Dabigatran: A New Oral Anticoagulant

David Green, MD, PhD

Journal Watch. 2007;6(12) 

In a large study, dabigatran was as effective as low-dose enoxaparin for preventing VTE after knee replacement.

Coumarin-derived drugs such as warfarin have been the mainstay of oral anticoagulant treatment for decades. However, they are slow-acting, are teratogenic, and have a narrow therapeutic index that necessitates frequent monitoring. An oral thrombin inhibitor, ximelagatran, was derailed in development because of unacceptable hepatotoxicity. Now, another oral thrombin inhibitor, dabigatran etexilate, is on the threshold of regulatory approval. It has a rapid onset of action, requires only once-daily dosing, and has predictable activity so that monitoring is not required.

Investigators from several European university centers (and some employed by dabigatran's manufacturer) examined the safety and effectiveness of this drug for preventing venous thromboembolism (VTE) after knee replacement surgery. They enrolled 2101 patients who were randomized to receive either daily oral dabigatran (150 mg or 220 mg) or daily subcutaneous enoxaparin (40 mg). To maintain blinding, all participants received capsules and subcutaneous injections. Most patients received enoxaparin (or placebo injections) on the evening before surgery (European standard practice) and then daily afterward. Half doses of dabigatran (or placebo) were given at 1 to 4 hours after surgery, and full doses were given starting on the next morning. Treatment was continued for 6 to 10 days; bilateral venography was performed at treatment cessation. Patients were followed for 3 months. If clinical evidence of deep venous thrombosis or pulmonary embolism was noted during that period, confirmatory duplex scanning or spiral computed tomography examinations were performed.

Major VTE and VTE-related mortality occurred in 13 of 506 patients in the 220-mg dabigatran group, in 20 of 527 in the 150-mg group, and in 18 of 511 in the enoxaparin group — differences were nonsignificant. The primary outcome measures (VTE or death) occurred in similar numbers of patients in all three groups, which indicated noninferiority of the oral agent. Major bleeding occurred in 10, 9, and 9 patients in the groups, respectively — again, nonsignificant differences. Importantly, elevated liver enzymes were reported in only 2.8%, 3.7%, and 4% of the groups, respectively; all abnormal enzyme levels returned to baseline during extended follow-up.

Although the results of the current trial demonstrate that dabigatran is as effective as enoxaparin, two issues cloud this picture. First, the study dose of enoxaparin, 40 mg daily, is low by current North American standards, where 30 mg twice daily usually is preferred. Indeed, in a recent abstract, researchers reported that dabigatran did not pass the noninferiority test when compared with the higher dose of enoxaparin (J Thromb Haemost 2007; 5:Suppl 2:O-W-051). Second, fondaparinux, a factor Xa inhibitor, is more effective than enoxaparin in preventing VTE after knee replacement surgery. Although fondaparinux currently is not the most popular product, one might argue that new agents should be compared with the best available drug rather than the one used most widely. Nevertheless, dabigatran is an attractive choice for surgical thromboprophylaxis because it is administered orally, does not require monitoring, and apparently is safe.

— David Green, MD, PhD

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