First novel blood thinner in 50 years for the prevention of strokes caused by common heart rhythm disorder, approved in Europe

Pradaxa® (dabigatran etexilate) could transform millions of lives of Europeans with atrial fibrillation at risk of stroke
ngelheim, Germany, 4 August 2011 – The European Commission (EC) today approved Boehringer Ingelheim’s oral blood thinner, Pradaxa® 1 (dabigatran etexilate 2), for the prevention of strokes in people with atrial fibrillation (AF), the most common sustained heart rhythm disorder. Millions of AF patients across Europe could now benefit from this new drug being seen as the biggest step forward in blood thinning treatments approved for stroke prevention for over 50 years. The EC has approved the use of dabigatran etexilate in the EU for the prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation with one or more risk factors.

One in four adults over the age of 40 develop AF in their lifetime, resulting in 4.5 million people suffering from AF in Europe. 3,4 AF patients have a five times increased risk of suffering a stroke, resulting in three million people worldwide having AF-related strokes each year. 3-8 Patients with AF have been shown to have a worse quality of life than for example patients who have previously suffered a heart attack, due in part to the constant fear of suffering a stroke. 9

Trudie Lobban, CEO of the Atrial Fibrillation Association commented, "AF is a major risk factor for stroke as it allows pooling of blood in the heart, causing blood clots to form. By travelling up to the vessels in the brain and blocking them, these clots can cause a stroke. Strokes from AF are particularly devastating as the clots are often very big, obstructing large vessels of the brain. This leads to greater disability, such as more severe loss of muscle function or loss of speech."
For over 50 years, the standard of care, to prevent patients with AF from strokes, has been vitamin K antagonists, like warfarin. Whilst effective, they have many limitations such as the need for regular monitoring and various food-drug and drug-drug interactions 10, resulting in only half of eligible patients receiving warfarin 11 and fewer than half of these patients being controlled within the desired therapeutic range. 12
In 2008, dabigatran etexilate was granted EU approval for the primary prevention of venous thromboembolic events (blood clots) in adults who have undergone elective total hip or elective total knee replacement surgery. Speaking about the new EU label extension for the prevention of stroke in patients with AF, Professor Gregory Lip, Consultant Cardiologist & Professor of Cardiovascular Medicine, University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Birmingham, United Kingdom, added, "Dabigratran etexilate is a major medical advance and its approval in Europe will be a huge opportunity for a great improvement in stroke prevention in atrial fibrillation. Finally, physicians in Europe have an effective and convenient option to provide anticoagulation therapy, which also has a good safety profile."
The approval of dabigatran etexilate for stroke prevention in AF patients is based on results from RE-LY®, one of the largest studies ever conducted in AF including over 18,000 patients.
The results for the 150mg twice daily dose showed dabigatran etexilate prevented 35% more strokes and systemic embolism than warfarin, while also significantly reducing the risk of bleeding into the brain (intracranial bleeds), a feared side-effect of warfarin. 13-15 The 110mg dose was shown to be as effective as warfarin in preventing strokes and systemic embolism and had a lower rate of major bleeding than warfarin. The RE-LY® trial had a PROBE (prospective, randomized, open-label with blinded endpoint evaluation) design, comparing two fixed doses of the oral direct thrombin inhibitor dabigatran etexilate (110mg and 150mg bid) each administered in a blinded manner, with open label warfarin. 13-15
Dabigatran etexilate does not require the frequent blood monitoring and dose changes, which make therapy with warfarin so challenging, is not affected by food and has a low potential for drug-drug interactions. 1,16-21
In addition to the label extension in Europe, dabigatran etexilate has already been approved for the prevention of stroke in atrial fibrillation in the US, Canada, Japan, Australia and several other countries across four continents. 1,22-25
"The European approval of dabigatran etexilate for the prevention of stroke and systemic embolism is another important step towards making this breakthrough treatment available to atrial fibrillation patients at risk of stroke around the world and helping to reduce the immense suffering caused by atrial fibrillation related strokes," said Professor Andreas Barner, Chairman of the Board of Managing Directors, Boehringer Ingelheim. "It is the result of nearly 20 years of research and development by our scientists. We will now ensure that this new breakthrough treatment is made available to physicians and atrial fibrillation patients throughout Europe as soon as possible."
About AF and stroke 
AF is the most common sustained heart rhythm condition, 26 affecting up to 70 million people worldwide, with one in four adults over the age of 40 developing the condition in their lifetime, rising to 10% in people over the age of 80. 3,4 Prevalence of AF is predicted to double by 2050, making the effective management of the condition a healthcare priority. 27 People with AF are more likely to experience blood clots, which increases the risk of stroke by five-fold. 3,4 Up to three million people worldwide suffer strokes related to AF each year, 5-8 which are typically severe and disabling, with one half of this population dying within one year. 28 Strokes due to AF tend to be severe, with an increased likelihood of death (20%), and disability (60%). 28 Many AF-related strokes can be prevented with appropriate antithrombotic therapy. 10,29
About RE-LY® 
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 blood thinner dabigatran (110mg and 150mg twice daily) each administered in a blinded manner, with well controlled (INR 2.0-3.0, median TTR 67%) open label warfarin. 13-15 Patients were followed-up in the study for a median of 2 years with a minimum of 1 year follow-up. 13,14
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 (blood clot in the lung), acute myocardial infarction (heart attack), and vascular death (including death from bleeding).
The results showed the following in patients with AF at risk of stroke: 13,14
    •    Dabigatran etexilate 150mg given twice daily prevented three out of four AF-related strokes, preventing 35% more strokes than current standard of care, warfarin. 10,13,14
    •    Dabigatran etexilate 110mg twice daily prevented similar levels of stroke to warfarin.
    •    Risk of bleeding into the brain (intracranial bleeds), a common and life-threatening side effect of warfarin, was reduced by nearly 60 per cent (59%) by dabigatran etexilate 150mg twice daily compared to warfarin.
    •    Dabigatran etexilate 150mg twice daily reduced the risk of death from vascular causes such as strokes.
About dabigatran etexilate 
Dabigatran etexilate is at the forefront of a new generation of oral blood thinning treatments, which prevent blood clots forming in the body that can cause devastating strokes in patients with atrial fibrillation.
Unlike warfarin, 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. 1,16-21
Dabigatran etexilate has already been approved for stroke risk reduction in patients with AF in the US, Canada, Japan, Australia and several other countries across four continents. 22-25 Details of these approvals may however differ from the label recommended by the EMA. 
It has also been approved for the primary prevention of venous thromboembolic events (blood clots) in adults who have undergone elective total hip or elective total knee replacement surgery in over 80 countries under the trademark Pradaxa® (in Canada: Pradax®, in Japan: Prazaxa®).
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 42,000 employees. Since it was founded in 1885, the family-owned company has been committed to researching, developing, manufacturing and marketing novel products 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 2010, Boehringer Ingelheim posted net sales of about 12.6 billion euro while spending almost 24% of net sales in its largest business segment Prescription Medicines on research and development.
Please be advised 
This release is from Boehringer Ingelheim Corporate Headquarters in Germany. Please be aware that there may be national differences between countries regarding specific medical information, including licensed uses. Please take account of this when referring to the information provided in this document. This press release is not intended for distribution within the USA or Canada.
* Previous stroke, transient ischemic attack, or systemic embolism (SEE); Left ventricular ejection fraction < 40 %; Symptomatic heart failure, ≥New York Heart Association (NYHA) Class 2; Age ≥75 years; Age ≥65 years associated with one of the following: diabetes mellitus, coronary artery disease, or hypertension.
1. Pradaxa®, Summary of Product Characteristics, 2011. Europe. 
2. Di Nisio M, et al. Direct Thrombin Inhibitors. N Engl J Med 2005; 353:1028-40. 
3. Lloyd-Jones DM, Wang TJ, Leip EP, et al. Lifetime risk for development of atrial fibrillation: the Framingham Heart Study. Circulation 2004; 110:1042-6. 
4. Fuster V, Rydn LE, Cannom DS, et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients with Atrial Fibrillation – executive summary. Circulation 2006; 114:700-52. 
5. Kannel WB, et al. Final Draft Status of the Epidemiology of Atrial Fibrillation. Med Clin North Am. 2008; 92(1): 17–40. 
6. Atlas of Heart Disease and Stroke, World Health Organization, September 2004. Viewed Dec 2010 at 
7. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 1991: 22(8);983-8. 
8. Marini C, De Santis F, Sacco S, et al. Contribution of atrial fibrillation to incidence and outcome of ischaemic stroke: results from a population-based study. Stroke 2005; 36:1115-9. 
9. Dorian P et al. The impairment of health-related quality of life in patients with intermittent atrial fibrillation: implications for the assessment of investigational therapy. J Am Coll Cardiol 2000; 36: 1303–9. 
10. Hart RG et al. Meta-analysis: Antithrombotic Therapy to Prevent Stroke in Patients Who Have Nonvalvular Atrial Fibrillation. Ann Intern Med 2007; 146: 857-867. 
11. Hylek EM, D’Antonio J, Evans-Molina C, et al. Translating the results of randomized trials into clinical practice. The challenge of warfarin candidacy among hospitalized elderly patients with atrial fibrillation. Stroke 2006; 37:1075-80. 
12. Samsa GP, Matchar DB, Goldstein LB, et al. Quality of anticoagulation management among patients with atrial fibrillation: results of a review of medical records from 2 countries. Arch Intern Med 2000; 160: 967-73. 
13. Connolly SJ, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361:1139-51. 
14. Connolly SJ, Ezekowitz MD, Yusuf S, Reilly PA, Wallentin L. Newly identified events in the RE-LY® trial. N Engl J Med 2010; 363(19): 1875-1876. 
15. FDA Advisory Committee Briefing Document, September 2010. Committee/UCM226009.pdf. 
16. Stangier J, et al. The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects. Br J Pharmacol 2007;64:292-303. 
17. Stangier J. Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate. Clin Pharmacokinet 2008;47:285–95. 
18. Stangier J, et al. Pharmacokinetics and pharmacodynamics of the direct oral thrombin inhibitor dabigatran in healthy elderly subjects. Clin Pharmacokinet 2008;28:47-59. 
19. Blech S, Ebner T, Ludwig-Schwellinger E, et al. The metabolism and disposition of the oral direct thrombin inhibitor, dabigatran, in humans. Drug Metab Dispos 2008;36:386–99. 
20. Stangier J, et al. Coadministration of dabigatran etexilate and atorvastatin: assessment of potential impact on pharmacokinetics and pharmacodynamics. Am J Cardiovasc Drugs 2009;9:59-68. 
21. Stangier J, Eriksson BI, Dahl OE, et al. Pharmacokinetic profile of the oral direct thrombin inhibitor dabigatran etexilate in healthy volunteers and patients undergoing total hip replacement. J Clin Pharmacol 2005;45:555–63. 
22. U.S. Food and Drug Administration – Pradaxa® Prescribing Information. Oct 19th, 2010. 
23. Health Canada – PRADAX™ Product Monograph. Oct 26th, 2010. 
24. Prazaxa® product information, January 2011, Japan. 
25. Pradaxa® product information, April 2011. Australia. 
26. Stewart S, Murphy N, Walker A, et al. Cost of an emerging epidemic: an economic analysis of atrial fibrillation in the UK. Heart 2004; 90:286-92. 
27. Miyasaka Y, et al. Secular trends in incidence of atrial fibrillation in Olmsted County, Minnesota 1980 to 2000, and implications on the projections for future prevalence. Circulation 2006; 114:119-125. 
28. Lin HJ, Wolf PA, Kelly-Hayes M, et al. Stroke severity in atrial fibrillation: the Framingham study. Stroke 1996; 27:1760-4. 
29. Hart RG, Benavente O, McBride R, Pearce LA. Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: a meta-analysis. Ann Intern Med 1999; 131:492-501.