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Anticoagulant Plus NSAID or Aspirin Use Associated With Increased Bleeding Risk


Clinical question

For patients with acute venous thromboembolism, is the use of anticoagulants plus nonsteroidal anti-inflammatory drugs or aspirin associated with an increased risk of bleeding?

Bottom line

For patients treated with anticoagulants for acute venous thromboembolism (VTE), the use of concomitant nonsteroidal anti-inflammatory drugs (NSAIDs) or aspirin is associated with an increased risk of bleeding. This can occur in patients treated with rivaroxaban, as well as in those treated with enoxaparin plus a vitamin K antagonist (VKA). (LOE = 2b)


Davidson BL, Verheijen S, Lensing AW, et al. Bleeding risk of patients with acute venous thromboembolism taking nonsteroidal anti-inflammatory drugs or aspirin. JAMA Intern Med 2014;174(6):947-953.

Study design

Cohort (prospective)

Funding source





Outpatient (any)


The worldwide EINSTEIN DVT and EINSTEIN PE clinical trials compared rivaroxaban with enoxaparin plus a VKA for the treatment of acute VTE. These investigators used data from this cohort to examine the association between rivaroxaban or enoxaparin-VKA plus concomitant NSAID or aspirin use and the risk of clinically relevant and major bleeding. Clinically relevant bleeding was defined as nonmajor bleeding that resulted in either medical intervention, temporary cessation of study treatment, or patient discomfort. Major bleeding was that which resulted in death, occurred at a critical site, required tranfusion of at least 2 units of red blood cells, or was associated with a 2 g/dL drop in hemoglobin. The cohort comprised 8246 patients, with half receiving rivaroxaban and half receiving enoxaparin-VKA. The NSAID analysis was adjusted for sex, as there were more women in the NSAID group. The aspirin analysis was adjusted for age and creatinine clearance, as patients in the aspirin group tended to be older with worse kidney function than the nonaspirin group. The NSAID or aspirin exposure period included 7 days after stopping the medication to reflect an ongoing risk. Clinically relevant bleeding was more likely to occur in the NSAID group as compared with the non-NSAID group (37.5 bleeding events per 100 patient-years vs 16.6 per 100 patient-years; hazard ratio [HR] = 1.77; 95% CI, 1.46-2.14). Findings were similar for both the NSAID-rivaroxaban-treated patients and NSAID-enoxaparin-VKA-treated patients. In the aspirin group, clinically relevant bleeding was also increased as compared with the nonaspirin group (36.6 bleeding events per 100 patient-years vs 16.9 per 100 patient-years; HR = 1.70; 1.38-2.11). For both the NSAID and the aspirin groups, the bleeding events were spread evenly over the duration of the use, suggesting that longer duration of use does not increase the risk of bleeding. Major bleeding increased 2.4-fold in the NSAID group and 1.5-fold in the aspirin group.

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

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