Co-administration of rivaroxaban and clopidogrel significantly prolonged bleeding time to 3.77 times baseline (90% CI 2.82-4.73) compared with either drug alone in healthy subjects.
RCT (n=14)
Open-label
Three-way crossover
Does co-administration of rivaroxaban and clopidogrel increase bleeding time in healthy male subjects compared to either drug alone?
Co-administration of rivaroxaban and clopidogrel significantly increases bleeding time compared to either drug alone, without altering the pharmacokinetics or pharmacodynamics of either agent.
Tasa de eventos absoluta: 3.77% vs 1.96%
Dual antiplatelet therapy with acetylsalicylic acid and a thienopyridine, such as clopidogrel, is effective for the secondary prevention of cardiovascular events in patients with acute coronary syndrome, but there is still a substantial residual risk of recurrence. Although anticoagulant therapy with a vitamin K antagonist (e.g. warfarin) in conjunction with antiplatelet therapy has been shown to reduce the risk of cardiovascular events, the rates of bleeding were increased with these combination therapies; hence, triple therapy with warfarin is currently only recommended in patients at low risk of bleeding. In addition, there are other limitations associated with vitamin K antagonist therapy, including the need for routine coagulation monitoring and dose adjustment to maintain the treatment within the therapeutic range. Rivaroxaban is an oral, direct Factor Xa inhibitor; in clinical practice, it is likely that rivaroxaban will be given to patients who also receive antiplatelet therapy, such as clopidogrel. This randomized, non-blinded, three-way crossover study investigated the effect of rivaroxaban on bleeding time when co-administered with clopidogrel. In addition, the influence of clopidogrel on the safety, tolerability, pharmacodynamics and pharmacokinetics of rivaroxaban was investigated. Of 27 healthy male subjects who received a single 300 mg dose of clopidogrel, 14 were identified as clopidogrel responders and were then randomized to the following three treatments: (A) two doses of clopidogrel on two consecutive days (300 mg on day 1; 75 mg on day 2); (B) one dose of rivaroxaban (15 mg); or (C) a combination of treatments A and B (rivaroxaban given on day 2). All treatments were well tolerated. Bleeding time with co-administration of rivaroxaban and clopidogrel was significantly prolonged in four subjects, compared with either drug alone: combination treatment increased the overall least squares-means to 3.77 times baseline (90% confidence interval CI 2.82-4.73), compared with 1.13 times baseline (90% CI 0.17-2.09) with rivaroxaban and 1.96 times baseline (90% CI 0.10-2.91) with clopidogrel. Co-administration of clopidogrel had no significant effect on the pharmacokinetics of rivaroxaban and, when compared with rivaroxaban alone, had no further effects on Factor Xa activity or prothrombin time. Inhibition of ADP-stimulated platelet aggregation by clopidogrel was not affected by rivaroxaban. As expected, owing to the mode of action of each study drug, the results of this study demonstrated that co-administration of the Factor Xa inhibitor rivaroxaban and the antiplatelet clopidogrel increased the bleeding time in healthy subjects without affecting other pharmacokinetic or pharmacodynamic parameters of each drug.
Kubitza et al. (Fri,) conducted a rct in Healthy subjects (n=14). Rivaroxaban and Clopidogrel vs. Clopidogrel alone or Rivaroxaban alone was evaluated on Bleeding time (95% CI 2.82-4.73 (90% CI)). Co-administration of rivaroxaban and clopidogrel significantly prolonged bleeding time to 3.77 times baseline (90% CI 2.82-4.73) compared with either drug alone in healthy subjects.
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