https://doi.org/10.1007/s00392-025-02625-4
1Universitäts-Herzzentrum Freiburg - Bad Krozingen Innere Medizin III, Kardiologie und Angiologie Freiburg im Breisgau, Deutschland; 2Institut für Medizinische Biometrie und Statistik (IMBI), Universitätsklinikum Freiburg Freiburg, Deutschland; 3Universitäts-Herzzentrum Freiburg - Bad Krozingen Klinik für Kardiologie und Angiologie Freiburg im Breisgau, Deutschland
Background: Most cardiovascular randomized clinical trials (RCT) aim to treat or prevent cardiovascular diseases. The overall benefit of the tested interventions in terms of mortality is unknown.
Purpose: We hypothesized that participation and randomization in a randomized clinical trial reduces the overall and cardiovascular mortality, assuming a randomization in the control group equals the standard of care at time of trial initiation.
Methods: We searched Medline for major cardiovascular (defined by MeSH terms) RCTs published in NEJM, JAMA or The Lancet between 2010 and 2019. Only RCTs with dichotomous primary endpoint, more than 100 participants and no more than two study arms were included. 344 RCTs were identified. RCTs that tested superiority and had total and/or cardiovascular mortality as a primary or secondary endpoint and hazard ratio (HR) as effect size measurement were considered for the meta-analysis. Mortality rates are presented as median and interquartile range (IQR). We used the DerSimonian and Laird method for random effects meta-analysis to depict the treatment effect. (Fig.1)
Results: 162 RCTs had death of any cause as an endpoint with a total of 898,150 participants. Cardiovascular death was an endpoint in 117 RCTs (823 365 participants).
103 RCTs (64%) tested a drug as an intervention, 38 trials (23%) a device, and 21 trials (13%) other interventions. 68 (42%) trials were industry-sponsored. 91 trials (56%) were designed as double blind and 11 trials (7%) as single blind. 60 trials (37%) were conducted with an open label design.
Trials with total mortality as an endpoint had a median mortality rate of 5.35% (IQR 2.75-11.30) for the intervention and 5.65% (IQR 2.55-12.25) for the control group. The median mortality rate for cardiovascular mortality was 2.90% (IQR 1.650-6.250) in the intervention and 3.00% (IQR 1.45-6.90) in the control group.
Using the DerSimonian and Laird method, we detected an overall HR of 0.959 (CI 0.937-0.981) for total and 0.961 (CI 0.934-0.988) for cardiovascular mortality. This means that participation and randomization in a major cardiovascular RCT reduced the total (and cardiovascular) mortality by 2% (absolute risk reduction) with a randomization ratio 1:1.
Conclusion: This meta-analysis depicts that participation and randomization in a major cardiovascular RCT reduced the total and cardiovascular mortality.