FDA perspective published in the New England Journal of Medicine reinforces safety of Pradaxa® (dabigatran etexilate)

Boehringer IngelheimA new perspective from the U.S. Food and Drug Administration (FDA) published in the New England Journal of Medicine(1) 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)

"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.

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 bid
  • 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.

Stroke Prevention in Atrial Fibrillation AF is the most common sustained heart rhythm condition(8), with one in four adults over the age of 408 developing the condition in their lifetime. People with AF are more likely to experience blood clots, which increases the risk of stroke by five-fold.(9) Up to three million people worldwide suffer strokes related to AF each year.(10,11) Strokes due to AF tend to be severe, with an increased likelihood of death (20%), and disability (60%).(12)

Ischaemic strokes are the most common type of AF-related stroke, accounting for 92% of strokes experienced by AF patients and frequently leading to severe debilitation.(13) Appropriate anticoagulation therapy can help to prevent many types of AF-related strokes and improve overall patient outcomes.(14) Pradaxa® 150mg bid is the only novel oral anticoagulant, for which its pivotal trial vs. warfarin has shown a statistically significant and clinically relevant reduction of both ischaemic and haemorrhagic strokes.(3,4) Additionally, treatment with Pradaxa® is associated with >2-fold lower rates of both fatal and non-fatal intracranial haemorrhage, one of the most devastating complications of anticoagulation therapy.(15,16)

Worldwide, AF is an extremely costly public health problem, with treatment costs equating to $6.65 billion in the US and over €6.2 billion across Europe each year.(17,18) Given AF-related strokes tend to be more severe, this results in higher direct medical patient costs annually.19 The total societal burden of AF-related stroke reaches €13.5 billion per year in the European Union alone.(20)

About Boehringer Ingelheim
The Boehringer Ingelheim group is one of the world's 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, it operates globally with 145 affiliates and more than 44,000 employees. Since it was founded in 1885, the family-owned company has been committed to researching, developing, manufacturing and marketing novel medications of high therapeutic value for human and veterinary medicine.

As a central element of its culture, Boehringer Ingelheim pledges to act socially responsible. Involvement in social projects, caring for employees and their families, and providing equal opportunities for all employees form the foundation of the global operations. Mutual cooperation and respect, as well as environmental protection and sustainability are intrinsic factors in all of Boehringer Ingelheim's endeavors.

In 2011, Boehringer Ingelheim achieved net sales of about 13.2 billion euro. R&D expenditure in the business area Prescription Medicines corresponds to 23.5% of its net sales.

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.
7. Pradaxa ®European Summary of Product Characteristics. Available at: http://www.emea.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000829/WC500041059.pdf
8. Lloyd-Jones DM, et al. Lifetime risk for development of atrial fibrillation: the Framingham Heart Study. Circulation. 2004;110:1042-6.
9. Camm JA, et al. 2012 focussed update of the ESC Guidelines for the management of atrial fibrillation. European Heart Journal. 2012;33:2719-41.
10. Atlas of Heart Disease and Stroke, World Health Organization, September 2004. Viewed March 2013 at http://www.who.int/cardiovascular_diseases/en/cvd_atlas_15_burden_stroke.pdf
11. Camm JA, et al. Guidelines for the management of atrial fibrillation. European Heart Journal. 2010;31:2369–429
12. Gladstone DJ, et al. Potentially Preventable Strokes in High-Risk Patients With Atrial Fibrillation Who Are Not Adequately Anticoagulated. Stroke. 2009;40:235-240.
13. Andersen KK, et al. Hemorrhagic and ischemic strokes compared: stroke severity, mortality, and risk factors. Stroke. 2009;40:2068−72.
14. Aguilar MI, Hart R. Oral anticoagulants for preventing stroke in patients with non-valvular atrial fibrillation and no previous history of stroke or transient ischemic attacks. Cochrane Database of Systematic Reviews. 2005, Issue 3. Art. No.: CD001927.
15. Hart RG, et al. Intracranial hemorrhage in atrial fibrillation patients during anticoagulation with Warfarin or Dabigatran: The RE-LY® Trial. Stroke. 2012;43(6):1511-17.
16. Fang MC, et al. Death and disability from warfarin-associated intracranial and extracranial hemorrhages. Am J Med. 2007;120:700–5.
17. Coyne KS, et al. Assessing the direct costs of treating nonvalvular atrial fibrillation in the United States. Value Health 2006;9:348-56.
18. Ringborg A, et al. Costs of atrial fibrillation in five European countries: results from the Euro Heart Survey on atrial fibrillation. Europace 2008;10:403-11.
19. Brüggenjürgen B, et al. The impact of atrial fibrillation on the cost of stroke: the Berlin acute stroke study. Value Health 2007;10:137-43.
20. Fuster V, et al. ACC/AHA/ESC 2006 Guidelines for the management of patients with atrial fibrillation – executive summary. Circulation. 2006;114:700-52.

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