Heart Failure with Preserved Ejection Fraction Trials Have Heterogeneous Control Groups: a Comparison of Kaplan-Meier Curves.

Purpose: Previous studies have evaluated intra-study heterogeneities of heart failure with preserved ejection fraction (HFpEF), but inter-study heterogeneities remain poorly understood. We investigate the heterogeneities of outcomes among control groups of HFpEF trials.

Methods: We included randomized controlled trials recruiting HFpEF patients with ejection fraction ≥ 40% and reporting Kaplan-Meier curves for at least 36 months. The Kaplan-Meier curves of control groups were extracted and calculated for hazard ratios and 95% confidence intervals. Two virtual trials were developed to validate the reliability and accuracy of our method.

Results: Of 4161 studies, we included six trials containing 7682 HFpEF patients in control groups. The DIG trial had the highest all-cause mortality, cardiovascular mortality, heart failure mortality, and composite endpoints of cardiovascular mortality and heart failure hospitalization (all p < 0.001). The TOPCAT trial had the lowest all-cause mortality, cardiovascular mortality, heart failure hospitalization, and composite of cardiovascular mortality and heart failure hospitalization (all p < 0.001). Adoption of different ejection fraction cut-off values for HFpEF diagnosis did not significantly change the outcomes of control groups in the DIG trial (45% vs. 50%: hazard ratio, 1.05, 95% confidence interval, 0.97-1.13, p = 0.271), or in the CHARM-Preserved trial (40% vs. 50%: hazard ratio, 1.01, 95% confidence interval, 0.93-1.09, p = 0.864) during 36-month follow-up.

Conclusions: The control groups of HFpEF trials have heterogeneous outcomes. Future trials should consider these heterogeneities when designing protocols.