Archief Roodbont

Current and Emerging Treatment Options

Although warfarin has been used in AF thromboprophylaxis for many years, its limitations have contributed to underuse. For long-term use, there is a need for safer and more effective oral anticoagulants that do not require routine monitoring of coagulation. A new generation of anticoagulants, oral direct antithrombin inhibitors and oral factor Xa inhibitors, are in clinical development. These agents can be orally administered and directly target specific factors in the coagulation cascade. Efficacy and safety of perioperative prophylaxis for venous thromboembolism after hip and knee surgery has been shown with the direct thrombin inhibitor dabigatran as well as for the oral factor Xa inhibitors rivaroxaban and apixaban, compared with low-molecular-weight heparins.^[89-92]

Dabigatran was recently approved by the US Food and Drug Administration (FDA) for the prevention of stroke in patients with AF. The Randomized Evaluation of Long-term anticoagulant therapY (RE-LY) trial compared warfarin (with target INR 2-3) with 2 doses of dabigatran in 18,000 patients with AF with a CHADS₂ score ≥ 1.^[93] Dabigatran 150 mg twice daily was superior to warfarin in efficacy (thromboembolism prevention) and similar to warfarin in safety (bleeding rates), whereas dabigatran 110 mg twice daily was noninferior to warfarin in efficacy and appeared to be safer.

Similar trials have been conducted for rivaroxaban (Rivaroxaban – Once-daily, oral, direct Factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation [ROCKET-AF]) and apixaban (Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation [ARISTOTLE]). In fact, findings from ROCKET-AF were reported on November 15, 2010 at a late-breaking clinical trials session at the AHA Scientific Sessions.^[94] In this trial, 14,264 patients with nonvalvular AF (average CHADS₂ score ≈3.47; 55% with previous embolic event) were randomly assigned to rivaroxaban (20 mg daily) or warfarin (with target INR 2-3). Rivaroxaban was found to be as effective as warfarin in preventing stroke. In the primary analysis, the rate of stroke and embolization was 1.71 per 100 patient-years in the rivaroxaban group and 2.16 per 100 patient-years in the warfarin group (hazard ratio, 0.79; 95% CI, 0.66-0.96; P < .001 for noninferiority; P = .018 for superiority). The incidence of major bleeding complications was comparable in the 2 groups. The trial investigators also reported that the median time spent within the therapeutic range was only 57.8% in the warfarin group.

Data from A Phase III Study of Apixaban in Patients With Atrial Fibrillation (AVERROES), presented at the 2010 ESC meeting, indicated that patients with AF unable to take warfarin had a significantly lower risk for stroke and systemic embolic events with apixaban 5 mg twice daily than with aspirin (81-324 mg/day).^[95] AVERROES was stopped early after a predefined interim analysis "revealed clear evidence of a clinically important reduction in stroke and systemic embolism." These new oral agents represent alternative therapies to stroke prevention in AF that is substantially different from the current agents, and potentially alters the current benefit-risk ratio associated with long-term anticoagulant treatment.

Left atrial appendage is considered the thromboembolic source in > 80% of AF-related thromboembolism. Consequently, percutaneous or surgical appendage closure is being evaluated as an alternative strategy for stroke prevention in AF. A few devices for left atrial appendage occlusion have been subject to clinical evaluation. The WATCHMAN Left Atrial Appendage System for Embolic PROTECTion in Patients with Atrial Fibrillation (PROTECT AF) Trial is evaluating the Watchman® Left Atrial Appendage Occluder (Atritech, Inc.; Plymouth, Massachusetts) compared with conventional warfarin therapy. After approximately 3 years' follow-up, the device appears to be noninferior in efficacy, but is associated with higher rate of adverse safety events compared with warfarin.