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Anticoagulants plus NSAIDs or aspirin increased bleeding risk in VTE
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Concomitant use of aspirin or an NSAID during anticoagulant therapy was associated with an increased risk for clinically relevant and major bleeding in patients with venous thromboembolism, according to study results.
The prospective analysis included data from the EINSTEIN deep vein thrombosis and pulmonary embolism clinical trials. The trials compared combined treatment with anticoagulants — either rivaroxaban (Xarelto, Janssen), or a regimen of enoxaparin (Lovenox, Sanofi Aventis) and vitamin K antagonist — and NSAID or aspirin therapy in 8,246 patients between 2007 and 2009.
Researchers compared bleeding rates during concomitant treatment with those observed during anticoagulation therapy alone.
Among patients treated with NSAIDs, the results showed significantly higher rates of clinically relevant bleeding (37.5 per 100 patient-years vs. 16.6 per 100 patient-years; HR=1.77; 95% CI, 1.46-2.14) and major bleeding (6.5 per 100 patient-years vs. 2 per 100 patient-years; HR=2.37; 95% CI, 1.51-3.75) during concomitant treatment than during anticoagulation therapy alone.
Among patients treated with aspirin, results showed higher rates of clinically relevant bleeding (36.6 per 100 patient-years vs. 16.9 per 100 patient-years; HR=1.7; 95% CI, 1.38-2.11) and major bleeding (4.8 per 100 patient-years vs. 2.2 per 100 patient-years; HR=1.5; 95% CI, 0.86-2.62) during concomitant treatment than during anticoagulation alone.
“The doubled risk for bleeding should urge physicians to combine anticoagulation with either NSAID or aspirin therapy with caution and only if genuinely indicated, with no similarly effective and safer alternative treatment available,” the researchers concluded. “If indicated, patients treated with VKAs should be monitored carefully to avoid prolonged periods in the supratherapeutic zone, especially in those with an a priori enhanced bleeding risk.”
Disclosure: The researchers reported payment from Bayer for steering committee and other work related to the EINSTEIN study; travel support from and employment relationships with Bayer; and paid speaker roles with Janssen.
Perspective
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Mary Cushman, MD
My first response to this paper was that I was surprised the question had not been previously addressed in venous thromboembolism patients. This study reinforces the concept that — across all specialties treating anticoagulated patients — practitioners need to be more vigilant about educating their patients about concomitant use of aspirin and NSAIDs, even for short-term use. Further, findings suggest for some lower-risk thrombosis patients that it might be appropriate to interrupt their anticoagulation during short periods when NSAID use is absolutely needed.
It was striking that the risk for major bleeding with dual treatment with NSAIDS and anticoagulants was 6.5 per 100 patient-years of use. This is similar to the risk for thrombosis recurrence in a patient with prior unprovoked VTE who is maintained off anticoagulation after their initial course. Thus, if a patient really requires ongoing therapy with an NSAID, the practitioner should carefully consider the risks for bleeding against the risk for thrombosis if anticoagulation is not continued chronically.
Further studies are needed to confirm these data. Participants here may have under-reported their use of NSAIDs, and this would lead to misclassification and likely to underestimation of the impact of concomitant NSAIDS on bleeding risk of anticoagulants. Also, patients eligible for and willing to participate in any trial differ from other patients in important ways, so the risk may indeed be higher than reported here. Lastly, the researchers did not account for all potential confounders in their analysis. Other studies with differing designs would be very useful. The researchers could not assess the bleeding risk associated with selective Cox-2 NSAIDs, so further studies on this are warranted.
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