PARADIGM-HF: In HFrEF, ENTRESTO reduced heart failure hospitalization and CV death vs an ACEi

ENTRESTO led to a 20% reduced risk of sudden cardiac death, compared to enalapril: HR 0.80 (95% CI: 0.68–0.94).^6§

PARADIGM-HF was a multinational, randomized, double-blind trial comparing ENTRESTO to enalapril in 8442 symptomatic (NYHA Class II–IV) adult HFrEF patients (LVEF ≤40%). After discontinuing their existing ACEi or ARB therapy, patients entered sequential single-blind, run-in periods during which they received enalapril, followed by ENTRESTO. Patients who successfully completed the run-in periods were then randomized to receive either ENTRESTO 200 mg BID (n=4209) or enalapril 10 mg BID (n=4233). The median follow-up duration was 27 months, and patients were treated up to 4.3 years.¹

Patients randomized 1:1 to enalapril or ENTRESTO

• Enalapril: patients (in-hospital) randomized to the enalapril treatment group received enalapril from the first dose (n=441)

• ENTRESTO: patients (in-hospital) randomized to the ENTRESTO treatment group received 2 doses of placebo before receiving any dose of ENTRESTO to ensure the minimum 36-hour washout period prior to initiation of ARNi (n=440)

• All patients had a 36-hour washout period prior to starting the open-label extension

Cohort Description

• This study included 881 patients ≥18 years of age who had been hemodynamically stabilized following hospitalization for a primary diagnosis of ADHF, including signs and symptoms of fluid overload

• LVEF ≤40%

• NYHA Class II–IV

• NT-proBNP ≥1600 pg/mL or BNP ≥400 pg/mL

Study Outcomes

• Primary end point: the time-averaged proportional change in NT-proBNP from baseline through Weeks 4 and 8

• Key safety: the incidence of worsening renal function, hyperkalemia, symptomatic hypotension, and angioedema

Patients taking low dose or no ACEi/ARB at randomization were initiated on ENTRESTO 49/51 mg if their SBP was ≥120 mmHg. Patients were up-titrated as early as Week 1 and again at Weeks 2, 4, and 6 up to ENTRESTO 97/103 mg BID or enalapril 10 mg BID, as tolerated, based on their blood pressure. Follow labeled dosing recommendations.

^‖Entering the open-label phase, regardless of prior drug or dose, all patients were administered ENTRESTO 49/51 mg BID and were titrated as early as Week 1 to the target dose 97/103 mg BID. Follow labeled dosing recommendations.

Readmission (rehospitalization) was defined as the first hospitalization after inpatient initiation of study drug. Adjudication of readmission for Heart Failure and cause of death were adjudicated post hoc.

PARADIGM-HF was a multinational, randomized, double-blind trial comparing ENTRESTO to enalapril in 8442 symptomatic (NYHA Class II–IV) adult HFrEF patients (LVEF ≤40%). After discontinuing their existing ACEi or ARB therapy, patients entered sequential single-blind, run-in periods during which they received enalapril, followed by ENTRESTO. Patients who successfully completed the run-in periods were then randomized to receive either ENTRESTO 200 mg BID (n=4209) or enalapril 10 mg BID (n=4233). The median follow-up duration was 27 months, and patients were treated up to 4.3 years.¹

PARAGON-HF was a randomized, double-blind, active-controlled trial comparing ENTRESTO to valsartan in 4796 adult patients with symptomatic (NYHA Class II–IV) HFpEF (LVEF ≥45%, elevated levels of natriuretic peptides, structural heart disease [LAE or LVH], and no prior echocardiographic LVEF <40%). After completing the run-in period with valsartan, followed by ENTRESTO, patients entered the double-blind period and were randomly assigned (1:1) to ENTRESTO 97/103 mg BID (n=2407) or valsartan 160 mg BID (n=2389). The median follow-up duration was 35 months, and patients were treated for up to 4.7 years.^1,12 At the primary end point, a composite of total (first and recurrent) HF hospitalizations and CV death, ENTRESTO did not achieve statistical significance vs valsartan (RR 0.87; 95% CI: 0.75–1.01; P=.06). In a prespecified subgroup analysis of PARAGON-HF patients with LVEF at or below the median (57%), ENTRESTO reduced the rate of total HF hospitalizations and CV death, driven by reduction in HF hospitalizations (RR 0.78; 95% CI: 0.64–0.95).