title: 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 During the clinical studies with ximelagatran, an oral direct thrombin inhibitor withdrawn due to hepatic side effects, investigators were instructed to manage bleedings with routine measures.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.
authors.affiliation: Patient Safety AstraZeneca R&D, Mölndal, Sweden. gunilla.fernlof@astrazeneca.com
authors.forename: Gunilla
authors.initials: G
authors.lastname: Fernlöf
authors.forename: Britta M
authors.initials: BM
authors.lastname: Sjöström
authors.forename: Klas M
authors.initials: KM
authors.lastname: Lindell
authors.forename: Ulrika E
authors.initials: UE
authors.lastname: Wall
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants / Q000009:adverse effects* / Q000627:therapeutic use; D001384:Azetidines / Q000627:therapeutic use*; D001596:Benzylamines / Q000627:therapeutic use*; D001803:Blood Transfusion; D019468:Disease Management; D005260:Female; D006470:Hemorrhage / Q000628:therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D013917:Thrombin / Q000037:antagonists & inhibitors; D016896:Treatment Outcome; D014812:Vitamin K / Q000627:therapeutic use; D014859:Warfarin / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D000925:Anticoagulants; D001384:Azetidines; D001596:Benzylamines; D014812:Vitamin K; C426686:ximelagatran; D014859:Warfarin; D013917:Thrombin