Sacubitril is a new type of drug known as a neprilysin inhibitor, which blocks the breakdown of natriuretic peptides. As well as promoting sodium and water excretion, these peptides cause vasodilatation, increase glomerular filtration rate and renal blood flow, and counteract the hypertrophic and fibrotic changes seen in heart failure.
The angiotensin II antagonist valsartan is already used as second-line treatment in heart failure. It inhibits aldosterone release and suppresses the deleterious cardiovascular and renal effects of angiotensin II by selectively blocking the AT1 receptor.
Dual blockade of the renin–angiotensin system and neprilysin showed additive benefits in experimental studies, but the combination of an ACE inhibitor and a neprilysin inhibitor was associated with serious angioedema in clinical trials. To minimise the risk of angioedema, sacubitril is combined with an angiotensin II antagonist in Entresto. The combination must not be given with an ACE inhibitor.
Entresto is licensed for the treatment of symptomatic chronic heart failure with reduced ejection fraction. It is available in three different strength combinations; the appropriate strength should be taken twice daily.
Superior to enalapril
PARADIGM-HF was a double-blind randomised study (n=8442) comparing sacubitril/valsartan to enalapril in patients with NYHA class II to IV chronic heart failure and an ejection fraction of 40% or less. Participants were switched from their existing ACE inhibitor or angiotensin receptor antagonist to sacubitril/valsartan or enalapril, but continued to receive other heart failure treatments.
The primary endpoint was a composite of cardiovascular death or hospitalisation for heart failure.
Results showed that sacubitril/valsartan was superior to enalapril. Cardiovascular death or hospitalisation for heart failure occurred in 21.8% of patients in the sacubitril/valsartan group and 26.5% of those in the enalapril group (hazard ratio in the combination group 0.80, 95% CI 0.73–0.87; p<0.001).
Over the duration of the study, 21 and 32 patients had to be treated to prevent one primary event and one death from cardiovascular causes, respectively.
Patients in the sacubitril/valsartan group were more likely to experience symptomatic hypotension than those in the ACE inhibitor group (14.0% vs 9.2%), although this rarely led to discontinuation. Fewer patients taking the combination than taking enalapril stopped their medication because of an adverse event (10.7% vs 12.3%; p=0.03).
"The striking results in the PARADIGM-HF trial led me to believe that once approved [sacubitril/valsartan] could quickly replace what has been the bedrock treatment for more than 20 years, ACE inhibitors," said Professor John McMurray of the University of Glasgow, one of the study's principal investigators. "Thousands of lives could be extended and hospital admissions prevented with [the combination's] unique ability to boost natriuretic peptides, heart-helpful hormones, while simultaneously inhibiting the RAAS system."
Risk of angioedema
The most common adverse effects of sacubitril/valsartan are hypotension, hyperkalaemia and renal impairment.
Angioedema was reported in some patients and if this occurs, sacubitril/valsartan should be discontinued immediately and not restarted. Appropriate treatment and monitoring should follow until angioedema has completely resolved. A higher incidence of angioedema was observed in black patients.
Draft NICE acceptance
In draft guidance currently under consultation, NICE recommends sacubitril/valsartan as an option for treating people with NYHA class II to III chronic heart failure who have a left ventricular ejection fraction of 35% or less and are already taking a stable dose of ACE inhibitors or angiotensin II antagonists. Final guidance is expected to be published in May 2016.