Pradaxa® (dabigatran etexilate) now approved in more than 100 countries for stroke prevention in atrial fibrillation

Boehringer IngelheimMore than 100 countries have now approved Boehringer Ingelheim's Pradaxa® for the prevention of stroke and systemic embolism for adult patients with the most common sustained heart rhythm condition (non-valvular atrial fibrillation, nvAF).(1) The 100th approval was announced by the Jordan Food and Drug Administration. Further regulatory approvals for Pradaxa® are expected to be received in the near future. The continuous flow of regulatory approvals from health authorities all over the world reaffirms the overarching benefits delivered to patients by the treatment and supports previous announcements by the U.S. Food and Drugs Administation (FDA) and the European Medicines Agency (EMA).(2,3) Pradaxa®, in addition, offers the most robust clinical data set and the longest real-world experience for stroke prevention in atrial fibrillation (SPAF) compared to any of the novel oral anticoagulants, providing ongoing support for physician use of the novel treatment.(4-14)

The efficacy and safety profile of Pradaxa® was established in the RE-LY® trial, one of the largest stroke prevention clinical studies ever conducted in patients with AF.(5,6,i) Pradaxa® 150mg bid is the only novel oral anticoagulant, study of which has shown a significant reduction in the incidence of ischaemic strokes in patients with non-valvular AF compared to warfarin, offering a relative risk reduction of 25 percent.(5,6)

With over nine out of ten strokes suffered by patients with AF being of ischaemic type,(15) protection against ischaemic stroke is the key clinical benefit that should be achieved by anticoagulant treatment.(16,17) Ischaemic strokes associated with AF are often fatal, and those patients who survive are on average left more disabled by their stroke and have a higher likelihood of stroke recurrence than patients with other causes of stroke.(18,19)

"Passing the landmark 100th approval of Pradaxa® for stroke prevention and with still more on the horizon, we come close to saying that this novel treatment can benefit patients around the world," commented Professor Klaus Dugi, Corporate Senior Vice President Medicine, Boehringer Ingelheim. "The regulatory approval achieved in Jordan, in addition to those achieved with 100 other health authorities around the world, speaks volumes. This is a reflection of the breadth of benefits that Pradaxa® offers to AF patients, including superior protection against ischaemic stroke compared to warfarin."

Boehringer Ingelheim led the anticoagulant field by bringing Pradaxa®, the first NOAC for stroke prevention in atrial fibrillation, to market.(20) Pradaxa® is the only novel oral anticoagulant with more than 6 years of long-term data supporting its beneficial role in this patient population,(4) in addition to over 2.7 million patient-years of clinical experience in all licensed indications to date,(1) making Pradaxa® the leading novel oral anticoagulant.

In November 2013, Boehringer Ingelheim announced plans to initiate two large, global clinical trials evaluating Pradaxa's efficacy and safety in stroke prevention therapy in two clinically highly relevant conditions. The RE-SPECT ESUS™ trial will investigate the efficacy and safety of dabigatran etexilate in patients whose first stroke was of embolic origin with unknown source (ESUS). The RE-DUAL PCI™ trial will evaluate the efficacy and safety of dabigatran etexilate in patients with non-valvular atrial fibrillation (NVAF) who have undergone percutaneous coronary intervention (PCI), also known as angioplasty, with stenting. The trials are scheduled to begin enrolment in mid-2014 and early 2015, respectively, and will form part of the extensive RE-VOLUTION® clinical trial programme.

A large programme to gather real world data in clinical practice, the GLORIA™-AF Registry Program is running as one of the largest registries in newly diagnosed patients with irregular heart beat (non-valvular atrial fibrillation) at risk for stroke. GLORIA™-AF is designed to investigate patient characteristics influencing choice of antithrombotic treatment for stroke prevention in atrial fibrillation and to assess the relative long-term effectiveness and safety of Pradaxa® (dabigatran etexilate) vs. warfarin. It is expected to provide meaningful knowledge on the global role and use of antithrombotic treatments for stroke prevention in patients with NVAF across different regions of the world.(21)

About Pradaxa® (dabigatran etexilate)
Clinical experience of Pradaxa® (dabigatran etexilate) exceeds that of all other novel oral anticoagulants, equating to over 2.7 million patient-years in all licensed indications worldwide.(1) Pradaxa® has already been in the market for more than 5 years and is approved in over 100 countries.(1) Currently approved indications for Pradaxa® are:(20)

  • Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (AF) and a risk factor for stroke
  • Primary prevention of venous thromboembolic events in patients undergoing elective total hip replacement surgery
  • Primary prevention of venous thromboembolic events in patients undergoing elective total knee replacement surgery

In June 2013 Boehringer Ingelheim started submitting new applications to regulatory authorities for Pradaxa® for the following indications:(1)

  • Treatment of acute deep vein thrombosis (DVT) and/or pulmonary embolism (PE) and prevention of related death
  • Prevention of recurrent deep vein thrombosis (DVT) and/or pulmonary embolism (PE) and related death

For the treatment of DVT and PE, Pradaxa® has been approved in Ecuador, Mexico, the Philippines and Colombia. Additional registration processes continue in individual markets.(20)

Pradaxa®, a direct thrombin inhibitor (DTI), was the first widely approved drug in a new generation of direct oral anticoagulants, available to target a high unmet medical need in the prevention and treatment of acute and chronic thromboembolic diseases.(22,23) Potent antithrombotic effects are achieved with direct thrombin inhibitors by specifically blocking the activity of thrombin, the central enzyme in the process responsible for clot (thrombus) formation.(24) In contrast to vitamin-K antagonists, which variably act via different coagulation factors, Pradaxa® provides effective, predictable and reproducible anticoagulation with a low potential for drug-drug interactions and no drug-food interactions, without the need for routine coagulation monitoring or dose adjustment.(22,24)

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 140 affiliates and more than 46,000 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.

Social responsibility is a central element of Boehringer Ingelheim's culture. 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 endeavours.

In 2012, Boehringer Ingelheim achieved net sales of about 14.7 billion euro. R&D expenditure in the business area Prescription Medicines corresponds to 22.5% of its net sales.

1. Boehringer Ingelheim data on file
2. European Medicines Agency Press release - 25 May 2012: EMA/337406/2012. European Medicines Agency updates patient and prescriber information for Pradaxa. http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2012/05/news_detail_001518.jsp&mid=WC0b01ac058004d5c1 Last accessed 6 August 2013.
3. FDA Drug Safety Communication: Update on the risk for serious bleeding events with the anticoagulant Pradaxa (dabigatran) - 2 November 2012 http://www.fda.gov/Drugs/drugsafety/ucm326580.htm Last accessed 6 August 2013.
4. Ezekowitz MD, et al. RE-LY and RELY-ABLE Long-term Follow-up of Patients with Non-valvular Atrial Fibrillation Receiving Dabigatran Etexilate for up to 6.7 Years. Oral Presentation #10684 on Monday 18 November 2013 at the American Heart Association Scientific Sessions, Dallas, Texas, USA.
5. Connolly SJ, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139-51.
6. Connolly SJ, et al. Newly identified events in the RE-LY trial. N Engl J Med. 2010;363:1875-6.
7. Connolly SJ, et al. The Long Term Multi-Center Extension of Dabigatran Treatment in Patients with Atrial Fibrillation (RELY-ABLE) study. Circulation. 2013;128:237-43.
8. Eriksson BI, et al. Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial. Lancet. 2007;370:949–56.
9. Eriksson BI, et al. Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty (RE-NOVATE II*). A randomised, doubleblind, non-inferiority trial. Thromb Haemost. 2011;105:721-9.
10. Eriksson BI, et al. Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial. Thromb Haemost. 2007;5:2178–85.
11. Ginsberg JS, et al. Oral thrombin inhibitor dabigatran etexilate vs North American enoxaparin regimen for prevention of venous thromboembolism after knee arthroplasty surgery. J Arthoplasty. 2009;24:1–9.
12. Schulman S, et al. Dabigatran versus warfarin in the Treatment of Acute Venous Thromboembolism. N Engl J Med. 2009;361:2342–52.
13. Schulman S, et al. A randomized trial of dabigatran versus warfarin in the treatment of acute venous thromboembolism (RE-COVER II). Oral presentation from Session 332: Antithrombotic Therapy 1. Presented on 12 December at the American Society of Hematology (ASH) Annual Meeting 2011.
14. Schulman S, et al. Extended use of dabigatran, warfarin or placebo in venous thromboembolism. N Engl J Med. 2013;368:709–18.
15. Andersen KK, et al. Hemorrhagic and ischemic strokes compared: stroke severity, mortality, and risk factors. Stroke. 2009;40(6):2068-72.
16. Marini C, et al. From a Population-Based Study Contribution of Atrial Fibrillation to Incidence and Outcome of Ischemic Stroke: Results From a Population-Based Study. Stroke. 2005;36:1115-9.
17. 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 Syst Rev. 2005;(3):CD001927.
18. Gladstone DJ, et al. Potentially Preventable Strokes in High-Risk Patients With Atrial Fibrillation Who Are Not Adequately Anticoagulated. Stroke. 2009;40(1):235-40.
19. Marini C, et al. Contribution of Atrial Fibrillation to Incidence and Outcome of Ischemic Stroke: Results: From a Population-Based Study. Stroke. 2005;36:1115-9.
20. Pradaxa® European Summary of Product Characteristics, 2013.
21. GLORIA-AF Registry. Registry objectives. https://www.gloria-af.com/public/about-objectives.html Last accessed 18 February 2014.
22. Stangier J. Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate. Clin Pharmacokinet. 2008;47(5):285–95.
23. Di Nisio M, et al. Direct thrombin inhibitors. N Engl J Med. 2005;353:1028–40.
24. Stangier J, et al. Pharmacokinetic Profile of the Oral Direct Thrombin Inhibitor Dabagitran Etexilate in Healthy Volunteers and Patients Undergoing Total Hip Replacement. J Clin Pharmacol. 2005;45:555–63.

i RE-LY® was a global, phase III, PROBE (prospective, randomized, open-label with blinded endpoint evaluation) design trial comparing two fixed doses of the oral direct thrombin inhibitor Pradaxa® (110mg and 150mg bid) each administered in a blinded manner, with open label warfarin.

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