Data Published in The Lancet Compare Dabigatran Etexilate to Dose-Adjusted Warfarin Across RE-LY® Trial Centers

RIDGEFIELD, Conn., Aug. 29 /PRNewswire/ -- Boehringer Ingelheim today announced results from a pre-specified, retrospective, un-blinded sub-analysis of the RE-LY® trial – the largest atrial fibrillation outcomes trial ever conducted(2) – were published in The Lancet.  The sub-analysis evaluated the primary outcomes of RE-LY® in relation to each center's average time in therapeutic range (cTTR) (INR 2.0-3.0) for patients taking warfarin.(1)

Study centers were placed into one of four groups based on cTTR (<57.1%, 57.1%-65.5%, 65.5%-72.6% and >72.6%).(1) Primary outcomes were assessed across the three treatment arms (dabigatran etexilate 110mg BID, dabigatran etexilate 150mg BID, warfarin)(1) and demonstrated:

• There was no significant interaction between cTTR and stroke and systemic embolism for either dabigatran etexilate 110mg BID or dabigatran etexilate 150mg BID compared to warfarin (interaction p=0.89 and 0.20)(1)

• There was no significant interaction between cTTR and major bleeding with dabigatran etexilate 110mg BID (interaction p=0.50); however, there was a significant interaction when comparing dabigatran etexilate 150mg BID to warfarin (interaction p=0.03), with lower rates at centers where INR control was low, and similar rates at centers where control was higher(1)

• There was no significant interaction between cTTR and intracranial bleeding for either dabigatran etexilate 110mg BID or dabigatran etexilate 150mg BID compared to warfarin (interaction p=0.71 and 0.89)(1)

"Well-controlled warfarin is very effective for the prevention of stroke in patients with atrial fibrillation; however, we know in clinical practice there can be large variations in the level of control," said Dr. Michael Ezekowitz, professor & vice president, clinical research, Lankenau Institute.  "The results of this sub-analysis suggest the level of control achieved across RE-LY trial centers did not influence the effects of dabigatran etexilate compared to warfarin for stroke prevention."

About the sub-analysis

The individual time in therapeutic range (iTTR) during the trial was calculated using the Rosendaal method for 5,791 patients randomized to warfarin, excluding INRs from the first week and after discontinuation of study drug.(1) For patients who temporarily discontinued warfarin, the time interval between temporary discontinuation and restart of medication was also not counted.(1)

Each center's time in therapeutic range was calculated based on the average iTTR in the group of patients randomized to warfarin.(1)  Among the 951 centers, cTTR could not be appropriately estimated at 45 centers because too few patients with serial INR values were available.(1)  Accordingly, 18,024 patients from 906 sites were included in the analysis.(1)

About RE-LY®: The largest AFib outcomes trial to date(2)

RE-LY® (Randomized Evaluation of Long-Term Anticoagulation Therapy, Warfarin, Compared with Dabigatran) was a global, Phase III, randomized trial(2) of 18,113(3) patients enrolled in 951 centers in 44 countries,(3) investigating whether dabigatran etexilate (two blinded doses) was as effective as well-controlled warfarin – INR 2.0 - 3.0 – (open label) for stroke prevention.(3) Patients with non-valvular atrial fibrillation 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.(3)

The primary endpoint of the trial was incidence of stroke (including hemorrhagic) and systemic embolism.(3) 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).(3) 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.(3)

The primary analysis was designed to test whether either dose of dabigatran etexilate was non-inferior to warfarin.(3)  After non-inferiority of both doses of dabigatran etexilate was established, statistical analysis allowed testing of superiority.(3)

About atrial fibrillation and stroke

Atrial fibrillation is the most common sustained heart rhythm abnormality(4) and is associated with up to 15 percent of all strokes in the U.S.(5)  Atrial fibrillation is associated with nearly a five-fold increased risk of stroke,(5) and atrial fibrillation-related strokes can be about twice as likely to be fatal(6) or severely disabling(7) as non-atrial fibrillation-related strokes.  An estimated 2.3 million Americans currently have atrial fibrillation(4) and the prevalence is expected to increase 2.5 fold to 5.6 million by 2050,(4) reflecting the growing population of elderly individuals.  The annual cost of stroke among Medicare atrial fibrillation patients is estimated to be $8 billion.(8)

About dabigatran etexilate

Dabigatran etexilate is not approved by the FDA.  Dabigatran etexilate is an investigational oral direct thrombin inhibitor(9) being studied in the prevention and treatment of acute and chronic thromboembolic diseases.(3) (10) (11) (12) (13) (14) (15)

About 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 142 affiliates in 50 countries and more than 41,500 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 2009, Boehringer Ingelheim posted net sales of US $17.7 billion (12.7 billion euro) while spending 21% of net sales in its largest business segment, Prescription Medicines, on research and development.

For more information, please visit http://us.boehringer-ingelheim.com and follow us on Twitter at http://twitter.com/boehringerus.

(1) Wallentin, L, et al."Efficacy and Safety of Dabigatran Compared to Warfarin at Different Levels of INR Control for Stroke Prevention in Atrial Fibrillation." Lancet. 2010.

(2) 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.

(3) Connolly S.J., et al. "Dabigatran versus Warfarin in Patients with Atrial Fibrillation." New England Journal of Medicine. 2009; 361.

(4) Go, Alan S., and Elaine M. Hylek, et al. "Prevalence of Diagnosed Atrial Fibrillation in Adults: National Implications for Rhythm Management and Stroke Prevention: the ATRIA Study." JAMA. 2001; 285:2370-2375.

(5) Wolf P.A., et al. "Atrial Fibrillation as an Independent Risk Factor for Stroke: The Framingham Study." Stroke. 1991; 22:983-988.

(6) Lin H.J., et al. "Stroke Prevention in Atrial Fibrillation: The Framingham Study." Stroke. 1996; 27:1760-1764.

(7) Dulli D, et al. "Atrial Fibrillation is Associated with Severe Ischemic Stroke." Neuroepidemiology. 2003; 22: 118-123.

(8) Caro, J. "An Economical Model of Stroke in Atrial Fibrillation: The Cost of Suboptimal Oral Anticoagulation." The American Journal of Managed Care. 2004; 10:S451-S461.

(9) Di Nisio M., et al. "Direct Thrombin Inhibitors." New England Journal of Medicine. 2005; 353:1028-40.

(10) 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.

(11) 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.

(12) 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.

(13) 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.

(14) 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.

(15) ClinicalTrials.gov. "RELY-ABLE Long Term Multi-center Extension of Dabigatran Treatment in Patients with Atrial Fibrillation Who Completed RE-LY Trial to Assess the Effect of a Knowledge Translation Intervention on Patient Outcomes." Available at: http://www.clinicaltrials.gov.ct2.show/NCT00808067?term=dabigatran&rank=10. Accessed on: July 23, 2009.

SOURCE Boehringer Ingelheim Pharmaceuticals, Inc.