RELY-ABLE® Study Demonstrates Benefits of Pradaxa® (Dabigatran Etexilate) Are Maintained for over Four Years

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RELY-ABLE® Study Demonstrates Benefits of Pradaxa® (Dabigatran Etexilate) Are Maintained for over Four Years PR Newswire BRACKNELL, England, November 8, 2012 BRACKNELL, England, November 8, 2012 /PRNewswire/ -- Pradaxa® (dabigatran etexilate) is the first and only novel oral anticoagulant supported by long-term clinical data of 4.3 years' duration Benefits for both doses shown to be sustained throughout study duration, providing evidence of long term efficacy and safety New data from the RELY-ABLE® study have provided additional support to the safety profile and efficacy of Pradaxa® (dabigatran etexilate) for stroke prevention in patients with nonvalvular atrial fibrillation (AF) over a period in excess of 2 [*][1]years. The new long-term results presented at the American Heart Association's (AHA) Scientific Sessions, are [†]consistent with the findings from the landmark RE-LY® trial . The rates of stroke and haemorrhage observed during an additional 2.3 years of blinded follow-up in RELY-ABLE® correspond to the initial RE-LY® results, with the benefit of [1]-[3]both doses of dabigatran etexilate sustained throughout the study duration. The combined data from RE-LY® and RELY-ABLE® provides over four years of clinical trial experience and constitutes the longest evaluation of the benefits and safety of any novel oral anticoagulant for stroke prevention in AF to date.

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• Publié par: boehringer-ingelheim-limited
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• Langue: English

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RELY-ABLE® Study Demonstrates Benefits of Pradaxa® (Dabigatran Etexilate) Are Maintained for over Four Years

PR Newswire BRACKNELL, England, November 8, 2012

BRACKNELL, England,November 8, 2012/PRNewswire/ --

Pradaxa® (dabigatran etexilate) is the first and only novel oral anticoagulant supported by long-term clinical data of 4.3 years' duration Benefits for both doses shown to be sustained throughout study duration, providing evidence of long term efficacy and safety

New data from the RELY-ABLE® study have provided additional support to the safety profile and efficacy of Pradaxa® (dabigatran etexilate) for stroke prevention in patients with nonvalvular atrial fibrillation (AF) over a period [*][1] in excess of 2 years. The new long-term results presented at the American Heart Association's (AHA) Scientific [†] Sessions, are consistent with the findings from the landmark RE-LY® trial . The rates of stroke and haemorrhage observed during an additional 2.3 years of blinded follow-up in RELY-ABLE® correspond to the initial R E-LY® [1]-[3] results, with the benefit of both doses of dabigatran etexilate sustained throughout the study duration.

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

The international multi-centre RELY-ABLE® study followed 5,851 patients on dabigatran etexilate for a further 28 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 randomised and blinded approach.

[1] The results from RELY-ABLE® support sustained dose benefits in the long-term use of dabigatran etexilate:

Rates of ischaemic stroke 1.15%/year on 150mg bid and 1.24%/year on 110mg bid Incidence of haemorrhagic stroke 0.13%/year on 150mg bid and 0.14%/year on 110mg bid Incidence of major bleeding 3.74%/year on 150mg bid and 2.99%/year on 110mg bid

The consistent incidences of ischaemic and haemorrhagic stroke as well as rates of intracranial bleeding observed indicate that dabigatran etexilate provides sustained benefits. Furthermore, both doses of dabigatran etexilate had a similar net clinical benefit and mortality rates. The safety profile of dabigatran etexilate was consistent with the findings from the RE-LY® trial.

"Most patients with atrial fibrillation need life-long anticoagulant treatment to reduce the risk of ischaemic stroke. The 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 atMcMaster University, Hamilton, Ontario. "RELY-ABLE® shows that the results seen in RE-LY® continue to be observed during longer-term follow up. We see similar rates of stroke and systemic embolism and similar rates of major bleeding with similar rates of intracerebral bleeding and intracranial haemorrhage."

"The results from RELY-ABLE® will be a valuable contribution to evidence-based decision-making in the selection of a treatment that is effective in patients with AF over the longer term," said Professor Gregory Lip, Professor of Cardiovascular Medicine at the University of Birmingham, UK. "Despite the prevalence of AF and the associated five-fold increase in risk of stroke, there remains significant scope for improvement in reducing the risk of stroke in the AF patient population. RELY-ABLE® will serve to give added confidence to physicians in the appropriate prescribing of dabigatran etexilate."

"We remain committed to the ongoing investigation of dabigatran etexilate in reducing the risk of stroke in patients living with AF," said Charles de Wet, Medical Director at Boehringer Ingelheim. "Providing further data of dabigatran's positive net benefits in clinical settings may support physicians in their prescribing decisions in managing this increasingly prevalent condition over the long term."

InMarch 2012, the National Institute for Health and Clinical Excellence (NICE) issued final guidance recommending [4] dabigatran etexilate as a cost-effective option for the prevention of stroke and systemic embolism in adult [5] patients with nonvalvular AF and one or more risk factors. This decision from NICE means dabigatran must be made available for use by the NHS and that patients have the right to receive it if clinicians deem it clinically

appropriate.

NOTES TO THE EDITORS

Stroke Prevention in Atrial Fibrillation

[6] [7] AF is the most common heart rhythm condition in the UK, affecting more than 1.2 million people and is a [8] [9] leading cause of stroke. Approximately 150,000 people have a stroke in the UK each year, of which an [10] estimated 15% are caused by AF. Lifetime risks for development of AF are 1 in 4 for both men and women 40 [11] [6],[12] years of age and older. The prevalence of AF rises to 10% in people over the age of 80. People with AF [13],[14] are at a five-fold increased risk of suffering a stroke, compared to those without AF. Over two million people [15],[16] worldwide suffer strokes related to AF each year. Strokes due to AF are more severe with an increased [14] likelihood of death and disability compared to non-AF stroke. The mortality rate of patients with AF is about [12] double that of patients in normal sinus rhythm. Ischaemic strokes are the most common type of AF-related stroke, accounting for 92% of strokes experienced by AF patients and frequently leading to severe [17]-[21] [22] debilitation. Many AF related strokes can be prevented with appropriate antithrombotic therapy.

It is estimated that stroke care costs the NHS £2.8 billion in direct care costs, and costs the wider economy an [23] additional £1.8 billion in loss of productivity and disability.

In the UK, the average cost of AF-related stroke per patient is over £10,000 which can increase by up to a further [24] £8,000 per year in follow-up costs if the stroke is disabling.

[1] About RELY-ABLE

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 effects of the two doses of dabigatran etexilate in patients who had completed RE-LY®. Enrolled patients continued to receive the same double-blind dose w ith 2,937 patients on dabigatran 150mg bid and 2,914 patients on dabigatran 110mg bid. Patients randomized to warfarin in [1] RE-LY® were not eligible for RELY-ABLE®. RELY-ABLE® provides 2.3 years of additional double-blind, [1] randomised follow-up of patients, after RE-LY®.

Patients continuing from RE-LY® into RELY-ABLE® differed in several respects from those RE-LY® patients who did not. Continuing patients were more likely to have permanent AF (38% vs 33%), less likely to have heart failure (27% vs 35%) and were younger (71 vs 72 years).

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

Both doses of dabigatran etexilate showed low rates of ischaemic strokes (1.24%/year on 110mg bid; 1.15%/year on 150mg bid) and haemorrhagic strokes (0.14%/year on 110mg bid; 0.13%/year on 150mg bid) Major bleeding rates were lower with the 110mg bid dose (2.99%/year) versus the 150mg dose (3.74%/year) Net clinical benefits and low mortality rates were consistent between doses. Both doses had similar rates of the net clinical benefit outcome (composite of all major ischaemic, haemorrhagic and fatal events) (HR 1.07, 95% CI, 0.94-1.22, p=0.29) and similar mortality rates (HR 0.97, 95% CI, 0.80-1.19, p=0.79).

Overall the results from RELY-ABLE® were 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®

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 direct thrombin inhibitor dabigatran (110mg and 150mg [2],[3] bid) each administered in a blinded manner, with open label warfarin (INR 2.0-3.0, median TTR 67%) . Patients [2] were followed-up in the study for a median of 2 years with a minimum of 1 year follow-up.

The primary endpoint of the trial was incidence of stroke (including haemorrhagic) and systemic embolism. Secondary outcome measures included all-cause death, incidence of stroke (including haemorrhagic), systemic embolism, pulmonary embolism, myocardial infarction, and vascular death (including death from bleeding).

[2],[3] Compared to warfarin, dabigatran etexilate showed in the trial:

Significant reduction in the risk of stroke and systemic embolism - including ischaemic strokes with dabigatran etexilate 150mg bid (1.11%/year, p<0.001 for superiority; compared to 1.69%/year in the warfarin group) Similar rates of stroke/systemic embolism with dabigatran etexilate 110mg bid (1.53%/year, p<0.001 for non- inferiority; compared to 1.69%/year in the warfarin group) Significantly lower major bleeding events with dabigatran etexilate 110mg bid (2.71%/year, p=0.003; compared to 3.36%/year in the warfarin group) Significantly lower life threatening and intracranial bleeding with both doses (1.22%/year and 0.23%/year respectively, in the 110mg bid group; and 1.45%/year and 0.30%/year in the 150mg bid group; compared to 1.8%/year and 0.74%/year in the warfarin group) Significant reduction in mortality rate with dabigatran etexilate 150mg bid (3.64%/year, p=0.051; compared to 4.13%/year in the warfarin group)

About dabigatran etexilate Dabigatran etexilate is the first of the new generation of oral anticoagulants to have been approved. It is a direct [25] thrombin inhibitor (DTIs) targeting a high unmet medical need in the prevention and treatment of acute and chronic thromboembolic diseases.

Potent antithrombotic effects are achieved with direct thrombin inhibitors by specifically blocking the activity of thrombin (both free and clot-bound), the central enzyme in the process responsible for clot (thrombus) formation. In contrast to vitamin-K antagonists, (which act by reducing the levels of a number of different coagulation factors) dabigatran etexilate provides effective, predictable and consistent anticoagulation with a low potential for drug-drug interactions and no known drug-food interactions, and has no need for routine anticoagulation monitoring or dose adjustment.

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 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. A central element of Boehringer Ingelheim's culture is to be 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 2010, Boehringer Ingelheim posted net sales of about12.6 billion eurowhile spending almost 24% of net sales in its largest business segment Prescription Medicines on research and development.

*. 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 Random ized Trial. Lead author: Stuart J Connolly. CS.04. Clinical Science: Special Reports: Valvular Heart Disease, PAD, Atrial Fibrillation: International Perspectives

†. RE-LY® was a PROBE trial (prospective, randomized, open-label with blinded endpoint evaluation), comparing two fixed doses of the oral direct thrombin inhibitor dabigatran etexilate (110mg bid and 150mg bid) each administered in a blinded manner, with open label w arfarin.

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For further information, please contact:

 Nick Johnson Tzu Wong  Communications Manager Porter Novelli  Boehringer Ingelheim Limited Tel: + 44(0)20-7853-2269  Tel: [phone] Tel: + 44(0)77-6774-5865