CFR 1.1 by Radcliffe Cardiology

Cardiac Failure Review Volume 1 • Issue 1 • Spring 2015

Volume 1 • Issue 1 • Spring 2015

www.CFRjournal.com

The Bi-directional Impact of Two Chronic Illnesses: Heart Failure and Diabetes – A review of the Epidemiology and Outcomes Patrick Campbell, Selim Krim and Hector Ventura

The Management of Heart Failure with Preserved Ejection Fraction Andrew JS Coats and Louise G Shewan

Sleep-disordered Breathing in Heart Failure – Current State of the Art Martin R Cowie, Holger Woehrle, Olaf Oldenburg, Thibaud Damy, Peter van der Meer, Erland Erdman, Marco Metra, Faiez Zannad, Jean-Noel Trochu, Lars Gullestad, Michael Fu, Michael Böhm, Angelo Auricchio and Patrick Levy

Left Ventricular Assist Devices in the Management of Heart Failure Edo Y Birati and Mariell Jessup

ISSN: 2057-7540

A third-generation continuous flow device for mechanical circulatory support

Anatomical sketch highlighting the pancreas and gallbladder

Device for delivering continuous positive airway pressure therapy

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Do not miss at the

ESC-HF 2015 in Seville the Satellite Symposium on

THE PATIENT PERSPECTIVE: effects of levosimendan on hemodynamics and quality of life on Monday, May 25, at 18:15-19:15 in room Athens Chairs: Markku S. Nieminen (Helsinki, Finland)

Ferenc Follath (Zürich, Switzerland)

Congestion: ino- or dilator?

Frank Ruschitzka (Zürich, Switzerland)

Exercise performance in advanced heart failure

Levosimendan: a unique mechanism of action Alexander Mebazaa (Paris, France) Piergiuseppe Agostoni (Milan, Italy) John Parissis (Athens, Greece)

Levosimendan: clinical use and patient quality of life

PRODUCT INFORMATION: Simdax 2.5 mg/ml concentrate for solution for infusion. Therapeutic indications Simdax is indicated for the short-term treatment of acutely decompensated severe chronic heart failure (ADHF) in situations where conventional therapy is not sufficient, and in cases where inotropic support is considered appropriate. Dosage and administration Simdax is for in-hospital use only. It should be administered in a hospital setting where adequate monitoring facilities and expertise with the use of inotropic agents are available. Simdax is to be diluted prior to administration. The infusion is for intravenous use only and can be administered by the peripheral or central route. Dosage: The dose and duration of treatment should be individualised according to the patient’s clinical condition and response. The recommended duration of infusion in patients with acute decompensation of severe chronic heart failure is 24 hours. No signs of development of tolerance or rebound phenomena have been observed following discontinuation of Simdax infusion. Haemodynamic effects persist for at least 24 hours and may be seen up to 9 days after discontinuation of a 24-hour infusion. Experience of repeated administration of Simdax is limited. Experience with concomitant use of vasoactive agents, including inotropic agents (except digoxin) is limited. Monitoring of treatment: Consistent with current medical practice, ECG, blood pressure and heart rate must be monitored during treatment and the urine output measured. Monitoring of these parameters for at least 3 days after the end of infusion or until the patient is clinically stable is recommended. In patients with mild to moderate renal or mild to moderate hepatic impairment monitoring is recommended for at least 5 days. Elderly: No dose adjustment is required for elderly patients. Renal impairment: Simdax must be used with caution in patients with mild to moderate renal impairment. Simdax should not be used in patients with severe renal impairment (creatinine clearance <30 ml/min). Hepatic impairment: Simdax must be used with caution in patients with mild to moderate hepatic impair-

ORION_PHARMA.indd 1

ment although no dose adjustment appears necessary for these patients. Simdax should not be used in patients with severe hepatic impairment. Children: Simdax should not be administered to children and adolescents under 18 years of age. Contraindications Hypersensitivity to levosimendan or to any of the excipients. Severe hypotension and tachycardia. Significant mechanical obstructions affecting ventricular filling or outflow or both. Severe renal impairment (creatinine clearance <30 ml/min) and severe hepatic impairment. History of Torsades de Pointes. Special warnings and special precautions for use An initial haemodynamic effect of levosimendan may be a decrease in systolic and diastolic blood pressure, therefore, levosimendan should be used with caution in patients with low baseline systolic or diastolic blood pressure or those at risk for a hypotensive episode. More conservative dosing regimens are recommended for these patients. Physicians should tailor the dose and duration of therapy to the condition and response of the patient. Severe hypovolaemia should be corrected prior to levosimendan infusion. If excessive changes in blood pressure or heart rate are observed, the rate of infusion should be reduced or the infusion discontinued. The exact duration of all haemodynamic effects has not been determined, however, the haemodynamic effects, generally last for 7-10 days. This is partly due to the presence of active metabolites, which reach their maximum plasma concentrations about 48 hours after the infusion has been stopped. Non-invasive monitoring for at least 4-5 days after the end of infusion is recommended. Monitoring is recommended to continue until the blood pressure reduction has reached its maximum and the blood pressure starts to increase again, and may need to be longer than 5 days if there are any signs of continuing blood pressure decrease, but can be shorter than 5 days if the patient is clinically stable. In patients with mild to moderate renal or mild to moderate hepatic impairment an extended period of monitoring maybe needed.

Simdax infusion should be used cautiously in patients with tachycardia atrial fibrillation with rapid ventricular response or potentially life-threatening arrhythmias. Interaction with other medicinal products and other forms of interaction Consistent with current medical practice, levosimendan should be used with caution when used with other intravenous vasoactive medicinal products due to a potentially increased risk of hypotension. No pharmacokinetic interactions have been observed in a population analysis of patients receiving digoxin and Simdax infusion. Simdax infusion can be used in patients receiving beta-blocking agents without loss of efficacy. Co-administration of isosorbide mononitrate and levosimendan in healthy volunteers resulted in significant potentiation of the orthostatic hypotensive response. Undesirable effects The most commonly (>1/10) reported adverse reactions include headache, hypotension and ventricular tachycardia. Overdose Overdose of Simdax may induce hypotension and tachycardia. High doses (at or above 0.4 microgram/ kg/min) and infusions over 24 hours increase the heart rate and are sometimes associated with prolongation of the QTc interval. Simdax overdose leads to increased plasma concentrations of the active metabolite, which may lead to a more pronounced and prolonged effect on heart rate requiring a corresponding extension of the observation period. Storage Store at 2°C-8°C (in a refrigerator). Do not freeze.

CONTACT INFORMATION: Orion Corporation, Orion Pharma, PO Box 65, FI-02101 ESPOO, FINLAND. Tel. +358 10 4261

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Volume 1 • Issue 1 • Spring 2015

www.CFRjournal.com

Editorial Board Andrew JS Coats Editor in Chief William T Abraham The Ohio State University, USA

Kenneth McDonald St Vincent’s Hospital, Ireland

Inder Anand University of Minnesota, USA

Ileana L Piña Montefiore Einstein Center for Heart & Vascular Care, USA

Michael Böhm Saarland University, Germany

A Mark Richards University of Otago, New Zealand

Alain Cohen Solal Paris Diderot University, France

Giuseppe Rosano St George’s University of London, UK

Henry J Dargie Western Infirmary, Glasgow

Allan D Struthers Ninewells Hospital & Medical School, UK

Carmine De Pasquale Flinders University, Australia

Michal Tendera University of Silesia, Poland

Michael Henein Heart Centre and Umea University, Sweden

Maurizio Volterrani IRCCS San Raffaele Pisana, Italy

Theresa A McDonagh King’s College Hospital, UK

Cheuk Man Yu The Chinese University of Hong Kong, Hong Kong

Design & Production Tatiana Losinska • Publication Manager Michael Schmool Publishing Director Liam O’Neill • Managing Director David Ramsey Commissioning Editor Lindsey Mathews commeditor@radcliffecardiology.com •

Circulation Contact David Ramsey david.ramsey@radcliffecardiology.com Commercial Contact Michael Schmool michael.schmool@radcliffecardiology.com •

Cover image

Cover design Tatiana Losinska

Radcliffe Cardiology

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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, 7/8 Woodlands Farm, Cookham Dean, Berks, SL6 9PN. © 2015 All rights reserved

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

Aims and Scope • Cardiac Failure Review aims to assist time-pressured physicians to stay abreast of key advances and opinion in cardiac failure practice. • 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 update on a range of salient issues to support physicians in continuously developing their knowledge and effectiveness in day-to-day clinical practice.

Structure and Format • • • •

Cardiac Failure Review is a bi-annual journal comprising review articles and editorials. The structure and degree of coverage of the journal is determined by 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 replicated 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 an Editorial Board comprising leading authorities from a variety of related disciplines. • Invited contributors are recognised authorities from 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 Commissioning Editor, following consultation with the Editor-in-Chief, and/or a member of the Editorial Board, sends the manuscript to members of the Peer Review Board, 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 either 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 returned to the reviewers to ensure the revised version meets their quality expectations. Once approved, the manuscript is sent to the Editor-in-Chief for final approval prior to publication.

Submissions and Instructions to Authors • • • •

Contributors are identified and invited by the Commissioning Editor with guidance from the Editorial Board. Following acceptance of an invitation, the author(s) and Commissioning Editor formalise the working title and scope of the article. Subsequently, the Commissioning Editor provides an ‘Instructions to Authors’ document and additional submission details. The journal is always keen to hear from leading authorities wishing to discuss potential submissions, and will give due consideration to any proposals. Please contact the Commissioning Editor for further details. The ‘Instructions to Authors’ information is available for download at www.CFRjournal.com.

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

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

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 Commissioning 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 and European Cardiology Review. n

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Congress Key Figures

Late Registration deadline 20 April 2015 4 days of scientific exchange +2 000m² of exhibition +100 scientific sessions including sessions dedicated to the 2nd World Congress on Acute Heart Failure

+300 4 500 +1 500 +20

international expert faculty members healthcare professionals from 70+ countries abstracts and clinical cases industry sessions (satellite, hands-on sessions...)

www.escardio.org/HFA 2 registration options

• Saturday Day ticket • Heart Failure 2015 registration 1 registration, 2 congresses, 1 place!

HEART FAILURE TAKING CENTRE STAGE: DRUGS, DEVICES AND MULTIDISCIPLINARY CARE

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29 August â&#x20AC;&#x201C; 2 September Where cardiology comes together

Bring your Heart Failure congress experience full circle by participating in ESC Congress 2015 In Village 9, you will find a comprehensive overview on the current management of Heart Failure. Sessions not to miss: . Science@Breakast . Guidelines in Daily Practice . Case-based Symposium . Spotlight sessions: Environment and the Heart, highlighting the many different kind of interactions between the heart and cardiovascular diseases

Discover the Scientific Programme www.escardio.org/ESC2015programme

5 days of scientific Sessions 150 CV Topics 30 000 healthcare professionals from 140 countries 11 000 abstracts submitted 500 expert sessions 180 exhibiting companies & all year long on ESC Congress 365

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Content Contents

Foreword 06 Andrew JS Coats and Giuseppe Rosano

Heart Failure and Diabetes

08 The Bi-directional Impact of Two Chronic Illnesses: Heart Failure and Diabetes – A review of the Epidemiology and Outcomes

Patrick Campbell, Selim Krim and Hector Ventura

Heart Failure with Preserved Ejection Fraction

11 The Management of Heart Failure with Preserved Ejection Fraction Andrew JS Coats and Louise G Shewan

Sleep Apnoea

S leep-disordered Breathing in Heart Failure – Current State of the Art

Left Ventricular Assist Devices

L eft Ventricular Assist Devices in the Management of Heart Failure

Edo Y Birati and Mariell Jessup

Patients Nearing the End of Life

Martin R Cowie, Holger Woehrle, Olaf Oldenburg, Thibaud Damy,Peter van der Meer, Erland Erdman, Marco Metra, Faiez Zannad, Jean-Noel Trochu, Lars Gullestad, Michael Fu, Michael Böhm, Angelo Auricchio, and Patrick Levy

31 Management of Heart Failure in Patients Nearing the End of Life—There is So Much More To Do

Lisa LeMond and Sarah J Goodlin

Cardiac Resynchronisation Therapy

35 Cardiac Resynchronisation Therapy and Heart Failure: Persepctive from 5P Medicine

Fang Fang, Zhou Yu Jie, Luo Xiu Xia, Liu Ming, Ma Zhan, Gan Shu Fen and Yu Cheuk-man

Pulmonary Oedema 38 Pulmonary Oedema—Therapeutic Targets

Ovidiu Chioncel, Sean P Collins, Andrew P Ambrosy, Mihai Gheorghiade, and Gerasimos Filippatos

Exercise Training 46 Assessment for Exercise Prescription in Heart Failure Marco Guazzi

Heart Failure Guidelines

50 Gaps in the Heart Failure Guidelines Bao Tran and Gregg C Fonarow

CARDIAC FAILURE REVIEW

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Foreword

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

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

ardiac Failure Review is a bi-annual journal designed for busy and time-pressured cardiologists to stay abreast of key advances and opinion in a rapidly advancing field. Major developments are occurring every year in the diagnosis, management

and treatment of heart failure. Guided by an experienced Editorial Board of leading physicians, this peer-reviewed journal will highlight review articles in all the areas relevant to a practising cardiologist: where advances have been made, when traditional thinking is being challenged and also where knowledge is limited and expert input can be so vital. All articles will be contributed by leading authorities within the specialist field. The journal will be distributed in print and eJournal format via controlled circulation to leading physicians within the community, and further disseminated through the free-to-access availability of its articles at CFRjournal.com

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ÂŠ RADCLIFFE CARDIOLOGY 2015

09/04/2015 23:59

Foreword

In this first issue we are proud to review some major themes in the world of heart failure research. Hector Ventura and colleagues from the Ochsner Clinical School review the epidemiology of the interaction of heart failure and diabetes – an area of increasing importance. These disorders cluster together more than by chance and interact to cause disability and heightened mortality, even over the already high mortality of heart failure alone. Diabetes plays an important role at every stage; it predicts the development of heart failure, it accelerates its course and it interferes with the effectiveness of certain heart failure therapies. The area is one of vital importance, especially as several new anti-diabetes therapies have been abandoned due to an excess of new cases of heart failure developing whilst on therapy. Marco Guazzi reviews practical advice of how to assess heart failure patients for an exercise prescription, while at the other end of the spectrum Mariell Jessup summarizes the exciting “tomorrow’s world” developments in the field of left ventricular assist devices, which are fast becoming a real option for increasing numbers of end-stage heart failure patients. We have an expert review by Lisa LeMond and Sarah J Goodlin on a topic that sadly affects so many of our patients – and yet one of enormous importance to them and their carers – that of modern and effective end-of-life care, a field for too long considered a Cinderella. There is an excellent and very detailed review of the state of the art of sleep disordered breathing in chronic heart failure. This is an enormous problem affecting 30–50 % of our heart failure clinic patients, but one about which until very recently we had little in the way of developed clinical pathways or effective services, swamped as most sleep clinics are. Martin Cowie is a leader in this field with colleagues at the Royal Brompton Hospital in London and he leads the exciting study of treatment of this condition in heart failure – Treatment of Predominant Central Sleep Apnoea by Adaptive Servo Ventilation in Patients With Heart Failure (SERVE-HF) – the results of which we eagerly await. Professor Coats reviews the confusing field of heart failure with preserved ejection fraction that has been ignored for so long and is now the subject of intense debate and study. How could a feature of half or more of our patients with heart failure have been left so poorly understood and so poorly treated for so long? Readers will want to see what is around the corner in this field as the next few years unfold. Another leading international expert, CM Yu from the Chinese University of Hong Kong leads his team in an excellent review of cardiac resynchronization therapy in the treatment of heart failure. Last, but certainly not least, Mihai Gheorghiade, Gerasimos Filippatos and colleagues review the cutting edge challenges of devising new therapies for a problem as old as the recognition of heart failure itself: what to do for the patient with acute pulmonary oedema? Welcome to the journal and we hope you will enjoy reading it as much as we do in putting the experts together to review the fields that excite us the most. n

CARDIAC FAILURE REVIEW

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Heart Failure and Diabetes

The Bi-directional Impact of Two Chronic Illnesses: Heart Failure and Diabetes – A review of the Epidemiology and Outcomes Patrick Campbell, Selim Krim and Hector Ventura Department of Cardiovascular Diseases, John Ochsner Heart and Vascular Institute Ochsner Clinical School-University of Queensland School of Medicine New Orleans, LA

Abstract Heart failure and diabetes mellitus contribute significantly to the morbidity and mortality of the US population. The combined economic impact on the US health care system reaches nearly $300 billion. Much of this cost stems from the frequent hospital admissions and direct cost of managing the two diseases. The presence of diabetes significantly increases the risk of developing heart failure compared to the general population and diabetics with heart failure experience significantly higher mortality. Patients with heart failure have a high incidence of insulin resistance and are at increased risk of developing diabetes mellitus. Traditionally these two chronic illnesses have been managed in relative isolation. However the adverse effects of each disease has significant impact on the other. The combination of heart failure and diabetes mellitus significantly increases the morbidity and mortality compared to either in isolation. This paper reviews the epidemiology and impact of the bidirectional effects of these two chronic illnesses.

Keywords Heart failure, diabetes mellitus, epidemiology, outcome, morbidity, mortality. Disclosure: None of the authors have any conflicts of interest in regards to this review. Received: 11 March 2015 Accepted: 23 March 2015 Citation: Cardiac Failure Review, 2015;1(1):8–10 Correspondence: Patrick Campbell, John Ochsner Heart and Vascular Institute Ochsner Clinical School-The University of Queensland School of Medicine 1514 Jefferson Highway New Orleans, LA, USA. E: pcampbell@ochsner.org

Heart failure remains a significant burden to the US healthcare system and contributes greatly to the morbidity and mortality of the population. The impact of an ageing population, improved survival in coronary artery disease (CAD) and adverse life-style choices will ultimately result in an increased burden on an already taxed health care system. Heart failure affects over 5 million people with approximately 550,000 new cases every year.1 While the prevalence of heart failure is significantly higher in the older population (>65 years), 1.4 million patients <60 years of age carry the diagnosis of heart failure. The estimated $32 billion cost of heart failure is due in large part to the more than 1 million hospital admissions for acute care. Following the first admission for acute decompensated heart failure (ADHF) the readmission rates are nearly 50 % at six months and mortality reaches 30 % at 1 year.2,3 The short-term risk of readmission remains unacceptably high, 15 % at 60 days and 30 % at 90 days. Unfortunately even with all of the advances in medical therapy the post-admission morbidity and mortality has not been significantly reduced. As with most chronic illness, the impact of co-morbidities adversely affects the outcomes in heart failure. Diabetes mellitus (DM) has been shown to be a significant risk factor for the development of heart failure and negatively impacts the prognosis. Over the past two decades the prevalence of diabetes has sharply increased from 3.5 % in the 1990s to greater than 9 % in 2012.4 Diabetes impacts the lives of nearly 30 million Americans and by the age of 65 nearly one quarter of the population carries the diagnosis.

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The cost of DM to the health care system is nearly $250 billion, with close to $175 billion in direct costs.5 Traditionally the two illnesses have been managed in relative isolation. However with the high incidence of the co-existence of these two chronic diseases, especially as the prevalence of both continue to grow, clinicians should be more cognisant of the impact each has on the other.

The Epidemiology of Heart Failure in Diabetes Mellitus The increased incidence of heart failure in diabetics was first described in the Framingham Heart Study. In the original publication, DM conferred twice the risk in men and nearly five times the risk in women for the development of heart failure.6 Since then the impact of DM on the incidence of heart failure has been repeatedly demonstrated. The incidence of heart failure is 2.5 times higher in diabetics than the general population.7 Diabetes contributes not only to the increased incidence of heart failure, but it is also an independent risk factor for left ventricular hypertrophy, a clearly defined precursor to heart failure. In the Cardiovascular Health Study, diabetes was shown to be an independent risk factor for the development of heart failure.8 The increased risk for the development of heart failure is magnified in two specific sub-populations. As the diabetic population ages the risk of developing heart failure increases. Demonstrated in a Kaiser Permanente registry the incidence of heart failure doubles in diabetics for every decade above 45 years of age9 and similarly in a study of the elderly (>65

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The Bi-directional Impact of Two Chronic Illnesses: Heart Failure and Diabetes

years), 39 % of diabetic patients developed heart failure compared to 23 % of non-diabetics after 3.5 years.10 In a study of 150,000 Medicare patients the incidence of heart failure was 13 % and the prevalence reached 24 %.11 Patients with a history of ischaemic heart disease and diabetes are also at increased risk for the development of heart failure compared to those without an ischaemic burden. Tenebaum A et al. demonstrated that heart failure developed more frequently in DM with ischaemic heart disease compared to those with non-ischaemic heart disease, 46 % vs 36 % respectively. Even the presence of impaired fasting glucose in ischaemic heart disease carried an increased risk of heart failure.12 While the diagnosis of diabetes is an independent risk factor for heart failure, recent data has shown that glycaemic control is an important prognostic marker for heart failure. Glycosylated haemoglobin (HgbA1c) is directly associated with the risk of heart failure. An increase in HgbA1c from 6.5 % to 10.5 % increases the risk of developing heart failure nearly 4-fold.13 The risk of heart failure increases linearly with increasing HgbA1c. For each 1 % increase in HgbA1c the risk of heart failure increase 8–12%.14,15 The risk for the development of heart failure in diabetics may be more closely related to overall long-term glycaemic control and duration of DM, rather than the HgbA1c at an individual point in time.

The Epidemiology of Diabetes Mellitus in Heart Failure Patients with heart failure demonstrate impaired glucose metabolism and insulin resistance is common.16 The altered glucose metabolism places them at increased risk for developing diabetes, 29 % vs 18 %, compared to the general population.17 Data from multiple randomised studies and registries agree that the prevalence ranges from 20 %18 to 26 %.19 In fact nearly one quarter of all HF patients have concomitant diabetes and this number rises drastically to 40 % in patients admitted with ADHF.20 In the SOLVD (Studies of Left Ventricular Dysfunction) trial 6 % of patients developed DM within three years of enrollment.17 The overall prevalence of DM in heart failure is significantly higher than in the general population, 25 % compared to 9 %. While the overall prevalence of DM is 25 % in heart failure, patients with Heart Failure with Preserved Ejection Fraction (HFpEF) have a slightly higher prevalence of DM reaching nearly 40 %.21

Outcomes in Heart Failure with Concomitant Diabetes The co-existence of heart failure and diabetes has significant impact on outcomes and confers a worse prognosis than heart failure alone.22 The diagnosis of diabetes in heart failure patients results in increased cardiovascular mortality, higher readmission rates 23 and increased hospital lengths of stay.24 Data from ALLHAT (The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) demonstrated significantly higher risk for heart failure admissions or death in diabetics, nearly twice as high than in those patients without diabetes.25 The presence of diabetes in heart failure confers a significantly higher rate of mortality compared to those without diabetes, 45 % versus 24 % respectively, at 5 years.11 The poor prognosis of concomitant DM and HF is more prominent in two sub-groups of patients with heart failure. The SOLVD trial showed an increased risk for HF admissions (RR:2.16) or a composite of death or symptoms in HF (RR:1.56) in patients with asymptomatic ischaemic cardiomyopathy26 and in the Framingham Heart Study 34 % of diabetic patients died within 1 year of the diagnosis of heart failure.27 The other sub-group of heart failure patients that experience worse outcomes

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

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Figure 1: The Bi-directional Impact of Diabetes Mellitus and Heart Failure

Hyperglycaemia

Diabetes Mellitus Insuline resistance Altered FFA metabolism Impaired myocyte Ca2+ sensitivity

Impaired LV contractile function

Microvascular dysfunction

Fibrosis

Neurohormonal abnormalities (RAAS)

LVH

Cardiac autonomic dysfunction

Endothelial dysfunction

Hyperglycaemic cellular damage

Heart failure

Relaxation abnormalities

Cardiomyopathy

Myocyte necrosis Altered myocyte metabolism

FFA = free fatty acids; Ca2+ = Calcium; RAAS = Renin-angiotensin aldosterone system; LVH = Left ventricular hypertrophy.

with DM are patients with HFpEF. As previously demonstrated, patients with HFpEF have a higher prevalence of DM. In the CHARM (Candesartan in Heart Failure: Assessment of Reduction in Morbidity and mortality) study patients with HFpEF and concomitant diabetes had higher rates of CV death and hospitalisations for heart failure compared to those with reduced EF.28 As was previously shown HgbA1c is directly related to the risk of developing heart failure. It has also been demonstrated that it directly impacts outcome in heart failure. In heart failure, the effect of HgbA1c on morality is U-shaped. Morality decreases with decreasing glycosylated haemoglobin until a nadir is reached, then the mortality begins to creep upwards again. The highest mortality is seen in patients with HgbA1c > 7.8 % and < 7.1 %, indicating that the optimal HgbA1c goal in DM to reduce the risk of death in heart failure is approximately 7.5 %.29 Glycaemic control has been thought to be paramount to reducing the risk and impact of DM on the development and prognosis of heart failure. Achieving adequate glycaemic control requires the use of hypoglycaemic agents and often exogenous insulin. However therapies utilised to improve glycaemic control are often a double-edged sword, especially in heart failure. Randomised controlled trials have failed to show a benefit of tighter glycaemic control on the incidence of heart failure.30,31 The use of insulin in heart failure is controversial, while excellent glycaemic control can be achieved, it has been associated with increased mortality in HF.32 The use of metformin is cautioned due to the increased risk of metabolic acidosis and is not recommended in advanced heart failure. Trials with thiazolidinediones (pioglitazone and rosiglitazone) have demonstrated adverse outcomes in heart failure, increasing the risk of heart failure and hospitalisations by nearly 2-fold.33,34 It is thought that these medicines promote fluid retention and alter sodium handling resulting in worsening heart failure. In a recent analysis of the dipeptidyl peptidase-4 (DPP-4) inhibitor saxagliptin its use was associated with a significant increase in heart failure admissions.35 Sulfonylureas, which increase endogenous insulin production, have not been shown to negatively impact the development of heart failure. Clearly the optimal therapeutic strategy remains elusive.

Conclusion Data presented here demonstrates that these two chronic comorbid conditions cannot be thought of as two separate and distinct entities, nor can they be treated in isolation. Diabetes affects myocardial glucose metabolism, cardiac fatty acid metabolism, intra-cellular calcium cycling, accelerates coronary artery disease, contributes to microvascular

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Heart Failure and Diabetes dysfunction, neurohormonal upregulation and increases cardiac fibrosis.20 The combination of these pathophysiological abnormalities increases the risk for developing heart failure and place added strain on an already taxed myocardium. Patients with heart failure have altered glucose metabolism and high rates of insulin resistance, increasing the risk for the development of DM. This bi-directional impact on the other disease process inexorably links these to chronic conditions together (see Figure 1). The combination of heart failure and diabetes mellitus portends worse prognosis than either comorbidity alone.

5. 6. 7.

10. 11.

12.

13.

14.

Go AS, Mozaffarian D, Roger VL, et al. Heart Disease and stroke statistics – 2013 update: a report from the American Heart Association. Circ 2013;127 :e6–e245. Kociol RD, Hammil BG, Fonarow GC, et al. Generalizability and longitudinal outcomes of a national heart failure registry clinical registry: Comparison of Acute Decompensated Heart Failure National Registry (ADHERE). Am Heart J 2010;160 :885–92. Giamouzis G, Kalogeropoulos A, Georgiopoulu V et al. Hospitalization epidemic in patients with heart failure: risk factors, risk prediction, knowledge gaps and future directions. J Card Fail 2011;17 :54–75. Geiss LS, Wang J, Cheng YJ, et al. Prevalence and Incidence Trends for Diagnosed Diabetes Among Adults Aged 20 to 79 Years, United States, 1980–2012. JAMA 2014;312 :1218–26. http://www.cdc.gov/diabetes/home - accessed on 2/15/15. Kannel WB, Mc Gee DL. Diabetes and cardiovascular disease. The Framingham Study. JAMA 1979;241 :2035–8. Nichols GA, Gullion CM, Koro CE, et al. The Incidence of Congestive Heart Failure in Type 2 Diabetes. An Update. Diabetes Care 2004;27 :1879–84. Gottdiener JS, Tracy RP, Arnold AM, et al. Predictors of congestive heart failure in the elderly: the cardiovascular health study. J Am Coll Cardiol 2000;35:B1628–37. Nichols GA, Hillier TA, Erbey JR, Brown JB. Congestive heart failure in type 2 diabetes: Prevalence, incidence and risk factors. Diabetes Care 2001;24 :1614–9. Aronow WS, Ahn C. Incidence of heart failure in 2,737 older persons with and without diabetes. Chest 1999;115:867–8. Bertoni AG, Hundley WG, Massing MW, et al. Heart Failure Prevalence, Incidence and Mortality in the Elderly with Diabetes. Diabetes Care 2004;27 :699–703. Tenebaum A, Motro M, Fisman EZ, et al. Status of glucose metabolism in patients with heart failure secondary to coronary artery disease. Am J Cardiol 2002;90 :529–32. Lind M, Bounias I, Olsson M, et al. Glycemic control and Incidence of Heart Failure in 20,895 patients with type I diabetes mellitus: an observational study. Lancet 2011;378 :140–6. Iribarren C, Karter AJ, Go AS, et al. Glycemic control and heart failure among adults patients with diabetes. Circ 2001;103 :2668–73.

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As the population of developed countries ages and the sedentary life-style, obesity rates and prevalence of hypertension increase, the prevalence of heart failure and diabetes will continue to grow. Therapies, both non-pharmacological and pharmacological, must focus on both the prevention of these devastating illnesses and on reducing their combined impact on morbidity and mortality in the population. Future research is required to address the risk and benefit of therapies directed towards each individual disease to reduce the impact on the other. n

15. Baliga V, Sapsford R. Diabetes mellitus and heart failure – an overview of epidemiology and management. Diab Vasc Dis Res 2009;6 :164–71. 16. Doehner W, Rauchhaus M, Ponikowski P, et al. Impaired insulin sensivity as an independent risk factor for mortality in patients with stable chronic heart failure. J Am Coll Cardiol 2005;46 :1019–26. 17. Vermes E, Ducharme A, Bourgassa MG, et al. Enalapril reduces the incidence of diabetes in patients with chronic heart failure Insights from the Studies of Left Ventricular Dysfunction (SOLVD). Circ 2003;107 :1291–6. 18. Cohn JN, Johnson G, Zeische S, et al. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med 1991;325 :303–10. 19. Shindler DM, Kostis JB, Yusuf S, et al. Diabetes mellitus, a predictor of morbidity and mortality in the Studies of Left Ventricular Dysfunction (SOLVD) Trials and Registry. Am J Cardiol 1996;77 :1017–20. 20. Dei Cas A, Khan SS, Butler J, et al. Impact of Diabetes on Epidemiology, Treatment and Outcomes of Patients with Heart Failure. JACC Heart Failure 2015;3 :136–45. 21. Owan T, Hodge DO, Herges RM, et al. Trends in Prevalence, Incidence and outcome of heart failure patients with preserved ejection fraction. N Engl J Med 2006 355 :251–9. 22. Sarma S, Mentz RJ, Kwasny MJ, et al. Association between diabetes mellitus and post-discharge outcomes in patients hospitalized with heart failure findings from the EVEREST trial. Eur J Heart Fail 2013;15 :194–202. 23. Nieminen MS, Brutsaert D, Dickstein K, et al. EuroHeart Failure Survey II (EHFS II): A survey on hospitalized acute heart failure patients: description of population. Eur Heart J 2006;27 :2725–36. 24. Greenberg BH, Abraham WT, Albert NM, et al. Influence of diabetes on characteristics and outcomes in patients hospitalized with heart failure: a report from the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF). Am Heart J 2007;154 :e271–8. 25. Davis BR, Piller LB, Cutler JA, et al. Role of diuretics in the prevention of heart failure: The Antihypertensive and

Lipid-Lowering Treatment to Prevent Heart Attack Trial. Circ 2006;113 : 2201–10. 26. Das SR, Drazner MH, Yancy CW, et al. Effects of diabetes mellitus amd ischemic heart disease on the progression from asymptomatic left ventricular dysfunction to symptomatic heart failure: A retrospective analysis from the Studies on Left Ventricular Dysfunction (SOLVD) prevention trial. Am Heart J 2004;148 :883–8. 27. Ho KK, Anderson KM, Kannel WB, Grossman W, et al. Survival after the onset of congestive heart failure in Framingham Heart Study subjects. Circ 1993;88 :107–15. 28. 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 Morbidity and mortality (CHARM) program. Eur Heart J 2008 29 :1377–85. 29. Aguilar D, Bozkurt B, Ramasubbu K, and Deswani A. Relationship of Hemoglobin A1C and Mortality in Heart Failure Patients with Diabetes. JACC 2009;54 :422–8. 30. Patel A, MacMahon S, Chalmers J, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008;358 :2560–72. 31. Gerstein HC, Miller ME, Byington RP, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358 :2545–59. 32. Smooke S, Horwich TB and Fonarow GC. Insulin-treated diabetes is associated with a marked increase in mortality in patients with advanced heart failure. Am Heart J 2005;149:168–74. 33. Holman RR, Sourij H, Califf RM. Cardiovascular outcome trials of glucose-lowering drugs or strategies in type 2 diabetes. Lancet 2014;383 :2008–17. 34. Dormandy JA, Charbonnel B, Eckland DJ, et al. PROactive investigators. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective piogli- tAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet 2005;366:1279–89. 35. Scirica BM, Bhatt DL, Braunwald E, et al. SAVOR-TIMI 53 Steering Committee and Investigators. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 2013;369 :1317–26.

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Heart Failure with Preserved Ejection Fraction

LE ATION.

e. lare.

The Management of Heart Failure with Preserved Ejection Fraction Andrew J S Co a t s 1 ,2 a n d L o u i s e G S h e w a n 1 ,2 ,3 1. Monash University, Melbourne, Australia; 2. University of Warwick, Coventry, UK; 3. Sydney Medical School, University of Sydney, Australia

Abstract Heart failure is defined as a clinical syndrome and is known to present with a number of different pathophysiological patterns. There is a remarkable degree of variation in measures of left ventricular systolic emptying and this has been used to categorise heart failure into two separate types: low ejection fraction (EF) heart failure or HF-REF and high EF heart failure or HF-PEF. Here we review the pathophysiology, epidemiology and management of HF-PEF and argue that sharp separation of heart failure into two forms is misguided and illogical, and the present scarcity of clinical trial evidence for effective treatment for HF-PEF is a problem of our own making; we should never have excluded patients from major trials on the basis of EF in the first place. Whilst as many heart failure patients have preserved EFs as reduced we have dramatically under-represented HF-PEF patients in trials. Only four trials have been performed in HF-PEF specifically, and another two trials that recruited both HF-PEF and HF-REF can be considered. When we consider the similarity in outcomes and neurohormonal activation between HF-REF and HF-REF, the vast corpus of trial data that we have to attest to the efficacy of various treatment (angiotensinconverting-enzyme [ACE] inhibitors, angiotensin receptor blockers [ARBs], beta-blockers and aldosterone antagonists) in HF-REF, and the much more limited number of trials of similar agents showing near statistically significant benefits in HF-PEF the time has come rethink our management of HF-PEF, and in particular our selection of patients for trials.

Keywords Heart failure, HF-PEF, clinical trials Disclosure: No disclosures to declare. Received: 23 March 2015 Accepted: 6 April 2015 Citation: Cardiac Failure Review, 2015;1(1):11–5 Correspondence: Andrew JS Coats, Academic Vice-President, Monash University, Australia and University of Warwick, UK. E: ajscoats@aol.com

What is Heart Failure? Heart failure (HF) is a diagnosis made on clinical grounds, requiring at its simplest only a clinical history and physical examination findings, although, of course, certain investigations can help, especially imaging to assess left ventricular (LV) mechanical function. Unlike cancer, or even myocardial infarction (MI), there is no pathological or biochemical test that is either sufficient or necessary to diagnose HF. Natriuretic peptides (B-type natriuretic peptide [BNP] or N-terminal-proBNP) are the closest tests we have to fulfilling this role, and although multiple studies have used elevated NPs as a diagnostic threshold, a guide to therapy or as an inclusion criterion for clinical trial entry, none has become established as an essential diagnostic test for HF.

Two (or Three) Types of Heart Failure The most recent guidelines of the European Society of Cardiology1 have a simple algorithm for what is needed to guide the diagnosis of HF (see Table 1). Deceptively simple because it actually indicates two separate diagnoses to be made: HF with reduced EF (HF-REF) and HF with preserved EF (HF-PEF). Unhelpfully the table does not indicate the definition of these terms, and only in the text is it revealed that HF-REF refers to those who otherwise fit a HF diagnosis, with, in addition, a LVEF of ≤35 %. Can one assume that this value is always known; is stable and reproducible; is an equivalent between different imaging modalities and methods of calculation; or even that by exclusion that cases with a LVEF >35 % must be cases of HF-PEF as they are not by definition HF-REF? Unfortunately none of these assumptions are valid. Often the EF is not known (even more frequently in general practice)

Coats and Shewan_FINAL.indd 11

and echo-based, magnetic resonance imaging (MRI) and nuclear estimates may differ in the same patient by as much as 10 percentage points, enough to turn a case from true HF-REF into not a case. Interestingly, the HF guidelines do not actually give recommendations for the treatment of HF; mostly they give recommendations for the treatment of HF-REF and give a very much smaller list of statements about what works in HF-PEF. Brief mention is made about a third group, those with all the symptoms and signs of HF, but whose LVEF is in the range of 35–50 %. They are sometimes referred to as the ‘grey zone’, ‘HF with mild systolic dysfunction’ or HF with intermediate EF (HF-IEF). All this is a problem of our making. If we had stuck with a clinical diagnosis we would have a condition of ‘HF’, which we then would have evaluated in clinical trials. Early on we recognised that this condition presented with multiple pathophysiological and aetiological subtypes, as indeed there are for many types of cancer even of one organ. We could have described these subtypes and tested their responses to therapy separately as subgroups in a larger trial of HF. Had we done this we would have tested drugs that might work in all HF and secondarily assessed relative efficacy in major subtypes, and we then would have found that different EF ranges predicted quantitatively, but unlikely qualitatively, different responses. Had we done this we would not have two (or three) diagnoses merely one diagnosis with a pathophysiological parameter (LVEF) that is later shown to be helpful in determining different relative responses to therapy. We would not have dichotomised HF and left many of our patients understudied and undertreated. It is against this background that we review the diagnosis, epidemiology and treatment of HF-PEF.

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Heart Failure with Preserved Ejection Fraction Table 1: Diagnostic Requirements for Heart Failure According to the European Society of Cardiology 2012 Guidelines The diagnosis of HF-REF requires three conditions to be satisfied: 1. Symptoms typical of HF

2. Signs typical of HFa

3. Reduced LVEF

The diagnosis of HF-PEF requires four conditions to be satisfied: 1. Symptoms typical of HF

2. Signs typical of HPa

3. Normal or only mildly reduced LVEF and LV not dilated

4. Relevant structural heart disease (LV hypertrophy/LA enlargement) and/or diastolic dysfunction

HF = heart failure; HF-PEF = heart failure with ‘preserved’ ejection fraction; HF-REF = heart failure and a reduced ejection fraction; LA = left atrial; LV = left ventricular; LVEF = left ventricular ejection fraction. aSigns may not be present in the early stages of HF (especially in HF-PEF) and in patients treated with diuretics.

11,015 patients in 115 hospitals in 24 countries

Women Men

12 10 8 6 4

–8 75

–7 70

–6

9 –5 55

9 –4

–5 50

–4 40

–3 35

–3 30

–2 25

–2 20

–1

<10

Percentage of patients

Figure 1: Distribution of Left Ventricular Ejection Fractions in Hospital-diagnosed Cases of Heart Failure in Europe 30

Left ventricular ejection fraction (%)

HF-PEF is what is left over when LVEFs below 50 % are excluded. It is not a positive diagnosis at all: it is one of exclusion. As a result of the lack of an established test, the identification, and therefore the treatment of HF, depends ultimately on the willingness or ability of a physician or medical team to call a particular case HF. As historically most cases of HF that have been enrolled in clinical trials or have been assessed for advanced therapies have been of the type with an enlarged left ventricle and poor systolic function (HR-REF), this particular type is often considered ‘real’ HF. This is of no concern where there is a fair degree of consensus about whether an individual case is or is not HF. Take the case of a younger man with a large MI who survives this initial insult and later presents with global poor LV function and fluid retention. This patient is easily recognised as fitting one of the clinical patterns of what we have for decades called the clinical spectrum of HF. Fortunately, this patient matches the inclusion criteria of any number of landmark clinical trials conducted over the period from the late 1980s to the late 2000s when most of our modern accepted HF therapies were first tested. Compare this situation to a second patient, who is older, female and has a small thick-walled left ventricle but who presents repeatedly to hospital with pulmonary and peripheral oedema who is limited markedly by exertional dyspnoea and who on echocardiography has a small chambered heart with a stiff, poorly compliant ventricle with incoordinate contraction. This patient in all likelihood has an EF of above 40 % or even 50 % and would not have matched the inclusion criteria of many of the landmark HF trials. She may also have a heightened amount of myocardial fibrosis, her diastolic function may be impaired and she may be at risk of atrial arrhythmias and subendocardial myocardial

Coats and Shewan_FINAL.indd 12

ischaemia due to vasomotor disturbance and endothelial dysfunction in her coronary vasculature. She has HF, her outlook is poor and she consumes a lot of healthcare resources with her recurrent emergency admissions. Yet she would not have been recruited into the landmark HF mortality and morbidity (M+M) randomised controlled trials (RCTs): CONSENSUS, SOLVD, Copernicus, Rales, Merit-HF, CIBIS-II, Ephesus, etc. As a result, we still do not know if she will respond to the treatments we offer our first patient and she is largely left untreated. This means we are failing approximately half of the patients with HF in the community, those who do not have HF-REF and who have been the subject of remarkably few major M+M RCTs.

The Epidemiology of Heart Failure with Preserved Ejection Fraction Figure 1 shows patients admitted to European hospitals with a diagnosis of HF. As we can see high EFs are just as likely as low, especially in females where they form the majority. Multiple epidemiological studies have suggested a prevalence of HF in western developed countries of between 1–2 % of the adult population,2 with a steeply increasing prevalence of HF with increasing age. More than 50 % of patients who ever develop HF will do so for the first time over the age of 75 years. Age is also of major importance in predicting the type of HF a patient is likely to present with. HR-REF predominates in younger patients and is most commonly secondary to coronary artery disease. The major RCTs of HF therapy have mainly recruited younger patients, with a mean age of 61 years in all the beta-blocker trials prior to SENIORS, which specifically targeted an older population. This is a decade and half younger than the average age in the community. The older patient, by contrast, is more likely to have hypertension as the predominant aetiology factor, to be female and to have the HF-PEF pattern of LV physiology. There has not been a single mortality and morbidity RCT of HF with an average age of recruits older than 76 years. The mortality of HF-PEF is said by many reports from hospital case series and clinical trials to be lower than that of HF-REF, suggesting it is a condition of lesser importance. In fact in large epidemiological studies in a community setting, or rigidly performed on a sound epidemiological basis, the prognosis of HF-PEF is virtually indistinguishable from that of HF-REF. The most worrying feature is that over the last 15 years only for HF-REF has there been any improvement in the risk of mortality, for HF-PEF it has remained unchanged. This period coincided with one of the most significant advances in the therapy of cardiovascular disease (CVD), the revolution in our treatment of chronic HF (CHF). Consecutively hospitalised decompensated HF patients at Mayo Clinic Hospitals in Olmsted County, Minnesota, US, from 1987 through 2001 show that over this period the proportion with HF-PEF has gone from just below 50 % to more than 50 % and that in contrast to HF-REF there has been no increase in long-term survival.3 See also Figure 2. More recent reports similarly show outcomes as poor for HF-PEF as for HF-REF.4 The reports that have been said to show much better prognosis of HF-PE compared with HF-REF patients are more commonly series of patients specifically investigated and chosen to enter clinical trials, where other co-morbidities (common in the elderly) are often exclusion criteria. Some reports of this nature suggest that survival is significantly better for HF-PEF compared with HF-REF,5 such as analyses comparing two different clinical trials, such as CHARM Preserved versus the two other CHARM studies, and such analyses also suggest prognostic6,7 and pathophysiological factors may be distinct;8–12 however, these comparisons are biased by the fact that recruitment to trials itself is

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The Management of Heart Failure with Preserved Ejection Fraction

Clinical Treatment Trials in Heart Failure with Preserved Ejection Fraction There have been remarkably few M+M RCTs in HF-PEF. These trials are of two types. In one type, all HF is recruited into a M+M trial and subsets include HF-PEF and HF-REF type patients. The trial is powered to establish its primary efficacy analysis based on the whole trial population then we investigate important subgroups to see if the treatment effect is statistically significantly (or even trending to) different in these subgroups. Occasionally, a subgroup treatment effect may be statistically significant in its own right, but this is not the principal analysis. The best estimate of the treatment effect in a subgroup, if there is no significant effect treatment/subgroup interaction, is that of the whole trial result itself. By this measure if the trial is positive, and if the HF-PEF patients show a similar result and no statistically interaction with treatment, then this is considered evidence the treatment also works in that subgroup, provided of course there are reasonable numbers and not just a handful. The second type is the standalone trial powered for and recruiting only HF-PEF type patients. In contrast to over 100 such trials in HF-REF there have only been four such trials: CHARM-Preserved, PEP-CHF, I-Preserve and TOPCAT that will be reviewed below.

The DIG trials The DIG trial was actually two trials, although the second one (DIG-PEF) has been largely forgotten. In what has been called the main trial (that restricted to HF-REF patients) 6,800 HF patients with LVEF of 45 % or less were randomly assigned to digoxin or placebo. The primary outcome of all-cause mortality was unchanged and of the secondary outcomes HF hospitalisation prevention showed a marked effect (26.8 % versus 34.7 %, risk ratio 0.72 [0.66 to 0.79]; p<0.001). The combined endpoint of death from any cause or hospitalisation for worsening HF was significantly lower in the digoxin group (risk ratio, 0.85; 95 % confidence interval [CI] 0.79 to 0.91; p<0.001). The HF-PEF study was smaller (988 patients with LVEF >45 %) and chose the combined endpoint of death or hospitalisation due to worsening HF as the primary outcome. The result of DIG-PEF as they quaintly put it the trial publication was “With

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Coats and Shewan_FINAL.indd 13

Figure 2: Changes In Survival Over Time For (A) Heart Failure With (A) Reduced And (B) Preserved Ejection Fraction 31 Survival in systolic HF

1.0

1987 – 1991 1992 – 1996 1997 – 2001

Surviving

0.8 0.6 0.4 0.2

P=0.005

0.0 0

336 395 319

274 331 210

220 273 114

Years

No. at risk

819 857 748

525 594 520

424 481 447

Survival in systolic HF-PEF

1.0

1987 – 1991 1992 – 1996 1997 – 2001

0.8 Surviving

biased against patients with HF-PEF. That is because trials exclude many patients on the basis of confounding co-morbidities, by the reasoning that co-morbidities confound the trial’s evaluation of a treatment on one condition. But if co-morbidities are, by their natural history, common in a certain disease state then excluding patients with these co-morbidities you are selecting for a very biased and unrepresentative group of patients. This cannot be corrected by analysing ever-larger numbers. We can only compare the outlook and prognosis of HF-PEF and HF-REF by recruiting patients from epidemiologically valid or whole population cohorts, not by analysing selected clinical trial cohorts. The mortality rate of trial HF-PEF patients is lower than that of HF-PEF trial patients because so many of the higher risk HF-PEF patients are excluded to find a ‘purer’ form of HF-PEF. Epidemiologically sound studies find the prognosis of HF-PEF and HF-REF are virtually indistinguishable. Early trials such as the DIG13 trial of digoxin recruited HF patients of both HF-PEF and HF-REF subtypes (sometimes called the DIG-REF trial and the DIG HF-PEF trial) and the effects were similar for the types. Later trials, in the interest of increasing event rates, over-recruited HF-REF and many restricted entry to patients with a LVEF less than 45 %, 40 %, 35 % or even lower (25 % for Copernicus).14 This was done to increase mortality rates, but had the effect of leaving HF-PEF patients unstudied and hence many years later untreated.

0.6 0.4 0.2

P=0.36

0.0 0 No. at risk

510 771 885

263 375 365

216 314 230

117 262 138

Years 377 537 629

313 447 513

regard to the combined outcome of death or hospitalisation due to worsening HF, the results in the ancillary trial (risk ratio, 0.82; 95 percent confidence interval, 0.63 to 1.07) were consistent with the findings of the main trial.” Thus although being manifestly underpowered, the DIG-PEF trial just missed its primary endpoint statistically. Had the combined DIG trial used this combined endpoint it would have been easily positive for the clinically acceptable combined endpoint of death or HF hospitalisation and the results in HF-REF and HF-PEF would have been indistinguishable.

SENIORS The SENIORS15,16 trial recruited both types if HF was powered with a single primary endpoint of death or CV hospitalisation. SENIORS in 2,128 HF patients aged ≥70 years showed a 14 % reduction in the primary outcome of all-cause mortality or CV hospital admission (hazard ratio [HR] 0.86, 95 % CI 0.74–0.99; p=0.039). It was a positive trial and LVEF had no impact of the treatment effect with the point estimate of benefit in those patients with a LVEF >35 % being slightly bigger than those with LVEF ≤35 % (see Figure 3). For SENIORS the overall trial was positive and the subset with preserved LVEF did just as well, there was no statistically significant interaction between LVEF and treatment effect yet guidelines fail to recommend nebivolol other than for lower EF. This is even though this is based on an analysis of a subset of the pre-specified question and the authors maintain that because the HF-PEF subset was not independently significant nebivolol cannot be recommended for this cohort. This is despite the fact that the correct statistical analysis is to assume any subset behaves as the whole cohort unless there is a reason or a statistical suggestion that it does not. Nebivolol should therefore be recommended for elderly HF

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Heart Failure with Preserved Ejection Fraction Figure 3: Subgroup Analysis of the Primary Endpoint of the SENIORS Trial Showing Similar Effects in HF-PEF as in Heart Failure with Preserved Ejection Fraction Patients.

All

P-value**

umber of patients Number of events (rate*) N Nebivolol/placebo Nebivolol/placebo 1,067/1,061 332 (20.3)/375 (23.9)

Sex Female Male

410/375 657/686

101 (15.5)/125 (21.8) 231 (23.5)/250 (25.2)

0.11

Ejection fraction ≤35 % 683/686 ≥ median (75.2 years) 380/372

219 (21.7)/249 (25.1) 110 (176)/125 (21.9)

0.42

Age < median (75.2 years) 539/525 ≥ median (75.2 years) 528/536

148 (16.6)/176 (21.4) 184 (24.6)/199 (26.7)

0.51

Diabetes Not present Present

780/793 287/268

217 (17.4)/267 (22.5) 115 (29.3)/108 (28.3)

0.13

Prior myocardial infarction Not present 600/597 Present 467/463

156 (16.2)/188 (19.9) 176 (26.2)/187 (30.0)

0.53

0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3 1.4 *Number of events per 100 patients–years of follow-up at risk.

patients irrespective of LVEF. None of the guidelines follow this logic, and in doing so are themselves illogical.

The Trials that did Recruit Heart Failure with Preserved Ejection Fraction Patients There have been four M+M trials that have specifically and solely recruited HF-PEF patients: CHARM-Preserved,17 PEP-CHF,18 I-Preserve19 and TOPCAT.20

CHARM-Preserved The CHARM programme actually represents a type of hybrid of the two types of trial mentioned above. The CHARM programme of candesartan is made up of three component trials that were in addition combined together prospectively with a single powered endpoint and recruited and analysed together. It thus could be thought of as a single trial (the programme) with a HF-PEF subset (CHARM-preserved)21 or three trials, one of which CHARM-preserved is in HF-PEF. If analysed the first way the overall programme was negative as the primary endpoint was not reached. Seven thousand five hundred and ninety-nine CHF patients were randomised to candesartan 32 mg or placebo and the primary endpoint of all-cause mortality was not statistically significantly reduced: 23 versus 25 %, HR 0.91, 95 % CI 0.83–1.00; p=0.055. We should therefore not even look at the HF-PEF or HF-REF cohorts for efficacy in these subsets. The CHARM-Preserved trial alone was powered for the composite of CV death or HF hospitalisation. In 3,023 patients, candesartan did not significantly reduce the primary endpoint (unadjusted HR 0.89 [95 % CI 0.77–1.03]; p=0.118), but it came very close (covariate adjusted HR 0.86 [0.74–1.0]; p=0.051).

PEP-CHF PEP-CHF was a randomised, double-blind trial, comparing placebo with perindopril, 4 mg/day in patients aged >70 years with a diagnosis of HF, and echocardiographic evidence of diastolic dysfunction and excluding substantial LV systolic dysfunction or valve disease.

Coats and Shewan_FINAL.indd 14

The primary endpoint was a composite of all-cause mortality and unplanned HF-related hospitalisation: 850 patients were randomised and followed-up for an average of 2.1 years. The power of the study to show a difference in the primary endpoint was reported to be only 35 % (because of poor recruitment and lower than expected event rates) showing only a one-third chance of showing an effect event if a real effect were present. Overall, 107 patients assigned to placebo and 100 assigned to perindopril reached the primary endpoint (HR 0.919, 95 % CI 0.700–1.208; P=0.545). By 1 year, before the extent of loss of adherence to randomised drug groups had become so catastrophically high as mentioned earlier, the reductions in the primary outcome (HR 0.692, 95 % CI 0.474–1.010; p=0.055) and hospitalisation for HF (HR 0.628, 95 % CI 0.408–0.966; p=0.033) were observed and functional class (p=0.030) and 6-minute corridor walk distance (p=0.011) had improved in those assigned to perindopril.

I-PRESERVE I-Preserve similarly was a randomised double-blind placebo-controlled trial in HF-PEF, but in this case was much larger. Four thousan one hundred and twenty-eight patients 60 years or older and LVEF >45 % were randomised for an average of 49.5 months to 300 mg of irbesartan or placebo. The primary endpoint was death or CV hospitalisation. The primary outcome occurred in 742 patients in the irbesartan group and 763 in the placebo group, giving primary event rates of 100.4 and 105.4 per 1,000 patient-years, respectively (HR 0.95, 95 % CI 0.86 to 1.05; p=0.35). The mortality rates were similar. This result seems disappointing but it is directionally and in scale not dissimilar to the result of VAL-Heft22 of valsartan in HF-REF where in 5,010 patients 160 mg of valsartan reduced the primary mortality/ morbidity endpoint, by 13.2 % (relative risk 0.87, 97.5 % CI 0.77 to 0.97; p=0.009), with no difference in mortality. Also in I-PRESERVE there was a high rate of discontinuation of study treatment (34 % by the end of the study) and a high rate of concomitant use of ACE inhibitors, spironolactone and beta-blockers.

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The Management of Heart Failure with Preserved Ejection Fraction

TOPCAT The most recent trial, TOPCAT, built upon earlier smaller trials, investigated another HF-REF-proven treatment.23 TOPCAT randomised 3,445 patients 50 years or older and LVEF >45 % to spironolactone 30 to 45 mg/day or placebo. The trial was not quite positive: the primary composite endpoint was reduced from 20.4 % to 18.6 % (HR 0.89 95 % CI 0.77–1.04; p=0.138) and HF hospitalisations reduced from 14.2 % to 12.0 % (HR 0.83, 95 % CI 0.69-0.99; p=0.04). Yet again a negative trial, but in its pattern not dissimilar to VAL-HEFT. Interestingly in what was both a pre-specified analysis and using a variable that was actually stratified for at randomisation (ensuring the likelihood of good balance between placebo and active) in those patients who qualified for TOPCAT on the basis of an elevated NP level (BNP ≥100 pg/ml or NT-proBNP ≥360 pg/ ml) there was a highly significant 35 % reduction in the primary endpoint. In the elevated NP group there were 78 primary events in 490 patients (15.9 %) compared with 116 events in 491 placebo patients (23.6 %, HR 0.65, 95 CI 0.49–0.87; p=0.003)24 entirely consistent with what has been seen in HF-REF with spironolactone or eplerenone.

The Long-term Effect of Trials that Excluded Heart Failure with Preserved Ejection Fraction We have seen that the major trials have largely been restricted to HF-REF patients. HF-PEF trials should be able to duplicate these results. This has not happened partly because of restricted funding. Some trials (e.g. I-PRESERVE) have recruited very slowly and have been funded publically rather than by a corporate sponsor where funding is usually more generous. Consider the case of the beta-blocker carvedilol.

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 J Heart Fail 2012;14 (8):803–69. 2. Mosterd A, Hoes AW. Clinical epidemiology of heart failure. Heart 2007;93 :1137–46. 3. 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 (3):251–9. 4. Senni M, Gavazzi A, Oliva F, et al.; IN HF Outcome Investigators. In-hospital and 1-year outcomes of acute heart failure patients according to presentation (de novo vs. worsening) and ejection fraction. Results from IN-HF Outcome Registry. Int J Cardiol 2014;173 (2):163–9. 5. 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 (23):2349–56. 6. Wu CK, Lee JK, Chiang FT, et al., Prognostic factors of heart failure with preserved ejection fraction: a 12-year prospective cohort follow-up study. Int J Cardiol 2014;171 (3):331–7. 7. Maeder MT, Kaye DM, Differential impact of heart rate and blood pressure on outcome in patients with heart failure with reduced versus preserved left ventricular ejection fraction. Int J Cardiol 2012;155 (2):249–56. 8. Wang J, Fang F, Yip GW, et al. Quantification of left ventricular performance in different heart failure phenotypes by comprehensive ergometry stress echocardiography. Int J Cardiol 2013;169 (4):311–5. 9. Zhong L, Ng KK, Sim LL, et al. Myocardial contractile dysfunction associated with increased 3-month and 1-year mortality in hospitalized patients with heart failure and preserved ejection fraction. Int J Cardiol 2013;168 (3):1975–83. 10. Kasner M, Aleksandrov AS, Westermann D, et al. Functional iron deficiency and diastolic function in heart failure with preserved ejection fraction. Int J Cardiol 2013;168 (5):4652–7. ] 11. Phan TT, Shivu GN, Abozguia K, et al. The pathophysiology of heart failure with preserved ejection fraction: from molecular mechanisms to exercise haemodynamics. Int J Cardiol

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Coats and Shewan_FINAL.indd 15

Carvedilol is now off-patent in most developed countries so further company sponsorship of large expensive trials is unlikely. The sponsors did however pay for three trials, the US Carvedilol program,25 Copernicus and COMET.26 None of these trials included HF-PEF patients. Where resources for trials are limited it seems a tragedy that the third major trial for this agent instead of recruiting the half of all HF that had been totally ignored instead targeted a question of only marginal scientific value, whether carvedilol was superior to a non-proven formulation of another beta-blocker, non-slow-release metoprolol. We cannot, sadly, depend on sponsors studying patient populations of need, they focus where their drug will look best and avoid the more difficult or uncertain areas. If we had recruited patients with HF irrespective of LVEF in a slightly enlarged Copernicus trial and performed subanalyses of HF-PEF and HF-REF we would be in a much stronger position today. It is hard to avoid the conclusion we should investigate27–29 and treat HF-PEF as rigorously as their HF-REF counterparts.

Conclusions HF is a spectrum of disorders that lead to a single clinical picture. Unfortunately early in the development of effective medication we restricted our attention to only one end of the spectrum, HF-REF, leaving the other conditions lumped together as HF-PEF to go virtually unstudied and untreated for nearly two decades. This lack of evidence for HF-PEF therapies is largely a problem of our own making and we now need to double our efforts to unravel the presentation, pathophysiology and treatment of a condition that remains a major burden and which continues to grow in importance as the population ages. n

2012;158 (3):337–43. 12. Ibrahimi P, Bajraktari G, Bytyçi I, et al. Global dyssynchrony correlates with compromised left ventricular filling and stroke volume but not with ejection fraction or QRS duration in HFpEF. International Cardiovascular Forum Journal 2014; in press. 13. Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med 1997;336 (8):525–33. 14. Packer M, Coats AJ, Fowler MB, et al.; Carvedilol Prospective Randomized Cumulative Survival Study Group. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 2001;344 (22):1651–8. 15. Flather MD, Shibata MC, Coats AJ, et al.; SENIORS Investigators. Randomized trial to determine the effect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failure (SENIORS). Eur Heart J 2005;26 (3):215–25. 16. van Veldhuisen DJ, Cohen-Solal A, Böhm M, et al.; SENIORS Investigators. Beta-blockade with nebivolol in elderly heart failure patients with impaired and preserved left ventricular ejection fraction: Data From SENIORS (Study of Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors With Heart Failure). J Am Coll Cardiol 2009;53(23):2150–8. 17. Swedberg K, Pfeffer M, Granger C, et al. Candesartan in heart failure-assessment of reduction in mortality and morbidity (CHARM): rationale and design. Charm-Programme Investigators. J Card Fail 1999;5 (3):276–82. 18. Cleland JG, Tendera M, Adamus J, et al.; PEP-CHF Investigators. The perindopril in elderly people with chronic heart failure (PEP-CHF) study. Eur Heart J 2006;27 (19):2338–45. 19. Massie BM, Carson PE, McMurray JJ, et al.; I-PRESERVE Investigators. Irbesartan in patients with heart failure and preserved ejection fraction. N Engl J Med 2008;359(23):2456–67. 20. Pitt B, Pfeffer MA, Assmann SF, et al.; TOPCAT Investigators. Spironolactone for heart failure with preserved ejection fraction. N Engl J Med 2014;370 (15):1383–92. 21. Yusuf S, Pfeffer MA, Swedberg K, et al.; CHARM Investigators and Committees. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial. Lancet

2003;362 (9386):777–81. 22. Cohn JN, Tognoni G, Valsartan Heart Failure Trial Investigators. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med 2001;345 (23):1667–75. 23. Edelmann F, Gelbrich G, Duvinage A, et al. Differential interaction of clinical characteristics with key functional parameters in heart failure with preserved ejection fraction – results of the Aldo-DHF trial. Int J Cardiol 2013;169 (6):408–17. 24. Available at: www.clinicaltrialresults.org/Slides/AHA%202013/ Pfeffer_TOPCAT.ppt (accessed 30 March 2015) 25. Packer M, Bristow MR, Cohn JN, et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group. N Engl J Med 1996;334 (21):1349–55. 26. Poole-Wilson PA, Swedberg K, Cleland JG, et al.; Carvedilol Or Metoprolol European Trial Investigators. Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol Or Metoprolol European Trial (COMET): randomised controlled trial. Lancet 2003;362 (9377):7–13. 27. Offen S, Celermajer D, Semsarian C, Puranik R, The role of diastolic filling in preserving left ventricular stroke volume–an MRI study. Int J Cardiol 2013;168 (2):1596–8. 28. van Empel VP, Kaye DM, Integration of exercise evaluation into the algorithm for evaluation of patients with suspected heart failure with preserved ejection fraction. Int J Cardiol 2013;168 (2):716–22. 29. Henein M, Mörner S, Lindmark K, Lindqvist P. Impaired left ventricular systolic function reserve limits cardiac output and exercise capacity in HFpEF patients due to systemic hypertension. Int J Cardiol 2013;168 (2):1088–93. 30. 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 (5):442–63. 31. 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(3):251–9.

10/04/2015 09:29

Sleep Apnoea

LE ATION.

Sleep-disordered Breathing in Heart Failure – Current State of the Art Martin R Cowie, 1 Holger Woehrle, 2,3 Olaf Oldenburg, 4 Thibaud Damy, 5 Peter van der Meer, 6 Erland Erdman, 7 Marco Metra, 8 Faiez Zannad, 9 Jean-Noel Trochu, 10 Lars Gullestad, 11 Michael Fu, 12 Michael Böhm, 13 Angelo Auricchio 14 and Patrick Levy 15 1. Imperial College London, London, UK; 2. Sleep and Ventilation Center Blaubeuren, Respiratory Center Ulm, Ulm, Germany; 3. ResMed Science Centre, ResMed Europe, Munich, Germany; 4. Heart and Diabetes Center North Rhine-Westphalia, Ruhr University Bochum, Bad Oeynhausen, Germany; 5. Henri Mondor Hospital, Créteil, France; 6. University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; 7. University of Cologne, Cologne, Germany; 8. University of Brescia, Brescia, Italy; 9. Academic Hospital (CHU), Nancy, France; 10. University Hospital (CHU), Nantes, France; 11. Oslo University Hospital, Rikshospitalet, Norway; 12. Sahlgrenska University Hospital/Östra Hospital, Göteborg, Sweden; 13. University of the Saarland, Hamburg, Germany; 14. Fondazione Cardiocentro Ticino, Lugano, Switzerland; 15. University Grenoble Alpes, Grenoble, France

e. lare.

Abstract Sleep-disordered breathing (SDB), either obstructive sleep apnoea (OSA) or central sleep apnoea (CSA)/Cheyne-Stokes respiration (CSR) and often a combination of the two, is highly prevalent in patients with heart failure (HF), is associated with reduced functional capacity and quality of life, and has a negative prognostic impact. European HF guidelines identify that sleep apnoea is of concern in patients with HF. Continuous positive airway pressure is the treatment of choice for OSA, and adaptive servoventilation (ASV) appears to be the most consistently effective therapy for CSA/CSR while also being able to treat concomitant obstructive events. There is a growing body of evidence that treating SDB in patients with HF, particularly using ASV for CSA/CSR, improves functional outcomes such as HF symptoms, cardiac function, cardiac disease markers, exercise tolerance and quality of life. However, conflicting results have been reported on ‘hard’ outcomes such as mortality and healthcare utilisation, and the influence of effectively treating SDB, including CSA/CSR, remains to be determined in randomised clinical trials. Two such trials (SERVE-HF and ADVENT-HF) in chronic stable HF and another in post-acute decompensated HF (CAT-HF) are currently underway.

Keywords Obstructive sleep apnoea, central sleep apnoea, heart failure, adaptive servoventilation, continuous positive airway pressure Disclosure: Professor Cowie is co-principal investigator of the SERVE-HF study, and receives research and consultancy fees from ResMed. Acknowledgement: Medical writing support was provided by Nicola Ryan, independent medical writer, funded by ResMed. Received: 1 December 2014 Accepted: 7 February 2015 Citation: Cardiac Failure Review, 2015;1(1):16–24 Correspondence: Martin R Cowie, Professor of Cardiology, National Heart and Lung Institute, Imperial College London, Dovehouse Street, London SW3 6LY, UK. E: m.cowie@imperial.ac.uk

Heart Failure

Sleep-disordered Breathing

In developed countries, approximately 1–2 % of the adult population has heart failure (HF), and the prevalence of this cardiovascular disease increases with age.1,2 HF can occur in the presence or absence of reduced left ventricular ejection fraction (LVEF), known as HF with reduced ejection fraction (HF-rEF) and HF with preserved ejection fraction (HF-pEF), respectively. The most widely studied of these is HF-rEF, which is particularly prevalent in men with ischaemic heart disease.3 HF-pEF is present in 40–50 % of HF patients.4,5 It is more prevalent in women and the underlying aetiology is more often non-ischaemic.3,6 Despite these differences, the negative prognostic impact of both HF-rEF and HF-pEF appears to be similar.6 The prevalence of renal disease and sleep-disordered breathing (SDB) is similar in patients with HF-rEF or HF-pEF, but the profile of other co-morbidities differs, with pulmonary disease, anaemia and obesity tending to be more prevalent in HF-pEF patients.7 Even with the wide range of therapeutic options available for patients with HF-rEF and treatment being optimised according to current guideline recommendations, most HF-rEF patients will eventually die from progressive disease; for HF-pEF there are still no evidence-based treatments available, so the focus is mainly on treatment of co-morbidities and optimising risk factors.3

There are two main types of breathing abnormalities seen during SDB: obstructive sleep apnoea (OSA) and central sleep apnoea (CSA), which may manifest as Cheyne-Stokes respiration (CSR), particularly in patients with HF. OSA is the most common type of SDB in the general population, and occurs secondary to recurrent collapse of the upper airway. The main features are repetitive complete (apnoea) or partial (hypopnoea) pauses in breathing during sleep, even in the presence of respiratory effort. CSA is characterised by a lack of drive to breathe during sleep, resulting in repetitive periods of reduced ventilation. CSR specifically consists of central apnoeas alternating with periods of crescendo–decrescendo respiratory tidal volume.

Cowie_FINAL.indd 16

The severity of SDB is reported as the number of respiratory events per hour of (estimated) sleep time (apnoea–hypopnoea index, AHI), with mild disease defined as an AHI of 5–15/h, moderate as 15–30/h and severe as ≥30/h. In addition, parameters documenting the extent of intermittent hypoxaemia (the oxygen desaturation index, ODI), sleep time or estimated sleep time spent with oxygen saturation <90 % and mean and minimal oxygen saturation are being used for this purpose.

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Sleep-disordered Breathing in Heart Failure – Current State of the Art

SDB is characterised by intermittent hypoxia, reoxygenation, hypercapnia, arousals and sleep deprivation, as well as increased negative intrathoracic pressure swings when an obstruction of the upper airway is present. SDB is both a cause and a consequence of HF (see Figure 1).8 Potential mechanisms for increased cardiovascular risk in patients with OSA include sympathetic activation, changes in heart rate and blood pressure (BP) variability, vasoconstriction, oxidative stress, endothelial dysfunction, systemic inflammation, increased thrombotic risk, and functional problems including impaired diastolic function and increased wall stress, afterload and atrial size.9 In terms of the cardiovascular effects of CSA, it is thought that this form of sleep apnoea is most likely to be a consequence, rather than a cause, of HF.9,10 However, some of the physiologic effects of CSA are similar to those of OSA and therefore CSA also has the potential to initiate a cycle of events that lead to deterioration in cardiovascular function (see Figure 2).10,11 This includes increased sympathetic nervous system activity, greater cardiac electrical instability and low-frequency oscillations in blood pressure and heart rate.9,10 In contrast with OSA, CSA does not cause negative intrathoracic pressure swings, and the role of some of the other mechanisms contributing to increased cardiovascular risk in OSA, including inflammation, oxidative stress and endothelial dysfunction, remains to be determined.9,10

Sleep-disordered Breathing in Heart Failure SDB is very common in patients with HF, much more common than in the general population, with prevalence rates of 50–75 %.12,13 SDB has been documented in patients with both HF-rEF14,15 or HF-pEF,16–18 with no difference in prevalence between groups19 and in patients with acute decompensated HF, where the prevalence can be even higher.20–22 One of the interesting features of SDB in patients with HF compared with general SDB patients is a relative lack of symptoms, especially of daytime somnolence,23–26 which could contribute to the lack of recognition and detection of SDB in HF patients.27 One possible explanation for a lack of daytime sleepiness in HF patients with SDB is the increased sympathetic nervous system activity in HF patients compared with healthy subjects,28,29 which is increased even further in the presence of OSA.30,31 Increased sympathetic stimulation could stimulate alertness to counteract the effects of sleep fragmentation and sleep deprivation.28 A significant inverse correlation between the degree of subjective daytime sleepiness and daytime muscle sympathetic nervous system activity has been documented in patients with HF and OSA.32 A study conducted in severe OSA patients with and without HF used very low frequency heart rate variability (VLF-HRV) as a marker of sympathetic nervous system activity at night. The results showed that patients with severe OSA, that was not associated with excessive daytime sleepiness, had higher VLF-HRV (and therefore higher sympathetic activity) than those with excessive daytime sleepiness, and concluded that this was due to the alertness-inducing effects of excessive sympathetic nervous system activity.33 Furthermore, patients with HF are often taking a variety of medications that cross the blood–brain barrier, and these could also impact on sleep and SDB.34 One such group of agents is ß-blockers, which have been shown to reduce daytime sleepiness and the prevalence of CSA in HF patients.35 Approximately 20–45 % of patients with chronic HF have OSA.14,15 European HF guidelines recognise that sleep apnoea is of concern in patients with HF.3 OSA is independently associated with a worse prognosis in HF patients,24 even in those who are receiving maximal and optimal HF therapy.36 OSA is also highly prevalent in patients with HF-pEF, with a prevalence of 69–81 %.16,18 The predominant type of SDB in HF-pEF appears to be OSA, which occurs more often than CSA in these patients.16,18

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Cowie_FINAL.indd 17

Figure 1: Links Between Sleep-disordered Breathing and Heart Failure Intrathoracic Pressure Changes Arrhythmia (Atrial Fibrillation) Myocardial Ischaemia OSA Sleep Apnoea

Heart Failure

(with oxygen desaturations)

CSA

Dyspnoea Hyperventilation

Sympathetic Activation (Arousals)

Prolonged Circulation Time

Inflammatior Oxygen Radicals Hypocapnia Below Apnoeic Threshold

Figure 2: Mechanisms Linking Central Sleep Apnoea and Heart Failure Left Ventricular Failure: ↓Cardiac Output ↑LV Filling Pressure Pulmonary oedema

Pulmonary afferent stimulation

↑Chemosensitivity

Fatigue

Hypersomnolence

Sleep Disruption

Hyperventilation

Arousal

↑SNA ↑Catecholamines ↑HR ↑BP

↓Cardiac O2 supply ↑Cardiac O2 demand

↓PaO2 ↑PaCO2

↓PaCO2 Central Apnoeas

Reprinted from Hall and Bradley11, copyright 1995, with permission from Wolters Kluwer Health. BP = blood pressure; HR = heart rate; LV = left ventricular; SNA = sympathetic nerve activity; PaO2 = arterial oxygen pressure; PaCO2 = arterial carbon dioxide pressure.

While rarely found in the general population, CSA/CSR is a common SDB pattern seen in patients with chronic HF, with a prevalence of 25–40 %.15 The prevalence of CSA/CSR appears to increase as the severity of HF increases,12,16 and the severity of CSA/CSR seems to mirror cardiac dysfunction.37–39 Furthermore, CSA is independently associated with a worse prognosis in patients with HF, including increased mortality.24,26,36,40–42 Even mild CSA, with an AHI of ≥5/h has been associated with increased mortality.36 Although effective pharmacological9,35,38,43,44 and device-based45 treatment of HF may improve CSA/CSR, the negative impact of this form of SDB persists even in patients who are receiving maximal and optimal HF therapy, including cardiac resynchronisation.26,46 For patients who have persistent CSA despite optimal medical therapy, it may be necessary to consider other interventions.

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Sleep Apnoea Table 1: Features of Different Types of Positive Airway Pressure Therapy

expiratory pressure

APAP

Maintain upper airways open

Continually adjusting expiratory pressure to optimal level for specific patient needs

BPAP

ASV

Support breathing in lung

Fixed expiratory pressure and pressure

disease-related respiratory

support at inspiration, usually with fixed

insufficiency

backup rate

Stabilises breathing and

Continually adjusting inspiratory and

maintains upper airway open

expiratory pressure with variable, on-demand, back up rate

Pressure Pressure Pressure Pressure

Pressure Profile

Pressure Pressure Pressure Pressure

Features Fixed or automatically adjusted

Pressure Pressure Pressure Pressure

Aim Maintain upper airways open

Pressure Pressure Pressure Pressure

Theraphy CPAP

Time Time Time Time

APAP = auto-adjusting positive airway pressure; ASV = adaptive servoventilation; BPAP = bilevel positive airway pressure; CPAP = continuous positive airway pressure.

At 44–97 %, the prevalence of CSA in patients with acute decompensated HF is even greater than that in those with stable HF.20–22 In addition, when present, CSA in acute decompensated HF patients is usually severe (AHI >30/h),21 and has been shown to be a predictor of readmission and mortality.47 It is interesting to note that optimal medical management, resolution of acute decompensation and return to baseline cardiopulmonary status are often not associated with a significant change in the severity of CSA.21,43,48,49 Insertion of a left ventricular assist device (LVAD) has been associated with improvements in SDB in refractory patients.50,51 These findings could indicate that severe CSA was present prior to the acute decompensation episode, and that more severe HF drives the higher prevalence and greater severity of CSA in these patients.48

Screening and Diagnosis of Sleep-disordered Breathing SDB can be reliably diagnosed with cardio-respiratory polygraphy, which records nasal flow, respiratory effort, saturation, pulse and position. The technology can be used in both in- and outpatient settings. Polygraphy has been shown to be a valid alternative to the gold standard polysomnography (PSG) for SDB screening and diagnosis.52–57 Attended PSG is currently the recommended option for assessing CSA in HF patients, but there is increasing evidence that polygraphy might be a valid alternative.56 Polygraphy records the same respiratory signals as PSG (nasal/oronasal airflow, chest and abdominal movements, and oxygen saturation) but many devices do not incorporate electroencephalography (EEG), electrooculography (EOG) and electromyography (EMO) monitoring and therefore do not provide data on total sleep time, sleep staging and arousals.56 As a result, polygraphy calculates SDB events per hour of monitoring time rather than per hour of actual sleep time like PSG, which may underestimate SDB severity in HF patients who have worse sleep quality and wake more times at night (known as lower sleep efficacy).56,58 Therefore, newer polygraphy devices that also estimate sleep quality using actigraphy or PSG may be needed in more difficult cases. Important advantages of polygraphy are that it is well-accepted by patients, more accessible and less costly than PSG.59,60

Cowie_FINAL.indd 18

Implantable cardiac electronic devices also have the ability to screen for SDB by analysing changes in intrathoracic impedance, and this feature is being built in to newer models.61 Detection of SDB using implantable cardiac devices is not yet part of routine clinical practice, but there are devices currently available that are being used in clinical settings. Questionnaires have not been useful in pre-screening patients with cardiovascular diseases including HF for SDB, because HF patients do not show the same symptoms and risk factors for SDB as patients without HF, and the screening questionnaires have only been validated for general OSA patients.23 In addition, the overlap of some HF and SDB symptoms make questionnaires less useful in this group of patients. Furthermore, mild SDB may not be associated with obvious symptoms but can still have a negative impact on prognosis.

Treating Sleep-disordered Breathing in Heart Failure Current Options and Interfaces In addition to oxygen therapy, there are a number of positive airway pressure (PAP) treatment options available to clinicians managing SDB in patients with HF. These include continuous positive airway pressure (CPAP), auto-adjusting positive airway pressure (APAP), bilevel positive airway pressure (BPAP) and adaptive servoventilation (ASV) (see Table 1). Within these broad groups, there are a number of different devices utilising different algorithms to choose from. In addition to the selected PAP device, an important part of therapy is the choice of patient interface for delivery of treatment. These include nasal pillows, nasal mask and oronasal mask (sometimes known as full face mask); custom-made interfaces may be required in a small group of patients. The interface used for initiation of PAP therapy plays an important role in the acceptability of therapy and thus needs to be chosen carefully. For all therapies, the goal is to normalise breathing (AHI <5/h). An AHI of >5/h still meets criteria for diagnosis of SDB,62 and the aim should be to eliminate this negative prognostic marker, if possible. Data from the Sleep Heart Health Study showed that men aged 40–70 years with an AHI of ≥30/h were 68 % more likely to develop CAD than those with an AHI <5/h.63

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Sleep-disordered Breathing in Heart Failure – Current State of the Art

Table 2: Summary of Key Findings for Studies Investigating Adaptive Servoventilation Treatment in Heart Failure Patients with Sleep-disordered Breathing ASV Versus Control or Baseline Author (Date)

N (ASV)

HF Characteristics

SDB Pattern

ASV Duration

SDB Outcomes

Teschler (2001)90

Stable

CSA/CSR

1 night

AHI 6.3/h versus 44.5/h (p<0.001)b NR

HF Outcomes

ArI 14.7/h versus 65.1/h (p<0.01)b

ODI 3 % >15/h

↑ SWS; ↑ REM sleep Pepperell (2003)94

Schädlich (2004)96

CSR

NYHA class II–IV

ODI >10/h

↑ objective wakefulness by

↓ urinary metadrenaline release

AHI 19.8 ± 2.6

8.9 min (p=0.014)

(p=0.019)

LVEF 20–50 %

CSA/CSR

4 weeks

AHI 5.0/h versus 20.6/h (p<0.001)a ↓ BNP by 56 pg/mL BNP (p=0.001)

Stable, symptomatic

1 year

AHI 3.4/h versus 44.3/h (p<0.0001)b LVEF 41.7 versus 37.1% (p<0.05) ArI 12.0/h versus 29.8/h (p<0.01)b 6MWD 277 m versus 192 m (p<0.01)

AHI >15/h

ODI 5.2/h versus 45.3/h (p<0.0001)b SpO2 93 versus 92 % (p<0.05)b SWS 13.7 versus 4.5 % of TST (p<0.0001)b Töpfer (2004)95

LVEF <40 %

CSR

6 weeks

AHI 6.4/h versus 48.2/h (p<0.001)b Improved MLHFQ score (p=0.02)b AI 18.4/h versus 33.9/h (p<0.05)b

Phillipe

(2006)124

Stable

CSA/CSR

NYHA class II–IV

AHI >15/h

6 months

↓ AHI to <10/h (p<0.05)b

↑ LVEF (p<0.05)b

1 night

AHI 14.0/h versus 30.0/h (p<0.05)a NR

LVEF ≤40 % Szollosi (2006)125

Stable

CSA

NYHA class II–III

AHI >5/h

AI 5.5/h versus 17.0/h (p<0.05)a ArI 23.7/h versus 39.6/h (p<0.05)a

LVEF <50 % Zhang (2006)97

Stable

CSR

2 weeks

AHI 6.5/h versus 34.5/h (p<0.01)bc LVEF 37.2 versus 30.2 % (p<0.05)bc SpO2 92.1 versus 84.3 % (p<0.01)bc

LVEF 30.8 ± 4.3 %

ArI 18.2/h versus 30.4/h Oldenburg (2008)39

NYHA class ≥II

CSA/CSR

LVEF ≤40 %

AHI ≥15/h

6MWD 340.7 versus 226.2 m (p<0.01)bc

(p<0.01)bc

5.8 ± 3.5 months AHI 3.8/h versus 37.4/h (p<0.001)b NYHA 1.93 versus 2.43 (p<0.001)b AI 0.7/h versus 22.8/h (p<0.001)b LVEF 35.2 versus 28.2 % (p=0.001)b Central AI 0.3/h versus 17.6/h

NT-proBNP 1,061 versus 2,285

(p<0.001)b

pg/mL (p=0.012)b

ODI 5.2/h versus 6.8/h (p=0.001)b SpO2 94.6 versus 92.9 % (p<0.001)b Bitter (2010)126

Hastings (2010)93

NHYA class II–III

CSR

LVEF normal

AHI >15/h

Stable

CSA

NHYA class II or III

AHI >15/h

11.6 ± 3 months AHI 3.5/h versus 43.5/h (p<0.001)b NT-proBNP 740 versus 1,480 ArI 17.5/h versus 30.7/h (p<0.01)b pg/mL (p=0.1)a

6 months

Haruki (2011)127

LAD 51.1 versus 49.8 mm (p<0.01)a

versus 82.8 % (p<0.01)b

↑ exercise capacity (p<0.01)a

AHI 8/h versus 49/h (p=0.001)b

LVEF 36.9 versus 29.0 % (p=0.03)b

Central AI 5/h versus 9/h (p=0.04)b Improved SF-36 energy vitality ArI 17/h versus 64/h (p=0.002)b

LVEF <45 % Kasai (2010)108

Maximum desaturation 88.1

Stable

CSA/CSR +

NYHA class ≥II

OSA

LVEF <45 %

AHI ≥15/h

Stable

AHI >15/h

3 months

score (p=0.005)b

AHI 1.9/h versus 37.4/h (p<0.01)b 6MWD 428.3 versus 393.3 m (p<0.05)b BNP 245.5 versus 281.0 pg/mL (p<0.05)b LVESD 45.5 mm versus 49.3 m (p<0.05)b

Mean 24 weeks

NHYA class 1.5 versus 2.4 (p<0.01)b

NYHA class ≥II

LVEF 43 versus 30 % (p<0.0001)b

LVEF <50 %

SV 56 versus 43 mL (p=0.001)b CO 3.83 versus 3.13 L/min (p=0.0037)b

Oldenburg (2011)128

Stable

AHI >15/h

NYHA class ≥II

>80 % central

6.7 ± 3.2 months AHI 6.1/h versus 39.7/h (p<0.01)b NHYA class 2.6 versus 1.9 (p<0.001)b

LVEF ≤40 %

Central AI 0.4/h versus 17.2/h

LVEF 34.0 versus 29.9 % (p=0.003)b

(p<0.01)b

LVEDD 64.5 versus 67.2 mm

Mean desaturation 4.8 versus

(p=0.007)b

6.7 % (p<0.01)b Koyama (2011)98

Stable

SDB

1 year

Moderate–severe Non-severe SDB

NYHA class II or III

SDB (AHI ≥20/h)

(AHI <20/h)

LVEF <55 %

LVEF 50.2 %

No change in

versus 45.5 %

LVEF, BNP or

(p=0.012)a

CV event-free

BNP 89.9 versus

survival

150.9 (p=0.033)a

↑ CV event-free survival (p=0.032)a

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Sleep Apnoea Table 2. Cont. ASV Versus Control or Baseline Author (Date)

N (ASV)

HF Characteristics

SDB Pattern

ASV Duration

Takama (2011)99

NYHA class II–IV

SDB

6 months

AHI improved to 19.9/h, 11.8/h and 2.4/h in pts with severe (AHI ≥40/h; p<0.0001), moderate (AHI ≥20/h; p<0.0001) or mild (AHI <20/h; p<0.05) SDBb Central AI and obstructive AI significantly improved in severe SDB pts, and obstructive AI in severe SDB pts (all p<0.005)b

SDB Outcomes

HF Outcomes

Yoshihisa (2011)129

Stable NYHA class ≥II

AHI >15/h >50 % central

6 months

AHI 9.0/h versus 38.8/h (p<0.01)b BNP 191.6 versus 499 pg/mL Central AI 1.6/h versus 19.5/h (p<0.05)b (p<0.01)b LVEF 46.4 versus 38.3 % (p<0.05)b ArI 15.9/h versus 24.5/h (p<0.01)b LVEDVI 75.7 versus 84.7 mL/m2 ODI 3 % 5.3/h versus 30.1/h (p<0.01)b (p<0.05)b Sleep efficiency 72.3 versus LVESVI 42.2 versus 56.3 mL/m2 66.7 % (p=0.04)b (p<0.05)b

Campbell (2012)130

Stable LVEF <50 %

CSA/CSR AHI >15/h

8 weeks

AHI 5.0/h versus 19.4/h (p=0.03)a LVEF 35.0 versus 32.5 % (p=0.24)a AHI <10/h in 86 % of pts

Miyata (2012)131

Stable NHYA class ≥II

CSA/CSR AHI >15/h

6 months

AHI 5.9/h versus 39.0/h (p<0.01)b BNP 221 versus 482 pg/mL (p<0.05)b Central AI 0.6/h versus 14.8/h LVEF 36.0 versus 30.5 % (p=0.03)b b (p<0.01) ArI 13.6/h versus 21.9/h (p<0.01)b ODI 3% 3.3/h versus 30.5/h (p<0.01)b

Randerath (2012)132

LVEF ≥20 %

AHI ≥15/h OSA & CSA

1 year

AHI 11.1/h versus 46.8/h (p<0.001)b NT-proBNP 230.4 versus 537.3 ng/L Central AHI 6.1/h versus 23.1/h (p<0.05)b (p<0.001)b Central AI 1.5/h versus 6.3/h (p<0.001)b Minimum SpO2 86.1 % versus 74.3 % (p<0.001)b

Arzt (2013)100

Stable LVEF ≤40 %

SDB AHI ≥20/h

12 weeks

AHI decreased by 39/h with ASV NT-proBNP reduced by 360 ng/mL versus 1/h in controls (p<0.001)a with ASV versus 135 ng/mL increase in controls (p=0.01)a No significant differences in LVEF or QOLa

Kourouklis (2013)102

Stable NYHA class II–III LVEF <40 %

CSA AHI ≥15/h

6 months

AHI 3.5/h versus 43.2/h (p<0.05)b ↑ LVEF (p<0.001)b AI 2.8/h versus 34.1/h (p<0.05)b ↑ NHYA class Central AI 0.2/h versus 2.4/h (p<0.05)b ODI 4.7/h versus 37.7/h (p<0.05)b SpO2 95.4 versus 93.3 % (p<0.05)b

Yoshihisa (2013)92

LVEF >50 %

SDB AHI >15/h

6 months

AHI 6.9/h versus 37.0/h (p<0.0125)b NYHA class 1.5 versus 2.3 Central AI 0.1/h versus 11.9/h (p<0.125)b b (p<0.125) Systolic BP 112.4 versus 124.2 Obstructive AI 0.3/h versus 2.1/h mmHg (p<0.125)b (p<0.125)b HR 63.8 versus 69.6 beats/min Hypopnoea index 2.6/h versus (p<0.125)b 16.4/h (p<0.125)b CAVI 7.7 versus 9.0 (p<0.125)b ArI 14.1/h versus 21.4/h (p<0.125)b BNP 58.1 versus 121.5 pg/mL Lowest SpO2 90.0 versus 77.9 % (p<0.125)b (p<0.125)b Reductions in NYHA class, HR Mean SpO2 96.6 versus 94.3 % and BNP also significant versus (p<0.125)b controls Reductions in AHI and central AI also significant versus controls

Birner (2014)101

Stable NYHA class II or III LVEF ≤40 %

SDB AHI ≥20/h

12 weeks

AHI 11/h versus 43/h (p<0.001)a

↓ BNP in pts with severe (AHI ≥40/h; p<0.05), moderate (AHI ≥20/h; p<0.05) or mild (AHI <20/h; p<0.01) SDBb ↑ LVEF in pts with severe (AHI ≥40/h; p<0.01) or moderate (AHI ≥20/h; p<0.001)b

LVEF 31 versus 32 % (p=0.75)a NT-proBNP 1,163 versus 1,042 ng/ mL (p=0.92)a

compared with control; b compared with baseline; c statistically significant differences also observed for ASV versus 14 days’ oxygen therapy (data not shown). 6MWD = 6-minute walk distance; AHI = apnoea-hypopnoea index; AI = apnoea index; ArI = arousal index; ASV = adaptive servoventilation; BNP = brain natriuretic peptide; BP = blood pressure; CAVI = cardio-ankle vascular index; CO = cardiac output; CSA = central sleep apnoea; CSR = Cheyne–Stokes respiration; CV = cardiovascular; HF = heart failure; HR = heart rate; LAD = left atrial diameter; LVEDD = left ventricular end-diastolic diameter; LVEDVI = left ventricular end-diastolic volume index; LVEF = left ventricular ejection fraction; LVESD = left ventricular end-systolic diameter; LVESVI = left ventricular end-systolic volume index; m = metres; MLHFQ = Minnesota Living with Heart Failure Questionnaire; NR = not reported; NT-proBNP = N-terminal pro-brain natriuretic peptide; NYHA = New York Heart Association; ODI = oxygen desaturation index; pts = patients; QOL = quality of life; SDB = sleep-disordered breathing; SpO2, = oxygen saturation; SV = stroke volume; SWS = slow-wave sleep; TST = total sleep time.

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Sleep-disordered Breathing in Heart Failure – Current State of the Art

Table 3: Summary of Ongoing Mortality Studies Investigating Adaptive Servoventilation in Patients with Heart Failure and Central Sleep Apnoea SERVE-HF109

ADVENT-HF110

CAT-HF111

Chronic symptomatic HF

AHA stage B–D HF

Acute decompensated HF

NYHA class III or IV

LVEF ≤45 %

HF-rEF or HF-pEF

LVEF ≤45 %

OSA or CSA

Sleep apnoea

Predominant CSA

AHI ≥15/h

ASV*

Control (no ASV)*

Multicentre

Randomised (1:1)

Randomised

Parallel

Event-driven sequential

Event-driven

Target enrolment, n

≈1200

860

Follow-up

≥2 years

Primary outcome

Time to first event#

Time to first event¶

Global rank endpoint†

Secondary outcomes

Time to death

6MWD

Time to unplanned hospitalisation

Number of CV hospitalisations/year

NT-proBNP

Pts alive and not hospitalised during f-up

Number of days alive and not hospitalised Biomarkers

Quality of life

LV function

Echocardiography

HF symptoms

Plasma BNP level

Sleep parameters

Health economics

CRT or ICD implantation

ESS

Echocardiography substudy

6MWD

PSQI

% Pts with change in NYHA class

Quality of life

AHI

Health status

Quality of life

Depression

Patient population

AHI >15/h Central AHI ≥10/h Treatment arms Design

215

HF hospitalisation Death Estimated completion

Mid-2015

Dec 2015

Sept 2016

6MWD = 6-minute walk distance; AHA = American Heart Association; AHI = apnoea–hypopnoea index; ASV = adaptive servoventilation; BNP = brain natriuretic peptide; CRT = cardiac resynchronisation therapy; CSA = central sleep apnoea; CV = cardiovascular; ESS = Epworth Sleepiness Scale; f-up = follow-up; HF = heart failure; HF-pEF = HF with preserved ejection fraction; HF-rEF = HF with reduced ejection fraction; ICD = implantable cardioverter defibrillator; LV = left ventricular; LVEF = left ventricular ejection fraction; NT-proBNP, N-terminal probrain natriuretic peptide; NYHA = New York Heart Association; OSA = obstructive sleep apnoea; PSQI = Pittsburgh Sleep Quality Index; pts = patients; *All patients are receiving optimal medical therapy. #Event = all-cause death, unplanned hospitalisation (or unplanned prolongation of a planned hospitalisation) for worsening chronic HF, cardiac transplantation, resuscitation of sudden cardiac arrest or appropriate life-saving shock for ventricular fibrillation and fast ventricular tachycardia in implantable cardioverter defibrillator (ICD) patients. ¶Death or first cardiovascular hospital admission or new onset atrial fibrillation/flutter requiring anti-coagulation but not hospitalisation or delivery of an appropriate shock from an ICD not resulting in hospitalisation. †Rank order response based on survival free from CV hospitalisation and improvement in functional capacity measured by 6MWD.

Treatment of Obstructive Sleep Apnoea CPAP maintains airway patency, enabling patients to breathe spontaneously and avoid intermittent hypoxia.64 Other beneficial cardiac effects in patients with HF include decreases in preload and afterload,65,66 a marked reduction in intrathoracic pressure swings64 and reduced sympathetic activity.67–69 CPAP treatment for OSA lowers BP, improves cardiac function 69–71 as well as quality of life, can decrease the arrhythmic burden, and has been shown to improve survival in a cohort of HF patients, although this evidence does not come from randomised controlled clinical trials.72 There are potential treatment alternatives for specific OSA phenotypes, including weight loss, oral appliances, tonsillectomy and, most recently, implantable devices for upper airway stimulation. However, none of these have been tested in patients with concurrent HF.

HF-rEF and CSA/CSR were reported in three separate publications.75–77 After 12 weeks home oxygen therapy, significant decreases were seen in the AHI (from 21/h at baseline to 10/h; p<0.001), the ODI (from 19.5/h to 5.9/h; p<0.001) and the Specific Anxiety scale score (from 4.0 to 5.0; p<0.001), and LVEF was significantly increased (from 34.7 % to 38.2 %; p=0.022).75 In a separate study, continuing treatment for one year showed that home oxygen therapy was well-tolerated and that the benefits of treatment were maintained over the longer term.76 A post hoc analysis of data from both trials showed that home oxygen therapy had no effect on the number of premature ventricular contractions, although there was evidence of benefit in the subgroup of patients with NYHA class >III and an AHI of >20/h.77 A study conducted in France in a similar patient population also showed that nocturnal oxygen therapy significantly decreased the central AHI and ODI compared with baseline, with treatment effects evident within 12 hours of initiating therapy and persisting during the six-month treatment period.78 In this study, oxygen therapy had no significant effects on the obstructive or mixed AHI values, quality of life or ventricular function.

Treatment of Central Sleep Apnoea Although available information is limited, home oxygen therapy has been shown to have some beneficial effects in patients with CSA and HF, with significant reductions in AHI of about 50 %.73,74 Data from two studies in Japanese patients with New York Heart Association (NYHA) class II or III

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The rationale for testing CPAP in patients with CSA and HF was that improving cardiac function by applying PAP would attenuate central SDB. Positive effects associated with CPAP therapy in patients with HF (usually HF-rEF) and CSR include improved LVEF and reduced AHI,68,79–81

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Sleep Apnoea but other studies have failed to document statistically significant improvement in outcomes when using CPAP to treat HF patients with CSA/CSR.82–84 Given significant heterogeneity between studies in approaches to CPAP titration, it is possible that therapy failure may be due to inadequate titration and inadequate reductions in AHI during treatment. A good example of this is the Canadian Positive Airway Pressure Trial for Heart Failure Patients with Central Sleep Apnea (CANPAP) study, a randomised controlled trial that investigated mortality in patients with HF-rEF and CSA/CSR treated with CPAP. The study was stopped prematurely after enrolment of 258 of the planned 408 when analysis did not show a beneficial effect of CPAP treatment on survival.85 However, a post hoc evaluation suggested that morbidity and mortality might be improved if there was an early and significant reduction in AHI to <15/h during CPAP therapy.86 Other data suggest that even if CPAP therapy is appropriately titrated there may be a subgroup of patients who do not respond to this treatment option.87,88 Meta-analysis showed a residual mean AHI of 15/h across eight included studies despite CPAP treatment.79 This lack of efficacy may limit the utility of CPAP in some HF patients, while others may have issues with tolerability.89 Recommendations vary, with some suggesting that the wide availability of, and familiarity with, CPAP means that this approach should be considered for initial treatment of CSA related to HF,79 while others say that CPAP should not be considered as standard therapy for this indication.9 Even if a CPAP trial is undertaken, an alternative treatment option needs to be considered when there is inadequate apnoea suppression.79

oxygen therapy for treating CSA/CSR in HF,90,105,106 and it has been reported that patients prefer ASV over both CPAP and BPAP.90 In one randomised, open-label study of HF-rEF patients, compliance with therapy (an important aspect of the effectiveness of treatment) was significantly better with ASV compared with CPAP (5.2 versus 4.4 h/night, respectively, p<0.05).108 The influence of effectively treating CSA/CSR in patients with HF-rEF on objective ‘hard’ outcomes such as mortality in randomised clinical trials remains to be determined. Data from the ongoing Treatment of Predominant Central Sleep Apnoea by Adaptive Servo Ventilation in Patients With Heart Failure (SERVE-HF) (NCT00733343),109 Effect of Adaptive Servo Ventilation on Survival and Hospital Admissions in Heart Failure (ADVENT-HF) (NCT01128816)110 and Cardiovascular Improvements With MV ASV Therapy in Heart Failure (CAT-HF) (NCT01953874)111 trials (see Table 3) will help to answer these important questions. A new treatment option for CSA currently under investigation is phrenic nerve stimulation. Preliminary data show that phrenic nerve stimulation with an implantable pacemaker can treat central apnoeas and thus attenuates respiratory abnormalities and reduces AHI by 50 %, but cannot treat hypopnoeas or other respiratory events.112 Trials to evaluate the clinical effect of this method on HF outcomes are not yet available.

Compliance with Positive Airway Pressure Therapy One such alternative for CSA/CSR in HF is ASV. A varying amount of inspiratory pressure (inspiratory positive airway pressure, IPAP) supports inspiration with decreasing breathing amplitude, and can also ensure sufficient inspiration when breathing efforts are absent.90,91 Different technologies use different methods to stabilise the breathing pattern, with monitoring of minute ventilation being the most widely used. ASV also ensures upper airway patency by providing a fixed or variable amount of end-expiratory positive airway pressure (EPAP), so concomitant OSA will also be treated. Given the different ASV devices and algorithms on the market, it is not clear whether effects of one device can be extrapolated to another. There is currently no consensus on whether treatment for CSA in HF should be initiated and what the optimal strategy might be. A number of smaller studies have documented improvements in symptoms, cardiac function, cardiac disease markers, exercise tolerance, short-term prognosis and quality of life when ASV treatment has been used in patients with HF and SDB, including CSR (see Table 2).39,92–102 The majority of studies have been conducted in patients with HF-rEF, but beneficial effects of ASV on respiratory and cardiovascular parameters have also been documented in patients with HF-pEF.92 Data from a recent meta-analysis showed that ASV significantly improved AHI, left ventricular function and exercise capacity compared with control in patients who had CSA and predominantly HF-rEF.103 Beneficial changes in sympathetic nervous system activity assessed by microneurography have also been documented.104 There were significant correlations between changes in the AHI and changes in both sympathetic nervous system activity and LVEF.104 Data from comparative studies provide some indication that ASV is a successful method for treating CSA/CSR in HF,90,105–107 although evidence from randomised controlled parallel-group trials is currently lacking. ASV appears to be more effective than CPAP, BPAP and

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Compliance in the context of PAP therapy refers to the consistency with which a patient uses the prescribed treatment. A number of studies have investigated the level of compliance required by OSA patients for the beneficial effects of CPAP therapy to be achieved, be that improved survival,113 decreases in BP,114–117 or improvements in sleepiness118–121 or memory.122 For example, one study analysing the dose–response relationship between CPAP therapy and cardiovascular mortality found evidence that increased usage correlates with improved survival rates, with a significant difference in five-year survival between patients using CPAP for <1 h/day compared with those using CPAP for 1–6 or >6 h/day.113 Similarly, a per-protocol analysis of randomised clinical trial data suggested that CPAP might reduce the incidence of hypertension or cardiovascular events in patients who were adherent to therapy for ≥4 h/night.123 While these studies were not specifically conducted in HF patients, they suggest that a minimum duration of PAP therapy usage will be required for the beneficial effects of treatment to be realised in HF patients. In addition, the relative lack of SDB symptoms in patients with HF might make compliance with therapy more difficult to achieve, meaning that strategies to improve compliance are more important.

Conclusion SDB is highly prevalent and associated with worse prognosis in all patients with HF, including those with HF-rEF, HF-pEF, chronic disease or acute decompensations. There are a number of treatment options, of which ASV appears to be the most consistently effective, particularly against CSA/CSR. Observational studies indicate that effective treatment of SDB improves functional parameters and surrogate endpoints and is well-tolerated in HF patients with SDB. Data from ongoing randomised clinical trials will further clarify the effects of treating SDB in HF on morbidity and mortality as well as healthcare utilisation. It is anticipated that treatment of co-morbidities such as SDB will become an important part of tailored HF therapy in the near future. n

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Sleep-disordered Breathing in Heart Failure – Current State of the Art

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Relationship between beta-blocker treatment and the severity of central sleep apnea in chronic heart failure. Chest 2007;131(1):130–5. 50. Harun NS, Leet A, Naughton MT. Improvement in sleepdisordered breathing after insertion of left ventricular assist device. Ann Am Thorac Soc 2013;10(3):272–3. 51. Schaffer SA, Bercovitch RS, Ross HJ, Rao V. Central sleep apnea interfering with adequate left ventricular filling in a patient with left ventricular assist device. J Clin Sleep Med 2013;9(2):161–2. 52. Chen H, Lowe AA, Bai Y, et al. Evaluation of a portable recording device (ApneaLink) for case selection of obstructive sleep apnea. Sleep Breath 2009;13(3):213–9. 53. Clark AL, Crabbe S, Aziz A, et al. Use of a screening tool for detection of sleep-disordered breathing. J Laryngol Otol 2009;123(7):746–9. 54. Erman MK, Stewart D, Einhorn D, et al. Validation of the ApneaLink for the screening of sleep apnea: a novel and simple single-channel recording device. J Clin Sleep Med 2007;3(4):387–92. 55. Dingli K, Coleman EL, Vennelle M, et al. Evaluation of a portable device for diagnosing the sleep apnoea/hypopnoea syndrome. Eur Respir J 2003;21(2):253–9. 56. Pinna GD, Robbi E, Pizza F, et al. Can cardiorespiratory polygraphy replace portable polysomnography in the assessment of sleep-disordered breathing in heart failure patients? Sleep Breath 2014;18(3):475–82. 57. Quintana-Gallego E, Villa-Gil M, Carmona-Bernal C, et al. Home respiratory polygraphy for diagnosis of sleep-disordered

breathing in heart failure. Eur Respir J 2004;24(3):443–8. 58. Arzt M, Young T, Finn L, et al. Sleepiness and sleep in patients with both systolic heart failure and obstructive sleep apnea. Arch Int Med 2006;166(16):1716–22. 59. Isakson SR, Beede J, Jiang K, et al. Prevalence of sleep disordered breathing in congestive heart failure as determined by ApneaLink, a simplified screening device. Sleep Diagnosis Ther 2008;3(7):52–7. 60. Masa JF, Corral J, Pereira R, et al. Effectiveness of home respiratory polygraphy for the diagnosis of sleep apnoea and hypopnoea syndrome. Thorax 2011;66(7):567–73. 61. Gutleben K-J, Fox H, Bitter T, et al. Cardiac or other implantable electronic devices and sleep-disordered breathing – implications for diagnosis and therapy. Arrhyth Electrophysiol Rev 2014;3(2):3. 62. Qaseem A, Dallas P, Owens DK, et al. Diagnosis of obstructive sleep apnea in adults: a clinical practice guideline from theAmerican College of Physicians. Ann Intern Med 2014;161(3):210–20. 63. Shahar E, Whitney CW, Redline S, et al. Sleep-disordered breathing and cardiovascular disease: cross-sectional results of the Sleep Heart Health Study. Am J Respir Crit Care Med 2001;163:19–25. 64. Oldenburg O. Cheyne-stokes respiration in chronic heart failure. Treatment with adaptive servoventilation therapy. Circ J 2012;76(10):2305–17. 65. Lenique F, Habis M, Lofaso F, et al. Ventilatory and hemodynamic effects of continuous positive airway pressure in left heart failure. Am J Respir Crit Care Med 1997;155(2):500–5. 66. Tkacova R, Rankin F, Fitzgerald FS, et al. Effects of continuous positive airway pressure on obstructive sleep apnea and left ventricular afterload in patients with heart failure. Circulation 1998;98(21):2269–75. 67. Kaye DM, Mansfield D, Aggarwal A, et al. Acute effects of continuous positive airway pressure on cardiac sympathetic tone in congestive heart failure. Circulation 2001;103(19):2336–8. 68. Naughton MT, Benard DC, Liu PP, et al. Effects of nasal CPAP on sympathetic activity in patients with heart failure and central sleep apnea. Am J Respir Crit Care Med 1995;152(2):473–9. 69. Usui K, Bradley TD, Spaak J, et al. Inhibition of awake sympathetic nerve activity of heart failure patients with obstructive sleep apnea by nocturnal continuous positive airway pressure. J Am Coll Cardiol 2005;45(12):2008–11. 70. Kaneko Y, Floras JS, Usui K, et al. Cardiovascular effects of continuous positive airway pressure in patients with heart failure and obstructive sleep apnea. N Engl J Med 2003;348(13):1233–41. 71. Mansfield DR, Gollogly NC, Kaye DM, et al. Controlled trial of continuous positive airway pressure in obstructive sleep apnea and heart failure. Am J Respir Crit Care Med 2004;169(3):361–6. 72. Kasai T, Narui K, Dohi T, et al. Prognosis of patients with heart failure and obstructive sleep apnea treated with continuous positive airway pressure. Chest 2008;133(3):690–6. 73. Krachman SL, Nugent T, Crocetti J, et al. Effects of oxygen therapy on left ventricular function in patients with CheyneStokes respiration and congestive heart failure. J Clin Sleep Med 2005;1(3):271–6. 74. Arzt M, Schulz M, Wensel R, et al. Nocturnal continuous positive airway pressure improves ventilatory efficiency during exercise in patients with chronic heart failure. Chest 2005;127(3):794–802. 75. Sasayama S, Izumi T, Seino Y, et al. Effects of nocturnal oxygen therapy on outcome measures in patients with chronic heart failure and cheyne-stokes respiration. Circ J 2006;70(1):1–7. 76. Sasayama S, Izumi T, Matsuzaki M, et al. Improvement of quality of life with nocturnal oxygen therapy in heart failure patients with central sleep apnea. Circ J 2009;73(7):1255–62. 77. Nakao YM, Ueshima K, Yasuno S, et al. Effects of nocturnal oxygen therapy in patients with chronic heart failure and central sleep apnea: CHF-HOT study. Heart Vessels 2014 [Epub ahead of print]. 78. Bordier P, Orazio S, Hofmann P, et al. Short- and long-term effects of nocturnal oxygen therapy on sleep apnea in chronic heart failure. Sleep Breath 2014 [Epub ahead of print]. 79. Aurora RN, Chowdhuri S, Ramar K, et al. The treatment of central sleep apnea syndromes in adults: practice parameters with an evidence-based literature review and meta-analyses. Sleep 2012;35(1):17–40. 80. Naughton MT, Rahman MA, Hara K, et al. Effect of continuous positive airway pressure on intrathoracic and left ventricular transmural pressures in patients with congestive heart failure. Circulation 1995;91:1725–31. 81. Tkacova R, Liu PP, Naughton MT, Bradley TD. Effect of continuous positive airway pressure on mitral regurgitant fraction and atrial natriuretic peptide in patients with heart failure. J Am Coll Cardiol 1997;30:739–45. 82. Buckle P, Millar T, Kryger M. The effect of short-term nasal CPAP on Cheyne-Stokes respiration in congestive heart failure. Chest 1992;102(1):31–5. 83. Davies RJ, Harrington KJ, Ormerod OJ, Stradling JR. Nasal continuous positive airway pressure in chronic heart failure with sleep-disordered breathing. Am Rev Respir Dis 1993;147(3):630–4. 84. Sin D, Logan A, Fitzgerald F, et al. Effects of continuous positive airway pressure on cardiovascular outcomes in heart failure patients with and without Cheyne-Stokes respiration.

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Sleep Apnoea Circulation 2000;102:61–6. 85. Bradley TD, Logan AG, Kimoff RJ, et al. Continuous positive airway pressure for central sleep apnea and heart failure. N Engl J Med 2005;353(19):2025–33. 86. Arzt M, Floras JS, Logan AG, et al. Suppression of central sleep apnea by continuous positive airway pressure and transplant-free survival in heart failure: a post hoc analysis of the Canadian Continuous Positive Airway Pressure for Patients with Central Sleep Apnea and Heart Failure Trial (CANPAP). Circulation 2007;115(25):3173–80. 87. Dohi T, Kasai T, Narui K, et al. Bi-level positive airway pressure ventilation for treating heart failure with central sleep apnea that is unresponsive to continuous postitive airway pressure. Circ J 2008;72:1100–5. 88. Javaheri S. Effects of continuous positive airway pressure on sleep apnea and ventricular irritability in patients with heart failure. Circulation 2000;101:392–7. 89. Lévy P, Ryan S, Oldenburg O, Parati G. Sleep apnoea and the heart. Eur Respir Rev 2013;22:333–52. 90. Teschler H, Dohring J, Wang YM, Berthon-Jones M. Adaptive pressure support servo-ventilation: a novel treatment for Cheyne-Stokes respiration in heart failure. Am J Respir Crit Care Med 2001;164(4):614–9. 91. Oldenburg O, Spiesshofer J, Fox H, et al. Performance of conventional and enhanced adaptive servoventilation (ASV) in heart failure patients with central sleep apnea who have adapted to conventional ASV. Sleep Breath 2014 [Epub ahead of print]. 92. Yoshihisa A, Suzuki S, Yamaki T, et al. Impact of adaptive servo-ventilation on cardiovascular function and prognosis in heart failure patients with preserved left ventricular ejection fraction and sleep-disordered breathing. Eur J Heart Fail 2013;15(5):543–50. 93. Hastings PC, Vazir A, Meadows GE, et al. Adaptive servoventilation in heart failure patients with sleep apnea: a real world study. Int J Cardiol 2010;139(1):17–24. 94. Pepperell JC, Maskell NA, Jones DR, et al. A randomized controlled trial of adaptive ventilation for CheyneStokes breathing in heart failure. Am J Respir Crit Care Med 2003;168(9):1109–14. 95. Töpfer V, El-Sebai M, Wessendorf TE, et al. [Adaptive servoventilation: effect on Cheyne-Stokes-Respiration and on quality of life]. Pneumologie 2004;58(1):28–32. 96. Schädlich S, Königs I, Kalbitz F, et al. [Cardiac efficiency in patients with Cheyne-Stokes respiration as a result of heart insufficiency during long-term nasal respiratory treatment with adaptive servo ventilation (AutoSet CS)]. Z Kardiol 2004;93(6):454–62. 97. Zhang XL, Yin KS, Li XL, et al. Efficacy of adaptive servoventilation in patients with congestive heart failure and Cheyne-Stokes respiration. Chin Med J (Engl) 2006;119(8):622–7. 98. Koyama T, Watanabe H, Igarashi G, et al. Short-term prognosis of adaptive servo-ventilation therapy in patients with heart failure. Circ J 2011;75(3):710–2. 99. Takama N, Kurabayashi M. Effectiveness of adaptive servo-ventilation for treating heart failure regardless of the severity of sleep-disordered breathing. Circ J 2011;75(5):1164–9. 100. Arzt M, Schroll S, Series F, et al. Auto-servoventilation in heart failure with sleep apnoea: a randomised controlled trial. Eur Respir J 2013;42(5):1244–54. 101. Birner C, Series F, Lewis K, et al. Effects of auto-servo

Cowie_FINAL.indd 24

ventilation on patients with sleep-disordered breathing, stable systolic heart failure and concomitant diastolic dysfunction: subanalysis of a randomized controlled trial. Respiration 2014;87(1):54–62. 102. Kourouklis SP, Vagiakis E, Paraskevaidis IA, et al. Effective sleep apnoea treatment improves cardiac function in patients with chronic heart failure. Int J Cardiol 2013;168(1):157–62. 103. Sharma BK, Bakker JP, McSharry DG, et al. Adaptive servoventilation for treatment of sleep-disordered breathing in heart failure: a systematic review and meta-analysis. Chest 2012;142(5):1211–21. 104. Joho S, Oda Y, Ushijima R, et al. Effect of adaptive servoventilation on muscle sympathetic nerve activity in patients with chronic heart failure and central sleep apnea. J Card Fail 2012;18(10):769–75. 105. D’Elia E, Vanoli E, La Rovere MT, et al. Adaptive servo ventilation reduces central sleep apnea in chronic heart failure patients: beneficial effects on autonomic modulation of heart rate. J Cardiovasc Med (Hagerstown) 2013;14(4):296–300. 106. Fietze I, Blau A, Glos M, et al. Bi-level positive pressure ventilation and adaptive servo ventilation in patients with heart failure and Cheyne-Stokes respiration. Sleep Med 2008;9(6):652–9. 107. Oldenburg O, Bitter T, Prib N, et al. Performance of ASV and enhanced ASV in HF patients with CSA. Sleep 2012;35(Suppl):A176. 108. Kasai T, Usui Y, Yoshioka T, et al. Effect of flow-triggered adaptive servo-ventilation compared with continuous positive airway pressure in patients with chronic heart failure with coexisting obstructive sleep apnea and CheyneStokes respiration. Circ Heart Fail 2010;3(1):140–8. 109. Cowie MR, Woehrle H, Wegscheider K, et al. Rationale and design of the SERVE-HF study: treatment of sleep-disordered breathing with predominant central sleep apnoea with adaptive servo-ventilation in patients with chronic heart failure. Eur J Heart Fail 2013;15(8):937–43. 110. Clinicaltrials.gov. Effect of adaptive servo ventilation (ASV) on survival and hospital admissions in heart failure (NCT01128816), 2013. Available at: https://clinicaltrials.gov/ ct2/show/NCT01128816 (Accessed 27 September 2013). 111. Cardiovascular improvements with MV ASV therapy in heart failure (CAT-HF). Available at: https://clinicaltrials.gov/ct2/ show/NCT01953874 (accessed 25 February 2015). 112. Ponikowski P, Javaheri S, Michalkiewicz D, et al. Transvenous phrenic nerve stimulation for the treatment of central sleep apnoea in heart failure. Eur Heart J 2012;33(7):889–94. 113. Campos-Rodriguez F, Peña-Griñan N, Reyes-Nuñez N, et al. Mortality in obstructive sleep apnea-hypopnea patients treated with positive airway pressure. Chest 2005;128(2):624–33. 114. Barbé F, Durán-Cantolla J, Capote F, et al. Long-term effect of continuous positive airway pressure in hypertensive patients with sleep apnea. Am J Respir Crit Care Med 2010;181(7):718–26. 115. Durán-Cantolla J, Aizpuru F, Montserrat JM, et al. Continuous positive airway pressure as treatment for systemic hypertension in people with obstructive sleep apnoea: randomised controlled trial. BMJ 2010;341:c5991. 116. Lozano L, Tovar JL, Sampol G, et al. Continuous positive airway pressure treatment in sleep apnea patients with resistant hypertension: a randomized, controlled trial. J Hypertens

2010;28(10):2161–8. 117. Montesi SB, Edwards BA, Malhotra A, Bakker JP. The effect of continuous positive airway pressure treatment on blood pressure: a systematic review and meta-analysis of randomized controlled trials. J Clin Sleep Med 2012;8(5):587–96. 118. Barnes M, Houston D, Worsnop CJ, et al. A randomized controlled trial of continuous positive airway pressure in mild obstructive sleep apnea. Am J Respir Crit Care Med 2002;165(6):773–80. 119. Engleman HM, Douglas NJ. Sleep. 4: Sleepiness, cognitive function, and quality of life in obstructive sleep apnoea/ hypopnoea syndrome. Thorax 2004;59(7):618–22. 120. Stradling JR, Davies RJ. Is more NCPAP better? Sleep 2000;23 Suppl 4:S150–3. 121. Weaver TE, Maislin G, Dinges DF, et al. Relationship between hours of CPAP use and achieving normal levels of sleepiness and daily functioning. Sleep 2007;30(6):711–9. 122. Zimmerman ME, Arnedt JT, Stanchina M, et al. Normalization of memory performance and positive airway pressure adherence in memory-impaired patients with obstructive sleep apnea. Chest 2006;130(6):1772–8. 123. Barbé F, Durán-Cantolla J, Sánchez-de-la-Torre M, et al. Effect of continuous positive airway pressure on the incidence of hypertension and cardiovascular events in nonsleepy patients with obstructive sleep apnea: a randomized controlled trial. JAMA 2012;307(20):2161–8. 124. Philippe C, Stoïca-Herman M, Drouot X, et al. Compliance with and effectiveness of adaptive servoventilation versus continuous positive airway pressure in the treatment of Cheyne-Stokes respiration in heart failure over a six month period. Heart 2006;92(3):337–42. 125. Szollosi I, O’Driscoll DM, Dayer MJ, et al. Adaptive servoventilation and deadspace: effects on central sleep apnoea. J Sleep Res 2006;15(2):199–205. 126. Bitter T, Westerheide N, Faber L, et al. Adaptive servoventilation in diastolic heart failure and Cheyne-Stokes respiration. Eur Respir J 2010;36(2):385–92. 127. Haruki N, Takeuchi M, Kaku K, et al. Comparison of acute and chronic impact of adaptive servo-ventilation on left chamber geometry and function in patients with chronic heart failure. Eur J Heart Fail 2011;13(10):1140–6. 128. Oldenburg O, Bitter T, Lehmann R, et al. Adaptive servoventilation improves cardiac function and respiratory stability. Clin Res Cardiol 2011;100(2):107–15. 129. Yoshihisa A, Shimizu T, Owada T, et al. Adaptive servo ventilation improves cardiac dysfunction and prognosis in chronic heart failure patients with Cheyne-Stokes respiration. Int Heart J 2011;52(4):218–23. 130. Campbell AJ, Ferrier K, Neill AM. Effect of oxygen versus adaptive pressure support servo-ventilation in patients with central sleep apnoea-Cheyne Stokes respiration and congestive heart failure. Intern Med J 2012;42(10):1130–6. 131. Miyata M, Yoshihisa A, Suzuki S, et al. Adaptive servo ventilation improves Cheyne-Stokes respiration, cardiac function, and prognosis in chronic heart failure patients with cardiac resynchronization therapy. J Cardiol 2012;60(3):222–7. 132. Randerath WJ, Nothofer G, Priegnitz C, et al. Long-term auto-servoventilation or constant positive pressure in heart failure and coexisting central with obstructive sleep apnea. Chest 2012;142(2):440–7.

CARDIAC FAILURE REVIEW

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Left Ventricular Assist Devices

LE ATION.

e. lare.

Left Ventricular Assist Devices in the Management of Heart Failure E d o Y B i ra t i a n d M a r i e l l J e s s u p Cardiovascular Division, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania

Abstract Mechanical circulatory support has emerged as an important therapy for advanced heart failure, with more than 18,000 continuous flow devices implanted worldwide to date. These devices significantly improve survival and quality of life and should be considered in every patient with end-stage heart failure with reduced ejection fraction who has no other life-limiting diseases. All candidates for device implantation should undergo a thorough evaluation in order to identify those who could benefit from device implantation. Long-term management of ventricular assist device patients is challenging and requires knowledge of the characteristic complications with their unique clinical presentations.

Keywords Ventricular assist device, complication, patient selection, advanced heart failure, mechanical circulatory support Disclosure: Edo Y. Birati received research and fellowship support from HeartWare Ltd. Mariell Jessup has no relevant disclosures. Received: 23 February 2015 Accepted: 4 March 2015 Citation: Cardiac Failure Review, 2015;1(1):25–30 Correspondence: Mariell Jessup, MD, Hospital of the University of Pennsylvania, 2 East Perelman Pavilion, 3400 Civic Center Boulevard, Philadelphia, PA 19104, US. E: jessupm@uphs.upenn.edu

Heart failure (HF) is a leading cause of morbidity and mortality worldwide, affecting 1–2 % of the adult population in western countries with incidence of 5–10 per 1000 persons per year.1,2 It is estimated that the prevalence of HF will continue to increase as the population ages and, according to the American Heart Association (AHA), by the year 2030 the prevalence of HF in the US alone will rise to over 8 million patients, representing a 25 % increase compared to the year 2010.3 HF is one of the common causes for hospitalisation, representing 1–2 % of all hospital admissions and the leading reason for admission in individuals above 65 years of age.4–6 HF is a progressive disease7 with approximately 5 % of HF patients suffer from end-stage disease refractory to medical therapy.8,9 The Heart Failure Association of the European Society of Cardiology (ESC) defined advanced HF as a state in which patients have significant cardiac dysfunction with severe HF symptoms, such as dyspnoea and/or fatigue, occurring at rest or with minimal exertion (NYHA functional class III or IV) despite maximal medical and device (cardiac resynchronisation therapy) therapy.10 In addition to the aforementioned symptoms, patients with advanced HF usually have objective measurements of peak VO2 (oxygen uptake) <14mL/kg/min, a 6-minute walk distance <300 meters, and poor cardiac function.10,11 The prognosis of patients with advanced HF is dismal, with life expectancy of less than two years.11,12 At this stage, advanced therapies are considered, including heart transplantation, continuous inotropic therapy, mechanical circulatory support or hospice.1,10,11 Heart transplantation remains the preferable therapy for advanced HF, but the number of transplants done worldwide is trivial compared to demand.13 Thus, durable mechanical circulatory support (MCS) devices have emerged as an important therapy for advanced HF.13,14 To date, over 18,000 continuous flow devices have been implanted worldwide.13,14 In the US alone, 131 hospital centres are approved to implant permanent MCS devices, demonstrating the staggering expansion of MCS as a therapeutic option for end-stage HF.15

Jessup_FINAL.indd 25

The Nomenclature of MCS A ventricular assist device (VAD) is a MCS device that is used to partially or completely support the function of a failing heart. Left ventricular assist devices (LVAD) pump blood from the left ventricle and transfer it to the ascending aorta. LVADs may be used as a bridge to transplant (BTT) for candidates awaiting heart transplantation; as destination therapy (DT) for patients who are not candidates for transplantation; as a bridge to decision for patients too sick to survive the transplant evaluation (so that their suitability for transplantation has not been determined at the time of VAD implantation) and as a bridge to recovery for selected patients who might recover their cardiac function. The latter patients are mostly those with acute cardiomyopathies (ie. fulminant lymphocytic myocarditis, peripartum cardiomyopathy, etc). 11 Interestingly, according to the Sixth annual report of the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) the proportion of patients treated with LVAD as DT in the United Sates has increased from 14.7 % in 2006–7 to 41.6 % in 2011–13.14 The first-generation VADs had pulsatile flow, designed to mimic the normal function of the heart. These devices were shown to increase survival and quality of life (QoL) of patients with end-stage HF compared to optimal medical therapy (OMT).16 The second and third generation devices currently in use (primarily HeartMate II, Thoratec Corp. and HVAD, HeartWare Ltd., see Figure 1), have continuous flow patterns, and can generate up to 10 litres/minute. Although these devices generate continuous flow, pulsatility may still be present in some patients since the flow delivered by the device is modified by native left ventricular (LV) contractility. Nevertheless, some studies suggest that pulsatile flow is not necessary for adequate perfusion of the end organs.17 In the ‘HeartMate II’ trial, treatment with continuous-flow HeartMate II devices as DT was associated with improved survival compared to

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Left Ventricular Assist Devices Figure 1: Second and Third Generation Devices Currently in Use A

A. HeartMate II device; B. HeartWare HVAD. A. Courtesy of Thoratec, Pleasanton, CA; with permission; B. Courtesy of HeartWare, Framingham, MA.

Table 1: American Heart Association Recommendations for Mechanical Circulatory Support Class of Rec. MCS for BTT indication should be considered for transplant-

eligible patients with end-stage HF who are failing optimal medical, surgical, and/or device therapies and at high risk of dying before receiving a heart transplantation. Implantation of MCS in patients before the development

IIa

of advanced HF (ie, hyponatraemia, hypotension, renal

To evaluate whether ‘real life’ outcomes are similar to those observed in the clinical trials, Jorde et al.19 followed the first 247 patients treated with HeartMate II devices as DT who were not in a clinical trial and compared their outcome with those achieved in the clinical trials. Survival in the later group trended to be better than in the initial clinical trial, with an absolute difference of 74 % versus 68 % at 1 year and 61 % versus 58 % at 2 years (p=0.2). Moreover, the rate of survival free of stroke (both haemorrhagic and ischaemic), device-related infection, or pump replacement was significantly higher in patients treated in the later group.19 These results are consistent with the outcomes summarised in the Sixth INTERMCAS annual report of 80 % 1-year survival and 70 % 2-year survival. 14 Treatment with the HeartWare HVAD device as a bridge to transplantation (BTT) was evaluated in the ADVANCE (HeartWare Ventricular Assist Device Bridge to Transplant) trial.20 In this study, the HeartWare HVAD device was compared to ‘commercially available devices’, mainly HeartMate II, in patients awaiting heart transplantation. The HVAD device was non-inferior to the HeartMate device with 1-year survival of 86 % and enhanced QoL and functional capacity similar to what was seen with the HeartMate II. 20 The safety and effectiveness of HeartWare HVAD as DT is being evaluated in the ENDURANCE trial, yet to be published.

Patient Selection LVAD therapy should be considered in every patient with endstage systolic (low LV ejection fraction) HF who has no other life-limiting diseases. Tables 1 and 2 summarise the current MCS recommendation from the AHA and the ESC. Table 3 details the indications and contraindication for MCS.

dysfunction, and recurrent hospitalisations) is associated with better outcomes. Therefore, early referral of advanced HF patients is reasonable. MCS with a durable, implantable device for permanent therapy

or DT is beneficial for patients with advanced HF, high one-year mortality resulting from HF, and the absence of other life-limiting organ dysfunction; who are failing medical, surgical, and/or device therapies; and who are ineligible for heart transplantation. Patients who are ineligible for heart transplantation

IIa

because of pulmonary hypertension related to HF alone should be considered for bridge to potential transplant eligibility with durable, long-term MCS. Careful assessment of RV function is recommended as

part of the evaluation for patient selection for durable, long-term MCS. Long-term MCS is not recommended in patients with

III

advanced kidney disease in whom renal function is unlikely to recover despite improved haemodynamics and who are therefore at high risk for progression to renal replacement therapy. Evaluation of potential candidates by a multidisciplinary

team is recommended for the selection of patients for MCS BTT = bridge to transplant; HF = heart failure; DT = destination therapy; MCS = mechanical circulatory support; Rec. = Recommendation; RV = right ventricle. Adapted from Peura JL, et al.11 and published with the permission of the American Heart Association.

pulsatile-flow devices.18 In addition, patients treated with continuous flow-devices as DT had a significant reduction in the rate of adverse events and hospitalisations and had improved QoL and functional capacity compared to patients treated with pulsatile-flow devices. 18

Jessup_FINAL.indd 26

A MCS evaluation is essential to identify those patients who could benefit from device implantation, and to exclude those considered futile for device therapy. The first step in patient selection is to accurately estimate the clinical severity of the HF syndrome. Many US clinicians 22 recommend the use of two prognostic scores, the Heart Failure Survival Score 23 and the Seattle Heart Failure Model, 24 to estimate the expected two-year survival on medical therapy in candidates who might benefit from LVAD support. 22 The ESC recommend assessing the patient’s prognosis using variables that have been shown to predict outcome, such as findings in history and physical examination (NYHA class, blood pressure, signs of congestions, etc.), laboratory tests (serum sodium, liver enzymes, troponins, etc.), neuro-hormonal activity (Plasma renin activity, Angiotensin II, etc.), and functional (peak VO2) and haemodynamic variables. 10,21 Likewise, it is now apparent that there are many phenotypes of advanced HF, which have been described with the INTERMACS profiles, a classification of 7 clinical profiles (see Table 4). 25 Patients with INTERMACS profile 1 to 3 are being managed with temporary mechanical or inotropic support, whereas patients with profile 4 to 7 are not inotrope dependent.11,25 The INTERMACS profiles have been shown to provide prognostic information and guidance for the optimal timing and the associated risk of implantation. 26,27 For example, INTERMACS profile 1 or 2 patients who are treated with LVAD have a 44 % higher post-implantation mortality than that of patients at INTERMACS profile 3 or 4. 27 In addition, several risk scores have been developed for the estimation of short-term mortality after LVAD implantation.11,22 The ‘Lietz-Miller score’ was the most frequently used risk score for DT patients (see

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

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Left Ventricular Assist Devices in the Management of Heart Failure

Table 2: European Society of Cardiology Recommendations For Mechanical Circulatory Support Class of Rec. An LVAD or BiVAD is recommended in selected patients

Table 4: INTERMACS Profiles

Profiles

Brief Description

Details

INTERMACS 1

Critical cardiogenic shock

Life-threatening hypotension

(Crash and burn)

despite rapidly escalating

with end-stage HF despite optimal pharmacological and

inotropic support.

device treatment and who are otherwise suitable for heart

INTERMACS 2

transplantation, to improve symptoms and reduce the risk of HF hospitalisation for worsening HF and to reduce the risk of

INTERMACS 3

premature death while awaiting transplantation. An LVAD should be considered in highly selected patients

IIa

who have end-stage HF despite optimal pharmacological

INTERMACS 4

and device therapy and who are not suitable for heart

Progressive decline (Sliding

Declining function despite

fast on inotropes)

intravenous inotropic support.

Stable but inotrope dependent Stable on continuous (Dependent stability)

intravenous inotropic support.

Resting symptoms on oral

Patient experiences daily

therapy at home

symptoms of congestion at rest or during activities of

transplantation, but are expected to survive >1 year with good functional status, to improve symptoms, and reduce the risk of HF hospitalisation and of premature death.

daily living. INTERMACS 5

Patient is comfortable at rest

Exertion intolerant

and with activities of daily

Rec. = Recommendation; HF = Heart failure; LVAD = left ventricular assist device; BiVAD = bi-ventricular assist device. Adapted from McMurray et al.21 with the permission of Oxford University Press (UK), © European Society of Cardiology, www.escardio.org/guidelines

living but unable to engage in any other activity. INTERMACS 6

Table 3: Indication and Contra-indication for Durable Mechanical Circulatory Support Absolute Contraindications

Frequent hospitalisations for HF

Irreversible hepatic disease

Intolerance to neurohormonal antagonists

Irreversible renal disease

NYHA IIIb–IV functional limitations despite Irreversible neurological disease

Patient has fatigue after

wounded)

the first few minutes of any meaningful activity.

INTERMACS 7 Indications

Exertion limited (Walking

Advanced NYHA class III

Patients living comfortably

(Placeholder)

with meaningful activity limited to mild physical exertion.

INTERMACS: Interagency Registry for Mechanically Assisted Circulatory Support; NYHA = New York Heart Association. Adapted from: Stevenson LW, et al.25

OMT End-organ dysfunction owing to low CO

Medical nonadherence

Increasing diuretic requirement

Severe psychosocial limitations

CRT nonresponder

Table 5: Risk Factors for Post-implant 90-Day Survival The Lietz Model Risk Factor

Score

Risk Category

Platelet <148x103/μl

Very high risk >19 17.9 %

Low peak Vo2 (<14mL/kg/min)

Alb ≤3.3 g/dL

HF = Heart failure; OMT = optimal medical therapy; NYHA = New York Heart Association; CO = cardiac output; CRT = cardiac resynchronisation therapy. Adapted from Peura et al.11 and published with the permission of the American Heart Association.

INR > 1.1

Vasodilator therapy

Mean PAP ≤25 mm Hg

AST > 45 U/mL

Hct ≤34 %

BUN >51 U/dL

No IV inotropes

Inotrope dependence

Table 5) 28, but is now limited in use as it was developed on the first generation HeartMate XVE device.28 The second step in the evaluation is to search for significant co-morbidities and other factors that might limit the patient’s suitability.11 This search should include the possibility of reversible causes of heart failure (for example: obstructive sleep apnoea), metabolic stress testing when feasible (stress tests are contra-indicated in patients on inotropes), invasive haemodynamic evaluation, laboratory evaluation of organ function including lungs (pulmonary function tests), renal, liver, and haematologic function. All patients should undergo a psychosocial evaluation to estimate patient psychological status, risk for substance abuse, compliance to treatment and supporting environment.22,29 Right ventricular (RV) failure is a leading cause of mortality after LVAD implantation,22 since LVAD optimal function relies on adequate filling of the left ventricle (LVAD preload), which in turn is dependent on RV function. Many studies have tried to predict which patients are at risk for RV failure after LVAD implantation.30–36 Table 6 summarises the major published predictors of post implant RV failure. The final step in evaluating LVAD candidates is an estimation of a patient’s overall frailty. Frailty was originally a geriatric term defined

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Jessup_FINAL.indd 27

High risk – 17–19

90-day Survival

38.9 %

Medium risk: 9–16 86.5 %

Low risk <9

93.7 %

INR = International normalisation ratio; alb = albumin; PAP = pulmonary artery pressures; AST = Aspartate aminotransferase; Hct = Haematocrit; BUN = Blood urea nitrogen; IV = intravenous. Adapted from Lietz K, et al.28

as a state of vulnerability to adverse outcomes and decreased physiologic reserve, reflecting the biologic rather than chronologic age.37,38 Frailty is very common among HF patients and adversely affects prognosis39,40. In LVAD patients, frailty is associated with higher post-implant complication rates and mortality.38,41

LVAD Complications Patients treated with long-term MCS may develop characteristic complications associated with the implantation of the VAD.

VAD Thrombosis VAD thrombosis, one of the most devastating complications of MCS, is defined as the development of a blood clot within one component of the device, including the inflow cannula, outflow cannula, and the rotor despite anticoagulation and antiplatelet therapy.42 Since 2011, for unknown reasons, there has been a reported abrupt increase in the incidence of HeartMate II VAD thrombosis from 2.2 % before 2011 to 8.4 % in 2013.42 Device thrombosis is also a complication in

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Left Ventricular Assist Devices Table 6: Pre-implant Predictors of Acute Right Ventricle Failure

Figure 2: The Clinical Presentation of Ventricular Assist Device Thrombosis

Comment Echocardiographic

RVEDV > 200 ml

findings

RVESV > 177 ml RV free wall strain RV fractional area change

Haemodynamics

RVSWI<600 – 38 % risk of

TPG>15 mmHg

RV failure

CVP >15 mmHg

RVSWI > 900 – 3 % risk

RVSWI < 300 mmHg.ml/m2

for RV failure.

CVP / PCWP ratio >0.63 Clinical

On vassopressors

Need for vassopressors

Cardiogenic shock and death

Pre-op mechanical ventilation

HeartWare HVAD devices, reported to occur in 8.1 % of the patients.43 However, unlike the increase in the incidence of HeartMate II VAD thrombosis, the incidence of HeartWare HVAD thrombosis has remained stable since 2008.43,44 With the growth in the number of patients treated with LVAD, the magnitude of this complication will continue to rise if there is no deployable strategy to mitigate the risk of pump thrombosis.45 VAD thrombosis has more than one clinical presentation, and can involve a wide spectrum of clinical features, ranging from an asymptomatic patient to one with refractory cardiogenic shock and subsequent death.45 The various clinical presentations are detailed in Figure 2. Even early stages of VAD thrombosis may cause haemolysis that can be identified with elevated lactate dehydrogenase (LDH) levels, indirect bilirubin and plasma free haemoglobin (PFHg) levels.22 Uriel et al.46 reported that an LDH higher than five times normal was 100 % sensitive and 92 % specific for the diagnosis of pump thrombosis46, but our series argue that any value above the normal LDH range can imply VAD thrombosis.45 Patients with a suspected diagnosis of VAD thrombosis should be started on intravenous heparin, unless contraindicated; patients with highly suspected VAD thrombosis should be considered for pump exchange.47 Starling et al.42 showed that the six-month mortality of HeartMate II patients treated with device replacement was similar to the mortality of patients who did not have pump thrombosis.42 In patients with HeartWare HVAD thrombosis it is reasonable to start thrombolysis if the patient is haemodynamically stable and has no contraindications for thrombolytic therapy. However, if the HVAD patient does not improve clinically or suffer from haemodynamic instability, pump replacement should be considered.47

Acute Right Ventricular Failure Acute RV failure is a frequent complication, occurring in 20–50 % of patients following LVAD implantation, and is associated with increased morbidity and mortality.48–50 Acute RV failure post-LVAD

Jessup_FINAL.indd 28

MPTOMATI ASY C

RVEDV = Right ventricle end diastolic volume; RVESV = Right ventricle end systolic volume; RV = right ventricle; AST = aspartate aminotransferase; WBC = white blood count; PVR = pulmonary vascular resistance; TPG = trans-pulmonary gradient; CVP = central venous pressure; RVSWI = Right ventricle stroke work index. Equal to the stroke volume index multiplied by the difference between the mean pulmonary artery pressure and the mean right pressure.30–36

RV F ailu re

PVR >4 woods unit

ias

Haematocrit <31 %

monary Congest Pul ion

WBC > 10.4X103/mL

ASYMPTOMA TIC

Creatinine > 2.3mg/dl

Arr yth m

AST >80 IU,

vent (CVA) lic e bo Em

Bilirubin > 2mg/dl

output Va diac lvu car lar

: MR, AI ncy cie ffi su

Laboratory

w Lo

MATIC TO MP SY

RV volumes assessed by 3D

MR = Mirtal regurgitation; AI = Aortic insufficiency; CVA = Cerebrovascular accident; RV = Right ventricle. Adapted from Birati EY, et al.45

implantation is defined as a need for inotropes longer than 14 days after LVAD implant or the need for temporary RVAD placement after LVAD surgery.48,51 After LVAD placement, there is an abrupt decrease in the left ventricular end-diastolic pressure (LVEDP), followed by a decrease in left pulmonary capillary wedge pressure. In most patients this, in turn, causes a decrease in the pulmonary vascular resistance (PVR), thus decreasing the afterload of the right ventricle.52 However, some patients have a significant shift of the inter-ventricular septum towards the LV secondary to the decrease in the LVEDP and LV size and consequently an increase in RV preload. This shift of the septum adversely affects the function of the RV. High device speeds enhance this inter-ventricular septum shift, and can further deteriorate the RV function. Thus, it is highly recommended to conduct repeat echocardiographic studies during the first days after the implantation and to adjust the pump speed according to the septal movement and the ventricles size. RV failure can result in inadequate filling of the LV. Since the LVAD is preload dependent, patients with acute RV failure may present with cardiogenic shock. Up to 15 % of patients with acute RV failure will require RVAD implantation.53 These patients suffer from severe RV failure leading to end organ dysfunction and cardiogenic shock refractory to inotropes.53 In an effort to prevent RV failure, some authors advocate for the routine use of phosphodiesterase type 5 inhibition, nitric oxide, or Epoprostenol Sodium (Flolan) therapy in every patient with pre-implant PVR above 3.11

Gastrointestinal Bleeding Approximately one forth of VAD patients suffer from gastrointestinal bleeding (GI)54; half of the bleeding episodes originate from the upper GI tract. Although angiodysplastic lesions are the predominant cause of bleeding, stress and peptic ulcers are common in this patient population as well.54

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Left Ventricular Assist Devices in the Management of Heart Failure

The increased risk of bleeding is associated with several factors. First, similar to the Heyde syndrome of aortic stenosis, LVAD rotors generate high shearing forces leading to degradation of von Willebrand factor and acquired von Willebrand syndrome.55–57 Second, the continuous-flow devices generate low pulse pressures, which may cause GI hypoperfusion leading to formation of angiodysplastic lesions.58 In addition, most VAD patients are treated regularly with anticoagulation and antiplatelet regimens, which further increases the risk of bleeding.54 Figure 3 summarises the recommended treatment strategy of GI bleeding.59

Table 7: ISHLT Infectious Diseases Working Group definition of infection in VAD patients 64 VAD-specific

Related to the device

infections

hardware, occurring only • Pocket Infections

• Pump and/or cannula Infections

in patients with VAD

• Percutaneous Driveline Infections

VAD-related

Occur also in patients

• Infective endocarditis

infections

who do not have VAD

• Bloodstream infections

non-VAD

Infections that are

• Lower respiratory tract infection

infections

unlikely to relate to

• Cholecystitis

the VAD therapy.

• Clostridium difficile

• Mediastinitis

Infection and Sepsis

• Urinary tract infection

Infection is a major cause for morbidity and mortality in LVAD patients. Although the prevalence of VAD associated infections is improving with second and third generation devices, it continues to be a worrisome complication, with 20 % of VAD deaths attributed to infection.60,61 According to the International Society of Heart and Lung Transplantation (ISHLT) data, 87 % of VAD infections are bacterial (primarily Staphylococcus and Pseudomonas species) with the reminder being mostly fungal.62,63 The clinical presentation of VAD infections may be nonspecific and misleading, with symptoms such as lethargy, fatigue, or anorexia, with or without fever or shock.64 Table 7 summarises the ISHLT Infectious Diseases Working Group definition of infection in VAD patients.

VAD = ventricular assist device. Modified from Hannan MM, et al.64

Figure 3: Treatment Strategy of GI Bleeding

Severe GI bleeding

1. 2. 3. 4. 5. 6.

Invasive haemodynamic monitoring TTE Stop anticoagulation and anti-platelet Pack cells Consider treatment with FFP and Platelet product Monitor the Hg level

Bleeding persist

Driveline infections are the most prevalent infections in VAD patients and may reflect the presence of a deeper infection of the device hardware (pump, cannula) or the pocket space. Due to the marked variability in the clinical presentation, vigilance is required for an early diagnosis of infection.

The Future of Ventricular Assist Device Therapy The surge in the prevalence of HF worldwide will result in a substantial rise in the number of patients treated with long-term MCS. The next generation devices are currently being evaluated in clinical trials. These devices are smaller and easier to implant. Moreover, they are designed to have more flexible percutaneous leads, in an effort to decrease the risk of infections.65,66 Future devices will be more physiologic and will be able to automatically accommodate to the patient’s physical activity and position. In addition, devices in the future will have trans-dermal charging so that the system is totally within the body, which will further decrease the risk of infection, and allow patients to swim and shower with no limitation on daily activities.

1. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: executive summary: a report of the American College of Cardiology Foundation/ American Heart Association Task Force on practice guidelines. Circulation 2013;128:1810–52. 2. Mosterd A, Hoes AW. Clinical epidemiology of heart failure. Heart . 2007;93 :1137–46. 3. Albert NM, Allen LA, Bluemke DA, et al. Forecasting the impact of heart failure in the United States: a policy statement from the American Heart Association. Circ Heart Fail 2013;6:606–19. 4. Blecker S, Paul M, Taksler G, et al. Heart failure–associated hospitalizations in the United States J Am Coll Cardiol , 2013;61 :1259–67. 5. Parissis J, Athanasakis K, Farmakis D, et al. Determinants of the direct cost of heart failure hospitalization in a public tertiary hospital. Int J Cardiol 2015;180:46–9. 6. Lloyd-Jones D, Adams RJ, Brown TM, et al. Heart disease and stroke statistics—2010 update. A report from the American Heart Association Statistics. Circulation 2010:121 :e46–215.

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– Consider adding PPI – Consider treatment with octreotide or desmopressin acetate

Bleeding resolved GI endoscopy

Bleeding resolved

– Consider restarting anticoagulation and antiplatelet theraphy – Consider decreasing RPM

GI = Gastrointestinal; TTE = Trans-esophageal echocardiogram; FFP = Fresh frozen plasma; Hg = Haemoglobin; PPI = Proton pump inhibitor. Modified from: Suarez J, et al. 59

With the accumulating experience and improved outcomes, it is likely that the indications for LVAD implantation will expand and include patients with less severe HF. Finally, there is an ongoing interest in treating HF patients with preserved LVEF with durable MCS.67 In conclusion, MCS has emerged as an essential option for advanced HF, with increasing number of patients treated with this modality. These devices significantly improve survival and quality of life in appropriately selected patients. Awareness of the unique complications and clinical presentations is crucial for the long-term management of VAD patients. n

7. Jessup M, Brozena S. Heart failure. N Engl J Med 2003;348 :2007–18. 8. Costanzo MR, Mills RM, Wynne J. Characteristics of “stage D” heart failure: insights from the Acute Decompensated Heart Failure National Registry Longitudinal Module (ADHERE LM). Am Heart J 2008;155 :339–47. 9. Adler ED, Goldfinger JZ, Kalman J, et al. Palliative care in the treatment of advanced heart failure. Circulation 2009;120 :2597–606. 10. Metra M, Ponikowski P, Dickstein K, et al. Advanced chronic heart failure: A position statement from the Study Group on Advanced Heart Failure of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail 2007;9 :684–94. 11. Peura JL, Colvin-Adams M, Francis GS, et al. Recommendations for the use of mechanical circulatory support: device strategies and patient selection: a scientific statement from the American Heart Association. Circulation 2012;126 :2648–67. 12. Birati EY, Rame JE. Left ventricular assist device management

and complications. Crit Care Clin 2014;30 :607–27. 13. Birati EY, Rame JE. Post-heart transplant complications. Crit Care Clin 2014;30 :629–37. 14. Kirklin JK, Naftel DC, Pagani FD, et al. Sixth INTERMACS annual report: a 10,000-patient database. J Heart Lung Transplant 2014;33 :555–64. 15. Patel CB, Cowger JA, Zuckermann A. A contemporary review of mechanical circulatory support. J Heart Lung Transplant 2014;33 :667–74. 16. Rose EA, Gelijns AC, Moskowitz AJ, et al. Long-term use of a left ventricular assist device for end-stage heart failure. N Engl J Med 2001;345 :1435–43. 17. Sayer G, Naka Y, Jorde UP. Ventricular assist device therapy. Cardiovasc Ther 2009;27 :140–50. 18. Slaughter MS, Rogers JG, Milano CA, et al. Advanced heart failure treated with continuous-flow left ventricular assist device. N Engl J Med 2009;361 :2241–51. 19. Jorde UP, Kushwaha SS, Tatooles AJ, et al. Results of the destination therapy post-food and drug administration approval study with a continuous flow left ventricular assist

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Left Ventricular Assist Devices device: a prospective study using the INTERMACS registry (Interagency Registry for Mechanically Assisted Circulatory Support). J Am Coll Cardiol 2014;63 :1751–7. 20. Aaronson KD, Slaughter MS, Miller LW, et al. Use of an intrapericardial, continuous-flow, centrifugal pump in patients awaiting heart transplantation. Circulation 2012;125 :3191–200. 21. McMurray JJ, Adamopoulos S, Anker SD, et al. ESC Committee for Practice Guidelines. 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. 22. Slaughter MS, Pagani FD, Rogers JG, et al. Clinical management of continuous-flow left ventricular assist devices in advanced heart failure. J Heart Lung Transplant 2010;29 (4 Suppl):S1–39. 23. Aaronson KD, Schwartz JS, Chen TM, et al. Development and prospective validation of a clinical index to predict survival in ambulatory patients referred for cardiac transplant evaluation. Circulation 1997;95 :2660–7. 24. Levy WC, Mozaffarian D, Linker DT, et al. The Seattle heart failure model: prediction of survival in heart failure. Circulation 2006;113 :1424–33. 25. Stevenson LW, Pagani FD, Young JB, et al. INTERMACS profiles of advanced heart failure: the current picture. J Heart Lung Transplant 2009;28 :535–41. 26. Alba AC, Rao V, Ivanov J, et al. Usefulness of the INTERMACS scale to predict outcomes after mechanical assist device implantation. J Heart Lung Transplant 2009;28 :827–33. 27. Boyle AJ, Ascheim DD, Russo MJ, et al. Clinical outcomes for continuous-flow left ventricular assist device patients stratified by pre-operative INTERMACS classification. J Heart Lung Transplant 2011;30 :402–7. 28. Lietz K, Long JW, Kfoury AG, et al. Outcomes of left ventricular assist device implantation as destination therapy in the post-REMATCH era: implications for patient selection. Circulation 2007;116 :497–505. 29. Halbreiner MS, Soltesz E, Starling R, Moazami N. Current Practice in Patient Selecting for Long-Term Mechanical Circulatory Support. Curr Heart Fail Rep 2015;12(2):120–9. 30. Matthews JC, Koelling TM, Pagani FD, Aaronson KD. The right ventricular failure risk score a pre-operative tool for assessing the risk of right ventricular failure in left ventricular assist device candidates. J Am Coll Cardiol 2008;51 :2163–72. 31. Grant ADM, Smedira NG, Starling RC, Marwick TH. Independent and incremental role of quantitative right ventricular evaluation for the prediction of right ventricular failure after left ventricular assist device implantation. J Am Coll Cardiol 2012;60 :521–8. 32. Raina A, Seetha Rammohan HR, Gertz ZM, et al. Postoperative right ventricular failure after left ventricular assist device placement is predicted by preoperative echocardiographic structural, hemodynamic, and functional parameters. J Card Fail 2013;19 :16–24. 33. Kiernan MS, French AL, DeNofrio D, et al. Preoperative Three Dimensional Echocardiography to Assess Risk of Right Ventricular Failure Following Left Ventricular Assist Device Surgery. J Card Fail. 2015;21:189–97. 34. Ochiai Y, McCarthy PM, Smedira NG, et al. Predictors of severe right ventricular failure after implantable left

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ventricular assist device insertion: analysis of 245 patients. Circulation 2002;106 :I198–202. 35. Schenk S, McCarthy PM, Blackstone EH, et al. Duration of inotropic support after left ventricular assist device implantation: risk factors and impact on outcome. J Thorac Cardiovasc Surg 2006;131 :447–54. 36. Kormos RL, Teuteberg JJ, Pagani FD, et al. Right ventricular failure in patients with the HeartMate II continuous-flow left ventricular assist device: incidence, risk factors, and effect on outcomes. J Thorac Cardiovasc Surg 2010;139 :1316–24. 37. Afilalo J, Karunananthan S, Eisenberg MJ, et al. Role of frailty in patients with cardiovascular disease. Am J Cardiol 2009;103 :1616–21. 38. Dunlay SM, Park SJ, Joyce LD, et al. Frailty and outcomes after implantation of left ventricular assist device as destination therapy. J Heart Lung Transplant 2014;33 :359–65. 39. Cacciatore F, Abete P, Mazzella F, et al. Frailty predicts longterm mortality in elderly subjects with chronic heart failure. Eur J Clin Invest 2005;35 :723–30. 40. Lupon J, Gonzalez B, Santaeugenia S, et al. Prognostic implication of frailty and depressive symptoms in an outpatient population with heart failure. Rev Esp Cardiol 2008;61 :835–42. 41. Chung CJ, Wu C, Jones M, et al. Reduced handgrip strength as a marker of frailty predicts clinical outcomes in patients with heart failure undergoing ventricular assist device placement. J Card Fail 2014;20 :310–5. 42. Starling RC, Moazami N, Silvestry SC, et al. Unexpected abrupt increase in left ventricular assist device thrombosis. N Engl J Med 2014;370 :33–40. 43. Aaronson KD, Slaughter MS, Miller LW, et al. Use of an intrapericardial, continuous-flow, centrifugal pump in patients awaiting heart transplantation. Circulation 2012;125 :3191–200. 44. Najjar SS, Slaughter MS, Pagani FD, et al. An analysis of pump thrombus events in patients in the HeartWare ADVANCE bridge to transplant and continued access protocol trial. J Heart Lung Transplant 2014;33 :23–34. 45. Birati EY, Quiaoit Y, Wald J, et al. Ventricular assist device thrombosis: A wide spectrum of clinical presentation. J Heart Lung Transplant 2014 Dec 24 [Epub ahead of print] 46. Uriel N, Morrison KA, Garan AR, et al. Development of a novel echocardiography ramp test for speed optimization and diagnosis of device thrombosis in continuous-flow left ventricular assist devices: the Columbia ramp study. J Am Coll Cardiol 2012;60 :1764–75. 47. Birati EY, Rame JE. Diagnosis and Management of LVAD Thrombosis. Curr Treat Options Cardiovasc Med 2015;17:361. 48. Meineri M, Van Rensburg AE, Vegas A. Right ventricular failure after LVAD implantation: prevention and treatment. Best Pract Res Clin Anaesthesiol 2012;26 :217–29. 49. Dang NC, Topkara VK, Mercando M, et al. Right heart failure after left ventricular assist device implantation in patients with chronic congestive heart failure. J Heart Lung Transplant 2006;25 :1–6. 50. Morgan JA, John R, Lee BJ, et al. Is severe right ventricular failure in left ventricular assist device recipients a risk factor for unsuccessful bridging to transplant and post-transplant mortality. Ann Thorac Surg 2004;77 :859–63. 51. Morgan JA, Paone G, Nemeh HW, et al. Impact of continuousflow left ventricular assist device support on right ventricular function. J Heart Lung Transplant 2013;32 :398–403. 52. Atluri P, Fairman AS, MacArthur JW, et al. Suarez Continuous

flow left ventricular assist device implant significantly improves pulmonary hypertension, right ventricular contractility, and tricuspid valve competence. J Card Surg 2013;28 :770–5. 53. MacGowan GA, Schueler S. Right heart failure after left ventricular assist device implantation: early and late. Curr Opin Cardiol 2012;27 :296–300. 54. Draper KV, Huang RJ, Gerson LB. GI bleeding in patients with continuous-flow left ventricular assist devices: a systematic review and meta-analysis. Gastrointest Endosc 2014;80:435–46. 55. Uriel N, Pak SW, Jorde UP, et al. Acquired von Willebrand syndrome after continuous-flow mechanical device support contributes to a high prevalence of bleeding during longterm support and at the time of transplantation. J Am Coll Cardiol 2010;56 :1207–13. 56. Klovaite J, Gustafsson F, Mortensen SA, et al. Severely impaired von Willebrand factor-dependent platelet aggregation in patients with a continuous-flow left ventricular assist device (HeartMate II). J Am Coll Cardiol 2009;53 :2162–7. 57. Bartoli CR, Restle DJ, Zhang DM, et al. Pathologic von Willebrand factor degradation with a left ventricular assist device occurs via two distinct mechanisms: Mechanical demolition and enzymatic cleavage. J Thorac Cardiovasc Surg 2015;149 :281–9. 58. Demirozu ZT, Radovancevic R, Hochman LF, et al. Arteriovenous malformation and gastrointestinal bleeding in patients with the Heart- Mate II left ventricular assist device. J Heart Lung Transplant 2011;30 :849–53. 59. Suarez J, Patel CB, Felker GM, et al. Mechanisms of bleeding and approach to patients with axial-flow left ventricular assist devices [review]. Circ Heart Fail 2011;4 :781. 60. Holman WL, Park SJ, Long JW, et al. Infection in permanent circulatory support: experience from the REMATCH trial. J Heart Lung Transplant 2004;23 :1359–65. 61. Miller LW, Pagani FD, Russell SD, et al. Use of a continuousflow device in patients awaiting heart transplantation. N Engl J Med 2007;357 :885–96. 62. Holman WL, Pae WE, Teutenberg JJ, et al. INTERMACS: interval analysis of registry data. J Am Coll Surg 2009;208:755–61. 63. Topkara VK, Kondareddy S, Malik F, et al. Infectious complications in patients with left ventricular assist device: etiology and outcomes in the continuous-flow era. Ann Thorac Surg 2010;90 :1270–7. 64. Hannan MM, Husain S, Mattner F, et al. International Society for Heart and Lung Transplantation. Working formulation for the standardization of definitions of infections in patients using ventricular assist devices. J Heart Lung Transplant 2011;30 :375–84. 65. Farrar DJ, Bourque K, Dague CP, et al. Design features, developmental status, and experimental results with the Heartmate III centrifugal left ventricular assist system with a magnetically levitated rotor. ASAIO J 2007;53 :310–5. 66. Mesa KJ, Ferreira A, Castillo S, et al.The MVAD® Pump: Motor Stator Core Loss Characterization. ASAIO J 2014 Nov 24. [Epub ahead of print] 67. Burkhoff D, Maurer MS, Joseph SM, et al. Left Atrial Decompression Pump for Severe Heart Failure With Preserved Ejection Fraction: Theoretical and Clinical Considerations. JACC Heart Fail 2015 Mar 3 [Epub ahead of print]

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Patients Nearing the End of Life

LE ATION.

e. lare.

Management of Heart Failure in Patients Nearing the End of Life— There is So Much More To Do Li s a L e M o n d 1 a n d S a r a h J G o o d l i n 2 1. Knight Cardiovascular Institute, Oregon Health and Science University, Portland, Oregon, US; 2. Oregon Health and Sciences University and the Portland VAMC, Portland, Oregon, US

Abstract As the population of patients living with heart failure increases, the number of patients who will die with and from heart failure increases as well. End-of-life care in patients with heart failure is an additive process, whereby therapies to treat symptoms not alleviated by guideline-based medical therapy are integrated into the care of these individuals. This review focuses on providing clinicians with a basic framework for administration of end-of-life care in patients with heart failure, specifically focusing on decision-making, symptom management and functional management.

Keywords End-of-life, heart failure, palliative care, implantable cardioverter defibrillator, hospice, advance directive, pain Disclosure: The authors of this paper have no disclosures to make. Received: 7 February 2015 Accepted: 6 March 2015 Citation: Cardiac Failure Review, 2015;1(1):31–4 Correspondence: Sarah J Goodlin, MD, Oregon Health and Sciences University and the Portland VAMC, P3-Med, PO Box 1034, Portland OR 97207-1034, US. E: sarah.goodlin@va.gov

In the infancy of the hospice and palliative care movements, Dame Cicely Saunders noted that terminally ill patients and their families were often told “there is nothing more to do.” Her unwavering belief was that those words betrayed the patient, and that “there is so much more to do.”1 Stage D heart failure (HF) is defined as HF in which refractory symptoms persist despite guideline-directed therapies.2 This stage of HF is highly morbid and is associated with a high burden of both physiologic and psychological suffering.3 Advances in care of cardiovascular diseases and an aging population have contributed to a burgeoning number of patients with Stage D HF. Current estimates of the number of patients who die from HF is approximately 60,000 per year versus approximately 300,000 per year who die with HF in the US (with a similar number in Europe).4 The fields of cardiology and palliative care have begun to recognize and address the complex needs of these patients. Their collaborative efforts have resulted in a growing body of literature aimed at providing guidance for practitioners caring for this population.5 This review will provide practitioners with focused recommendations for the care of individuals with HF who are nearing the end of life.

Decision-making Providers have varying degrees of comfort with the provision of end-oflife care in HF.6 At or near the end of life, 52 % of providers hesitated to discuss end-of-life care, due to provider discomfort (11 %), perceived unreadiness on behalf of the patient or family (33 %), fear of destroying hope (9 %), or lack of time (8 %). Furthermore, 30 % of these providers reported low or very low confidence in initiation of the discussions, enrolling in hospice, or providing end-of-life care. Opinions differ among providers about whose responsibility it is to address end-of-life care

Goodlin_FINAL.indd 31

in patients with HF, with 66 % of cardiology providers citing that the responsibility is that of the primary care physician (PCP), while 57 % of PCPs believe the converse. We suggest that all providers should review preferences and planning for the end of life with HF patients and that any invested provider may initiate end-of-life care. Decision-making for end-of-life matters should be patient-centered and should be a collaborative effort between providers, patients, and involved family and friends of the patient. The decisions needing to be made at the end of life generally fall under the umbrella of an advance care plan (ACP). Realistically, a large number of patients will die without either a wellthought-out ACP and signed advance directive (AD), however, the exercise of going through these questions with patients may help them to formulate opinions regarding their end-of-life care. Having an ACP and AD can help to alleviate anxiety, increase hospice utilization, and decrease the use of life-prolonging and invasive therapies at the end of life.7 The first step in helping a patient to create an ACP is to understand the patient’s goals and values. The next step is to inform the patient that they are nearing the end stage of the disease process and review reasonable treatment options in the context of their stated values and goals. Specific topics that should be addressed in a complete ACP, as well as useful language, are found in Table 1. Importantly, the ACP should be an iterative process, and should be readdressed throughout the course of illness, as patient preferences can change as their illness worsens.8 The use of device-based therapies, such as implantable cardioverter defibrillators (ICDs) and cardiac resynchronization therapy, for HF is becoming integrated into the care of a greater percentage of patients, with over 50 % of patients with HF qualifying for devicebased therapy. 9 Challenges encountered by providers initiating

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Patients Nearing the End of Life Table 1: Contents of a Comprehensive Heart Failure Advance Care Plan with Language Useful for Initiating Decision-making Conversations Healthcare proxy

“If you were unable to make decisions on your own,

who would you like to make decisions for you?”

Values and preferences

“What is important to you at this point in your life?”

“As you look back, what has given your life value?”

Current and future

“Would you like to receive noninvasive therapies for

goals of care

easily reversible problems, such as antibiotics?”

“If you became very ill and needed a lot of care,

would you want to go to an intensive care unit?”

“Would you like to avoid further hospitalizations?”

“At your current health state, we should set goals

that we can work on with you. Based on what I

heard you say, we should focus on helping you feel

as good as you can, but when the time comes,

allow you to die outside the hospital, at home.”

Symptom palliation

“As your disease progresses, your shortness of

breath and pain may worsen, we should have a

plan in place for what to do if that happens.”

Device deactivation

“If you were dying of another process, such

as cancer, would you like to have the shock function

of your implantable cardioverter defibrillator turned

off so that you may die naturally?”

“If your disease worsens and we change the focus

of our efforts to making you comfortable, may we

turn off the shock function of your implantable

cardioverter defibrillator to allow you to pass

naturally?”

“Because you have a device, we should make a

plan for a time that we would like to turn off

the device.”

Location of death

“Have you thought about where you would

ultimately like to die?”

Code status

“When your heart stops beating, should we allow

you to die naturally or try to revive you?”

conversations regarding device deactivation can be due to provider discomfort, lack of counseling prior to implantation, and patient misconceptions.10–12 However, ICD discharges at the end of life are associated with pain and anxiety at the end of life and should be averted. To that end, a plan should be in place for device deactivation for every patient. Planning for device deactivation should start before implantation, but findings from the Multicenter Automatic Defibrillator Implantation Trial II (MADITII) cohort suggest that using clinical status changes (such as hospitalization or changes in functional status) to prompt discussion regarding deactivation may not expose the patient to additional risk for shocks at the end of life.13 Deactivation of mechanical circulatory support is equally important to plan for, but will not be discussed in this review.

Symptom Management Patients with HF nearing end of life are likely to encounter worsening of symptoms or development of new symptoms. The goal of palliative care is to lessen suffering in all forms: physical, psychological, social, or existential; recognition of each of these forms of suffering as a contributor to suffering is called the theory of “total pain.”1 A comprehensive approach to care addresses each of these forms of suffering in the dying patient. Whereas the transition to palliative care in other disease processes is marked by the removal of potentially curative or otherwise aggressive therapies, the transition to palliative care in those with HF should be additive.14 The key is to medically

Goodlin_FINAL.indd 32

optimize to the fullest extent achievable with guideline-based medical therapy and then to add therapies directed at the underlying root cause of symptoms that are still present after traditional medical therapy has been exhausted.15 As patients with end-stage HF experience a high burden of symptoms, a multidisciplinary care team may be beneficial.16 This team usually involves both a PCP and a cardiologist, social work, nursing staff, and also, perhaps, a palliative care specialist. A randomized study of 232 patients admitted with HF at a tertiary referral center found that inpatient palliative care consultation improved symptoms burden (p<0.001) and quality of life (p<0.001) at serial follow-up.17

Dyspnea Dyspnea is a defining feature of functional class for HF patients and is a hallmark of worsening functional status. The pathogenesis of dyspnea in HF is defined by overactivation of ergoreceptors, which are afferent nerves sensitive to the metabolic effects of muscular work.18 Exercise, particularly thigh muscle strengthening, improves dyspnea, presumably by altering the myopathy and ergoreflex abnormalities in persons with HF.19 In a recent study of 100 consecutive patients with New York Heart Association (NYHA) functional class II–IV HF exercise was shown to improve dyspnea, peak VO2 (28 %; p=0.001) and quality of life (p=0.003).20 For these reasons, exercise should be the initial prescription for dyspnea. Maintenance of euvolemia improves, but does not eliminate, dyspnea. It is also important to continue (when able) guideline-directed medical therapies including angiotensin converting enzyme (ACE) inhibitors, beta-blockers, and mineralocorticoid antagonists. Once traditional medical therapies and nonpharmacologic therapies have been exhausted, low-dose opioids are generally felt to be first-line adjuvant therapy to treat dyspnea. Opioids decrease chemosensitivityrelated dyspnea and improve exercise tolerance and peak VO2.21 Sedation may be an untoward effect, and thus the dose should be titrated to symptom relief while attempting to avoid narcosis.

Physical Pain Up to 75 % of patients with advanced HF will experience pain.22 Nonpharmacologic therapies for pain, such as physical therapy, massage, and ice should be attempted first.23 Of the non-opioid pain medications, acetaminophen has the most favorable safety profile for patients with HF with mild to moderate somatic pain.24 Nonsteroidal anti-inflammatory drug (NSAIDs) are contraindicated in patients with HF due to propensity for causing fluid retention and exasperating renal dysfunction. Many NSAIDs, such as cyclooxygenase (COX) inhibitors, also carry black box warnings for patients with cardiovascular disease. Oral opiates may be used for management of moderate to severe pain in patients with HF. Attention should be paid to active metabolites that may accumulate in renal dysfunction, leading to delirium, or neuroexcitation. Fentanyl and methadone have no renally excreted active metabolites likely to accumulate in HF. If providers are uncomfortable with utilization of more potent opiates, consultation with a pain or palliative care specialist may be useful. Unrecognized psychological, social, and spiritual needs will often explain a nonresponding physical pain.25

Depression and Anxiety Depression is common in those with HF.26 As functional status worsens, the incidence of depression increases: up to 42 % of patients with NYHA class IV disease experience this symptom.27 Comorbid depression is also associated with worsening of HF symptoms.28 Depression can contribute to poor adherence that can increase symptomatology,

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Management of Heart Failure in Patients Nearing the End of Life—There is So Much More To Do

Figure 1: Algorithm for Discussing Resuscitation Preferences for Patients Nearing the End of Life with Heart Failure with some Helpful Phrases 45 “When your heart stops beating, should we allow a natural death to occur, or should we try to revive you”

Attempt to revive

Allow natural death to occur Plan for management of:

“Are there any situations in which you would not want to be kept alive?” • If you were unable to communicate • If you were unable to function independently

• Basic care needs and who will provide care • All current medications • LVAD • Defibrillator • Pacemaker “Given your wishes, we need to plan how to manage your treatments to let death occur naturally” “I would like to talk to you about plans for turning off the shock function of your implantable cardioverter defibrillator” “Under what circumstances would you would like to have your LVAD turned off?”

YES “Lets talk about which situations you would not like to have your life prolonged” "Some people prefer we try to keep them alive for a period of time, but if they do not become independent then allow natural death – what do you think of that?"

hospitalizations, and, ultimately, mortality.29–31 Selective serotonin re-uptake inhibitors (SSRIs), such as sertraline and paroxetine, have been found to be safe and effective as first-line therapy for depression in patients with HF.32,33 These medications should be started at a low dose and increased until depression improves or until recommended dose is achieved. Because both of these drugs are metabolized in the liver and excreted by the kidneys, dose reduction may be required for both renal and hepatic dysfunction.34 SSRIs can cause hyponatremia or fluid retention, particularly in patients with renal dysfunction. In addition to medical therapies for depression, exercise can result in modest improvements in depressive symptoms.35 Collaborative care is an important component of the care patients with HF who develop symptoms of depression.36 Some data suggest that cognitive behavioral therapy can decrease depressive symptoms, as well as anxiety, and that relaxation exercises with elements of CBT may decrease symptom burden.37

“I am committed to helping you and respect your decisions” “With what has happened now your chance of meaningful recovery if you were resuscitated would be very low” “I will continue to address these issues with you”

Table 2: The FICA Questions can be Utilized by Providers to Address Existential Needs of Patients FICA questions for addressing spirituality F Faith or belief: what is your faith or belief? I

Importance: is faith or spirituality important in your life?

Community: are you part of a religious or spiritual community?

Address: How would you like me, your health-care provider, to

address these issues in your health care?

memory problems interfere with self-care and problem-solving, though many patients seemingly converse normally despite moderate-tosevere impairment. Cognitive function can improve with improved volume status, but is unlikely to resolve. Exercise has been shown to improve vascular dementia.43 While many patients retain the ability to discuss options and may express their preferences, it is important to include their designated surrogate decision-makers in planning care.

Existential Pain Spiritual well-being is an important component of holistic care. Though often equated to faith, spirituality is a broader term that refers to the way that a person views the meaning of their life in terms of their own values.38 Objective spirituality scoresinclude meaning of life, peace, purpose, and faith.39 Higher spirituality scores appear to confer some degree of protection against the development of depression.40 Clinicians can identify spiritual beliefs and sources of support by simply asking “What gives you hope and where, or how, do you find support in your life?” The FICA questions (see Table 2) can also help guide discussions about spirituality.41

Cognitive Impairments with Heart Failure Cognitive impairment at the end of life is extremely prevalent in patients with HF and can impair a patient’s ability to interact with family and friends as well as impair independence.42 Patients with decompensated HF can experience difficulty with short-term memory, working memory, executive control and processing speed. Executive dysfunction and

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Goodlin_FINAL.indd 33

Functional Management The functional decline towards death is often slow and lasts many years. Patients and families need additional support such as assistance with medication management, self-care, home care, and activities of daily living (ADLs) as they approach the end of life. Attention to functional needs of the patient is important for both patients and care-providers who may experience significant care-giver fatigue and burnout.44 Knowledgeable home health providers can help patients to avoid hospitalizations. Physicians caring for HF patients should develop a network of skilled community partners with whom to work. It can be difficult to estimate when HF patients have a 6-month lifeexpectancy, but the combination of HF with several other significant medical problems, or recurrent volume overload and a decision to not be hospitalized again are some indicators of hospice appropriateness. Because HF care differs significantly from cancer care, which is what hospice care is modeled on, it is important to build HF care with one or more hospice companies.

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Patients Nearing the End of Life Summary As a patient transitions to the end of life with HF, there is “so much more to do.” A provider can best address the complex needs of these patients by having a thoughtful ACP in place and by adhering

1. 2.

5. 6.

8. 9.

10.

11.

12.

13.

14. 15. 16.

17.

Available at: http://www.stchristophers.org.uk/about/ damecicelysaunders (accessed 6 February 2015). Hunt SA, Abraham WT, Chin M, et al. 2009 Focused update incorporated into the ACC/AHA 2005 guidelines for the diagnosis and management of heart failure in adults. Circulation . 2009;119 :e391–e479. Walke LM, Byers A, Tinetti M, et al. Range and severity of symptoms over time among older adults with chronic obstructive pulmonary disease and heart failure. Arch Intern Med . 2007;167 (22):2503-8. Go AS, Mozaffarian D, Rocer V, et al. Heart Disease and stroke statistics – 2014 update: a report from the American Heart Association. Circulation . 2014;129 :e28-e292. Goodlin SJ, Palliative care in congestive heart failure. J Am Coll Cardiol . 2009;54 (5):386–96. Dunlay SM, Foxen J, Cole T, et al. A survey of clinician attitudes and self-reported practices regarding end-of-life care in heart failure. Palliat Med. 2015;29 (3):260–7. Teno JM, Grunier A, Schwartz Z, et al. Association Between advance directives and quality end-of-life care: a national study, J Am Geriatr Soc , 2007;55 (2):189–94. Smith R, A Good Death. An Important Aim for Health Services and For Us All. BJM . 2000;320 :129–30. Lyons KG, Podder M, Ezekowitz J, Rates and reasons for device-based guideline eligibility in patients with heart failure. Heart Rhyhtm . 2014;11 (11):1983–90. Zapka JG, Moran W, Goodlin S, et al. Advanced heart failure: prognosis, uncertainty, and decision making. Congset Heart Fail . 2007;13 (5):268–74. Dodson JA, Fried TR, Van Ness PH, et al. Patient preferences for deactivation of implantable cardioverter-defibrillators. JAMA Intern Med. 2013;173(5):377–9. Stromberg A, Fluur C, Miller J, et al. ICD recipients’ understanding of ethical issues, ICD function, and practical consequences of withdrawaing the ICD in the end of life. Pacing and Clin Electrophys . 2014;37 (7):837–42. Sherazi S, McNitt S, Aktas M, et al. End-of-life care in patients with implantable cardioverter defibrillators: A MADIT-II Substudy. Pacing and Clin Electrophys. 2013;36(10):1273–9. LeMond LM, Allen LA, Palliative care and hospice in advanced heart failure. Prog Cardiovasc Dis. 2011;54 (2):168–78. Goodlin SJ, Palliative care in congestive heart failure. J Am Coll Cardiol . 2009;54 (5):386–96. Ryder M, Beattie J, O’Hanlon R, et al. Multidisciplinary heart failure management and end-of-life care. Curr Opinion Supp Pall Care . 2011;5 (4):317–21. Sidebottom AC, Jorgeson A, Richards H, et al. Inpatient palliative care for patients with acute heart failure: outcomes

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to the theory of total pain (see Figure 1). Though this document is by no means a comprehensive guide to the end-of-life care of these patients, the above should serve as a starting point to inform providers caring for this special population of patients. n

from a randomized trial. J Palliat Med . 2015;18 (2):134–42. 18. Ponikowski PP, Chua T, Francis D, et al. Muscle ergoreceptor overactivity reflects deterioration in clinical status and cardiorespiratory reflex control in chronic heart failure. Circulation . 2001;104 :2324-2330. 19. Beniaminovitz A, Lang C, Lamanca J, et al. Selective low-level leg muscle traning alleviates dyspnea in patients with heart failure. J Am Coll Cardiol . 2002;40 (9):1602–8. 20. Chrysohoou C, Angelis A, Tsitsinakis G, et al. Cardiovascular Effects of High-Intensity Interval Aerobic Training Combined with Strength Exercise in Patients with Chronic Heart failure. A Randomized Phase III Clinical Trial. Int J Cardiol. 2015;179 :269–74. 21. Chua TP, Harrington D, Ponikowski P, et al. Effects of Dihydrocodeine on Chemosensitivity and Exercise Tolerance in Patients with Chronic Heart Failure. J Am Coll Cardiol . 1997;29 (1):147–52. 22. Godfrey C, Harrison M, Medves J, Tranmer J, The Symptom of Pain with Heart Failure, a Systematic Review. J Card Fail . 2012;18 :307–13. 23. Chen W, Liu G, Yeh S, et al. Effect of back massage intervention on anxiety, comfort and physiologic responses in patients with congestive heart failure. J Altern Complement Med . 2013;19 (5):464–70. 24. Whelton A, Clinical implications of nonopioid analgesia for relief of mild-to-moderate pain in patients with or at risk for cardiovascular disease. Am J of Cardiol . 2006:97 (9A):3–9. 25. Harris GH. Management of pain in advanced diseases. Brit Med Bull . 2014;110 :117–28. 26. Angermann CE, Gelbrich G, Stork S, et al. Somatic correlates of comorbid major depression in patients with systolic heart failure. Int J of Cardiol . 2011;147 :66–73. 27. Rutledge T, Reis V, Linke S, et al. Depression in heart failure: a meta-analytic review of prevalences, intervention effects and associations with clinical outcomes. J Am Coll Cardiol . 2006;48 :1527–37. 28. Morgan K, Villiers-Tuthill A, Barker M, et al. The contribution of illness perception to psychological distress in heart failure patients. BMC Psychol . 2014;2 (1):50. 29. Luyster FS, Hughes J, Gunstad J, Depression and anxiety symptoms are associated with reduced dietary adherance in heart failure patients treated with an implantable cardioverter defibrillator. J Cardiovasc Nurs . 2009;24 (1):10–7. 30. Adams J, Buchibhatla M, Christopher EJ, et al. Association of depression and survival in patients with chronic heart failure over 12 years. Psychosomatics . 2012;53 (4):339–46. 31. Johnson TJ, Basu S, Pisani BA, et al. Depression predicts repeated heart failure hospitalizations. J Card Fail .

2012;18 (3):246–52. 32. Gottlieb SS, Kop W, Thomas S, et al. A double-blind placebocontrolled pilot study of controlled-release paroxetineon depression and quality of life in chronic heart failure. Am Heart J . 2007;153 (5):868–73. 33. O’Connor C, Jiang W, Kuchibhatla M, et al. Safety and efficacy of sertraline for depression in patients with heart failure. J Am Coll Cardiol . 2010;56 :692–9. 34. Harris J, Heil J, Managing depression in patients with advanced heart failure awaiting transplantation. A J HealthSystem Pharm . 2013;70 (10):867–73. 35. Blumenthal JA, Babyak MA, O’Connor C, et al. Effects of exercise training on depressive symptoms in patients with chronic heart failure: the HF-ACTION randomized trial. JAMA . 2012;308 (5):465–74. 36. Huffman JC, Mastromauro C, Beach S, et al. Collaborative care for depression and anxiety disorders in patients with recent cardiac events: The Management of Sadness and Anxiety in Cardiology (MOSAIC) Randomized Clinical Trial. JAMA Intern Med . 2014;174 (6):927–35. 37. Lundgren J, Andersson G, Johansson P, Can Cognitive Behaviour Therapy Be Beneficial for Heart Failure Patients? Curr Heart Fail Rep . 2015;12 (2):166–72. 38. Bekelman DB, Dy S, Becker D, et al. Spiritual well-being and depression in patients with heart failure. J Gen Intern Med . 2007;22 (4):470–7. 39. Bekelman DB, Parry C, Curlin F, et al. A comparison of two spirituality instruments and their relationshiop to depression and quality of life in chronic heart failure. J Pain Symptom Manage . 2010;39 (3):515–26. 40. Mills PJ, Wilson K, Iqbal F, et al. Depressive symptoms and spiritual wellbeing in asymptomatic heart failure patients. J Behav Med . 2014 [Epub ahead of print]. 41. Puchalski CM, The FICA Spiritual History Tool #274. J Pall Med . 2014;17 (1):105–6. 42. Dodson JA, Truong T, Towle V, et al. Cognitive Impairment in Older Adults with Heart Failure: Prevalence, Documentation, and Impact on Outcomes. Am J Med . 2013;126 :120–6. 43. Alosco ML, Spitznagel M, Cohen R, et al. Cardiac Rehabilitiation is Associated with Lasting Improvements in Cognitive Function in Older Adults with Heart Failure. Acta Cardiol . 2014;60 (4):704–14. 44. Strömberg A, Luttik M, Burden of caring: risks and consequences imposed on caregivers of those living and dying with advanced heart failure. Curr Opin Supp Pall Care .2015;9 (1):26–30. 45. Goodlin S, Rich M, End-of-Life Care in Cardiovascular Disease, London: Springer, 2014.

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Cardiac Resynchronisation Therapy

LE ATION.

e. lare.

Cardiac Resynchronisation Therapy and Heart Failure: Persepctive from 5P Medicine Fang Fa ng , 1 ,2 Z hou Yu Jie, 2 Luo X i u Xi a , 1 L i u M i n g , 1 M a Z h a n , 1 G a n S h u Fe n 1 a n d Yu Ch e u k - man 1 1. Institute of Vascular Medicine, Institute of Innovative Medicine, Heart Education and Research Training (HEART) Centre, Division of Cardiology, Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR; 2. Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing

Abstract Chronic heart failure is still a major challenge for healthcare. Currently, cardiac resynchronisation therapy (CRT) has been incorporated into the updated guideline for patients with heart failure, left ventricular ejection fraction ≤35 % and prolonged QRS duration. With 20 years of development, the concept of ‘from bench to bedside’ has been illustrated in the field of CRT. Given the fact that the indications of CRT keep evolving, the role of CRT is not limited to the curative method for heart failure. We therefore summarise with the perspective of 5P medicine – preventive, personalised, predictive, participatory, promotive, to review the benefit of CRT in the prevention of heart failure in those with conventional pacemaker indications, the individualised assessment of patient’s selection, the predictor of responders of CRT, and the obstacles hindering the more application of CRT and the future development of this device therapy.

Keywords Heart failure, cardiac resynchronisation therapy, 5P medicine Disclosure: The authors have no conflicts of interest to declare. Received: 10 February 2015 Accepted: 3 March 2015 Citation: Cardiac Failure Review, 2015;1(1):35–7 Acknowledgements: The publication of this article was supported by a research grant from the University Grants Committee of Hong Kong (RGC Collaborative Research Fund 2010/11: CUHK9/CRF/10). Correspondence: Professor Cheuk-Man Yu, Division of Cardiology, Department of Medicine and Therapeutics, Prince of Wales Hospital, Institute of Vascular Medicine, Institute of Innovative Medicine, Heart Education And Research Training (HEART) Center, Li Ka Shing Institute of Health Sciences; The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR. E: cmyu@cuhk.edu.hk

The prevalence of heart failure (HF) is still high1 and is rising in developing countries.2 Despite optimal medical therapy, refractory HF is a common occurrence and remains a “global disease requiring global response.”3 The emergence of cardiac resynchronisation therapy (CRT), has brought a new paradigm in the management of HF. CRT has been the most promising device therapy in mild-to-severe HF over the past two decades,4 has improved the prognosis of HF and has been incorporated into therapeutic guidelines.5,6 The 20-year history of CRT illustrates the concept of “from bench to bedside” and this article aims to review the use of CRT in the context of 5P medicine-prevention, personalisation, prediction and participation as well as promotion.

Preventive Role of Cardiac Resynchronisation Therapy in Heart Failure The role of CRT is continually evolving, and recently has extended to patients with bradycardia requiring frequent ventricular pacing (> 40 %) and left ventricular ejection fraction (LVEF) ≤35 %,5 who are candidates for a conventional pacemaker. A growing body of evidence shows that right ventricular (RV) pacing has a detrimental effect on left ventricular (LV) function and remodeling despite normal ejection fraction before implantation. Both pacing-induced cardiomyopathy7 and new-onset of HF8 are frequently encountered in patients undergoing RV pacing, even in those with less than 40 % accumulative pacing and in the shortterm (less than one month) pacing. Despite satisfactory response to CRT upgrading in patients with RV pacing-induced LV remodeling or

Yu_FINAL.indd 35

HF,9 this is a “wait-and-see” approach, especially for outpatients with infrequent echocardiographic examination. Therefore, pacing-induced LV dysfunction might be avoided with de novo implantation of CRT. The results of the Biventricular versus Right Ventricular Pacing in Heart Failure Patients with Atrioventricular Block (BLOCK HF trial) supported the superiority of CRT to RV pacing as demonstrated by the significant reduction of total mortality, urgent HF care, or an increase in LV endsystolic volume index in patients with HF and conventional indications for pacing.10 The inclusion criteria for the BLOCK-HF trial included patients with LV ejection fraction <50 %, not confined to <35 % as in other HF and CRT trials. In terms of patients with bradycardia and normal ejection fraction, the Pacing to Avoid Cardiac Enlargement (PACE) trial and extended follow-up consistently demonstrated the superiority of CRT over RV pacing in prevention of LV remodeling and deterioration of systolic function, as well as reduction of HF in the long-term followup.11–13 However, preliminary results of the Biventricular pacing for atrIoventricular BlOck to Prevent cArdiaC dEsynchronisation (BIOPACE) trial showed that CRT failed to significantly improve outcomes compared to RV pacing in atrioventricular (AV) block (preliminary result, in annual scientific meeting in ESC 2014). Nevertheless, data from this trial should be interpreted with care due to the relatively high failure rate of implantation and lower accumulative ventricular pacing percentage (90 % at one month), which might have an impact on the primary end-point. Currently, CRT is unlikely to completely replace conventional RV pacing, even in patients with high-degree AV block;

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Cardiac Resynchronisation Therapy however, its preemptive role in HF deterioration and HF occurrence should be acknowledged although further study is necessary to fully elucidate its effects.

Personalisation and Predictive Medicine in Cardiac Resynchronisation Therapy Non-responder and Super-responder The concept of non-responders14,15 was proposed in CRT therapy since there is a wide range of response to CRT and around 30 % of patients do not respond to CRT. There remains a lack of standard criteria to define non-responders, but LV reverse remodeling is considered to be an acceptable parameter with better predictive value for cardiovascular mortality compared with other criteria.16 Numerous studies aiming to predict CRT responders have been conducted, including clinical, electrical and imaging predictors at time points pre-, during and post-implantation.17 Potential parameters to facilitate patient selection have included QRS pattern and width, LV ejection fraction and dyssynchrony parameters. However, no parameters have been found to conclusively identify responders to CRT; a composite scoring system with several strong predictors may be needed. In addition, some patients demonstrate dramatic improvement after CRT, even approaching normal cardiac function; they are termed “super-responders”.18 In these patients, a reduction of risk of ventricular arrhythmias has also been observed.19 Compared to non-responders, super-responders are understudied but the concept is clinically relevant for the secondary prevention of sudden death with CRT-defibrillator or CRT-pacemaker.20

Vulnerable Patients in Conventional Pacemaker Indications Despite encouraging outcomes of CRT in bradycardia patients, LV dysfunction does not develop in all patients receiving RV pacing; a proportion of population may be resistant to pacing-induced systolic dyssynchrony.21,22 Therefore not every patient should be given CRT due to its high cost and relatively high complication rate. It is important to select vulnerable patients who are likely to develop systolic dyssynchrony when undergoing frequent ventricular pacing in bradycardia. Although it would be desirable to identify baseline predictors related to pacing-induced systolic dyssynchrony, there are a lack data to inform patient selection. The presence of RV pacing induced ventricular dyssynchrony may direct DDDR/CRT-Pacemaker device implant in patients with heart block and normal LVEF. The Efficacy of the Presence of Right Ventricular Apical Pacing Induced Ventricular Dyssynchrony as a Guiding Parameter for Biventricular Pacing in Patients with Bradycardia and Normal Ejection Fraction (ENHANCE) trial aims to address this crucial clinical issue.

Identification of Candidates Developing CRT-induced Proarrhythmia Another emerging issue is that CRT-induced proarrhythmia, which might be related to the LV lead located within the epicardial scar.23 This is a rare but serious complication and is refractory to antiarrhythmic drugs. Switching off LV pacing presents a clinical dilemma since HF may deteriorate. Arrhythmia recurrence can be managed with catheter ablation but patients require a further intervention. An enhanced understanding of this complex clinical entity and early identification of patients developing CRT-induced proarrhythmia is important, and may amplify our knowledge of the potential complications of CRT.

Yu_FINAL.indd 36

Women and CRT Clinical data have shown that women benefit more from CRT in comparison with men24; however, fewer women than men were enrolled in CRT clinical trials. Greater recruitment of female candidates may improve the non-responders rate.24 Although CRT is not recommended in narrow QRS patients,25 in a study of individual patient data, women demonstrated benefit from CRT-defibrillator at a shorter QRS duration compared to men,26 which highlights the importance of genderspecific medicine.

Participation of Cardiac Resynchronisation Therapy in Clinical Practice Despite demonstrating substantial benefits, CRT is underutilised even in developed countries like US and Europe.27 It was estimated that, between 2002–2013, 100,000–430,000 HF patients in the US were potential candidates for CRT but did not receive the implantation.27 There are several reasons for the apparent gap between guidelines and real-world practice, the most important being risk and cost-related issues. (1) CRT is an expensive therapy, which is an obstacle in terms of reimbursement. Currently, the benefit of CRT outweighs the cost of HF within health systems and CRT is considered a cost-effective treatment compared with optimal medical therapy or implantable cardioverter-defibrillator (ICD). Data shows that the additional costeffectiveness ratio is $7,320 per quality-adjusted life year. A study conducted in Europe (Belgium) found that CRT in New York Heart Association (NYHA) class III and IV patients resulted in an incremental cost-effectiveness ratio of about €11,200 per quality-adjusted life year.28 Though CRT is a worthwhile investment in severe HF, its high expense hinders its use in developing countries. (2) Another issue affecting the use of CRT in clinical practice is its relatively high complication rate due to the complicated anatomy of the coronary vein. Implantation requires greater experience, skill and training compared with ICD or RV pacing implantation. Risks associated with CRT implantation include implantation dissection, lead displacement and dislodgement as well as phrenic nerve stimulation. (3) During a 20-year history, it is unsurprising that the benefits of CRT have been challenged, and was doubted its long-term results. A large percentage of patients received ICD despite showing indications for CRT. In addition, around on quarter of HF patients were implanted with RV pacing with frequent ventricular pacing percentage. More education with guideline-directed medical therapy in both patients and physician groups is required to tackle the low participation rate.

Promotion of Cardiac Resynchronisation Therapy in the Future The development of CRT keeps evolving, and is now applied in hypertrophic cardiomyopathy; congenital heart disease with different phenotypes of HF (systemic LV failure, RV failure and single ventricular failure); RV failure due to pulmonary hypertension and in patients with HF with preserved ejection fraction.29 The effectiveness of CRT is attenuated in atrial fibrillation, therefore a multimodal therapeutic approach, such as AV junction ablation30 or pulmonary vein isolation combined with CRT, may accentuate the response to CRT by means of rate control. In order to overcome technical hurdles to the wide application of CRT, the development of new technology is required. Access route of LV leads need to be improved in difficult patients including transventricular passage or percutaneous

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Cardiac Resynchronisation Therapy and Heart Failure: Angle from 5P Medicine

subxiphoid approach. The implantation of CRT using a sensor-based electromagnetic tracking system to facilitate LV placement has proven safe and successful.31 Multisite stimulation has emerged as a method of potentially overcoming non-response; this may be achieved by means of multiple leads or multipolar (quadripolar) LV leads.32 A leadless ultrasound-based technology for LV endocardial resynchronisation showed promising results in a pilot study.33 Safer and more effective lead and system extraction will be required in the

1. Heidenreich PA, Albert NM, Allen LA, et al. Forecasting the impact of heart failure in the United States: a policy statement from the American Heart Association. Circ Heart Fail 2013;6:606–19. 2. Sakata Y, Shimokawa H. Epidemiology of heart failure in Asia. Circ J 2013;77:2209–17. 3. Sanderson JE, Tse TF. Heart failure: a global disease requiring a global response. Heart 2003;89:585–6. 4. Steffel J, Milosevic G, Hurlimann A, et al. Characteristics and long-term outcome of echocardiographic super-responders to cardiac resynchronisation therapy: ‘real world’ experience from a single tertiary care centre. Heart 2011;97:1668–74. 5. Russo AM, Stainback RF, Bailey SR, et al. ACCF/HRS/AHA/ ASE/HFSA/SCAI/SCCT/SCMR 2013 appropriate use criteria for implantable cardioverter-defibrillators and cardiac resynchronization therapy: a report of the American College of Cardiology Foundation appropriate use criteria task force, Heart Rhythm Society, American Heart Association, American Society of Echocardiography, Heart Failure Society of America, Society for Cardiovascular Angiography and Interventions, Society of Cardiovascular Computed Tomography, and Society for Cardiovascular Magnetic Resonance. Heart Rhythm 2013;10:e11–e58. 6. Brignole M, Auricchio A, Baron-Esquivias G, et al. 2013 ESC Guidelines on cardiac pacing and cardiac resynchronization therapy: the Task Force on cardiac pacing and resynchronization therapy of the European Society of Cardiology (ESC). Developed in collaboration with the European Heart Rhythm Association (EHRA). Eur Heart J 2013;34:2281–329. 7. Khurshid S, Epstein AE, Verdino RJ, et al. Incidence and Predictors of Right Ventricular Pacing-Induced Cardiomyopathy. Heart Rhythm 2014;11:1619-25 8. Zhang XH, Chen H, Siu CW, et al. New-onset heart failure after permanent right ventricular apical pacing in patients with acquired high-grade atrioventricular block and normal left ventricular function. J Cardiovasc Electrophysiol 2008;19:136–41. 9. Frohlich G, Steffel J, Hurlimann D, et al. Upgrading to resynchronization therapy after chronic right ventricular pacing improves left ventricular remodelling. Eur Heart J 2010;31:1477–85. 10. Curtis AB, Worley SJ, Adamson PB, et al. Biventricular pacing for atrioventricular block and systolic dysfunction. N Engl J Med 2013;368:1585–93.

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event of system infection or dislodgement for CRT system. Last but not least, stand-alone devices with lower cost and remote monitoring will further consolidate the advantages of CRT. In summary, from proof-of-concept studies to clinical trials, CRT is undoubtedly an important therapy for a subgroup of HF patients. Further studies and initiatives are required to increase its utilisation in eligible patients. n

11. Chan JY, Fang F, Zhang Q, et al. Biventricular pacing is superior to right ventricular pacing in bradycardia patients with preserved systolic function: 2-year results of the PACE trial. Eur Heart J 2011;32:2533–40. 12. Yu CM, Chan JY, Zhang Q, et al. Biventricular pacing in patients with bradycardia and normal ejection fraction. N Engl J Med 2009;361:2123–34. 13. Yu CM, Fang F, Luo XX, et al. Long-term follow-up results of the pacing to avoid cardiac enlargement (PACE) trial. Eur J Heart Fail 2014;16:1016–25. 14. Alonso C, Leclercq C, Victor F, et al. Electrocardiographic predictive factors of long-term clinical improvement with multisite biventricular pacing in advanced heart failure. Am J Cardiol 1999;84:1417-1421. 15. Reuter S, Garrigue S, Barold SS, et al. Comparison of characteristics in responders versus nonresponders with biventricular pacing for drug-resistant congestive heart failure. Am J Cardiol 2002;89:346–50. 16. Yu CM, Bleeker GB, Fung JW, et al. Left ventricular reverse remodeling but not clinical improvement predicts long-term survival after cardiac resynchronization therapy. Circulation 2005;112:1580–6. 17. Zhang Q, Zhou Y, Yu CM. Incidence, definition, diagnosis, and management of the cardiac resynchronization therapy nonresponder. Curr Opin Cardiol 2015;30:40–9. 18. Hsu JC, Solomon SD, Bourgoun M, et al. Predictors of super-response to cardiac resynchronization therapy and associated improvement in clinical outcome: the MADIT-CRT (multicenter automatic defibrillator implantation trial with cardiac resynchronization therapy) study. J Am Coll Cardiol 2012;19;59:2366–73. 19. Castellant P, Fatemi M, Bertault-Valls V, et al. Cardiac resynchronization therapy: “nonresponders” and “hyperresponders”. Heart Rhythm 2008;5:193–7. 20. Fang F, Yu CM. Shall CRT-D be downgraded to CRT-P in superresponders of cardiac resynchronization therapy? Rev Esp Cardiol (Engl Ed) 2014;67:875–7. 21. Fang F, Chan JY, Yip GW, et al. Prevalence and determinants of left ventricular systolic dyssynchrony in patients with normal ejection fraction received right ventricular apical pacing: a real-time three-dimensional echocardiographic study. Eur J Echocardiogr 2010;11:109–18. 22. Fang F, Zhang Q, Chan JY, et al. Early pacing-induced systolic dyssynchrony is a strong predictor of left ventricular

23.

24.

25.

26.

27. 28.

29.

30.

31.

32.

33.

adverse remodeling: analysis from the Pacing to Avoid Cardiac Enlargement (PACE) trial. Int J Cardiol 2013;168:723–8. Roque C, Trevisi N, Silberbauer J, et al. Electrical storm induced by cardiac resynchronization therapy is determined by pacing on epicardial scar and can be successfully managed by catheter ablation. Circ Arrhythm Electrophysiol 2014;7:1064–9. Cipriani M, Ammirati E, Landolina M, et al. Cumulative analysis on 4802 patients confirming that women benefit more than men from cardiac resynchronization therapy. Int J Cardiol 2015;182C:454–6. Ruschitzka F, Abraham WT, Singh JP, et al. Cardiacresynchronization therapy in heart failure with a narrow QRS complex. N Engl J Med 2013;369:1395-1405. Zusterzeel R, Selzman KA, Sanders WE, et al. Cardiac resynchronization therapy in women: US Food and Drug Administration meta-analysis of patient-level data. JAMA Intern Med 2014;174:1340–8. Bank AJ, Gage RM, Olshansky B. On the underutilization of cardiac resynchronization therapy. J Card Fail 2014;20:696–705. Neyt M, Stroobandt S, Obyn C et al. Cost-effectiveness of cardiac resynchronisation therapy for patients with moderateto-severe heart failure: a lifetime Markov model. BMJ Open 2011;1:e000276. Fang F, Sanderson JE, Yu CM. Potential role of biventricular pacing beyond advanced systolic heart failure. Circ J 2013;77:1364–9. Wilton SB, Leung AA, Ghali WA, et al. Outcomes of cardiac resynchronization therapy in patients with versus those without atrial fibrillation: a systematic review and metaanalysis. Heart Rhythm 2011;8:1088–94. Richter S, Doring M, Gaspar T, et al. Cardiac resynchronization therapy device implantation using a new sensor-based navigation system: results from the first human use study. Circ Arrhythm Electrophysiol 2013;6:917–23. Rinaldi CA, Burri H, Thibault B, et al. A review of multisite pacing to achieve cardiac resynchronization therapy. Europace 2015;17:7–17. Auricchio A, Delnoy PP, Butter C, et al. Feasibility, safety, and short-term outcome of leadless ultrasound-based endocardial left ventricular resynchronization in heart failure patients: results of the wireless stimulation endocardially for CRT (WiSE-CRT) study. Europace 2014;16:681–8.

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Pulmonary Oedema

LE ATION.

e. lare.

Pulmonary Oedema—Therapeutic Targets Ovidiu Chioncel, 1 Sean P Collins, 2 Andrew P Ambrosy, 3 Mihai Gheorghiade 4 and Gerasimos Filippatos 5 1. Institute of Emergency for Cardiovascular Diseases ‘Prof. C.C. Iliescu’, University of Medicine and Pharmacy Carol Davila, Bucuresti, Romania; 2. Department of Emergency Medicine, Vanderbilt University, Nashville, Tennessee, US; 3. Duke University Medical Center, Durham, NC, US; 4. Center for Cardiovascular Innovation, Northwestern University Feinberg School of Medicine, Chicago, Illinois, US; 5. Athens University Hospital, Attikon, Athens, Greece

Abstract Pulmonary oedema (PO) is a common manifestation of acute heart failure (AHF) and is associated with a high-acuity presentation and with poor in-hospital outcomes. The clinical picture of PO is dominated by signs of pulmonary congestion, and its pathogenesis has been attributed predominantly to an imbalance in Starling forces across the alveolar–capillary barrier. However, recent studies have demonstrated that PO formation and resolution is critically regulated by active endothelial and alveolar signalling. PO represents a medical emergency and treatment should be individually tailored to the urgency of the presentation and acute haemodynamic characteristics. Although, the majority of patients admitted with PO rapidly improve as result of conventional intravenous (IV) therapies, treatment of PO remains largely opinion based as there is a general lack of good evidence to guide therapy. Furthermore, none of these therapies showed simultaneous benefit for symptomatic relief, haemodynamic improvement, increased survival and end-organ protection. Future research is required to develop innovative pharmacotherapies capable of relieving congestion while simultaneously preventing end-organ damage.

Keywords Pulmonary oedema, afterload, alveolar active signalling, therapies Disclosure: Dr Chioncel reports that he participated in the Executive Committee of trials sponsored by Novartis, outside the submitted work; Dr Collins reports grants from NIH/NHLBI, Medtronic, Cardiorentis, Abbott Point-of-Care, Novartis, The Medicines Company, Astellas, Intersection Medical, Radiometer, Trinity, Cardioxyl, and consulting from Trevena, Novartis, Otsuka, Radiometer, The Medicines Company, Medtronic, Intersection Medical, Cardioxyl, Abbott-Point-of-Care, outside the submitted work; Dr Ambrosy has nothing to disclose; DrGheorghiade reported research grants from Abbott Laboratories, Astellas, AstraZeneca, Bayer Schering Pharma AG, Cardiorentis Ltd, CorThera, Cytokinetics, CytoPherx, Inc, DebioPharm S.A., Errekappa Terapeutici, GlaxoSmithKline, Ikaria, Intersection Medical, INC, Johnson & Johnson, Medtronic, Merck, Novartis Pharma AG, Ono Parmaceuticals USA, Otsuka Pharmaceuticals, Palatin Technologies, Pericor Therapeutics, Protein Design Laboratories, Sanofi-Aventis, Sigma Tau, Solvay Pharmaceuticals, Sticares InterACT, Takeda Pharmaceuticals North America, Inc and Trevena Therapeutics; and has received signficant (> $10,000) support from Bayer Schering Pharma AG, DebioPharm S.A., Medtronic,Novartis Pharma AG, Otsuka Pharmaceuticals, Sigma Tau, Solvay Pharmaceuticals, Sticares InterACT and Takeda Pharmaceuticals North America, Inc., outside the submitted work; Dr Filippatos reports that he participated in the Executive Committee of trials sponsored by Novartis, Cardiorentis, Bayer, European Union, outside the submitted work. Received: 13 February 2015 Accepted: 4 March 2015 Citation: Cardiac Failure Review, 2015;1(1):38–45 Correspondence: Ovidiu Chioncel, MD, PhD, Institute of Emergency for Cardiovascular Diseases, University of Medicine and Pharmacy Carol Davila, Bucuresti, Romania. E: ochioncel@yahoo.co.uk

Acute heart failure (AHF) is a heterogeneous clinical including diverse phenotypes sharing similar presenting symptoms.1 The diversity of aetiologies and precipitants their specific pathophysiologic mechanisms, may result clinical profiles requiring specific treatment approaches.

syndrome signs and of HF and in distinct

Pulmonary oedema (PO) is a common manifestation of AHF associated with a high-acuity presentation and significant haemodynamic abnormalities. PO is defined as alveolar or interstitial oedema verified by chest X-ray and/or with arterial oxygen saturation <90 % on room air accompanied by severe respiratory distress.2

Epidemiology PO is the second most common clinical presentation of AHF syndromes (AHFS), though the prevalence and in-hospital mortality may exhibit substantial geographic variation (see Table 1).3–10 Moreover, overlapping features among AHF clinical profiles and/or the confounding presence

Chioncel_FINAL.indd 38

of noncardiac comorbidities may lead to incomplete or inaccurate classification. These patients are often not included in clinical trials due to their disease severity and inability to wait for study medication to be initiated. PO may be a deadly clinical manifestation of HF (see Table 1) and recent experience11 suggests the vast majority of deaths occurred soon after admission.

Pathophysiologic Mechanisms The pathogenesis of hydrostatic PO has been attributed predominantly to a difference in Starling forces12,13 (i.e. fluid extravasation attributable to an increased hydrostatic or reduced oncotic pressure gradient across the intact alveolo-capillary barrier). Furthermore, capacity of the lymphatic system to remove fluid from the interstitial space and to drain into the systemic veins is dependent on systemic venous pressure and the integrity of the lymphatics. The clinical picture of PO is dominated by pulmonary congestion due to an acutely increased afterload. Increases in afterload can be the primary mechanism

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Table 1: Prevalence, Demography, Clinical Presentation, In-Hospital Management, and In-Hospital Mortality Rate of Patients Admitted with Pulmonary Oedema in Recent European Heart Failure Registries EHFS II3 (2004–2005)

HF pilot4 (2009–2010)

RO-AHFS5 (2008–2009)

ALARM HF6 (20062007)

AHEAD7 (2006–2009)

OFICA8 (2009)

PO prevalence (%)

16.2

13.3

28.7

18.4

Age (years)

71.2±11

72.7±11

70.9 ± 10.4

–

73.8

Male (%)

59.4

–

49.7

–

55.9

Ischemic etiology (%)

56.5

70.8

31.8

67.4

LVEF >45 % (%)

38.4

26.7

25.3

AFib (%)

28.1

26.3

25.1

24.7

21.4

–

SBP (mmHg)

–

146±37

167.2±43.3

138.5+37.1

145 (95; 218)

130 (110–150)

HR (beats/minute)

100

97±24

103.4±25.3

109.5+25.2

98 (63; 141)

88 (73–104)

IV diuretics (%)

94.5

88.6

94.9

–

IV vasodilators (%)

72.7

62.5

73.6

50.3

–

IV inotropes (%)

14.6

18.4

20.1

8.8

NIMV (%)

20.5

–

1.8

10.8

9.2

15.4

IMV (%)

–

15.8

17.1

–

PO–ACM (%)

9.1

5.6

7.4

7.1

7.3

ACM = all-cause mortality; AFib = atrial fibrillation; AHEAD = Acute Heart Failure Database; ALARM-HF = Acute Heart Failure Global Survey of Standard Treatment; ESC-HF pilot = European Society of Cardiology – Heart Failure pilot study; EHFS II = European Heart Failure Survey II; HR = heart rate; IV = intravenous; LVEF = left ventricular ejection fraction; NIMV = noninvasive mechanical ventilation; OFICA = French Observational Survey on Acute Heart Failure; PO = pulmonary oedema; RO-AHFS = Romanian Acute Heart Failure Syndromes; SBP = systolic blood pressure.

Figure 1: Illustration of Pressure-dependent- and Pressure-independent Mechanisms Responsible for Pulmonary Oedema Formation and Resolution

O H2

Na CI

P AT

ATP

I Na C

Venous pool

Alveoli Na H2O

Na Na

ATP

O H2

O Na H2

K P AT

Na H2O

PCWP

Alveolar fluid clearance

O H2

Lymphatic drainage

LVEPD

PCWP

Capillaries SV

Primary increase in afterload

Decrease of inotropy

LVEPD Acute increase in afterload increases fluid transfer across alveolo-capillary membrane. Alveolar epithelial cells are involved in fluid formation and fluid clearance by regulation of sodium and chloride transfer via active signalling processes. Pulmonary oedema resolution depends on active sodium reabsorption as well as on capacity of intact lymphatics to drain fluids out of alveoli into systemic veins. LVEDP = left ventricular end diastolic pressure; PCWP = pulmonary capillary wedge pressure; SV = stroke volume.

responsible of PO inducing acute cardiac dysfunction and pulmonary congestion, or can be secondary to large cardiac dysfunction (see Figure 1).

than an acute adaptation in cardiac dimensions.11 This suggests there are smaller cardiac dimensions and a higher HR and diastolic blood pressure (DBP) in PO patients compared with other profiles.11

In a recent study,14 the mechanism of PO was described as a consequence of acutely increased afterload in patients with decreased systolic and diastolic capacity to adapt to changes in loading in the presence of maintained right ventricular function. It has been hypothesized that PO patients respond to increased afterload with an increase in heart rate (HR) and peripheral vasoconstriction rather

Peripheral congestion and body weight increases are documented in a relatively small proportion of PO patients, suggesting that relative volume redistribution as opposed to an absolute increase in total body fluid may play a major role in the pathophysiology of the PO phenotype (see Figure 2). The concept of fluid redistribution in PO is further supported by the studies, which have documented that the majority

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Pulmonary Oedema Figure 2: A. Clinical Signs at Initial Clinical Presentation; B. Time Delay to Presentation in Terms of Symptom Onset A. Clinical presentation

Pulmonary congestion Peripheral hypoperfusion Peripheral congestion Weight gain

100

(%)

80 60 40 20 0

ADHF

RHF

HTHF

B. Time delay to presentation 100

(%)

80 60

<6h 6–24h >24h

40 20 0

ADHF

RHF

HTHF

ADHF = acute decompensated heart failure; CS = cardiogenic shock; HTHF = hypertensive heart failure; PO = pulmonary oedema; RHF = right heart failure. Reproduced and modified from Chioncel et al., 2014.11 Figure 2 was originally published in the Journal of Cardiovascular Medicine as a publish-ahead-of-print version and may be subject to change upon final publication. It is reproduced here with the permission of Wolters Kluwer.

of patients gain little or no weight before heart failure hospitalization, despite the fact that filling pressures rise significantly.15–17 Sympathetically stimulated reduction in venous capacitance acts to shift volume out of the splanchnic vessels and increase the effective circulating blood volume,18 leading to increases in preload in the absence of any changes in total body weight. Although pressure-related mechanisms were considered sufficient to explain PO, recent studies show that cardiogenic PO is critically regulated by active signalling processes (see Figure 1), suggesting that endothelial and alveolar responses may contribute critically to the formation of hydrostatic PO. Absorption of excess alveolar fluid is an active process (see Figure 1) that involves transport of sodium out of alveolar air spaces with water following the sodium osmotic gradient. Active transepithelial transport of sodium from the airspaces to the lung interstitial space is a primary mechanism driving alveolar fluid clearance. This mechanism depends on sodium uptake by amiloridesensitive sodium channels on the apical membrane of alveolar type II cells followed by extrusion of sodium on the basolateral surface by the Na-K-ATPase.19–22 A major part of cardiogenic PO formation results from active epithelial secretion of chlorine and secondary fluid flux into the alveolar space.23 Transepithelial chlorine secretion is triggered by inhibition of epithelial sodium uptake and mediated via cystic fibrosis transmembrane conductance regulator (CFTR) and Na-K-2Cl-co-transporter 1 (NKCC1).23 Active sodium transport across the alveolar epithelium is also regulated via basolateral Na-K-ATPase and acute elevation of left atrial pressure inhibits active sodium transport by decreasing the number of Na-K-ATPase at the basolateral membrane of alveolar epithelial cells.22 Regulation of the Na-K-ATPase is elicited by stimulation of dopaminergic,24 β2 adrenergic receptors,25,26 and aldosterone, and

Chioncel_FINAL.indd 40

inhibited by oabain-like compounds.22,24–26 Furthermore, recent data suggest that lung injury and barrier dysfunction may play a role in the formation and resolution of congestion and pulmonary oedema.26

Therapeutic Targets As PO represents a medical emergency, treatment should be individually tailored to the urgency of the presentation, underlying pathophysiological mechanism, and acute haemodynamic characteristics. Clinical severity must be identified at the time of presentation, since the majority of the deaths occurred on the first day of admission.11 Systolic blood pressure (SBP) at presentation is one of the most cited predictors of in-hospital mortality in this subset of HF patients (see Table 2), and the recent guidelines recommend that patients with PO can be risk stratified even from the time of diagnosis and subjected to intense monitoring and treatments according to the value of SBP at admission.27 Beyond decongestion, rapid identification of precipitants and underlying aetiologies is a critical step in management of PO. As reported by registries, clinical scenario (acute myocardial infarction [AMI], cardiomyopathy) is predictive of short-term prognosis (see Table 2). The immediate objectives of PO treatment are to improve symptoms, reestablish tissue oxygenation, and stabilize the patient’s haemodynamic condition. Rapid improvement of dyspnea constitutes a major treatment goal and offers an estimate of treatment efficacy. Although dyspnea is directly attributed to pulmonary congestion as result of acute increases in filling pressure, its mechanisms are multifactorial. Overall, imbalance between the neural output of the brain and the resulting work performed by the respiratory muscles may result in dyspnea.28,29 Sensation of dyspnea can be increased by vascular distension and interstitial oedema, which may directly stimulate pulmonary vascular nerve endings. 30 Furthermore, an abrupt increase in pulmonary congestion directly leads to decreased pulmonary compliance, which further contributes to the tachypnea, tachycardia, and hypoxemia. Although, improved standardisation of dyspnea measurements has been proposed,31 a large area of uncertainty persists in terms of the factors associated with dyspnea relief.32 In spite of grading and scoring systems, in current clinical practice, evaluation of symptomatic improvement in the PO clinical profile is largely subjective and often based on clinician judgment. The clinical picture of PO is dominated by pulmonary congestion along with acutely increased afterload. As relative volume redistribution plays a major role in the pathophysiology of the PO,13 the therapeutic strategies should focus on transitioning back into the venous reservoir. This aim can be achieved by: 1) reducing pulmonary capillary hydrostatic pressure; 2) increasing lymphatic drainage by reducing systemic venous pressure; or 3) removing or displacing fluid from the alveoli (see Figure 1). An increase of left ventricular (LV) filling pressure and imbalances in Starling forces may explain transfer of fluids across alveolarcapillary membrane (see Figure 1). Further, the physiologic ability of alveolar epithelial cells to clear alveolar spaces from excess fluid is an active signalling process involving ion channels, mechanosensitive receptors, or adrenoreceptors.19,20,21,25 Very recent data suggest that targeting mechanisms that prevent barrier dysfunction26 and augment transepithelial sodium transport and enhance the clearance of alveolar oedema may lead to more effective prevention or treatment for PO.25,33 A search for the precipitant and underlying aetiology must be conducted early in the course of hospitalisation. It is important to identify

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those aetiologies that will not respond to conventional intravenous (IV) therapies, such as mechanical complications of AMI, valvular endocarditis, and prosthetic valve dysfunction. For these patients, mechanical circulatory support or rapid cardiac surgery may be life saving. Precipitant factors responsible for haemodynamic instability and the clinical presentation must also be identified and addressed. Even if decreasing afterload is the main target for therapeutic intervention in PO patients, in some instances, hypoxemia may be too severe or may not be promptly improved by pharmacotherapies. Mechanical ventilation (MV), either invasive or noninvasive, when appropriately addressed, is an effective measure to correct hypoxemia by displacing fluid out of the alveoli. The need for MV, either invasive or noninvasive, must be anticipated in order to avoid waiting too long or in a place without the proper facilities. Noninvasive MV (NIMV) should be considered as adjunctive therapy in patients with PO who have severe respiratory distress and early initiation of NIMV may potentially correct metabolic abnormalities and reduce the proportion of patients requiring intubation.34 In particular circumstances, aggressive treatment of pulmonary congestion may alter the fine balance between end-diastolic pressure and end-diastolic volume, which will negatively impact cardiac output (CO), SBP, and end-organ perfusion (renal, coronary). As a result, some patients may experience worsening of ischemia, life-threatening arrhythmias, or a decline in renal function during hospitalisation. Consequently, in addition to decreasing pulmonary congestion, therapeutic strategies should prevent end-organ damage and not increase the risk for ischemia, propensity for cardiac arrhythmias, and/ or permanently alter intrarenal haemodynamics.

Treatment Although, recent clinical registries3–8,11 have suggested the majority of patients admitted with PO rapidly improve as a result of conventional IV therapies, treatment of PO remains largely opinion-based as there is a general lack of good evidence to guide therapy.27 Moreover, most of the trial data are derived from an AHF population that does not resemble PO patients, and thus the data are not entirely generalisable to the PO clinical profile. Although multicenter, randomized, controlled trials have been conducted in patients with AHF, none of studied agents showed simultaneous benefit for symptomatic relief, haemodynamic improvement, preservation of end-organ function, and increased survival. Furthermore, with the exception of RELAX II35 and PRONTO,36 the timing of the interventions was more than 24 hours after presentation, raising relevant questions about the applicability of the results to PO patients.

Table 2: Prognostic Variables for All-cause Mortality in Pulmonary Oedema Patients A. Independent Prognostic Factors Associated with In-hospital Mortality in Observational Studies POPS (n=276 patients)10

–Low SBP at presentation

–WBC count

–AMI at presentation

–Heart rate

ALARM-HF survey (n=1,820 patients)6

–History of previous cardiovascular event

–Cardiomyopathy

–Low LVEF

–Low SBP

–Serum creatinine at presentation

–Treatment with diuretics

RO–AHFS study (n=924 patients)11

–Need for inotrope

–Need for invasive MV

–VFib, sVT during hospitalisation

–Acute coronary syndromes at presentation

–LBBB at admission

–BUN at presentation

–Age B. Independent Prognostic Factors Associated with 7–days Mortality in Clinical Trials 3CPO trial (n=1,062 pts)34

–Ability to obey commands

–Low SBP at presentation

–Age 3CPO = 3 Interventions in Cardiogenic Pulmonary Oedema; AMI = acute myocardial infarction; BUN = blood urea nitrogen; LBBB = left bundle brunch block; LVEF = left ventricular ejection fraction; MV = mechanical ventilation; POPS = Pulmonary Oedema Prognostic Score; RBBB = right bundle brunch block; SBP = systolic blood pressure; sVT = sustained ventricular tachycardia; VFib = ventricular fibrillation; WBC = white blood cell count.

hunger’). In vivo experiments have confirmed that IV morphine results in significant reduction in systemic vascular resistance (SVR) and venous return.37,38 Morphine may induce respiratory depression39 that may worsen hypoxemia in a patient already hypoxicemic and altered cerebral perfusion, leading to intubation. Furthermore, data from Acute Coronary Syndrome (ACS) registries40 and from HF registries41 suggest that morphine therapy was associated with an increase in mortality, need for intensive care unit (ICU) admission, and intubation. The use of IV diuretics and vasodilators can decrease pulmonary congestion and avoid morphine’s adverse effects on respiratory drive. Morphine may be useful in some patients with PO in the setting of myocardial ischemia when analgesia is required, as morphine reduces anxiety and relieves the pain.

Diuretics In clinical practice, acute management of PO is based on IV opiates, diuretics, vasodilators, inotropes, and MV. In approximately 70–80 % of cases, PO patients are treated with combinations of IV therapies.6,11 Data from recent registries11 showed there is a specific pattern of utilisation of IV therapies (i.e. high doses for short duration), which may explain the patients’ in-hospital course and adverse outcomes.

Morphine Morphine is commonly used in the treatment of PO, despite the lack of evidence supporting its efficacy. Morphine is given to cause systemic vasodilatation and alleviate the anxiety related to dyspnea (i.e. ‘air

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Intravenous loop diuretics are an essential component of PO treatment, and recent guidelines27 consider IV diuretics as first-line therapy. Analysis of recent registries (see Table 1) shows that IV diuretics are administered to approximately 90 % of patients who are hospitalized for PO. Furosemide was the most commonly used diuretic. Loop diuretics inhibit reabsorption of NaCl and produce natriuresis and diuresis. The diuretic effect occurs 35–45 minutes after IV administration. They act by inhibiting the renal Na/2Cl/K co-transporter in the luminal membrane of the thick ascending limb of loop of Henle, which is responsible for the reabsorption of 35 % of filtered sodium.42 Of note, furosemide inhibits the same Na/2Cl/K

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Pulmonary Oedema co-transporter in alveolar epithelial cells altering transepithelial chloride secretion and increasing alveolar fluid clearance and oedema resolution.23

tolerance,50 defined as a loss of hemodynamic effect despite dose escalation, may develop within hours, and may contribute to the pattern of IV nitrate utilisation observed in registries.

Furthermore, IV furosemide produces direct venodilation, an effect that can be seen as rapidly as 2–5 minutes after administration. The direct venodilation was inhibited by local indomethacin administration but not by blockade of nitric oxide (NO) synthesis, indicating that the direct vascular venodilation is dependent on local prostaglandin but not on NO production.43 The rapid reduction in venous return produced by furosemide usually occurs before diuresis and may be therapeutically relevant for obtaining symptomatic improvement in PO. However, the net venodilatory effect of furosemide is difficult to assess, since the decrease of circulating volume produced by furosemide is at the cost of neurohormonal activation.44 Historically, direct venodilation has been one argument for IV diuretic use in PO since the main pathophysiology of PO is represented by fluid redistribution rather than overall fluid accumulation. The efficacy of loop diuretic use is also balanced by limitations of diuretic resistance, neurohormonal activation, and worsening renal function (WRF).

Nesiritide, a recombinant B-type natriuretic peptide (BNP) with vasodilatory properties, is associated to significant decrease of pulmonary capillary wedge pressure (PCWP).52,53 Compared with NTG, nesiritide resulted in significant decrease of filling pressure but there was no difference between nesiritide and NTG in terms of dyspnea improvement.54 In the pivotal ASCEND-HF trial,55 nesiritide showed moderate dyspnea improvement, but neutral effects on mortality and re-hospitalisations and was associated with an increase in rates of hypotension.

One major concern with use of IV loop diuretic is the phenomenon of nephron adaptation, which occurs in patients previously exposed to long-term use of oral furosemide. Chronic furosemide treatment may induce ‘nephron adaptation’, respectively a reactive increase in active transcellular sodium transport capacity in the tubular segments situated distally to the site of action of furosemide.45 This

Relaxin is a hormone that induces NO activation of guanylate cyclase (GC) and triggers haemodynamic adaptive changes that occur during pregnancy. The recombinant human form, serelaxin, demonstrated potential hemodynamic benefits for AHF patients. In experimental studies,56,57 serelaxin decreased SVR concomitant to increase (CO) and renal blood flow. In a phase III placebo-controlled trial, which enrolled patients within 16 hours of presentation,58 serelaxin improved visual analog scale (VAS)-assessed dyspnea, but did not significantly improve dyspnea as measured by a Likert scale. In spite of the lack of benefit on in-hospital mortality, serelaxin significantly improved 180-day allcause mortality. A recent exploratory analysis of the mortality benefit in RELAX-AHF suggested serelaxin improved markers of cardiac, renal, and hepatic function early during AHF hospitalisation.59 Hence,

may result in a reduced natriuretic response at conventional IV diuretic doses45,46 and possibly explain utilisation of higher doses of IV diuretics in PO patients.

improved dyspnea relief, preserved end-organ function, and less use of concomitant IV therapies may support improved long-term outcomes with novel agents in AHF.

There are substantial variations in clinical practice concerning dosing, mode of administration, and duration of therapy, since there is very little Level A, Class I evidence available. A prospective trial comparing four strategies (high versus low dose; bolus versus continuous administration) showed no significant differences in terms of dyspnea improvement or 60-day outcomes.47 However, the high-dose strategy was associated to a trend with a trend toward greater dyspnea improvement at the cost of transient WRF that did not appear to have long-term consequences. Current guidelines27 recommend as the first IV furosemide dose to be 2.5 times the existing oral dose in PO patients already taking diuretic.

Although, some studies have shown that soluble guanylyl cyclase (sGC) activators may offer organ-protective qualities,60,61 particularly for renal function, a recent study with cinaciguat suggested no clear symptomatic benefit of this therapy.62 In spite of decreasing PCWP, cinaciguat decreased SBP without improving dyspnea or cardiac index.

Vasodilators According to recent guidelines,27 vasodilators may be considered as an adjuvant to diuretic therapy for dyspnea relief when SBP remains >110 mmHg. Interestingly, SBP is used as a safety signal and not as marker of efficacy. IV nitroglycerin (NTG) is primarily a venodilator that lowers preload and reduce pulmonary congestion.48 The hemodynamic benefit of NTG is produced by activation of cyclic guanosine monophosphate (cGMP)-dependent protein kinases.49 NTG produces redistribution of blood from the central circulation into larger capacitance veins, decreasing pulmonary venous congestion and decreasing LV impedance, which results in a decrease in left atrial pressure.50 Concomitant high-dose nitrate therapy and low-dose IV furosemide51 was associated with a reduced need for intubation and a lower risk of other cardiovascular events compared with highdose IV furosemide in PO patients. Utilisation of IV nitrates in AHF is limited by reactive neurohormonal activation and tolerance. Nitrate

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Clevipidine, an ultra-short-acting dihydropyridine calcium antagonist with a high degree of vascular selectivity, has been studied in hypertensive AHF in an open-label design study.36 Clevidipine was initiated very shortly after presentation (i.e. median time 149 minutes) and was associated with marked improvement of dyspnea, lower rates of ICU admissions, and reduced length of stay compared with usual care supporting a new model of intervening within the first few hours after presentation.

Inotropes The majority of patients admitted with PO have pulmonary congestion related to high LV filling pressures. Although most are hypertensive or normotensive on admission, approximately 10–15 % of PO patients present with low SBP as a result of low CO6,11 and inotropic agents are required. Other PO patients may experience an unexpected and abrupt decrease of SBP during hospitalisation as result of aggressive treatment of pulmonary congestion or resolution of a reactive stress response. This subset subsequently requires IV inotropes to maintain CO and perfusion pressure. Low SBP at presentation or signs of tissue hypoperfusion, as well as need of inotropic therapies, were all variables associated with short-term mortality in registries enrolling PO patients (see Table 2). The most commonly used inotropes are sympatomimethic agents (i.e. dobutamine and dopamine). These

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agents have been associated with adverse events such as ischemia, tachyarrhythmias, and hypotension, and may increase in-hospital and postdischarge mortality.63,64 However, as systemic hypoperfusion in the setting of low CO occurs, sympathomimetic agents remain a mainstay of therapy, despite their associated long-term adverse events, probably mediated through worsening myocardial injury. For sympathomimetic agents, previous treatment with beta-blockers may greatly influence the anticipated clinical response. Other inotropic agents, non-AmpC dependent, have been tested in clinical trials but with unfavourable results. The short-term use of milrinone, an IV inotrope with vasodilatory properties, has been associated with an increase in postdischarge mortality.65,66 The negative impact on mortality of these agents is considered to be related to myocardial injury as a result of a reduction in SBP and subsequently in coronary perfusion. Levosimendan exerts positive inotropic effects by enhancing calcium sensitivity of the cardiac contractile elements and exerts direct peripheral vasodilator effects by blocking ATP-dependent potassium channels in vascular smooth muscle.67 These effects are not attenuated by concomitant treatment with beta-blockers and are sustained beyond the duration of the drug infusion because levosimendan has an active metabolite with a long half-life.1,63,64,66,67 Levosimendan demonstrated a favorable haemodynamic profile in preclinical and clinical studies63 as it reduced PCWP and increased CO, suggesting potential benefit for patients with PO with low or normal SBP. However, when tested in rigorous randomized double-blind trials,68,69 levosimendan showed only modest clinical improvement, and was associated with hypotension, atrial and ventricular arrhythmias, and, in one trial, a trend toward an increase in early mortality.68 Istaroxime is a new agent with dual inotropic and lusitropic properties. Istaroxime inhibits Na/K ATPase and stimulates sarcoplasmic reticulum calcium ATPase.70 In patients hospitalized with HF, istaroxime decreased PCWP and improved diastolic function. Compared with sympathomimetic agents, istaroxime increased SBP and decreased HR and myocardial oxygen demand, characteristics suggesting a possible role in preventing myocardial injury.71 Although this agent was studied only in chronic HF: reduced ejection fraction (HFrEF), it seems to be an ideal agent for PO patients presenting with low or normal SBP. Stresscopin, a corticotropin-releasing factor type 2 receptor (CRFR2) selective agonist,71 has intrinsic inotropic properties via stimulation of G-protein family. In a recent trial,72 stresscopin increased CO and decreased SVR without significantly affecting HR or SBP, highlighting its potential advantage over standard inotropic agents. However, there was a significant decrease in DBP, which could have an unfathomable effect on coronary perfusion pressure.72

Even if invasive MV is a life-saving therapy in the care of critically ill patients, it use must be balanced with the potential deleterious cardiac effects.73 In a PO patient with hypertension, a decrease in preload may be beneficial. However, in a hypotensive patient a decrease in preload may lead to a decrease in CO and SBP. Other potential complications need to be considered, such as barotrauma, and systemic infections.74 Although the use of invasive MV was predictive of ACM (see Table 2), the prognosis of PO patients treated with MV may depend more on the severity of the hemodynamic perturbation rather than the degree of respiratory failure.73 NIMV may be considered as adjunctive therapy in patients with PO who have severe respiratory distress or whose condition does not improve with pharmacologic therapy.34 In a randomized study75 early NIMV therapy for PO patients decreased the need for invasive MV and its attendant complications and appeared to augment the response to therapies. PO patients with early NIMV exhibited significantly less respiratory fatigue and translated in lower rate of tracheal intubation. The treatment delay relative to time of hospital presentation may have substantial consequences on patient outcomes such as mortality, need for subsequent tracheal intubation, or subsequent cardiovascular deterioration requiring further medical care. When NIMV fails to improve oxygenation and respiratory acidosis, or encephalopathy worsens, intubation should be considered without delay.

Therapies Targeting Alveolar Ion and Fluid Transport Pathways Although these agents were studied only in experimental studies, their knowledge may be clinically relevant as some of IV therapies and particular HF background therapies, such as digoxin, mineralocorticoid receptor antagonists, and diuretics may interfere with function of these channels. Clinical studies show that impaired alveolar ionic and fluid transport mechanisms contribute to the development, severity, and outcome of PO in humans. β2-adrenergic receptor signalling is required for upregulation of alveolar epithelial active sodium transport in the setting of excess alveolar oedema. The positive, protective effects of β2-adrenergic receptor signalling on alveolar active sodium transport provide substantial support for the use of β2-adrenergic agonists to accelerate alveolar fluid clearance in patients with PO, and some evidence suggests that pharmacologic treatment with β2-adrenergic agonists facilitate recovery from experimental PO.25,26

The objectives of MV, either invasive or noninvasive, are to improve oxygenation, to reduce work of breathing, to move alveolar and interstitial fluids into capillaries, to reverse respiratory acidosis and hypercapnia, and finally to improve tissue perfusion.

Active sodium transport across the alveolar epithelium is controlled by basolateral Na-K-ATPase.19,22,25,76 Na-K-ATPase is positively regulated by GCs, aldosterone, catecholamines (β2 and dopaminergic), and growth hormones, and inhibited by oabain-like compounds and mechanical signalling induced by increased left atrial pressure.19,22,24,25,77 In some experimental studies,78 aldosterone increased the Na-KATPase function and accelerated the clearance of hydrostatic PO, suggesting that aldosterone may be used as a strategy to increase lung oedema clearance.

The decision to initiate MV must be anticipated and should be based on clinical judgment, considering the overall clinical picture, but should not be delayed until the patient is in extremis or has an altered level of consciousness.

Transient receptor potential vanilloid receptor 4 (TRPV4) is as one of the most potent agents that inhibit pressure-induced alveolar permeability and it was identified as a promising therapeutic strategy for the treatment of PO.79,80–82 TRPV4 was linked to elevated pulmonary

Ventilation

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Pulmonary Oedema vascular pressure-mediated Ca2+ uptake by lung endothelium and subsequent acute lung injury. 80,83 TRPV4 is involved in multiple pathways 81,82 including a role in lung vasomotor control, the inflammatory response, and its specific role in resolving PO should be carefully judged.

Conclusions Patients with PO can be risk stratified from the time of initial presentation and diagnosis, and require intense therapy, which is often

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a rat model of elevated left atrial pressure, Circulation, 2002;105:497–501. Solymosi EA, Kaestle-Gembard SM, Vadász I, et al. Chloride transport-driven alveolar fluid secretion is a major contributor to cardiogenic lung edema, Proc Natl Acad Sci U S A, 2013;110:E2308–16. Guerrero C, Lecuona E, Pesce L, et al. Dopamine regulates Na-K-ATPase in alveolar epithelial cells via MAPKERKdependent mechanisms, Am J Physiol Lung Cell Mol Physiol, 200;281:L79–L85. Mutlu GM, Snajder JI, Mechanisms of pulmonary edema clearance, Am J Physiol Lung Cell Mol Physiol, 2005;289:L685–95. Alexanian IP, Farmakis D, Korovesi I, et al. Exhaled breath condensate in acute and chronic heart failure: new insights into the role of lung injury and barrier dysfunction, Am J Respir Crit Care Med, 2014;190:342–5. McMurray JJ, Adamopoulos S, Anker G, 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 Fail, 2012;14:803–69. Manning HL, Schwartzstein RM, Pathophysiology of dyspnea, N Engl J Med, 1995;333:1547–53. Gehlbach BK, Geppert E, The pulmonary manifestations of left heart failure, Chest, 2004;125:669–82. Snashall PD, Chung KF, Airway obstruction and bronchial hyperresponsiveness in left ventricular failure and mitral stenosis, Am Rev Respir Dis, 1991;144:945–56. Mebazaa A, Pang PS, Tavares M, et al. The impact of early standard therapy on dyspnoea in patients with acute heart failure: the URGENT-dyspnoea study, Eur Heart J, 2010;31:832–41. Gheorghiade M, Follath F, Ponikowski P, et al. Assessing and grading congestion in acute heart failure: a scientific statement from the acute heart failure committee of the heart failure association of the European Society of Cardiology and endorsed by the European Society of Intensive Care Medicine, Eur J Heart Fail, 2010;12:423-33 Sartori C, Matthay MA, Scherrer U, Transepithelial sodium and water transport in the lung. Major player and novel therapeutic target in pulmonary edema, Adv Exp Med Biol, 2001;502:315–38. Gray A, Goodacre S, Newby DE, et al. Noninvasive ventilation in acute cardiogenic pulmonary edema, N Engl J Med, 2008;359:142–51. Teerlink JR, Cotter G, Davison BA, et al. Serelaxin, recombinant human relaxin-2, for treatment of acute heart failure (RELAX-AHF): a randomised, placebo-controlled trial, Lancet, 2013;381:29–39. Peacock WF, Chandra A, Collins S, et al. Clevidipine in acute heart failure: Results of the A Study of Blood Pressure Control in Acute Heart Failure–A Pilot Study (PRONTO), Am Heart J, 2014;167:529–36. Vismara LA, Leaman DM, Zelis R, The effects of morphine on venous tone in patients with acute pulmonary oedema, Circulation, 1976;54:335. Grossmann M, Abiose A, Tangphao O, et al. Morphineinduced venodilation in humans, Clin Pharmacol Ther, 1996;60:554–60. Dahan A, Aarts L, Smith TW, Incidence, reversal, and prevention of opioid-induced respiratory depression, Anesthesiology, 2010;112:226–38. Meine TJ, Roe MT, Chen AY, et al. The association of intravenous morphine use and outcomes in acute coronary syndromes: Results from the CRUSADE Quality Improvement initiative, Am Heart J, 2005;149:1043–9. Peacock WF, Hollander JE, Diercks DB, et al. Morphine and outcomes in acute decompensated heart failure: an ADHERE analysis, Emerg Med J, 2008;25:205–9. Brater DC, Pharmacology of diuretics, Am J Med Sci, 2000;319:38–50. Pickkers P1, Dormans TP, Russel FG, et al. Direct vascular effects of furosemide in humans, Circulation, 1997;96:1847– 52. Francis GS, Benedict C, Johnstone DE, et al. Comparison of neuroendocrine activation in patients with left ventricular dysfunction with and without congestive heart failure. A substudy of the Studies of Left Ventricular Dysfunction (SOLVD), Circulation, 1990;82:1724–9. Kaissling B, Bachmann S, Kriz W, Structural adaptation of the distal convoluted tubule to prolonged furosemide treatment,

Am J Physiol, 1985;248:F374–F381. 46. Loon NR, Wilcox CS, Unwin RJ, Mechanism of impaired natriuretic response to furosemide during prolonged therapy, Kidney Int, 1989;36:682–9. 47. Felker GM, Lee KL, Bull DA, et al. Diuretic strategies in patients with acute decompensated heart failure, N Engl J Med, 2011;364:797–805. 48. Elkayam U, Akhter MW, Singh H, et al. Comparison of effects on left ventricular filling pressure of intravenous nesiritide and high-dose nitroglycerinin patients with decompensated heart failure, Am J Cardiol, 2004;93:237–40. 49. Munzel T, Feil R, Mulsch A, et al. Physiology and pathophysiology of vascular signaling controlled by guanosine 3_,5_-cyclic monophosphate-dependent protein kinase, Circulation, 2003;108:2172–83. 50. Münzel T, Daiber A, Gori T, Nitrate Therapy New Aspects Concerning Molecular Action and Tolerance, Circulation, 2011;123:2132–44. 51. Cotter G, Metzkor E, Kaluski E, et al. Randomised trial of highdose isosorbide dinitrate plus low-dose furosemide versus high-dose furosemide plus low-dose isosorbide dinitrate in severe pulmonary edema, Lancet, 1998;351:389–93. 52. Clarkson PB, Wheeldon NM, Macleod C, et al. Brain natriuretic peptide: effect on left ventricular filling patterns in healthy subjects, Clin Sci (Lond), 1995;88:159–64. 53. Colucci WS, Elkayam U, Horton DP, et al. Intravenous nesiritide, a natriuretic peptide, in the treatment of decompensated congestive heart failure, N Engl J Med, 2000;343:246–53. 54. Publication Committee for the VMAC Investigators (Vasodilatation in the Management of Acute CHF). Intravenous nesiritide vs nitroglycerin for treatment of decompensated congestive heart failure: a randomized controlled trial, JAMA, 2002;287:1531–40. 55. O’Connor CM, Starling RC, Hernandez AF, et al. Effect of nesiritide in patients with acute decompensated heart failure, N Engl J Med, 2011;365:32–43. 56. Debrah DO, Conrad KP, Jeyabalan A, et al. Relaxin increases cardiac output and reduces systemic arterial load in hypertensive rats, Hypertension, 2005;46(4):745–50. 57. Conrad KP, Debrah DO, Novak J, et al. Relaxin modifies systemic arterial resistance and compliance in conscious, nonpregnant rats, Endocrinology, 2004;145:3289–96. 58. Teerlink JR, Metra M, Felker GM, et al. Relaxin for the treatment of patients with acute heart failure (Pre-RELAXAHF): a multicentre, randomised, placebo controlled, parallel-group, dose-fi nding phase IIb study, Lancet, 2009;373:1429–39. 59. Metra M, Cotter G, Davison BA, et al. Effect of serelaxin on cardiac, renal, and hepatic biomarkers in the Relaxin in Acute Heart Failure (RELAX-AHF) development program: correlation with outcomes, J Am Coll Cardiol, 2013;61:196–206. 60. Tamargo J, Duarte J, Caballero R, Delpon E, Cinaciguat, a soluble guanylate cyclase activator for the potential treatment of acute heart failure, Curr Opin Investig Drugs, 2010;11:1039–47. 61. Benz K, Orth SR, Simonaviciene A, et al. Blood pressureindependent effect of long-term treatment with the soluble heme-independent guanylyl cyclase activator HMR1766 on progression in a model of noninflammatory chronic renal damage, Kidney Blood Press Res, 2007;30:224–33. 62. Gheorghiade M, Greene SJ, Filippatos G, et al. Cinaciguat, a soluble guanylate cyclase activator: results from the randomized, controlled, phase IIb COMPOSE programme in acute heart failure syndromes, Eur J Heart Fail, 2012;14:1056– 66. 63. Thackray S, Easthaugh J, Freemantle N, Cleland JG, The effectiveness and relative effectiveness of intravenous inotropic drugs acting through the adrenergic pathway in patients with heart failure—a meta-regression analysis, Eur J Heart Fail, 2002;4:515–29. 64. Gheorghiade M, Vaduganathan M, Ambrosy A, Current management and future directions for the treatment of patients hospitalized for heart failure with low blood pressure, Heart Fail Rev, 2013;18:107–22. 65. Cuffe MS, Califf RM, Adams KF Jr, et al. Short-term intravenous milrinone for acute exacerbation of chronic heart failure: a randomized controlled trial, JAMA, 2002;287:1541–7. 66. De Luca L, Mebazaa A, Filippatos G, et al. Overview of emerging pharmacologic agents for acute heart failure syndromes, Eur J Heart Fail, 2008;10:201–13.

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67. Nieminen MS, Akkila J, Hasenfuss G, Hemodynamic and neurohumoral effects of continuous infusion of levosimendan in patients with congestive heart failure, J Am Coll Cardiol, 2000;36:1903–12. 68. Packer M, Colucci W, Fisher L, et al. Effect of levosimendan on the short-term clinical course of patients with acutely decompensated heart failure, JACC Heart Fail, 2013;1:103–11. 69. Mebazaa A, Nieminen MS, Packer M, et al. Levosimendan vs dobutamine for patients with acute decompensated heart failure: the SURVIVE randomized trial, JAMA, 2007;297:1883–91. 70. Hsu SY, Hsueh AJ, Human stresscopin and stresscopinrelated peptide are selective ligands for the type 2 corticotropin-releasing hormone receptor, Nat Med, 2001;7:605–11. 71. Gheorghiade M, Blair JE, Filippatos GS, et al. Hemodynamic, echocardiographic, and neurohormonal effects of istaroxime, a novel intravenous inotropic and lusitropic agent: a randomized controlled trial in patients hospitalized

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Biol, 2001;47:347–61. 77. Pesce L, Comellas A, Sznajder JI, Beta-adrenergic agonists regulate Na-K-ATPase via p70S6k, Am J Physiol Lung Cell Mol Physiol, 2003;285:L802-7. 78. Olivera WG1, Ciccolella DE, Barquin N, et al. Aldosterone regulates Na,K-ATPase and increases lung edema clearance in rats, Am J Respir Crit Care Med, 2000;161(2 Pt 1):567–73. 79. Vincent F, Duncton AJ, TRPV4 Agonists and Antagonists, Curr Top Med Chem, 2011;1117:2216–26. 80. Bakthavatchalam R, Kimball SD, Modulators of Transient Receptor Potential Ion Channels, Annu Rep Med Chem, 2010;45:37–53. 81. TRPV4: an exciting new target to promote alveolocapillary barrier function, Am J Physiol Lung Cell Mol Physiol, 2014 307:L817–L821. 82. Yue Z, Xie J, Yu AS, Role of TRP channels in the cardiovascular system, Am J Physiol Heart Circ Physiol, 2015;308:H157–H182.

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Exercise Training

LE ATION.

e. lare.

Assessment for Exercise Prescription in Heart Failure Marco Guazzi Heart Failure Unit, IRCCS Policlinico San Donato, University of Milano, Italy

Abstract Exercise training (ET) is a Guidelines Class 1A level of evidence adjunct therapy for heart failure (HF) with reduced ejection fraction treatment. As yet less certain is the role of ET for HF with preserved ejection fraction. Different ET types (endurance and resistance) and levels of intensity or domains (light, light-to-moderate and high-to-moderate) are used for ET programmes in patients with cardiac failure. Assessment of ET prescription can be performed through indirect (heart rate reserve) or direct metabolic measures (VO2 reserve, ventilatory threshold) with the most precise methodology based on the analysis of VO2 kinetics during constant work rate protocols of different workloads. The goals of assessing the effects of exercise prescription on functional capacity are traditionally represented by changes in VO2 during peak exercise by cardiopulmonary exercise testing (CPET). Nonetheless, the specific evaluation of how ET may favourably affect the abnormal patterns of VO2 linearity for work rate increase and the effects on ventilation seem important adjunctive parameters to be evaluated and monitored. Although a minority, some HF patients may not respond to ET programmes. This specific phenotype, once appropriately identified, needs a different approach and – intriguingly – should be switched to a higher ET intensity domain to yield the most comprehensive benefits from a personalised ET intervention.

Keywords Exercise training, heart failure, oxygen uptake, exercise ventilation, oxygen kinetics Disclosure: The author has no conflicts of interest to declare. Acknowledgements: The present investigation was supported by a grant provided by the Monzino Foundation, Milano, Italy. Received: 3 February 2015 Accepted: 4 March 2015 Citation: Cardiac Failure Review, 2015;1(1):46–9 Correspondence: Marco Guazzi, MD, PhD, FACC, FAHA, University of Milano, Department of Biomedical Sciences for Health, Heart Failure Unit-Cardiology, IRCCS Policlinico San Donato, Piazza E. Malan 2, 20097, San Donato Milanese, Milano, Italy. E: marco.guazzi@unimi.it

One of the most challenging nonpharmacological interventions to face heart failure (HF) and its consequent hallmark exercise intolerance is exercise training (ET), which is an approach used since early 1990s in HF with reduced ejection fraction (HFrEF) to mitigate the abnormal pathophysiology of cardiac failure and its influence on clinical outcomes.1,2 Its practice has been more recently extended to HF with preserved ejection fraction (HFpEF) as this population3 is similarly limited by fatigue and dyspnoea. ET benefits involve multiple organ systems, but the extent and targets of ET vary according to the protocol used.4 ET can be planned according to different modalities (bike or treadmill); types (endurance versus resistance or their combination); intensity (continuous low or moderate intensity, or high intensity interval); frequency (weekly volume) and session dose or duration. Frequency and dose of ET are intuitively and casually dependent on the intensity, i.e. for the lower intensity the most frequent and longer session. The purpose of this review is to briefly describe: how to plan a training session and determine the correct ET intensity level or domain; how to assess benefits of exercise prescription by monitoring functional capacity and its related phenotypes; and how to identify subjects who – despite adherence to the programme – are non- or poor-responders to this multilevel intervention.

intensity domain by gas exchange analysis through cardiopulmonary exercise testing (CPET). Even when exercise intensity is indirectly estimated, measurement of VO2 by CPET should be considered.5–7 The most common and widely applied indirect method for ET prescription is based on heart rate (HR), which is used as a reference variable assuming that the relationship between HR and work rate (WR) is linear.8,9 Thus, with the peak exercise corresponding to peak HR, the intensity is indirectly determined by regression equations or tables as the percentage of the peak HR value at a given percentage of peak VO2 – generally ranging between 70 and 85 % of maximum predicted VO2.7 An important concept when using HR for exercise prescription is the concept of HR reserve (HRR), defined as the difference between HR at rest and peak exercise. An HRR percentage equal to 60 % has been identified as corresponding at the first ventilatory threshold (1st VT) in both normal and HF patients (see Figure 1).10 Practically, ET sessions for cardiac patients are proposed at a range of 40–70 % HRR.11 Another indirect parameter proposed by the most recent joint position statement 7 for planning ET programmes, is the VO2 reserve calculated as: (peak VO2-rest VO2) x (% intensity desired) + rest VO2. VO2 reserve provides an indicator of exercise intensity by reflecting the true amount of energy for maximal exercise attainment, taking into account baseline levels.7

How to Plan an ET Programme Exercise intensity for an ET programme may be planned by indirect exercise intensity assessment or through a direct identification of exercise

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In order to optimise ET prescription, a comprehensive use of CPETderived information is highly suggested for a pathophysiologically

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Assessment for Exercise Prescription in Heart Failure

and clinically precise determination of ET intensity level. A range of aerobic exercise testing, from light- to moderate- to high- to severe-intensity aerobic training, have been used with HF patients with variable effectiveness, according to patients’ characteristics and predefined target of intervention.12,13 The simpler and more effective way to plan ET programmes of mild to moderate intensity is the assessment of VO2 at the first ventilatory threshold, that is the metabolic condition above which blood lactic acid and pH starts to increase and decrease, respectively, generating a HCO3 buffering of the incoming acidosis. The 1st VT can be determined by three CPET-derived methods. The first is the V-slope, the point at which the incremental VCO2 production becomes higher than VO2 due to the additional CO2 produced by lactic acid buffering (see Figure 1a) with a slope of less than one to greater than one. There are two other gas exhange derived methods. One relies on the pattern of changes in ventilation (VE) to carbon dioxide (VCO2) production and VE to VO2 ratios, identifying the point of continuous increase in VE/VO2 and stable VE/VCO2 kinetics (see Figure 1b). The other is based on the definition of the point of divergent kinetics of the end-tidal partial pressure (PET) of CO2 vs the PETO2 (see Figure 1C).5

Figure 1: Non-invasive Identification of the 1st VT and 2nd VT by CPET Evaluation VCO2

2nd VT

1st VT

V slope

VO2 B VE/VO2 vs VE/VCO2

VE/VCO2 VE/VO2

With increasing exercise intensity and lactic acid production above the 1st VT a second point is reached when bicarbonates no longer adequately compensate for metabolic acidosis. This is the second ventilatory threshold (2nd VT) (see Figure 1a) and is when hyperventilation occurs and ventilatory alkalosis develops. At this stage the VE/VCO2 ratio increases and inverts its trend and

PETO2 2nd VT

PETO2 vs PETCO2

PETCO2

PETCO2 decreases (see Figure 1 b,c). The 1st VT signals the limit between mild-to-moderate and the moderate-to-high intensity domains corresponding to around 50–60 % of peak VO2 and 60–70 % of peak HR. Admittedly, in advanced HF and in a rate of approximately 20 %, VO2 at 1st VT cannot be determined. When identifiable, the 2nd VT is usually attained at around 70–80 % peak VO2 and 80–90 % peak HR reached during incremental exercise.

Figure 2: Study of VO 2 kinetics A

VO2∞

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

Guazzi_FINAL.indd 47

Intensity damains

Asymptotic value

Light-to-moderate Moderate-to-high

Exercise

VO2

Recovery

High-to-severe Severe-to-extreme

Rest

VO20

} }

Continuous

Interval

T1 t1+ ł1

Time

VO2t1+ ł1- VO20= 0.63 .(VO2∞ - VO20)

VO2 kinetics at increasing constant work rate VO2 max 120 % 2nd VT (CP)

100 %

80 % data

High to severe 40 % data

VO2

(ml/min) 1st VT

The recent joint position statement of the European Association for Cardiovascular Prevention and Rehabilitation, the American Association of Cardiovascular and Pulmonary Rehabilitation and the Canadian Association of Cardiac Rehabilitation provides directions on the identification of ET intensity domains by using constant WR exercise tests, and looking at the different VO2 on kinetics response,7 which – though in most cases is impractical – remains the most accurate physiology-based approach. Briefly, VO2 kinetics during constant WR exercise reflects three phases of adaptation of the organ systems and factors involved in alveolar-to-cell O2 coupling: phase I, or cardiodynamic, during which the increase in VO2 is mediated by the immediate increase in cardiac output and pulmonary blood flow at the start of exercise; phase II, or cell respiration, reflecting decreased

VO2 kinetics at constant work rate

∞

It is unknown if these methods can be interchangeably applied to ET programme prescriptions in the HF setting. It has also to be considered that VO2 at 1st VT may be affected by the type of exercise; use of a treadmill leads to a 10 % higher peak VO2 compared to bike. Thus, ET programmes should be promoted and performed with the same modality with which they are planned.14 Despite these caveats, there is evidence that ET programmes based on VO2 at 1st VT compared to HRR method provide significantly higher improvements in peak VO2 and cardiac output as assessed by O2 pulse.15

WR Three methods are vailable for identification of VTs by gas exchange analysis: the V-slope (a), the VE/VCO2 vs VE/VCO2 ratios behaviour; (b) and the pattern of PETCO2 vs PETO2 behaviour (c).

Slow component Moderate-to-high 90 % 1st VT 70 % Light-to-moderate

Time

(A) Constant work rate exercise helps define the physiological background leading to O2 uptake and is the gold standard for the precise identification of four ET intensity: light-tomoderate, moderate-to-high, high-to-severe and severe-to-extreme. (B) Intensity domains are identified in light-to-moderate when VO2 steady state is reached rapidly and no lactate production occurs (steady state below 1st VT); moderate to severe that corresponds to workloads between the 1st and snd VTs. This is the maximal attained aerobic effort and a slow component is detectable due to a progressive loss of muscle efficiency. The high-tosevere domain comprises all work rate above the 2nd VT with the severe to extreme domain that is the condition that can not be sustainable unless for few minutes.

O2 content (muscle extraction) and increased CO2 content in venous blood secondary to increased cell respiration as well as a further increase in cardiac output; phase III, or the steady state, during which

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Exercise Training Figure 3: Different Patterns in VO 2 vs WR Linear Increase During Maximal Exerciset Test

Table 1: Studies Assessing Changes in VE/VCO 2 Slope in HF Patients Undergoing ET Programmes

Study

VO2

Type of HF / N of pts

Type of ET

VO2

Changes in VE VCO2 Slope

Coats et al.1

HFrEF/17

8 weeks/low

From 38.0–34.0

shallow VO2/WR slope around 10 ml/min x watt

Davey et al.17

HFrEF/22

8 weeks/

From 39.0–35.0

low intensity WR

D VO2

C VO2

intensity

Myers et al.18

HFrEF/25

8 weeks/

From 33.0–27.0

high intensity

flattening

Guazzi et al.19

HFrEF/16

8 weeks/

From 33.0–28.0

moderate

downsloping

intensity Anaya et al.20 WR

HFrEF/401

During a maximal symptom-limited exercise, VO2 increase lineraly to the increase in work rate (WR) and accurately reflects the extent of aerobically regenerated ATP. In physiological conditions, the VO2/WR linearity corrisponds to 10 ml/min increase (a). In HF, the pattern of VO2 increase may change in a shallow downward shift (b) or in a VO2 flattening at a given WR c). There are then unfrequent worrysome conditions with a VO2 downsloping associated with acute drop in blood pressure and cardiac output (d).

Zurek et al.21

HFrEF/52

8 weeks/mild

1.7 unit reduction

to moderate

in high risk

intensity

women

8 weeks/

From 35.0–32.0

moderate intensity Smart et al.22

HFpEF/30

16 weeks/

From 33.9–29.6

moderate

an equilibrium is reached between O2 extraction and CO2 production rates. If WR is above the subject’s 1st VT, the rate of increase during phase III is not steady and correlates strongly with the increase of lactate (see Figure 2a). This allows for the precise identification of four ET domains, whose intensity is based on the physiology of O2 uptake kinetics: light to moderate, moderate to high, high to severe and severe to extreme (see Figure 2b). Light-to-moderate and moderate-to-high intensity programmes comprise continuous exercise, a condition that is not sustainable for high-to-severe and severe-to-extreme protocols requiring an interval exercise approach. Light-to-moderate intensity domains encompass the corresponding WR that engender a VO2 steady-state value below the corresponding 1st VT (see Figure 2c). During this WR and in this domain, a VO2 steady state is attained relatively rapidly following the commencement of exercise and there is no lactate production. For this reason, exercise can be well-tolerated and is generally sustainable for longer periods of time (30–40 min) with only a mild sense of fatigue and breathlessness. The moderate-to-high intensity domain corresponds to those workloads between the 1st and 2nd VTs. The 2nd VT represents the maximal WR sustainable in conditions of both VO2 and lactate steady state and are the highest limit of sustainable prolonged aerobic exercise in HF patients. This work intensity determines a slow component (see Figure 2c) increase of VO2 after 2–3 minutes of constant WR, a component that is not detectable during incremental exercise. Interestingly, the VO2 slow component elevates the VO2 above the level expected for a given WR, yielding a delayed attainment of the VO2 steady-state by 10–15 minutes or more. The VO2 steady-state is attained at a level higher then expected for a below 1st VT VO2/WR relationship. The slow component represents an additional cost due to progressive loss of muscle efficiency. The high-to-severe intensity domain comprises all the work rates above the 2nd VT that determine a peak VO2 attainment with no steady state. In this intensity domain, no slow component is evident

Guazzi_FINAL.indd 48

intensity

and VO2 rises close to a monoexponential pattern that is terminated at maximal VO2 (see Figure 2c). The severe-to-extreme intensity is a domain characterised by a very short tolerable duration; fatigue occurs before peak VO2 can be achieved.

How to Assess Benefits on Functional Capacity and Exercise Performance An improvement in functional capacity is the most immediate and objective result of an effective ET programme. Despite the fact that functional capacity is governed by an integrated response of multiple organ systems, ET intervention outcomes are generally quantified as changes in VO2. The wide physiological background behind exercise capacity response and the progressive familiarisation of the cardiac rehab personel with gas exchange analysis technique point represent, however, the solid bases for a more indepth analysis and comprehensive interpretation of results of exercise intervention trial. Further understanding is required of the determinants of exercise improvement that may add to peak VO2 and result in even more remarkable efficacy. The question of how much ET may improve VO2 kinetics – rather than peak VO2 – is intriguing. Specifically, during maximal symptom-limited exercise, the VO2 increase is linearly related to the increase in WR and accurately reflects the extent of aerobically regenerated adenosine triphosphate (ATP). In physiological conditions, the VO2/WR linearity corresponds to a 10 ml/min increase per watt, irrespective of the load imposed and slightly changing according to exercise duration (see Figure 3a). This assumption, however, is not true in cardiovascular disorders such as HF and the pattern of VO2 increase may change in a shallow downward shift (see Figure 3b) or in a VO2 flattening at a given WR (see Figure 3c). Consequently, there are infrequent concerning conditions with a VO2 decrease associated with acute drop in blood pressure and cardiac output (see Figure 3d). Aside from this extreme condition, the other abnormal phenotypes may represent a very likely target of ET interventions worth of consideration even when changes in peak VO2 per se are not remarkable.

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Assessment for Exercise Prescription in Heart Failure

The other set of abnormalities that are typical of HF and may considerably benefit from ET interventions are those involving the inefficient ventilation (VE), which is an integral part of the abnormal response to exercise and represents a mainstay target of therapeutic interventions. Ventilation inefficiency is described by the slope of the rate of increase of VE vs carbon dioxide production (VCO2).16 VE/VCO2 slope is a clear, but underestimated, endpoint of ET. Studies that have addressed how exercise interventions may modulate exercise hyperpnoea have not been numerous, however, they have been consistent in showing a positive effect of ET (see Table 1).1,17–22 These studies have been performed with aerobic continuous ET of variable intensity and, on average, a reduction in the VE/VCO2 slope of around 10 % has been observed. Mechanisms implicated in this beneficial effects may be multifactorial, including a modulatory activity on chemoreflex sensistivity and an improved perfusion of lung microvessels. Another important target of ET programmes is exercise oscillatory ventilation (EOV), a phenomenon charcaterised by a cyclic fluctuation of ventilation and expired gas kinetics, occurring in approximately 20–30 % of heart failure patients. The proposed aetiology includes a prolonged circulatory time with failure of cardiac output to adequately increase, causing delay in circulatory time and a demodulated chemoreflex sensitivity to blood gas tension.16 ET seems to be the most comprehensive intervention that is able to modulate at a multisystem level the pathogenetic mechanisms involved in this relevant ventilatory abnormality, by ‘resetting’ the central and peripheral control of VE23 and preventing the haemodynamic perturbations responsible for an increased circulatory time.24 In a trial by Zurek et al.21 the hypothesis was tested and confirmed: ET programmes may effectively impact EOV. Patients were optimally treated, 100 % were receiving renin–angiotensin system inhibitors and 90 % β-blockers, suggesting that EOV is a phenomenon that may not be responsive to standard HF therapy, requiring a targeted ad hoc approach, such as ET.

1. Coats AJ, Adamopoulos S, Radaelli A, et al. Controlled trial of physical training in chronic heart failure. Exercise performance, hemodynamics, ventilation, and autonomic function. Circulation 1992;85 :2119–31. 2. Belardinelli R, Georgiou D, Cianci G, et al. Exercise training improves left ventricular diastolic filling in patients with dilated cardiomyopathy. Clinical and prognostic implications. Circulation 1995;91 :2775–84. 3. Pandey A, Parashar A, Kumbhani DJ, et al. Exercise training in patients with heart failure and preserved ejection fraction: Meta-analysis of randomized control trials. Circulation. Heart failure 2015;8 :33–40. 4. Ismail H, McFarlane JR, Nojoumian AH, et al. Clinical outcomes and cardiovascular responses to different exercise training intensities in patients with heart failure: A systematic review and meta-analysis. JACC Heart failure 2013;1 :514–22. 5. Balady GJ, Arena R, Sietsema K, et al. American Heart Association Exercise CR, Prevention Committee of the Council on Clinical C, Council on E, Prevention, Council on Peripheral Vascular D, Interdisciplinary Council on Quality of C, Outcomes R. Clinician’s guide to cardiopulmonary exercise testing in adults: A scientific statement from the american heart association. Circulation 2010;122 :191–225. 6. Guazzi M, Adams V, Conraads V, et al. European Association for Cardiovascular P, Rehabilitation, American Heart A. Eacpr/ aha scientific statement. Clinical recommendations for cardiopulmonary exercise testing data assessment in specific patient populations. Circulation 2012;126 :2261–74. 7. Mezzani A, Hamm LF, Jones AM, et al. Canadian Association of Cardiac R. Aerobic exercise intensity assessment and prescription in cardiac rehabilitation: A joint position statement of the european association for cardiovascular prevention and rehabilitation, the american association of cardiovascular and pulmonary rehabilitation and the canadian association of cardiac rehabilitation. Eur J Prev

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Future studies performed in large cohort of patients should aim to clarify how much ventilatory abnormalities may benefit from ET programmes, extending clinical endpoints to variables that, although pathophysiologically relevant, are still poorly analysed and considered.

Identification of ET Nonresponders Some patients performing supervised ET do not show any improvement in exercise capacity and peak VO2 and represent a subset worthy of attention. Few studies have, however, addressed the clinical relevance of poor response to ET, though predicting nonresponders and how to successfully intervene by selecting appropriate and personalised intensity domain defined ET programmes would be of use. In 155 HF patients undergoing an ET programme (aerobic continuous training at 1st VT workload), Tabet et al.25 identified a subgroup at higher risk that did not improve peak VO2 much and in need of a tight monitored. No mechanistic explanations were provided except for evidence at multivariate analysis of B-type natriuretic peptide level along peak VO2 as only independent predictive factors of outcome (p=0.01). Interestingly, in a large group of HF patients Scmidt et al.26 provided the only available characterisation of ET responders identified as patients who did not improved peak VO2 by more than 5 % and work load by more than 10 %, or reduced VE/VCO2 slope by more than 5 %. Subjects who did not fulfil at least one of the above criteria were classified as non-responders. The best predictors of positive ET were HR recovery at 1 min, and peak HR and optimal thresholds separating responders from non-responders were at less than 30 bpm for HR reserve, less than 6 bpm for HR recovery and less than 101 bpm for peak HR. In summary, it is intriguing to prospect that once more attention is posed on the nonresponder phenotype, ET should conceivably be switched to a personalised ET intensity domain that would yield to the most efficient and of ET-derived benefits across the wide spectrum of HF syndrome. n

Cardiol 2013;20 :442–67. 8. Belardinelli R, Georgiou D, Cianci G, Purcaro A. Randomized, controlled trial of long-term moderate exercise training in chronic heart failure: Effects on functional capacity, quality of life, and clinical outcome. Circulation 1999;99 :1173–82. 9. Kitzman DW, Brubaker PH, Morgan TM, et al. Exercise training in older patients with heart failure and preserved ejection fraction: A randomized, controlled, single-blind trial. Circulation. Heart Failure 2010;3 :659–67. 10. Brawner CA, Keteyian SJ, Ehrman JK. The relationship of heart rate reserve to vo2 reserve in patients with heart disease. Med Sci Sports Exerc 2002;34 :418–22. 11. Durstine JL, Moore G, Painter P, Roberts S. ACSM’s exercise management for persons with chronic diseases and disabilities. American Colege of Sports Medicine. Champaign: Human Kinetics. 2009. 12. Demopoulos L, Bijou R, Fergus I, et al. Exercise training in patients with severe congestive heart failure: Enhancing peak aerobic capacity while minimizing the increase in ventricular wall stress. J Am Coll Cardiol 1997;29 :597–603. 13. Wisloff U, Stoylen A, Loennechen JP, et al. Superior cardiovascular effect of aerobic interval training versus moderate continuous training in heart failure patients: A randomized study. Circulation 2007;115 :3086–94. 14. Beckers PJ, Possemiers NM, Van Craenenbroeck EM, et al. Impact of exercise testing mode on exercise parameters in patients with chronic heart failure. Eur J Prev Cardiol 2012;19 :389–95. 15. Vallet G, Ahmaidi S, Serres I, et al. Comparison of two training programmes in chronic airway limitation patients: Standardized versus individualized protocols. Eur Respir J 1997;10 :114–22. 16. Guazzi M. Abnormalities in cardiopulmonary exercise testing ventilatory parameters in heart failure: Pathophysiology and clinical usefulness. Curr Heart Fail Rep . 2014;11 :80–7.

17. Davey P, Meyer T, Coats A, et al. Ventilation in chronic heart failure: Effects of physical training. Br Heart J 1992;68 :473–7. 18. Myers J, Dziekan G, Goebbels U, Dubach P. Influence of high-intensity exercise training on the ventilatory response to exercise in patients with reduced ventricular function. Med Sci Sports Exerc 1999;31 :929–37. 19. Guazzi M, Reina G, Tumminello G, Guazzi MD. Improvement of alveolar-capillary membrane diffusing capacity with exercise training in chronic heart failure. J Appl Physiol 2004;97:1866–73. 20. Anaya SA, Church TS, Blair SN, et al. Exercise dose-response of the v(e)/vco(2) slope in postmenopausal women in the drew study. Med Sci Sports Exerc 2009;41 :971–6. 21. Zurek M, Corra U, Piepoli MF, et al. Exercise training reverses exertional oscillatory ventilation in heart failure patients. Eur Respir J 2012;40 :1238–44. 22. Smart NA, Haluska B, Jeffriess L, Leung D. Exercise training in heart failure with preserved systolic function: A randomized controlled trial of the effects on cardiac function and functional capacity. J Card Fail 2012;18 :295–301. 23. Stickland MK, Miller JD. The best medicine: Exercise training normalizes chemosensitivity and sympathoexcitation in heart failure. J Appl Physiol 2008;105 :779–81. 24. Erbs S, Hollriegel R, Linke A, et al. Exercise training in patients with advanced chronic heart failure (nyha iiib) promotes restoration of peripheral vasomotor function, induction of endogenous regeneration, and improvement of left ventricular function. Circulation Heart Failure 2010;3 :486–94. 25. Tabet JY, Meurin P, Beauvais F, et al. Absence of exercise capacity improvement after exercise training program: A strong prognostic factor in patients with chronic heart failure. Circulation. Heart Failure 2008;1 :220–6. 26. Schmid JP, Zurek M, Saner H. Chronotropic incompetence predicts impaired response to exercise training in heart failure patients with sinus rhythm. Eur J Prev Cardiol 2013;20 :585–92.

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Heart Failure Guidelines

LE ATION.

Gaps in the Heart Failure Guidelines B a o Tr a n a n d G r e g g C F o n a r o w Ahmanson-UCLA Cardiomyopathy Center, Ronald Reagan-UCLA Medical Center, Los Angeles, California, USA

Abstract There are still many aspects of heart failure care for which gaps remain in the evidence base, resulting in gaps in the guidelines. We aim to highlight these guideline gaps including areas that warrant further research and other areas where new data are forthcoming.

Keywords Heart failure, guidelines, quality of care Disclosure: Bao Tran has no conflicts of interest to declare. Gregg C Fonarow is a consult for Amgen, Bayer, Gambro, Janssen, Medtronic and Novartis. Received: 15 September 2014 Accepted: 4 November 2014 Citation: Cardiac Failure Review, 2015;1(1):50–5 Correspondence: Gregg C Fonarow, Ahmanson-UCLA Cardiomyopathy Center, Ronald Reagan-UCLA Medical Center, 10833 LeConte Ave, Room 47-123 CHS, Los Angeles, CA 90095-1679, US. E: gfonarow@mednet.ucla.edu

Disclaimer: This article first appeared in European Cardiology Review 2014;9(2):104–9. It is republished here with the kind permission of the authors.

Heart failure (HF) remains a major public health problem resulting in substantial morbidity, mortality and healthcare expenditures globally. The European Society of Cardiology (ESC) 2012 Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure and the American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) 2013 Guideline for the Management of Heart Failure both provide comprehensive evidence-based recommendations in caring for patients with HF.1,2 Both guidelines use similar predefined scales for strength of recommendation and level of evidence for particular treatment options. The classes of recommendations range from Class I (where a given treatment is beneficial) to Class III (where a given treatment is not useful and in some cases may be harmful). The levels of evidence (LOE) range from Level A (where data have been derived from multiple randomised clinical trials [RCTs]) to Level C (where recommendations are based on consensus of expert opinions). The ACCF/AHA Guideline also emphasises the concept of optimal treatment, termed guideline-directed medical therapy (GDMT). Although guidelines do not substitute individual clinical judgment, improved adherence to HF guidelines translates to improved clinical outcomes in real world patients. It has been shown that each 10 % improvement in ACCF/AHA HF guideline recommended composite care was associated with a 13 % lower odds of 24-month mortality.3 However, there are still many aspects of HF care for which gaps remain in the evidence base, resulting in gaps in the guidelines. Only 19.5 % of the ACCF/AHA Guideline recommendations are considered well established by RCTs – 24 Level of Evidence A recommendations compared with 99 Level B or C. Similarly, only 34.4 % of the ESC Guideline recommendations are considered well established – 43 Level A compared with 82 Level B or C. Additionally, there are areas where new evidence has emerged but has not yet been incorporated into the guidelines. We aim to highlight these guideline gaps including areas that warrant further research, areas where data are conflicting and other areas where new data are forthcoming (see Table 1).

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Gaps in Pharmacological Therapy Substantial progress has been made in pharmacological therapy for HF with reduced ejection fraction (HFrEF) including angiotensin-converting enzyme inhibitors (ACEIs), beta-blockers and aldosterone antagonists, and novel agents continue to be developed. However, uncertainty remains with some of the oldest class of drugs. The vasodilator combination hydralazine and isosorbide dinitrate (H-ISDN) is the first therapy proven in a RCT to improve outcome in HFrEF. The initial Vasodilator-Heart Failure Trial 1 (V-HeFT I) showed 28 % mortality reduction compared with placebo, although this finding only reached borderline statistical significance (p=0.053).4 The follow-up V-HeFT II actually showed 28.2 % higher mortality with H-ISDN when compared with enalapril (p=0.016).5 Definitive mortality benefit of H-ISDN was finally established with the subsequent African-American Heart Failure Trial (A-HeFT) that enrolled self-identified African Americans with symptomatic HFrEF who were already on modern GDMT.6 The study terminated early as the H-ISDN arm showed 43 % decrease in all-cause mortality (p=0.01) and 33 % reduction in rate of hospitalisation (p=0.001) compared with placebo. However, the role of H-ISDN in non-African American patients with HFrEF in the modern era remains uncertain and warrants further research. The ESC Guideline currently gives H-ISDN an equivocal recommendation of Class IIb/LOE B in patients with HFrEF. The ACC/AHAF Guideline recognises the differential treatment effect and gives H-ISDN Class I/LOE A in African Americans with HFrEF and Class IIa/LOE B in other patients with HFrEF who cannot tolerate ACE inhibitor or angiotensin receptor blocker (ARB). The use of digoxin, the oldest compound in cardiovascular medicine, declined after the disappointing Digitalis Investigation Group (DIG) trial, which showed a 28 % reduction in hospitalisations (p<0.001) but no difference in mortality.7,8 This trial, however, was done in an era where the current GDMT and device therapy were not commonly part of background therapy. Subsequent meta-analysis, retrospective studies and post-hoc analysis of more contemporary clinical databases have

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Gaps in the Heart Failure Guidelines

yielded conflicting conclusions, suggesting potential benefit as well as harm.9–13 Prospective RCT data would help clarify the role of digoxin in modern clinical practice in HFrEF with and without atrial fibrillation (AF). The benefit of anticoagulation for stroke prevention in patients with AF is well established. However, in patients with very depressed ejection fraction (EF) who are at risk for intracardiac thrombi, anticoagulation has not been shown to be beneficial. Two RCTs of patients with HFrEF in sinus rhythm showed no clinical benefit and increased bleeding with warfarin when compared with aspirin.14,15 Given the improved safety and efficacy of the new oral anticoagulants (dabigatran, apixaban and rivaroxaban), these agents should be studied in subsets of patients with HFrEF in sinus rhythm that are at highest risk for thromboembolism.

Table 1: Gaps in Heart Failure Guidelines

Newer agents, ivabradine, aliskiren and LCZ696, are still establishing their roles in HF. The ESC Guideline gives ivabradine a Class IIa/LOE B recommendation in patients with symptomatic HFrEF and heart rate >70 beats per minute (BPM) based on the Systolic Heart Failure Treatment with the If Inhibitor Ivabradine Trial (SHIFT), which showed 26 % decrease in HF hospitalisations (p<0.0001) and a previous trial, which established its safety.16,17 In the US, ivabradine is still awaiting US Food and Drug Administration (FDA) approval and has not received formal recommendation in the ACCF/AHA Guideline. Aliskiren is a novel agent that targets the renin–angiotensin–aldosterone system (RAAS) to reduce blood pressure. The Aliskiren Trial on Acute Heart Failure Outcomes (ASTRONAUT) investigated aliskiren in patients with HFrEF and acute decompensated heart failure (ADHF). It showed increased rates of adverse effects, such as hyperkalaemia (relative risk [RR] 1.19 [0.98–1.46]), hypotension (RR 1.36 [1.07–1.72]) and renal failure (RR 1.37 [1.08–1.75]) in the aliskiren arm without benefit in mortality or hospitalisation.18 An ongoing RCT is investigating the

• Transcatheter mitral valve repair for secondary MR

role of aliskiren or aliskiren/enalapril combination in patients with chronic HFrEF (NCT00853658). Aliskiren has not received formal recommendation by the ACCF/AHA or ESC guidelines and its role in HF appears uncertain. In contrast to this is LCZ696, a novel dual-acting angiotensin receptor–neprilysin inhibitor (ARNI), which has the potential to shift the foundation of HFrEF therapy. The recent Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial was stopped early with LCZ696 demonstrating significant reduction in all-cause mortality (hazard ratio [HR] 0.84, 95 % confidence interval [CI] 0.76–0.93) and HF hospitalisations (HR 0.79, 95 % CI 0.71–0.89) as well as improvement in quality of life compared with enalapril.19 Based on these findings, we anticipate expedited approval of LCZ696 by both US and European regulatory agencies, and the addition of ARNI in the next ESC and ACCF/AHA Guideline update.

Gaps in Device Therapy Cardiac resynchronisation therapy (CRT) has played an important role in the past decade in decreasing hospitalisations and increasing survival of patients with HFrEF. Though benefits are clear for symptomatic patients in sinus rhythm with typical left bundle branch block (LBBB) (particularly with QRS width >150 ms), there are some populations where data are equivocal.20 Post-hoc analysis of the major CRT trials showed no significant benefit in subgroups with non-LBBB morphology or subgroups with QRS duration <150 msec.21,22 Results are pending of the recently completed Pacing Affects Cardiovascular Endpoints in Patients with Right Bundle-Branch Block (PACE-RBBB) trial, which is evaluating whether univentricular right ventricular (RV) pacing can restore synchronisation in patients with right bundle branch block (RBBB) (NCT01169493). The benefits of CRT are also unclear in patients

CARDIAC FAILURE REVIEW

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Diagnosis • Unified diagnostic criteria for HFpEF • Classification of borderline systolic dysfunction and HF with recovered EF • Utility of advanced imaging and biomarkers Pharmacological Therapy • Values of digoxin, H-ISDN, IV vasodilators and inotropes in the modern era • Novel agents ivabradine, aliskiren and LCZ696 for chronic HF • Novel agents serelaxin, ularitide and omecamtiv mecarbil for ADHF • Effective therapy for HFpEF Device Therepy • Role of CRT in non-LBBB or AF and approach to CRT non-responders • Long-term role of ventricular assist devices in advanced HF Other Non-pharmacological Therapy • Viability testing and revascularisation in CAD and severely reduced EF • Sodium and fluid restriction • Ultrafiltration in ADHF • Remote clinical management interventions Co-morbidities • Optimal HF therapy for patients with significant co-morbidities • Optimal treatment of underlying co-morbidities Variation of Care • Generalizability of HF therapy to women and underrepresented minorities • Ideal therapy and role of palliative care for patients with end-stage HF • Strategies to improve guideline implementation and patient adherence ADHF = acute decompensated heart failure; CAD = coronary artery disease; CRT = cardiac resynchronisation therapy; EF = ejection fraction; HF = heart failure; HFpEF = HF with preserved ejection fraction; H-ISDN = hydralazine and isosorbide dinitrate; IV = intravenous; LBBB = left bundle branch block; MR = mitral regurgitation.

with AF where efficient CRT delivery is compromised by underlying conduction. Thus these patients have been excluded from most major CRT trials.23 In the Resynchronization–Defibrillation for Ambulatory Heart Failure Trial (RAFT) that evaluated CRT in patients with mild-tomoderate HF, subsets of patients with permanent AF had no clinical benefit with CRT.24 An ongoing RCT is evaluating the strategy of atrioventricular junction ablation to increase CRT response in patients with permanent AF (NCT01522898). Finally, although up to 30–45 % of CRT-implanted patients receive little benefit, the management of these CRT non-responders remains controversial.25 A meta-analysis suggests small improvement in left ventricular ejection fraction (LVEF) with CRT optimisation procedures, but it is unclear whether this would translate into hard outcomes, and the ideal optimisation protocol remains undefined.26 Device-based clinical management interventions for HF have shown mixed results. Previous trials of thoracic impedance monitoring and remote monitoring systems have failed to show improvement in outcomes.27,28 More recently, however, the Influence of Home Monitoring on Mortality and Morbidity in Heart Failure Patients with Impaired Left Ventricular Function (IN-TIME) trial showed that an implantable cardioverter defibrillator (ICD)-based telemonitoring system dramatically reduced mortality when compared with standard care (HR 0.37, 95 % CI 0.16–0.83).29 Another device, an implantable pulmonary artery pressure monitor, was shown in the CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in NYHA Functional Class III Heart Failure Patients (CHAMPION) trial to decrease HF hospitalisation (HR 0.72, 95 % CI 0.60–0.85).30 However, in both these positive trials the contribution of additional

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Heart Failure Guidelines patient–physician interaction on outcomes cannot be underestimated. Notably there was a delay in FDA approval of the pulmonary artery pressure monitoring device over question of potential bias in preferential support of treatment group.31 Neither the ACCF/AHA nor the ESC Guideline endorses a remote monitoring strategy.

LOE C recommendation, and the ESC Guideline gives only a general recommendation supporting sodium restriction and fluid restriction for symptomatic HF. Well-powered outcome trials are needed. Given the complexity of sodium and fluid homeostasis, perhaps the answer may be individualised targets based on the patient’s clinical status.

From a structural standpoint, new data about transcatheter mitral valve repair is encouraging. Secondary mitral regurgitation (MR) is a common consequence of left ventricular (LV) enlargement and dysfunction, but surgical repair has not been proven to be superior to medical therapy for functional MR.32 Two recent non-randomised trials reported results of transcatheter mitral valve repair MitraClip in patients with severe MR who were deemed too high-risk for surgery.33,34 In both studies more than 70 % of patients had functional MR. After mitral valve repair using MitraClip device, patients experienced improved clinical symptoms, decreased LV dimensions, and in one of the trials decreased mortality compared with a propensity matched cohort. Further prospective controlled trials are ongoing to define transcatheter mitral valve repair’s role in patients with symptomatic functional MR (NCT01626079 and NCT01772108). Pending results from these RCTs, the ACCF/AHA Guideline gives transcatheter mitral valve repair for functional MR an ambivalent Class IIb/LOE B recommendation, and the ESC Guideline does not give a specific class of recommendation about this topic.

Other non-pharmacological interventions, such as self-management counselling, telephone support and home visitation have been advocated. However, there is no definitive evidence supporting an individual approach.46 While intensive multidisciplinary programmes have been found to reduce mortality and hospitalisation, the resources required to maintain this strategy have limited its ability to reach a wide spectrum of patients.47

Gaps in Non-pharmacological Therapy Coronary artery disease (CAD) is the most common aetiology of HFrEF.35 While revascularisation with concurrent use of viability studies in severe ischaemic cardiomyopathy is logically sound, recent studies have challenged this dictum. The Surgical Treatment for Ischemic Heart Failure (STICH) trial showed no mortality benefit with coronary artery bypass grafting (CABG) when compared to medical therapy in patients with EF <35 %.36 Though notably, after taking into account patient crossover from the medical therapy arm, the ‘as-treated’ analysis showed decreased mortality with CABG (HR 0.70, 95 % CI 0.58–0.84). An imaging substudy of STICH showed that viability assessment by single-photon emission computed tomography (SPECT) or dobutamine echocardiography did not identify patients who would benefit from CABG.37 Cardiac magnetic resonance and position emission tomography imaging promise improved sensitivities and specificities in identifying viable myocardium, but their impact on clinical outcomes has not been rigorously tested.38 Thus the roles of viability testing and revascularisation in patients with CAD and severely reduced EF remain debatable. The ESC Guideline gives a viability testing Class IIa/LOE C recommendation and recommends against revascularisation in patients without viable myocardium (Class III/LOE C). The ACCF/AHA Guideline gives viability testing and revascularisation in patients with LVEF <35 % a Class IIa/LOE B recommendation. Though sodium and fluid restriction in patients with HF appears intuitive, its role is controversial. Even though sodium restriction is endorsed by many guidelines, small RCTs have shown worse neurohormonal profiles and increase in HF admissions for patients with HFrEF assigned to low-sodium diet.39–41 Similarly, other small trials have shown no significant benefit with fluid restriction in patients with HF.42,43 More recently, one RCT showed New York Heart Association (NYHA) class improvement in patients with chronic HF randomised to modest sodium and fluid restriction,44 while another RCT showed no clinical benefit with aggressive sodium and fluid restriction in hospitalised patients with ADHF.45 Despite conflicting data, the ACCF/ AHA Guideline gives sodium restriction and fluid restriction Class IIa/

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Gaps in Acute Heart Failure Therapy Despite significant advances in understanding the pathophysiology of HF, treatment of ADHF has changed little in the past decade. The mainstays of parenteral pharmacological treatments, such as diuretics, vasodilators and positive inotropes, improve haemodynamics but have not been shown to improve outcomes.48 The optimal diuretic regimen remains at the discretion of the clinician as the Diuretic Optimization Strategies Evaluation (DOSE) trial did not show clear benefits for low-dose or high-dose diuretics and bolus or continuous infusion.49 Contemporary trial of a common clinical practice, low-dose dopamine in ADHF, failed to show clinical benefits in the Renal Optimization Strategies Evaluation (ROSE) trial.50 Though intravenous nitrates and nitroprusside are widely used in practice, data demonstrating their safety and efficacy are sparse. The vasodilator nesiritide was widely used based on improvement in dyspnoea from the Vasodilation in the Management of Acute Congestive Heart Failure (VMAC) trial, but it fell out of favour after safety concerns were raised.51 Confirmatory trials demonstrated safety but also no significant clinical benefits.50,52 Ironically, given the number of trials, nesiritide has one of the largest bodies of evidence demonstrating safety compared with other pharmacological therapies for ADHF. Novel agents for ADHF that improve outcomes are urgently needed. The most promising of these is serelaxin, a peptide hormone with vasodilatory effect. In the Relaxin in Acute Heart Failure (RELAX-AHF) trial, serelaxin significantly reduced the primary endpoint of dyspnoea in patients with both HFrEF and HF with preserved ejection fraction (HFpEF).53,54 Unexpectedly there was a large reduction in the non-predefined endpoint of mortality (HR 0.63, 95 % CI 0.42–0.93), and a larger trial is looking to confirm this finding (NCT01870778). Another phase III trial is ongoing to evaluate ularitide, a synthetic natriuretic peptide, in ADHF (NCT01661634). Omecamtiv mecarbil, a novel inotrope-like agent, is awaiting phase III trial though phase II did not achieve the primary endpoint of reducing dyspnoea.55 From a non-pharmacological standpoint, contemporary ultrafiltration devices used for rapid fluid removal promised rapid decongestion in treatment of ADHF. The Ultrafiltration versus intravenous Diuretics for Patients Hospitalized for Acute Decompensated Congestive Heart Failure (UNLOAD) and Continuous Ultrafiltration for Congestive Heart Failure (CUORE) trials showed reduced readmission rates with ultrafiltration compared with diuretics (HR 0.56, 95 % CI 0.28–0.51 and HR 0.14, 95 % CI 0.04–0.48, respectively).56,57 However, the Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF) trial evaluating patients with ADHF and renal dysfunction showed only excess adverse events in the ultrafiltration group (72 versus 57 %, p=0.03), driven by worsened renal function, bleeding complications and intravenous catheter-related complications.58 Unfortunately, a

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larger trial to evaluate the role of ultrafiltration on readmissions for HF has been terminated due to patient recruitment challenges (NCT01474200). The ESC Guideline does not provide specific recommendation for ultrafiltration, and the ACCF/AHA Guideline gives it an equivocal Class IIB/LOE B recommendation. The ideal patient population who would benefit from ultrafiltration remains uncertain until more definitive data from larger trials are available. Future clinical trials of therapies for ADHF should target HFpEF and HFrEF separately in addition to stratifying patients based on severity of decompensation and co-morbidities. Pressure to expand inclusion criteria to enrol enough patients to power studies for mortality benefits may ultimately dilute findings by increasing patient heterogeneity.

Gaps in Diagnosis and Treatment of Heart Failure with Preserved Ejection Fraction The management of HFrEF has made substantial gains over the past three decades. In contrast, despite the high prevalence, mortality and morbidity of HFpEF, little progress has been made in establishing unified diagnostic criteria.59 The treatment of HFpEF remains largely opinion-based with little good evidence to guide therapy. Though promising in theory, trials of beta-blocker, ACEI, ARB, aldosterone antagonists, digoxin and phosphodiesterase type 5 (PDE-5) inhibitors have all shown largely disappointing results.60 Establishing broadly applicable therapies is hampered by the heterogeneity of the syndrome. LCZ696, discussed previously in HFrEF, was found to reduce N-terminal pro-brain natriuretic (NT-proBNP) and left atrial size in patients with HFpEF when compared with valsartan in a phase II RCT.61 The followup phase III trial powered to evaluate mortality has recently started recruiting patients (NCT01920711). Future studies should more distinctly subclassify different clinical phenotypes of HFpEF to target the dominant pathophysiology. And while mortality and hospitalisation are important clinical endpoints, they may be too insensitive for this heterogeneous population with multiple co-morbidities. There should be more focus on using health-related quality of life and other measures of health status as part of clinical trial endpoints to elicit meaningful results. Additional ambiguity is seen in the intermediate group with EF between 40 and 50 %. These patients are often treated with therapy recommended for patients with HFrEF despite being underrepresented or excluded from most HFrEF trials.1 Finally, patients with a history of HFrEF where EF have recovered represent another subset where little is known about the natural history and prognosis. They likely represent a distinct phenotype in the spectrum of HFrEF and HFpEF and need further characterisation to determine the need for continued therapies.62

Gaps in Treatment of Co-morbidities Common non-cardiac co-morbidities, such as anaemia, lung disease, kidney disease, diabetes and depression, likely play important roles in progression of HF and may interfere with diagnosis and therapy. Anaemia and chronic obstructive pulmonary disease (COPD) may confound the diagnosis of worsening HF. Depression may interfere with a patient’s ability to self-manage. Kidney disease often limits the use of ACEI/ARB, and severe lung disease may limit the use of beta-blocker. Frailty, cancer, gout, obesity and other co-morbidities may also directly affect HF therapy. The long-term safety and efficacy of many treatments for these co-morbidities in patients with HF are unknown. Moreover, as HF trials commonly exclude patients with significant co-morbidities, it is not clear whether GDMT have differential effects in these particular patients.63

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Chronic obstructive pulmonary disease (COPD) can co-exist and confound the diagnosis of HF. Unfortunately, patients with severe COPD are often excluded from HF trials, so data are limited in this population.64 Despite concern about beta-blockers exacerbating COPD, it has been shown that even non-selective beta-blockers, such as carvedilol, are not associated with worse outcomes in patients with chronic HF and COPD.65 However, in the setting of an acute COPD exacerbation, the role of beta-blockers remains unknown. Additionally, the use of beta-2 agonist bronchodilators have been implicated in worsening HF, though this finding is limited by the observational nature of the data.66 Anaemia is a common finding in patients with HF and is independently associated with increased mortality risk.67 However, It is unclear whether anaemia is simply a marker of disease severity or a direct mediator of poor outcomes. Reduction of Events by Darbepoetin Alfa in Heart Failure (RED-HF), the largest RCT to evaluate erythropoiesis-stimulating agents in patients with HFrEF and anaemia, showed no difference in death or HF hospitalisation but increased thromboembolic events in the darbepoetin alfa group (13.5 % versus 10.0 %, p=0.009).68 In patients with HF and iron deficiency, however, the Ferinject Assessment in Patients with Iron Deficiency and Chronic Heart Failure (FAIR-HF) trial showed that Intravenous (IV) ferric carboxymaltose improved NYHA class, six-minute walk distance and quality of life.69 A multicentre RCT evaluating oral iron in patients with HFrEF and iron deficiency is expected to start soon (NCT02188784). Diabetes mellitus (DM) is highly associated with poor clinical status in patients with HF.70 The interaction between these two clinical syndromes is complex, and patients with DM have been shown to respond differently to HFrEF therapy compared with non-diabetics.71 From a DM therapy standpoint, while thiazolidinedione has clearly been shown to increase HF, the safety of newer therapies for DM – glucagon-like peptide-1 (GLP-1) receptor agonists, dipeptidyl peptidase 4 (DPP-4) inhibitors and sodium/glucose cotransporter 2 (SGLT-2) inhibitors – are unknown for patients with HF. Even insulin, an established treatment, has been associated with higher mortality in patients with advanced HF, though this may be more related to severity of diabetes.72 Chronic kidney disease (CKD) and the associated cardiorenal syndrome portend poorer prognosis and significantly impact management of HF patients.73 Significant renal dysfunction may preclude the use of ACEIs, ARBs and mineralocorticoids in patients with HFrEF. In addition, patients with advanced kidney disease (stage 4 and stage 5 CKD) and end-stage renal disease are frequently excluded from HF trials.74 In the setting of ADHF, no effective therapy for cardiorenal syndrome has been found, perhaps mirroring the lack of progress in ADHF care in the last decade. Depression is also highly prevalent in patients with HF and independently predicts increased hospitalisation and mortality.75 However, there has been surprisingly little work done on defining the interaction between the two diseases and finding effective therapy. Although data have contested conventional wisdom that beta-blocker is associated with depression, beta-blocker’s effect on patients with concomitant HF and depression is unclear.76 While tricyclic antidepressants should be avoided in patients with HF due to known risks of QT interval prolongation and ventricular arrhythmia, the ideal antidepressant in HF patients is unknown. Sertraline Against Depression and Heart Disease in Chronic Heart Failure

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Heart Failure Guidelines (SADHART-CHF), one of the few RCTs to date on this topic, found no benefit with sertraline in patients with HF and depression.77 Finally, pulmonary hypertension (PH) is a common complication of HF and is independently associated with poor prognosis.78 Unfortunately, there is no validated treatment for PH due to left heart disease. Perhaps due to patient heterogeneity, clinical trials have not shown benefits with prostanoids, endothelin-1 antagonists or guanylate cyclase stimulators in patients with HFrEF.79 For patients with HFpEF and PH, one small placebo-controlled trial showed that sildenafil increased exercise capacity and improved haemodynamic status.80 However a larger trial, Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart Failure (RELAX), evaluated sildenafil in HFpEF and showed no difference in clinical outcomes compared to placebo.81 Ongoing trials are evaluating the role of sildenafil (NCT01616381) and tadalafil (NCT01910389) in patients with PH and HFrEF, and the role of riociguat in patients with PH and HFpEF (NCT01172756). Neither the ACCF/AHA nor the ESC Guideline specifically addresses patients with HF and PH.

Gaps in Variation of Heart Failure Care In negative trials, the clinical heterogeneity of patient population is sometimes invoked as a reason why a therapy does not reach statistical significance. However, from a population perspective, most RCTs that form the current evidence base do not randomise a sufficient number of women and underrepresented minorities, thus limiting their generalizability. Women and various racial and ethnic groups have significant differences in aetiology of HF and response to treatment due to underlying biological differences and disparities in healthcare utilisation.82 Future trials should strive to enrol higher proportions of these underrepresented populations. Encouragingly,

1. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, J Am Coll Cardiol, 2013;62:e147–239. 2. 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 J Heart Fail, 2012;14:803–69. 3. Fonarow GC, Albert NM, Curtis AB, et al. Associations between outpatient heart failure process-of-care measures and mortality, Circulation, 2011;123:1601–10. 4. Cohn JN, Archibald DG, Ziesche S, et al. Effect of vasodilator therapy on mortality in chronic congestive heart failure. Results of a Veterans Administration Cooperative Study, N Engl J Med, 1986;314:1547–52. 5. Cohn JN, Johnson G, Ziesche S, et al. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure, N Engl J Med, 1991;325:303–10. 6. Taylor AL, Ziesche S, Yancy C, et al. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure, N Engl J Med, 2004;351:2049–57. 7. Digitalis Investigation Group, The effect of digoxin on mortality and morbidity in patients with heart failure, N Engl J Med, 1997;336:525–33. 8. Ambrosy AP, Butler J, Ahmed A, et al. The use of digoxin in patients with worsening chronic heart failure: reconsidering an old drug to reduce hospital admissions, J Am Coll Cardiol, 2014;63:1823–32. 9. Turakhia MP, Santangeli P, Winkelmayer WC, et al. Increased mortality associated with digoxin in contemporary patients with atrial fibrillation: findings from the TREAT-AF study, J Am Coll Cardiol, 2014;64:660–8. 10. Ahmed A, Rich MW, Love TE, et al. Digoxin and reduction in mortality and hospitalization in heart failure: a comprehensive post hoc analysis of the DIG trial, Eur Heart J, 2006;27:178–86. 11. Hood WB Jr, Dans AL, Guyatt GH, et al. Digitalis for treatment of congestive heart failure in patients in sinus rhythm: a systematic review and meta-analysis, J Card Fail, 2004;10:155–64. 12. Gheorghiade M, Fonarow GC, van Veldhuisen DJ, et al. Lack of evidence of increased mortality among patients

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data from the Get With The Guidelines®-Heart Failure registry shows that a concerted national quality improvement programme can deliver equally effective care across racial and ethnic groups.83 In clinical trials, the impact of therapy on quality of life can sometimes be deemed less important than the primary endpoint of mortality. This issue is particularly relevant for very elderly patients or patients with poor long-term prognosis, where symptom control may be more valuable than mortality benefits. Additionally, palliative services and hospice remain underutilised in patients with advanced HF, especially when compared with patients with cancer.84 Determining the optimal timing and palliative care approach is difficult in HF because of the undulating course of disease and availability of advanced therapies for end-stage HF, such as heart transplantation and ventricular assist devices.

Conclusion The economic burden of HF continues to grow and HF is one of the single most expensive and deadly healthcare problems. Additional clinical and comparative effectiveness research studies are urgently needed, along with development of new and innovative therapies. Significant gaps remain in the evidence base and guidelines for HF, particularly in the care of patients with HFpEF, patients with ADHF and patients with HF, and multiple co-morbidities. Other gaps in evidence that we did not address include the increasing use of ventricular assist devices, novel cardiac biomarkers and advanced cardiac imaging techniques. Along with encouraging novel devices and pharmacological therapies, it remains important to refine the roles of established therapies. When such evidence-based, guideline-directed therapies exist or emerge, every effort should be made to effectively implement these HF therapies to optimise care and outcomes. n

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Association and the European Heart Rhythm Association, Eur J Heart Fail, 2010;12:1143–53. 24. Healey JS, Hohnloser SH, Exner DV, et al. Cardiac resynchronization therapy in patients with permanent atrial fibrillation: results from the Resynchronization for Ambulatory Heart Failure Trial (RAFT), Circ Heart Fail, 2012;5:566–70. 25. Zacà V, Mondillo S, Gaddi R, Favilli R, Profiling cardiac resynchronization therapy patients: responders, nonresponders and those who cannot respond--the good, the bad and the ugly?, Int J Cardiovasc Imaging, 2011;27:51–7. 26. Kosmala W, Marwick TH, Meta-analysis of effects of optimization of cardiac resynchronization therapy on left ventricular function, exercise capacity, and quality of life in patients with heart failure, Am J Cardiol, 2014;113:988–94. 27. van Veldhuisen DJ, Braunschweig F, Conraads V, et al. Intrathoracic impedance monitoring, audible patient alerts, and outcome in patients with heart failure, Circulation, 2011;124:1719–26. 28. Anker SD, Koehler F, Abraham WT, Telemedicine and remote management of patients with heart failure, Lancet, 2011;378:731–9. 29. Hindricks G, Taborsky M, Glikson M, et al. Implant-based multiparameter telemonitoring of patients with heart failure (IN-TIME): a randomised controlled trial, Lancet, 2014;384:583–90. 30. Abraham WT, Adamson PB, Bourge RC, et al. Wireless pulmonary artery haemodynamic monitoring in chronic heart failure: a randomised controlled trial, Lancet, 2011;377:658–66. 31. Loh JP, Barbash IM, Waksman R, Overview of the 2011 Food and Drug Administration Circulatory System Devices Panel of the Medical Devices Advisory Committee Meeting on the CardioMEMS Champion Heart Failure Monitoring System, J Am Coll Cardiol, 2013;61:1571–6. 32. Wu AH, Aaronson KD, Bolling SF, et al. Impact of mitral valve annuloplasty on mortality risk in patients with mitral regurgitation and left ventricular systolic dysfunction, J Am Coll Cardiol, 2005;45:381–7. 33. Glower DD, Kar S, Trento A, et al. Percutaneous mitral valve repair for mitral regurgitation in high-risk patients: results of the EVEREST II study, J Am Coll Cardiol, 2014;64:172–81. 34. Swaans MJ, Bakker AL, Alipour A, et al. Survival of transcatheter mitral valve repair compared with surgical and conservative treatment in high-surgical-risk patients, JACC Cardiovasc Interv, 2014;7:875–81. 35. Gheorghiade M, Bonow RO, Chronic heart failure in the

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United States: a manifestation of coronary artery disease, Circulation, 1998;97:282–9. 36. Velazquez EJ, Lee KL, Deja MA, et al. Coronary-artery bypass surgery in patients with left ventricular dysfunction, N Engl J Med, 2011;364:1607–16. 37. Bonow RO, Maurer G, Lee KL, et al. Myocardial viability and survival in ischemic left ventricular dysfunction, N Engl J Med, 2011;364:1617–25. 38. Srichai MB, Jaber WA, Viability by MRI or PET would have changed the results of the STICH trial, Prog Cardiovasc Dis, 2013;55:487–93. 39. Parrinello G, Di Pasquale P, Licata G, et al. Long-term effects of dietary sodium intake on cytokines and neurohormonal activation in patients with recently compensated congestive heart failure, J Card Fail , 2009;15:864–73. 40. Paterna S, Gaspare P, Fasullo S, et al. Normal-sodium diet compared with low-sodium diet in compensated congestive heart failure: is sodium an old enemy or a new friend?, Clin Sci (Lond), 2008;114:221–30. 41. Paterna S, Parrinello G, Cannizzaro S, et al. Medium term effects of different dosage of diuretic, sodium, and fluid administration on neurohormonal and clinical outcome in patients with recently compensated heart failure, Am J Cardiol, 2009;103:93–102. 42. Holst M, Stromberg A, Lindholm M, Willenheimer R, Liberal versus restricted fluid prescription in stabilised patients with chronic heart failure: result of a randomised cross-over study of the effects on health-related quality of life, physical capacity, thirst and morbidity, Scand Cardiovasc J, 2008;42:316–22. 43. Travers B, O’Loughlin C, Murphy NF, et al. Fluid restriction in the management of decompensated heart failure: no impact on time to clinical stability, J Card Fail, 2007;13:128–32. 44. Philipson H, Ekman I, Forslund HB, et al. Salt and fluid restriction is effective in patients with chronic heart failure, Eur J Heart Fail, 2013;15:1304–10. 45. Aliti GB, Rabelo ER, Clausell N, et al. Aggressive fluid and sodium restriction in acute decompensated heart failure: a randomized clinical trial, JAMA Intern Med, 2013;173:1058–64. 46. Bui AL, Fonarow GC, Home monitoring for heart failure management, J Am Coll Cardiol , 2012;59:97–104. 47. McAlister FA, Stewart S, Ferrua S, McMurray JJ, Multidisciplinary strategies for the management of heart failure patients at high risk for admission: a systematic review of randomized trials, J Am Coll Cardiol, 2004;44:810–9. 48. Selby VN, Teerlink JR, What’s new in the treatment of acute heart failure?, Curr Cardiol Rep, 2013;15:393. 49. Felker GM, Lee KL, Bull DA, et al. Diuretic strategies in patients with acute decompensated heart failure, N Engl J Med, 2011;364:797–805. 50. Chen HH, Anstrom KJ, Givertz MM, et al. Low-dose dopamine or low-dose nesiritide in acute heart failure with renal dysfunction: the ROSE acute heart failure randomized trial, JAMA, 2013;310:2533–43. 51. Topol EJ, Nesiritide - not verified, N Engl J Med, 2005;353:113–6. 52. O’Connor CM, Starling RC, Hernandez AF, et al. Effect of nesiritide in patients with acute decompensated heart failure,

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