Key Points
- The PARADISE-MI trial randomized patients to receive sacubitril/valsartan or ramipril after high-risk myocardial infarction. The initial results demonstrated no significant benefit of sacubitril/valsartan, however examination of adjudicated events demonstrated a trend toward benefit with sacubitril/valsartan.
- A post-hoc win ratio analysis of the primary results were presented at the 2022 European Society of Cardiology Congress, in which the primary outcome was analyzed in a hierarchical order as opposed to a composite.
- Sacubitril/valsartan was compared to ramipril on a patient-by-patient basis, and resulted in an estimated unmatched win ratio of 1.17, demonstrating a larger number of “wins” with respect to the primary outcomes, when compared to ramipril.
- These results do not replace the initial neutral trial results, but can be rather used to aid in decision-making.
Sacubitril/valsartan did not provide a lower rate of cardiovascular death, heart failure hospitalization, or outpatient development of heart failure when compared to ramipril in the PARADISE-MI study, results of which were released in May of 2021. The results of the trial were neutral, with implications of superiority of the study drug when the primary and recurrent adjudicated events were included. As such, the study investigators thought a post-hoc analysis of the trial was warranted. In a Hot Line Session at the 2022 European Society of Cardiology Congress today, Dr. Otavio Berwanger (Sao Paulo, Brazil), presented the results of this post-hoc analysis.
The original PARADISE-MI results were previously reported by Cardiology Now News. Briefly, the study was a double-blind, active comparator-controlled trial that tested the safety and efficacy of sacubitril/valsartan against ramipril, an angiotensin-converting enzyme inhibitor, in patients following acute myocardial infarction in 41 countries. Inclusion criteria required evidence of pulmonary congestion requiring intravenous therapy and/or left ventricular ejection fraction ≤ 40% along with other high-risk features (including but not limited to age >70 years, GFR <60 mL/min/1.73 m2, the pr
esence of diabetes, among other characteristics). Patients with prior heart failure were excluded. During a median follow-up of 23 months, 711 patients experienced the primary adjudicated outcome, a composite of CV death, HF hospitalization or outpatient HF. Sacubitril/valsartan did not significantly lower the primary outcome when compared to ramipril by adjudicated primary events (P=0.17).
In this post-hoc study, a win-ratio analysis was performed, such the primary composite outcome was analyzed in the following hierarchical order: death due to cardiovascular causes, first hospitalization for heart failure, and first outpatient episode of symptomatic heart failure. The outcomes were augmented with events confirmed by the clinical event classification committee and investigator-reported events that may not have met original study definitions. The results were then analyzed using a win ratio method, by which each patient in the study arm was compared individually to each patient in the active comparator arm, after which a winner and loser is assigned. A win ratio that exceeded 1.0 meant that the outcome favored sacubitril/valsartan.
The hierarchical analysis of the primary composite outcome then demonstrated a larger number of wins for sacubitril/valsartan with respect to cardiovascular death, hospitalization for heart failure, and outpatient heart failure (1,265,767 [15.7%] wins and 1,079,502 [13.4%] losses), for a total win ratio of 1.17 (95% CI 1.03-1.33; p =0.015). The win ratio was driven mostly by death due to cardiovascular causes and hospitalization for heart failure. “These exploratory analyses do not alter the primary neutral results for the drug in acute myocardial infarction,” says Dr. Berwanger, “but they do provide supportive evidence to guide decisions to replace ACE inhibitors with sacubitril/valsartan once symptomatic heart failure has developed.”