

Comorbidities

Challenges of Treating Acute Heart Failure in Patients with Chronic Obstructive Pulmonary Disease Jelena Cˇelutkiene˙, 1,2 Mindaugas Balcˇ iuˉnas, 1,3 Denis Kablucˇ ko, 2 Liucija Vaitkevicˇ iuˉte˙, 4,5 Jelena Blašcˇ iuk 4 and Edvardas Danila 6,7 1. Clinic of Cardiac and Vascular Diseases, Vilnius University, Vilnius, Lithuania; 2. Centre of Cardiology and Angiology, Vilnius University Hospital Santariškiu˛ Klinikos, Vilnius, Lithuania; 3. Department of Cardiothoracic Anaesthesia and Intensive Care, Papworth Hospital NHS Foundation Trust, Cambridge, UK; 4. Emergency Department, Vilnius University Hospital Santariškiu˛ Klinikos, Vilnius, Lithuania; 5. Clinic of Internal Disease, Family Medicine and Oncology, Vilnius University, Vilnius, Lithuania; 6. Clinic of Infectious and Chest Diseases, Dermatovenereology and Allergology, Vilnius University, Vilnius, Lithuania; 7. Vilnius University Hospital Santariškiu˛ Klinikos, Centre of Pulmonology and Allergology, Vilnius, Lithuania

Abstract Heart failure (HF) and chronic obstructive pulmonary disease (COPD) comorbidity poses substantial diagnostic and therapeutic challenges in acute care settings. The specific role of pulmonary comorbidity in the treatment and outcomes of cardiovascular disease patients was not addressed in any short- or long-term prospective study. Both HF and COPD can be interpreted as systemic disorders associated with low-grade inflammation, endothelial dysfunction, vascular remodelling and skeletal muscle atrophy. HF is regularly treated as a broader cardiopulmonary syndrome utilising acute respiratory therapy. Based on observational data and clinical expertise, a management strategy of concurrent HF and COPD in acute settings is suggested. Concomitant use of beta2-agonists and beta-blockers in a comorbid cardiopulmonary condition seems to be safe and effective.

Keywords Acute heart failure, chronic obstructive pulmonary disease, bronchodilators, acute respiratory therapy, beta-blockers Disclosure: JC and MB were supported by a grant from the Research Council of Lithuania MIP-049/2015. The remaining authors have no conflicts of interest to declare. Received: 13 October 2016 Accepted: 25 January 2017 Citation: Cardiac Failure Review 3(1):56–61. DOI: 10.15420/cfr.2016:23:2 Correspondence: Jelena Cˇ elutkiene˙, Vilnius University Hospital Santariškiu˛ Klinikos, A Corpus, Room A229, Santariškiu˛ 2, LT 08661, Vilnius, Lithuania. E: Jelena.celutkiene@santa.lt

Heart failure (HF) and chronic obstructive pulmonary disease (COPD) comorbidity poses substantial diagnostic and therapeutic challenges in acute care settings. Outcomes of this comorbidity are worse than in either disease alone.1,2 A hospital diagnosis of COPD is an independent predictor of all-cause and non-cardiovascular mortality in HF patients,3–5 associated with decrease in use of evidence-based HF medications and longer hospitalisation durations.6 Prevalence of co-existent COPD diagnosis in hospitalised HF patients is summarised in Table 1.5–16 Half of the patients with an acute exacerbation of COPD are reported to have echocardiographic evidence of left ventricular failure.1,2

Pathophysiology of Cardiopulmonary Continuum in Acute Exacerbations Evidence increasingly suggests that both HF and COPD can be interpreted as systemic disorders associated with low-grade inflammation, endothelial dysfunction, vascular remodelling and skeletal muscle atrophy.5,17,18 Abrupt haemodynamic, ventilatory and fluid content changes superimpose on chronic structural and functional abnormalities caused by long-term co-existence of cardiac and pulmonary conditions. Patients with COPD and HF have a combined obstructive and restrictive type of pulmonary dysfunction.19 COPD is characterised by obstructed airflow, destruction of pulmonary tissue in emphysema and respiratory muscle weakness. In turn, progressive heart enlargement taking thoracic space, venous congestion, interstitial fibrosis, pleural

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effusions and substantial atelectasis all contribute to pulmonary compression in HF. Typically for COPD, decrease in Oxygen (O2) arterial pressure and an increase in carbon dioxide (CO2) arterial pressure in case of coincident HF is combined with alteration of lung diffusion capacity due to the thickening of the alveolar septa, reduction in alveolar–capillary membrane conductance and lung remodelling with collagen deposition.17–19 Acute pulmonary oedema typically causes the dynamic airflow obstruction due to interstitial fluid and bronchial mucosal swelling (see Figure 1).20–22 In 19 % of patients hospitalised for congestive systolic HF, initial airway obstruction was found but had disappeared in 47 % of these patients after re-compensation. Bacterial and viral infections as well as inflammatory process in the small airways are important precipitating factors.23 Progressive respiratory failure usually increases airway obstruction, hypoxaemia and ventilation–perfusion mismatch. In acute phases of both entities, elevated biomarkers of neurohumoral activation, myocardial damage and inflammation have been found.4 Severe hypoxaemia, cardiac stress, increased sympathetic nervous and platelet activation may contribute to myocardial necrosis. Of note, undiagnosed subendocardial infarctions are revealed in autopsies of patients who have died during acute exacerbation of COPD.24 Importantly, the substantial elevation of natriuretic peptides was reported even when the COPD patient had no clinical or echo signs of overt right ventricular failure, with the subsequent fall of concentration

Treating Acute Heart Failure with Chronic Obstructive Pulmonary Disease Table 1: Prevalence of Chronic Obstructive Pulmonary Disease in Hospitalised Heart Failure Patients Author

Year of Publication

Patients (n)

Prevalence of COPD (%)

Definition of COPD Presence

Ni et al.7

1998

5,821

Study Name

Discharge database

Iversen et al.8

2008

532

Spirometry (GOLD criterion)

Lainscak et al.9

2009

638

Medical history and clinical data

Recio-Iglesias et al.10

2010

391

Clinical criteria or spirometry

Mentz et al.11

2012

4,133

EVEREST

Medical history and clinical data

Mentz et al.6

2012

48,612

OPTIMIZE-HF

Medical history and clinical data

Macchia et al.12

2012

201

Spirometry (GOLD criterion)

Dharmarajan et al.13

2013

164,494

39*

Clinical data and treatment

Yoshihisa et al.5

2014

378

Spirometry (GOLD criterion)

Parissis et al.14

2014

4,953

ALARM-HF

Medical history and clinical data

Fisher et al.15

2015

9,748

Worcester HF study

Medical history and clinical data

Krahnke et al.16

2015

550

CHAMPION

Medical history and clinical data

*Prevalence of chronic lung disease (including asthma). ALARM-HF = Acute Heart Failure Global Survey of Standard Treatment; CHAMPION = CardioMEMS Heart Sensor Allows Monitoring of Pressures to Improve Outcomes in NYHA Class III Heart Failure Patients; COPD = chronic obstructive pulmonary disease; EVEREST = Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan; GOLD = Global Initiative for Chronic Obstructive Lung Disease; HF = heart failure; OPTIMIZE-HF = Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure.

Figure 1: Pathogenetic Mechanisms of Cardiopulmonary Continuum in Acute Settings

Acute hypervolaemia

Sympathetic overdrive

Myocardial wall stress ( BNP)

Activation of RAAS system

Precipitating bacterial and viral infections

Activation in inflammatory state ( CRP) Myocardial damage ( hs troponin)

Increase in LV filling pressure

Increase in pulmonary vascular resistance Increased congestion

Increased RV afterload

Increased airflow obstruction

Pulmonary oedema

Reduced stroke volume

Impaired lung diffusion

Decreased LV filling

Worsening hypoxaemia

Increased hyperinflation

Severe hypercapnia

Increased intrathoracic pressure Decrease in cardiac output

BNP = brain natriuretic peptide; CRP = C-reactive protein; hs troponin = high-sensitivity troponin; LV = left ventricular; RAAS = renin-angiotensin-aldosterone system; RV = right ventricular.

during the first days of treatment in parallel with the decrease in pulmonary arterial pressures. The CardioMEMS Heart Sensor Allows Monitoring of Pressures to Improve Outcomes in NYHA Class III Heart Failure Patients (CHAMPION) study analysis proved the importance of pulmonary

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vascular resistance and increased pulmonary artery pressure for decompensation of both diseases.16 Pulmonary vascular disease associated with hypoxic vasoconstriction was shown to be an important risk factor for respiratory exacerbations and mortality in patients with COPD. It is believed that products of tobacco smoke induce inflammatory changes and further pulmonary vasculature remodelling.

Comorbidities The true prevalence of pulmonary hypertension among COPD patients is not known, and genetic predispositions may have a role in different susceptibility of COPD patients towards pulmonary hypertension.17,23

Regular Respiratory Treatment in Acute Heart Failure

Diagnostic Challenges of Dyspnoea in Patients with Heart Failure and Chronic Obstructive Pulmonary Disease

Data from Premier Perspective® database showed that among 164,494 HF hospitalisations, 53 % received acute respiratory therapies during the first two hospital days: 37 % received short-acting inhaled bronchodilators, 33 % received antibiotics and 10 % received highdose corticosteroids.13 Acute respiratory therapy was associated with higher odds of in-hospital mortality, admissions to an intensive care unit, late intubation, and was more frequent among the 60,690 hospitalisations with chronic lung disease. Such co-treatment may be explained by complexity in differential diagnosis of cause of acute dyspnoea in typical practice. Rates of initial co-treatment were above 50 % even among patients who underwent an early diagnostic testing with natriuretic peptides or chest radiographs. Therefore, HF is regularly treated as a broader cardiopulmonary syndrome, with less than half of patients treated exclusively for HF. Bronchial mucosal swelling, peribronchial oedema, bronchoconstriction and alveolar fluid accumulation may lead to a reversible airway obstruction in singular acute HF; however, whether bronchodilators improve symptoms of dyspnoea in this case is unknown.

Only 37 % of patients with a history of pulmonary disease were correctly identified as presenting with HF by the emergency physicians.25 Wheezing may be audible in HF patients with acute congestion, while crackles of pulmonary oedema are frequently not heard in a hyperinflated chest.26 The radiographic appearance of pulmonary oedema may be atypical in patients with emphysema because of the destruction of the pulmonary vascular bed or additional shadows. Vascular redistribution may be due to COPD rather than raised left atrial pressure. When differential diagnosis includes parenchymal lung disease, a computed tomography (CT) scan of the chest could be useful. Characteristic findings include ground-glass opacities, pleural effusions and cardiomegaly. However, the cardiothoracic ratio may remain normal if the heart tends to become long and narrow in a hyperinflated chest. Echocardiography also has limitations in the differentiation between acute HF and COPD. The estimated prevalence of unsatisfactory ultrasound image quality reaches up to 50 % in severe airflow obstruction.27 High pulmonary hypertension is diagnosed in almost one-fifth of HF patients irrespective of left ventricular ejection fraction. Due to elevation in leftsided filling pressures, 52.5 % patients with HF with preserved ejection fraction have been diagnosed with pulmonary hypertension.22,23 Lung ultrasonography is recommended as a useful tool to identify and monitor congestion in acute care.28–30 Simultaneously, it helps visualise pleural effusion, pneumothorax or lung consolidation. When the fluid leaks into the interstitial space the air–fluid interface creates the acoustic substrate for B-lines. Non-invasive indices of right ventricular size and function may add incremental prognostic value in patients with acute dyspnoea.31 B-type natriuretic peptide (BNP) plasma levels serve as an early sensitive indicator of right ventricular (RV) dysfunction.25 Values >500 pg/ml are highly suggestive of overt congestive heart failure (CHF). Values between 100 and 500 pg/ml should alert to the possible presence of HF complicating COPD.32 A high negative predictive value of concentration <100 pg/ml is preserved in cohorts of patients with a dual diagnosis.

Therapeutic Dilemmas in Comorbid Cardiopulmonary Disorder No large prospective studies have specifically examined the impact of beta2-agonists on HF outcomes, as well as safety and effectiveness of beta-blockers for patients with co-existent HF and COPD. Management of these patients is based mainly on clinical expertise and observational data, which currently are reassuring for concomitant use of beta2agonists and beta-blockers in a comorbid cardiopulmonary condition. Information about the treatment of this patient population in acute settings is particularly limited. Suggested management pathways of concurrent HF and COPD are presented in Figure 2.

Surprisingly, many acute decompensated HF patients receive inhaled bronchodilators even without a history of COPD.13,33

Use of Beta 2-agonists and Cardiovascular Outcomes Beta-agonists were reported to significantly increase tachycardia in patients with obstructive airway disease, which in turn may increase myocardial oxygen consumption and electrical instability; these effects are specifically detrimental in failing myocardium. Several retrospective analyses raised concerns about the higher risk of arrhythmias, acute ischaemic events, HF hospitalisations and mortality in patients using beta2-agonists.34–36 However, these data were mostly collected two decades ago, when beta-blockers were roughly used by 30 % of HF patients, and overall treatment for HF and ischaemic heart disease was substantially different. Later studies demonstrated a strong protective effect of cardiac agents against bronchodilator associated risks.37–40 A recent multicentre study (Towards a Revolution in COPD Health [TORCH]) with more than 6,000 patients with COPD (41 % of them taking cardiovascular medications) showed no increase in overall and cardiovascular-related adverse events in the salmeterol group.38–39 Likewise, adjustment to detailed clinical information and levels of natriuretic peptide in a longitudinal cohort study of HF patients eliminated differences in mortality between beta2-agonist users and non-users, thus suggesting that bronchodilator use may be a marker of a more severe disease.40 Nevertheless, in view of the absence of strong evidence or accepted recommendations, bronchodilators should be used with caution in acute settings with patients with underlying HF, especially in those having tachyarrhythmias. Given the previously reported dosedependent increase of risk of adverse cardiovascular outcomes in observational studies, reduction of dose and frequency of beta2agonists or temporary withdrawal until haemodynamic stabilisation may be considered, until safety data are available.36,37

Beta-blockers Improve Outcomes in Respiratory Decompensation To date, extensive observational data have been accumulated of protective effects of beta-blockers on mortality and exacerbations in patients with COPD.41–49 Two studies were performed in acute settings.50,51 A single-centre analysis found that beta-blocker use was

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Treating Acute Heart Failure with Chronic Obstructive Pulmonary Disease Figure 2: Management of Exacerbated Respiratory Symptoms in Patients with Co-existent Heart Failure and Chronic Obstructive Pulmonary Disease

Suspected dominating airway obstruction

Suspected dominating congestion

Short acting beta2-agonists ± cholinolytics ± steroids ± antibiotics

Low doses of diuretics

Confirmed leading acute exacerbation of COPD

Confirmed leading decompensated heart failure

Significant hypercapnia YES

Markedly elevated BNP O2 therapy Add mild diuretics and consider vasodilators

Guidelines – directed HF treatment

Non-invasive ventilation

Continue usual HF treatment with ACEIs/ARBs, MRAs diuretics

Diagnostic tests: arterial blood gases, ECG, BNP, D-dimers, hs-troponin, CRP, Echo (heart, lung), chest X-ray, other routine blood tests

Persistent respiratory distress

Hypoxaemia

History, symptoms and clinical signs

Continue usual COPD treatment

Treat alternative causes of dyspnoea accordingly

Continue or initate beta1-selective blockers

In persistent sinus tachycardia consider ivabradine ACEIs = angiotensin-converting-enzyme inhibitors; ARBs = angiotensin receptor antagonists; BNP = brain natriuretic peptide; COPD = chronic obstructive pulmonary disease; CRP = C-reactive protein; ECG = electrocardiogram; HF = heart failure; hs-troponin = high sensitivity troponin; MRAs = mineralocorticoid receptor antagonists; O2 = oxygen.

an independent predictor of survival to hospital discharge, with no evidence that these agents reduce the beneficial effects of shortacting beta2-agonists in collateral use.51 In a cohort of patients with cardiovascular disease admitted due to acute COPD exacerbation to 404 acute care hospitals, there was no association between betablocker therapy and in-hospital mortality, 30-day readmission or late mechanical ventilation.50 Of note, receipt of non-selective betablockers was associated with an increased risk of 30-day readmission compared with beta1-selective blockers. In a meta-analysis of 15 retrospective studies of 21,596 patients with COPD, the pooled estimate for reduction in overall mortality attributed to the use of beta-blockers was 28 % (95 % confidence interval [CI], 17–37 %) and for exacerbations was 38 % (95 % CI, 18–58 %). The reduction in mortality was 26 % (95 % CI, 7–42 %) in the subgroup with known HF.52 However, no results from randomised controlled trials are available to date. Despite evidence-based indications, numerous reports reveal that most COPD patients with concurrent cardiovascular disease are denied the protective effect of beta-blockers. Underuse of beta-blockers stems from the concern regarding beta-2 receptor antagonism and associated bronchoconstriction. For example, among patients with COPD admitted to hospital for acute HF in a large Acute Heart Failure Global Survey of Standard Treatment (ALARM-HF) registry, beta-

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blockers were underutilised at discharge.14 Recent data suggest that the prescription of beta-blockers in patients with heart disease has doubled in the last decade in both patients with and without COPD.41 A number of studies indicate that cardioselective beta-blockers exert minimal impact on reversible or severe airflow obstruction. A cochrane review including 20 randomised trials of cardio-selective beta-blockers in COPD found no significant effect on forced expiratory volume in 1 second (FEV1) or bronchodilator response after a single dose or up to 12 weeks of treatment.42 In three small randomised controlled trials examining beta-blockers in patients with HF and concurrent COPD,43–45 cardioselective beta-blockade was well-tolerated and beneficial effects on lung function were seen. Besides clear cardioprotective action, beta-blockers may be beneficial due to modulation of the immune response and improved clearance of bacteria from the circulation during systemic infections. All these data together advocate continuation or initiation of beta-blockers (preferably beta1-selective) during acute respiratory exacerbation in patients having concurrent HF and COPD.

The Interference of beta-blockers and beta-agonists Data on drug interaction between beta-blockers and bronchodilators are scarse. In a retrospective cohort study of acute exacerbation of COPD, no evidence that beta-blockers reduce the beneficial effects of

Comorbidities short-acting beta-agonists when the two are used in combination was found.51 Contrary, it has been suggested that beta-blockers may be beneficial by enhancing sensitivity to endogenous or exogenous betaadrenergic stimulation and improve bronchodilator responsiveness by upregulation of beta-receptors within the lung.41,42 Moreover, beta-blockers may blunt the potential cardiac toxicity of short-acting beta-agonists. The aim to preserve bronchodilator action of beta2agonists grounds the choice of selective beta1-blockers in acute cardiorespiratory decompensation. In acute COPD, normal doses of selective beta1-blockers appear to be safe and well tolerated.

Role of Diuretics and Vasodilators in Co-existent Heart Failure and Chronic Obstructive Pulmonary Disease Treatment of acute HF in COPD patients with diuretics improves gas exchange by removal of lung water, improvement of lung compliance and increase in FEV1.53,54 Impressive reduction of respiratory hospitalisation rates in the COPD cohort in the CHAMPION trial was driven by changes in diuretic therapies in response to elevated pulmonary artery pressure data.16 A BNP level of >500 pg/ml indicates that HF therapy should be initiated or upgraded in addition to COPD treatment.55 Intriguing data are published suggesting that BNP is a bronchorelaxant and a potential new drug for COPD.56 Early administration of diuretics and vasodilators may improve outcomes of patients with acute exacerbation of comorbid HF and COPD.

Effects of Renin-angiotensin-aldosterone System Blockers and Ivabradine in Chronic Obstructive Pulmonary Disease In patients with HF and co-existent COPD, angiotensin-convertingenzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) carry an additional benefit by decreasing levels of angiotensin-II, which is a potent pulmonary airway constrictor.57 Therefore, these HF medications reduce airways obstruction, decrease pulmonary inflammation and pulmonary vascular constriction, and improve the alveolar membrane

1. Sin DD, Anthonisen NR, Soriano JB, Agusti AG. Mortality in COPD: role of comorbidities. Eur Respir J 2006;28:1245–57. DOI: 10.1183/09031936.00133805; PMID: 17138679 2. Almagro P, Calbo E, Ochoa de Echagüen A, et al. Mortality after hospitalization for COPD. Chest 2002;121:1441–8. DOI: 10.1378/chest.121.5.1441; PMID: 12006426 3. Holguin F, Folch E, Redd SC, Mannino DM. Comorbidity and mortality in COPD-related hospitalizations in the United States, 1979 to 2001. Chest 2005;128:2005–11. DOI: 10.1378/ chest.128.4.2005; PMID: 16236848 4. Staszewsky L, Wong M, Masson S, et al. Clinical, neurohormonal, and inflammatory markers and overall prognostic role of chronic obstructive pulmonary disease in patients with heart failure: data from the Val-HeFT heart failure trial. J Card Fail 2007;13:797–804. DOI: 10.1016/ j.cardfail.2007.07.012; PMID: 18068611 5. Yoshihisa A, Takiguchi M, Shimizu T, et al. Cardiovascular function and prognosis of patients with heart failure coexistent with chronic obstructive pulmonary disease. J Cardiol 2014;64:256–64. DOI: 10.1016/j.jjcc.2014.02.003; PMID: 24674751 6. Mentz RJ, Fiuzat M, Wojdyla DM, et al. Clinical characteristics and outcomes of hospitalized heart failure patients with systolic dysfunction and chronic obstructive pulmonary disease: findings from OPTIMIZE-HF. Eur J Heart Fail 2012;14:395–403. DOI: 10.1093/eurjhf/hfs009; PMID: 22302663 7. Ni H, Nauman D, Hershberger RE. Managed care and outcomes of hospitalization among elderly pateints with congestive heart failure. Arch Intern Med 1998;158:1231–6. PMID: 9625402 8. Iversen KK, Kjaergaard J, Akkan D, et al. Chronic obstructive pulmonary disease in patients admitted with heart failure. J Intern Med 2008;264:361–9. DOI: 10.1111/j.13652796.2008.01975.x; PMID: 18537871 9. Lainscak M, Hodoscek LM, Düngen HD, et al. The burden of chronic obstructive pulmonary disease in patients hospitalized with heart failure. Wien Klin Wochenschr 2009;121:309–13. DOI: 10.1007/s00508-009-1185-8; PMID: 19562292 10. Recio-Iglesias J, Grau-Amorós J, Formiga F, et al. [Chronic

gas exchange. Aldosterone antagonists also exhibit a positive effect on gas diffusion protecting the alveolar–capillary membrane. The heart rate-reducing agent, ivabradine, which selectively inhibits sinoatrial funny current (If) channels, has been shown to similarly reduce cardiovascular risk in both COPD and non-COPD patients, thus presenting an effective alternative measure to reduce sinus tachycardia in case of a complicated comorbid decompensation.57

Non-invasive Ventilation Non-invasive ventilation (NIV) improves the outcomes of patients with acute respiratory failure due to hypercapnic exacerbation of COPD or HF with acute pulmonary oedema. NIV improves gas exchange, accelerates the remission of symptoms, reducing the need for endotracheal intubation, hospital mortality and hospital stay when compared with conventional O2 therapy.30,31 In patients with cor pulmonale secondary to a chronic pulmonary disease like COPD, the use of biphasic positive airway pressure can improve the right ventricular function and decrease plasma levels of natriuretic peptides. Currently there is no direct evidence for the treatment of concomitant HF or COPD that is different from the accepted clinical guidelines for both diseases.57,58 The specific role of pulmonary comorbidity in the treatment and outcomes of cardiovascular disease patients was not addressed in any long-term prospective study. Randomised controlled trials to elucidate effects of cardioselective beta1-blockers on pulmonary function in COPD as well as to evaluate their interaction with long-acting bronchodilators are ongoing (clinicaltrials.gov/show/NCT01656005). The common practice of withholding beta-blockers in COPD patients seems to be unsafe, and cardioselective beta1-blockers may be preferable to non-selective until new evidence is available. ■

obstructive pulmonary disease on inpatients with heart failure. GESAIC study results]. Med Clin (Barc) 2010;134: 427–32. DOI: 10.1016/j.medcli.2009.09.046. PMID: 20149399 11. Mentz RJ, Schmidt PH, Kwasny MJ, et al. The impact of chronic obstructive pulmonary disease in patients hospitalized for worsening heart failure with reduced ejection fraction: an analysis of the EVEREST Trial. J Card Fail 2012;18:515–23. DOI: 10.1016/j.cardfail.2012.04.010; PMID: 22748484 12. Macchia A, Rodriguez Moncalvo JJ, Kleinert M, et al. Unrecognised ventricular dysfunction in COPD. Eur Respir J 2012;39:51–8. DOI: 10.1183/09031936.00044411; PMID: 21700606 13. Dharmarajan K, Strait KM, Lagu T, et al. Acute decompensated heart failure is routinely treated as a cardiopulmonary syndrome. PLoS One 2013;8:e78222. DOI: 10.1371/journal. pone.0078222; PMID: 24250751; PMCID: PMC3824040 14. Parissis JT, Andreoli C, Kadoglou N, et al. Differences in clinical characteristics, management and short-term outcome between acute heart failure patients chronic obstructive pulmonary disease and those without this co-morbidity. Clin Res Cardiol 2014;103:733–41. DOI: 10.1007/s00392-014-0708-0; PMID: 24718849 15. Fisher KA, Stefan MS, Darling C, et al. Impact of COPD on the mortality and treatment of patients hospitalized with acute decompensated heart failure: the Worcester Heart Failure Study. Chest 2015;147(3):637–45. DOI: 10.1378/chest.14-0607; PMID: 25188234; PMCID: PMC4347532 16. Krahnke JS, Abraham WT, Adamson PB, et al. Heart Failure and Respiratory Hospitalizations Are Reduced in Patients With Heart Failure and Chronic Obstructive Pulmonary Disease With the Use of an Implantable Pulmonary Artery Pressure Monitoring Device. J Card Fail 2015;21:240–9. DOI: 10.1016/ j.cardfail.2014.12.008; PMID: 25541376; PMCID: PMC4405122 17. Le Jemtel TH, Padeletti M, Jelic S. Diagnostic and therapeutic challenges in patients with coexistent chronic obstructive pulmonary disease and chronic heart failure. J Am Coll Cardiol 2007;49:171–80. DOI: 10.1016/j.jacc.2006.08.046; PMID: 17222727 18. Barnes PJ, Celli BR. Systemic manifestations and comorbidities of COPD. Eur Respir J 2009;33:1165–85. DOI:

10.1183/09031936.00128008; PMID: 19407051 19. O’Donnell DE, Neder JA, Elbehairy AF. Physiological impairment in mild COPD. Respirology 2016;21:211–23. DOI: 10.1111/resp.12619; PMID: 26333038 20. Brenner S, Guder G, Berliner D, et al. Airway obstruction in systolic heart failure – COPD or congestion? Int J Cardiol 2013;168:1910–6. DOI: 10.1016/j.ijcard.2012.12.083; PMID: 23369673 21. Guder G, Brenner S, Stork S, et al. Chronic obstructive pulmonary disease in heart failure: accurate diagnosis and treatment. Eur J Heart Fail 2014;16:1273–82. DOI: 10.1002/ ejhf.183; PMID: 25345927 22. Barr RG, Bluemke DA, Ahmed FS, et al. Percent emphysema, airflow obstruction, and impaired left ventricular filling. N Engl J Med 2010;362:217–27. DOI: 10.1056/NEJMoa0808836 23. Ghoorah K, De Soyza A, Kunadian V. Increased cardiovascular risk in patients with chronic obstructive pulmonary disease and the potential mechanisms linking the two conditions: a review. Cardiol Rev 2013;21:196–202. DOI: 10.1097/ CRD.0b013e318279e907; PMID: 23095685 24. Søyseth V, Bhatnagar R, Holmedahl NH, et al. Acute exacerbation of COPD is associated with fourfold elevation of cardiac troponin T. Heart 2013;99:122–6. DOI: 10.1136/ heartjnl-2012-302685; PMID: 23024006 25. McCullough PA, Hollander JE, Nowak RM, et al. Uncovering heart failure in patients with a history of pulmonary disease: rationale for the early use of B-type natriuretic peptide in the emergency department. Acad Emerg Med 2003;10:198–204. DOI: 10.1197/aemj.10.3.198; PMID: 12615582 26. Beghé B, Verduri A, Roca M, Fabbri LM. Exacerbation of respiratory symptoms in COPD patients may not be exacerbations of COPD. Eur Respir J 2013;41:993–5. DOI: 10.1183/09031936.00180812; PMID: 23543648 27. Hawkins NM, Virani S, Ceconi C. Heart failure and chronic obstructive pulmonary disease: the challenges facing physicians and health services. Eur Heart J 2013;34:2795–803. DOI: 10.1093/eurheartj/eht192; PMID: 23832490 28. Volpicelli G, Elbarbary M, Blaivas M, et al. International evidence-based recommendations for point-of-care lung ultrasound. Intensive Care Med 2012;38:577–91. DOI: 10.1007/

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Treating Acute Heart Failure with Chronic Obstructive Pulmonary Disease

s00134-012-2513-4; PMID: 22392031 29. Lancellotti P, Price S, Edvardsen T, et al. The use of echocardiography in acute cardiovascular care: recommendations of the European Association of Cardiovascular Imaging and the Acute Cardiovascular Care Association. Eur Heart J Acute Cardiovasc Care 2015; 4:3–5. DOI: 10.1177/2048872614568073; PMID: 25635106 30. Mebazaa A, Yilmaz MB, Levy P, et al. Recommendations on pre-hospital & early hospital management of acute heart failure: a consensus paper from the Heart Failure Association of the European Society of Cardiology, the European Society of Emergency Medicine and the Society of Academic Emergency Medicine. Eur J Heart Fail 2015;17:544–58. DOI: 10.1002/ejhf.289; PMID: 25999021 31. Harjola VP, Mebazaa A, Cˇelutkiene˙ J, et al. Contemporary management of acute right ventricular failure: a statement from the Heart Failure Association and the Working Group on Pulmonary Circulation and Right Ventricular Function of the European Society of Cardiology. Eur J Heart Fail 2016;18:226–41. DOI: 10.1002/ejhf.478; PMID: 26995592 32. Kim HN, Januzzi JL Jr. Natriuretic peptide testing in heart failure. Circulation 2011;123:2015–9. DOI: 10.1161/ CIRCULATIONAHA.110.979500; PMID: 21555724 33. Singer AJ, Emerman C, Char DM, et al. Bronchodilator therapy in acute decompensated heart failure patients without a history of chronic obstructive pulmonary disease. Ann Emerg Med 2008;51:25–34. DOI: 10.1002/ejhf.289; PMID: 17949853 34. Wilchesky M, Ernst P, Brophy JM, et al. Bronchodilator use and the risk of arrhythmia in COPD: part 2: reassessment in the larger Quebec cohort. Chest 2012;142:305–11. DOI: 10.1378/ chest.11-1597; PMID: 22871756 35. Hawkins NM, Wang D, Petrie MC, et al. Baseline characteristics and outcomes of patients with heart failure receiving bronchodilators in the CHARM programme. Eur J Heart Fail 2010;12:557–65. DOI: 10.1093/eurjhf/hfq040; PMID: 20356870 36. Salpeter SR, Ormiston TM, Salpeter EE. Cardiovascular effects of beta-agonists in patients with asthma and COPD: a meta-analysis. Chest 2004;125:2309–21. DOI: 10.1378/ chest.125.6.2309; PMID: 15189956 37. Macie C, Wooldrage K, Manfreda J, et al. Cardiovascular morbidity and the use of inhaled bronchodilators. Int J Chron Obstruct Pulmon Dis 2008;3:163–9. PMCID: PMC2528211 38. Calverley PM, Anderson JA, Celli B, et al. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med 2007;356:775–89. DOI:

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10.1056/NEJMoa063070; PMID: 17314337 39. Decramer ML, Hanania NA, Lötvall JO, Yawn BP. The safety of long-acting beta2-agonists in the treatment of stable chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis 2013;8:53–64. DOI: 10.2147/COPD.S39018; PMCID: PMC3558319 40. Bermingham M, O’Callaghan E, Dawkins I, et al. Are beta2agonists responsible for increased mortality in heart failure? Eur J Heart Fail 2011;13:885–91. DOI: 10.1093/eurjhf/hfr063; PMID: 21791542 41. Lipworth B, Wedzicha J, Devereux G, et al. Beta-blockers in COPD: time for reappraisal. Eur Respir J 2016;48:880–8. DOI: 10.1183/13993003.01847-2015; PMID: 27390282 42. Salpeter S, Omiston T, Salpeter E. Cardioselective betablockers for chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2005;(4):CD003566. DOI: 10.1002/14651858. CD003566.pub2; PMID: 16235327 43. Hawkins NM, Macdonald MR, Petrie MC, et al. Bisoprolol in patients with heart failure and moderate to severe chronic obstructive pulmonary disease: a randomized controlled trial. Eur J Heart Fail 2009;11:684–90. DOI: 10.1093/eurjhf/hfp066; PMID: 19460848 44. Lainscak M, Podbregar M, Kovacic D, et al. Differences between bisoprolol and carvedilol in patients with chronic heart failure and chronic obstructive pulmonary disease: a randomized trial. Respir Med 2011;105 Suppl 1: S44–9. DOI: 10.1016/S0954-6111(11)70010-5; PMID: 22015086 45. Jabbour A, Macdonald PS, Keogh AM, et al. Differences between beta-blockers in patients with chronic heart failure and chronic obstructive pulmonary disease: a randomized crossover trial. J Am Coll Cardiol 2010;55:1780–7. DOI: 10.1016/ j.jacc.2010.01.024; PMID: 20413026 46. Short PM, Lipworth SI, Elder DH, et al. Effect of beta blockers in treatment of chronic obstructive pulmonary disease: a retrospective cohort study. BMJ 2011;342:d2549. DOI: 10.1136/ bmj.d2549; PMID: 21558357; PMCID: PMC3091487 47. Rutten FH, Zuithoff NP, Hak E, et al. Beta-blockers may reduce mortality and risk of exacerbations in patients with chronic obstructive pulmonary disease. Arch Intern Med 2010;170:880–7. DOI: 10.1001/archinternmed.2010.112; PMID: 20498416 48. Andell P, Erlinge D, Smith JG, et al. beta-blocker use and mortality in COPD patients after myocardial infarction:a Swedish nationwide observational study. J Am Heart Assoc 2015;4:e001611. DOI: 10.1161/JAHA.114.001611; PMID: 25854796; PMCID: PMC4579937 49. Farland MZ, Peters CJ, Williams JD, et al. beta-Blocker Use

and Incidence of Chronic Obstructive Pulmonary Disease Exacerbations. Ann Pharmacother 2013;47:651–6. DOI: 10.1345/ aph.1R600; PMID: 23585645 50. Stefan MS, Rothberg MB, Priya A, et al. Association between b-blocker therapy and outcomes in patients hospitalised with acute exacerbations of chronic obstructive lung disease with underlying ischaemic heart disease, heart failure or hypertension. Thorax 2012;67:977–84. DOI: 10.1136/ thoraxjnl-2012-201945; PMID: 22941975; PMCID: PMC4454610 51. Dransfield MT, Rowe SM, Johnson JE, et al. Use of b blockers and the risk of death in hospitalised patients with acute exacerbations of COPD. Thorax 2008;63:301–5. DOI: 10.1136/ thx.2007.081893; PMID: 17951276 52. Du Q, Sun Y, Ding N, et al. Beta-blockers reduced the risk of mortality and exacerbation in patients with COPD: a metaanalysis of observational studies. PLoS One 2014;9:e113048. DOI: 10.1371/journal.pone.0113048. eCollection 2014; PMID: 25427000; PMCID: PMC4245088 53. Pison C, Malo JL, Rouleau JL, et al. Bronchial hyperresponsiveness to inhaled methacholine in subjects with chronic left heart failure at a time of exacerbation and after increasing diuretic therapy. Chest 1989;96:230–5. PMID:2666041 54. Light RW, George RB. Serial pulmonary function in patients with acute heart failure. Arch Intern Med 1983;143:429–33. PMID:6830378 55. Zhang J, Zhao G, Yu X, Pan X. Intravenous diuretic and vasodilator therapy reduce plasma brain natriuretic peptide levels in acute exacerbation of chronic obstructive pulmonary disease. Respirology 2012;17:715–20. DOI: 10.1111/j.14401843.2012.02162.x; PMID: 22394412 56. Calzetta L, Orlandi A, Page C, et al. Brain natriuretic peptide: Much more than a biomarker. Int J Cardiol 2016;221:1031–8. DOI: 10.1016/j.ijcard.2016.07.109; PMID: 27447810 57. 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.DOI: 10.1093/eurheartj/ehw128; PMID: 27206819 58. The Global Initiative for Chronic Obstructive Lung Disease (GOLD), Global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease (GOLD, updated 2015). Available at: www.goldcopd.org (Accessed 27 January 2017).

Comorbidities

Cardiac Atrophy and Heart Failure In Cancer Mark Sweeney, 1 Angela Yiu 2 and Alexander R Lyon 1,2 1. Cardio-Oncology Service, Royal Brompton Hospital, London, UK; 2. Faculty of Medicine, National Heart and Lung Institute, Imperial College London, UK

Abstract Functional changes in the heart in patients with cancer can be a result of both the disease itself and various cancer therapies, and limiting cardiac damage has become an increasingly important issue as survival rates in patients with cancer have improved. Processes involved in cancer-induced cardiac atrophy may include cardiomyocyte atrophy and apoptosis, decreased protein synthesis, increased autophagy and proteolysis via the ubiquitin-proteosome system. Further to direct effects of malignancy on the heart, several chemotherapeutic agents are known to affect the myocardium, in particular the anthracyclines. The aim of this report is to review the effects of cancer and cancer treatment on the heart and what is known about the underlying mechanisms. Furthermore, clinical strategies to limit and treat cancer-associated cardiac atrophy are discussed, emphasising the benefit of a multidisciplinary approach by cardiologists and oncologists to optimise models of care to improve outcomes for patients with cancer.

Keywords cardiac atrophy, cardiac dysfunction, cancer, chemotherapy, anthracyclines, oncology Disclosure: The authors have no conflicts of interest to declare. Received: 21 December 2016 Accepted: 30 March 2017 Citation: Cardiac Failure Review 2017;3(1):62–5. DOI: 10.15420/cfr.2017:3:2 Correspondence: Alexander R Lyon, Cardiovascular Biomedical Research Unit, Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK. E: a.lyon@ic.ac.uk

Cancer and the anti-cancer treatments prescribed by oncologists have long been known to have significant effects on muscle, causing a catabolic muscle wasting state and resulting in widespread and progressive atrophy of most muscle groups.1 This process contributes significantly to the cancer cachexia seen in up to 80 % of all patients with cancer, resulting in progressive weight loss, loss of muscle mass and decline in functional abilities.2 Cardiac atrophy describes the reduction in myocardial mass caused by a combination of a reduction in cell size and decreased cell numbers because of cell death. There is growing evidence that cancer and anti-cancer treatments cause cardiac atrophy,3 which results in impairment of the systolic and diastolic function of the heart. This impairment significantly adds to the burden of symptoms in such patients, including breathlessness, lethargy, reduced exercise tolerance and – on occasion – overt congestive cardiac failure as well as increased mortality.4 Improvements in cancer treatment and resulting survivorship have led to cardiovascular health in cancer patients becoming increasingly important. In one large registry of breast cancer patients, cardiovascular causes of death overtook breast cancer as the leading cause of death at nine years following the cancer diagnosis.5 As cardiologists and oncologists work together to explore models of care to improve outcomes for cancer patients, there is increasing understanding the functional changes to the heart resulting from both the cancer itself and various cancer therapies.

Cardiac Atrophy Induced by Cancer As early as 1968, Burch et al. recognised that patients who died from malignancy had a heart mass smaller than average at post mortem.6 Histological analysis revealed a reduction in the size and number of cardiac muscle fibres and increased extracellular stroma surrounding the myocytes. More recently post-mortem studies by Springer et al. in patients who died of pancreatic, lung and colorectal cancer found

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extensive loss of cardiomyocyte volume and replacement with fibrotic tissue in all cancer patients.7 A subset of these patients who had experienced significant cancer-related weight loss and cachexia were noted to have reduced left ventricular (LV) wall thickness and total heart weight compared with cancer patients without cachexia. This finding suggests that cardiac atrophy in cancer is part of a complex, systemic metabolic syndrome caused by the cancer that results in widespread muscle wasting, including the myocardium. Rodent models of cancer cachexia also show characteristics of cardiac atrophy, including decreased heart weight and LV mass, the thinning of septal, interventricular and posterior walls and chamber dilation as shown by echocardiography.8–11 Cardiac atrophy in cancer cachexia is likely to be driven more by cellular atrophy than cell death by apoptosis,8,9 and the imbalance between protein degradation and protein synthesis is the major cause of cardiac atrophy in cancer cachexia.3 Heart size decreases when the protein degradation rate exceeds the protein synthesis rate, which is likely to be because of a combination of decreased protein synthesis,9 increased autophagy8–10 and increased proteolysis via the ubiquitin-proteosome system (UPS).11,12 The putative mechanisms for cardiac atrophy in cancer patient are summarised in Table 1. Significant reduction in cardiac myofibrillar protein synthesis rate has been demonstrated in cachectic ApcMin/+ mice – a colorectal cancer model – via the suppression of the mechanistic target of rapamycin pathway.13 This reduction in myofibrillar protein levels in atrophic hearts has also been replicated in other studies.8,9,11 Increased autophagy in cardiac atrophy has been demonstrated by the upregulation of biomarkers beclin-1, p62 and LC3B in various rodent models.8–10 Cosper et al.8 also observed abundant autophagic vacuoles in atrophic hearts using electron microscopy. Musolino et al.10 showed that megestrol

Cardiac Atrophy and HF In Cancer acetate treatment can improve cardiac function in cachectic rats by downregulating autophagy, revealing the contribution of autophagy to cardiac atrophy. The role of UPS in the pathogenesis of cardiac atrophy is unclear. Two studies have reported the induction of the E3 ubiquitin ligases muscle RING finger-1, atrogin-1 and muscle atrophy F-box in colon-26 tumour-bearing mice11 and murine adenocarcinoma of the colon 16-inoculated mice.12 The authors suggested that UPS is upregulated by pro-inflammatory cytokine interleukin-6 via the P44/42 mitogen-activated protein kinase (MAPK) pathway,11 or high levels of oxidative stress in the heart.12 However, other studies8,9 found no changes in protein ubiquitination in atrophic hearts compared with controls. The discrepancies among the studies could be a result of differences in cancer models, time points in the progression of cardiac atrophy and the dynamic nature of the UPS.

Table 1: Putative Mechanisms for Cardiac Atrophy in Cancer Patients  Cardiomyocyte atrophy  Cardiomyocyte apoptosis  Decreased protein synthesis  Increased autophagy  Increased proteolysis via the ubiquitin-proteosome system  Anthracycline chemotherapy

Cardiac Atrophy Induced by Cancer Treatments

mediators of muscle size.3 In cardiomyocytes, doxorubicin binds irreversibly to cardiolipin in the inner mitochondrial membrane, therefore concentrating doxorubicin in the mitochondria.25 Mitochondriatargeted antioxidants are shown to attenuate cardiotoxic effects of doxorubicin in rats,13,26 revealing the importance of mitochondrial ROS in doxorubicin-induced cardiotoxicity.

In addition to the direct effects of malignancy on the health of the myocardium, a number of chemotherapeutic agents – in particular anthracyclines – have been associated with the development of heart failure in cancer survivors.4 Doxorubicin is associated with dosedependent cardiotoxicity, which limits its clinical use and efficacy as a chemotherapy treatment.14 Rodent models of doxorubicin-induced cardiomyopathy have shown significant reduction in heart weight,15–17 and the thinning of septal and LV posterior wall.13 This suggests that doxorubicin-induced cardiomyopathy sometimes involves cardiac atrophy. However, other doxorubicin-induced cardiotoxicity models have demonstrated cardiomyocyte hypertrophy, suggesting the response to doxorubicin varies depending on conditions and genetic predisposition, rather than representing a single pathological entity.15

Like cancer cachexia, doxorubicin can induce cellular atrophy in cardiomyocytes by disrupting the balance of protein synthesis and degradation. Doxorubicin induces protein ubiquitination27 and activates ubiquitin ligase atrogin-1 in cardiomyocytes both in vitro and in vivo via the p38-MAPK pathway.17 Wang et al. demonstrated that doxorubicin induces autophagy in mouse hearts, which in turn increases apoptosis and decreases cardiomyocyte size.28 Min et al. demonstrated that doxorubicin activates calpain in cardiac muscles in vivo.13 Active calpain can degrade over 100 cellular proteins including key sarcomeric proteins.29 The calpain specific inhibitor SJA attenuates doxorubicininduced cardiac wall thinning as well as reducing caspase-3 activation and apoptosis.13

Direct measurement of heart mass is not possible in the clinical setting. Non-invasive estimates of LV mass can be calculated most accurately using cardiac magnetic resonance imaging (cMRI). In patients presenting with anthracycline-associated cardiomyopathy there is a dose-related reduction in LV mass in keeping with atrophic changes in the myocardium.18 Similarly, cMRI measures of extracellular volume are higher in asymptomatic patients three years after treatment with anthracyclines. This supports the observation that reduction in cardiomyocyte density and increased fibrotic change appears before the onset of cardiac dysfunction or heart failure symptoms in cancer patients treated with anthracycline chemotherapy.19 Doxorubicin induces cell death in cardiomyocytes, which contributes directly to cardiac atrophy as the turnover of adult cardiomyocytes is too limited to replace cell loss.20 The molecular mechanisms of doxorubicin-induced cardiotoxicity are not fully understood. Proposed mechanisms include reactive oxygen species (ROS) generation and oxidative stress, topoisomerase-IIb (Top2b) inhibition and mitochondrial damage. The most widely accepted mechanism is the generation of excessive ROS by redox cycling between quinone and semiquinone forms of doxorubicin.21 ROS accumulation brings deleterious effects such as lipid peroxidation, destruction of mitochondrial membranes and DNA damage.22 Zhang et al. demonstrated the crucial role of Top2b using a mouse model with cardiomyocyte-specific deletion of Top2b that was protected against doxorubicin-induced cardiotoxicity.23 Damage to mitochondrial structure and function are one of the early cardiotoxic effects of doxorubicin observed in both animal and cell models.15,16,24 Mitochondrial dysfunction and damage contribute to cardiac atrophy as mitochondrial content and function are important

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Clinical Observations Cardiac dysfunction is the physiological consequence of the molecular changes of cardiac atrophy and fibrosis. A reduction in the quantity and quality of contractile cells will cause deterioration in systolic function, and as cardiomyocytes are replaced by fibrotic tissue the diastolic relaxation of the heart deteriorates. Ideally identifying patients who have atrophic changes in the heart prior to the onset of cardiac dysfunction could enable earlier treatment and should improve outcomes.30 However, detecting myocardial damage prior to the onset of dysfunction is challenging. Endomyocardial biopsy and histological biopsy scoring allows direct quantification of the degree of cardiomyocyte damage and cardiac atrophy. This correlates well with the development of cardiac dysfunction as measured by invasive cardiac haemodynamics, and appears prior to functional deterioration when measured by echocardiogram.31 However, this is an invasive test with significant risks and is not justifiable or practical to perform as a screening test in asymptomatic patients. Currently, measurement of LV ejection fraction (LVEF) by 2D echocardiography is the most widely available and practical tool to monitor deterioration in cardiac function following cancer.32 Its usefulness is limited by poor reproducibility and accuracy; moreover, deterioration in ejection fraction represents a late change in the development of cancer-induced cardiomyopathy.33 This deterioration in function only occurs after significant cellular damage and death has already occurred.31 Techniques to improve the sensitivity of echocardiography have been used including LVEF by 3D echocardiography, dobutamine stress

Comorbidities echo and global longitudinal strain by 2D echocardiography. All of these methods have been shown to be more sensitive at detecting deterioration in cardiac function in patients following cancer.33–35 However they all suffer from the same disadvantage: they are measuring a late feature of cardiomyocyte damage and cell death. cMRI has several benefits over echocardiography. It provides the most accurate and reproducible measure of LVEF36 therefore allowing earlier and more reliable detection of a deterioration in cardiac function. It also allows measurement of several structural changes which precede functional changes. In particular measurement of T1-weighted early gadolinium signal enhancement in the myocardium and comparison with skeletal muscle signal intensity 3 days after anthracycline therapy predicts deterioration in LVEF at both 3 and 6 months.37 Measurement of myocardial oedema with T2-weighted imaging has also been shown in rodent and preliminary human studies to predict subsequent deterioration in LVEF following anthracycline treatment.38 As yet these methods are not in common clinical use, but trials are ongoing to confirm the ability of these methods to predict the diagnosis of anthracycline-mediated cardiotoxicity and expedite treatment of affected individuals. Several studies have measured cardiac biomarkers in cancer patients receiving chemotherapy. Detection of rises in cardiac troponin during and after anthracycline-containing chemotherapy predicted future reduction in LVEF and clinical cardiac events.39 A similar study utilising contemporary higher sensitivity troponin assays also detected rises in breast cancer patients receiving anthracycline and human epidermal growth factor receptor 2-targeted therapies, and combined with measurement of the inflammatory biomarker myeloperoxidase, the increase in troponin predicted future decline in left ventricular function.40 These troponin rises during cardiotoxic chemotherapy are an indicator of cardiac injury, but it is not clear if they specifically relate to cardiac atrophy. A recent report measured cardiac biomarkers in patients at diagnosis of a new malignancy, prior to cancer treatment. Elevated troponin or natriuretic peptide levels in the blood of treatment-naïve cancer patients predicted all-cause mortality.41 This may relate to cardiac stress secondary to the underlying malignancy, with cardiac atrophy one of the potential contributing factors.

Clinical Treatment Strategies Treatment of cardiac atrophy caused by cancer and chemotherapy is challenging, and the development of cardiac dysfunction has been associated with a poor prognosis. 30 However, recent studies using conventional heart failure treatment have begun to show benefits in this setting and the importance of early initiation of treatment appears even more pertinent in this group of patients. 30 Table 2 provides a summary of preventive and treatment strategies in cardiac atrophy. Beta-blockers are a mainstay of systolic heart failure treatments and there is evidence supporting their use in cancer-induced cardiac atrophy. Beta-blockers have been shown to improve both symptoms and LVEF in humans; in rats they also increase total heart mass and reduce the overall body weight loss suggesting they have effects on the more generalised cachexia process.7,42 Beta-blockers represent a range of different molecular entities, and some appear to possess more apoptotic properties than others. For example, carvedilol has specific anti-apoptotic and antioxidant properties independent of its actions on beta-adrenergic receptors.

Table 2: Preventive and Treatment Strategies in Cardiac Atrophy  Exercise training  Beta-blockers  Aldosterone antagonists  Angiotensin receptor blockers  Prevention of anthracycline cardiotoxicity (i.e. dexrazoxane, angiotensinconverting enzyme inhibitors, beta-blockers)

Similarly, aldosterone levels are significantly raised in cancer patients and the detrimental effects of mineralocorticoids on the myocardium are well studied.43 Treatment with the mineralocorticoid receptor antagonist spironolactone has been shown in a mouse model to reduce the level of fibrosis, reduce apoptotic cell death and improve markers of myocardial function.7 The role of angiotensin-converting-enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) in cancer-related cardiac atrophy is less clear. In pre-clinical models ACE-inhibitors have failed to prevent loss of cardiac mass or improved markers of cardiac function and in some studies have exacerbated the loss of cardiac mass.3 Interestingly, losartan has shown more promise at improving LV mass and function and this raises the possibility that angiotensin-1 receptor activation may increase atrophy via transforming growth factor-beta signalling, and ARBs may have a specific protective effect in preventing cardiac atrophy.3 Perhaps the most clinically applicable and interesting is the role of exercise training to treat cancer cachexia as it promotes muscle development and improves cardiovascular fitness, and may have beneficial effects on cancer mortality. It is therefore likely to also be beneficial in cardiac atrophy, although at present evidence to support this is limited.44 There have also been attempts to prevent doxorubicin-induced cardiomyopathy by co-administration with the iron chelator dexrazoxane. Current understanding is that dexrazoxane reduces the production of iron-mediated ROS produced by doxorubicin, although it may also block doxorubicin binding to cardiac topoisomerase II-beta. Dexrazoxane has shown promising results to date in preventing future heart failure in paediatric oncology patients, and adults with metastatic breast and lung cancer by preventing a reduction in LVEF and reducing the incidence of symptomatic heart failure.45 The use of this has been limited by concerns about myelosuppression and a detrimental effect on the anticancer properties of doxorubicin, but further studies are ongoing to clarify its safety profile.46 Preventative treatment with carvedilol and enalapril in patients being treated for haematological malignancies was shown to have a small but statistically significant effect on preserving LVEF in the Prevention Of Left Ventricular Dysfunction With Enalapril And Carvedilol In Patients Submitted To Intensive Chemotherapy For The Treatment Of Malignant Hemopathies (OVERCOME) trial. 47 Carvedilol monotherapy has also been shown to protect systolic and diastolic function when pre-emptively co-administered with anthracyclines 48 and similarly spironolactone prevents deterioration in ejection fraction in patients treated with anthracyclines for breast cancer. 49 These studies have relatively short follow-up duration and the longer-term outcomes of this approach remain unclear. Further studies are required before

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Cardiac Atrophy and HF In Cancer co-administration of heart failure treatments with anthracycline chemotherapy becomes routine practice.

Conclusion The potential mechanisms underlying cardiac atrophy in cancer are complex, multifactorial and incompletely understood. Both cancer itself and chemotherapy may contribute to cardiac atrophy through a multitude of pathways, including disrupting the balance of protein metabolism and inducing cell death via

10.

11.

12.

13.

14.

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16.

17.

Katz AM, Katz PB. Diseases of the heart in the works of Hippocrates. Br Heart J 1962;24:257–64. DOI: 10.1136/ hrt.24.3.257; PMID: 14454369 von Haehling S, Anker SD. Cachexia as a major underestimated and unmet medical need: facts and numbers. J Cachexia Sarcopenia Muscle 2010;1:1–5. DOI: 10.1007/s13539-010-0002-6; PMID: 21475699 Murphy KT. The pathogenesis and treatment of cardiac atrophy in cancer cachexia. Am J Physiol Heart Circ Physiol 2016;310:H466–77. DOI: 10.1152/ajpheart.00720.2015; PMID: 26718971 Von Hoff DD, Rozencweig M, Layard M, et al. Daunomycininduced cardiotoxicity in children and adults. A review of 110 cases. Am J Med 1977;62:200–8. DOI: 10.1016/00029343(77)90315-1; PMID: 835599 Patnaik JL, Byers T, DiGuiseppi C, et al. Cardiovascular disease competes with breast cancer as the leading cause of death for older females diagnosed with breast cancer: a retrospective cohort study. Breast Cancer Res 2011;13:R64. DOI: 10.1186/bcr2901; PMID: 21689398 Burch GE, Phillips JH, Ansari A. The cachectic heart. A clinicopathologic, electrocardiographic and roentgenographic entity. Dis Chest 1968;54:403–9. DOI: 10.1378/chest.54.5.403; PMID: 5698585 Springer J, Tschirner A, Haghikia A, et al. Prevention of liver cancer cachexia-induced cardiac wasting and heart failure. Eur Heart J 2014;35:932–41. DOI: 10.1093/eurheartj/eht302; PMID: 23990596 Cosper PF, Leinwand LA. Cancer causes cardiac atrophy and autophagy in a sexually dimorphic manner. Cancer Res 2011;71:1710–20. DOI: 10.1158/0008-5472.CAN-10-3145; PMID: 21163868 Manne NDPK, Lima M, Enos RT, et al. Altered cardiac muscle mTOR regulation during the progression of cancer cachexia in the ApcMin/+ mouse. Int J Oncol 2013;42:2134–40. DOI: 10.3892/ijo.2013.1893; PMID: 23589074 Musolino V, Palus S, Tschirner A, et al. Megestrol acetate improves cardiac function in a model of cancer cachexiainduced cardiomyopathy by autophagic modulation. J Cachexia Sarcopenia Muscle 2016;7:555–66. DOI: 10.1002/jcsm.12116; PMID: 27239419 Tian M, Asp ML, Nishijima Y, Belury MA. Evidence for cardiac atrophic remodeling in cancer-induced cachexia in mice. Int J Oncol 2011;39:1321–6. DOI: 10.3892/ijo.2011.1150; PMID: 21822537 Hinch EC, Sullivan-Gunn MJ, Vaughan VC, et al. Disruption of pro-oxidant and antioxidant systems with elevated expression of the ubiquitin proteosome system in the cachectic heart muscle of nude mice. J Cachexia Sarcopenia Muscle 2013;4: 287–93. DOI: 10.1007/s13539-013-0116-8; PMID: 24030522 Min K, Kwon O-S, Smuder AJ, et al. Increased mitochondrial emission of reactive oxygen species and calpain activation are required for doxorubicin-induced cardiac and skeletal muscle myopathy. J Physiol 2015;593:2017–36. DOI: 10.1113/ jphysiol.2014.286518; PMID: 25643692 Octavia Y, Tocchetti CG, Gabrielson KL, et al. Doxorubicininduced cardiomyopathy: From molecular mechanisms to therapeutic strategies. J Mol Cell Cardiol 2012;52:1213–25. DOI: 10.1016/j.yjmcc.2012.03.006; PMID: 22465037 Cove-Smith L, Woodhouse N, Hargreaves A, et al. An integrated characterization of serological, pathological, and functional events in doxorubicin-induced cardiotoxicity. Toxicol Sci 2014;140:3–15. DOI: 10.1093/toxsci/kfu057; PMID: 24675088 Moulin M, Piquereau J, Mateo P, et al. Sexual dimorphism of doxorubicin-mediated cardiotoxicity: potential role of energy metabolism remodeling. Circ Heart Fail 2015;8:98–108. DOI: 10.1161/CIRCHEARTFAILURE.114.001180; PMID: 25420486 Yamamoto Y, Hoshino Y, Ito T, et al. Atrogin-1 ubiquitin ligase is upregulated by doxorubicin via p38-MAP kinase in cardiac myocytes. Cardiovasc Res 2008;79:89–96. DOI: 10.1093/cvr/ cvn076; PMID: 18346979

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ROS and mitochondrial damage. Understanding the mechanisms involved in driving cardiac atrophy can aid early identification of patients who are high risk or in the early stages of developing cardiac dysfunction. Further research in this area will focus on understanding the molecular pathways, developing more sensitive imaging modalities to facilitate early detection in patients and the development of targeted treatments which hopefully will have a beneficial impact on clinical outcomes including symptoms and mortality. n

18. N eilan TG, Coelho-Filho OR, Pena-Herrera D, et al. Left ventricular mass in patients with a cardiomyopathy after treatment with anthracyclines. Am J Cardiol 2012;110:1679–86. DOI: 10.1016/j.amjcard.2012.07.040; PMID: 22917553 19. Jordan JH, Vasu S, Morgan TM, et al. Anthracycline-associated T1 mapping characteristics are elevated independent of the presence of cardiovascular comorbidities in cancer survivors. Circ Cardiovasc Imaging 2016;9:pii: e004325. DOI: 10.1161/ CIRCIMAGING.115.004325; PMID: 27502058 20. Bergmann O, Jovinge S. Cardiac regeneration in vivo: mending the heart from within? Stem Cell Res. 2014;13(3 Pt B):523–31. DOI: 10.1016/j.scr.2014.07.002; PMID: 25108891 21. Ghigo A, Li M, Hirsch E. New signal transduction paradigms in anthracycline-induced cardiotoxicity. Biochim Biophys Acta 2016;1863(7 Pt B):1916–25. DOI: 10.1016/j.bbamcr.2016.01.021; PMID: 26828775 22. Shakir DK, Rasul KI. Chemotherapy induced cardiomyopathy: Pathogenesis, monitoring and management. J Clin Med Res 2009;1:8–12. DOI: 10.4021/jocmr2009.02.1225; PMID: 22505958 23. Zhang S, Liu X, Bawa-Khalfe T, et al. Identification of the molecular basis of doxorubicin-induced cardiotoxicity. Nat Med 2012;18:1639–42. DOI: 10.1038/nm.2919; PMID: 23104132 24. Burridge PW, Holmström A, Wu JC. Chemically defined culture and cardiomyocyte differentiation of human pluripotent stem cells. Curr Protoc Hum Genet 2015;87:21.3. 1-15. DOI: 10.1002/0471142905.hg2103s87; PMID: 26439715 25. Goormaghtigh E, Brasseur R, Huart P, Ruysschaert JM. Study of the adriamycin-cardiolipin complex structure using attenuated total reflection infrared spectroscopy. Biochemistry 1987;26:1789–94. PMID: 3593690 26. Chandran K, Aggarwal D, Migrino RQ, et al. Doxorubicin inactivates myocardial cytochrome c oxidase in rats: cardioprotection by Mito-Q. Biophys J 2009;96:1388–98. DOI: 10.1016/j.bpj.2008.10.042; PMID: 19217856 27. Sishi BJ, Loos B, van Rooyen J, Engelbrecht AM. Doxorubicin induces protein ubiquitination and inhibits proteasome activity during cardiotoxicity. Toxicology 2013;309:23–9. DOI: 10.1016/j.tox.2013.04.016; PMID: 23639627 28. Wang X, Wang XL, Chen HL, et al. Ghrelin inhibits doxorubicin cardiotoxicity by inhibiting excessive autophagy through AMPK and p38-MAPK. Biochem Pharmacol 2014;88:334–50. DOI: 10.1016/j.bcp.2014.01.040; PMID: 24522112 29. Campos EC, O’Connell JL, Malvestio LM, et al. Calpain-mediated dystrophin disruption may be a potential structural culprit behind chronic doxorubicin-induced cardiomyopathy. Eur J Pharmacol 2011;670:541–53. DOI: 10.1016/j.ejphar.2011.09.021; PMID: 21946105 30. Cardinale D, Colombo A, Lamantia G, et al. Anthracyclineinduced cardiomyopathy: clinical relevance and response to pharmacologic therapy. J Am Coll Cardiol 2010;55:213–20. DOI: 10.1016/j.jacc.2009.03.095; PMID: 20117401 31. Bristow MR, Mason JW, Billingham ME, Daniels JR. Doseeffect and structure-function relationships in doxorubicin cardiomyopathy. Am Heart J 1981;102:709–18. DOI: 10.1016/ 0002-8703(81)90096-X; PMID: 7282516 32. Poulin F, Thavendiranathan P. Cardiotoxicity due to chemotherapy: role of cardiac imaging. Curr Cardiol Rep 2015;17:564. DOI: 10.1007/s11886-015-0564-1; PMID: 25648628 33. Poterucha JT, Kutty S, Lindquist RK, et al. Changes in left ventricular longitudinal strain with anthracycline chemotherapy in adolescents precede subsequent decreased left ventricular ejection fraction. J Am Soc Echocardiogr 2012;25:733–40. DOI: 10.1016/j.echo.2012. 04.007; PMID: 22578518 34. Khouri MG, Hornsby WE, Risum N, et al. Utility of 3-dimensional echocardiography, global longitudinal strain, and exercise stress echocardiography to detect cardiac dysfunction in breast cancer patients treated with doxorubicin-containing adjuvant therapy. Breast Cancer Res

Treat 2014;143:531–9. DOI: 10.1007/s10549-013-2818-1; PMID: 24390149 35. M archandise B, Schroeder E, Bosly A, et al. Early detection of doxorubicin cardiotoxicity: interest of Doppler echocardiographic analysis of left ventricular filling dynamics. Am Heart J 1989;118:92–8. PMID: 2741800 36. Grothues F, Smith GC, Moon JCC, et al. Comparison of interstudy reproducibility of cardiovascular magnetic resonance with two-dimensional echocardiography in normal subjects and in patients with heart failure or left ventricular hypertrophy. Am J Cardiol 2002;90:29–34. DOI: 10.1016/S00029149(02)02381-0; PMID: 12088775 37. Wassmuth R, Lentzsch S, Erdbruegger U, et al. Subclinical cardiotoxic effects of anthracyclines as assessed by magnetic resonance imaging-a pilot study. Am Heart J 2001;141:1007–13. DOI: 10.1067/mhj.2001.115436; PMID: 11376317 38. Thavendiranathan P, Wintersperger BJ, Flamm SD, Marwick TH. Cardiac MRI in the assessment of cardiac injury and toxicity from cancer chemotherapy: a systematic review. Circ Cardiovasc Imaging 2013;6:1080–91. DOI: 10.1161/ CIRCIMAGING.113.000899; PMID: 24254478 39. 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. DOI: 10.1161/01.CIR.0000130926.51766.CC; PMID: 15148277 40. 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. DOI: 10.1016/ j.jacc.2013.10.061; PMID: 24291281 41. Pavo N, Raderer M, Hülsmann M, et al. Cardiovascular biomarkers in patients with cancer and their association with all-cause mortality. Heart 2015;101:1874–80. DOI: 10.1136/ heartjnl-2015-307848; PMID: 26416836 42. Shaddy RE, Olsen SL, Bristow MR, et al. Efficacy and safety of metoprolol in the treatment of doxorubicin-induced cardiomyopathy in pediatric patients. Am Heart J 1995;129: 197–9. DOI: 10.1016/0002-8703(95)90061-6; PMID: 7817916 43. Pitt B, Zannad F, Remme WJ, Cody R, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med 1999;341:709–17. DOI: 10.1056/ NEJM199909023411001; PMID: 10471456 44. Oldervoll LM, Loge JH, Lydersen S, et al. Physical exercise for cancer patients with advanced disease: a randomized controlled trial. Oncologist 2011;16:1649–57. DOI: 10.1634/ theoncologist.2011-0133; PMID: 21948693 45. Speyer JL, Green MD, Zeleniuch-Jacquotte A, et al. ICRF-187 permits longer treatment with doxorubicin in women with breast cancer. J Clin Oncol 1992;10:117–27. DOI: 10.1200/ JCO.1992.10.1.117; PMID: 1727913 46. Hutchins KK, Siddeek H, Franco VI, Lipshultz SE. Prevention of cardiotoxicity among survivors of childhood cancer. Br J Clin Pharmacol 2016;83:455–65. DOI: 10.1111/bcp.13120; PMID: 27591829 47. Bosch X, Rovira M, Sitges M, et al. Enalapril and carvedilol for preventing chemotherapy-induced left ventricular systolic dysfunction in patients with malignant hemopathies: the OVERCOME trial (preventiOn of left Ventricular dysfunction with Enalapril and caRvedilol in patients submitted t o intensive ChemOtherapy for the treatment of Malignant hEmopathies). J Am Coll Cardiol 2013;61:2355–62. DOI: 10.1016/ j.jacc.2013.02.072; PMID: 23583763 48. Kalay N, Basar E, Ozdogru I, et al. Protective effects of carvedilol against anthracycline-induced cardiomyopathy. J Am Coll Cardiol 2006;48:2258–62. DOI: 10.1016/j.jacc.2006.07.052; PMID: 17161256 49. Akpek M, Ozdogru I, Sahin O, et al. Protective effects of spironolactone against anthracycline-induced cardiomyopathy. Eur J Heart Fail 2015;17:81–9. DOI: 10.1002/ ejhf.196; PMID: 25410653

Comorbidities

Cancer and Heart Failure: Understanding the Intersection Carine E Hamo and Michelle W Bloom Department of Medicine, Stony Brook University Hospital, Stony Brook, New York, US

Abstract Cancer and cardiovascular disease account for nearly half of all deaths in the US. The majority of cancer therapies are known to cause potential cardiac toxicity in some form. Patients with underlying cardiac disease are at a particularly increased risk for worse outcomes following cancer therapy. Most alarming is the potential for heart failure as a result of cancer treatment, which may lead to early disruption or withdrawal of life-saving cancer therapies and can potentially increase cardiovascular mortality. A multi-disciplinary cardio-oncology approach can improve outcomes through early surveillance, prevention and treatment strategies.

Keywords Heart failure, cancer, cardiotoxicity, biomarkers, imaging, surveillance Disclosure: MWB reports grant support from Gilead. CEH has no conflicts of interest to declare. Received: 21 November 2016 Accepted: 14 January 2017 Citation: Cardiac Failure Review 2017;3(1):66–70. DOI: 10.15420/cfr.2016:24:2 Correspondence: Michelle W Bloom, Outpatient Services, Heart Failure and Cardiomyopathy Center and Co-Director, Cardiology Division, Stony Brook University, Health Sciences Center, T-16, Room 080, SUNY at Stony Brook, NY 11794, US. E: michelle.bloom@stonybrookmedicine.edu

Heart disease and cancer are the two leading causes of death, together accounting for almost 50 % of deaths in the US.1 Unfortunately, the tremendous success in improving cancer survival is often attenuated by downstream cardiovascular complications from cancer therapy. Acute cardiac toxicity may limit the ability to use life-saving cancer therapy and chronic toxicity limits overall survival. As novel agents with more specific targets become available, unanticipated cardiac complications arise. The spectrum of cardiac toxicities is broad, ranging from ischaemia and arrhythmias to hypertension, left ventricular dysfunction (LVD) and the development of clinical heart failure (HF). Notably, there is increasing evidence that suggests an underlying relationship between cancer and the heart, independent of cancer therapies’ effect on left ventricular ejection fraction (LVEF) and heart rate.2,3 HF caused by chemotherapy portends a worse prognosis compared with idiopathic and ischaemic cardiomyopathy,4 highlighting the need for enhanced understanding and management.

Definitions of Cancer Therapy-related Cardiac Toxicity There is currently no universally accepted definition of cancer therapyrelated cardiac toxicity; however, several definitions pertaining to specific agents have been proposed. A recent consensus defines cancer therapy-related cardiac dysfunction (CTRCD) as a decrease in LVEF of >10 % to a value of <53 %.5 The Cardiac Review and Evaluation Committee involved in trials with trastuzumab defines cardiotoxicity as a decrease in LVEF that is either global or more severe in the septum and decline in LVEF of at least 5 % to <55 % with signs or symptoms of HF, or a decline of at least 10 % to <55 % without HF signs or symptoms.6 According to the Food and Drug Administration, anthracycline cardiotoxicity is defined as a >20 % decrease in LVEF when the baseline LVEF is normal, or >10 % decrease when baseline LVEF is abnormal.7 The American Society of Echocardiography and the European Association of Cardiovascular Imaging define cardiac toxicity as a decrease in LVEF of >10 %, to a value <53 % confirmed by repeat imaging.5

Access at: www.CFRjournal.com

Cancer Therapy-induced Heart Failure Anthracyclines Anthracylines are a class of chemotherapies that include doxorubicin and daunorubicin, widely used in the treatment of various solid and liquid tumours. Their mechanism of action involves the generation of reactive oxygen species as well as DNA intercalation to impair protein synthesis and inhibition of topoisomerase II, inhibiting DNA repair.8 In contrast to topoisomerase II-alpha, which is located on rapidly dividing cells, topoisomerase II-beta, located on cardiac myocytes is the proposed mechanism behind the cardiotoxicity.9 Anthracycline use has been shown to result in LVD with an incidence of 1–5 %, ranging from acute to late onset.10 Anthracycline-induced HF is thought to be cumulative and dose-dependent, with an incidence reaching 5 % at a total doxorubicin dose of 450 mg/m2.11 However, examination of endomyocardial biopsies reveals histopathological changes with doses as low as 240 mg/m2, suggesting that subclinical cardiotoxity may be present as early as the first dose.12

HER2-targeted Agents Trastuzumab, a monoclonal antibody targeted against humanised epidermal growth factor receptor 2 (HER2) has played a pivotal role in breast cancer patients whose tumours overexpress HER2. Under normal circumstances, in cardiac myocytes, the HER2 signalling pathway is responsible for adaptation to stress.8 The incidence of LVD with trastuzumab ranges from 2 % to 28 %,10 with a 1.7–4.1 % incidence of HF.13 Other HER2-targeted agents, such as lapatinib and pertuzumab, used in combination with trastuzumab have not shown additive cardiotoxicity.14

Mitotic Inhibitors Taxanes such as paclitaxel and docetaxel impair cell division through inhibition of microtubule disassembly during mitosis.15 The incidence of HF from docetaxel has been shown to range from 2.3 % to 8.0 %.16 Combination of doxorubicin and paclitaxel resulted in an unanticipated

Cancer and Heart Failure Table 1: Cancer Therapies Associated with Left Ventricular Dysfunction and Heart Failure Cancer Therapy

Drug

Mechanism of Cardiotoxicity

Incidence of LVD and/or HF (%)

Anthracyclines

• Doxorubicin • Daunorubicin

Impaired DNA repair and protein synthesis, formation of reactive oxygen species

1–5

HER2 inhibitors • Trastuzumab

Inhibition of HER2, impairing adaptation to stress

1.7– 4.1

Mitotic inhibitors

• Docetaxel • Paclitaxel

Impaired cell division

2.3–8.0

Alkylating agents

• Cyclophosphamide • Ifosfamide

Impaired protein synthesis

7–28

Proteasome inhibitors

• Bortezomib • Carfilzomib

Impaired degradation of cell cycle proteins

2–5

Small tyrosine kinase inhibitors

• Sunitinib • Imatinib

Impaired cell cycle regulation Impaired cell signal transduction

2–11 0.5–1.7

Immune modulators

• Ipilimumab • Nivolumab

Immune response activation

Unknown

Radiation

Micro- and macrovascular injury, valvular dysfunction

HER2 = humanised epidermal growth factor receptor 2; HF = heart failure; LVD = left ventricular dysfunction.

increase in HF, thought to occur from an increase in plasma levels of doxorubicin by paclitaxel. This in turn results in increased anthracycline uptake into the heart.17 The increased risk can be attenuated by increasing the duration between the administration of agents or using docetaxel instead of paclitaxel as an interaction; this was not observed with this combination.17

with melanoma.23 However, the combination of these agents has been associated with an immune-mediated myocarditis, thought to occur from immune activation of cardiac as well as tumour tissue.24

Radiation

Alkylating agents such as cyclophosphamide and ifosfamide impair protein synthesis via inhibition of DNA transcription.18 LVD from cyclophosphamide has been shown to occur in 7–28 % of patients, with a risk that is dose-dependent.16

Radiation therapy results in the fragmentation of DNA, interfering with cell reproduction and viability, primarily impacting rapidly dividing cancer cells.20 Radiation to the chest at doses >30 Gy can affect the cardiovascular system, albeit toxicity usually manifests years after exposure. Risk factors for cardiovascular injury include higher doses, longer intervals from the time of radiation, younger age at time of irradiation, and coexisting cardiovascular risk factors (see Table 1).25

Proteasome Inhibitors

Prevention and Surveillance

Proteasome inhibitors such as bortezomib and carfilzomib interfere with the degradation of cell cycle proteins, ultimately resulting in cell death. Compared with other tissues, proteasome activity is increased in the heart and thus disruption of protein homeostasis in cardiac myocytes results in cardiotoxic effects, including HF.19 The incidence of HF from bortezomib ranges from 2 % to 5 %.20 In a recent study of patients with relapsed multiple myeloma, the addition of carfilzomib to lenalidomide and dexamethasone resulted in a 6.4 % incidence of HF compared with 4.1 % with lenalidomide and dexamethasone alone.21

Biomarkers

Alkylating Agents

Small Tyrosine Kinase Inhibitors Sunitinib is a non-selective inhibitor of vascular endothelial growth factor (VEGF) with multiple downstream target effects such as hypertension, arrhythmia and HF with a reported incidence of 2–11 %.10 Imatinib, an inhibitor of the fusion protein breakpoint cluster region (BCR)/Abelson (ABL) has been instrumental in the treatment of chronic myelogenous leukaemia; however, there has been a reported 0.5–1.7 % incidence of LVD, thought to be caused by mitochondrial abnormalities within cardiac myocytes following treatment with imatinib.10,22

Immune modulators Immunotherapy has played an increasing role in cancer treatment, as targeting inhibitory T cells helps overcome tumour-induced immune evasion. The anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) antibody, ipilimumab, and the anti-programmed death-1 (PD-1) antibody, nivolumab, have been shown to improve survival in patients

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Various biomarkers have been studied with regard to detection of cancer therapy-related cardiotoxicity.26 While their role is not firmly established, they may provide an additive benefit in the diagnosis of cardiotoxicity, cardiac risk stratification, prevention of cardiac events and assessment of cardioprotective effectiveness. Among cancer patients receiving high-dose chemotherapy, elevations in troponin-I were predictive of a higher incidence of cardiac events and LVEF reduction.27 In children with high-risk acute lymphoblastic leukaemia, increases in N-terminal pro-brain natriuretic peptide (NT-proBNP) were associated with abnormal LV thickness-to-dimension ratio, suggestive of LV remodelling.28 Other studies with natriuretic peptide have not shown similar promise.29–31 Abnormal high-sensitivity C-reactive protein (hs-CRP) was predictive of LVEF decline in breast cancer patients treated with trastuzumab.32

Imaging Multigated acquisition (MUGA) scan has been the imaging modality of choice for periodic assessment of LVEF; however, it poses a risk of radiation exposure and provides limited information on systolic and diastolic function.28 Echocardiography with strain imaging enables regional and global assessment of cardiac function, and is more sensitive for subtle damage to myocardial ultrastructure, which is otherwise only confirmed histologically. LVEF is based on assumptions of cardiac geometry, depends on 2D image quality and cannot detect subtle regional alterations in myocardial mechanics.29

Comorbidities Figure 1: Algorithm for Surveillance and Treatment of Cardiac Toxicity Prior (A), During (B) and Following (C) Therapy A

B During Therapy

Prior to Therapy Biomarkers?4

Oncologic Risk Factors:

Cardiac Risk Factors: History of MI/CAD Known LVD History of CHF Diabetes* HTN* Smoking HLD Family Hx CAD* Female gender Age <15 or >753*

Plan for high dose anthracycline (>200 mg/m2) Plan for combination with other cardiotoxic agents: - cyclophosphamide - trastuzumab - paclitaxel

Baseline imaging (CMR, Echo)1,2

History of mediastinal radiation

Medium-high risk

Low risk

Expedited cardiooncology evaluation

Proceed with chemo

Surveillance

Biomarkers4 For Herceptin: At every cycle For Anthracyclines: At every cycle No change Imaging2 For Herceptin5: 3,6,9,12 mos

Symptomatic LVD

For Anthracyclines5: Every 50 mg/m2 ≥240 mg/m2 OR At completion of theraphy for ≤240 mg/m2

Risk factor modification Initiation of ACE-I/BB/Statin Ischemic evaluation Dexrazoxane?

OR Development of sx’s/clinical change

ACE-I/BB Spironolactone Diuretics statin?

Modify/D/C chemo?

Asymptomatic LVD

ACE-I/BB statin?

C Following Therapy Surveillance Low risk

Medium-high risk

2D/3D echo with strain at therapy completion

Trastuzumab/Other “Type II” agents:

Anthracyclines alone or with Trastuzumab +/- RT

No need for further post-chemo imaging if asymptomatic

2D/3D Echo with strain at completion of therapy (further surveillance not established)

2D/3D Echo with strain at completion of therapy, 6–12 mos versus 12 mos, 18 mos post rx (further surveillance not established)

*Continuous variables of risk; 1MUGA scan may be considered if echocardiography or CMR not available; 2for high-risk patients or when available, strain imaging, use of Echo contrast when indicated; 365–74 may represent an intermediate risk group; 4troponin, BNP; and 5consider earlier imaging if higher baseline risk. ACE-I = angiotensin-converting enzyme inhibitors; BB = betablocker; BNP = B-type natriuretic peptide; CAD = coronary artery disease; CHF = congestive heart failure; CMR = cardiac magnetic resonance; D/C = discontinue; HLD = hyperlipidaemia; HTN = hypertension; Hx = history; LVD = left ventricular dysfunction; MI = myocardial infarction; MUGA = multigated acquisition; RT = radiation therapy; Sx = symptoms. Source: Hamo, et al.45 © 2016 reproduced with permission from Wolters Kluwer Health.

Reduction of longitudinal strain (>10 % from baseline) after three months can predict future reduction in LVEF (after six months) with a sensitivity of 78–79 % and specificity of 79–82 %.30 In patients treated with trastuzumab, a decrease in global longitudinal and radial strain but not LVEF was observed as early as three months in patients who later developed cardiotoxicity.31 In a study of breast cancer patients treated with anthracyclines, systolic dysfunction could be detected with strain imaging within seven days of completing anthracyclines without similar change in LVEF. Furthermore, findings showed that low-dose anthracycline-induced myocardial injury was transient; however, persistently reduced global strain occurred in approximately 16 % of HER2/neu negative patients when systolic strain was reduced ≤-17.2 % at six months following therapy.32 Cardiac MRI is the gold standard of ventricular volume quantification and function, and may play a role in the detection of early as well as late cardiac toxicity.5

Therapies for Prevention Several therapeutic agents including dexrazoxane, statins, angiotensinconverting-enzyme (ACE)-Inhibitors and beta-blockers have been shown to be beneficial in reducing cardiotoxicity.33 Patients previously treated with anthracyclines who were given dexrazoxane with anthracycline treatment showed decreased cardiac events, decreased incidence of HF and increased cardiac event-free survival. Additionally, there was a threefold decline in the risk of developing cardiac events, and the risk of developing HF was reduced by 90 %. The proposed mechanisms behind the cardiac protection include reduction of free radical formation as well as prevention of topoisomerase II-DNA complex formation.34,35 The protective effect of antioxidants has been reinforced in animal studies of carvedilol, which has the ability to chelate iron, enabling the prevention of the cardiac histopathology caused by doxorubicin.

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Cancer and Heart Failure Interesting, this same benefit was not seen in other beta-blockers such as atenolol.36 The use of a beta-blocker, initiated before chemotherapy and maintained after treatment, has been shown to preserve LV systolic function.37,38 However, one of these studies was a small prospective trial37 and the other was a retrospective analysis of a larger cohort of patients in which the use of beta-blockers was associated with fewer clinical HF events.38 When used in combination, enalapril and carvedilol, given 1–2 weeks post chemotherapy, increased LVEF recovery. After twelve months, the chance of getting partial LVEF improvement was lost, reinforcing the importance of early treatment.39 In patients receiving chemotherapy with anthracyclines plus or minus trastuzumab, candesartan, given in parallel with cancer therapy reduced LVEF decline.40 Interestingly, in this small clinical trial, the use of the beta-blocker metoprolol succinate was not associated with a reduction in LVEF decline.40 Although the benefit of certain agents has been suggested for prevention of a decrease in LVEF or HF, the data are primarily based on small clinical or observational studies, and as such larger clinical trials are needed to definitively demonstrate the utility of these agents.

Surveillance Strategies Primary prevention and early detection of subclinical toxicity may provide the key to mortality benefit within the field of cardiooncology. Early and diligent surveillance allows for the detection of cardiac dysfunction prior to the development of symptoms and downstream toxicity. Although many algorithms for surveillance have been proposed,5,41–43 there are currently no universally accepted guidelines regarding how to approach these patients. Ideally, a careful screening of oncological and cardiovascular risk factors as well as baseline imaging, inclusive of echocardiography with strain, should occur prior to initiation of potentially cardiotoxic chemotherapy.

CDC. Leading Causes of Death, 2014. Available at: www.cdc. gov/nchs/fastats/leading-causes-of-death.htm (Accessed 20 November 2016). 2. Cramer L, Hildebrandt B, Kung T, et al. Cardiovascular function and predictors of exercise capacity in patients with colorectal cancer. J Am Coll Cardiol 2014;64:1310–9. DOI:10.1016/j. jacc.2014.07.948; PMID:25257631 3. Anker MS, Ebner N, Hildebrandt B, et al. Resting heart rate is an independent predictor of death in patients with colorectal, pancreatic, and non-small cell lung cancer: results of a prospective cardiovascular long-term study. Eur J Heart Fail 2016;18:1524–34. DOI:10.1002/ejhf.670; PMID: 27910284 4. 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. DOI:10.1056/ NEJM200004133421502; PMID:10760308 5. 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. DOI:10.1093/ehjci/jeu192; PMID:25239940; PMCID:PMC4402366 6. Seidman A, Hudis C, Pierri MK, et al. Cardiac dysfunction in the trastuzumab clinical trials experience. J Clin Oncol 2002;20:1215–21. DOI:10.1200/jco.2002.20.5.1215; PMID:11870163 7. FDA Drug Label for DOXIL- doxorubicin hydrochloride injection, suspension, liposomal, 2016. Available at: https://dailymed.nlm.nih.gov/dailymed/drugInfo. cfm?setid=21d9c619-7e94-49e2-ac41-31e9ea96554a (Accessed 20 November 2016). 8. Monsuez JJ, Charniot JC, Vignat N, Artigou JY. Cardiac sideeffects of cancer chemotherapy. Int J Cardiol 2010;144:3–15. DOI:10.1016/j.ijcard.2010.03.003; PMID:20399520 9. Vejpongsa P, Yeh ET. Topoisomerase 2beta: a promising molecular target for primary prevention of anthracyclineinduced cardiotoxicity. Clin Pharmacol Ther 2014;95:45–52. DOI:10.1038/clpt.2013.201; PMID:24091715 10. Wells QS, Lenihan DJ. Reversibility of left ventricular dysfunction resulting from chemotherapy: can this be reversed? Prog Cardiovasc Dis 2010;53:140–8. DOI:10.1016/

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Cardiac risk factors include but are not limited to age, female gender, history of myocardial infarction or LVD and tachycardia, as this may be an early sign of cardiac damage.44 Cardiac biomarkers may provide an additive role in this setting. For patients considered to be at higher risk for the development of cardiotoxicity, a cardio-oncology consultation should be offered. In a context of a multidisciplinary approach to cancer care, the cardiac component of the evaluation should not translate to a delay in initiation of cancer therapy. Imaging and biomarker surveillance during and after cancer therapy should be tailored based on individual risk factors.45 According to the Food and Drug Administration, trastuzumab should be withheld for four weeks if the LVEF decreases ≥16 % from pre-treatment values or decreases below normal and ≥10 % absolute decrease in LVEF from pre-treatment values with resumption of chemotherapy once LVEF normalises for the absolute decrease from baseline is ≤15 % within 4–8 weeks.46 Doxorubicin should be discontinued upon development of HF. 47 However, guidelines for withholding or stopping cancer therapy in the setting of asymptomatic LVD are not clearly delineated (see Figure 1).

Conclusion Whether patients with pre-existing cardiovascular disease require cancer therapy with potentially cardiotoxic agents or previously healthy patients develop cardiac complications from cancer therapy, a collaborative patient-centred approach between the cardiologist and oncologist is essential to successful patient care. The rapid and vast advancement in cancer therapies suggests that we are perhaps only witnessing the beginning of what can be expected in the realm of downstream cardiovascular complications. The overarching goal of a cardio-oncology partnership should encompass a multifaceted approach to best facilitate early detection and appreciation of subclinical toxicity to enable successful uninterrupted completion of cancer therapy and prevent cardiovascular mortality. n

j.pcad.2010.06.005; PMID:20728701 11. Von Hoff DD, Layard MW, Basa P, et al. Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med 1979;91:710–7. PMID:496103 12. Billingham ME, Mason JW, Bristow MR, Daniels JR. Anthracycline cardiomyopathy monitored by morphologic changes. Cancer Treat Rep 1978;62:865–72. 13. Bowles EJ, Wellman R, Feigelson HS, et al. Risk of heart failure in breast cancer patients after anthracycline and trastuzumab treatment: a retrospective cohort study. J Natl Cancer Inst 2012;104:1293–305. DOI:10.1093/jnci/djs317; PMID:22949432; PMCID:PMC3433392 14. Valachis A, Nearchou A, Lind P, Mauri D. Lapatinib, trastuzumab or the combination added to preoperative chemotherapy for breast cancer: a meta-analysis of randomized evidence. Breast Cancer Res Treat 2012;135: 655–62. DOI:10.1007/s10549-012-2189-z; PMID: 22875745 15. Field JJ, Kanakkanthara A, Miller JH. Microtubule-targeting agents are clinically successful due to both mitotic and interphase impairment of microtubule function. Bioorg Med Chem 2014;22:5050–9. DOI:10.1016/j.bmc.2014.02.035; PMID:24650703 16. Curigliano G, Mayer EL, Burstein HJ, et al. Cardiac toxicity from systemic cancer therapy: a comprehensive review. Prog Cardiovasc Dis 2010;53:94–104. DOI:10.1016/j.pcad.2010.05.006; PMID:20728696 17. Minotti G, Menna P, Salvatorelli E, et al. Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol Rev 2004;56:185–229. DOI:10.1124/pr.56.2.6; PMID:15169927 18. Gershwin ME, Goetzl EJ, Steinberg AD. Cyclophosphamide: use in practice. Ann Intern Med 1974;80:531–40. PMID: 4621265 19. Grandin EW, Ky B, Cornell RK, et al. Patterns of cardiac toxicity associated with irreversible protesome inhibition in the treatment of multiple myeloma. J Card Fail 2015;21:138–44. DOI:10.1016/j.cardfail.2014.11.008; PMID:25433360 20. Herrmann J, Lerman A, Sandhu NP, et al. Evaluation and management of patients with heart disease and cance: cardio-oncology. Mayo Clin Proc 2014;89:1287–306. DOI:10.1016/j.mayocp.2014.05.013; PMID:25192616; PMCID:PMC4258909

21. Stewart AK, Rajkumar SV, Dimopoulos MA, et al. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med 2015;372:142–52. DOI:10.1056/ NEJMoa1411321; PMID:25482145 22. Kerkelä R, Grazette L, Yacobi R, et al. Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nat Med 2006;12:908–16. DOI:10.1038/nm1446; PMID:16862153 23. Postow MA, Chesney J, Pavlick AC, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med 2015;372:2006–17. DOI:10.1056/NEJMoa1414428; PMID:25891304 24. Johnson DB, Balko JM, Compton ML, et al. Fulminant Myocarditis with Combination Immune Checkpoint Blockade. N Engl J Med 2016;375:1749–55. DOI:10.1056/NEJMoa1609214; PMID:27806233 25. Groarke JD, Nguyen PL, Nohria A, et al. Cardiovascular complications of radiation therapy for thoracic malignancies: the role for non-invasive imaging for detection of cardiovascular disease. Eur Heart J 2014;35:612–23. DOI:10.1093/eurheartj/eht114; PMID:23666251; PMCID:PMC3945797 26. Bloom MW, Hamo CE, Cardinale D, et al. Cancer TherapyRelated Cardiac Dysfunction and Heart Failure: Part 1: Definitions, Pathophysiology, Risk Factors, and Imaging. Circ Heart Fail 2016;9:e002661. DOI:10.1161/ CIRCHEARTFAILURE.115.002661; PMID:26747861; PMCID:PMC4709035 27. 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. DOI:10.1161/01.CIR.0000130926.51766.CC; PMID:15148277 28. Lipshultz SE, Miller TL, Scully RE, et al. Changes in cardiac biomarkers during doxorubicin treatment of pediatric patients with high-risk acute lymphoblastic leukemia: associations with long-term echocardiographic outcomes. J Clin Oncol 2012;30:1042–9. DOI:10.1200/JCO.2010.30.3404; PMID:22370326; PMCID:PMC3341148 29. 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. DOI:10.1016/j. jacc.2013.10.061; PMID:24291281; PMCID:PMC4286181

Comorbidities 30. 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. DOI:10.1161/ CIRCIMAGING.112.973321; PMID:22744937; PMCID:PMC3703313 31. 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. DOI:10.1007/s00392007-0633-6; PMID:18193371 32. Onitilo AA, Engel JM, Stankowski RV, et al. High-sensitivity C-reactive protein (hs-CRP) as a biomarker for trastuzumabinduced cardiotoxicity in HER2-positive early-stage breast cancer: a pilot study. Breast Cancer Res Treat 2012;134:291–8. DOI:10.1007/s10549-012-2039-z; PMID:22476854 33. Kalam K, Marwick TH. Role of cardioprotective therapy for prevention of cardiotoxicity with chemotherapy: a systematic review and meta-analysis. Eur J Cancer 2013;49:2900–9. DOI:10.1016/j.ejca.2013.04.030; PMID:23706982 34. Marty M, Espié M, Llombart A, et al. Multicenter randomized phase III study of the cardioprotective effect of dexrazoxane (Cardioxane) in advanced/metastatic breast cancer patients treated with anthracycline-based chemotherapy. Ann Oncol 2006;17:614–22. DOI:10.1093/ annonc/mdj134; PMID:16423847 35. Hahn VS, Lenihan DJ, Ky B. Cancer therapy-induced cardiotoxicity: basic mechanisms and potential cardioprotective therapies. J Am Heart Assoc 2014;3: e000665.

36. Oliveira PJ, Bjork JA, Santos MS, et al. Carvedilol-mediated antioxidant protection against doxorubicin-induced cardiac mitochondrial toxicity. Toxicol Appl Pharmacol 2004;200:159–68. DOI:10.1016/j.taap.2004.04.005; PMID:15476868 37. Kalay N, Basar E, Ozdogru I, et al. Protective effects of carvedilol against anthracycline-induced cardiomyopathy. J Am Coll Cardiol 2006;48:2258–62. DOI:10.1016/j.jacc.2006.07.052; PMID:17161256 38. Seicean S, Seicean A, Alan N, et al. Cardioprotective effect of beta-adrenoreceptor blockage in patients with breast cancer undergoing chemotherapy: a follow up study of heart failure. Circ Heart Fail 2013;6:420–6. DOI:10.1161/ CIRCHEARTFAILURE.112.000055; PMID:23425978 39. Cardinale D, Colombo A, Lamantia G, et al. Anthracyclineinduced cardiomyopathy: clinical relevance and response to pharmacologic therapy. J Am Coll Cardiol 2010;55:213–20. DOI:10.1016/j.jacc.2009.03.095; PMID:20117401 40. Gulati G, Heck SL, Ree AH, et al. Prevention of cardiac dysfunction during adjuvant breast cancer therapy (PRADA): a 2 x 2 factorial, randomized, placebo-controlled, doubleblind clinical trial of candesartan and metoprolol. Eur Heart J 2016;37:1671–80. DOI:10.1093/eurheartj/ehw022; PMID:26903532; PMCID:PMC4887703 41. Eschenhagen T, Force T, Ewer MS, et al. Cardiovascular side effects of cancer therapies: a position statement from the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail 2011;13:1–10. DOI:10.1093/eurjhf/ hfq213; PMID:21169385 42. Curigliano G, Cardinale D, Suter T, et al. Cardiovascular toxicity induced by chemotherapy, targeted agents and

43.

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radiotherapy: ESMO Clinical Practice Guidelines. Ann Oncol 2012;23 Suppl 7:vii155–66. DOI:10.1093/annonc/mds293; PMID:22997448 Lancellotti P, Nkomo VT, Badano LP, et al. Expert consensus for multi-modality imaging evaluation of cardiovascular complications of radiotherapy in adults: a report from the European Association of Cardiovascular Imaging and the American Society of Echocardiography. J Am Soc Echocardiogr 2013;26:1013–32. DOI:10.1016/j.echo.2013.07.005; PMID:23998694 Senkus E, Jassem J. Cardiovascular effects of systemic cancer treatment. Cancer Treat Rev 2011;37:300–11. DOI:10.1016/j. ctrv.2010.11.001; PMID:21126826 Hamo CE, Bloom MW, Cardinale D, et al. Cancer Therapy-Related Cardiac Dysfunction and Heart Failure: Part 2: Prevention, Treatment, Guidelines, and Future Directions. Circ Heart Fail 2016;9:e002843. DOI:10.1161/ CIRCHEARTFAILURE.115.002843; PMID:26839395; PMCID:PMC4743885 FDA Drug Label for HERCEPTIN- trastuzumab, 2016. Available at: https://dailymed.nlm.nih.gov/dailymed/ drugInfo.cfm?setid=492dbdb2-077e-4064-bff3-372d6af0a7a2 (Accessed 23 December 2016). McMurray JJ, Adamopoulos S, Anker SD, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J 2012;33:1787–847. DOI:10.1093/eurheartj/ehs104; PMID:22611136

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