Risk of bleeding with single, dual, or triple therapy with warfarin, aspirin, and clopidogrel in patients with atrial fibrillation.
BACKGROUND
Patients with atrial fibrillation (AF) often require anticoagulation and platelet inhibition, but data are limited on the bleeding risk of combination therapy.


METHODS
We performed a cohort study using nationwide registries to identify all Danish patients surviving first-time hospitalization for AF between January 1, 1997, and December 31, 2006, and their posthospital therapy of warfarin, aspirin, clopidogrel, and combinations of these drugs. Cox proportional hazards models were used to estimate risks of nonfatal and fatal bleeding.


RESULTS
A total of 82,854 of 118,606 patients (69.9%) surviving AF hospitalization had at least 1 prescription filled for warfarin, aspirin, or clopidogrel after discharge. During mean (SD) follow-up of 3.3 (2.6) years, 13,573 patients (11.4%) experienced a nonfatal or fatal bleeding. The crude incidence rate for bleeding was highest for dual clopidogrel and warfarin therapy (13.9% per patient-year) and triple therapy (15.7% per patient-year). Using warfarin monotherapy as a reference, the hazard ratio (95% confidence interval) for the combined end point was 0.93 (0.88-0.98) for aspirin, 1.06 (0.87-1.29) for clopidogrel, 1.66 (1.34-2.04) for aspirin-clopidogrel, 1.83 (1.72-1.96) for warfarin-aspirin, 3.08 (2.32-3.91) for warfarin-clopidogrel, and 3.70 (2.89-4.76) for warfarin-aspirin-clopidogrel.


CONCLUSIONS
In patients with AF, all combinations of warfarin, aspirin, and clopidogrel are associated with increased risk of nonfatal and fatal bleeding. Dual warfarin and clopidogrel therapy and triple therapy carried a more than 3-fold higher risk than did warfarin monotherapy.
Hansen
Morten L
ML
Department of Cardiology, Copenhagen University Hospital Gentofte, Niels Andersens Vej 65 2900, Hellerup, Copenhagen, Denmark. mlh@heart.dk
Sørensen
Rikke
R
Clausen
Mette T
MT
Fog-Petersen
Marie Louise
ML
Raunsø
Jakob
J
Gadsbøll
Niels
N
Gislason
Gunnar H
GH
Folke
Fredrik
F
Andersen
Søren S
SS
Schramm
Tina K
TK
Abildstrøm
Steen Z
SZ
Poulsen
Henrik E
HE
Køber
Lars
L
Torp-Pedersen
Christian
C
D000368:Aged; D000925:Anticoagulants / Q000009:adverse effects* / Q000627:therapeutic use; D001241:Aspirin / Q000009:adverse effects* / Q000627:therapeutic use; D001281:Atrial Fibrillation / Q000188:drug therapy*; D002545:Brain Ischemia / Q000139:chemically induced* / Q000453:epidemiology; D000077144:Clopidogrel; D015331:Cohort Studies; D015897:Comorbidity; D003718:Denmark / Q000453:epidemiology; D004359:Drug Therapy, Combination; D005260:Female; D006470:Hemorrhage / Q000139:chemically induced* / Q000453:epidemiology; D006801:Humans; D015994:Incidence; D008297:Male; D016016:Proportional Hazards Models; D012042:Registries; D012306:Risk; D020521:Stroke / Q000139:chemically induced* / Q000453:epidemiology; D013988:Ticlopidine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D014859:Warfarin / Q000009:adverse effects* / Q000627:therapeutic use
D000925:Anticoagulants; D014859:Warfarin; D000077144:Clopidogrel; D013988:Ticlopidine; D001241:Aspirin