How FDA can help reduce dabigatran (PRADAXA) bleeding risks
February 13, 2014

Two new studies of the anticoagulant dabigatran (PRADAXA) show that the high risk of hemorrhage in older patients can be substantially reduced with two options currently available to healthcare providers in Canada and Europe, but not in the US: 1) a lower dose option (110 mg BID), and 2) a new laboratory monitoring test capable of identifying patients at highest risk for serious bleeding. While the US Food and Drug Administration (FDA) previously disallowed a lower dose and the new laboratory test monitoring in the US, the stakes are high—a dabigatran clinical trial showed that 16% of patients experienced a bleed in 1 year, including 3.3% with bleeds that required emergency medical treatment.1

The FDA approved dabigatran in October 2010 in a one-dose-fits-all therapeutic dose of 150 mg BID for reducing the risk of stroke in patients with nonvalvular atrial fibrillation. It appeared to work as well as, or better, than standard therapy with warfarin (COUMADIN) and did not require regular laboratory test monitoring and dose adjustments. Even if a healthcare professional’s clinical assessment of a patient suggested a higher risk of bleeding, the single approved therapeutic dose of 150 mg BID left clinicians with no options for a dose reduction because the FDA explicitly rejected a lower 110 mg BID dose, which is available in Canada, Australia, New Zealand, Japan, and Europe.2 In the US, a 75 mg BID dose was approved only for use in patients with severe renal impairment (CrCl 15-30 mL/min).

ISMP’s 2010 (4th quarter) QuarterWatch™ detected a strong signal of a safety problem with dabigatran as it monitored the serious adverse drug events reported to FDA in the first months after the drug’s approval.3 Our monitoring program detected unexpectedly large numbers of serious and fatal reports of bleeding, particularly in older patients. We expanded our analysis in three later issues of QuarterWatchTM, noting severe and fatal bleeding events in patients with a median age of 80.4-6 By the end of 2012, FDA had received 7,387 domestic reports of serious injury associated with dabigatran, including 1,158 patient deaths. QuarterWatchTM ranked anticoagulants as the leading drug safety risk for both 2011 and 2012. In the reports, we urged FDA to reconsider the 110 mg BID dose of dabigatran and to improve monitoring to identify high-risk older patients.

A new perspective on this safety problem emerged in two studies published recently in the Journal of the American College of Cardiology,7,8 and from confidential company documents unsealed in litigation against the manufacturer, Boehringer Ingelheim, brought by patients alleging injury from dabigatran ( These studies and documents showed that a one-dose-fits-all approach raises the risk of major bleeding in many patients without any gain in efficacy in preventing strokes. The lower dose (110 mg BID) had similar efficacy but lower bleeding risk. The studies also indicated that it was known in advance that a single-dose strategy was extremely risky because of 5-fold variations in plasma levels in 80% of patients receiving this dose, with still larger differences at the extremes. Although the analysis was just published, the data were collected in the original major efficacy trial completed in 2009, prior to FDA approval, and were available to the agency during the review process.

ISMP reviewed the documents unsealed in the dabigatran litigation9 after they were made publicly available. The documents showed that the company conducted studies and simulations indicating that the higher bleeding risk in older patients could be reduced. However, it appears the drug company was reluctant to publish the findings, fearing it would lead regulators to require monitoring to improve safety, which would result in a commercial disadvantage with the competing anticoagulants, rivaroxaban (XARELTO) and apixaban (ELIQUIS).

Also unavailable in the US is an assay to determine the plasma concentrations of dabigatran. Boehringer Ingelheim tested the assay and reported in a scientific journal, “This rapid, standardized and calibrated assay should provide accurate and consistent results.”10 The test, called the Hemoclot Thrombin Inhibitor assay, is available in Europe, Australia, and Canada, but only for research purposes in the US.11 Given the recent but long-delayed publication of plasma level-outcome data, this test now has greater value because it can identify the 10% of patients with extremely high blood levels even outside the 5-fold variation range.

FDA should strongly consider this important additional information about dabigatran, reassess the one-dose-fits-all recommendation, and reevaluate the Hemoclot Thrombin Inhibitor assay to reduce the risk of serious injury from one of the highest risk outpatient drug treatments.

1) Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12):1139–51.
2) Beasley BN, Unger EF, Temple R. Anticoagulant options—why the FDA approved a higher but not a lower dose of dabigatran. N Engl J Med. 2011;364(19):1788–90.
3) Moore TJ, Cohen MR, Furberg CD. QuarterWatch: 2010 Quarter 4: signals for two newly approved drugs and 2010 Annual Summary. ISMP. 2011.
4) Moore TJ, Cohen MR, Furberg CD. QuarterWatch 2011 Quarter 1: signals for dabigatran and metoclopramide. ISMP. 2012.
5) Moore TJ, Cohen MR, Furberg CD. QuarterWatch 2011 Quarters 3-4: anticoagulants the leading reported drug risk in 2011. ISMP. 2012.
6) Moore TJ, Cohen MR, Furberg CD, Mattison DR. QuarterWatch 2012 Quarter 4: leading drug safety issues of 2012. ISMP. 2013.
7) Eikelboom JW, Connolly SJ, Hart RG, et al. Balancing the benefits and risks of 2 doses of dabigatran compared with warfarin in atrial fibrillation. J Am Coll Cardiol. 2013;62(10):900–7.
8) Reilly PA, Lehr T, Haertter S, et al. The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients. J Am Coll Cardiol. 2014;63(4):321–8.
9) Thomas K. Study of drug for blood clots caused a stir, records show. The New York Times. February 6, 2014:B1.
10) Stangier J, Feuring M. Using the HEMOCLOT direct thrombin inhibitor assay to determine plasma concentrations of dabigatran. Blood Coagul Fibrinolysis Int J Haemost Thromb. 2012;23(2):138–43.
11) Aniara/Dabigatran (Pradaxa) testing.  

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