Br J Cardiol 2016;23(suppl 1):S1–S16doi:10.5837/bjc.2016.s01 Leave a comment
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Sponsorship Statement: This 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
Entresto™ (sacubitril/valsartan) prescribing information is available here

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.


Screen shot 2016-06-02 at 17.35.50Heart 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 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

Screen shot 2016-06-07 at 11.20.11

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 Screen shot 2016-06-07 at 12.02.26

Challenges for treatment

The 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 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.

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.


1. Mozaffarian D, Benjamin EJ, Go AS et al. Heart disease and stroke statistics – 2015 update: a report from the American Heart Association. Circulation 2015;131:e29–e322.

2. Mosterd A, Hoes AW. Clinical epidemiology of heart failure. Heart 2007;93:1137–46.

3. van Riet EE, Hoes AW, Wagenaar KP, Limburg A, Landman MA, Rutten FH. Epidemiology of heart failure: the prevalence of heart failure and ventricular dysfunction in older adults over time. A systematic review. Eur J Heart Fail 2016;18:242–52.

4. Cowie MR, Wood DA, Coats AJ et al. Incidence and aetiology of heart failure; a population-based study. Eur Heart J 1999;20:421–8.

5. Mitchell P, Marle D, Donkor A et al. National heart failure audit. April 2013 – March 2014. London: NICOR, 2014. Available from:

6. Smolina K, Wright FL, Rayner M, Goldacre MJ. Determinants of the decline in mortality from acute myocardial infarction in England between 2002 and 2010: Linked National Database Study. BMJ 2012;344:d8059.

7. Ramsay G. Quality and Outcomes Framework – prevalence, achievements and exceptions report. Leeds: Health and Social Care Information Centre, 2015;22.

8. Cook C, Cole G, Asaria P, Jabbour R, Francis DP. The annual global economic burden of heart failure. Int J Cardiol 2014;171:368–76.

9. National Institute for Health and Care Excellence. New NICE guidance will improve diagnosis and treatment of chronic heart failure. London: NICE, 2010. Available from:

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.

11. Go AS, Mozaffarian D, Roger VL et al. Heart disease and stroke statistics – 2014 update: a report from the American Heart Association. Circulation 2014;129:e28–e292.

12. Maggioni AP, Anker SD, Dahlstrom U et al. Are hospitalized or ambulatory patients with heart failure treated in accordance with European Society of Cardiology guidelines? Evidence from 12,440 patients of the ESC Heart Failure Long-Term Registry. Eur J Heart Fail 2013;15:1173–84.

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.

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.

Disclaimer: Medinews Cardiology Limited advises healthcare professionals to consult up-to-date Prescribing Information and the full Summary of Product Characteristics available from the manufacturers before prescribing any product. Medinews Cardiology Limited cannot accept responsibility for any errors in prescribing which may occur.