Volume 23 Supplement 1 I April–June 2016€¦ · 657 Fulham Road, London, SW6 5PY...

Perspectives in chronic heart failure – new treatment advances

The British Journal of Cardiology

www.bjcardio.co.uk

Volume 23 Supplement 1 I April–June 2016

Supplement 1

This supplement has been funded by Novartis. Entresto™ (sacubitril/valsartan) prescribing information is available on the back cover.

ENT16-CO51; May 2016

Copyright Medinews (Cardiology) Limited Reproduction Prohibited


Copyright Medinews (Cardiology) Limited Reproduction ProhibitedCo

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S2 | The British Journal of Cardiology | April–June 2016 | Volume 23 Supplement 1

SPONSORED SUPPLEMENT SPONSORED SUPPLEMENT

ISSN 0969-6113 (Print) ISSN 1753-4313 (Online)

The British Journal of Cardiology The peer-reviewed journal linking primary and secondary care

www.bjcardio.co.uk

www.bjcardio.co.uk

doi: 10.5837/bjc.2016.s01 Br J Cardiol 2016;23(suppl 1):S1-S16

Editors Kim Fox Terry McCormack Henry Purcell

Associate Editor Katharine White

Editorial Assistant Tim Kelleher

Administrative Assistant Mary Robbins

Editorial Office and Publishers MediNews (Cardiology) Limited 657 Fulham Road, London, SW6 5PY ([email protected]) Tel: +44 (0)20 7731 4945 Design and Layout Consultants in Design

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Published four times a year and distributed on a controlled circulation to general practitioners with an interest in cardiology, hospital cardiologists, diabetologists, vascular and cardiothoracic surgeons. The Journal may be provided, free, on request to other registered medical practitioners and GP trainees.

Supplement editor Paul R Kalra

Article authors

1. Introduction (pages S2–S3)Sameer Kurmani British Heart Foundation Clinical Research Fellow

Iain Squire Professor of Cardiovascular Medicine

Department of Cardiovascular Sciences, Glenfield Hospital, Leicester LE3 9QP

Correspondence to: Dr S Kurmani ([email protected])

2. Neurohumoral activation in heart failure and the implications for treatment (pages S5–S8)Legate Philip Cardiology Registrar

Paul R Kalra Consultant Cardiologist

Cardiology Department, Portsmouth Hospitals NHS Trust, Cosham, Portsmouth, PO6 3LY

Correspondence to: Dr P Kalra ([email protected])

3. Clinical evidence to support the use of sacubitril/valsartan (LCZ696) (pages S9–S10)Pierpaolo Pellicori Research Fellow

Andrew L Clark Chair of Clinical Cardiology and Honorary Consultant Cardiologist

Department of Cardiology, Hull York Medical School (at University of Hull), Hull and East Yorkshire Medical Research and Teaching Centre, Castle Hill Hospital, Kingston upon Hull, HU16 5JQ

Correspondence to: Dr P Pellicori ([email protected])

4. The use of sacubitril/valsartan (LCZ696) in clinical practice (pages S11–S13)John McMurray Professor of Medical Cardiology

Institute of Cardiovascular and Medical Science, University of Glasgow, Glasgow, G12 8SA.

Correspondence to: Professor J McMurray ([email protected])

5. A comment from primary care (pages S13–S14)Yassir Javaid General Practitioner and Cardiovascular Lead Primary Care, East Midlands Strategic Clinical Network

Danes Camp Medical Centre, East Hunsbury, Northampton, NN4 0NY

Correspondence to: Dr Yassir Javaid ([email protected])

The opinions, data and statements that appear are those of the contributors. The publishers, editors, and members of the editorial board do not necessarily share the views expressed herein. Although every effort is made to ensure accuracy and avoid mistakes, no liability on the part of the publisher, editors, the editorial board or their agents or employees is accepted for the consequences of any inaccurate or misleading information. © Medinews (Cardiology) Ltd 2016. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without the prior written permission of the publishers, Medinews (Cardiology) Ltd.

Dosing of sacubitril/valsartan Throughout this supplement, the dosing of sacubitril/ valsartan (Entresto™ , Novartis Pharmaceuticals) has been split to show the constituent doses.

In clinical trials, sacubitril/valsartan – initially known as the investigational agent LCZ696 – was used in 100 mg and 200 mg doses. These translate to the licensed doses of 49 mg sacubitril/51 mg valsartan and 97 mg sacubitril/103 mg of valsartan, respectively.

A smaller 50 mg dose, which equates to 24 mg sacubitril/26 mg valsartan, is also available.

Sponsorship statementThis sponsored supplement was initiated and funded by Novartis. Editorial control, however, was retained by the authors and editors but Novartis reviewed the supplement for technical accuracy only before publication.

ENT16-CO51; May 2016

Conflict of interestAndrew L Clark reports personal fees and fees for departmental support from Novartis. Yassir Javaid has received honoraria and travel expenses for attending medical meetings and/or advisory boards from Astra Zeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichhi Sankyo, MSD, Novartis and Pfizer. Paul R Kalra has received consultancy and speaker fees from Novartis. Sameer Kurmani: none declared. John McMurray’s employer, Glasgow University, has received funding from Novartis for his time spent as co-principal investigator of the PARADIGM-HF and PARAGON-HF trials using sacubitril/valsartan and meeting/presentations relating to these trials and sacubitril/valsartan. He received travel and accommodation expenses from Novartis for some of these meetings. Pierpaolo Pellicori: none declared. Iain Squire has received honoraria from Novartis for participation in advisory boards and educational events. His department has also received research support from Novartis.

Front cover credit: iStockphoto.com




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Volume 23 Supplement 1 | April–June 2016 | The British Journal of Cardiology | S3

SPONSORED SUPPLEMENTSPONSORED SUPPLEMENT

IntroductionSameer Kurmani, Iain Squire

Heart failure is a leading cause of morbidity and mortality and

presents many treatment challenges. Its prognosis is poor yet many patients do not receive optimal therapy. In the UK, the increasingly ageing population means rates of heart failure hospitalisation are estimated to rise by 50% over the next 25 years.

BackgroundHeart failure, a constellation of signs and symptoms in the presence of abnormal cardiac function, continues to represent a significant health problem within the UK, and, indeed, the wider developed world. In 2011, one in nine death certificates in the United States recorded heart failure as a contributing cause, and it was ascribed to being the direct underlying cause in 20% of cases.1 The current prevalence estimate for heart failure in the developed world is approximately 2%, which is a significant proportion of adults in industrialised society.2 Van Reit and colleagues have demonstrated from a systematic analysis of 25 study populations that the prevalence of isolated left ventricular systolic dysfunction in those aged over 65 years is 5.5%,3 which is corroborated by data from the general population in whom 5–9% of those over the age of 65 years have heart failure.2

The UK picture Studies, such as the Hillingdon Heart Failure cohort of circa 150,000 patients, demonstrate an incidence of 0.02/1,000 cases of heart failure per year in the 24–34 age group as compared with 11.6/1,000 per year in those aged over 85 years and a median age of presentation of 76 years.4 In the UK National Heart Failure Audit 2013–14, the mean age of patients admitted to hospital with a diagnosis of heart failure was 78 years.5

Although there are a myriad of causes for left ventricular systolic dysfunction, in approximately two thirds of patients with

Trial acronyms used ASCEND-HF (Acute Study of Clinical

Effectiveness of Nesiritide in Decompensated Heart Failure)

CIBIS-II (Carvedilol Insufficiency Bisoprolol Study II)

CONSENSUS (Cooperative North Scandinavian Enalapril Survival Study)

COPERNICUS (Carvedilol Prospective Randomised Cumulative Survival study)

EMPHASIS-HF (Eplerenone in Patients with Systolic Heart Failure and Mild Symptoms)

IMPRESS (Inhibition of Metaloprotease by Omapatarilat in a Randomised Exercise and Symptoms Study of Heart Failure)

MERIT-HF (Effect of Metoprolol CR/XL in Chronic Heart Failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure)

OCTAVE (Omapatrilat Cardiovascular Treatment versus Enalapril) study

OVERTURE (Omapatrilat Versus Enalapril Randomised Trial of Utility in Reducing Events)

PARADIGM-HF (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure trial)

PARAGON (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction)

RALES (The Effect of Spironolactone on Morbidity and Mortality in Patients with Severe Heart Failure)

SOLVD (Studies of Left Ventricular Dysfunction) TITRATION (Safety and Tolerability of Initiating

LCZ696 in Heart Failure Patients) V-HeFT (Veterans Administration Cooperative

Study)

‘Even on gold-standard therapy, the prognosis for patients with heart failure remains poor.’

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SPONSORED SUPPLEMENT

heart failure and reduced ejection fraction, the cause is directly attributable to coronary artery disease. This phenomenon might partly be explained by the fact that survival following myocardial infarction has improved significantly in the developed nations.6

Currently, within the UK, data from the Quality and Outcomes Framework 2014/15 estimate approximately 500,000 people live with heart failure.7 The prevalence of heart failure in the population leads inevitably to significant impacts on health spending. Data from the World Bank estimates the global economic cost of heart failure at US$108 billion per annum.8 Within the UK, the cost of heart failure is driven predominantly by the need for hospitalisation – inpatient care accounts for 60% of a total £980 million spend per year.9

Challenges for treatmentThe past 20–30 years have accrued a slew of prospective cohort and randomised-controlled trials aiming to reduce mortality and morbidity from heart failure through the targeting of maladaptive neurohumoral mechanisms both through pharmacology and device-based therapies. Prior to 1990, and the modern era of evidence-based therapy, mortality for patients was in the order of 60–70% at five years,10 which, although improved, still remains poor, as patients with a diagnosis of

Key messages• Heart failure continues to

represent a significant health burden worldwide

• Mortality and morbidity, even with gold-standard, evidence-based therapy, continues to be unacceptably high and is often inadequately implemented in clinical practice

• Neprilysin inhibition may have a role in addressing issues surrounding the management of heart failure

heart failure continue to experience a one-year mortality of 30–40%.11

Despite the presence of guidelines for the management of heart failure, omission and underuse of appropriate evidence-based therapies continues to present a significant problem. National Institute for Cardiovascular Outcomes Research (NICOR) audit data for the UK estimate that the overall mortality for patients admitted with heart failure in 2013/2014 at one year was 27%, rising to 45.5% at five years.5 Importantly, 15% of patients discharged from hospital with a diagnosis of left ventricular systolic dysfunction were not prescribed either an angiotensin-converting enzyme (ACE) inhibitor/angiotensin-receptor blocker (ARB) or beta blocker and were more likely to die within one year (HR 1.46, p<0.05). Furthermore, only 41% of patients with a diagnosis of heart failure were prescribed a combination of ACE inhibitor, beta blocker and mineralocorticoid receptor antagonist (MRA) who, as a patient group, had a better mortality outcome when compared with those not on triple therapies. The clinical practice in the UK is reflected in European data, which show a significant minority of patients receive low and potentially subtherapeutic doses of ACE inhibitors and ARBs.12 This highlights the fact that not all patients receive evidence-based therapy.

It is important to note that even on gold-standard therapy, the prognosis for patients with heart failure remains poor. In PARADIGM-HF, the novel agent sacubitril/valsartan was compared with enalapril at a target dose of 20 mg/day. Patients in the trial had stable New York Heart Association (NYHA) II–IV symptoms with excellent background therapy in terms of evidence-based pharmacology; more than 90% of patients were on a beta blocker and over 50% were on a MRA. Even in this extremely well-treated cohort, event rates were high, with 19.8% of patients on ‘gold-standard’ therapy (i.e high-dose ACE inhibitor) experiencing death and 26.5% either cardiovascular death or first hospitalisation for heart failure during a median follow-up of 27 months.13

Thus, even in an era of evidence-based, disease-modifying therapy, the outlook for patients with heart failure and reduced left ventricular ejection fraction remains unacceptably poor. Not only are epidemiological and trial data a testimony to this effect, but the implementation of gold-standard care in routine clinical practice is also suboptimal, thereby mitigating the effect of these drugs on a population level. At the current impasse in the management of heart failure, the introduction of the neprilysin inhibitor/angiotensin-receptor antagonist sacubitril/valsartan comes at a propitious moment •

References for this article are available on page S15

‘Inpatient care for heart failure in the UK accounts for 60% of a total £980 million spend per year.’

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Neurohumoral activation in heart failure and the implications for treatmentLegate Philip, Paul R Kalra

The pathophysiology of heart failure is complex. This article describes

the neurohumoral pathways that are active in chronic heart failure with left ventricular systolic dysfunction (also known as heart failure with reduced ejection fraction [HFREF]). It also explains the rationale behind the development of therapies to favourably modulate the neurohumoral imbalance seen in this condition.

IntroductionAn acute pathological insult to the heart leads to a reduction in cardiac output (i.e. any cause of left ventricular systolic dysfunction [LVSD]), which activates a series of innate protective mechanisms. In the short term, activation of neurohumoral systems aim to preserve central arterial pressure and thereby vital organ perfusion, and include the sympathetic nervous system (SNS) and the renin–angiotensin–aldosterone system (RAAS). The net main effects of this process are: i) vasoconstriction; ii) sodium and water retention by the kidneys. While in the acute setting these adaptive responses may be beneficial, long-term overactivation, such as that seen in patients with chronic heart failure, results in maladaptive processes, such as left ventricular remodelling and disease progression. Opposing counter-regulatory vasodilatory pathways, such as the natriuretic peptide system, contribute to physiological homeostasis.

The neurohumoral hypothesis1,2 of heart failure development/progression has been tested in a number of landmark studies. This has resulted in combined antagonism of the RAAS and SNS with angiotensin-converting enzyme (ACE) inhibitors or angiotensin-

receptor blockers (ARBs), beta blockers, and mineralocorticoid receptor antagonists (MRAs), forming the evidence-based treatment for patients with chronic heart failure secondary to LVSD.3,4

Recent results from the PARADIGM-HF study5 have enhanced our understanding of the counter regulatory pathways provided by other vasoactive peptides, particularly, the natriuretic peptide system.

Figure 1. Summary of the complex interaction between key neurohumoral pathways involved in the pathophysiology of heart failure. In heart failure, arterial under filling due to diminished cardiac output and/or reduced peripheral vascular resistance activates various mechanoreceptors, resulting in RAAS and SNS activation and vasopressin release. These, in turn, cause sodium and water retention and vasoconstriction, which have beneficial effects in the initial stages of heart failure. In the long term, these effects along with cardiac hypertrophy and remodelling and renal parenchymal fibrosis, have a detrimental effect culminating in the progression of heart failure. Natriuretic peptides secreted in response to myocyte stretch have a beneficial counter-regulatory effect. This includes increased water and sodium excretion, vasodilatation and reduced cardiac hypertrophy and fibrosis.9 These pathways interact with each other in a complex fashion

Vasoconstriction

Sodium and water retention

Natriuresis and diuresis

Kidneys

Renin

Angiotensin II

Aldosterone

Sympathetic nervous system

Vasopressin

Free water retention

SNS (other functions)• Increases vasopressin• Increases heart rate

and contractility• Cardiac fi brosis

RAAS (other functions)• Cardiac hypertrophy

and fi brosis• Renal parenchymal

fi brosis

NP (other functions)• Vasodilatation• Reduces vasopressin• Reduces hypertrophy

and fi brosis

Decreased distal renal tubular sodium and decreased renal perfusion pressure

High and low pressure mechanoreceptors

Osmotic andnon-osmotic stimuli

ANP

Increasedatrial stretch

BNP

Increased ventricularwall stress

NP

KEY

Positive response

Negative response

Key: ANP = atrial natriuretic peptide; BNP = brain natriuretic peptide; NP = natriuretic peptide; RAAS = renin–angiotensin–aldosterone system; SNS = sympathetic nervous system

Adapted from Kalra et al.6




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Sensing mechanisms A failure in the pumping capacity of the heart leads to haemodynamic changes that activate various sensing mechanisms. These, in turn, activate and regulate various neurohumoral pathways in an attempt to maintain circulatory integrity. Afferent sensing mechanisms triggered in heart failure can be subdivided into:

• low-pressure volume receptors – present mainly in the cardiac atria

• high-pressure mechanoreceptors – located in the left ventricle, aortic arch, carotid sinus and renal juxtaglomerular apparatus.6

Low-pressure receptorsIn heart failure, atrial stretch – caused by either volume expansion or increased transmural pressures – activates the low-pressure mechanoreceptors. This leads to release of natriuretic peptides, suppression of sympathetic outflow and decrease in renin and vasopressin release, ultimately leading to diuresis and natriuresis.7

High-pressure mechanoreceptorsA decrease in arterial pressure sensed at the high-pressure mechanoreceptors located in the aortic arch and carotid sinus, results in a reduction in the tonic inhibition of the sympathetic system. The net result is activation of the SNS and RAAS and non-osmotic release of vasopressin.

The mechanoreceptors in the renal juxtaglomerular apparatus respond to the reduction in renal perfusion or tubular sodium load typically seen in heart failure by enhancing renin release.6

Pathophysiological RAAS and SNS activation in chronic heart failure (figure 1)Activation of the SNS with release of endogenous catecholamines results in increased myocardial contractility, heart rate, vasoconstriction, sodium and water retention and RAAS activation. These all work to increase cardiac output and vital organ perfusion by linked pathways, which include expansion of the circulatory volume. Activation of the SNS, for example, plays an important stimulatory role in renal tubular

sodium and water re-absorption;8 SNS renal nerve stimulation leads to RAAS activation by stimulating renin release.5,9 While these mechanisms help maintain cardiac output, they also increase strain on an already failing heart.

As cardiac output decreases, increased sympathetic stimulation and decreased renal perfusion leads to an increase in secretion of renin by the kidneys. Renin acts on a circulating substrate called angiotensinogen to form angiotensin I. Cleavage of angiotensin I to form angiotensin II primarily occurs by the actions of ACE, which is found predominantly in the vascular endothelium, especially in the lungs.

Angiotensin II has a number of key functions, including:

• increasing systemic vascular resistance and arterial pressure (potent vasoconstrictor)

• sodium and water retention by directly stimulating sodium transport at renal tubular sites, promoting the release of aldosterone and vasopressin and

activation of the SNS. The subsequent release of aldosterone results in a further important contribution to sodium retention.

It is apparent that these neurohumoral systems also influence each other and the net result after chronic activation is adverse loading of the left ventricle. This is both by increased afterload (vasoconstriction) and pre-load as a consequence of circulating volume expansion (sodium and water retention). However, aldosterone, angiotensin II and the SNS, are also potent stimulants for myocardial hypertrophy and fibrosis, adverse vascular remodelling and renal parenchymal fibrosis.10-12 When left unchecked, these systems contribute to heart failure disease progression.

SNS and RAAS blockadeTherapeutic manipulation of these pathways with beta blockers, ACE inhibitors, ARBs and MRAs has become the cornerstone of the management of chronic heart failure with LVSD. Manipulation of these neurohumoral pathways results in beneficial reduction in ventricular afterload and reverse cardiac remodelling.12,13

ACE inhibitorsThe landmark trials that established ACE inhibitors as the cornerstone for heart failure management were CONSENSUS (1987),14 SOLVD-Treatment (1991),15 V-HeFT II (1991)16 and SOLVD-Prevention (1992).17 The CONSENSUS14 and SOLVD-Treatment15 trials showed that treatment with enalapril reduced overall mortality by 16–40% in patients with heart failure as compared with placebo. V-HeFT II16 showed that enalapril was superior to the combination of hydralazine and isosorbide dinitrate, which had previously been established as beneficial in the V-HeFT I trial (1986).18 The SOLVD-Prevention trial17 confirmed that enalapril was also beneficial in asymptomatic patients with reduced ejection fraction.

‘Results from PARADIGM-HF study have enhanced our understanding of the counter regulatory pathways

provided by other vasoactive peptides’

Cardiac myocytes release two of the natriuretic peptides that play a significant role in water and salt homeostasis

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ARBsARBs are only generally used in patients who cannot tolerate ACE inhibitors due to side effects, such as cough. They have not been proven to be superior to ACE inhibitors. The concept of using ARBs in heart failure was introduced in the Val-HeFT trial (2001).19

Beta blockersThe role of beta blockers in heart failure was initially viewed with scepticism due to concerns of further worsening inotropy. Evidence from a number of large trials, such as COPERNICUS (2001),20 showed that carvedilol led to a 35% reduction in mortality in patients with chronic heart failure compared to placebo. A substantial mortality benefit has also been demonstrated with bisoprolol and sustained release metoprolol (CIBIS-II,21 MERIT-HF22); these trials have greatly aided our understanding of the role of the SNS in heart failure.

MRAsSpironolactone, was evaluated in the RALES trial (1999)23 and was associated with a 30% reduction in mortality among patients with severe heart failure already receiving an ACE inhibitor and a loop diuretic. These results were further strengthened by the EMPHASIS-HF trial (2011),24 which evaluated eplerenone, another MRA, in patients with mild symptoms of heart failure and LVSD and demonstrated marked additional benefit when added to patients receiving optimal therapy with ACE inhibitors and beta blockers.

Current guidelines recommend combination therapy with both an ACE inhibitor and beta blocker as first line for management of chronic heart failure. A MRA is generally added to patients with symptomatic LVSD.3,4

Natriuretic peptide modulation – new to the armamentarium (figure 1)Natriuretic peptides are a group of peptide hormones that play a significant role in water and salt homeostasis. They provide counter-regulatory balance to the neurohumoral pathways already discussed; beneficial effects include direct vasodilatation, lowering of blood pressure, natriuresis, diuresis, lowering the release of renin from the kidneys, increasing

renal blood flow and decreasing cardiac hypertrophy and fibrosis.25

The natriuretic peptide system consists of three main peptides:

• atrial natriuretic peptide (ANP)

• B-type natriuretic peptide (BNP)

• C-type natriuretic peptide (CNP).

ANP and BNP are released from myocytes in response to cardiac stretch (elevated filling pressures). CNP is mainly released from endothelial cells.25

Elevated circulating levels of natriuretic peptides are found in patients with chronic heart failure and assessment of BNP (or its inactive N-terminal fragment, NTproBNP) is now a key component of the diagnostic pathway for patients with suspected heart failure.4 As such, it might seem counter-intuitive that there could be merit in enhancing natriuretic peptide activity in chronic heart failure. Yet data suggest that the natriuretic peptide system functions abnormally in people with cardiovascular diseases, such as hypertension and chronic heart failure.25

Recent studies using sensitive mass spectrometric techniques have shown that there are both active and inactive components of BNP. It appears that patients with chronic heart failure often exhibit an abnormal pattern of circulating BNP – with a relative deficiency of the protective (active) BNP and elevation of the inactive form.25 As a consequence of this, research has focused on increasing active BNP in heart failure, with a view to establishing if this can translate into improved patient outcomes.

Augmentation of natriuretic peptides in chronic heart failureExogenous administration of recombinant natriuretic peptide (neseritide) was assessed in the ASCEND-HF trial,26 and showed some benefit in symptoms (dyspnoea) in the acute phase but did not show any reduction in mortality or rehospitalisation rates, or improvement of renal function. Due to additional safety concerns this drug is not used in the UK.

Another method of increasing natriuretic peptide concentration is to reduce its degradation through the inhibition of neprilysin or neutral endopeptidase (NEP) – an enzyme that breaks down several peptide hormones including natriuretic peptides. In mammals, NEP is widely expressed in organs, such as the kidney, lung, endothelial cells, vascular smooth muscle cells and cardiac myocytes, with the highest concentrations being present in the renal proximal tubule.25

Several NEP inhibitors have been developed and tested in clinical trials; one of the earliest ones to be developed for clinical use was candoxatril, an orally administered prodrug.25 Candoxatril produced favourable effects in heart failure patients such as natriuresis and increased plasma ANP. However it was also found to increase angiotensin II and endothelin I levels.25 This was one of the limitations of using NEP inhibitors alone; while there is an increase in beneficial vasodilatory peptides, such as natriuretic peptides and bradykinin, there is also an increase in unwanted peptides such as angiotensin II

Figure 2. Impact of NEP (neprilysin) inhibition on various endogenous vasoactive peptides27

Reduces Increases

Increa

sesIncreases NEP inhibition

• Natriuretic peptides• Adrenomedullin• Bradykinin• Substance P

• Angiotensin II• Endothelin I

Maladaptive processes in heart failure

• Neurohumoral activation• Vascular tone• Cardiac hypertrophy and

fi brosis• Sodium retention

NEP inhibition potentiates action of vasoactive peptides




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Benefi cial physiological response Pathophysiological response

Vasodilation ▼Blood pressure ▼Sympathetic tone ▼Aldosterone levels

NatriuresisDiuresisAntifi brotic effects

Vasoconstriction ▲Blood pressure ▲Sympathetic tone ▲Aldosterone ▲Sodium

Fibrosis

Damage

Heart failuresymptoms/progression

Neurohumoral imbalancein heart failure

Natriuretic peptides

Neprilysin

RAASNP system

Inactive fragment

Angiotensin II (AT1)

AT1-receptor

and endothelin I (vasoconstrictors). These unwanted peptides counterbalance the beneficial effects (figure 2).27

Combining inhibitorsThis led to the idea of combining a NEP inhibitor with an inhibitor of the RAAS system; a combination often referred to as vasopeptidase inhibition.25,28 The rationale for combining an NEP inhibitor with a RAAS inhibitor is that the former can increase endogenous naturietic peptide levels while the latter can counteract the undesired increases in angiotensin II.

Omapatrilat, a dual blocker of NEP and ACE, was evaluated in the IMPRESS trial29 with lisinopril as the comparator in patients with heart failure. The data suggested potential benefits with omapatrilat and led onto a further study OVERTURE30 (versus enalapril in patients with chronic heart failure). It proved non-superior in comparison to enalapril in terms of lowering the primary end point of death and hospital admission requiring intravenous treatment. Further

concerns were raised from the OCTAVE31 trial, where omapatrilat was tested against enalapril for the treatment of 25,302 hypertensive patients. Although omapatrilat was found to help patients reach the target blood pressure more quickly, as compared with enalapril, the likelihood of early-onset of angioedema was significantly higher in patients treated with omapatrilat compared with those treated with enalapril. These concerns were highlighted in a review of omapatrilat conducted by the US Food and Drug Administration (FDA) body. Cases of angioedema were higher in African-American patients and those with a history of smoking. These findings led to omapatrilat not receiving FDA approval.25

The advent of ARNIsThe cause for angioedema with vasopeptidase inhibitors was initially thought to be secondary to increased levels of bradykinin from dual ACE and NEP inhibition. Newer data, however, suggest that inhibition of aminopeptidase P also plays an important role in bradykinin

Figure 3. Heart failure is a state of neurohumoral imbalance

Adapted from Langenickel TH, Dole WP. Angiotensin receptor-neprllysin inhibition with LCZ696: a novel approach for the treatment of heart failure. Drug Discovery Today: Therapeutic Strategies 2012;9:e131–e139.

Key: NP = natriuretic peptide; RAAS = renin-angiotensin-aldosterone-system

degradation when ACE is inhibited.25 This led to the development of an alternative strategy which combined an ARB and a NEP inhibitor – in this situation the ARB offers the advantage of not interfering with bradykinin metabolism as much as ACE inhibitors with the hope of reduced risk of angioedema.32 This group of drugs were collectively called ARB with NEP inhibition – or the angiotensin-receptor–neprilysin inhibitors (ARNIs).

The development molecule LCZ696 was the first of the ARNI class of drugs and combines valsartan (an ARB) with sacubitril (a NEP inhibitor). The key pathways targeted by the ARNI class of drugs are shown in figure 3.33 Pharmacokinetic and pharmacodyamic studies34 indicated sacubitril/valsartan is a potent dual-acting angiotensin receptor and NEP inhibitor. Following oral administration in healthy participants, it was shown to rapidly deliver NEP inhibition and angiotensin-receptor blockade.

These early clinical studies paved the way for the large, randomised, double-blind, controlled trial, PARADIGM-HF, where the safety and efficacy of sacubitril/valsartan was tested over the ACE inhibitor, enalapril, an established therapy in patients with chronic heart failure and LVSD5 •

Key messages• Chronic activation of the

sympathetic nervous and renin–angiotensin–aldosterone systems contribute to disease progression in patients with chronic heart failiure

• Pharmacological therapies proven to improve prognosis in chronic heart failure (ACE inhibitors, beta blockers, MRAs) antagonise these activated neurohumoral systems

• The natriuretic peptide family provides counter-regulatory vasodilatory and natriuretic pathways and, therefore, is a target for potential beneficial pharmacological modulation





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Table 1. Difference between the condensed and conservative regimens used in the TITRATION study in any of the specified adverse events

Percentage with … Condensed (n=247)

Conservative (n=251)

p value

Hypotension 9.7 8.4 0.57

Renal dysfunction 7.3 7.6 0.99

Hyperkalaemia 7.7 4.4 0.11

Angioedema 0.0 0.8 –

SBP <95 mmHg 8.9 5.2 0.10

K >5.5 mmol/L 7.3 4.0 0.10

K ≥6.0 mmol/L 1.2 0.4 0.32

Serum creatinine >3.0 mg/dL 0.4 0.0 –

Cum

ulat

ive

prob

abili

ty

Days since randomisation

0.6

0.5

0.4

0.3

0.2

0.1

0.0

1.0

0 180 360 540 720 900 1,080 1,260

Hazard ratio: 0.80 (95% CI 0.73–0.87)p<0.001

Enalapril

LCZ696

Figure 1. Kaplan Meier curves for the primary end point (a composite of death from cardiovascular causes or hospitalisation for heart failure) in the PARADIGM-HF trial1

Pierpaolo Pellicori, Andrew L Clark

PARADIGM-HF was the first study to compare the long-term efficacy

and safety of the angiotensin-receptor–neprilysin inhibitor (ARNI), sacubitril/valsartan (previously known as LCZ696), against standard care with the angiotensin-converting enzyme (ACE) inhibitor, enalapril, in patients with chronic symptomatic heart failure and reduced ejection fraction (HFREF). The trial was stopped early due to benefit.

The evidence in heart failure and reduced left ventricular ejection fraction PARADIGM-HF1 was a double-blind, randomised-controlled trial in which 8,442 patients with chronic symptomatic heart failure (New York Heart Association [NYHA] class II–IV) and a reduced left ventricular ejection fraction (LVEF) <40% (changed to ≤35% during the course of the study) were randomised to receive enalapril (10 mg

Clinical evidence to support the use of sacubitril/valsartan (LCZ696)

twice daily) or sacubitril/valsartan (200 mg twice daily)*. Entry criteria also included a raised natriuretic peptide (NP) level (brain natriuretic peptide [BNP] ≥150 pg/ml or N-terminal proBNP [NTproBNP] ≥600 pg/ml, although for patients who had been hospitalised for heart failure in the previous 12 months, a slightly lower cut-off was used for BNP [≥100 pg/ml] or NTproBNP [≥400 pg/ml]). Exclusions included significant valvular heart disease; systolic blood pressure below 100 mmHg at screening; an estimated glomerular filtration rate (eGFR) <30 ml/min/1.73m2; and hyperkalaemia.

All patients had to tolerate 10 mg enalapril twice daily followed by sacubitril/valsartan 100 mg twice daily, up-titrated to 200 mg twice daily, during a six-week run-in period before they could be randomised. During this run-in period, 2,079 patients discontinued the study, most commonly because of side effects or abnormal blood tests secondary to enalapril (n=657) or the subsequent sacubitril/valsartan treatment (n=605).

The mean age of the patients was 64 years, 22% were female, mean systolic blood pressure was 122 mmHg, and median NTproBNP plasma level was around 1,600 ng/L. More than 90% were treated with a beta blocker, the vast majority were taking a diuretic (80%) and 55% were also on mineralcorticoid antagonists.

The study was interrupted early (in March 2014) because of the benefit in the sacubitril/valsartan arm after a median follow-up of 27 months. The results were presented in September 2014 at the Congress of the European Society of Cardiology.2 Compared with patients randomised to enalapril, the use of sacubitril/valsartan led to a 20% risk reduction (4.7% absolute risk reduction [ARR]) in the primary end point (a composite of death from cardiovascular causes or hospitalisation for heart failure; figure 1), a 20% risk reduction in death from cardiovascular causes (3.2% ARR), a 21% risk reduction for the first hospitalisation for worsening heart failure (2.8% ARR), and a 16% risk reduction for death of any cause (2.8% ARR).

*For information on how the clinical trial doses of sacubitril/valsartan translate to the licensed doses, see the box on page S2

Key: SBP = systolic blood pressure; K = potassium

Note: these results must be considered preliminary until the paper is published in full.

Reproduced from McMurray et al.1 with permission © Massachusetts Medical Society.

Key: CI = confidence interval




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also a small proportion of patients naïve to both drugs (7%).

Of the 540 patients enrolled in the short (five days) run-in phase, in which patients received open-label sacubitril/valsartan 50 mg twice daily, 498 were randomised (92%), and 429 (86%) finished the study.

There was no difference between the two regimens in any of the specified adverse events including hypotension, renal dysfunction, hyperkalaemia, angioedema, systolic blood pressure below 95 mmHg, potassium >5.5 mmol/L or >6.0 mmol/L (table 1).

There was no difference between the groups in the secondary end point of treatment success, defined as the number of patients achieving the sacubitril/valsartan 200 mg twice-daily target dose without any down-titration or dose interruption over 12 weeks. Success was achieved in 78% patients in the condensed strategy arm versus 84% in the conservative strategy arm (p=0.07), but the analysis excluded patients who discontinued sacubitril/valsartan because of death or ”non-adverse events”. The results should be considered preliminary; in particular, the exclusion of ”non-adverse events” is difficult to assess until the paper is published in full9 •

The most common adverse event was symptomatic hypotension, which was more frequent in patients taking sacubitril/valsartan (14%) than enalapril (9.2%, p<0.001). Those taking enalapril were more likely to have a rise in creatinine (≥2.5 mg/dL; 4.5% vs. 3.3%, p=0.007) or potassium (>6.0 mmol/L; 5.6% vs. 4.3%, p=0.007) and to have a cough (14.3% vs. 11.3%, p<0.001). There was no difference in the (very low) incidence of angioedema between the groups.

There have been further analyses from the PARADIGM-HF study.

Age PARADIGM-HF recruited patients across a wide age range. Older patients were more likely to be female, had higher systolic blood pressure and circulating NTproBNP plasma levels, worse symptoms and renal function, and were more likely to have ischaemic heart disease or atrial fibrillation.3 Despite these differences, the effect of sacubitril/valsartan was similar across all ages (ranges defined post hoc: <55 years, 55–64 years, 65–74 years, >75 years). The hazard ratio (HR) was in favour (<1) of sacubitril/valsartan in all age categories for all the end points considered. The incidence of adverse events (apart from angioedema) increased with age, and the most common were again symptomatic hypotension, reported in 17.7% of patients older than 75 years in the sacubitril/valsartan group (vs. 11.9% in the enalapril group), and hyperkalaemia (more common in those taking enalapril).

Mode of deathDuring the trial, 1,546 patients died, including 711 in the sacubitril/valsartan arm and 835 patients in the enalapril group.4 Around 81% of deaths were attributed to cardiovascular causes, the majority of which were related to worsening heart failure or had happened suddenly; for 66 deaths the cause was not available. Fatal myocardial infarction and fatal stroke were rare events (<1%). Those who died were older, more likely to be male, and had more features of advanced heart failure than those who survived. The reduction in mortality seen with sacubitril/valsartan compared with enalapril was mainly due to the lower incidence of sudden

death and death related to worsening heart failure. Sacubitril/valsartan had no effect on the incidence of non-cardiovascular death compared with enalapril.

Worsening heart failureSacubitril/valsartan was superior to enalapril in preventing symptoms and disease progression.5 Compared with patients randomised to enalapril, those receiving sacubitril/valsartan required intensification of anti-heart failure treatment less frequently, including the need for intravenous inotropic support, or the need for emergency department visits. Furthermore, patients in the sacubitril/valsartan arm were less likely to be hospitalised multiple times. Patients in the sacubitril/valsartan group had significantly lower levels of circulating troponin and NTproBNP, evident within four weeks of starting the trial and sustained after eight months of treatment.

Severity of heart failure The MAGGIC score6 was used to define categories of baseline risk for the patients in PARADIGM-HF.7 An increase of one in the score is associated with an increase in the risk of the primary end point of 6%. Sacubitril/valsartan conferred a similar relative risk reduction across all the levels of risk, although the absolute benefit was markedly greater for those in the highest risk group.

Starting sacubitril/valsartanA potential concern about the clinical use of sacubitril/valsartan is the speed of up-titration. In PARADIGM-HF, there was quite a long run-in period, and patients only received sacubitril/valsartan once they had already been tolerant of enalapril 10 mg twice daily.

The randomised, double-blind, TITRATION study8 assessed the safety and tolerability of up-titrating sacubitril/valsartan from 50 mg twice daily to the target dose of 200 mg twice daily over three weeks (condensed strategy) or six weeks (conservative strategy) in patients with heart failure and LVEF <35%. The study included inpatients pre-treated with an angiotensin-converting enzyme (ACE) inhibitor or angiotensin-receptor blocker (11%), and

Key messages• The PARADIGM-HF trial showed

that, compared to enalapril, sacubitril/valsartan led to a 20% risk reduction (4.7% absolute risk reduction) in a composite end point of death from cardiovascular causes or hospitalisation for heart failure in patients with HFREF

• Benefits were consistent across different age ranges and risk profiles

• Compared to enalapril, sacubitril/valsartan lowered the incidence of sudden death and death related to worsening heart failure

• Sacubitril/valsartan was superior to enalapril in preventing the progression of heart failure





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The use of sacubitril/valsartan (LCZ696) in clinical practice John McMurray

Professsor John McMurray, the principal investigator in the

PARADIGM-HF study, writes about his experience with sacubitril/valsartan (known as LCZ696 at the time of the study) and how to optimally use this new agent in clinical practice, including how to switch patients to this treatment.

IntroductionA patient who seems to be doing well on conventional treatment will naturally be surprised and probably discomforted by the suggestion that his or her treatment should be changed, especially if this means an extra visit or two to the doctor or nurse, along with blood pressure checks and the taking of blood samples (and maybe the doctor or nurse looking after the patient might have similar thoughts!). Of course, those familiar with heart failure will know that the idea that a patient with heart failure is ‘doing well’ (or is ‘stable’) is a myth and that there is a high rate of disease progression, even with the currently best available treatment.

Sometimes, practitioners think they can wait until things get worse before needing to intervene. Unfortunately, the first manifestation of worsening may be death and, for many years, we have recognised that in patients with mild symptoms (i.e. the ones that might appear most stable), the most common mode of death is sudden, presumed arrhythmic, death. Why does all this matter? It matters because, if we wait, we may miss the boat. We won’t get warning. Our patient might not declare his or herself as someone in imminent danger.

Is this a real concern? In the PARADIGM-HF trial,1 in which the majority of patients had mild symptoms, we found 41% of ‘first events’ (or ‘end points’) in the trial were deaths and about half of those were sudden. So given the statistically overwhelming evidence that the angiotensin-receptor–neprilysin inhibitor (ARNI)

sacubitril/valsartan is superior to an evidence-based angiotensin-converting enzyme (ACE) inhibitor used in an evidence-based dose, in a broad spectrum of patients with heart failure and reduced ejection fraction (HFREF), I would argue that potentially all such patients treated with an ACE inhibitor or angiotensin-receptor blocker (ARB) should be considered for switching to the ARNI.

As with any drug, however, there are specific indications and contraindications and I will review these in the next section, taking account of the European Medicines Agency (EMA) and Medicines and Healthcare Products Regulatory Agency (MHRA) product labelling for sacubitril/valsartan. As we have learnt with ACE inhibitors/ARBs and beta blockers, aiming for the evidence-based target dose of treatment is important. But we also know, with all treatments, adverse effects may limit dose titration or even result in treatment intolerance. Therefore, I will also review what we know about the adverse effects of sacubitril/valsartan and how to manage these.

Indications and contraindicationsSacubitril/valsartan is indicated in adult patients for the treatment of symptomatic chronic heart failure with reduced ejection fraction. The product labelling for sacubitril/valsartan largely reflects the inclusion and exclusion criteria for the PARADIGM-HF study. The key indications are symptomatic heart failure and reduced ejection fraction (≤40%). Thereafter, the major consideration is tolerability. Because the neprilysin inhibitor component of the molecule (sacubitril) results in additional blood pressure lowering (beyond that of the ARB valsartan alone), sacubitril/valsartan is only recommended in patients with a systolic blood pressure ≥100 mmHg.

Neprilysin, like ACE, breaks down bradykinin, the chemical substance that when it accumulates can rarely cause angioedema in susceptible patients. Consequently, no patient with a history of angioedema should receive

‘The idea that a patient with heart failure is doing well or is stable is a myth’

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sacubitril/valsartan (because neprilysin inhibition leads to an increase in bradykinin). Likewise, ACE inhibitor treatment should be stopped for at least 36 hours before switching to sacubitril/valsartan so as to avoid the possibility of simultaneous ACE and neprilysin inhibition (and greater accumulation of bradykinin).

Although not specifically mentioned, kidney function must be monitored when switching to sacubitril/valsartan because the ARB component of this molecule, as with any other renin–angiotensin system (RAS) blocker, may lead to a rise in creatinine in some patients. This is unlikely if switching from an evidence-based dose of another RAS blocker, especially since renal dysfunctions were less common with sacubitril/valsartan than with enalapril in PARADIGM-HF. The same considerations apply to potassium, and sacubitril/valsartan is not recommended in patients with a potassium of >5.4 mmol/L.

Adverse effectsAs alluded to above, hypotension may occur on switching from an ACE inhibitor or ARB to sacubitril/valsartan because the latter increases natriuretic peptides and other vasoactive substances, which lead to vasodilatation. Among the 8,399 patients randomised to sacubitril/valsartan in PARADIGM-HF, 14.0% reported hypotension (9.2% in the enalapril group). In 2.7%, this was accompanied by a systolic blood pressure <90 mmHg (1.4% in the enalapril group). However, only 0.9% of sacubitril/valsartan treated patients stopped the study drug because of hypotension (0.7% in the enalapril group). This demonstrates that although relatively common in patients with heart failure, hypotension rarely is severe enough to lead to treatment discontinuation. We knew this already from our experience with ACE inhibitors/ARBs and beta blockers and, certainly, in my own practice patients are often willing to accept hypotensive symptoms (which are often postural e.g. transient dizziness on rising quickly from a chair) if fully informed of the benefits of persisting with treatment (i.e. that the risks of death and hospitalisation may be reduced).

The incidence of hypotension (and need to discontinue life-saving therapy) can be minimised by stopping any unnecessary blood pressure lowering drugs – the main culprits are nitrates, calcium-channel blockers and alpha-adrenoceptor antagonists. I find the latter to be the biggest problem. If administered for prostatic symptoms, it may be possible to substitute a 5-alpha reductase inhibitor (e.g. finasteride). Likewise, the much less common problem of hyperkalaemia (which was less frequent in the sacubitril/valsartan group than in the enalapril group) can often be avoided by discontinuation of drugs causing hyperkalaemia. The obvious ones are potassium supplements and potassium-sparing diuretics (the latter category does not include mineralocorticoid receptor antagonists, such as spironolactone). Other drugs causing potassium problems include trimethoprim and dietary sources should also be considered, e.g. ‘low-sodium’ salt-substitutes and bananas.

How to use sacubitril/valsartanThe best evidence we have for the use of sacubitril/valsartan comes from PARADIGM-HF, which enrolled patients already treated with an ACE inhibitor or ARB. To be eligible, patients had to be taking the equivalent of enalapril 10 mg daily (see table 1 of equivalent ACE inhibitor and ARB doses). The recommended starting dose of sacubitril/valsartan in these patients is 49/51 mg (i.e. 100 mg LCZ696 as used in PARADIGM-HF), taken twice daily. As mentioned earlier, patients should have a systolic blood pressure ≥100 mmHg and a serum potassium concentration ≤5.4 mmol/L.

The target dose of sacubitril/valsartan is 97/103 mg twice daily and the dose should be increased two to four weeks after initiation of therapy, provided the patient does not experience symptomatic hypotension, hyperkalaemia (potassium >5.4 mmol/L) or significant deterioration in renal function. Deterioration in renal function is only likely in patients subjected to greater inhibition of the RAS than with their previous dose of ACE

Table 1. Dose of commonly prescribed angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers equivalent to a daily dose of 10 mg of enalapril (based upon PARADIGM-HF protocol)

Angiotensin-converting enzyme inhibitors

Captopril 100 mg

Cilazapril 2.5 mg

Fosinopril 20 mg

Lisinopril 10 mg

Moexipril 7.5 mg

Perindopril 4 mg

Quinapril 20 mg

Ramipril 5 mg

Trandolapril 2 mg

Zofenopril 30 mg

Angiotensin-receptor blockers

Candesartan 16 mg

Eprosartan 400 mg

Irbesartan 150 mg

Losartan 50 mg

Olmesartan 10 mg

Telmisartan 40 mg

Valsartan 160 mg

‘Adult patients with symptomatic chronic heart failure and reduced ejection fraction should be

offered this new breakthrough treatment’

inhibitor or ARB, as a result of the valsartan component of sacubitril/valsartan. The valsartan component of the 49/51 mg dose of sacubitril/valsartan is equivalent to 80 mg of conventional valsartan. However, patients in PARADIGM-HF treated with sacubitril/valsartan had less renal dysfunction than those treated with enalapril, suggesting neprilysin inhibition protects the kidney to some extent.

In patients taking a lower dose of ACE inhibitor or ARB (or who have not previously been treated with one of these drugs), a lower starting dose of sacubitril/valsartan (24/26 mg) should be used, twice daily, and the dose doubled every three to four weeks with the aim of reaching the same target of 97/103 mg twice daily (but taking the same precautions in ensuring tolerability at each dose-titration step).

It is important to reiterate the absolute necessity of omitting existing ACE inhibitor treatment for 36 hours before starting sacubitril/valsartan.




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A comment from primary careYassir Javaid

Much of the work in reducing the mortality and morbidity from heart

failure will be carried out in primary care. Treatment of these patients with optimal therapy will bring significant benefits. As the armamentarium of agents to treat this condition grows, this article considers why many patients are inappropriately treated in primary care and which patients will most benefit from the new angiotensin-receptor–neprilysin inhibitor (ARNI) class of drugs.

IntroductionHeart failure, if left untreated, has a worse prognosis than the majority of cancers. Yet with the best possible treatment − most of which can and possibly should be delivered in primary care − the one-year mortality can be as low as 10%.

Earlier articles in this supplement have described how beta blockers, angiotensin-converting enzyme (ACE) inhibitors and mineralocorticoid receptor antagonists (MRAs) offer significant incremental survival benefits to patients with heart failure and reduced ejection fraction (HFREF) that can be further augmented by device therapy. Consider:

• an implantable cardioverter defibrillator (ICD) in patients with severe left ventricular systolic dysfunction (LVSD), i.e. left ventricular ejection fraction ≤35%

Key messages• Sacubitril/valsartan reduces the risk of

each of death from cardiovascular causes and hospital admission for worsening heart failure by 20% (4.7% absolute risk reduction) compared with an ACE inhibitor

• Even heart failure patients with mild symptoms have a poor prognosis and the first manifestation of worsening is death,

which is often sudden i.e. the physician is not alerted to progression of heart failure until it is too late

• As the benefits of sacubitril/valsartan over an ACE inhibitor occur early after initiation of treatment, there is a clear indication to switch patients to an ARNI as soon as possible

SummaryIn summary, the ARNI sacubitril/valsartan is the first new class of drug in 15 years to reduce the risk of premature death in heart failure patients and is clearly superior to one of our most effective existing treatments, namely an ACE inhibitor. Not only does sacubitril/valsartan reduce the risk of death but it also decreased the risk of hospital admission for worsening heart failure and even deterioration in quality of life. Eligible patients with HFREF should be offered this new breakthrough treatment •

‘Key considerations for primary care will be how to switch patients and up-titrate the new drug’

• cardiac resynchronisation therapy (CRT), with or without a defibrillator, in patients with co-existing left bundle branch block.

The benefits of ensuring patients with HFREF are on the appropriate combination of drugs at appropriate doses are likely to increase survival and reduce the short-term risk of hospitalisation compared with untreated heart failure patients. It is, therefore, unfortunate that many patients with LVSD remain poorly treated in primary care and are often left on suboptimal doses or, inappropriately, exception reported for treatment (i.e. those patients who are not included when determining Quality and Outcome Framework [QOF] achievement).

A common (inappropriate) rationale given for exclusion of beta blockade is chronic obstructive pulmonary disease (COPD). Up to a third of COPD patients are thought to have significant underlying LVSD (often undiagnosed) and residual breathlessness in these patients is often solely attributed to underlying obstructive airways disease. Measurement of serum natriuretic peptides (e.g. brain natriuretic peptide [BNP] or N-terminal proBNP

[NTproBNP]) in such patients is a useful screening test for possible co-existing heart failure. If clinicians are anxious about beta blockade in patients with obstructive airways disease, spirometry to rule out significant reversibility should provide reassurance.

Unmet needThe size of the unmet need in heart failure in England can be demonstrated by primary care QOF figures. The most recent data (March 2015)1 relate to heart failure care; these showed a Read-coded ‘heart failure’ prevalence of 0.73% and a Read-coded ‘LVSD’ prevalence of 0.21%. This is likely to represent significant underdetection/miscoding as the true UK prevalence of heart failure is likely to be 1–2%. Of the patients that are coded as LVSD in primary care, 86% are on an ACE inhibitor or angiotensin-receptor blocker (ARB) but only 65% are on both an ACE inhibitor/ARB and beta blocker. Across Clinical Commissioning Groups in England, exception reporting rates for beta blockers vary more than four-fold.

QOF data give no indication of whether patients are on optimised doses but there




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is anecdotal evidence that dosing is often suboptimal. Patients tend to be initiated on low doses of ACE inhibitors and beta blockers in hospital at the time of diagnosis, then often not subsequently up-titrated appropriately in primary care. Part of the explanation is that QOF does not incentivise optimisation. There are also likely to be capacity and educational gaps that contribute to the problem.

Effective use of community heart failure nurses can help address the unmet clinical and educational need within primary care. This precious resource can facilitate the optimisation process as well as provide advice and mentorship to clinicians to improve confidence in managing complex patients in primary care.

Patients suitable for ARNIsThe angiotensin-receptor–neprilysin inhibitor (ARNI) sacubitril/valsartan is the first in a new class of drug therapy that may help address the challenge of improving outcomes in HFREF. As we have seen in earlier articles, PARADIGM-HF2 demonstrated a benefit for sacubitril/valsartan over enalapril 10 mg twice daily in symptomatic patients with a left ventricular ejection fraction ≤40%.

NICE recommendationAs with any new agent, we need to work out which patients are likely to derive the most benefit. Recent National Institute of Health and Care Excellence (NICE) guidance in the technology appraisal guidance (TAG)2 for sacubitril/valsartan has recommended the drug as an innovative and cost-effective option for treating symptomatic chronic HFREF, in people:

• with New York Heart Association (NYHA) class II to IV symptoms and

• with a left ventricular ejection fraction of ≤35% or less

• who are already taking a stable dose of ACE inhibitors or ARBs.

NICE recommends that treatment with sacubitril/valsartan should be started by a heart failure specialist with access to a multi-disciplinary heart failure team. Dose titration and monitoring should be performed by the most appropriate team

member as defined in previous NICE guidance on the management of chronic heart failure in adults.3

Switching patientsKey considerations for primary care will be how to switch patients and then up-titrate the new drug. The previous article by John McMurray (see pages S11–S13) describes how to use sacubitril/valsartan and its contraindications including the concomitant use of ACE inhibitors due to the risk of angioedema necessitating a washout period of 36 hours before starting treatment.

The NICE TAG (TA388)2 recommends:

• a starting dose of sacubitril/valsartan of 49/51 mg (100 mg) twice daily

• or a starting dose of 24/26 mg (50 mg) twice daily for people not currently taking (or on low doses of) an ACE inhibitor or an ARB

• the dose should be doubled every two to four weeks to the target of 97/103 mg (200 mg) twice daily, as tolerated by the patient.

FutureIn future, in view of the potential mortality and hospitalisation benefit, there may be a compelling case for using sacubitril/valsartan as an upstream therapy with the tantalising possibility that this could significantly reduce downstream hospitalisation costs and also the need for costly device therapy •

Key messages• HFREF has a very poor prognosis

and is significantly underdiagnosed and undertreated with many diagnosed patients not on appropriate beta-blocker therapy

• Mortality and hospitalisation can be improved by medical therapy overseen in primary care

• Sacubitril/valsartan should be considered in patients with severe HFREF (EF ≤35%) who remain symptomatic despite otherwise optimal medical therapy.

Case historyThe case

• A 76-year-old patient with long-standing COPD presents with gradually worsening breathlessness on exertion over the previous six months despite good COPD treatment

• He has a significant smoking history: an ex-smoker with a 30 pack year history

• He also has longstanding hypertension but no specific cardiac history

• Recent spirometry confirms moderate/severe COPD: FEV1/FVC 0.6; FEV1 48% expected

DiscussionAlways consider the possibility of co-existing heart failure in a patient with COPD and residual dyspnoea despite optimal COPD treatment.

Patients with COPD commonly have co-existing left ventricular systolic failure or HFREF due to common risk factors, such as smoking. This patient also has long-standing hypertension, which is the second commonest cause of HFREF after ischaemic heart disease. BNP or N-terminal proBNP (NTproBNP) testing would be useful to determine the requirement of echocardiography to assess ventricular function.

COPD can also lead to right-sided heart failure secondary to pulmonary hypertension – look for raised jugular venous pressure and peripheral oedema. Significant tricuspid regurgitation and elevated right ventricular systolic pressure on echocardiography are suggestive of significant pulmonary hypertension. References for this article are available on page S16

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10. Jhund PS, Macintyre K, Simpson CR et al. Long-term trends in first hospitalization for heart failure and subsequent survival between 1986 and 2003: a population study of 5.1 million people. Circulation 2009;119:515–23. http://dx.doi.org/10.1161/CIRCULATIONAHA.108.812172

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13. McMurray JJ, Packer M, Desai AS et al. Angiotensin–neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014;371:993–1004. http:// dx.doi.org/10.1056/NEJMoa1409077

2. Neurohumoral activation in heart failure and the implications for treatment1. Packer M. The neurohormonal hypothesis: a theory to explain the mechanism of disease progression in heart failure. J Am Coll Cardiol 1992;20:248–54. http://dx.doi.org/10.1016/0735-1097(92)90167-L2. Ferrara R, Mastrolilli F, Pasanisi G et al. Neurohormonal modulation in chronic heart failure. Eur Heart J 2002;4:D3–D11. http://dx.doi.org/10.1016/S0195-668X(02)80022-73. McMurray JJV, Adamopoulos S, Anker SD et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012. Eur Heart J 2012;33:1787–847. http://dx.doi.org/10.1093/eurheartj/ehs1044. National Institute for Health and Care Excellence. Chronic heart failure in adults: management. NICE guidelines CG108. London: NICE, August 2010. Available from: https://www.nice.org.uk/guidance/cg108 (accessed 12 December 2015).5. McMurray JJ, Packer M, Desai AS et al.; for the PARADIGM-HF Investigators and Committees. Angiotensin–neprilysin inhibition versus enalapril in heart failure (PARADIGM-HF). N Engl J Med 2014;371:993–1004. http://dx.doi.org/10.1056/NEJMoa14090776. Kalra PR, Angnostopoulos C, Bolger AP, Coats AJ, Anker SD. The regulation and measurement of plasma volume in heart failure. J Am Coll Cardiol 2002;39:1901–08. http://dx.doi.org/10.1016/S0735-1097(02)01903-47. Alpern RJ, Caplan MJ, Moe OW. Seldin and Giebisch’s The Kidney: Physiology & Pathophysiology. 5th edition. London: Academic Press, 2013;1286–8.8. Bell-Reuss E, Trevino DL, Gottschalk CW. Effect of renal sympathetic nerve stimulation on proximal water and sodium re-absorption. J Clin Invest 1976;57:1104–07. http://dx.doi.org/10.1172/JCI1083559. Schrier RW, Abraham WT. Hormones and haemodynamics in heart failure. N Engl J Med 1999;341:577–85. http://dx.doi.org/10.1056/NEJM19990819341080610. Schlaich MP, Kave DM, Lambert E, Sommerville M, Socratous F, Esler MD. Relationship between cardiac sympathetic activity and hypertensive left ventricular hypertrophy. Circulation 2003;108:560–5. http://dx.doi.org/10.1161/01.CIR.0000081775.72651.B611. Levick SP, Murray DB, Janicki JS, Brower GL. Sympathetic nervous system modulation of inflammation and remodelling in the hypertensive heart. Hypertension 2010;55:270–6. http://dx.doi.org/10.1161/HYPERTENSIONAHA.109.14204212. Klabunde RE. Renin-angiotensin-aldosterone system. Cardiovascular physiology concepts. Available from: http://cvphysiology.com/Blood%20Pressure/BP015.htm [accessed 27 November 2015].

13. Triposkiadis F, Karayannis G, Giamouzis G, Skoularigis J, Louridas G, Butler J. The sympathetic nervous system in heart failure. Physiology, pathophysiology and clinical implications. J Am Coll Cardiol 2009;54:1747–62. http://dx.doi.org/10.1016/j.jacc.2009.05.01514. CONSENSUS trial study group. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med 1987;316:1429–35. http://dx.doi.org/10.1056/NEJM19870604316230115. SOLVD investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive cardiac failure. N Engl J Med 1991;325:293–302. http://dx.doi.org/10.1056/NEJM19910801325050116. Cohn JN, Johnson G, Ziesche S et al. A comparison of enalapril with hydralazine- isosorbide dinitrate in the treatment of chronic congestive heart failure. V-HeFT II, 1991. N Engl J Med 1991;325:303–10. http://dx.doi.org/10.1056/NEJM19910801325050217. SOLVD investigators. Effect of enalapril on mortality and development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med 1992;327:685–691. http://dx.doi.org/10.1056/NEJM19920903327100318. Cohn JN, Archibald DG, Ziesche S et al. Effect of vasodilator therapy on mortality in chronic congestive heart failure. V-HEFT I. N Engl J Med 1986;314:1547–52. http://dx.doi.org/10.1056/NEJM19860612314240419. 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;345:1667–75. http://dx.doi.org/10.1056/NEJMoa01071320. Packer M, Coats AJS, Fowler MD et al.; for the COPERNICUS Study Group. Effect of carvedilol on the morbidity of patients with severe chronic heart failure. N Engl J Med 2001;344:1651–8. http://dx.doi.org/10.1056/NEJM20010531344220121. CIBIS-II trial investigators. The cardiac insufficiency bisoprolol study II (CIBIS-II): a randomised trial. Lancet 1999;353:9–13. http://dx.doi.org/10.1016/S0140-6736(98)11181-922. MERIT-HF trial investigators. Effect of metoprolol CR/XL in chronic heart failure: metoprolol CR/XL randomised intervention trial in congestive heart failure (MERIT-HF). Lancet 1999;353:2001–07. http://dx.doi.org/10.1016/S0140-6736(99)04440-223. Pitt B, Zannad F, Remme WJ et al.; for the Randomized Aldacotone Evaluation Study (RALES) Investigators. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 1999;341:709–17. http://dx.doi.org/10.1056/NEJM19990902341100124. Zannad F, McMurray JJ, Krum H et al.; for the EMPHASIS-HF study group. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med 2011;364:11–21. http://dx.doi.org/10.1056/NEJMoa100949225. Mangiafico S, Costello-Boerrigter LC, Andersen IA, Cataliotti A, Burnett JC. Neutral endopeptidase inhibition and the

natriuretic peptide system – an evolving strategy in cardiovascular therapeutics. Eur Heart J 2013;34:886–93. http://dx.doi.org/10.1093/eurheartj/ehs26226. O’Conner 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. http://dx.doi.org/10.1056/NEJMoa110017127. Ferro CJ, Spratt JC, Haynes WG, Webb DJ. Inhibition of neutral endopeptidase causes vasoconstriction of human resistance vessels in vitro. Circulation 1998;97:2323–30. http://dx.doi.org/10.1161/01.CIR.97.23.232328. Burnett JC Jr. Vasopeptidase inhibition: a new concept in blood pressure management. J Hypertension Suppl 1999;17:S37–S43.29. Rouleau JL, Pfeffer MA, Stewart DJ et al. Comparison of vasopeptidase inhibitor, omapatrilat, and lisinopril on exercise tolerance and morbidity in patients with heart failure: IMPRESS randomised trial. Lancet 2000;356:615–20. http://dx.doi.org/10.1016/S0140-6736(00)02602-730. Packer M, Califf R, Konstam M et al.; for the OVERTURE Study Group. Comparison of omapatrilat and enalapril in patients with chronic heart failure. Circulation 2002;106:920–6. http://dx.doi.org/10.1161/01.CIR.0000029801.86489.5031. Kostis JB, Packer M, Black HR, Schmieder R, Henry D, Levy E. Omapatrilat and enalapril in patients with hypertension: The Omaptrilat Cardiovascular Treatment vs. Enalapril (OCTAVE) trial. Am J Hypertens 2004;17:103–11. http://dx.doi.org/10.1016/j.amjhyper.2003.09.01432. Adam A, Cugno M, Molinaro G, Perez M, Lepage Y, Agostoni A. Aminopeptidase P in individuals with a history of angio-oedema on ACE-inhibitors. Lancet 2002;359:2088–9. http://dx.doi.org/10.1016/S0140-6736(02)08914-633. McMurray JJV. Neprilysin inhibition to treat heart failure: a tale of science, serendipity, and second chances. Eur Heart J Fail 2015;17:242–7. http://dx.doi.org/10.1002/ejhf.25034. Gu J, Noe, A, Chandra P et al. Pharmacokinetics and pharmacodynamics of LCZ696, a novel dual-acting angiotensin receptor−neprilysin inhibitor (ARNi). J Clin Pharmacol 2010;50:401–14. http://dx.doi.org/10.1177/0091270009343932

3. Clinical evidence to support the use of sacubitril/valsartan (LCZ696)1. McMurray JJ, Packer M, Desai AS et al.; PARADIGM-HF Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014;371:993–1004. http://dx.doi.org/10.1056/NEJMoa14090772. Clark AL, Pellicori P. Clinical trials update from the European Society of Cardiology meeting 2014: PARADIGM-HF, CONFIRM-HF, SIGNIFY, atrial fibrillation, beta-blockers and heart failure, and vagal stimulation in heart failure. ESC Heart Failure 2014;1:82–6. http://dx.doi.org/10.1002/ehf2.12012

ADD PRESCRIBING INFORMATION ON BACK COVER

Prescribing Information:

ENTRESTO™ (sacubitril/valsartan) Important note: Before prescribing, consult Summary of Product Characteristics (SmPC). Presentation: Film-coated tablets of 24 mg/26 mg, 49 mg/51 mg and 97 mg/103 mg of sacubitril and valsartan respectively (as sacubitril valsartan sodium salt complex). Indications: In adult patients for treatment of symptomatic chronic heart failure with reduced ejection fraction. Dosage & administration: The recommended starting dose of Entresto is one tablet of 49 mg/51 mg twice daily, doubled at 2-4 weeks to the target dose of one tablet of 97 mg/103 mg twice daily, as tolerated by the patient. In patients not currently taking an ACE inhibitor or an ARB, or taking low doses of these medicinal products, a starting dose of 24 mg/26 mg twice daily and slow dose titration (doubling every 3 - 4 weeks) are recommended. A starting dose of 24 mg/26 mg twice daily should be considered for patients with SBP 100 to 110 mmHg, moderate or severe renal impairment (use with caution in severe renal impairment) and moderate hepatic impairment. Do not co-administer with an ACE inhibitor or an ARB. Do not start treatment for at least 36 hours after discontinuing ACE inhibitor therapy. Entresto may be administered with or without food. The tablets must be swallowed with a glass of water. Contraindications: Hypersensitivity to the active substances or to any of the excipients. Concomitant use with ACE inhibitors. Do not administer until 36 hours after discontinuing ACE inhibitor therapy. Known history of angioedema related to previous ACE inhibitor or ARB therapy. Hereditary or idiopathic angioedema. Concomitant use with aliskiren-containing medicinal products in patients with diabetes mellitus or in patients with renal impairment (eGFR <60 ml/min/1.73 m2). Severe hepatic impairment, biliary cirrhosis and cholestasis. Second and third trimester of pregnancy. Warnings/Precautions: Dual blockade of the renin angiotensin-aldosterone system (RAAS): Combination with an ACE inhibitor is contraindicated due to the increased risk of angioedema. Entresto must not be initiated until 36 hours after taking the last dose of ACE inhibitor therapy. If treatment with Entresto is stopped, ACE inhibitor therapy must not be initiated until 36 hours after the last dose of Entresto. Combination of Entresto with direct renin inhibitors such as aliskiren is not recommended. Entresto should not be co administered with another ARB containing product. Hypotension: Treatment should not be initiated unless SBP is 100 mmHg. Patients with SBP <100 mmHg were not studied. Cases of symptomatic hypotension have been reported in patients treated with Entresto during clinical studies, especially in patients 65 years old, patients with renal disease and patients with low SBP (<112 mmHg). Blood pressure should be monitored routinely when initiating or during dose titration with Entresto. If hypotension occurs, temporary down-titration or discontinuation of Entresto is recommended. Impaired or worsening renal function: Limited clinical experience in patients with severe renal impairment (estimated GFR <30 ml/min/1.73m2). There is no experience in patients with end-stage renal disease and use of Entresto is not recommended. Use of Entresto may be associated with decreased renal function, and down-titration should be considered in these patients. Hyperkalaemia: Entresto should not be initiated if the serum potassium level is >5.4 mmol/l. Monitoring of serum potassium is recommended, especially in patients who have risk factors such as renal impairment, diabetes mellitus or hypoaldosteronism or who are on a high potassium diet or on mineralocorticoid antagonists. If clinically significant hyperkalaemia occurs, consider adjustment of concomitant medicinal products or temporary down-titration or discontinuation of Entresto. If serum potassium level is >5.4 mmol/l discontinuation should be considered. Angioedema: Angioedema has been reported with Entresto. If angioedema occurs, discontinue Entresto immediately and provide appropriate therapy and monitoring until complete and sustained resolution of signs and symptoms has occurred. Entresto must not be re

administered. Patients with a prior history of angioedema were not studied. As they may be at higher risk for angioedema, caution is recommended if Entresto is used in these patients. Black patients have an increased susceptibility to develop angioedema. Patients with renal artery stenosis: Caution is required and monitoring of renal function is recommended. Patients with NYHA functional classification IV: Caution should be exercised due to limited clinical experience in this population. Patients with hepatic impairment: There is limited clinical experience in patients with moderate hepatic impairment (Child Pugh B classification) or with AST/ALT values more than twice the upper limit of the normal range. Caution is therefore recommended in these patients. B-type natriuretic peptide (BNP): BNP is not a suitable biomarker of heart failure in patients treated with Entresto because it is a neprilysin substrate. Interactions: Contraindicated with ACE inhibitors, 36 hours washout is required. Use with aliskiren contraindicated in patients with diabetes mellitus or in patients with renal impairment (eGFR <60 ml/min/1.73 m2). Should not be co-administered with another ARB. Use with caution when co-administering Entresto with statins or PDE5 inhibitors. Monitoring serum potassium is recommended if Entresto is co-administered with potassium-sparing diuretics or substances containing potassium (such as heparin). Monitoring renal function is recommended when initiating or modifying treatment in patients on Entresto who are taking NSAIDs concomitantly. Interactions between Entresto and lithium have not been investigated. Therefore, this combination is not recommended. If the combination proves necessary, careful monitoring of serum lithium levels is recommended. Co-administration of Entresto and furosemide reduced Cmax and AUC of furosemide by 50% and 28%, respectively, with reduced urinary excretion of sodium. Co-administration of nitroglycerin and Entresto was associated with a treatment difference of 5 bpm in heart rate compared to the administration of nitroglycerine alone, no dose adjustment is required. Co administration of Entresto with inhibitors of OATP1B1, OATP1B3, OAT3 (e.g. rifampicin, ciclosporin), OAT1 (e.g. tenofovir, cidofovir) or MRP2 (e.g. ritonavir) may increase the systemic exposure of LBQ657 or valsartan. Appropriate care should be exercised. Co-administration of Entresto with metformin reduced both Cmax and AUC of metformin by 23%. When initiating therapy with Entresto in patients receiving metformin, the clinical status of the patient should be evaluated. Fertility, pregnancy and lactation: The use of Entresto is not recommended during the first trimester of pregnancy and is contraindicated during the second and third trimesters of pregnancy. It is not known whether Entresto is excreted in human milk, but components were excreted in the milk of rats. Entresto is not recommended during breastfeeding. A decision should be made whether to abstain from breast feeding or to discontinue Entresto while breast feeding, taking into account the importance of Entresto to the mother. Undesirable effects: Very common ( 1/10): Hyperkalaemia, hypotension, renal impairment. Common ( 1/100 to <1/10): Anaemia, hypokalaemia, hypoglycaemia, dizziness, headache, syncope, vertigo, orthostatic hypotension, cough, diarrhoea, nausea, gastritis, renal failure, acute renal failure, fatigue, asthenia. Uncommon ( 1/1,000 to <1/100): Hypersensitivity, postural dizziness, pruritis, rash, angioedema. Packs and price: Entresto 24 mg/26 mg £45.78 per 28 tablet pack; Entresto 49 mg/51 mg £45.78 per 28 tablet pack, £91.56 per 56 tablet pack; Entresto 97 mg/103 mg £91.56 per 56 tablet pack. Legal classification: POM. Marketing Authorisation Holder: Novartis Europharm Ltd, Frimley Business Park, Camberley, GU167SR. Marketing Authorisation Numbers: Entresto 24 mg/26 mg film coated tablets EU/1/15/1058/001; Entresto 49 mg/51 mg film coated tablets EU/1/15/1058/002-004; Entresto 97 mg/103 mg film coated tablets EU/1/15/1058/005-007. Date of last revision of prescribing information: November 2015. Full Prescribing Information available from: Novartis Pharmaceuticals UK Ltd, Frimley Business Park, Frimley, Surrey, GU16 7SR. Tel: (01276) 692255 Fax: (01276) 692508.

Adverse events should be reported. Reporting forms and information can be found at http://mhra.gov.uk/yellowcard

Adverse events should also be reported to Novartis (01276) 698370 [email protected]

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3. Jhund PS, Fu M, Bayram E et al.; PARADIGM-HF Investigators and Committees. Efficacy and safety of LCZ696 (sacubitril-valsartan) according to age: insights from PARADIGM-HF. Eur Heart J 2015;36:2576–84. http://dx.doi.org/10.1093/eurheartj/ehv3304. Desai AS, McMurray JJ, Packer M et al. Effect of the angiotensin-receptor-neprilysin inhibitor LCZ696 compared with enalapril on mode of death in heart failure patients. Eur Heart J 2015;36:1990–7. http://dx.doi.org/10.1093/eurheartj/ehv1865. Packer M, McMurray JJ, Desai AS et al.; PARADIGM-HF Investigators and Coordinators. Angiotensin receptor neprilysin inhibition compared with enalapril on the risk of clinical progression in surviving patients with heart

failure. Circulation 2015;131:54–61. http://dx.doi.org/10.1161/CIRCULATIONAHA.114.0137486. Pocock SJ, Ariti CA, McMurray JJ et al.; Meta-Analysis Global Group in Chronic Heart Failure. Predicting survival in heart failure: a risk score based on 39 372 patients from 30 studies. Eur Heart J 2013;34:1404–13. http://dx.doi.org/10.1093/eurheartj/ehs3377. Simpson J, Jhund PS, Silva Cardoso J et al.; PARADIGM-HF Investigators and Committees. Comparing LCZ696 with enalapril according to baseline risk using the MAGGIC and EMPHASIS-HF risk scores: an analysis of mortality and morbidity in PARADIGM-HF. J Am Coll Cardiol 2015;66:2059–71. http://dx.doi.org/10.1016/j.jacc.2015.08.8788. Pellicori P, Clark AL. Clinical trials

update from the European Society of Cardiology – Heart Failure meeting 2015: AUGMENT-HF, TITRATION, STOP-HF, HARMONIZE, LION HEART, MOOD-HF, and renin-angiotensin inhibitors in patients with heart and renal failure. Eur J Heart Fail 2015;17:979–83. http://dx.doi.org/10.1002/ejhf.340

4. The use of sacubitril/valsartan (LCZ696) in clinical practice1. McMurray JJ, Packer M, Desai AS et al.; for the PARADIGM-HF Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure (PARADIGM-HF). N Engl J Med 2014;371:993–1004. http://dx.doi.org/10.1056/NEJMoa1409077

5. A comment from primary care1. Health and Social Care Information Centre. Quality and Outcomes Framework (QOF) 2014−15. Available from: http://www.hscic.gov.uk [accessed April 5th 2015].2. National Institute for Health and Care Excellence. Technology appraisal guidance (TA388). Sacubitril valsartan for treating symptomatic chronic heart failure with reduced ejection fraction. London: NICE, 27 April 2016. Available from: http://www.nice.org.uk/guidance/ta388 [accessed 26 May 2016].3. National Institute for Health and Care Excellence. Chronic heart failure in adults: management (CG108). London: NICE, August 2010. Available from: https://www.nice.org.uk/guidance/cg108 [accessed 5 April 2016].

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