Clinical Question

Does inhibition of angiotensin and neprilysin offer benefits beyond those of angiotensin inhibition alone?

Bottom Line

The combination of an angiotensin receptor blocker (valsartan) and neprilysin inhibitor (sacubitril) reduces cardiovascular mortality more than an angiotensin-converting enzyme (ACE) inhibitor (enalapril [Vasotec]) alone, with an acceptable safety and tolerability profile. The choice of dosage is concerning, however, because the study compared a fairly high dose of valsartan with a moderate dose of enalapril. (Level of Evidence = 1b)

Synopsis

Neprilysin is an endopeptidase that breaks down vasoactive peptides such as natriuretic peptide, bradykinin, and adrenomedullin. Sacubitril inhibits this compound's activity, which has the effect of blocking the vasoconstriction, sodium retention, and cardiac remodeling that accompany more advanced stages of heart failure. A previous trial compared sacubitril with an ACE inhibitor, but angioedema was a problem. In the current trial, patients were randomized to receive the combination of sacubitril and the angiotensin receptor blocker valsartan or to receive enalapril, an older ACE inhibitor. All patients were adults with New York Heart Association (NYHA) class II, III, or IV heart failure; an ejection fraction no greater than 40% (later changed to 35%); and an elevated B-type natriuretic peptide level. The authors excluded those with hypotension, a glomerular filtration rate of less than 30 mL per minute per 1.73 m², a serum potassium level greater than 5.2 mEq per L (5.2 mmol per L), or a history of angioedema or other adverse effects of ACE inhibitors or angiotensin receptor blockers.

The authors ultimately enrolled 10,513 patients. They then had to run a gauntlet of two separate run-in phases: 1,102 patients left the study because they did not tolerate enalapril, 977 left because they did not tolerate the valsartan/sacubitril combination, and another 43 left primarily because of protocol violations. This meant a total of 8,399 patients were randomized to receive valsartan/sacubitril, 200 mg, or enalapril, 10 mg, each given twice daily. The dosage of valsartan is near the top of the recommended dosing range, whereas the dosage of enalapril is closer to the middle of the recommended range (10 to 40 mg per day) for that drug. Groups were balanced at the start of the study, with an average age of 63 years, 22% women, and the majority with NYHA class II (70%) or class III (24%) heart failure. Patients were followed for a median of 27 months, at which time an independent data monitoring committee halted the trial.

The primary outcome was a cardiovascular death or hospitalization for worsening heart failure. Obviously, this is an inappropriate composite, because they are very different outcomes. Looking at each outcome individually, however, there were fewer cardiovascular deaths in the intervention group (13.3% vs. 16.5%; P < .001; number needed to treat [NNT] = 31) and fewer hospitalizations in the intervention group (12.8% vs. 15.6%; P < .001; NNT = 36). All-cause mortality was also significantly lower in the intervention group (17.0% vs. 19.8%; NNT = 36), as was a validated symptom score. There were no significant differences in rates of renal function decline or new onset atrial fibrillation. Subgroup analyses showed similar benefits by age, sex, race, and comorbidities. Significant hypotension was more common in the valsartan/sacubitril group (14.0% vs. 9.2%; P < .001; number needed to treat to harm = 21), whereas cough and elevated serum creatinine levels were more common in the enalapril group. The valsartan/sacubitril group had lower mean blood pressures, supporting concerns of a “straw man” comparison with the selected dose of enalapril.

Study design: Randomized controlled trial (double-blinded)

Funding source: Industry

Allocation: Concealed

Setting: Outpatient (any)

Reference: McMurrayJJPackerMDesaiASet alPARADIGM-HF Investigators and CommitteesAngiotensinneprilysin inhibition versus enalapril in heart failure. N Engl J Med.2014; 371( 11): 993– 1004.