Beneficial effects of therapeutic drugs are controversial for heart failure with preserved ejection fraction (HFpEF). This meta-analysis aimed to evaluate and compare the interactive effects of different therapeutic drugs and placebo in patients with HFpEF. A comprehensive search was conducted using PubMed, Google Scholar, and Cochrane Central Register to identify related articles published before March 2021. The primary outcome was all-cause mortality. Secondary outcomes were cardiovascular

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... tality, heart failure (HF) hospitalization, and worsening HF events. A total of 14 randomized controlled trials, comprising 19,573 patients (intervention group, n 9,954; control group, n 9,619) were included in this network meta-analysis. All-cause mortality, cardiovascular mortality, and worsening HF events among therapeutic drugs and placebo with follow-up of 0.5-4 years were not found to be significantly correlated. The angiotensin receptor neprilysin inhibitor (ARNI) and angiotensin-converting enzyme inhibitor (ACEI) significantly reduced the HF hospitalizations compared with placebo (hazard ratio [HR] 0.73, 95% confidence interval [CI] 0.60-0.87 and HR 0.64, 95% CI 0.43-0.96, respectively), without heterogeneity among studies. The ARNI was superior to angiotensin receptor blocker (ARB) in reducing HF hospitalizations (HR 0.80, 95% CI 0.71-0.91), and vericiguat 10 mg ranked worse than beta-blockers for reducing all-cause mortality in patients with HFpEF (HR 3.76,. No therapeutic drugs can significantly reduce mortality, but the ARNI or ACEI is associated with the low risk of HF hospitalizations for patients with HFpEF.