Schulman S, Kearon C, Kakkar AK, Mismetti P, Schellong S, Eriksson H, et al.
N Engl J Med. 2009;361(24):2342-2352
Background:
The direct oral thrombin inhibitor dabigatran has a predictable anticoagulant effect and may be an alternative therapy towarfarin for patients who have acute venous thromboembolism.
Methods:
In a randomized, double-blind, noninferiority trial involving patients with acute venous thromboembolism who were initially given parenteral anticoagulation therapy for a median of 9 days (interquartile range, 8 to 11), we compared oral dabigatran, administered at a dose of 150 mg twice daily, with warfarin that was dose-adjusted to achieve an international normalized ratio of 2.0 to 3.0. The primary outcome was the 6-month incidence of recurrent symptomatic, objectively confirmed venous thromboembolism and related deaths. Safety end points included bleeding events, acute coronary syndromes, other adverse events, and results of liver-function tests.
Results:
A total of 30 of the 1274 patients randomly assigned to receive dabigatran (2.4%), as compared with 27 of the 1265 patients randomly assigned to warfarin (2.1%), had recurrent venous thromboembolism; the difference in risk was 0.4 percentage points (95% confidence interval [CI], -0.8 to 1.5; P<0.001 for the prespecified noninferiority margin). The hazard ratio with dabigatran was 1.10 (95% CI, 0.65 to 1.84). Major bleeding episodes occurred in 20 patients assigned to dabigatran (1.6%) and in 24 patients assigned to warfarin (1.9%) (hazard ratio withdabigatran, 0.82; 95% CI, 0.45 to 1.48), and episodes of any bleeding were observed in 205 patients assigned to dabigatran (16.1%) and 277 patients assigned to warfarin (21.9%; hazard ratio with dabigatran, 0.71; 95% CI, 0.59 to 0.85). The numbers of deaths, acute coronary syndromes, and abnormal liver-function tests were similar in the two groups. Adverse events leading to discontinuation of the study drug occurred in 9.0% of patients assigned to dabigatran and in 6.8% of patients assigned to warfarin (P=0.05).
Conclusions:
For the treatment of acute venous thromboembolism, a fixed dose of dabigatran is as effective as warfarin, has a safety profile that is similar to that of warfarin, and does not require laboratory monitoring.
Comentario del Dr. Fernando Arribas
Es un ensayo clínico del que deriva la aprobación del uso de dabigatrán en el tratamiento y prevención secundaria de tromboembolia pulmonar y la trombosis venosa profunda. En este ensayo clínico aleatorizado y doble ciego, se comparó el tratamiento con 150 mg de dabigatrán dos veces al día frente a warfarina, en pacientes con un evento tromboembólico venoso agudo. Se incluyeron 2564 pacientes en 228 centros de 29 países. En todos los pacientes, tras el tratamiento inicial con heparina de bajo peso molecular o no fraccionada (que se administró durante un periodo medio de 10 días), se mantuvo la anticoagulación durante 6 meses. La variable principal del estudio fue un compuesto de eventos tromboembólicos o de muerte relacionada.
El estudio mostró una incidencia similar para la variable principal en el grupo de dabigatrán respecto al de warfarina (2,4% vs. 2,1%; p<0,001, para no inferioridad) durante los seis meses de seguimiento. Aunque tampoco se encontraron diferencias en la tasa de sangrado mayor entre ambos grupos (1,6% vs. 1,9%), al comparar el compuesto de sangrado mayor o sangrado no mayor pero clínicamente relevante dabigatrán se asoció a un menor riesgo (5,6% vs. 8,8%; p= 0,002).
