Optimization of Clinical Trial Design and Decision-Making for Heart Failure with Preserved Ejection Fraction (HFpEF): A Meta-Analysis Based on a Placebo Response Model.

Objective: The aim of this study was to establish a placebo response model for efficacy indicators in heart failure with preserved ejection fraction (HFpEF) clinical trials, facilitating sample size estimation and trial optimization. Methods: PubMed, EMBASE, and Cochrane Library databases were searched systematically for placebo-controlled trials of HFpEF up to May 26, 2024. Using model-based meta-analysis (MBMA), we analyzed cardiovascular death or heart failure hospitalization, cardiovascular death, heart failure hospitalization, all causes of death, and changes from baseline in the 6-min walk distance (6MWD) of the placebo group. The final model simulated the placebo effect distribution for these indicators under varying scenarios. Results: A total of 29 studies and 14,302 participants were analyzed. A log-normal risk function was developed to describe four event rate indicators, and typical event rates for the placebo group over 6 years were simulated. After 1 year, rates for cardiovascular death or heart failure hospitalization (composite event), heart failure hospitalization, all causes of death, and cardiovascular death were 11.1%, 10.5%, 2.91%, and 2.33%, respectively. We used a linear model to describe the time-effect relationship of the change value of change from baseline in 6MWD, revealing typical changes at 1, 3, and 6 months as 1.47, 4.76, and 9.57 m, respectively. These values indicated that using the composite event as criteria could reduce the sample size by 500-12,000 cases, while 548 cases were sufficient for changes in 6MWD. The placebo effect model was also used as an external control in evaluating Sacubitril/Valsartan and exercise training efficacy. Conclusion: This placebo response model provides essential support for sample size estimation, trial optimization, and drug efficacy evaluation in future HFpEF clinical trials.