A new pharmacological approach to managing chronic heart failure with reduced ejection fraction Back

Heart failure (HF) is a complex clinical syndrome resulting from any structural or functional cardiac or non-cardiac disorder that impairs the ability of the heart to effectively pump blood around the body. It is estimated that there are around 550 000 people in the UK living with HF, with potentially many more undiagnosed cases.1,2 Outcomes in the management of HF have improved as recommended disease-modifying therapies have become more widely used.3 However, morbidity and mortality remain high, and HF is a leading cause of hospital admission in patients aged 65 years and over in the UK.4

Epidemiology of heart failure

HF with reduced ejection fraction is a progressive condition,5 where patients are at risk of hospitalisation for acute decompensation and are at high risk of sudden death.6 The overall prevalence is around 0.7% in England, 0.8% in Scotland and Northern Ireland, and 1.0% in Wales.7 Estimated prevalence increases with age, rising from 1.12% at age 55–64 to 2.92% at 65–74 and 7.84% at 75+ in men, and 0.45%, 1.32% and 5.89%, respectively, in women.1 Applying current prevalence figures to population estimates suggests that around 550 000 people in the UK are living with HF; a figure that closely matches the 486 000 individuals listed in the Quality and Outcomes Framework (QoF).1 On average, a general practitioner will look after 30 patients with HF, and suspect a new diagnosis of HF in perhaps 10 patients annually.8

Each year, there are around 70 000 new cases of HF.9 Of patients newly diagnosed with HF, 30–40% die within a year and thereafter the mortality is <10% per year.8 In fact, the five-year survival rate in HF is worse than for common cancers such as breast and prostate cancer.8,10 Patients on general practitioner HF registers, representing prevalent cases of HF, continue to be at significant mortality risk, with a five-year survival of 58% as compared to 93% in the age- and sex-matched general population.11

The National Heart Failure Audit aims to collect data each year on unscheduled HF admissions. In 2013/14, HF accounted for approximately 160 000 inpatient episodes (53% men) – equivalent to 0.7% of all inpatient episodes and 9.5% of those due to diseases of the circulatory system.7 In England and Wales, the median length of hospital stay was about eight days, with an interquartile range of 4–16 days.12 Overall in-hospital mortality was 9.5%. Of those who survive and are discharged after an acute admission for HF, 6.2% die within 30 days; one-year mortality is 27%. Specialist care and prescription of recommended therapies are significant factors in reducing 30-day and one-year mortality.12 As a result, HF places a considerable burden on the NHS, costing £2.3 billion of the NHS budget – a figure set to rise along with the UK’s aging population.8,13


HF is a complex clinical syndrome of breathlessness, fluid retention and fatigue that impairs quality of life and reduces life expectancy. Structural and functional impairment reduces cardiac efficiency and output, leading to inadequate tissue oxygenation.

The haemodynamic changes secondary to cardiac dysfunction result in compensatory neurohormonal activation and autonomic imbalance in which the sympathetic nervous system (SNS) is activated and the renin–angiotensin–aldosterone system (RAAS) is over-activated. This initially supports cardiac output and circulatory homeostasis, but chronically it contributes to the progression and worsening of HF.14–16

Understanding of the impact of SNS and RAAS activation established a central role for beta-blockers and angiotensin- converting enzyme (ACE) inhibitors/angiotensin receptor blockers (ARBs) in the pharmacological treatment of HF. To date, there has been less awareness of the patho-physiological role of the natriuretic peptides (NPs). NPs provide a counter-regulatory system, and are released from the cardiac atria and ventricles in response to stretch.

Levels of NPs are increased in HF (such that brain natriuretic peptide [BNP] is a prognostic marker).17 They act as a counter-regulatory mechanism to the SNS and RAAS, and exert favourable effects on blood pressure and cardiac function by increasing glomerular filtration rate, natriuresis and diuresis; reducing cardiac preload and inhibiting remodelling; and suppressing RAAS and SNS activation, causing vaso-relaxation (Figure 1). They also have antihypertrophic and antifibroblast activity.17

Regulation of NPs occurs by a clearance receptor and by the neutral endopeptidase neprilysin.18 Early work looking at the inhibition of neprilysin as a therapeutic strategy in HF suggested some benefit.19 Due to the impact of neprilysin inhibition on angiotensin II, the addition of RAAS blockade to neprilysin inhibition proved more effective.19

Sacubitril/valsartan ▼

Entresto (sacubitril/valsartan) is a sodium salt complex comprised of the neprilysin inhibitor sacubitril and the ARB valsartan. It is indicated in adult patients for the treatment of symptomatic chronic HF with reduced ejection fraction.17 This first-in-class angiotensin receptor neprilysin inhibitor (ARNI) therefore offers cardiovascular benefits by enhancing the effects of NPs and simultaneously inhibiting the effects of angiotensin II.

Evidence for the efficacy of sacubitril/ valsartan is provided by the Prospective comparison of ARNI with ACEI (angiotensin-converting enzyme inhibitor) to Determine Impact on Global Mortality and morbidity in Heart Failure (PARADIGM-HF) trial.19 The trial was designed to establish whether the long-term effects of sacubitril/valsartan on morbidity and mortality were superior to those of ACE inhibition with enalapril in patients with HF with reduced ejection fraction. This double-blind, randomised, active-controlled trial involved 8442 patients with HF (mostly class II, 71% or class III, 24%) and an ejection fraction of 35% or less (initially <40%) (mean 29–30%). Eligible patients underwent two screening phases to ensure tolerability of the comparator treatments before being randomised to treatment with either sacubitril/valsartan 97mg/103mg twice daily or enalapril 10mg twice daily in addition to recommended therapy. Other treatments at randomisation included diuretics (80%), beta-blockers (93%), mineralocorticoid antagonists (56%) and digitalis (30%). The primary outcome was a composite of death from cardiovascular causes or a first hospitalisation for HF. The secondary outcomes, including all-cause mortality, are listed in Table 1.

PARADIGM-HF was carried out between December 2009 and November 2012. By March 2014, the predefined cut-off for clear benefit had been reached and the study was terminated early. The median duration of follow-up was 27 months. Out of 10 513 patients entering the enalapril run-in phase, 1102 discontinued the study, of whom 657 (6.2%) had an adverse event or abnormal laboratory or other test result (most commonly hypotension, hyperkalaemia or renal dysfunction) when taking ACE inhibitors. During the sacubitril/valsartan run-in phase, a further 977 of the 9419 remaining patients withdrew; of these, 605 (6.4%) left the study because they were unable to tolerate sacubitril/valsartan. A total of 8442 patients then underwent randomisation.


Over the median follow-up period of 27 months, sacubitril/valsartan significantly reduced the risk of death from cardio-vascular cause or first hospitalisation for HF by 20% (absolute risk reduction [ARR] 4.7%) compared with enalapril (Table 1). A difference in hospitalisation data was evident 30 days after randomisation (Figure 2).20 The individual components of the primary endpoint contributed equally to this finding, with a 20% reduction in the risk of cardiovascular death (ARR 3.2%) and 21% reduction in the risk of first HF hospitalisation (ARR 2.8%). Sudden cardiac death (hazard ratio, HR, 0.80; 95% confidence interval, CI, 0.68–0.94; p=0.008; ARR 1.4%) and death due to worsening HF (HR 0.79; 95% CI 0.64–0.98, p=0.034; ARR 0.9%) were also reduced by sacubitril/valsartan compared with enalapril.21 The numbers of patients who would need to be treated to prevent one primary event and one death from cardiovascular causes over the period of the trial were, respectively, 21 and 32.19 All-cause mortality was also significantly lower (16%, ARR 2.8%) with sacubitril/valsartan (17.0% versus 19.8%; HR 0.84, 95% CI 0.76–0.93; p<0.001).19

Significantly fewer patients had worsening of New York Health Association (NYHA) class at 8 and 12 months (though not at 4 months) or worsening clinical symptom scores, as measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ), at 4, 8 and 12 months (Table 2).20


Sacubitril/valsartan had a safety and tolerability profile comparable to that of enalapril. Of those assigned to treatment with sacubitril/valsartan, 17.8% prematurely discontinued treatment compared with 19.8% of those assigned to enalapril (p=0.02). This was due to adverse events in 10.7% and 12.3%, respectively (p=0.03). Discontinuations due to renal impairment occurred in 0.7% and 1.4%, respectively (p=0.002).19

Sacubitril/valsartan was significantly more frequently associated with symptomatic hypotension (14.0% versus 9.2%; p<0.001), although few patients discontinued therapy because of this (0.9% versus 0.7%; p=0.38). Enalapril was more often associated with serum creatinine raised ≥221µmol/L (4.5% versus 3.3%; p<0.007), serum potassium elevated >6.0mmol/L (5.6% versus 4.3%; p<0.007) and cough (14.3% versus 11.3%; p<0.001). Angioedema occurred in 19 patients (0.45%) treated with sacubitril/valsartan and 10 patients (0.24%) taking enalapril (p=0.13), with no airway compromise or mechanical airway protection required.19

Prescribing sacubitril/valsartan

The National Institute for Health and Care Excellence (NICE) recommends sacubitril/valsartan as an option for treating adult patients with symptomatic chronic HF with reduced ejection fraction, in people with NYHA class II–IV symptoms, LVEF <35% and who are already taking stable doses of ACE inhibitors or ARBs.22 The patient’s comorbidities and concomitant treatment should be taken into account when initiating treatment with sacubitril/valsartan (Table 3). Use of sacubitril/valsartan with an ACE inhibitor is contraindicated, and there must be a washout period of at least 36 hours between cessation of ACE inhibitor and initiation of treatment with sacubitril/valsartan due to the risk of angioedema. Sacubitril/valsartan should not be co-administered with another ARB-containing product. As with other HF medications, blood pressure, renal function and electrolytes (serum potassium) should be monitored before starting treatment and at each dose titration.

Note that BNP is not a suitable bio- marker of HF in patients treated with sacubitril/valsartan because it is a neprilysin substrate. Full details of prescribing cautions and contraindications and interactions with other drugs are provided in the Entresto Summary of Product Characteristics.


Sacubitril/valsartan offers a new alternative to ACE inhibitor and ARB treatment in adult patients for the treatment of symptomatic chronic HF with reduced ejection fraction. Robust evidence from the PARADIGM-HF trial shows that this combination significantly reduces morbidity and mortality compared with an ACE inhibitor and had a safety and tolerability profile comparable to that of enalapril.19,21,22


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Prescribing information