Dabigatran for the Prevention of Ischemic Stroke in Patients with Acute or Chronic Atrial Fibrillation

PICHON-RIVIERE, A.; AUGUSTOVSKI, F. A.; GARCIA MARTI, S.; GLUJOVSKY, D.; ALCARAZ, A.; LOPEZ, A.; BARDACH, A.; CIAPPONI, A; ROMANO, M

Documento de Evaluación de Tecnologías Sanitarias

IECS

Año: 2012 p. 1 - 30

1668-2793

Atrial Fibrillation (AF) is the most common pathological tachycardia. Its prevalence increases with age: 0.2% under 30 years and more than 12% at the age of 75. The thromboembolic disease is a severe complication of AF, the risk of ischemic stroke (IS) is approximately 5.4% per year. The standard treatment is aspirin or vitamin K antagonists (VKA) according to the risk of IS.TechnologyDabigatran is a direct thrombin inhibitor. It is orally administered in 110 and 150mg capsules bid. It does not require dose titration or prothrombin time monitoring. There is no antidote to bleeding.PurposeThe purpose of this report is to assess the evidence available on the efficacy, safety and issues related to coverage policies on the use of dabigatran for the prevention of IS in patients with acute or chronic AF.MethodsA bibliographic search was carried out on the main databases: DARE, NHS EED, on Internet general search engines, in health technology evaluation agencies and health sponsors. Priority was given to the inclusion of systematic reviews; controlled, randomized clinical trials (RCTs); health technology assessments and economic evaluations; clinical practice guidelines and coverage policies of other health systems.ResultsWe found a Phase III Open-Label study (RE-LY) published in 2009, with 18,000 AF patients for the prevention of IS and embolic events. Patients were randomized to dabigatran 110mg bid, 150mg bid and warfarin at adjusted doses for an average 2-year follow up. The enrolled patients were patients at low risk of IS. Annual rates for the compound outcome (IS and systemic embolism) were 1.69% per year in the warfarin group versus 1.53% per year in the dabigatran 110mg, group (RR 0.91 95% CI 0.74-1.11). For the dabigatran 150mg group it was 1.11% per year (RR with warfarin 0.66 95% CI 0.53 to 0.82).In a planned analysis per subgroup, the benefit of dabigatran 150mg bid versus the adjusted doses of warfarin was observed in sites where the INR control was inadequate.The annual incidence of major bleeding was similar for warfarin (3.57%) and dabigatran 150mg (3.32%), but significantly higher for warfarin when compared with dabigatran 110mg (2.87%). The rate of hemorrhagic stroke was 0.38 % per year in the warfarin group compared with 0.12 % per year in the dabigatran 110 mg group (p<0.001) and 0.10 % per year in the dabigatran 150mg group (p<0.001)In our country, VKA acenocumarol is used as standard of care and we have not found studies comparing it with dabigatran.Costs: AR$ 750.00 (Argentine pesos, 2011) per month (150mg or 110mg bid).Surveyed coverage policies recommend its use mainly for patients who have failed in maintaining an adequate INR with good adherence to treatment or who are warfarin-hypersensitive.European and American clinical practice guidelines recommend dabigatran as an alternative to the use of warfarin, and doses of dabigatran 110mg are recommended in patients at high risk of bleeding.ConclusionsIn the only randomized clinical trial, dabigatran 150mg bid is slightly better than warfarin in preventing IS, embolic events and vascular death and 100mg big is non inferior to warfarin, with no significant increase in major bleeding. It is worth mentioning that this was an open-label study, with just two-year follow up. The applicability of results is uncertain due to inadequate INR control in some countries. Quality of life in these patients, which is a primary reason for cost-effectiveness studies, was not assessed in the study. The use of dabigatran in patients with AF as an alternative to VKA might be specially considered when: Patients receiving VKA therapy present unstable INR, when there is increased risk of drug and food interactions and in those who are warfarin-hypersensitive.In AF patients receiving VKA and who have adequate INR control, dabigatran might be an alternative, its comfort and higher cost should be taken into account. In patients at risk of increased bleeding, its use might be considered at 110mg doses bid, since it is as efficient as VKA but presents lower risk of bleeding.