Safety and Efficacy of Dabigatran Etexilate vs Dose-Adjusted Warfarin in Patients With Cerebral Venous Thrombosis: A Randomized Clinical Trial

Abstract

Importance: Patients with cerebral venous thrombosis (CVT) are at risk of recurrent venous thrombotic events (VTEs). Non-vitamin K oral anticoagulants have not been evaluated in randomized controlled trials in CVT.

Objective: To compare the efficacy and safety of dabigatran etexilate with those of dose-adjusted warfarin in preventing recurrent VTEs in patients who have experienced a CVT.

Design, setting, and participants: RE-SPECT CVT is an exploratory, prospective, randomized (1:1), parallel-group, open-label, multicenter clinical trial with blinded end-point adjudication (PROBE design). It was performed from December 21, 2016, to June 22, 2018, with a follow-up of 25 weeks, at 51 tertiary sites in 9 countries (France, Germany, India, Italy, the Netherlands, Poland, Portugal, Russia, and Spain). Adult consecutive patients with acute CVT, who were stable after 5 to 15 days of treatment with parenteral heparin, were screened for eligibility. Patients with CVT associated with central nervous system infection or major trauma were excluded, but those with intracranial hemorrhage from index CVT were allowed to participate. After exclusions, 120 patients were randomized. Data were analyzed following the intention-to-treat approach.

Interventions: Dabigatran, 150 mg twice daily, or dose-adjusted warfarin for a treatment period of 24 weeks.

Main outcomes and measures: Primary outcome was a composite of patients with a new VTE (recurrent CVT, deep vein thrombosis of any limb, pulmonary embolism, and splanchnic vein thrombosis) or major bleeding during the study period. Secondary outcomes were cerebral venous recanalization and clinically relevant non-major bleeding events.

Results: In total, 120 patients with CVT were randomized to the 2 treatment groups (60 to dabigatran and 60 to dose-adjusted warfarin). Of the randomized patients, the mean (SD) age was 45.2 (13.8) years, and 66 (55.0%) were women. The mean (SD) duration of exposure was 22.3 (6.16) weeks for the dabigatran group and 23.0 (5.20) weeks for the warfarin group. No recurrent VTEs were observed. One (1.7%; 95% CI, 0.0-8.9) major bleeding event (intestinal) was recorded in the dabigatran group, and 2 (3.3%; 95% CI, 0.4-11.5) (intracranial) in the warfarin group. One additional patient (1.7; 95% CI, 0.0-8.9) in the warfarin group experienced a clinically relevant non-major bleeding event. Recanalization occurred in 33 patients in the dabigatran group (60.0%; 95% CI, 45.9-73.0) and in 35 patients in the warfarin group (67.3%; 95% CI, 52.9-79.7).

Conclusions and relevance: This trial found that patients who had CVT anticoagulated with either dabigatran or warfarin had low risk of recurrent VTEs, and the risk of bleeding was similar with both medications, suggesting that both dabigatran and warfarin may be safe and effective for preventing recurrent VTEs in patients with CVT.

Trial registration: ClinicalTrials.gov identifier: NCT02913326.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Ferro reported receiving personal fees from Boehringer Ingelheim during the conduct of the study; personal fees from Bristol-Myers Squibb and Bayer outside the submitted work; and a grant for José Ferro Lab at Instituto de Medicina Molecular from Bayer. Dr Coutinho reported his employer received fees from Boehringer Ingelheim during the conduct of the study and from Bayer outside the submitted work. Dr Dentali reported receiving personal fees from Boehringer Ingelheim, Bristol-Myers Squibb, and Bayer as well as a grant to the Department of Medicine and Surgery, Insubria University, from Bayer outside the submitted work. Dr Kobayashi reported receiving personal fees from Boehringer Ingelheim during the conduct of the study as well as lectureship fees and conference travel expenses from Boehringer Ingelheim outside the submitted work. Dr Alasheev reported receiving personal fees from Boehringer Ingelheim during the conduct of the study and outside the submitted work. Dr Canhão reported receiving personal fees from Boehringer Ingelheim during the conduct of the study and from Bayer outside the submitted work. Dr Karpov reported receiving fees from Boehringer Ingelheim. Dr Nagel reported receiving grants from Boehringer Ingelheim during the conduct of the study; fees paid to his institution from Boehringer Ingelheim; and personal fees from Brainomix, Pfizer, and Medtronic outside the submitted work. Drs Caria, Frässdorf, Huisman, and Reilly reported being full-time employees of Boehringer Ingelheim International. Dr Diener reported receiving personal fees from Boehringer Ingelheim during the conduct of the study; honoraria for participation in clinical trials and contribution to advisory boards or oral presentations from Abbott, Achelios, Allergan, AstraZeneca, Bayer Vital, Bristol-Myers Squibb, Boehringer Ingelheim, Covidien, Daiichi-Sankyo, D-Pharm, Johnson & Johnson, Lilly, Merck Sharp & Dohme, Medtronic, MindFrame, Neurobiological Technologies, Novartis, Pfizer, Portola, Sanofi-Aventis, Servier, St. Jude, Syngis, Talecris, and WebMD Global; and financial support for research projects from AstraZeneca, GlaxoSmithKline, Boehringer Ingelheim, Lundbeck, Novartis, Janssen-Cilag, Sanofi-Aventis, Syngis, and Talecris; he reported owning no stocks in any pharmaceutical company. No other disclosures were reported.

Figures

Figure 1.. RE-SPECT Cerebral Venous Thrombosis (CVT) Trial Design

INR indicates international normalized ratio; LMWH, low-molecular-weight heparin; UFH, unfractionated heparin. Adapted with permission from SAGE Publications, Ltd.

Figure 2.. Enrollment, Randomization, and Treatment

CVT indicates cerebral venous thrombosis.