Review: New Oral Anticoagulants for Afib, VTE, and ACS
This was a randomized, double-blind, placebo-controlled study with 12 healthy male volunteers to evaluate the potential of prothrombin complex concentrate (PCC) to reverse the anticoagulant effect of rivaroxaban or dabigatran. Half of the volunteers were randomized to receive rivaroxaban 20 mg twice daily for 2.5 days, while the other half received dabigatran 150 mg twice daily for the same 2.5 days. Afterwards, the volunteers were randomized to receive either a single infusion bolus of 50 IU/kg of PCC or saline infusion as placebo. The brand name of PCC used was Cofact, which contains factor II, VII, IX, X, protein C, S and antithrombin. Volunteers were not blinded to type of anticoagulant, but were blinded to PCC or saline. Laboratory technicians were blinded to anticoagulant and type of infusion. Blood was collected from each volunteer at baseline, on the third day of anticoagulant use prior to infusion of PCC or saline, and at multiple time intervals post infusion (15 minutes, 30 minutes, one hour, two hours, four hours, six hours, and 24 hours). This was followed by an 11-day washout period and the volunteers repeated the process with the other oral anticoagulant.
Rivaroxaban increased prothrombin time (PT) that was immediately and completely reversed by PCC (p<0.001). Rivaroxaban also inhibited endogenous thrombin potential (ETP) that was normalized with PCC (p<0.001). Dabigatran increased activated partial thromboplastin time (aPTT), ecarin clotting time (ECT) and thrombin time; however, none of these coagulation tests were reversed by PCC. Dialysis is an alternative for reversal of dabigatran, but it has limited effectiveness because 1/3 of dabigatran is bound to plasma and therefore not dialyzable. Rivaroxaban is 95% bound to protein, and therefore cannot be dialyzed.
This is the first study conducted in humans that shows that nonactivated PCC immediately reverses the effect of full-dose rivarobaxan and is a promising option for reversal in the setting of bleeding or emergent pre-operative measures. The study used randomization and a crossover design to minimize bias, however, the study was limited. The test subjects were healthy males around 24 years old and there were only 12 subjects. It would be difficult to generalize to an older patient population and or those with medical co-morbidities. Coagulation profiles were analyzed as a surrogate marker for bleeding risk, and this may be difficult to translate directly into clinical practice. In addition, the dose of PCC was chosen from animal study data and further studies are needed to confirm the efficacy of a lower dose of PCC to reverse rivaroxaban. Future studies should also test alternative formulations of PCC for their possible reversal effects.
Eerenberg ES, Kamphuisen PW, Sijpkens MK, Meijers JC, Buller HR, Levi M. Reversal of Rivaroxaban and Dabigatran by Prothrombin Complex Concentrate: A Randomized, Placebo-Controlled, Crossover Study in Healthy Subjects. Circulation. 2011; 124: 1573-1579.
This was a randomized, double-blind, placebo-controlled study with 12 healthy male volunteers to evaluate the potential of prothrombin complex concentrate (PCC) to reverse the anticoagulant effect of rivaroxaban or dabigatran. Half of the volunteers were randomized to receive rivaroxaban 20 mg twice daily for 2.5 days, while the other half received dabigatran 150 mg twice daily for the same 2.5 days. Afterwards, the volunteers were randomized to receive either a single infusion bolus of 50 IU/kg of PCC or saline infusion as placebo. The brand name of PCC used was Cofact, which contains factor II, VII, IX, X, protein C, S and antithrombin. Volunteers were not blinded to type of anticoagulant, but were blinded to PCC or saline. Laboratory technicians were blinded to anticoagulant and type of infusion. Blood was collected from each volunteer at baseline, on the third day of anticoagulant use prior to infusion of PCC or saline, and at multiple time intervals post infusion (15 minutes, 30 minutes, one hour, two hours, four hours, six hours, and 24 hours). This was followed by an 11-day washout period and the volunteers repeated the process with the other oral anticoagulant.
Rivaroxaban increased prothrombin time (PT) that was immediately and completely reversed by PCC (p<0.001). Rivaroxaban also inhibited endogenous thrombin potential (ETP) that was normalized with PCC (p<0.001). Dabigatran increased activated partial thromboplastin time (aPTT), ecarin clotting time (ECT) and thrombin time; however, none of these coagulation tests were reversed by PCC. Dialysis is an alternative for reversal of dabigatran, but it has limited effectiveness because 1/3 of dabigatran is bound to plasma and therefore not dialyzable. Rivaroxaban is 95% bound to protein, and therefore cannot be dialyzed.
This is the first study conducted in humans that shows that nonactivated PCC immediately reverses the effect of full-dose rivarobaxan and is a promising option for reversal in the setting of bleeding or emergent pre-operative measures. The study used randomization and a crossover design to minimize bias, however, the study was limited. The test subjects were healthy males around 24 years old and there were only 12 subjects. It would be difficult to generalize to an older patient population and or those with medical co-morbidities. Coagulation profiles were analyzed as a surrogate marker for bleeding risk, and this may be difficult to translate directly into clinical practice. In addition, the dose of PCC was chosen from animal study data and further studies are needed to confirm the efficacy of a lower dose of PCC to reverse rivaroxaban. Future studies should also test alternative formulations of PCC for their possible reversal effects.
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