The PARADIGM-HF study compared Entresto (sacubitril/valsartan) with enalapril in chronic heart failure patients with reduced ejection fraction (HFrEF). PARADIGM-HF demonstrated that Entresto was superior to enalapril in reducing the risks of cardiovascular death and first hospitalization for heart failure. The study was terminated early due to the significantly greater benefit of Entresto. PARADIGM-HF is hitherto the largest study involving heart failure patients.
PARADIGM-HF was a double-blind study involving 8,442 HFrEF patients, which compared Entresto 97 mg/103 mg bid with enalapril 10 mg bid.
- The primary endpoint was the time until first hospitalisation due to heart failure or cardiovascular mortality.
- A secondary endpoint was the time to death from any cause.
- Other secondary endpoints were the change from baseline to 8 months in the clinical summary score on the Kansas City Cardiomyopathy Questionnaire (KCCQ), the time to a new onset of atrial fibrillation, and the time to the first occurrence of a decline in renal function.
Patients were required to have an age of at least 18 years, NYHA class II-IV and ejection fraction ≤ 40% (was later changed to ≤ 35%). Furthermore, patients were required to have ≥ 4 weeks of stable treatment with either an ACE inhibitor or an ARB and a beta blocker, and to have BNP (or NT-proBNP) levels as follows:
- BNP: ≥ 150 pg/ml (or NT-proBNP: ≥ 600 pg/ml),
- Or if hospitalisation within the last 12 months due to heart failure with a reduced ejection fraction, BNP: ≥ 100 pg/ml (or NT-proBNP: ≥ 400 pg/ml)
The patients were randomised 1:1 to receive either Entresto (n = 4,187) or enalapril (n = 4,212).
Entresto demonstrated a 20% relative reduction in risk of death from cardiovascular causes or first hospitalization for heart failure vs. enalapril: Death from cardiovascular causes or first hospitalization for heart failure (the primary endpoint) occurred in 914 patients (21.8%) in the Entresto group and 1,117 patients (26.5%) in the enalapril group (HR in the Entresto group, 0.80; 95% CI, 0.73 to 0.87; P<0.001).
Entresto demonstrated a 16% relative reduction in risk of all-cause mortality vs. enalapril: 711 patients (17.0%) receiving Entresto and 835 patients (19.8%) receiving enalapril died (HR: 0.84; 95% CI, 0.76-0.93, P<0.001).
Entresto demonstrated a 20% relative reduction in risk of death from cardiovascular causes vs. enalapril: A total of 558 deaths (13.3%) in the Entresto group and 693 (16.5%) in the enalapril group were due to cardiovascular causes (HR, 0.80; 95% CI, 0.71 to 0.89; P<0.001)
Entresto demonstrated a 21% relative reduction in risk of first hospitalization for heart failure vs. enalapril: 537 (12.8%) were hospitalized for heart failure, as compared with 658 patients (15.6%) receiving enalapril (HR, 0.79; 95% CI, 0.71 to 0.89; P<0.001)
Safety: Fewer patients in the Entresto group than in the enalapril group discontinued treatment due to an adverse event (10.7% vs 12.3%, p = 0.03) or because of renal impairment (0.7% vs. 1.4%, p=0.002).
Entresto was superior to enalapril in reducing the risks of cardiovascular death and first hospitalization for heart failure.
* Dosage corresponding to enalapril ≥ 10 mg daily
McMurray JJ et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371(11):993–1004.