Current Drug Therapy

Dabigatran: Will it change clinical practice?

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ABSTRACTDabigatran (Pradaxa) is a new oral anticoagulant approved in the United States for the primary prevention of stroke and systemic embolization in patients with nonvalvular atrial fibrillation. It offers clinicians an alternative to warfarin (Coumadin), and it has received considerable interest because of its convenience of use, clinical efficacy, and safety profile. However, it is more expensive, and this may limit its widespread use.

KEY POINTS

  • Dabigatran is a potent, reversible, direct thrombin inhibitor. Available only in oral form, it has a rapid onset of action, a predictable anticoagulant response, and few major interactions.
  • Dabigatran does not require dose adjustments (except for renal insufficiency) or monitoring of its effect during treatment.
  • In trials in patients with nonvalvular atrial fibrillation, two different doses of dabigatran were compared with warfarin. Less bleeding occurred with the lower dose than with warfarin, while the higher dose was more effective than warfarin in preventing stroke and systemic embolization.
  • The American College of Cardiology, the American Heart Association, and the Heart Rhythm Society have given dabigatran a class I B recommendation for secondary stroke prevention in patients with nonvalvular atrial fibrillation.


 

References

Dabigatran etexilate (Pradaxa) is a new oral anticoagulant that has distinct advantages over warfarin (Coumadin) in terms of its ease of administration, efficacy, and safety.

In the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY trial),1 in patients with nonvalvular atrial fibrillation, dabigatran 110 mg twice a day was found to be as good as warfarin in preventing systemic embolization and stroke (the primary outcome of the study), and at 150 mg twice a day it was superior.1 It has also shown efficacy in treating acute deep vein thrombosis and pulmonary embolism and in preventing these complications in orthopedic surgical patients.2–4

Dabigatran has been approved in 75 countries. It carries the trade name Pradaxa in Europe and the United States and Pradax in Canada. In October 2010, the US Food and Drug Administration (FDA) Cardiovascular and Renal Drugs Advisory Committee endorsed two twice-daily doses (75 mg and 150 mg) of dabigatran for the prevention of systemic embolization and stroke in patients with nonvalvular atrial fibrillation.

However, dabigatran is relatively expensive, and its current high cost might be a barrier to its wider use.

MANY PATIENTS NEED ANTICOAGULATION

Anticoagulation plays a vital role in the primary and secondary prevention of stroke in patients with atrial fibrillation and of pulmonary embolism in patients with venous thromboembolism. It is also used during cardiothoracic and vascular surgery, endovascular procedures, and dialysis and in patients with mechanical heart valves and hypercoagulable conditions.

Atrial fibrillation affects 3.03 million people in the United States (2005 figures), and this number is predicted to be as high as 7.56 million by 2050.5 More than 10% of people over the age of 80 years have it, and the lifetime risk of developing it is approximately 25%.6,7 Its most serious complication is ischemic stroke (the risk of which increases with age) and systemic embolization.5,8

Until the recent introduction of dabigatran, the only oral anticoagulant available in the United States for treating patients with atrial fibrillation was warfarin. Although warfarin has a number of disadvantages (see below), it is actually very effective for preventing ischemic stroke, reducing the incidence by as much as 65%.9,10

Venous thromboembolism is the third most common cardiovascular disorder after myocardial infarction and stroke.11 Although its exact incidence is unknown, nearly 1 million cases of it (incident or recurrent, fatal and nonfatal events) occur in the United States each year.12 Many patients with venous thromboembolism need oral anticoagulation long-term, and currently warfarin remains the only option for them as well.

NEEDED: A BETTER ANTICOAGULANT

Warfarin has been the most commonly prescribed oral anticoagulant in the United States for more than 60 years. As of 2004, more than 30 million outpatient prescriptions for it were filled annually in this country alone.13 However, warfarin has several important limitations.

Warfarin has a narrow therapeutic index. Patients taking it require monitoring of their international normalized ratio (INR) and frequent dose adjustments, and this is time-consuming and inconvenient. The target INR for patients with venous thromboembolism and atrial fibrillation is 2.0 to 3.0, whereas patients with a mechanical heart valve need a higher INR (2.5 to 3.5). If the INR is below these ranges, warfarin is less effective, with a risk of new thrombosis. On the other hand, if the INR is too high, there is a risk of bleeding.14 In fact, the most important side effect of warfarin is the risk of major and minor bleeding.13 However, even in well-designed clinical trials in which patients are closely managed, only 55% to 60% of patients regularly achieve their therapeutic target INR.1,2,14,15

Warfarin also interacts with many drugs and with some foods. Compliance is difficult. It has a slow onset of action. Genetic variations require dose adjustments. When switching from a parenteral anticoagulant, overlapping is required. Skin necrosis is a possible side effect. And warfarin is teratogenic.

Despite these limitations, the American College of Chest Physicians endorses warfarin to prevent or treat venous thromboembolism, and to prevent stroke in patients with atrial fibrillation.16

Recently, a number of new oral and parenteral anticoagulants have been developed (Table 1) with the aim of overcoming some of the drawbacks of warfarin and the other currently available agents, and to improve the prevention and treatment of thromboembolic disorders.

DABIGATRAN, A THROMBIN INHIBITOR

Dabigatran, developed by Boehringer Ingelheim, is a potent, competitive, and reversible inhibitor of both free and clot-bound thrombin, inhibiting both thrombin activity and generation (Table 2).17,18

A prodrug, dabigatran is rapidly absorbed and converted to its active form. Its plasma concentration reaches a peak 1.5 to 3 hours after an oral dose, and it has an elimination half-life of 12 to 14 hours. About 80% of its excretion is by the kidneys and the remaining 20% is through bile.

Dabigatran is not metabolized by cytochrome P450 isoenzymes, and therefore it has few major interactions with other drugs. An exception is rifampin, a P-glycoprotein inducer that blocks dabigatran’s absorption in the gut, so this combination should be avoided. Another is quinidine, a strong P-glycoprotein inhibitor that is contraindicated for use with dabigatran. Also, amiodarone (Cordarone), another P-glycoprotein inhibitor, increases blood levels of dabigatran, and therefore a lower dose of dabigatran is recommended if these drugs are given together.18–20

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Proceedings of the 2010 Heart-Brain Summit

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