New long-term data reinforce safety profile of Pradaxa for stroke prevention in AF

INELHEIM, Germany I June 17, 2013 I New long-term data from the RELY-ABLE® study, the long-term extension of the pivotal RE-LY®  trial of Pradaxa® (dabigatran etexilate) in patients with non-valvular atrial fibrillation (AF), were today published online in Circulation,¹ the journal of the American Heart Association. Pradaxa® is the only treatment among the new generation of direct oral anticoagulants, which has been evaluated in a large set of AF patients for more than four years.¹The long-term results reinforce the safety profile of Pradaxa®, which was originally established in the landmark RE-LY® trial.^1,2,3 The new data from RELY-ABLE® contribute to the already available evidence supporting the safety profile of Pradaxa®. This evidence also includes the most recent analyses of real-world safety data from the US FDA Mini-Sentinel initiative⁴ as well as assessments by other regulatory bodies, including the European Medicines Agency.⁵

“Before RELY-ABLE®, we already had data on the effects of two years of dabigatran etexilate treatment in patients with non valvular AF,” said RELY-ABLE® lead investigator Professor Stuart Connolly, Director of the Division of Cardiology at McMaster University, Hamilton, Ontario. “The additional long-term data from RELY-ABLE® provide reassuring safety information for the long-term treatment of patients taking dabigatran etexilate.” The international multi-centre RELY-ABLE® trial was designed to evaluate the long-term safety of ongoing Pradaxa® therapy (110mg bid or 150mg bid) in patients with AF, following RE-LY®.¹ Patients enrolled in RELY-ABLE® continued Pradaxa® therapy for an additional 2.3 years in an ongoing blinded comparison, bringing the mean duration of treatment to 4.3 years. A total of 5,851 patients participated in the extension study.¹ The unique results support the benefits of Pradaxa® over more than four years of long-term treatment.¹

• During the additional 2.3 years of treatment following RE-LY®, rates of major events for both dabigatran 110 mg and 150 mg twice daily were consistent with those seen in RE-LY®
• There were no new safety findings identified during the additional observation period of RELY-ABLE®

Key results from RELY-ABLE® include:¹

• Rates of major bleeding were 3.74 percent per year (n=238) and 2.99 percent per year (n=190) on Pradaxa® 150mg bid and 110mg bid respectively (HR = 1.26; 95% CI1.04-1.53)
• Very low rates of intracranial bleeding were sustained throughout the RELY-ABLE® study: 0.33 percent per year (n=21) and 0.25 percent per year (n=16) on Pradaxa® 150mg bid and 110mg bid respectively
• Incidence of haemorrhagic stroke was very low and similar between treatment arms: 0.13 percent per year (n=8) and 0.14 percent per year (n=9) on Pradaxa® 150mg bid and 110mg bid respectively

“We are pleased that the new long-term data from RELY-ABLE® add to the growing body of positive evidence for Pradaxa® in stroke prevention in atrial fibrillation. Pradaxa® is an important advancement in the treatment of patients with AF,” commented Professor Klaus Dugi, Corporate Senior Vice President Medicine, Boehringer Ingelheim. “Boehringer Ingelheim is a science-based company that is proud to bring innovative products, like Pradaxa®, to patients and the medical community.”Additional findings from RELY-ABLE® include:¹

• Rates of stroke or systemic embolism: 1.46 percent per year (n=93) and 1.60 percent per year (n=102) on Pradaxa® 150mg bid and 110mg bid respectively
• Rates of myocardial infarction were also low and similar between the two doses of Pradaxa® at 0.69 percent per year (n=44) and 0.72 percent per year (n=46) on Pradaxa® 150mg and 110mg, during the extended follow-up period.¹

The efficacy and safety of Pradaxa® was established in the RE-LY® trial, one of the largest stroke prevention clinical studies ever conducted in patients with AF. Pradaxa® 150mg bid is the only novel oral anticoagulant, study of which has shown a significant reduction in the incidence of ischaemic strokes in patients with non-valvular AF compared to warfarin, offering a relative risk reduction of 25 percent.^2,3 Nine out of ten strokes are ischaemic strokes,⁶ which can result in irreversible neurological injury with profound long-term consequences such as paralysis or inability to move one’s limbs or formulate speech.⁷Furthermore in RE-LY®, Pradaxa® 150mg bid provided a 36 percent reduction in the overall risk of stroke versus warfarin, demonstrating superior protection.^2,3 Pradaxa® 110mg bid was as effective as warfarin for the prevention of stroke and systemic embolism.^2,3 Both doses of Pradaxa® were associated with significantly lower total, intracranial and life-threatening bleeding compared to warfarin.^2,3 Pradaxa® 150mg bid showed a similar risk of major bleeds versus warfarin while Pradaxa® 110mg bid demonstrated a significantly lower risk.^2,3Pradaxa® is already widely approved for stroke prevention in atrial fibrillation and for primary prevention of VTE following total hip replacement or total knee replacement surgery.⁸ Over 1.6 million patient years of experience in all licensed indications in over 100 countries support Pradaxa® as the leading novel oral anticoagulant.⁹

NOTES TO THE EDITORS

About Pradaxa® (dabigatran etexilate)
Pradaxa® is approved in over 100 countries worldwide.⁹ It is licensed for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation and for the primary prevention of venous thromboembolism in patients undergoing total hip replacement or total knee replacement surgery.⁸

Pradaxa®, a direct thrombin inhibitor (DTI)¹⁰, was the first of a new generation of direct oral anticoagulants 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 variably act via different coagulation factors, 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.

About RELY-ABLE®
RELY-ABLE® (Long Term Multi-center Extension of Dabigatran Treatment in Patients with Atrial Fibrillation) was designed to evaluate the long-term safety of ongoing Pradaxa® therapy (150mg bid and 110mg bid) in patients who had completed RE-LY®.¹ From the beginning of RE-LY® to the end of RELY-ABLE®, the median duration of follow-up for patients was 4.3 years, with the longest duration reported at 5.5 years, and the median follow-up duration being 4.3 years.¹ 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.¹

There were some limitations to the RELY-ABLE® study.¹ Only half of the patients continued from RE-LY® to RELY-ABLE®. Patients were eligible if they did not prematurely discontinue Pradaxa® therapy. It was at the investigator’s discretion to determine if it was clinically appropriate for patients to continue receiving long-term treatment. Patients randomized to warfarin in RE-LY® were not eligible for RELY-ABLE®. With regards to the outcome analysis, there was no event adjudication in RELY-ABLE®, meaning confirmation by an independent team or group, whereas there was event adjudication in RE-LY®.

Patients continuing in RELY-ABLE® differed in several respects from those who did not: Continuing patients were more likely to be male, less likely to have permanent AF or a history of heart failure and less likely to have had a major clinical event during the RE-LY® trial.¹

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 bid) each administered in a blinded manner, with open label warfarin (INR 2.0-3.0, median TTR 67%⁸).^2,3 Patients were followed-up in the study for a median of 2 years with a minimum of 1 year follow-up.²The 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, acute myocardial infarction, and vascular death (including death from bleeding).^2,3Compared to warfarin, dabigatran etexilate showed in the trial:^2,3

• Significant reduction in the risk of stroke and systemic embolism – including ischaemic strokes with dabigatran etexilate 150mg bid
• Similar rates of stroke/systemic embolism with dabigatran etexilate 110mg bid
• Significantly lower major bleeding events with dabigatran etexilate 110mg bid
• Significantly lower life threatening and intracranial bleeding with both doses
• Significant reduction in vascular mortality with dabigatran etexilate 150mg bid.

Stroke Prevention in Atrial Fibrillation (AF)
AF is the most common sustained heart rhythm condition,¹¹ with one in four adults over the age of 401¹ developing the condition in their lifetime. People with AF are more likely to experience blood clots, which increases the risk of stroke by five-fold.¹² Up to three million people worldwide suffer strokes related to AF each year.^13,14 Strokes due to AF tend to be severe, with an increased likelihood of death (20%), and disability (60%).¹⁵Ischaemic strokes are the most common type of AF-related stroke, accounting for 92% of strokes and frequently leading to severe debilitation.⁶ Appropriate anticoagulation therapy can help to prevent many types of AF-related strokes and improve overall patient outcomes.¹⁶ Pradaxa® 150mg bid is the only novel oral anticoagulant, for which its pivotal trial vs. warfarin has shown a statistically significant and clinically relevant reduction of both ischaemic and haemorrhagic strokes.^2,3 Additionally, treatment with Pradaxa® is associated with substantially lower rates of both fatal and non-fatal intracranial haemorrhage, one of the most devastating complications of anticoagulation therapy.^17,18Worldwide, AF is an extremely costly public health problem, with treatment costs equating to $6.65 billion in the US and over €6.2 billion across Europe each year.^19,20 Given AF-related strokes tend to be more severe, this results in higher direct medical patient costs annually.²¹ The total societal burden of AF-related stroke reaches €13.5 billion per year in the European Union alone.²²

Boehringer Ingelheim
The Boehringer Ingelheim group is one of the world’s 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, it operates globally with 140 affiliates and more than 46,000 employees. Since it was founded in 1885, the family-owned company has been committed to researching, developing, manufacturing and marketing novel medications of high therapeutic value for human and veterinary medicine.Social responsibility is a central element of Boehringer Ingelheim’s culture. 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 2012, Boehringer Ingelheim achieved net sales of about 14.7 billion euro. R&D expenditure in the business area Prescription Medicines corresponds to 22.5% of its net sales.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, UK or Canada.

ⁱ 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 warfarin.^2,3