FDA Perspective Published in the New England Journal of Medicine Reinforces Safety of Pradaxa® (Dabigatran Etexilate)

Ingelheim, Germany, March 26, 2013 – A new perspective from the U.S. Food and Drug Administration (FDA) published in the New England Journal of Medicine¹ states that the agency has not changed its recommendations regarding Pradaxa^® (dabigatran etexilate), following the November 2012 Mini-Sentinel evaluations.² The FDA stated that bleeding rates associated with new use of Pradaxa^® do not appear to be higher than those with new use of warfarin, which is consistent with observations from the pivotal RE-LY^® trial.^1,2,3,4 The perspective was published online on March 13, 2013.¹

The Mini-Sentinel evaluated new information about the risk of serious bleeding associated with the use of blood thinners (anticoagulants): Pradaxa^® and warfarin. The FDA investigated the actual rates of bleeding occurring in the stomach and intestines (gastrointestinal bleeding, GIH) and a type of bleeding in the brain (intracranial hemorrhage, ICH) for new users of Pradaxa^® compared to new users of warfarin. This assessment was done using insurance claims and administrative data from the FDA’s ongoing Mini-Sentinel pilot of the Sentinel Initiative.

In the November 2012 Mini-Sentinel evaluations, the FDA stated: “For the populations in the Mini-Sentinel data assessment, the combined incidence rate (ICH and GIH events per 100,000 days at risk) was 1.8 to 2.6 times higher for new users of warfarin than for new users of Pradaxa^®.”² and that “Pradaxa^® provides an important health benefit when used as directed.”²

Professor Klaus Dugi, Corporate Senior Vice President Medicine, Boehringer Ingelheim

“We are encouraged that this article in the New England Journal of Medicine provides important context about the safety of Pradaxa^®, reaffirming the findings from the landmark RE-LY^® trial and the important health benefit of Pradaxa^® when used as directed,” said Professor Klaus Dugi, Corporate Senior Vice President Medicine, Boehringer Ingelheim.

NOTES TO THE EDITORS

Dabigatran etexilate

Dabigatran etexilate was the first of a new generation of oral anticoagulants/direct thrombin inhibitors (DTIs)⁵ targeting a high unmet medical need in the prevention and treatment of acute and chronic thromboembolic diseases.

Potent antithrombotic effects are achieved with direct thrombin inhibitors by specifically blocking the activity of thrombin (both free and clot-bound), the central enzyme in the process responsible for clot (thrombus) formation. In contrast to vitamin-K antagonists, which variably act via different coagulation factors, dabigatran etexilate provides effective, predictable and consistent anticoagulation with a low potential for drug-drug interactions and no drug-food interactions, without the need for routine coagulation monitoring or dose adjustment.

Clinical experience of Pradaxa^® exceeds that of all other novel oral anticoagulants: It equates to over 1.4 million patient-years in all licensed indications and spans over 80 countries worldwide.⁶

One patient year equates to the treatment of a single patient over a whole year (365 days). The expression of clinical experience in patient years provides a more realistic assessment of experience with a treatment than the mere number of patients treated without relation to their individual treatment time.

The RE-LY^® trial

RE-LY^® (Randomized Evaluation of Long term anticoagulant therapY) was a global, phase III, PROBE (prospective, randomized, open-label with blinded endpoint evaluation) trial of 18,113 patients enrolled in over 900 centres in 44 countries designed to compare two fixed doses of the oral direct thrombin inhibitor dabigatran (110mg and 150mg bid) each administered in a blinded manner, with open label warfarin (INR 2.0-3.0, median TTR 67%⁷).^3,4 Patients were followed-up in the study for a median of 2 years with a minimum of 1 year follow-up.³

The primary endpoint of the trial was incidence of stroke (including haemorrhagic) or systemic embolism. Secondary outcome measures included all-cause death, incidence of stroke (including haemorrhagic), systemic embolism, pulmonary embolism, acute myocardial infarction, and vascular death (including death from bleeding).³

Compared to well controlled warfarin, dabigatran etexilate showed in the trial:^3,4

• Significant reduction in the risk of stroke and systemic embolism – including ischaemic strokes with dabigatran etexilate 150mg bid
• Similar rates of stroke/systemic embolism with dabigatran etexilate 110mg
• Significantly lower major bleeding events with dabigatran etexilate 110mg bid, similar rates with dabigatran etexilate 150 mg bid
• Significantly lower life threatening and intracranial bleeding with both doses
• Significant reduction in vascular mortality with dabigatran etexilate 150mg bid.

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References 

¹ Ross Southworth M, et al. Dabigatran and postmarketing reports of bleeding. New Eng J Med. 2013; DOI: DOI: 10.1056/NEJMp1302834. Available at: http://www.nejm.org
² Food and Drug Administration FDA Drug Safety Communication: Update on the risk for serious bleeding events with the anticoagulant Pradaxa. Viewed March 2013. Available at http://www.fda.gov/Drugs/DrugSafety/ucm326580.htm
³ Connolly SJ, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139-51.
⁴ Connolly SJ, et al. Newly identified events in the RE-LY® trial. N Engl J Med. 2010;363(19):1875-76.
⁵ Di Nisio M, et al. Direct thrombin inhibitors. N Engl J Med 2005;353:1028-40.
⁶ Boehringer Ingelheim data on file.