Effects of Angiotensin-Neprilysin Inhibition in Women Versus Men with Mildly Reduced or Preserved Ejection Fraction and Worsening Heart Failure: Insights from PARAGLIDE-HF

Introduction Significant sex-specific differences exist in heart failure with preserved ejection fraction (HFpEF). In particular, sub-analyses of key trials suggest a preferential benefit of specific HFpEF therapies in women. Hypothesis This work investigated potential differential treatment effects between women and men in the PARAGLIDE-HF (Prospective Comparison of ARNI with ARB given following Stabilization in Decompensated HFpEF) trial. We hypothesized that there would be no significant difference in treatment effect among women versus men in this high-risk population with LVEF>40%. Methods In this pre-specified subgroup analysis, we examined outcomes according to sex in the PARAGLIDE-HF trial. The primary endpoint was time-average proportional change in amino terminal pro-B type natriuretic peptide (NT-proBNP) from baseline through weeks 4 and 8. We also examined secondary outcomes and tolerability among women and men. Results Overall, 224 men (48%) and 242 women (52%) were randomized. Women had significantly higher LVEF, worse renal function, and less comorbid atrial fibrillation and coronary artery disease than men. In the overall study population, time-averaged reduction in NT-proBNP was significantly greater for Sacubitril-Valsartan (Sac/Val) than Valsartan (ratio of change 0.85; 95% CI:0.73-0.999). When examined according to sex, time-averaged reduction in NT-proBNP was numerically greater with Sac/Val than Valsartan in both men (ratio of change 0.84; 95% CI:0.67-1.05) and women (ratio of change 0.86; 95% CI:0.69-1.070), especially those with LVEF≤60% (ratio of change 0.75; 95% CI:0.59-0.96 for men; ratio of change 0.79; 95% CI:0.60-1.05 for women), with no significant differential treatment effect based on sex (P for interaction in overall sample=0.91, Figure 1). Similarly, the secondary hierarchical endpoint favored Sac/Val over Valsartan in both men and women but was not statistically significant (Figure 2). With regards to tolerability, study drug dosage levels were similar between Sac/Val and Valsartan across men and women. Likewise, there were no sex-specific differences in the incidence of adverse events. Conclusions The efficacy, safety and tolerability of Sac/Val versus Valsartan were similar in both men and women in the PARAGLIDE-HF trial.