For U.S. Media Only

RE-LY Trial Met Primary Outcome for Reducing Incidence of Stroke or Systemic Embolism in Non-valvular Atrial Fibrillation Patients

• Study compared two doses (110mg BID and 150mg BID dabigatran etexilate) to warfarin titrated to INR 2.0 to 3.0¹
• Both doses were non-inferior to warfarin for the primary outcome²
• 150mg BID dose reduced the incidence of stroke by 34% (p<0.001 for superiority) compared to warfarin²
  

Ridgefield, CT, August 30, 2009 - Boehringer Ingelheim today announced that results from the RE-LY^® (Randomized Evaluation of Long-Term Anticoagulant Therapy, Warfarin, Compared with Dabigatran) study - the largest atrial fibrillation (AF) outcomes trial ever conducted¹ (18,113 patients in 44 countries worldwide) – were presented for the first time at the European Society of Cardiology Congress and published online in the New England Journal of Medicine.² The primary objective of RE-LY was to assess the safety and efficacy of the investigational oral direct thrombin inhibitor, dabigatran etexilate against warfarin (titrated to INR 2.0 to 3.0) for the prevention of stroke in patients with non-valvular atrial fibrillation.¹

The RE-LY study results have shown:

• Both doses of dabigatran etexilate were non-inferior to warfarin on the primary endpoint of reducing the incidence of stroke (including hemorrhagic) and systemic embolism (p<0.001)²
  
• Dabigatran etexilate 150mg BID was superior to warfarin in reducing the incidence of stroke (including hemorrhagic) and systemic embolism by 34% (RR 0.66, 95% CI, 0.53-0.82, p<0.001)²
  
• There was no significant difference in the rate of major bleeding for dabigatran 150mg BID compared to warfarin (3.11 percent/year, 3.36 percent/year, respectively p=0.31).²
• The rate of major bleeding with dabigatran etexilate 110mg BID (2.71 percent/year) was 20 percent lower compared to warfarin (p=0.003)²   

Also presented and published today were results in other outcomes from the RE-LY trial, including significantly lower incidence of  hemorrhagic strokes with both 150mg and 110mg BID doses (RRR 74 percent, p<0.001 and RRR 69 percent, p<0.001, respectively),² and a lower incidence of  vascular mortality with the 150mg BID dose (RRR 15 percent, p=0.04).² Abnormal liver function (ALT or AST > 3xULN with concurrent bilirubin >2xULN) did not occur more frequently among patients taking dabigatran etexilate 110mg BID, 150mg BID than warfarin (0.2 percent, 0.2 percent, and 0.3 percent respectively).²

"Up to 20 percent of strokes in the U.S. each year are associated with atrial fibrillation.  As clinicians, our main objective in managing patients with atrial fibrillation is to prevent stroke without increasing the risk of dangerous or life-threatening bleeds," said Dr. Michael Ezekowitz, professor & vice president, clinical research, Lankenau Institute.  "The study results seen with the two respective doses of dabigatran evaluated in RE-LY indicate that this compound has the potential to improve patient care.”

Over 2.3 million Americans³ have atrial fibrillation.  Atrial fibrillation is associated with a five-fold increase in the incidence of stroke.⁴   Strokes that are associated with AF tend to be especially severe and disabling,⁵ with half of people dying within one year.⁶   Warfarin and other vitamin-K antagonists are highly effective when patients’ blood clotting value is maintained within the therapeutic INR range of 2.0-3.0.⁷ However in clinical practice approximately half of patients with atrial fibrillation eligible for anticoagulation don not receive warfarin.⁸ For those patients receiving warfarin, only about half are controlled within the therapeutic range.⁹

“As a research-driven company focused on improving patient care, we are very pleased with the findings from the RE-LY study,” said J. Martin Carroll, president and CEO of Boehringer Ingelheim Pharmaceuticals, Inc. “The results suggest that dabigatran etexilate, a compound discovered and developed from the earliest stages in our laboratories, may bring a long-awaited advancement in oral anticoagulation to the millions of people living with atrial fibrillation.”
 
About RE-LY^® : The largest AF outcomes trial to date
RE-LY was a global, Phase III, randomized trial of 18,113 patients enrolled in more than 900 centers in 44 countries, investigating whether dabigatran etexilate (two blinded doses) was as effective as well-controlled warfarin – INR 2.0 - 3.0 – (open label) for stroke prevention.¹ 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 dysfunction, age > 75 years, age > 65 years with either diabetes mellitus, history of coronary artery disease, or hypertension) were enrolled in the study for two years with a minimum follow-up period of one year.¹

The primary endpoint of the trial was incidence of stroke (including hemorrhagic) and systemic embolism.¹⁰ Secondary outcome measures included a composite of incidence of stroke (including hemorrhagic), systemic embolism and all death, as well as a composite of incidence of stroke (including hemorrhagic), systemic embolism, pulmonary embolism, acute myocardial infarction, and vascular death (including death from bleeding).¹  Additional safety endpoints included bleeding events (major and minor), intracerebral hemorrhage, other intracranial hemorrhage, elevations in liver transaminases, bilirubin and hepatic dysfunction, and other adverse events.¹

The primary analysis was designed to test whether either dose of dabigatran was non-inferior to warfarin.   After non-inferiority of both doses of dabigatran was established, statistical analysis allowed testing of superiority.

About AF and stroke
Atrial fibrillation is the most common sustained heart rhythm abnormality in the U.S.¹⁰ The prevalence of AF in the U.S. is expected to increase 2.5 fold to 5.6 million by 2050, reflecting the growing population of elderly individuals.³  Atrial fibrillation is associated with up to 20 percent of strokes in the U.S.¹⁰ Strokes related to AF are twice as likely to be fatal⁵ and twice as likely to be debilitating as non-AF related strokes.¹¹ Total annual costs for the treatment of AF are estimated to be more than U.S. $6.65 billion.¹²

About dabigatran etexilate
Dabigatran etexilate is an investigational oral direct thrombin inhibitor (DTI)¹³ , being studied in the prevention and treatment of acute and chronic thromboembolic diseases.^{1,14,15,16,17,18,19}

Dabigatran etexilate is not approved by the FDA.  Dabigatran etexilate is approved and marketed as Pradaxa^® in 40 countries outside the U.S. for the primary prevention of venous thromboembolic events (blood clots) in patients who have undergone elective total hip or elective total knee replacement surgery.

About the dabigatran etexilate clinical trial program
RE-LY® is part of Boehringer Ingelheim’s clinical trial program evaluating the efficacy and safety of dabigatran etexilate.^{1,15,16,17,18,19,20,21} In addition to RE-LY, the development program encompasses studies in:

• Primary prevention of venous thromboembolism (VTE) in patients undergoing elective total hip and knee replacement surgeries ^15,16,17
• Treatment of acute VTE¹⁹
• Secondary prevention of VTE¹⁸
• Prevention of atherothrombotic events in patients with acute coronary syndrome¹⁴
• Stroke prevention in atrial fibrillation

Boehringer Ingelheim Pharmaceuticals, Inc.
Boehringer Ingelheim Pharmaceuticals, Inc., based in Ridgefield, CT, is the largest U.S. subsidiary of Boehringer Ingelheim Corporation (Ridgefield, CT) and a member of the Boehringer Ingelheim group of companies.

The Boehringer Ingelheim group is one of the world’s 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, it operates globally with 138 affiliates in 47 countries and approximately 41,300 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.

In 2008, Boehringer Ingelheim posted net sales of U.S. $17 billion (11.6 billion euro) while spending approximately one-fifth of net sales in its largest business segment, Prescription Medicines, on research and development.

For more information, please visit http://us.boehringer-ingelheim.com.

 

---

References

1. 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.
2. Connolly SJ, et al. “Dabigatran versus Warfarin in Patients with Atrial Fibrillation.” New England Journal of Medicine. 2009; 361.
3. Go AS, et al. “Prevalence of Diagnosed Atrial Fibrillation in Adults: National Implications for Rhythm Management and Stroke Prevention: the AnTicoagulation and Risk Factors In Atrial Fibrillation (ATRIA) Study.” Journal of the American Medical Association. 2001; 285(18):2370-2375.
4. Kannel WB, et al. “Final Draft Status of the Epidemiology of Atrial Fibrillation.“ Medical Clinics of North America. 2008; 92(1):17-ix.
5. Lin HJ, et al. “Stroke Prevention in Atrial Fibrillation: The Framingham Study.” Stroke. 1996; 27:1760-1764
6. Marini C, et al. “Contribution of Atrial Fibrillation to Incidence and Outcome of Ischemic Stroke: Results From a Population-Vased Study.“ Stroke. 2005; 36:1115-9
7. Hart RG, et al. “Meta-Analysis: Antithrombotic Therapy to Prevent Stroke in Patients Who Have Non-Valvular Atrial Fibrillation.“ Annals of Internal Medicine. 2007; 146:857-67
8. Hylek EM, 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
9. Samsa GP, et al. “Quality of Anticoagulation Management Among Patients with Atrial Fibrillation: Results of a Review of Medical Records from 2 Communities.“ Archives of Internal Medicine. 2000; 160:967-73
   
10. Wolf PA, et al. “Atrial fibrillation as an independent risk factor for stroke: the Framingham Study.” Stroke. 1991; 22:983-988.
11. Dulli D, et al. “Atrial Fibrillation is Associated with Severe Ischemic Stroke.” Neuroepidemiology. 2003; 22: 118-123.
12. Coyne KS, et al. “Assessing the Direct Costs of Treating Non-valvular Atrial Fibrillation in the United States.” Value Health. 2006; 9:348–56.
13. Di Nisio, et al. “Direct Thrombin Inhibitors.” New England Journal of Medicine. 2005; 353: 1028-40.
14. ClinicalTrials.gov. “RandomizEd Dabigatran Etexilate Dose Finding Study in Patients With Acute Coronary Syndromes Post Index Event With Additional Risk Factors for Cardiovascular Complications Also Receiving Aspirin and Clopidogrel: Multi-Centre, Prospective, Placebo Controlled, Cohort Dose Escalation Study (RE-DEEM).” Available at: http://www.clinicaltrials.gov/ct2/show/NCT00621855?term=dabigatran&rank=11. Accessed on: January 28, 2009.
15. Eriksson BI, et al. “Dabigatran Etexilate Versus Enoxaparin for Prevention of Venous Thromboembolism After Total Hip Replacement: a Randomized, Double-Blind, Non-Inferiority Trial.” The Lancet. 2007; 370:949-956.
16. The RE-MOBILIZE Writing Committee. “Oral Thrombin Inhibitor Dabigatran Etexilate vs North American Enoxaparin Regimen for Prevention of Venous Thromboembolism After Knee Arthroplasty Surgery.“ The Journal of Arthroplasty. 2009; 24: 1-9
17. ClinicalTrials.gov. “A Phase III Randomised, Parallel Group, Double-Blind, Active Controlled Study to Investigate the Efficacy and Safety of Orally Administered 220 mg Dabigatran Etexilate Capsules (110 mg Administered on the Day of Surgery Followed by 220 mg Once Daily) Compared to Subcutaneous 40 mg Enoxaparin Once
    Daily for 28-35 Days, in Prevention of Venous Thromboembolism in Patients With Primary Elective Total Hip Arthroplasty Surgery. (RE-NOVATE II).” Available at: http://www.clinicaltrials.gov/ct2/show/NCT00657150?term=dabogatran&rank=7. Accessed on: January 28, 2009.
18. ClinicalTrials.gov. “A Randomised, Multicenter, Double-Blind, Active Controlled Study to Investigate the Efficacy and Safety of Dabigatran Etexilate, 150 mg b.i.d Administered Orally (Capsules) for 18 Months, Compared to Warfarin Tablets p.r.n. (Target INR) for the Secondary Prevention of Venous Thromboembolism.” Available at: http://www.clinicaltrials.gov/ct2/show/NCT00329238?term=dabigatran&rank=12. Accessed on: January 28, 2009.
19. ClinicalTrials.gov. “A Phase III, Randomised, Double Blind, Parallel-Group Study of the Efficacy and Safety of Oral Dabigatran Etexilate (150 mg Bid) Compared to Warfarin (INR 2.0-3.0) for 6 Month Treatment of Acute Symptomatic Venous Thromboembolism, Following Initial Treatment (5-10 Days) With a Parenteral Anticoagulant Approved for This Indication.” Available at: http://www.clinicaltrials.gov/ct2/show/NCT00680186?term=dabigatran&rank=5. Accessed on: January 28, 2009.
20. ClinicalTrials.gov. “Twice-Daily Oral Direct Thrombin Inhibitor Dabigatran Etexilate in the Long-Term Prevention of Recurrent Symptomatic Proximal Venous Thromboembolism in Patients With Symptomatic Deep-Vein Thrombosis or Pulmonary Embolism.” Available at: http://www.clinicaltrials.gov/ct2/show/NCT00558259?term=dabigatran&rank=1. Accessed on: April 15, 2009.
21. 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.” Journal of Thrombosis and Haemostasis. 2007; 5: 2178-2185.
    

© 2009-2010 Boehringer Ingelheim Corporation or an affiliated company. All rights reserved. Use of this site is subject to the terms and conditions set out in the Agreement to use the Boehringer Ingelheim Corporation and its U.S. affiliates' web sites. All content intended for U.S. residents only. Terms of Use and Privacy Policy.