Dual antithrombotic therapy increases severe bleeding events in patients with stroke and cardiovascular disease: a prospective, multicenter, observational study.
OBJECTIVE
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.
Toyoda
Kazunori
K
Cerebrovascular Division, National Cardiovascular Center, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan. toyoda@ hsp.ncvc.go.jp
Yasaka
Masahiro
M
Iwade
Kazunori
K
Nagata
Ken
K
Koretsune
Yukihiro
Y
Sakamoto
Tomohiro
T
Uchiyama
Shinichiro
S
Gotoh
Jun
J
Nagao
Takehiko
T
Yamamoto
Masahiro
M
Takahashi
Jun C
JC
Minematsu
Kazuo
K
D000368:Aged; D000925:Anticoagulants / Q000009:adverse effects; D002318:Cardiovascular Diseases / Q000188:drug therapy* / Q000453:epidemiology*; D015984:Causality; D002543:Cerebral Hemorrhage / Q000139:chemically induced / Q000453:epidemiology* / Q000503:physiopathology; D002985:Clinical Protocols; D015897:Comorbidity; D004338:Drug Combinations; D004359:Drug Therapy, Combination; D005260:Female; D005343:Fibrinolytic Agents / Q000009:adverse effects*; D006801:Humans; D015994:Incidence; D007564:Japan / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors / Q000009:adverse effects; D011446:Prospective Studies; D012307:Risk Factors; D020521:Stroke / Q000188:drug therapy* / Q000453:epidemiology*; D014859:Warfarin / Q000009:adverse effects
D000925:Anticoagulants; D004338:Drug Combinations; D005343:Fibrinolytic Agents; D010975:Platelet Aggregation Inhibitors; D014859:Warfarin