The Oral Thrombin Inhibitor Dabigatran: Strengths and Weaknesses

 

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Abstract

Since the quest for a better replacement of warfarin started several decades ago and new compounds were brought forward to clinical trials, the concept of an ideal anticoagulant frequently became presented in lectures and articles. We have here reviewed strengths and weaknesses of the oral thrombin inhibitor dabigatran in terms of pharmacokinetics and clinical data. When strengths clearly exceed the weaknesses for any characteristic, the drug fits into the concept of an ideal anticoagulant in that domain. It is evident that dabigatran does not accomplish that concept for all characteristics but it reaches well above warfarin. We believe it is unlikely that any drug will fulfill all criteria for the ideal anticoagulant. Laboratory testing for dabigatran will not be discussed in any detail in this article, which is instead the focus of other articles from this issue of Seminars in Thrombosis & Hemostasis.

Addendum

During August–December 2011, regulatory authorities in Japan, Australia, Europe and the United States (in chronological order) issued a safety advisory/announcement/update regarding reported serious bleeding complications related to dabigatran. Most of these were from the gastrointestinal canal. By November 6, 2011 a total of 256 spontaneous case reports of serious bleeding leading to death had been submitted. Several of the regulatory agencies commented that increased vigilance is typical after registration of a new drug but that they will follow the situation closely. The EMA had already, before their update on safety, issued a recommendation that (1) renal function must be assessed before starting a patient on dabigatran and (2) renal function has to be assessed annually thereafter for patients over the age of 75 years or with reduced renal function at start.

During October 2010–August 2011, 371,000 patients in the United States alone had been prescribed dabigatran (www.fda.gov/Drugs/DrugSafety/ucm282724.htm). For comparison, with the same number of patients receiving warfarin and an annual risk of approximately 0.4% for ICH[58] 1480 patients would have suffered that complication. The authors do not know the worldwide denominator for patients prescribed dabigatran. A meta-analysis of all randomized controlled trials with dabigatran and reporting on myocardial infarction or acute coronary syndromes showed a significantly higher incidence (1.19%) compared to different controls (0.79%).[59]

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