Sex Differences in Clinical Characteristics and Outcomes After Myocardial Infarction With Low Ejection Fraction: Insights From PARADISE-MI

Abstract

Background Studies demonstrated sex differences in outcomes following acute myocardial infarction, with women more likely to develop heart failure (HF). Sacubitril/valsartan has been shown to reduce cardiovascular death and HF hospitalizations in patients with HF with reduced ejection fraction. Methods and Results A total of 5661 patients (1363 women [24%]) with acute myocardial infarction complicated by reduced left ventricular ejection fraction (≤40%), pulmonary congestion, or both and ≥1 of 8 risk-augmenting factors were randomized to receive sacubitril/valsartan or ramipril. The primary outcome was cardiovascular death or incident HF. Baseline characteristics, clinical outcomes, and safety events were compared according to sex, a prespecified subgroup. Female participants were older and had more comorbidities. After multivariable adjustment, women and men were at similar risks for cardiovascular death or all-cause death. Women were more likely to have first HF hospitalization (hazard ratio [HR], 1.34 [95% CI, 1.05-1.70]; P=0.02) and total HF hospitalizations (HR, 1.39 [95% CI, 1.05-1.84]; P=0.02). Sex did not significantly modify the treatment effect of sacubitril/valsartan compared with ramipril on the primary outcome (P for interaction=0.11). Conclusions In contemporary patients who presented with reduced left ventricular ejection fraction, pulmonary congestion, or both, following acute myocardial infarction, women had a higher incidence of HF during follow-up. Sex did not modify the treatment effect of sacubitril/valsartan relative to ramipril. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02924727.

Keywords: heart failure; myocardial infarction; sacubitril/valsartan; sex differences.

Figure 1. The cumulative incidence for the primary composite outcome according to sex and treatment assignment in PARADISE‐MI.

The HR (reference=ramipril) is adjusted for percutaneous coronary intervention and geographic region, stratified by type of myocardial infarction. HR indicates hazard ratio; PARADISE‐MI, Prospective ARNI (Angiotensin Receptor–Neprilysin Inhibitor) Versus ACE (Angiotensin‐Converting Enzyme) Inhibitor Trial to Determine Superiority in Reducing Heart Failure Events After Myocardial Infarction; and S/V, sacubitril/valsartan.

Figure 2. The cumulative incidence for incident heart failure (heart failure hospitalization or outpatient heart failure) and heart failure hospitalization according to sex and treatment assignment in PARADISE‐MI.

The HR (reference=ramipril) is adjusted for percutaneous coronary intervention and geographic region, stratified by type of myocardial infarction. HR indicates hazard ratio; PARADISE‐MI, Prospective ARNI (Angiotensin Receptor–Neprilysin Inhibitor) Versus ACE (Angiotensin‐Converting Enzyme) Inhibitor Trial to Determine Superiority in Reducing Heart Failure Events After Myocardial Infarction; and S/V, sacubitril/valsartan.

Figure 3. The cumulative incidence for all‐cause and cardiovascular death, according to sex and treatment assignment in PARADISE‐MI.

The HR (reference=ramipril) is adjusted for percutaneous coronary intervention and geographic region, stratified by type of myocardial infarction. HR indicates hazard ratio; PARADISE‐MI, Prospective ARNI (Angiotensin Receptor–Neprilysin Inhibitor) Versus ACE (Angiotensin‐Converting Enzyme) Inhibitor Trial to Determine Superiority in Reducing Heart Failure Events After Myocardial Infarction; and S/V, sacubitril/valsartan.

Figure 4. The cumulative incidence of study drug discontinuation because of adverse events, according to sex and treatment assignment in PARADISE‐MI.

The HR (reference=ramipril) is adjusted for baseline estimated glomerular filtration rate. HR indicates hazard ratio; PARADISE‐MI, Prospective ARNI (Angiotensin Receptor–Neprilysin Inhibitor) Versus ACE (Angiotensin‐Converting Enzyme) Inhibitor Trial to Determine Superiority in Reducing Heart Failure Events After Myocardial Infarction; and S/V, sacubitril/valsartan.