Value through Innovation31 October 2014
10 December 2012

Treatment with Pradaxa® associated with better patient outcomes after a major bleeding event compared to warfarin

• In RE-LY®, patients had better survival prognosis and spent less time in intensive care following a major bleed with Pradaxa® (dabigatran etexilate) than with warfarin
• Data provide further support for the favourable safety profile of Pradaxa®
• Presentation at American Society of Hematology (ASH) 2012 highlighted as ‘Best of ASH’

Ingelheim, Germany, 10 December 2012 – Results from a new post-hoc analysis of the landmark RE-LY®i trial show that in patients experiencing a major bleeding event, treatment with Pradaxa® (dabigatran etexilate) was associated with lower mortality and a shorter length of stay in intensive care compared to warfarin. In a pooled post-hoc analysis of five Phase III trials with Pradaxa®, the data show a clear trend towards a better prognosis after a major bleed with Pradaxa® than with warfarin. These new data were presented at the American Society of Hematology (ASH) Annual Meeting 2012 in Atlanta, Georgia, USA.1 In the RE-LY® trial, rates of major bleeding events were similar with Pradaxa® 150 mg when compared to warfarin and significantly lower for Pradaxa® 110 mg.2,3

"Bleeding is a known possible treatment complication of all anticoagulant therapies. The results of our analysis indicate that patients who have a major bleeding while on treatment with dabigatran appear to have a better survival prognosis than those on warfarin," said Prof. Sam Schulman, Division of Hematology and Thromboembolism, McMaster University, Hamilton, Canada. "The data also indicate that standard clinical support measures for patients with bleeding events work just as well in patients on dabigatran as for those on warfarin, and no greater use of medical resources is required."

The new post-hoc analyses compare clinical management and outcomes following major bleeding events associated with both Pradaxa® and warfarin in the RE-LY® trial alone as well as in a pooled analysis of five Phase III studies in the indications for stroke prevention in non-valvular atrial fibrillation (AF), acute treatment as well as secondary prevention of venous thromboembolism (VTE). These trials had a duration of six to 36 months and included 26,757 patients.1 More patients in the Pradaxa® group had high risk factors compared to those in the warfarin group – they were older, had a lower creatinine clearance indicating a slightly worse kidney function, and had a more frequent use of acetylsalicylic acid or non-steroidal anti-inflammatory drugs (NSAIDs).1

For the RE-LY® trial, the adjustedii analysis of major bleeding with fatal outcomes showed a significantly lower mortality for patients treated with Pradaxa® compared to patients on warfarin (Odds Ratio 0.56 for dabigatran 150 mg + 110 mg vs. warfarin, p=0.009). Additionally, in RE-LY®, the length of stay in the intensive care unit (ICU) and coronary care unit (CCU) was significantly shorter for patients on Pradaxa® compared with those on warfarin (1.6 nights vs. 2.7 nights, p=0.01).1

In the pooled analysis of the five Phase III studies including AF and also VTE patients, the outcome across all trials showed a clear statistical trend (p=0.052, not significant) towards a lower 30-day mortality after the first major bleed associated with Pradaxa® compared to warfarin.1

Professor Klaus Dugi, Corporate Senior Vice President Medicine, Boehringer Ingelheim

Professor Klaus Dugi, Corporate Senior Vice President Medicine, Boehringer Ingelheim

"These analyses are important news for physicians and patients", commented Professor Klaus Dugi, Corporate Senior Vice President Medicine, Boehringer Ingelheim. "They suggest that in the absence of a specific antidote patients treated with Pradaxa® may nonetheless expect better outcomes to those treated with warfarin should a major bleeding occur."

The favourable benefit-risk profile of Pradaxa® is supported by safety assessments from regulatory authorities including the European Medicines Agency and the U.S. Food and Drug Administration (FDA).4,5 The latest FDA update reports the results of a Mini-Sentinel assessment that indicated the bleeding rates associated with new use of Pradaxa® are not higher than those associated with new use of warfarin. Specifically, for intracranial haemorrhage and gastrointestinal haemorrhage, the combined incidence rate (per 100,000 days at risk) was 1.8 to 2.6 times higher for new users of warfarin than for new users of Pradaxa®.5 Recently presented results from the RELY-ABLE® study indicate that the treatment effects and favourable safety profile of Pradaxa® are consistent over the long-term.6

NOTES TO THE EDITORS

Stroke Prevention in Atrial Fibrillation
AF is the most common sustained heart rhythm condition7, with one in four adults over the age of 40 developing the condition in their lifetime.7 People with AF are more likely to experience blood clots, which increases the risk of stroke by five-fold.8 Up to three million people worldwide suffer strokes related to AF each year.9,10 Strokes due to AF tend to be severe, with an increased likelihood of death (20%), and disability (60%).11

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 debilitation.12 Appropriate anticoagulation therapy can help to prevent many types of AF-related strokes and improve overall patient outcomes.13

Worldwide, 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.14,15 Given AF-related strokes tend to be more severe, this results in higher direct medical patient costs annually.16 The total societal burden of AF reaches €13.5 billion per year in the European Union alone.17

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%18)2,3. Patients were followed-up in the study for a median of 2 years with a minimum of 1 year follow-up.2

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).

The RE-LY® trial is the pivotal study for Pradaxa®. Pradaxa® 150 mg bid is the only novel oral anticoagulant, study of which (RE-LY®) has shown a significant reduction in the incidence of ischaemic strokes in patients with non-valvular AF compared to warfarin (INR 2.0-3.0, median TTR 67%)18, offering a relative risk reduction of 25%.2,3 Nine out of ten strokes caused by AF are ischemic strokes,12 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.19

Overall in RE-LY®, Pradaxa® 150 mg bid provided a 35% reduction in the overall risk of stroke and systemic embolism versus warfarin. Pradaxa® 110 mg bid was non-inferior compared to warfarin for the prevention of stroke and systemic embolism.2,3 Pradaxa® 150 mg showed a similar risk of major bleeds versus warfarin while Pradaxa® 110 mg bid demonstrated significantly lower major bleeding. Both doses of Pradaxa® were associated with significantly lower total, intracranial and life-threatening bleeding compared to warfarin.2,3 Overall in RE-LY® there was no significant mortality benefit for Pradaxa® compared to warfarin.2,3

About dabigatran etexilate
Dabigatran etexilate is at the forefront of a new generation of oral anticoagulants/direct thrombin inhibitors (DTIs)20 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 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 surgery
  • Treatment of acute VTE
  • Secondary prevention of VTE
  • Stroke prevention in AF
  • Prevention of thromboembolism after heart valve replacement.

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 44,000 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.

As a central element of its culture, Boehringer Ingelheim pledges to act 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 endeavors.

In 2011, Boehringer Ingelheim achieved net sales of about 13.2 billion euro. R&D expenditure in the business area Prescription Medicines corresponds to 23.5% 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 (110 mg and 150 mg bid) each administered in a blinded manner, with open label warfarin.3

ii Adjusted for sex, age, weight, renal function and additional antithrombotic therapy.

References

1. Majeed A, et al. Management and Outcomes of Major Bleeding On Dabigatran or Warfarin. Poster 19 from Session 332: Antithrombotic Therapy 11. Presented on 8 December at the American Society of Hematology (ASH) Annual Meeting 2012.
2. Connolly SJ, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139-51.
3. Connolly SJ, et al. Newly identified events in the RE-LY trial. N Engl J Med. 2010;363:1875-6.
4. European Medicines Agency: Opinions on annual re-assessments, renewals of marketing authorisations and accelerated assessment procedures. Adopted at the CHMP meeting of 15-18 October 2012. Viewed October 2012 http://www.ema.europa.eu/docs/en_GB/document_library/Other/2012/10/WC500134406.pdf
5. Food and Drug Administration FDA Drug Safety Communication: Update on the risk for serious bleeding events with the anticoagulant Pradaxa. Viewed November 2012 http://www.fda.gov/Drugs/DrugSafety/ucm326580.htm
6. Connolly SJ, et al. 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 Randomized Trial. CS.04. Clinical Science: Special Reports: Valvular Heart Disease, PAD, Atrial Fibrillation: International Perspectives. Presented on 7 November 2012 at the American Heart Association Scientific Sessions 2012
7. Lloyd-Jones DM, et al. Lifetime risk for development of atrial fibrillation: the Framingham Heart Study. Circulation. 2004;110:1042-6.
8. Camm JA, et al. 2012 focussed update of the ESC Guidelines for the management of atrial fibrillation. European Heart Journal. 2012;33:2719-41.
9. Atlas of Heart Disease and Stroke, World Health Organization, September 2004. Viewed Nov 2012 at http://www.who.int/cardiovascular_diseases/en/cvd_atlas_15_burden_stroke.pdf
10. Camm JA, et al. 2010 focussed update of the ESC Guidelines for the management of atrial fibrillation. European Heart Journal. 2012;31:2369-2429.
11. Gladstone DJ, et al. Potentially Preventable Strokes in High-Risk Patients With Atrial Fibrillation Who Are Not Adequately Anticoagulated. Stroke. 2009;40:235-240.
12. Andersen KK, et al. Hemorrhagic and ischemic strokes compared: stroke severity, mortality, and risk factors. Stroke 2009;40:2068-72.
13. Aguilar MI, Hart R. Oral anticoagulants for preventing stroke in patients with non-valvular atrial fibrillation and no previous history of stroke or transient ischemic attacks. Cochrane Database of Systematic Reviews. 2005, Issue 3. Art. No.: CD001927.
14. Coyne KS, et al. Assessing the direct costs of treating nonvalvular atrial fibrillation in the United States. Value Health. 2006;9:348-56.
15. Ringborg A, et al. Costs of atrial fibrillation in five European countries: results from the Euro Heart Survey on atrial fibrillation. Europace 2008;10:403-11.
16. Brüggenjürgen B, et al. The impact of atrial fibrillation on the cost of stroke: the Berlin acute stroke study. Value Health. 2007;10:137-43.
17. Fuster V, et al. ACC/AHA/ESC 2006 Guidelines for the management of patients with atrial fibrillation – executive summary. Circulation. 2006;114:700-52.
18. Pradaxa European Summary of Product Characteristics, 2012
19. NHLBI website. “What is Stroke?” Available at: http://www.nhlbi.nih.gov/health/health-topics/topics/stroke. Accessed on: October 10, 2012.
20. Di Nisio M, et al. Direct thrombin inhibitors. N Engl J Med. 2005;353:1028-40.

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