PARADISE-MI Fails to Meet Primary Endpoint, But Provides Insight into Effects of Entresto in Acute MI

Patrick Campbell

The PARADISE-MI study missed achieving a statistically significant reduction in its primary endpoint, but offers insight into the effects of sacubitril/valsartan in patients with a history of acute MI.

Data from the PARADISE-MI study indicate sacubitril/valsartan (Entresto) failed to provide significant reductions in rate of heart failure or cardiovascular death compared to ramipril in patients with acute myocardial infarction (MI).

Presented at the American College of Cardiology’s 70th Annual Scientific Session (ACC.21), results of the trial demonstrate sacubitril/valsartan did not meet the primary endpoint of reducing the study’s composite outcome by 15%, but investigators pointed out the therapy achieved a 10% reduction in the composite outcome and could still provide incremental clinical benefits in acute MI patients compared to use of an ACE inhibitor.

“Although we did not significantly reduce our primary endpoint, there were consistent findings that sacubitril/valsartan could represent an incremental improvement over ramipril,” said lead investigator Marc Pfeffer, MD, PhD, Distinguished Dzau Professor of Medicine at Harvard Medical School and cardiologist at Brigham and Women’s Hospital, in a statement. “The results are encouraging, especially when considering recurrent heart failure events and not just the first heart failure events, but the study is not definitive. We did notice several aspects of heart failure development that were lessened with sacubitril/valsartan but to investigate these observations would require further evaluations.”

With approval for treatment of heart failure dating back to 2015, many clinicians and researchers have awaited further information related to use of angiotensin receptor neprilysin inhibition in other populations of patients with cardiovascular conditions. Funded by Novartis Pharmaceuticals, PARADISE-MI enrolled more than 5600 patients from 41 countries, all of whom had suffered a heart attack less than a week prior to enrollment.

To identify and include a high-risk population without heart failure at time of enrollment, inclusion criteria included having an ejection fraction of at least 40% and/or transient pulmonary congestion and at least one additional factor augmenting risk. Patients were included if they had a history of heart failure, history of angioedema, were considered clinically unstable, or had an eGFR less than 30 ml/min/1.73m2. To assess use of sacubitril/valsartan in this patient population, investigators chose a primary endpoint defined as a composite of cardiovascular death, heart failure hospitalization, or development of symptomatic heart failure.

Event-driven by design, the trial randomized 2830 patients to receive sacubitril/valsartan and 2831 to 5 mg ramipril. Among the 5661 patients randomized, 711 events occurred during a median follow-up of 23 months. Of note, the overall patient population had a mean age of 64±12 years, 24% were women, and ST-elevation was present among 76%. Investigators also pointed out PCI was performed in 87% and the mean time to randomized occurred 4.3±1.8 days after prevention for acute myocardial infarction.

Upon analysis, investigators found a primary outcome event occurred in 11.9% (n=338) of patients receiving sacubitril/valsartan and 13.2% (n=373) of patient receiving ramipril (HR, 0.90; 95% CI, 0.78-1.04; P=.17). For individual endpoints, sacubitril/valsartan was associated with a lower rate of cardiovascular death ([5.9% vs 6.7]; HR, 0.87; 95% CI, 0.71-1.08; P=.20), hospital for heart failure ([6.0% vs 6.9%]; HR, 0.87; 95% CI, 0.70-1.06; P=.17), and development of outpatient heart failure ([1.4% vs2.0%]; HR, 0.68l 95% CI, 0.45-1.03; P=.07).

Further analysis of total adjudicated events indicated sacubitril/valsartan was associated with a 21% lower relative risk of experiencing hospitalization for heart failure, an outpatient heart failure event, and cardiovascular death (RR, 0.79; 95% CI, 0.65-0.97; P =.02). In safety analyses, results suggested there were no significant difference in rates of angioedema, abnormal potassium levels, renal impairment, or liver abnormalities.

This study, “Prospective ARNI versus ACE inhibitor trial to DetermIne Superiority in reducing HF Events after MI,” was presented at ACC.21.