Even occasional use of NSAID or aspirin confers extra bleeding risk when on anticoagulation

Bleeding Risk of Patients With Acute Venous Thromboembolism Taking Nonsteroidal Anti-Inflammatory Drugs or Aspirin

Literature - Davidson BL et al., JAMA Intern Med. 2014 - JAMA Intern Med. 2014 Apr 14

Davidson BL, Verheijen S, Lensing AW, et al.
JAMA Intern Med. 2014 Apr 14. doi: 10.1001/jamainternmed.2014.946


Patients with acute deep vein thrombosis (DVT) or pulmonary embolism (PE) require anticoagulation to prevent recurrent venous thromboembolism (VTE). DVT and PE commonly coexist with comorbid conditions, thus patients may receive anticoagulant therapy in combination with aspirin and/or nonsteroidal anti-inflammatory drugs (NSAIDs) [1,2]. Combined anticoagulant therapy and aspirin use has been associated with an increased risk of bleeding in patients with atrial fibrillation or ischemic heart disease and prosthetic heart valves.
For patients receiving therapy for DVT or PE, the bleeding risks of combined therapy of anticoagulation with aspirin or NSAID have not been reported. This study therefore benefitted from the EINSTEIN DVT and PE study cohort to investigate the incidence of clinically relevant bleeding and major bleeding in patients with VTE (n=8246), receiving anticoagulant therapy (rivaroxaban or enoxaparin-VKA) with or without NSAID or aspirin.

Main results

  • 22.8% of patients receiving rivaroxaban and 14.6% of patients on enoxaparin-VKA received concomitant NSAID or aspirin therapy at any time during study treatment.
  • 127 clinically relevant bleeding occurred during 339 patient-years (PY) of NSAID use (37.5 per 100 PY), while 673 events were observed during 4054 PY of non-use of NSAIDs (16.6 per 100 PY), yielding an adjusted HR of 1.77 (95%CI: 1.46-2.14). Rates of major bleeding were 6.5 per 100 PY with NSAID, and 2.0 per 100 PY of non-use of NSAIDs (adj HR: 2.37, 95%CI: 1.51-3.75).
  • When split for type of anticoagulation therapy, patients on rivaroxaban and NSAIDs showed a HR of 1.90 (95%CI: 1.45-2.49) for clinically relevant bleeding as compared to non-users of NSAID, while in enoxaparin-VKA-treated patients HR was 1.65 (95%CI: 1.26-2.17). HR of major bleedings was 2.56 (95%CI: 1.21-5.39) with rivaroxaban+NSAID vs. non-use of NSAID, and 2.28 (95%CI: 1.28-4.04) for enoxaparin-VKA with vs. without NSAID.
  • Patients treated with anticoagulation and aspirin were at higher risk for clinically relevant bleeding than nonusers of aspirin (36.6 per 100 PY vs 16.9 per 100 PY, adj HR: 1.70, 95%CI: 1.38-2.11), and for major bleeding events (4.8 per 100 PY vs. 2.2 per 100 PY, adj HR: 1.50, 95%CI: 0.86-2.62).
  • Rivaroxaban + aspirin users were at higher risk for clinically relevant bleedings than nonusers of aspirin (HR: 1.81, 95%CI: 1.36-2.41), and for major bleeding (HR: 1.50, 95%CI: 0.63-3.61). For combined use of enoxaparin-VKA and aspirin HR for clinically relevant bleeding was 1.59 (95%CI: 1.17-2.17), and HR: 1.50 (95%CI: 0.74-3.05) for major bleeding.
  • Bleeding occurred with similar frequency at any time during the study period, thus there is no indication that a long period of exposure to concomitant use of anticoagulation with aspirin or NSAIDs is needed before a bleeding event.


A clinically important increase in bleedings was observed in patients treated for VTE, who are simultaneously using NSAIDs and anticoagulation. An increased bleeding risk was also observed with aspirin use in addition to anticoagulation, although less pronounced than with NSAIDs, and non-significant for major bleeding.
Although the study protocol discouraged NSAID use, 22% of patients took NSAID at some point. A short duration of exposure to NSAIDs and aspirin gives a similar risk of bleeding to longer exposure. Therefore, physicians should combine anticoagulation and NSAID or aspirin with caution and only if truly indicated, and patients should be informed that also casual use confers extra bleeding risk.

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1. Levine MN, Raskob G, Beyth RJ, et al. Hemorrhagic complications of anticoagulant treatment: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126(3)(suppl):287S-310S.
2. Olesen JB, Lip GYH, Lindhardsen J, et al. Risks of thromboembolism and bleeding with thromboprophylaxis in patients with atrial fibrillation: a net clinical benefit analysis using a ‘real
world’ nationwide cohort study. Thromb Haemost. 2011;106(4):739-749.

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