Published Online
on April 3, 2008

A more recent version of this article appeared on June 1, 2008

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Submitted on September 19, 2007
Revised on October 11, 2007
Accepted on October 19, 2007

Dual Antithrombotic Therapy Increases Severe Bleeding Events in Patients With Stroke and Cardiovascular Disease. A Prospective, Multicenter, Observational Study

Kazunori Toyoda MD^*; Masahiro Yasaka MD; Kazunori Iwade MD; Ken Nagata MD; Yukihiro Koretsune MD; Tomohiro Sakamoto MD; Shinichiro Uchiyama MD; Jun Gotoh MD; Takehiko Nagao MD; Masahiro Yamamoto MD; Jun C. Takahashi MD; Kazuo Minematsu MD; for the Bleeding with Antithrombotic Therapy (BAT) Study Group

From the Bleeding with Antithrombotic Therapy (BAT) Study Group: Cerebrovascular Division, Departments of Medicine (K.T., K.M.) and Neurosurgery (J.C.T.), National Cardiovascular Center, Suita; Department of Cerebrovascular Disease (M. Yasaka), National Hospital Organization Kyushu Medical Center, Fukuoka; Department of Cardiology (K.I.), National Hospital Organization Yokohama Medical Center, Yokohama; Department of Neurology (K.N.), Research Institute for Brain and Blood Vessels, Akita; Clinical Research Institute (Y.K.), National Hospital Organization Osaka National Hospital, Osaka; Department of Cardiovascular Medicine (T.S.), Graduate School of Medical Sciences, Kumamoto University, Kumamoto; Department of Neurology (S.U.), Tokyo Women's Medical University School of Medicine, Tokyo; Department of Neurology (J.G.), National Hospital Organization Saitama Hospital, Saitama; Department of Neurology (T.N.), Tokyo Metropolitan HMTC Ebara Hospital, Tokyo; and Department of Neurology (M. Yamamoto), Yokohama City Brain and Stroke Center, Yokohama, Japan.

^* To whom correspondence should be addressed. E-mail: toyoda{at}hsp.ncvc.go.jp.

Background and Purpose—We sought to determine the incidence and severity of bleeding events in patients with stroke and cardiovascular diseases who were taking oral antithrombotic agents in Japan, where the incidence of hemorrhagic stroke is higher than in Western countries.

Methods—A prospective, multicenter, observational study was conducted; 4009 patients who were taking oral antithrombotic agents for stroke and cardiovascular diseases were enrolled. The patients were classified into 4 groups according to their antithrombotic treatment: the single antiplatelet agent group (47.2%); the dual antiplatelet agent group (8.7%); the warfarin group (32.4%); and the warfarin plus antiplatelet agent group (11.7%). The primary end point was life-threatening or major bleeding according to the MATCH trial definition.

Results—During a median follow-up of 19 months, there were 57 life-threatening and 51 major bleeding events, including 31 intracranial hemorrhages. The annual incidence of the primary end point was 1.21% in the single antiplatelet agent group, 2.00% in the dual antiplatelet agent group, 2.06% in the warfarin group, and 3.56% in the warfarin plus antiplatelet agent group (P<0.001). After adjustment for baseline characteristics, adding an antiplatelet agent to warfarin increased the risk of the primary end point (relative risk=1.76; 95% CI, 1.05 to 2.95), and adding another antiplatelet agent to single antiplatelet agent therapy increased the secondary end point of any bleeding, including minor events (relative risk=1.37; 95% CI, 1.07 to 1.76).

Conclusions—The incidence of bleeding events during antithrombotic therapy in Japan was similar to that reported for Western countries, although the trials used different study designs. Dual antithrombotic therapy was independently related to an increased risk of bleeding events.

Key words: antiplatelet therapy • aspirin • anticoagulation • warfarin • intracerebral hemorrhage

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