Bleeding Complications With Dual Antiplatelet Therapy Among Patients With Stable Vascular Disease or Risk Factors for Vascular Disease

Background—
Uncertainty exists about the frequency, correlates, and clinical
significance of bleeding with dual antiplatelet therapy
(DAPT), particularly over an extended period in a
stable population. We sought to determine the frequency and time course
of bleeding with DAPT in patients with
established vascular disease or risk factors only; identify correlates
of bleeding;
and determine whether bleeding is associated
with mortality.

Methods and Results—
We analyzed 15 603 patients enrolled in the Clopidogrel for High
Atherothrombotic Risk and Ischemic Stabilization, Management,
and Avoidance (CHARISMA) trial, a double-blind,
placebo-controlled, randomized trial comparing long-term clopidogrel 75
mg/d
versus placebo; all patients received aspirin
(75 to 162 mg) daily. Patients had either established stable vascular
disease
or multiple risk factors for vascular disease
without established disease. Median follow-up was 28 months. Bleeding
was assessed
with the use of the Global Utilization of
Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO) criteria.
Severe bleeding
occurred in 1.7% of the clopidogrel group versus
1.3% on placebo (P=0.087); moderate bleeding occurred in 2.1% versus 1.3%, respectively (P<0.001).
The risk of bleeding was greatest the first year. Patients without
moderate or severe bleeding during the first year
were no more likely than placebo-treated
patients to have bleeding thereafter. The frequency of bleeding was
similar in patients
with established disease and risk factors only.
In multivariable analysis, the relationship between moderate bleeding
and
all-cause mortality was strong (hazard ratio,
2.55; 95% confidence interval, 1.71 to 3.80; P<0.0001), along with myocardial infarction (hazard ratio, 2.92; 95% confidence interval, 2.04 to 4.18; P<0.0001) and stroke (hazard ratio, 4.20; 95% confidence interval, 3.05 to 5.77; P<0.0001).

Conclusions— In CHARISMA, there was an increased risk of bleeding with long-term clopidogrel. The incremental risk of bleeding was greatest
in the first year and similar thereafter. Moderate bleeding was strongly associated with mortality.