Risk of Bleeding with With Warfarin, Aspirin, and Clopidogrel

"Triple therapy" with aspirin, clopidogrel,
and warfarin has become an increasingly common clinical scenario in the
drug-eluting stent era. While there is general acceptance that
multiagent antithrombotic regimens are associated with a higher risk of
bleeding, the degree of risk has not been well characterized. A recent
retrospective cohort study (Hansen et al, 2010) takes advantage of a
national registry capturing all hospital admission (including primary
and secondary diagnoses), pharmacy-dispensed medications, and cause of
death for all Danish citizens. The authors examined bleeding events
necessitating hospital admission in patients with an admission diagnosis
of atrial fibrillation over a 10-year period, as a function of
prescriptions filled for aspirin, clopidogrel, and warfarin.


For the purposes of analysis, patients were subdivided into 7 groups:
aspirin alone (47,541 patients), clopidogrel alone (3717 patients),
warfarin alone (50,919 patients), warfarin plus aspirin (18,345
patients), warfarin plus clopidogrel (1430 patients), clopidogrel plus
aspirin (2859 patients), and triple therapy (1261 patients). Bleeding
events occurred in 11.4% of patients, with incidence rates highest in
the first month following the index admission. Compared with warfarin
monotherapy, hazard ratios for bleeding events were 0.93 [95% confidence
interval (CI), 0.88–0.98] for aspirin, 1.06 (95% CI, 0.87–1.29) for
clopidogrel, 1.66 (95% CI, 1.34–2.04) for dual antiplatelet therapy,
1.83 (95% CI, 1.72–1.96) for warfarin plus aspirin, 3.08 (95% CI,
2.32–3.91) for warfarin plus clopidogrel, and 3.70 (95% CI, 2.89–4.76)
for triple therapy. In Cox proportional hazards analysis, warfarin was
superior to aspirin, clopidogrel, dual antiplatelet therapy, and
warfarin plus aspirin in the prevention of ischemic stroke; the other
combination regimens did not provide any greater protection from
ischemic stroke than did warfarin.


The widely discrepant sample sizes across treatment groups speak to
current practice patterns, with warfarin monotherapy and aspirin
monotherapy representing the dominant antithrombotic approaches to
atrial fibrillation. The latter is presumably utilized in patients felt
to be at low risk for cardioembolic events and/or at unacceptably high
risk of bleeding. The rate of bleeding events with aspirin was similar
to that with warfarin in this study, whereas warfarin provided
significantly greater protection from stroke; however, the observational
nature of the study limits our ability to draw strong conclusions from
those observations. Importantly, while this registry does advance our
understanding of the bleeding risks of multiagent antithrombotic
therapy, it falls short of fully characterizing the risk-versus-benefit
ratio that should guide clinical decision-making. Cardiovascular
endpoints (stent thrombosis, myocardial infarction) influenced by
antiplatelet agents were not examined in the study. A recent analysis of
antiplatelet therapy following drug-eluting stent placement found that
patients on anticoagulation had an odds ratio of 3.88 for premature
(i.e., <1 year following drug-eluting stent placement)
discontinuation of an antiplatelet agent in the absence of bleeding
complications (Ferreira-Gonzalez et al, 2010). This suggests that
concerns about bleeding risk are influencing clinical practice in
patients with indications for antiplatelet therapy. Understanding the
risk-versus-benefit ratio for a given anticoagulation/antiplatelet
regimen requires that all pertinent cardiovascular and bleeding outcomes
be assessed in concert. This analysis does not provide all of the
answers, but it does significantly advance our understanding of bleeding
risk as a function of antithrombotic regimen.

Joseph Loscalzo MD, PhD, Amy Leigh Miller MD, PhD

Disclosures

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