Assessment of Nonfatal Bleeding Events as a Surrogate for Mortality in Coronary Artery Disease

Background: Bleeding events are frequently applied as safety end points for randomized controlled trials (RCTs) investigating the effect of antithrombotic agents in patients with coronary artery disease. However, whether a bleeding event is a valid surrogate for death remain uncertain. Objectives: This study aimed to assess the correlation between the treatment effect on bleeding events and mortality. Methods: Multiple databases were searched to identify RCTs studying antithrombotic agents for patients with coronary artery disease through August 2022. Major and minor bleeding events were defined in included trials, mostly defined with BARC (Bleeding Academic Research Consortium) or TIMI (Thrombolysis In Myocardial Infarction) criteria. Trial-level correlations between nonfatal bleeding events and mortality were assessed. We performed subgroup analyses by the definitions of bleeding (BARC vs TIMI criteria), study year, and follow-up duration. We used a cutoff with a lower limit of 95% confidence interval of R² >0.72 as a strong correlation and with an upper limit of 95% confidence interval of R² <0.50 as a weak correlation. Results: A total of 48 RCTs with 181,951 participants were analyzed. Overall, trial-level R² for major and minor bleeding were 0.09 (95% CI: 0.00-0.26) and 0.09 (95% CI: 0.00-0.27) for all-cause or cardiovascular death, respectively. When confined to major bleeding, R² were 0.03 (95% CI: 0.00-0.13) and 0.01 (95% CI: 0.00-0.05), respectively. All of the subgroup analyses did not show any significant correlations. Conclusions: We demonstrated a trial-defined bleeding event may not be a valid surrogate for mortality in RCTs investigating the effect of antithrombotic agents for coronary artery disease.