Sub-Analysis Shows Primary Benefits seen with RE-LY® are Independent of Level of Centre-Based International Normalized Ratio Control

Ingelheim, Germany, August 29, 2010 - Boehringer Ingelheim today announced that results from a pre-specified sub-group analysis of the RE-LY® study (Randomized Evaluation of Long-Term Anticoagulation Therapy, Warfarin, Compared with Dabigatran) - the largest atrial fibrillation outcomes trial ever completed - were published in The Lancet. ¹ The sub-group analysis assessed the effects of centre-based international normalized ratio (INR) control on study outcomes.

"These findings support the superiority of 150mg dabigatran twice daily and the non-inferiority of 110mg dabigatran twice daily versus warfarin for protection against stroke in atrial fibrillation irrespective of the quality of INR control that a centre can achieve," said Professor Lars Wallentin, Professor of Cardiology and Director of the Uppsala University, Sweden. "For secondary outcomes, such as non-haemorrhagic events and mortality, advantages of dabigatran were reported for sites with poorer INR control, whereas results were comparable in sites with better INR control. Overall, these results show that local standards of care affect the benefits of switching to new treatment alternatives."

Addendum: The superiority of dabigatran etexilate 150 mg bid over well-controlled warfarin in stroke prevention in atrial fibrillation was shown in RE-LY®, a PROBE (prospective, randomized, open-label with blinded endpoint evaluation) trial designed to compare two fixed doses of the oral direct thrombin inhibitor dabigatran (110 mg and 150 mg bid) each administered in a blinded manner, with open label warfarin.⁵

For each patient involved in the warfarin arm of the RE-LY® trial, the quality of warfarin treatment was calculated by establishing the time in therapeutic range (TTR). The average individual time in therapeutic range (iTTR; with a target INR of 2.0 – 3.0) for patients randomised to warfarin was 64%, which is a similar level of control seen in recently published prospective, randomised trials^2,3. There were considerable variations in time in therapeutic range among the trial centres across the participating 44 countries. In the present sub-group analysis, each centre’s average of TTR (cTTR) was calculated as the average of all individual patient TTRs in the warfarin group. The distribution of cTTRs across study centres was investigated and interquartile limits were identified. The quartiles of cTTR for the warfarin patients were 72.6%. Outcomes were assessed across the three treatment arms (dabigatran etexilate 110mg BID, 150mg BID and warfarin).

Results demonstrated that:¹

• Dabigatran etexilate 150mg BID was superior to warfarin in the reduction of stroke and systemic embolism independent of the level of centre-based INR control
• Dabigatran etexilate 110mg BID was similar to warfarin in the reduction of stroke and systemic embolism with lower rates of major bleeding independent of the level of centre-based INR control
• Both dosages of dabigatran etexilate were superior to warfarin in terms of intracranial hemorrhage (ICH) irrespective of centre based INR control
• Both dosages of dabigatran etexilate demonstrated advantages over warfarin in the reduction of secondary outcomes such as the composite of all cardiovascular events, total mortality and major bleeding at centres with poor INR control. The results for secondary outcomes were comparable between dabigatran etexilate and warfarin in centres with better INR control.
• Addendum: RE-LY® was a PROBE (prospective, randomized, open-label with blinded endpoint evaluation) trial designed to compare two fixed doses of the oral direct thrombin inhibitor dabigatran (110 mg and 150 mg bid) each administered in a blinded manner, with open label warfarin.

About the pre-specified sub-group analysis design
The hypothesis of the sub-group analysis was to test whether the centre-based TTR may influence the relative effects of dabigatran etexilate versus warfarin. All outcomes were evaluated in relation to quartiles of centre-based TTR.

The individual time in therapeutic range of every patient in the warfarin arm of the RE-LY® trial was calculated using the Rosendaal method.⁴ Each cTTR was then calculated as the average of all individual patient TTRs in the warfarin group. The distributions of cTTRs across study centres were investigated and interquartile limits were identified. The quartiles of cTTR for the warfarin patients were 57.1%-65.5%, 65.5%-72.6% and >72.6%.

About RE-LY®
RE-LY® (Randomized Evaluation of Long term anticoagulant therapy) was a global, phase III, randomized trial of 18,113 patients enrolled in over 900 centres in 44 countries, investigating whether dabigatran etexilate (2 blinded doses) is as effective as well-controlled warfarin with target INR of 2.0-3.0 for stroke prevention. Patients 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) 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).

Compared to well controlled warfarin, dabigatran etexilate showed in the trial:⁵

• Significant reduction in the risk of stroke and systemic embolism – including haemorrhagic strokes with dabigatran etexilate 150 mg bid
• Significantly lower major bleeding events with dabigatran etexilate 110 mg bid
• Significantly lower life threatening and intracranial bleeding with both doses
• Significant reduction in vascular mortality with dabigatran etexilate 150 mg bid.
• Addendum: RE-LY® was a PROBE (prospective, randomized, open-label with blinded endpoint evaluation) trial designed to compare two fixed doses of the oral direct thrombin inhibitor dabigatran (110 mg and 150 mg bid) each administered in a blinded manner, with open label warfarin.

About AF and stroke
AF is the most common heart rhythm condition, affecting around 1% of the total population, rising to 10% in people over the age of 80.⁶ A total of 6.3 million people in the US, Japan, Germany, Italy, France, UK and Spain were living with AF in 2007 and this is expected to increase to 7.5 million by 2017 primarily due to the ageing population.⁷ People with AF are at increased risk of blood clots, which raises stroke risk by five times.^8,9 Up to 3 million people worldwide suffer strokes related to AF each year.^10-12 Strokes due to AF tend to be severe, with an increased likelihood of death (20%), and disability (60%), with resultant societal costs and burden to the healthcare system.13 AF alone is associated with a cost of up to €13.5 billion across the European Union.⁸ Warfarin is the current standard of care for reducing stroke in patients with AF. It is highly effective when patients blood clotting value is maintained within the narrow therapeutic INR range of 2.0-3.0 as in a clinical trial setting.¹⁴ However in clinical practice, due to the well-known limitations with warfarin only 51% of diagnosed patients with AF at risk of stroke receive warfarin¹⁵ and fewer than half of these are controlled within the narrow therapeutic range.¹⁶

About dabigatran etexilate
Dabigatran etexilate is at the forefront of a new generation of oral anticoagulants/direct thrombin inhibitors (DTIs)¹⁷ 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.

Dabigatran etexilate has already been approved in 75 countries under the trademark Pradaxa® for the primary prevention of venous thromboembolic events (blood clots) in adults who have undergone elective total hip or elective total knee replacement surgery.

Disclaimer
Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial prevention. This information is provided for medical education purposes only.

About the dabigatran etexilate clinical trial programme
Boehringer Ingelheim’s clinical trial programme to evaluate the efficacy and safety of dabigatran etexilate encompasses studies in:

• Primary prevention of venous thromboembolism (VTE) in patients undergoing elective total hip and knee replacement surgeries
• Treatment of acute VTE
• Secondary prevention of VTE
• Secondary prevention of cardiac events in patients with acute coronary syndrome (ACS)
• Stroke prevention in atrial fibrillation (AF).

Boehringer Ingelheim
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 12.7 billion euro while spending 21% of net sales in its largest business segment Prescription Medicines on research and development.

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