Abstract

• Standard medical treatment of chronic heart failure in patients with reduced left ventricular ejection fraction is based on an ACE inhibitor such as enalapril, a beta-blocker such as carvedilol, or a diuretic such as furosemide. An angiotensin II receptor blocker (ARB, alias sartan) such as valsartan is an alternative if the ACE inhibitor is poorly tolerated.
   
• A fixed-dose combination of sacubitril + valsartan has been authorised in the European Union for patients with symptomatic chronic heart failure and reduced left ventricular ejection fraction. The active metabolite of sacubitril inhibits neprilysin, an enzyme whose actions include breaking down natriuretic peptides.
   
• A randomised controlled trial of sacubitril + valsartan versus enalapril in 8442 patients with heart failure and a reduced left ventricular ejection fraction showed a statistically significant reduction in mortality with the combination: 17% versus 20% after a median follow-up of 27 months. The patients in this trial were relatively young and mildly symptomatic, had a marked decrease in the left ventricular ejection fraction but were stable on treatment with a beta-blocker, a diuretic and an ACE inhibitor or an ARB. Few patients had implantable cardiac devices. Patients who did not tolerate the gradual introduction (over 3 to 6 weeks) of the high-dose sacubitril + valsartan combination were excluded. It is not known whether the results were influenced by the use of a high-dose ARB in the sacubitril + valsartan group versus a standard dose of an ACE inhibitor in the enalapril group.
   
• The sacubitril + valsartan combination exposes patients to the adverse effects of ARBs. A possible increase in the risk of angioedema should be borne in mind, as sacubitril inhibits bradykinin metabolism. This risk was probably underestimated in the principal trial.
  
  
• The sacubitril + valsartan combination provoked more hypotension and hypokalaemia than enalapril, but less hyperkalaemia.
   
• Neprilysin is involved in the breakdown of amyloid beta peptide in the brain. Inhibition of neprilysin by the active metabolite of sacubitril could conceivably increase the long-term risk of dementia.
   
• Numerous interactions can be anticipated with the sacubitril + valsartan combination, including potentiation of furosemide and certain statins such as atorvastatin. In addition, additive adverse effects are likely with hypotensive drugs, for example. Renal failure, which is an adverse effect of valsartan, is a risk factor for sacubitril overdose.
   
•  POSSIBLY HELPFUL  Replacing an ACE inhibitor or an ARB with the high-dose sacubitril + valsartan combination in the hope of reducing mortality by a few percentage points after 27 months of treatment should be envisaged with care, and solely for heart failure patients comparable to those included in the only available trial: relatively young patients with minimal symptoms, a significant decrease in the left ventricular ejection fraction, stabilised by a beta-blocker + diuretic + ACE inhibitor or an ARB, and generally without an implantable cardiac device. This treatment switch requires careful monitoring for adverse effects, in particular hypotension and angioedema. Patients must be informed of the uncertainties associated with the sacubitril + valsartan combination, particularly concerning cognitive disorders and dementia. Other patients should be advised to continue to use better-assessed drugs.

©Prescrire 1 February 2017

"Sacubitril + valsartan in chronic heart failure. Favourable results in highly selected patients" Prescrire Int 2017; 26 (179): 33-37. (Pdf, subscribers only)