Hemorrhagic Stoke with Dual Antiplatelet Therapy

Abstract & Commentary

By Michael H. Crawford, MD, Editor

Source: Ducrocq G, et al. A history of stoke/transient ischemic attack indicates high risks of cardiovascular event and hemorrhagic stroke in patients with coronary artery disease. Circulation 2013;127:730-738.

The REduction of Atherothrombosis for Continued Health (REACH) study is an international registry of patients on antithrombic therapy that provides an opportunity to evaluate the risk of ischemic and bleeding outcomes in patients with coronary artery disease (CAD). Among 26,380 REACH patients with CAD, there were 4460 (17%) with a history of prior stroke/transient ischemic attack (TIA). The prior cerebrovascular event (CVE) patients were older, more frequently female, and more likely to have diabetes, hypertension, or atrial fibrillation as compared to the rest of the CAD patients. Also, they were more likely to be taking dual antiplatelet therapy and oral anticoagulants. Over a 4-year follow-up, the CAD plus CVE patients had a higher death rate (18% vs 11%) and more cardiovascular events (25% vs 13% death, myocardial infarction, or stroke). Stroke was especially common (13% vs 4%) with twice as many hemorrhagic strokes. The increased risk for hemorrhagic stroke was greatest the first year and was particularly high in those on dual antiplatelet therapy (hazard ratio [HR], 5.21; 95% confidence interval [CI], 1.24-21.90). Oral anticoagulants plus dual antiplatelet therapy augmented the risk, but not anticoagulant therapy alone. Bleeding rates were higher in the CAD plus CVE vs the rest of the CAD patients (3.5% vs 2.5%). The authors concluded that in CAD patients, a history of CVE increased the risk of subsequent cardiovascular events, including hemorrhagic stroke, which was especially augmented in those on dual antiplatelet therapy in the first year after a prior CVE.


This study has important clinical implications. Among CAD patients, a history of CVE is common (17% in this study) and these patients have a higher risk of subsequent cardiovascular events such as cardiac death, myocardial infarction, and stroke. Thus, they are candidates for aggressive antithrombic therapy, including dual antiplatelet therapy and, in some cases, oral anticoagulants. However, they also have higher rates of bleeding, including hemorrhagic stroke, especially if they are on dual antiplatelet therapy. Hence, we have a therapeutic dilemma. Although the absolute risk of hemorrhagic stroke was small (0.6%) vs ischemic stroke (12%), it is most often fatal. In fact, the authors speculated that the incidence of hemorrhagic stroke may have been underestimated because some were classified as sudden deaths only.

These observations have been seen in other trials. For example, the use of prasugrel in acute coronary syndromes in patients with prior CVEs showed an increase in hemorrhagic stroke (HR, 1.54; 95% CI, 1.02-2.32; P = 0.04). Also, in the MATCH study, among patients with a recent CVE, those on dual antiplatelet therapy vs clopidogrel alone showed a higher rate of major bleeding and little effect on ischemic events.

Given these findings, how do we manage CAD patients with a history of CVE? This study provides some guidance. Those with a prior TIA have far less risk than those with a prior stroke. So, only stoke patients should create caution with regard to dual antiplatelet therapy. Also, the first year after a CVE was the highest risk period, so perhaps those in this time frame should be treated with single antiplatelet therapy or have coronary stenting delayed if possible. What to do with oral anticoagulation therapy is not clear from this study due to small numbers, but triple therapy in post CVE patients would probably be especially risky.