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Dabigatran:  A New Anticoagulant for Stroke Prevention in Patients with Atrial Fibrillation

Published in Missouri Medicine, the journal of the Missouri State Medical Association, March/April 2012

By Richard Weachter, MD

University of Missouri Hospital and Clinics

Division of Cardiovascular Medicine

Abstract

Ischemic stroke is arguably the most feared complication of atrial fibrillation.  While warfarin has been the most effective pharmacologic treatment for stroke prevention in patients with nonvalvular atrial fibrillation, several limitations have led to its underutilization.   This article reviews, dabigatran (Pradaxa), a new oral anticoagulant with several potential advantages over warfarin (Coumadin), became available for use in the United States for prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. 

Introduction

Atrial fibrillation (AF), characterized by chaotic atrial electrical activity, is the most common sustained arrhythmia requiring treatment.  Prevalence increases with age effecting about 0.1% of individuals less than 55 years of age and about 10% of individuals more than 80 years of age. ^{1, 2} At age 40, the likelihood of developing AF later in life is about 25%. ³

While associated symptoms of palpitations, dyspnea and chest pain are significant concerns, arguably the preeminent concern is the risk of ischemic stroke. ^{4, 5} AF increases the risk of stroke 5-fold, which typically is associated with greater morbidity and mortality than for stroke patients without AF.  ^{4, 5}

The CHADS₂ score remains a widely utilized stroke risk stratification scheme in patients with AF.  ⁶    Of the 5 risk factors that make up the CHADS₂ score, 4 factors (Congestive heart failure, Hypertension, Age ˃75 and Diabetes mellitus) each receive a point value of 1 and a single factor, TIA or Stroke, considered a high-risk factor, receives a point value of 2.  Typically, a score of 2 or greater indicates significant stroke risk from AF and warrants subsequent treatment with warfarin (and now dabigatran).⁷   (Table 1)

Table 1

While warfarin has been the most effective pharmacologic treatment for stroke prevention in patients with nonvalvular AF, only 50-60% of eligible patients receive therapy. ⁸ Several factors have contributed to warfarin’s underutilization including increased bleeding risk, slow onset and offset of action, need for regular coagulation monitoring, and multiple drug and dietary interactions.  These limitations have led to the development of newer, and hopefully, equally effective, safer and more easily administered anticoagulant drugs.  Dabigatran etexilate (Pradaxa), the focus of this review, was approved by the FDA in October 2010, and endorsed by updated guidelines from the American College of Cardiology, the American Heart Association, and the Heart Rhythm Society, for use as an alternative to warfarin (Coumadin) in the treatment of nonvalvular AF patients. ⁹

RE-LY Study

Dabigatran’s efficacy for the prevention of stroke and systemic embolism in patients with nonvalvular AF was demonstrated in the recently published RE-LY (Randomized Evaluation of Long-term Anticoagulant Therapy) study. ¹²   Approximately 18,000 patients with paroxysmal, persistent or permanent AF, and mean CHADS₂score of 2.1, were randomized to warfarin (target INR 2.0-3.0) or dabigatran (110mg or 150 mg BID).  Pertinent findings included:

a)     dabigatran 150 mg BID was significantly more effective than warfarin at stroke and systemic embolism prevention (with a similar risk of major bleeding)

b)    dabigatran 110 mg BID was comparable to warfarin at stroke and systemic embolism prevention ( but with a significantly lower risk of major bleeding)

c)     both doses of dabigatran were associated with significantly lower risks of intracranial bleeding and hemorrhagic stroke than warfarin (possibly due to dabigatran not crossing the blood- brain barrier) ₁₆ 

d)    both doses of dabigatran were associated with slightly higher rates of myocardial infarction than warfarin

e)     no significant difference in overall mortality

Pharmacologic Properties

Dabigatran etexilate (Pradaxa) inhibits thrombin (the most potent agonist of platelet aggregation) and decreases thrombin generation.  (Figure 1)

Figure 1.

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