Reversal of the Antithrombotic Action of Rivaroxaban and Dabigatran: A Clinical Study in Healthy Volunteers.

Bleeding is still a frequent complication for patients on treatment with new oral anticoagulants. There is a lack of information on therapies that could reverse the effects of new oral anticoagulants in patients that require a rapid restoration of their impaired hemostatic mechanisms.

We present preliminary results of an ongoing clinical trial (Eudra CT2010–022985–29; ClinicalTrials.gov Identifier:NCT01478282) with focus on: 1) assessment of the effects of new oral anticoagulants rivaroxaban and dabigatran on hemostasis; 2) evaluation of the impact of prothrombin complex concentrates (PCCs) and rFVIIa to reverse the alterations of hemostasis induced by these new anticoagulants.

Ex vivo studies were performed using blood samples from healthy individuals (n=6, as of July 2012) subjected to treatments with 20 mg/day for rivaroxaban and 150 mg/12 h for dabigatran doses separated by a washout period of 14 days. Blood samples were spiked in vitro with: a) prothrombin complex concentrates (PCCs) (50 IU/kg); b) activated PCCs (aPCCs) at 75 IU/kg, or c) rFVIIa at 270 μg/kg. A series of laboratory tests were performed to explore modifications in hemostatic mechanism using technologies implying steady and flow conditions. Effects on thrombin generation (TG), thromboelastometry parameters (TEM) and standard coagulation parameters were assessed. Special attention was paid to studies evaluating modifications on platelets and fibrin deposition on damaged subendothelial surfaces performed under flow conditions.

Standard coagulation parameters (PT, INR and APTT) were variably affected by rivaroxaban and dabigatran. aPCCs and rFVIIa totally reversed the effects of rivaroxaban in these routine tests, whereas only aPCC were capable to reverse the effects of dabigatran on APTT. Rivaroxaban caused a moderate reduction of TG with delayed time to peak and decreased velocity index (p<005). These alterations were corrected by aPCCs. PCCs showed only a moderate improvement on thrombin peak and rFVIIa had no effect in this test. Impact of dabigatran on TG was more evident with significant reductions in time to peak, velocity index (p<0.01) and thrombin peak (p<0.05). Reversion of these alterations were accomplished to a variable extent by the different concentrates (aPCC=PCC>rFVIIa). Viscoelastic properties of clot were affected after rivaroxaban or dabigatran treatments. All the coagulation concentrates were able to reverse the effects of rivaroxaban (aPCC=rFVIIa>PCC; p<0.05). In contrast, only PCCs caused a partial reversion of dabigatran effects on clot firmness with not effect on remaining viscoelastic parameters. Treatment with rivaroxaban or dabigatran did not cause marked alterations on platelet reactivity towards damaged vascular surfaces, but both anticoagulants demonstrated a consistent effect decreasing fibrin formation on the subendothelium (p<0.01 for rivaroxaban and p<0.05 for dabigatran). Reductions in fibrin formation observed after rivaroxaban were significantly improved (p<0.05) by the different concentrates, with the following order of efficacy aPCC>rFVIIa=PCC. Alterations in fibrin formation following dabigatran treatment were only reverted by aPCCs (p<0.05).

Rivaroxaban and dabigatran treatments resulted in alterations of the different laboratory tests related to their recognized anticoagulant action. These alterations were variably compensated or even reversed by the different factor concentrates. Reversal strategies may differ depending on the anticoagulant agent and its specific mechanism of action. Results of studies with blood circulating through vascular surfaces, that would more closely reproduce the bleeding situation, indicate that while alterations in hemostasis induced by rivaroxaban were reversed to a variable extent by all the concentrates tested (PCCs, aPCCs and rFVIIa), reversion of dabigatran effects was only observed with aPCCs.

No relevant conflicts of interest to declare.