Pradaxa, Bleeding and Tort Litigation Solicitation

Since the release of dabigatran (Pradaxa), (Dabigatran: A New Anticoagulant for Stroke Prevention in Patients with Atrial Fibrillation by Richard Weachter, MD, Missouri Medicine, March/April 2012, 146–149) major bleeding in Japan and Australia has been reported with this anticoagulant, prompting an FDA investigation¹ and the institution of hotlines (1-800-BADDRUG) which provide legal counseling information to individuals who have experienced bleeding and encourage lawsuits against the manufacturer and often the prescribing physician. As a member of the Steering Committee for the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY), I can provide additional information about these issues.

Dabigatran (Pradaxa) is a highly selective and potent anticoagulant currently approved for use in the United States to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. It offers a number of advantages over warfarin including a quicker onset and offset of action, fewer drug interactions, and less CNS bleeding. It does not require anticoagulation monitoring, a distinct disadvantage for many patients who receive warfarin.

The decision by the FDA to approve this drug was based on RE-LY which compared two doses of dabigatran, 150 mg twice daily or 110 mg twice daily with open label warfarin (intended INR 2.0–3.0) for patients with atrial fibrillation and risk factors for stroke. In this trial the 150 mg twice daily dose was more effective than warfarin in the prevention of stroke or systemic embolism at a comparable rate of bleeding. The 110 mg twice daily dose was comparable to warfarin in the prevention of stroke and systemic embolism but was associated with less bleeding than warfarin.² The FDA approved the 150 mg twice daily dose but not 110 mg twice daily dose, reasoning that stroke were more clinically significant than nonfatal and extracranial bleeding and that physicians would preferentially use the lower dose.³

Every anticoagulant has increased bleeding risks. However, there is concern that dabigatran is being used inappropriately. The approved dose of dabigatran is 150 mg twice daily for patients with a creatinine clearance > 30 ml/min. A dose of 75 mg twice daily, clinically untested in large trials, is approved for use in patients with a creatinine clearance of 15–30 ml/min. Dabigatran is not recommended for use in patients with a creatinine clearance of < 15 ml/min.

In RE-LY, gastrointestinal bleeding was more common with dabigatran than with warfarin. This may be due to the fact that dabigatran etexilate is a prodrug which has a low bioavailability. Dabigatran etexilate is converted to the active drug dabigatran by gut esterases and local concentrations of the prodrug may account for some gastrointestinal bleeding. Since dabigatran etexilate is a substrate for the p-glycoprotein enzyme, potent inducers of the p-glycoprotein system, such as rifampin, may result in localized increased levels of dabigatran and more gastrointestinal bleeding. Several common cardiac medications also make use of the p-glycoprotein enzymes system including amiodarone and verapamil. Increased levels of dabigatran are noted when these drugs are combined, although the manufacturer does not recommend a dose adjustment of dabigatran when used with these drugs. There is concern about the use of antiplatelet agents when used concomitantly with dabigatran. Preliminary RE-LY data published in abstract form at the European Society of Cardiology 2011 showed that when antiplatelet agents were used in conjunction with warfarin, the risk of major bleeding was 4.8%/year compared with 2.8%/year when warfarin was not combined with antiplatelet agents. The risk of major bleeding with dabigatran 150 mg twice daily was 4.4% when used in conjunction with antiplatelet agents and 2.6%/year when dabigatran was not combined with antiplatelet agent. Consequently, the clinician must evaluate the need for aspirin and other antiplatelet agents when using dabigatran.

Did RE-LY include patients different from clinical practice? Currently, a registry is enrolling patients, tracking the rate of major bleeding, myocardial infarction, and other clinical events (ClinicalTrials.gov Identifier NCT 01491178) which will help answer this important question.

Dabigatran is a major advance in anticoagulant therapy but should be used for the appropriate patient, at the appropriate dose. I encourage physicians to follow the guidelines listed by the manufacturer. The rapidity and ferocity with which the US tort bar is creating a another area of lucrative litigation against a new, useful drug that is likely safer than drugs it will replace is, unfortunately, a typical modus operandi.