Bleeding, mortality, and antiplatelet therapy: Results from the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial

Background The association between bleeding severity and cause of mortality in the non-acute setting is unclear. We sought to investigate the association between bleeding and mortality subtype, and assess whether this association differs in patients on dual antiplatelet therapy (DAPT) versus aspirin alone. Methods Using multivariable Cox proportional hazards survival regression, we examined the association between moderate or severe bleeding and all-cause, cardiovascular, and cancer mortality in 15,603 patients with cardiovascular disease or multiple risk factors enrolled in the CHARISMA trial. Results Patients with moderate or severe bleeding had a higher incidence of all-cause, cardiovascular, and cancer mortality (P < .001 for each). After multivariable adjustment, moderate/severe bleeding remained independently associated with not only all-cause mortality (adjusted hazard ratio [HR] 1.66; 95% confidence interval [CI] 1.24-2.21) and cardiovascular mortality (HR 2.05, 95% CI 1.38-3.04) but also cancer mortality (HR 4.76, 95% CI 2.60-8.69). However, there was a significant interaction between bleeding and potency of antiplatelet therapy for all-cause (P = .002), cardiovascular (P = .02), and cancer mortality (P = .03); in subjects on aspirin alone, moderate/severe bleeding was associated with all-cause (HR 5.27, 95% CI 3.56-7.80), cardiovascular (HR 4.33, 95% CI 2.55-7.37), and cancer mortality (HR 9.01, 95% CI 4.41-18.43), but not in subjects on DAPT (all-cause: HR 1.48, 95% CI 0.93-2.34; cardiovascular: HR 1.04, 95% CI 0.58-1.86; and cancer mortality: HR 1.79, 95% CI 0.56-5.74). Conclusions In stable patients, moderate or severe bleeding is associated with a significantly increased risk of all-cause, cardiovascular, and cancer mortality. However, this risk appeared different in subjects on single antiplatelet therapy versus DAPT. (Am Heart J 2011;162:98-105.e1.)