1. Among patients with venous thromboembolism, clinically relevant bleeding and major bleeding increased with concomitant anticoagulant and NSAID use.
2. Concomitant Aspirin use also increased risk of major bleeding and clinically relevant bleeding.
Evidence Rating Level: 2 (Good)
Study Rundown: Anticoagulation is the standard of care for the treatment of acute deep vein thrombosis (DVT) and pulmonary embolism (PE). Although the bleeding risk associated with concomitant aspirin and anticoagulation use has been studied in other trials, the risk of bleeding with concomitant NSAID use has limited data. The EINSTEIN DVT and PE trials were phase 3 trials designed to evaluate the safety and efficacy of oral rivaroxaban vs. enoxaparin followed by vitamin K antagonist (VKA) therapy. Using this study cohort, the investigators examined the incidence of clinically relevant bleeding and major bleeding among patients on the anticoagulant alone or in combination with either NSAID or aspirin. The authors found an increased incidence of clinically relevant bleeding and major bleeding in both the NSAID group and the aspirin group. Although the results are quite remarkable, readers should be aware that this is a post hoc analysis. Also, in the EINSTEIN trials, patients at high risk of bleeding were excluded. Therefore, a randomized trial examining bleeding risk as a primary endpoint, examining not only patients with DVT and PE but also patients with atrial fibrillation would give us a better estimate of the true incidence of bleeding (which would most likely be even higher).
In-Depth [post hoc analysis]: This study performed a post hoc analysis on the data collected in the EINSTEIN DVT and PE trials, which recruited 8246 patients at 336 sites in 39 countries. 4130 patients received rivaroxaban and 4116 patients received enoxaparin and VKA. 22.8% and 14.6% of these groups received concomitant aspirin or NSAID dosages respectively. Major bleeding events were defined as either being fatal, occurring at a critical site, or were associated with at least a 2 g/dL drop in hemoglobin. Clinically relevant bleeding was defined as bleeding that was not major but associated with a medical intervention such as contact with a physician, temporary cessation of study treatment, discomfort, or impairment of activities of daily living. In the NSAID-anticoagulant group as compared to the anticoagulant group, clinically relevant bleeding occurred at an event rate of 37.5 per 100 patient-years vs. 16.6 per 100 patient-years (hazard ratio [HR], 1.77 [95% CI, 1.46-2.14]). Major bleeding also occurred at a higher rate in the combination group (HR, 2.37 [95% CI, 1.51-3.75]). In the aspirin-anticoagulant vs. anticoagulant alone groups, once again clinically relevant bleeding was seen at a higher rate in the combination group (HR, 1.70 [95% CI, 1.38-2.11]). Major bleeding was also increased in the combination group (HR, 1.50 [95% CI, 0.86-2.62]).
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