Drug Interactions of Newer Oral Anticoagulants Dabigatran, Rivaroxaban, and Apixaban with Routinely Used Nonanticoagulant/Antiplatelet Drugs

Introduction: The newer non-vitamin K antagonist oral anticoagulant drugs (NOACs) such as dabigatran, apixaban and rivaroxaban are now commonly used for various indications in a large group of patients who are simultaneously managed with several other routinely used drugs. Given the lack of available information on the interaction of newer oral anticoagulant drugs (NOACs) with commonly used non-anticoagulants / anti-platelet drugs, it is important to recognize the impact of these interactions on the safety and efficacy of these agents. We hypothesized that some of the commonly used drugs may modulate the anticoagulant effects of NOACs. This study aims to determine the antiplatelet, anticoagulant, and bleeding effects of the NOACs at varying concentrations with and without routinely used drugs both in the in vivo and in vitro systems.

Materials and Methods:Dabigatran (Boehringer Ingelheim, Ridgefield, CT), rivaroxaban (Janssen Pharmaceuticals, Inc., Titusville, NJ), and apixaban (Bristol-Myers Squibb Company, Princeton, NJ and Pfizer Inc., New York, NY); and such routinely used drugs as alendronate sodium, chondroitin sulfate, hydrocodone-acetaminophen, klonopin, penicillin, tacrolimus, tramadol chlorhydrate, and tranexamic acid were commercially obtained and supplemented in citrated plasma at projected therapeutic ranges. Such tests as PT, APTT, dRVVT, TT, Heptest, and Anti- Xa and anti-IIa tests were performed. Agonist induced platelet aggregation studies using ADP, AA, Collagen, Epinephrine, and Thrombin agonists were performed on the Platelet Aggregation Profiler- 8 (PAP-8) (Biodata corporation, Horsham, PA) with dabigatran, apixaban and rivaroxaban alone and with the routinely used drugs. For the in-vivo bleeding studies a model of rat tail transection was used, following ketamine and xylazine anesthesia, 6-8 weeks old male Sprague-Dawley rats weighing 250-300g (n=15) were used to perform the rat tail transection bleeding time using dabigatran alone and dabigatran followed by tranexamic acid. Blood was drawn by cardiac puncture for ex vivo analysis. The collected data from the bleeding and ex vivo studies were tabulated and statistically analyzed using ANOVA.

Results: In the in vitro studies, all of the NOACs produced assay dependant anticoagulant and antiprotease effects. Rivaroxaban and apixaban did not exhibit any interactions at the projected therapeutic dosage range when combined with any of the routinely used drugs. However dabigatran at a fixed concentration of 1 µg/ml combined with the commonly used drugs at a fixed concentration of 0.1 µg /ml or 1 µg/ml produced augmented assay-dependent anticoagulant and antiprotease activity. The most pronounced interaction was noticed with tacrolimus (111% difference in PT, 231% difference in APTT, and 46% difference in anti-IIa assay), followed by tramadol (57% difference in PT and 54% difference in Anti-IIa assay). Platelet Aggregation studies revealed no modulation of antiplatelet effects (<10%) with the addition of the commonly used drugs and the NOACs. In the rat tail transection bleeding model, there was a significant difference (p=0.03, α=0.05) between the bleeding time with dabigatran (100 µg/kg) alone (13.1 ±1.5 minutes) intravenously compared to dabigatran with tranexamic acid (10 mg/kg) (10.3 ±1.8 minutes) in each study. Ex-vivo analysis showed a reduction in PT and Heptest assay responses with dabigatran and tranexamic acid by 38% and 80%, respectively, and minimal change (5%) in APTT.

Conclusion: In contrast to rivaroxban and apixaban in vitro, dabigatran exhibited stronger interactions with the commonly used drugs and variable assay dependent augmentation of anticoagulant and antiprotease responses. Tacrolimus and tramadol showed the strongest interactions. Agonist induced platelet aggregation studies did not show any interactions. Interestingly, tranexamic acid reduced the anticoagulant effect of dabigatran in the in vivo and ex vivo studies. These results warrant a review of post-marketing surveillance on the reported bleeding in patients concomitantly treated with NOACs and the reported routinely used drugs. Furthermore, these observations underscore the need to screen other commonly used drugs and supplements for their potential interactions with NOACs.