RELY-ABLE®: Unprecedented long-term data support safety profile and sustained efficacy of PRADAX® for stroke prevention in AF

• Presented at AHA's Scientific Sessions 2012, first long-term results from the RELY-ABLE® study demonstrate that advantages of PRADAX® (dabigatran etexilate) treatment are maintained over more than four years
• PRADAX® is the first and only novel oral anticoagulant supported by long-term clinical data
• Sustained benefits for both doses allow for persistent brain protection and tailored treatment according to patient needs

BURLINGTON, ON, Nov. 8, 2012 /CNW/ - Data from the *RELY-ABLE® study have provided additional data to support the long-term safety profile and efficacy of PRADAX® (dabigatran etexilate) for stroke prevention in patients with non-valvular atrial fibrillation (AF). ^**1 The new long-term results presented at the American Heart Association's (AHA) Scientific Sessions, are highly consistent with the findings from the landmark RE-LY® trial, the basis for the approval of PRADAX® in countries all over the world. The rates of stroke and hemorrhage observed during the 2.3 years of blinded follow-up in RELY-ABLE® correspond to the initial RE-LY® results, supporting the benefit of both doses of PRADAX® for tailored brain protection.^1-3

The combined data from RE-LY® and RELY-ABLE® equates to over four years of experience and provides the most comprehensive evaluation of the benefits and safety of any novel oral anticoagulant for stroke prevention in AF to date.¹

"Most patients with atrial fibrillation need life-long anticoagulant treatment to be protected from ischemic stroke. The unique long-term data we now have for dabigatran etexilate are reassuring for both patients and physicians," said RELY-ABLE® lead investigator Professor Stuart Connolly, Director of the Division of Cardiology at McMaster University, Hamilton, Ontario. "RELY-ABLE® shows that the results seen in RE-LY® continue to be observed during long-term follow up. We see similar rates of stroke or systemic embolism and similar rates of major bleeding with similar rates of intracerebral bleeding and intracranial hemorrhage."

*Data from RELY-ABLE® has not been reviewed by Health Canada

**Randomized Comparison of the Effects of Two Doses of Dabigatran Etexilate on Clinical Outcomes Over 4.3 Years: Results of the RELY-ABLE® Double-blind Randomized Trial. Lead author: Stuart J Connolly. CS.04. Clinical Science: Special Reports: Valvular Heart Disease, PAD, Atrial Fibrillation: International Perspectives

The international multi-centre RELY-ABLE® study followed 5,851 patients on PRADAX® for more than 27 months after completion of the RE-LY® trial.  It examined the long-term benefits of the two treatment doses (110mg bid and 150mg bid) in an ongoing randomized and blinded comparison.¹

The results from RELY-ABLE® support sustained dose benefits in the long-term use of PRADAX®:¹

• Rates of ischemic stroke
  1.13%/year on 150mg bid and 1.24%/year on 110mg bid
• Incidence of hemorrhagic stroke
  0.14%/year on the 150mg bid and 0.14%/year on 110mg bid
• Incidence of major bleeding
  3.74%/year on 150 mg bid and 2.99%/year on 110 mg bid
• Rates of intracranial bleeding
  0.33 %/year on the DE 150mg bid and 0.25%/year on DE 110mg bid ⁴

The consistent incidences of ischemic and hemorrhagic stroke as well rates of intracranial bleeding observed indicate that PRADAX® provides ongoing protection to the brain. Furthermore, both doses of PRADAX® had similar net clinical benefit and mortality rates.¹

"The results from the RELY-ABLE® study are consistent with the excellent results we have seen in the RE-LY® trial and strongly support the long-term safety profile and efficacy of PRADAX® for stroke prevention in atrial fibrillation," stated Professor Klaus Dugi, Corporate Senior Vice President Medicine, Boehringer Ingelheim. "Physicians can be confident in the sustained brain protection and treatment advantages offered by both doses of PRADAX®, and can tailor their treatment according to patient needs, as the first long-term clinical data for a novel oral anticoagulant show."

In the RE-LY® trial, PRADAX® 150mg bid is the only novel oral anticoagulant which has shown a significant reduction in the incidence of ischemic strokes in patients with non-valvular AF compared to warfarin, offering a relative risk reduction of 25 per cent.² In a study conducted by Hannon et al, nine out of 10 strokes caused by AF are ischemic strokes,⁵ which can result in significant disabilities, such as paralysis; loss of speech and understanding; effects on the memory, thought and emotional processes.⁶

Furthermore in RE-LY®, PRADAX® 150mg bid provided a 35 per cent reduction in the overall risk of stroke and systemic embolism versus warfarin (INR 2-3, median TTR 67 per cent)². PRADAX® 110mg bid, which is indicated for patients at higher risk for bleeding and/or for patients aged 80 years and older, was shown to be non-inferior compared to warfarin for the prevention of stroke and systemic embolism.^2,15 Both doses of PRADAX® were associated with significantly lower major and minor, intracranial and life-threatening bleeding compared to warfarin.² PRADAX® 150mg bid showed a similar risk of major bleeds versus warfarin.  PRADAX® 110mg bid additionally demonstrated significantly lower major bleeding compared to warfarin.^2,3

Clinical experience of PRADAX® in all licensed indications is well established and continues to grow, equating to over one million patient-years in all licensed indications worldwide in over 70 countries⁷ and exceeding that of all other novel oral anticoagulants.⁸

About AF and Stroke in Canada
Atrial fibrillation is an irregular heart rhythm known as an arrhythmia.⁹ While AF is rare in people under 40, its prevalence increases with age.⁹ In fact, after the age of 55, the incidence of AF doubles with each decade of life.¹⁰

Atrial fibrillation affects up to 350,000 Canadians.⁹ People with AF are three to five times more at risk of having a stroke than those without the condition.⁹   After age 60, one-third of all strokes are caused by AF.⁹ Strokes due to AF tend to be more severe and can cause greater disability.¹¹ Appropriate anticoagulation therapy can help to prevent many types of AF-related strokes and improve overall patient outcomes.¹²

About RELY-ABLE®¹
RELY-ABLE® (Long Term Multi-center Extension of Dabigatran Treatment in Patients with Atrial Fibrillation) was designed to provide additional information on the long-term safety and efficacy of the two doses of dabigatran etexilate in patients who had completed RE-LY®. Enrolled patients continued to receive the same double-blind dose with 2,937 patients on dabigatran 150 mg bid and 2,914 patients on dabigatran 110 mg bid. Patients randomized to warfarin in RE-LY® were not eligible for RELY-ABLE®.

Patients continuing in RELY-ABLE® differed in several respects from those who did not. Continuing patients were more likely to have permanent AF and less likely to have heart failure during the RE-LY® trial.

The primary outcomes were the occurrence of major ischemic and hemorrhagic stroke, as well as death and net clinical benefit (composite of all major ischemic, hemorrhagic and fatal outcomes).

• Both doses of dabigatran etexilate showed low rates of ischemic and hemorrhagic strokes
• Major bleeding rates were lower with the 110 mg bid dose versus the 150mg bid dose
• Net clinical benefits and low mortality rates were consistent between doses

Overall the results from RELY-ABLE® were highly consistent with the event rates experienced during the RE-LY® trial, providing support for the sustained efficacy and safety of dabigatran etexilate during long-term treatment.

About RE-LY®
The RE-LY® (Randomized Evaluation of Long term anticoagulant therapY) study was a global, Phase III, randomized trial of 18,113 patients¹³, enrolled in over 950 centres in 44 countries, including 52 centres in Canada and 1,150 Canadian patients,¹⁴ investigating whether dabigatran etexilate (two blinded doses) was as effective as well-controlled warfarin - INR 2.0 - 3.0 - (open label) for stroke prevention.¹³

Patients with non-valvular AF and at least one other risk factor for stroke (i.e., previous ischemic stroke, transient ischemic attack, or systemic embolism, left ventricular ejection fraction 40%, symptomatic heart failure, ≥ 75 years, ≥ 65 with either diabetes (on treatment), history of coronary artery disease, or hypertension requiring treatment)¹³ were enrolled in the study for two years with a minimum follow-up period of one year.¹³

The RE-LY® trial utilized the established PROBE (prospective, randomized, open-label, blinded endpoint evaluation) clinical trial protocol,¹³ which has been used in the majority of previous trials of anticoagulation for stroke prevention in patients with AF. A PROBE design is more reflective of the differences in the management of warfarin and dabigatran in clinical practice and it is reflective of the standard of care for patients.

About dabigatran etexilate (PRADAX®)
PRADAX® is a novel, reversible oral direct thrombin inhibitor. It provides its anticoagulant effect by selectively blocking the activity of thrombin, the central enzyme in clot formation. ^15,16

The Canadian approval of PRADAX® for stroke prevention in atrial fibrillation is based on data from the landmark RE-LY® Trial (Randomized Evaluation of Long term anticoagulant therapY) published in 2009 the New England Journal of Medicine.² The study population included patients with high, moderate, and low risk of stroke. PRADAX® 150 mg twice-daily was proven to be more effective than warfarin at preventing strokes in AF patients, with comparable safety.²

Specifically, PRADAX® 150 mg twice-daily significantly reduced the risk of stroke and systemic embolism by 35 per cent versus warfarin, (p=0.0001) without increasing the risk of major bleeding, and reducing the risk of intracranial bleeding by 59 per cent (p0.0001).² In addition, PRADAX® 150 mg twice-daily statistically significantly reduces ischemic and hemorrhagic stroke better than well-controlled warfarin.²  

The adverse events reported in the RE-LY® trial that were significantly more common with dabigatran etexilate than with warfarin were gastrointestinal (GI) disorders, such as abdominal pain, diarrhea, dyspepsia and nausea.¹⁵ In patients with atrial fibrillation treated for the prevention of stroke and systemic embolism, the co-administration of oral anti-platelet (including aspirin and clopidogrel) and NSAID therapies increases the risk of bleeding, by about two-fold.¹⁵ This higher rate of bleeding events by ASA or clopidogrel co-medication was, however, also observed for warfarin. Close clinical surveillance (looking for signs of bleeding or anaemia) is recommended throughout the treatment.¹⁵

Health Canada has approved the 150mg dose of PRADAX® to be taken twice-daily for prevention of stroke and systemic embolism in patients with atrial fibrillation in whom anti-coagulation is appropriate. The 110mg dose has been recommended for use in patients 80 years of age or older and may be considered for patients at higher risk of bleeding.¹⁵

PRADAX® was first approved in 2008 for the prevention of venous thromboembolic events (VTE) in patients who have undergone elective total hip replacement or total knee replacement surgery.  In 2010, it was then approved for the prevention of stroke and systemic embolism in patients with atrial fibrillation, in whom anticoagulation is appropriate. ¹⁵ In the RE-LY® trial, all clinical outcomes were adjudicated in a blinded manner to minimize bias in assessment of outcomes for each treatment.¹³

About Boehringer Ingelheim (Canada) Ltd.
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 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 endeavours.

In 2011, Boehringer Ingelheim posted net sales of 13.2 billion euro while spending almost 24% of net sales in its largest business segment Prescription Medicines on research and development.

The Canadian headquarters of Boehringer Ingelheim was established in 1972 in Burlington, Ontario, Canada. Boehringer Ingelheim (Canada) Ltd. is home to more than 750 employees including 170 scientists across the country.

For more information please visit www.boehringer-ingelheim.ca

References:

1. Connolly SJ, et al. Randomized Comparison of the Effects of Two Doses of Dabigatran Etexilate on Clinical Outcomes Over 4.3 Years: Results of the RELY-ABLE Double-blind Randomized Trial. CS.04. Clinical Science: Special Reports: Valvular Heart Disease, PAD, Atrial Fibrillation: International Perspectives.  Presented on 7 November 2012 at the American Heart Association Scientific Sessions 2012.
2. Connolly SJ, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139-51.
3. Connolly SJ, et al. Newly identified events in the RE-LY trial. N Engl J Med. 2010;363:1875-6.
4. Boehringer Ingelheim Data on File. The Long Term Multi-Center Extension of Dabigatran Treatment in Patients with Atrial Fibrillation (RELY-ABLE) study. November 2012
5. Hannon, N., et al. "Stroke Associated with Atrial Fibrillation - Incidence  and Early Outcomes in the North Dublin Population Stroke Study." Cerebrovascular Diseases. 2010;29:43-49.
6. National Institute of Disorders and Stroke http://www.ninds.nih.gov/disorders/stroke/poststrokerehab.htm: July 2011 Last accessed June 15, 2012.
7. Boehringer Ingelheim Data on File. Prevented Stroke With Pradaxa. July 30th, 2011
8. Eikelboom JW. et al. Does dabigatran improve stroke-prevention in atrial fibrillation? Reply to a rebuttal. J Thromb Haemost. 2010;8:1438-9.
9. http://www.heartandstroke.on.ca/site/c.pvI3IeNWJwE/b.3581877/k.A37/Stroke__Heart_disease__atrial_fibrillation.htm Last accessed June 15, 2012
10. http://www.heartandstroke.on.ca/site/c.pvI3IeNWJwE/b.3581729/k.359A/Statistics.htm Last accessed June 15, 2012
11. Kimura, K, Minematsu K, et al. Atrial fibrillation as a predictive factor for severe stroke and early death in 15,831 patients with actue ischaemic stroke. J Neurol Neurosurg Psychiatry 2005;76:679-683.
12. Hart RG, et al. Meta-analysis: Antithrombotic Therapy to Prevent Stroke in Patients Who Have Nonvalvular Atrial Fibrillation Ann Intern Med. 2007;146:857-67.
13. Ezekowitz MD, et al. Rationale and Design of RE-LY®: Randomized Evaluation of Long-Term Anticoagulation Therapy, Warfarin, Compared with Dabigatran. American Heart Journal 2009; 157:805-810.
14. Data on file at Boehringer Ingelheim.
15. PRADAX Product Monograph. July 6, 2012.
16. Van Ryn J, Hauel, N, Waldmann L. et al. Dabigatran inhibits both clot-bound and fluid-phase thrombin in vitro: comparison to heparin and hirudin. 2008 ATVB Oral Presentations (P570). Arterioscler Thromb Vasc Biol 2008; 28:el36-7

Video with caption: "RELY-ABLE Data Presentation by Dr. Stuart Connolly (Data from RELY-ABLE® has not been reviewed by Health Canada)". Video available at: http://stream1.newswire.ca/cgi-bin/playback.cgi?file=20121108_C5862_VIDEO_EN_20372.mp4&posterurl=http://photos.newswire.ca/images/20121108_C5862_PHOTO_EN_20372.jpg&clientName=Boehringer%20Ingelheim%20%28Canada%29%20Ltd%2E&caption=RELY%2DABLE%20Data%20Presentation%20by%20Dr%2E%20Stuart%20Connolly%20%28Data%20from%20RELY%2DABLE%26%23174%3B%20has%20not%20been%20reviewed%20by%20Health%20Canada%29&title=BOEHRINGER%20INGELHEIM%20%28CANADA%29%20LTD%2E%20%2D%20RELY%2DABLE%26%23174%3B%3A%20Unprecedented%20long%2Dterm%20data%20confirm%20favourable%20safety%20profile%20and%20sustained%20efficacy%20of%20PRADAX%26%23174%3B%20for%20stroke%20prevention%20in%20AF&headline=RELY%2DABLE%26%23174%3B%3A%20Unprecedented%20long%2Dterm%20data%20support%20safety%20profile%20and%20sustained%20efficacy%20of%20PRADAX%26%23174%3B%20for%20stroke%20prevention%20in%20AF

SOURCE: Boehringer Ingelheim (Canada) Ltd.

For further information:

Sara McClelland
Boehringer Ingelheim (Canada) Ltd.
905-631-4713

Jeanelle Frampton
Environics Communications
416-969-2670
[e-mail]