Management of major bleedings during anticoagulant treatment with the oral direct thrombin inhibitor ximelagatran or warfarin

Abstract

Several new oral anticoagulants are currently investigated in phase III programmes, mainly with inhibition of factor Xa or thrombin as their pharmacological target. Advantages are expected with these new drugs compared with vitamin K antagonists, but one potential drawback is the lack of specific antidotes. During the clinical studies with ximelagatran, an oral direct thrombin inhibitor withdrawn due to hepatic side effects, investigators were instructed to manage bleedings with routine measures. We have retrospectively tried to assess whether this was sufficient or whether there was a need for reversal strategies. The study population consisted of patients with major bleedings in three long-term studies (104 ximelagatran, 155 warfarin). All individual patient narratives were reviewed with respect to management of the bleeding. Complementary data were retrieved from the data-based case report forms. Approximately, two of three of the patients in both groups were subject to some kind of treatment. One-third (1/3) in both groups had transfusions documented and/or received specific medication. Vitamin K was given more often to warfarin patients. Two ximelagatran patients received prothrombin complex (four-factor concentrate), but one was a patient with a severe hepatopathy suspected to be drug-induced. Overall, the case descriptions did not reveal any apparent differences in the course of events between groups. We found no indications that the lack of an antidote posed a clinical problem in patients treated with ximelagatran as compared with warfarin. The relatively short half-life of melagatran, the active metabolite of ximelagatran, may have contributed to these results.

Dabigatran etexilate – a novel, reversible, oral direct thrombin inhibitor: Interpretation of coagulation assays and reversal of anticoagulant activity

“…Concern regarding potential overdosing or uncontrolled bleeding has prompted testing of agents known to reverse haemostatic defects and enhance wound-localised thrombin generation. At present, there are no published clinical data on the use of these agents in patients receiving dabigatran etexilate and limited information on other new oral anticoagulants (36). Thus, their use in treating anticoagulant-associated bleeding is generally based on a combination of pre-clinical data, anecdotal case reports and the absence of alternative therapies that might be effective (37).…”

Antithrombotic Therapy in Atrial Fibrillation - Evaluation and Positioning of New Oral Anticoagulant Agents -

“…However, there are no published clinical data on the use of these agents in patients receiving dabigatran and information is limited for the other new oral anticoagulants. 57 Therefore, their use in treating anticoagulant-associated bleeding is based on a combination of preclinical data, anecdotal case reports, and the absence of alternative therapies that might be effective. 58…”

Comprehensive Coagulation Profiling at the Point-of-Care Using a Novel Laser-Based Approach

“…38,39 Anticoagulation management in these patients is challenging due to narrow therapeutic windows and the need to balance bleeding versus adequate coagulation, influenced by numerous food and drug interactions and interindividual variability in dose response. [40][41][42] Therefore, with some anticoagulants, patients require frequent laboratory testing of coagulation status, imposing a staggering load on primary care services. [43][44][45][46] Vitamin K antagonists (VKAs) were the only oral anticoagulants available to patients for decades.…”