Neprilysin is an endopeptidase that degrades several endogenous vasoactive peptides (e.g. natriuretic peptides; bradykinin). Combined inhibition of the renin-angiotensin system (RAS) and neprilysin has been found in experimental studies to have superior effects to monotherapy with either; serious angioedema was however seen with combined inhibition of ACE (enalapril) and neprilysin.
In order to minimise the risk of angioedema, the intervention trialled in the current study (LCZ696) combines the neprilysin inhibitor sacubitril (AHU377) with the angiotensin receptor blocker (ARB) valsartan. The study compared this to enalapril, in addition to standard therapy, for the treatment of adults with heart failure (NYHA class II-IV) and a reduced ejection fraction (≤40%; later amended to ≤35%). The participants were similar to those in other studies involving patients with mild to moderately severe heart failure.
The study (PARADIGM-HF) began with a single-blind run-in phase (n=10,513), during which patients received open-label treatment with enalapril (2 weeks), and then LCZ696 (4-6 weeks). Doses of the study drugs were increased to target levels during the run-in phase, primarily to ensure that patients in the enalapril group received doses that have been shown to reduce mortality. Only those without any unacceptable side-effects with either medication at target doses were permitted to enter randomisation. Of note, a total of 2079 patients discontinued the study during the run-in phase; this was due to an adverse event in 1138 (around 12%).
A total of 8,442 patients were randomised to double-blind treatment with enalapril (10mg BD) or LCZ696 (200mg BD); the median follow-up was 27 months. LCZ696 was associated with a lower risk of a composite of death from cardiovascular causes or a first hospitalisation for heart failure (21.8% v 26.5% with enalapril; HR 0.80; 95% CI 0.73-0.87; p<0.001). This is equal to a number needed to treat (NNT) to prevent one primary event of 21. When the endpoints were analysed individually:
• Death due to cardiovascular causes: 13.3% with LCZ696 v 16.5% with enalapril (NNT over 27 months to prevent one CV death: 32)
• Hospitalisation for heart failure: 12.8% with LCZ696 v 15.6% with enalapril (NNT 36)
After randomisation, LCZ696 was associated with a higher incidence of symptomatic hypotension (due to greater vasodilator effects); rises in serum creatinine (>221 μmol per litre) and serum potassium (>6.0 mmol/L) and cough were however reported less frequently than with enalapril. Angioedema was confirmed in 19 patients in the LCZ696 group and in 10 patients in the enalapril group (P=0.13).
Novartis plans to file an application for marketing authorisation of LCZ696 in the European Union in early 2015.