What is the efficacy of direct thrombin inhibitors for stroke prevention in patients with atrial fibrillation (AF)?

Updated: Dec 18, 2018
  • Author: Salvador Cruz-Flores, MD, MPH, FAHA, FCCM, FAAN, FACP, FANA; Chief Editor: Helmi L Lutsep, MD  more...
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The RE-LY study evaluated the efficacy and safety of 2 different doses of dabigatran relative to warfarin in more than 18,000 patients with atrial fibrillation. Patients were randomized to 1 of 3 arms: (1) adjusted dose warfarin, (2) dabigatran 110 mg bid, or (3) dabigatran 150 mg bid. Dabigatran 110 mg was noninferior to warfarin for the primary efficacy endpoint of stroke or systemic embolization, while dabigatran 150 mg was significantly more effective than warfarin or dabigatran 110 mg. Major bleeding occurred significantly less often with dabigatran 110 mg than warfarin; dabigatran 150 mg had similar bleeding to warfarin. [30]

Dabigatran, a competitive, direct thrombin inhibitor, was approved by the US Food and Drug Administration in 2010 for prevention of stroke and thromboembolism associated with nonvalvular atrial fibrillation. The dose is 150 mg PO bid (decrease to 75 mg PO bid with renal impairment). When converting from warfarin, discontinue warfarin and initiate dabigatran when INR < 2.0.

The FDA approved a monoclonal antibody reversal agent (idarucizumab [Praxbind]) for patients treated with dabigatran when reversal of dabigatran’s anticoagulant effects are needed for emergency surgery or urgent procedures, or in the event of life-threatening or uncontrolled bleeding. Idarucizumab is specific for reversing dabigatran, although other NOAC reversal agents are currently in clinical trials or awaiting FDA approval (eg, andexanet alfa, PER977).

Accelerated approval for idarucizumab was based on interim analysis of the Re-VERSE AD trial. Investigators found that, among 39 patients who had been receiving dabigatran and required an urgent procedure were then given idarucizumab, 36 underwent their urgent procedure—with 33 (92%) having normal hemostasis during the event. Two of the remaining patients had mildly abnormal bleeding (with slight oozing), while just one had moderately abnormal yet controlled bleeding. Among 35 of 51 patients who had serious bleeding were able to be assessed, hemostasis, as determined by local investigators, was restored at a median of 11.4 hours. [31]

Guidelines from the American College of Cardiology Foundation (ACCF)/American Heart Association (AHA)/Heart Rhythm Society (HRS) on atrial fibrillation have been updated to include the use of oral direct thrombin inhibitors (ie, dabigatran). [32] The guidelines include a class Ib recommendation (ie, treatment is useful/effective based on a single randomized trial) for dabigatran. The guidelines recommend dabigatran may be used as an alternative to warfarin for the prevention of stroke and systemic thromboembolism in patients with paroxysmal-to-permanent atrial fibrillation and risk factors for stroke or systemic embolization. Patients with atrial fibrillation who are not candidates include those with prosthetic heart valves or hemodynamically significant valve disease, severe renal failure (creatinine clearance ≤15 mL/min), or advanced liver disease.

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