Effect of non-specific reversal agents on anticoagulant activity of dabigatran and rivaroxaban

Abstract

The new anticoagulants dabigatran and rivaroxaban can be responsible for haemorrhagic complications. As for any anticoagulant, bleeding management is challenging. We aimed to test the effect of all putative haemostatic agents on the anticoagulant activity of these new drugs using thrombin generation tests. In an ex vivo study, 10 healthy white male subjects were randomised to receive rivaroxaban (20 mg) or dabigatran (150 mg) in one oral administration. After a two weeks washout period, they received the other anticoagulant. Venous blood samples were collected just before drug administration (H0) and 2 hours thereafter. Reversal of anticoagulation was tested in vitro using prothrombin complex concentrate (PCC), rFVIIa or FEIBA® at various concentrations. Rivaroxaban affects quantitative and kinetic parameters, including the endogenous thrombin potential (ETP-AUC and more pronouncedly the thrombin peak), the lag-time and time to peak. PCC strongly corrected ETP-AUC, whereas rFVIIa only modified the kinetic parameters. FEIBA corrected all parameters. Dabigatran specially affects the kinetics of thrombin generation with prolonged lag-time and time to peak. Although PCC increased ETP-AUC, only rFVIIa and FEIBA corrected the altered lag-time. For both anticoagulants, lower doses of FEIBA, corresponding to a quarter to half the dose usually used, have potential reversal profile of interest. In conclusion, some non-specific reversal agents appear to be able to reverse the anticoagulant activity of rivaroxaban or dabigatran. However, clinical evaluation is needed regarding haemorrhagic situations, and a meticulous risk-benefit evaluation regarding their use in this context is required.

Managing target-specific oral anticoagulant associated bleeding including an update on pharmacological reversal agents

“…Human studies (dabigatrantreated healthy volunteers) PCC No reduction in blood loss after tail transection in mice [44] Reduced intracranial hematoma expansion and 24-hr mortality in mice [45] Reduced blood loss following kidney incision in rabbits [46] Reduced bleeding time, but not coagulation tests in rat tail transection model [18] Corrected some TG indices [25] Corrected PT, aPTT, TT and some TG indices [13] No correction of Hemoclot assay [13] No correction of aPTT, ECT, TT [9] aPCC No reduction in blood loss after tail transection in mice [44] Reduced bleeding time, but not coagulation tests in rat tail transection model [18] Corrected some TG indices [25] Corrected PT, aPTT and some TG indices [13] [23],…”

“…Reduced bleeding time, but not coagulation tests in rat tail transection model [18] Corrected some TG indices [25] No correction of PT, aPTT and TG…”

“…Human studies (factor Xa-inhibitor-treated volunteers) PCC Rivaroxaban Corrected aPTT [48] Variably corrected PT [48,49] No reduction of blood loss in rabbits [48] Reduced bleeding time in rats, but not primates [49] Apixaban No correction PT [50] No reduction hepatosplenic blood loss in rabbits [50] Rivaroxaban Corrected PT [13] Variably corrected TG indices [13,25] No correction of anti-Xa activity [13] Rivaroxaban aPCC Rivaroxaban Corrected aPTT [48] Variably corrected PT [48,49] No reduction of blood loss in rabbits [48] Reduced bleeding time in rats and primates [49] Edoxaban…”

“…Rivaroxaban Corrected PT [13] Corrected TG indices [13,25] No correction of anti-Xa activity [13] rVIIa Rivaroxaban Corrected PT [49] Reduced bleeding time in rats, but not primates [49] Apixaban Corrected PT [50] No reduction hepatosplenic blood loss in rabbits [50] Edoxaban…”

“…Rivaroxaban Corrected PT [13] Variably corrected TG indices [25] No correction anti-Xa activity [13] Adapted from [47]. aPTT activated partial thromboplastin time, aPCC activated prothrombin complex concentrate, ETP endogenous thrombin potential, INR international normalized ratio, LT lag time, PCC prothrombin complex concentrate, PT prothrombin time, rVIIa recombinant activated factor VII, TEM thromboelastometry, TG thrombin generation, TP thrombin potential, TTP time to peak developed as a bypassing agent to treat bleeding complications in hemophilia patients with inhibitors [20].…”