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

Study Questions:

What is the incidence of clinically relevant and major bleeding in patients with venous thromboembolism receiving study anticoagulant therapy combined with either nonsteroidal anti-inflammatory drugs (NSAIDs) or aspirin, compared to patients receiving anticoagulant therapy?


This was a post-hoc analysis of the EINSTEIN-DVT and EINSTEIN-PE studies, in which investigators established the safety and efficacy of oral rivaroxaban (an oral factor Xa inhibitor) versus subcutaneous enoxaparin overlapping with and followed by international normalized ratio-adjusted vitamin K antagonists (VKAs). Of note, patients with escalated bleeding risk were excluded from the EINSTEIN trials. Concomitant medications during the study were collected at each of 336 study sites (the use of NSAIDs was discouraged in the trials). The main outcome of interest was clinically relevant bleeding, a composite of major and clinically relevant nonmajor bleeding. The use of NSAID or aspirin therapy was categorized as either “with” or “without” for each day between the day of randomization and the end of the patient’s “at risk” period (i.e., drug discontinuation). A person-time-based approach was used to characterize the rate per 100 patient-years of a first detected bleeding event while a patient was taking NSAID or aspirin.


Twenty-two percent of patients took NSAIDs at some time during the study period. During 339 patient-years of NSAID use (37.5 per 100 patient-years), 127 clinically relevant bleeding events occurred, compared to 673 events during 4,054 patient-years of nonuse of NSAIDS (16.6 per 100 patient-years), for a gender-adjusted hazard ratio (HR) of 1.77 (95% confidence interval [CI], 1.46-2.14). During 284 patient-years of aspirin use (36.6 per 100 patient-years), 104 clinically relevant bleeding events occurred, compared to 696 events during 4,109 patient-years of nonuse of aspirin, for an HR of 1.70 (95% CI, 1.38-2.11), adjusted for age and plasma creatinine clearance rate. The increase in bleeding was similar in rivaroxaban-treated and enoxaparin-VKA-treated patients. The risk of aspirin and anticoagulant was not significant for major bleeding.


The authors concluded that in the EINSTEIN-DVT and EINSTEIN-PE studies, concomitant use of NSAID or aspirin with either rivaroxaban or enoxaparin-VKA is associated with an increased risk of clinically relevant bleeding.


The limitations of this post-hoc analysis aside, the authors provide convincing evidence to more strongly discourage the concomitant use of NSAIDs or aspirin in patients receiving anticoagulant therapy. Of interest, concomitant aspirin and anticoagulant therapy did not confer an increased risk of major bleeding (in contrast to NSAIDs). Over one in every five patients took NSAIDs during some point during the study. As concluded by the authors, ‘Physicians should inform patients about the potential for increased bleeding with these readily available commonly used drugs and advise patients to curtail their casual use.’

Clinical Topics: Anticoagulation Management, Dyslipidemia, Pulmonary Hypertension and Venous Thromboembolism, Vascular Medicine, Anticoagulation Management and Venothromboembolism, Lipid Metabolism, Novel Agents

Keywords: Vitamin K, Morpholines, Cyclooxygenase 2 Inhibitors, Pulmonary Embolism, Thiophenes, Venous Thromboembolism, Blood Coagulation, Enoxaparin, Venous Thrombosis, Factor Xa, Confidence Intervals, Hemorrhage

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