Dabigatran Etexilate: A Novel Oral Direct Thrombin Inhibitor

Matthew L. Blommel; Amy L. Blommel

Disclosures

Am J Health Syst Pharm. 2011;68(16):1506-1519. 

In This Article

Abstract and Introduction

Abstract

Purpose. The pharmacology, pharmacokinetics, clinical efficacy, tolerability, dosage and administration, and place in therapy of dabigatran etexilate are reviewed.
Summary. Dabigatran is a reversible direct thrombin inhibitor (DTI) that has rapid and predictable anticoagulant effects and does not require the anticoagulation monitoring seen with oral vitamin K antagonists. Dabigatran etexilate has demonstrated efficacy in several clinical studies in preventing venous thromboembolism (VTE) for patients undergoing total hip or knee replacement, in preventing strokes in patients with nonvalvular atrial fibrillation, and in treating acute VTE. Dabigatran etexilate is a prodrug that is orally absorbed and completely converted to the active form dabigatran by carboxylesterases. Neither the conversion of dabigatran etexilate nor the metabolism of active dabigatran involves the cytochrome P-450 isoenzyme system. Other than hemorrhage, dabigatran is generally well tolerated, with gastrointestinal effects being the most commonly reported adverse events. All dosages should be adjusted in patients with reduced renal function. Dabigatran is currently being investigated for several thromboembolic disorders. It was approved by the Food and Drug Administration in October 2010 for stroke and VTE prevention in adult patients with nonvalvular atrial fibrillation, and it was approved by the European Medicines Agency in March 2009 for the prevention of VTE in adult patients undergoing elective total hip or knee replacement.
Conclusion. Dabigatran etexilate, the first oral DTI marketed in the United States, is indicated to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation. Dabigatran may be a viable option for anticoagulation in some patients due to its oral administration, rapid onset of action, and predictable anticoagulant effects.

Introduction

Venous thromboembolism (VTE) is the third most common cause of vascular death after myocardial infarction and stroke, affecting 1 to 2 of every 1000 adults annually.[1,2] Atrial fibrillation increases the risk of stroke and death. Thromboprophylaxis agents, such as low-molecular-weight heparins (LMWHs) and vitamin K antagonists (VKAs), are commonly used to reduce VTE risk but have several limitations (i.e., frequent monitoring of laboratory test values due to multiple food and drug interactions, a narrow therapeutic range, significant variability in patient anticoagulant response, and a slow onset and offset of action). Because of these limitations, oral anticoagulation is only prescribed for approximately 50% of elderly patients who have appropriate indications for VKAs.[3] Further, patients enrolled in clinical trials who were well monitored maintained therapeutic International Normalized Ratio (INR) values for 60–68% of the time during treatment.[4–6] It may be possible for patients to increase the percentage of time that their INRs are within the therapeutic range if anticoagulant management services are utilized.[7,8] However, these services are not available to all patients, and the percentage of time that the INR is within the therapeutic range for patients taking warfarin and receiving usual care may be lower than that reported in clinical trials.[7,8] LMWHs require parenteral administration, are costly, and can become challenging when dealing with outpatient administration of doses.[9–11] These challenges include educating patients or caregivers on proper administration techniques for subcutaneous injections and overcoming potential patient reluctance to receive an injectable medication versus an orally administered agent.

Direct thrombin inhibitors (DTIs) have been investigated for their anticoagulant properties, but, until recently, the available DTIs have been limited to parenterally administered agents. Orally administered DTIs would be preferred to parenteral administration and would overcome many of the limitations of commonly used anticoagulants. The first oral DTI developed was ximelagatran, a prodrug that is metabolized to the active metabolite melagatran before exerting its anticoagulant effects.[12] Ximelagatran was ultimately denied Food and Drug Administration (FDA) marketing approval for prophylaxis and treatment of VTE due to efficacy and safety concerns. Safety concerns included hepatotoxicity in ximelagatran-treated patients in short-term and long-term (over 35 days) trials and unexpected higher rates of coronary artery disease events in long-term trials.[12]

Dabigatran etexilate (Pradaxa, Boehringer Ingelheim, Ridgefield, CT), an oral DTI, was approved for marketing by FDA in October 2010 as a preventive agent to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.[13] Dabigatran etexilate was approved for marketing by the European Medicines Agency (EMA) in March 2009 for the prevention of VTE in adult patients who have undergone elective total hip replacement (THR) or total knee replacement (TKR) surgery, and the EMA's Committee for Medicinal Products for Human Use recently recommended its approval for prevention of stroke and VTE in adults with nonvalvular atrial fibrillation with one or more risk factors.[14]

This article reviews the pharmacology, pharmacokinetics, clinical efficacy, safety, and dosage and administration of dabigatran etexilate. Dabigatran's place in anticoagulation therapy is also reviewed.

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