Boehringer Ingelheim announced new data analyses show positive treatment effect of Pradaxa® (dabigatran etexilate) in patients with acute deep vein thrombosis or pulmonary embolism

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• The efficacy and safety profile of Pradaxa® (dabigatran etexilate) was maintained regardless of patient characteristics^1,2,3,4
• Pooled safety data favour Pradaxa® treatment over warfarin and provide further reassurance^1-4
• The analysed patient characteristics included age, renal function, simultaneous use of anti-inflammatory drugs (NSAIDs) or low-dose acetylsalicylic acid (ASA) and the presence of cancer^1-4
• Data also showed that taking commonly used NSAIDs or low-dose ASA with Pradaxa® did not increase the risk of bleeding¹

Ingelheim, Germany, 12-12-2013 — /EuropaWire/ — New data analyses show that the positive treatment effect (efficacy and safety profile) of Pradaxa® (dabigatran etexilate) 150mg twice daily was consistent in a wide range of patients with acute deep vein thrombosis (DVT), a blood clot in the leg veins, or pulmonary embolism (PE), a blood clot in the lung, regardless of age, renal function, simultaneous use of non-steroidal anti-inflammatory drugs (NSAIDs) or low-dose acetylsalicylic acid (ASA), or the presence of cancer.^1-4 These new findings from the pooled safety analysis of the RE-COVER™ and RE-COVER™ II phase III clinical trials were presented this week during the American Society of Hematology Annual Meeting, New Orleans, USA.^1-4

“Knowing that the positive efficacy and safety profile of dabigatran is consistent regardless of patient characteristics in the treatment of acute DVT and PE is important as there is an ongoing need to improve treatment outcomes,” said Professor Sam Schulman, Principal Investigator, Division of Hematology and Thromboembolism, Department of Medicine, McMaster University, Canada. “The pooled data from these analyses favour dabigatran treatment over warfarin and provide further reassurance to both physicians and patients especially regarding the safety of the treatment.”

Previous data from the RE-COVER™ and RE-COVER™ II phase III clinical trials showed that in the acute treatment of DVT and PE, Pradaxa® 150 mg twice daily was an effective and well-tolerated treatment.^5,6

• Comparable efficacy for Pradaxa® 150 mg and warfarin: 2.7% vs. 2.4% (non-inferiority for primary endpoint of venous thromboembolism (VTE) or related death in trial period plus 6 month follow-up)

The rapid and full effect of Pradaxa® in less than two hours allows for an easy transition from initial heparin treatment with no overlap required.7 Due to one fixed-dose treatment with Pradaxa® from the beginning, patient management is simplified, as there is no need to titrate or adjust once prescribed.

Pooled data from RE-COVER™ and RE-COVER™ II show that, after the end of treatment with heparin, once patients are only treated with Pradaxa® compared to warfarin, they had significant safety benefits:6

• 40% lower risk of major bleeding events (Pradaxa® 150mg vs. warfarin, HR 0.60, CI 0.36-0.99)
• 44% lower risk of major or clinically relevant bleeding (Pradaxa® 150mg vs. warfarin, HR 0.56, CI 0.45-0.71)
• 33% lower risk of total bleeding events (Pradaxa® 150mg vs. warfarin, HR 0.67, CI 0.59-0.77)

“The presented data from the different RE-COVER trials sub-analyses show that the efficacy and safety profile of Pradaxa® 150 mg in the treatment of acute DVT or PE is very consistent, without a need for dose adjustments,” commented Professor Klaus Dugi, Corporate Senior Vice President Medicine, Boehringer Ingelheim. “The data confirm the potential of Pradaxa® as an effective treatment with safety benefits for a wide range of patients, including older patients and patients with a moderately impaired renal function.”

Pradaxa® is already widely approved for stroke prevention in atrial fibrillation and for primary prevention of venous thromboembolism following total hip replacement or total knee replacement surgery.7 Collective clinical experience across all licensed indications exceeds five years, with two million patient-years placing Pradaxa® first among the novel oral anticoagulants.^8,9

NOTES TO THE EDITORS

About Pradaxa® (dabigatran etexilate) DVT and PE clinical trials
The data presented during the American Society of Hematology Annual Meeting included patients who took part in the RE-COVER™ and RE-COVER™ II phase III clinical trials. Patient characteristics were defined as follows:

• Age groups of patients under 65, 65 to 75, and over 75 years; and in another grouping, patients either younger or older than 80⁴
• Renal dysfunction considered low, mild or moderate (Creatinine clearance over or equal to 80 mL/minute – low, of 50 to 80 mL/minute – mild, or 30 to less than 50 mL/minute – moderate)³
• Simultaneous use of anti-inflammatories or aspirin, or not (12hr NSAID and low-dose ASA)1
• Presence or absence of cancer at any time during the study²

Boehringer Ingelheim clinical trials investigating Pradaxa® in the prevention and treatment of DVT and PE (collectively venous thromboembolism or VTE) are part of the extensive RE-VOLUTION® trial programme. Results from phase III trials demonstrate Pradaxa® has a good efficacy and safety profile across primary prevention and treatment of acute as well as prevention of recurrent DVT and PE events:^{5,6,10,11,12,13}

• In preventing VTE after total knee or hip replacement surgery, Pradaxa® has been studied in four trials (RE-NOVATE®, RE-NOVATE II®, RE-MODEL™ and RE-MOBILIZE®) including more than 10,000 patients. The trials have shown that Pradaxa® is as effective as once daily enoxaparin with a similar safety profile.^{11 -14}
• For the treatment of acute DVT or PE, Pradaxa® has been studied in two trials (RE-COVER™ and RE-COVER™ II) including over 5,000 patients. The trials have shown that Pradaxa® is comparable to standard of care, and has a favourable safety profile.^5,6
• For the prevention of recurrent DVT or PE, which was investigated in two trials (RE-MEDY™ and RE-SONATE™) including over 4,000 patients, Pradaxa® is comparable to warfarin and showed a significant reduction in the incidence of recurrent DVT or PE compared to placebo. Major bleeding rates observed were low and confirmed again the favourable safety profile.¹⁰

About Pradaxa® (dabigatran etexilate)
Clinical experience of Pradaxa® (dabigatran etexilate) exceeds that of all other novel oral anticoagulants, equating to over 2 million patient-years in all licensed indications worldwide.⁹ Pradaxa® has already been in the market for more than 5 years and is approved in over 100 countries. Currently approved indications for Pradaxa® are:⁷

• Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (AF) and a risk factor for stroke
• Primary prevention of venous thromboembolic events in patients undergoing elective total hip replacement surgery
• Primary prevention of venous thromboembolic events in patients undergoing elective total knee replacement surgery

In June 2013 Boehringer Ingelheim started submitting new applications to regulatory authorities for Pradaxa® for the following indications:⁹

• Treatment of acute deep vein thrombosis (DVT) and/or pulmonary embolism (PE) and prevention of related death
• Prevention of recurrent deep vein thrombosis (DVT) and/or pulmonary embolism (PE) and related death

Pradaxa®, a direct reversible thrombin inhibitor (DTI), was the first widely approved drug in a new generation of direct oral anticoagulants, available to target a high unmet medical need in the prevention and treatment of acute and chronic thromboembolic diseases.^7,15 Potent antithrombotic effects are achieved with direct thrombin inhibitors by specifically blocking the activity of thrombin, the central enzyme in the process responsible for clot (thrombus) formation.¹⁶ In contrast to vitamin-K antagonists, which variably act via different coagulation factors, Pradaxa® provides effective, predictable and reproducible anticoagulation with a low potential for drug-drug interactions and no drug-food interactions, without the need for routine coagulation monitoring or dose adjustment.^{15, 17}

About Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE)
A venous thrombosis is a blood clot (thrombus) that forms within a vein. Most often, it develops in the deep veins of the leg or pelvis and is known as a deep vein thrombosis (DVT). An embolism occurs if the clot, or a part of it, breaks off from the site of formation and travels through the circulatory system. If the clot lodges in the lung then a potentially fatal pulmonary embolism (PE) may occur.¹⁸ Venous thromboembolism (VTE) is estimated to be the third most common cardiovascular disorder after coronary heart disease and stroke.¹⁹ The risk of experiencing a recurrent DVT or PE event increases cumulatively in patients who are not treated with standard therapy, up to 40% after 10 years.20Anticoagulant treatment is the standard therapy against venous blood clots.²¹

For more information on the prevalence, medical background and societal burden of DVT or PE please visit: http://www.newshome.com/dvt-pe.aspx

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 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 endeavours.

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 U.S., the UK or Canada.

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*Important note: Pradaxa® (dabigatran etexilate) is currently not approved for the acute treatment of DVT or PE.

References:
1. Schulman S, et al. Influence Of Concomitant NSAID Or ASA On The Efficacy and Safety Of Dabigatran Versus Warfarin For The Treatment Of Acute Venous Thromboembolism: A Pooled Analysis From RE-Cover and RE-Cover II. Poster presentation #1136 on Saturday 7 December 2013 at American Society of Hematology Annual Meeting and Exposition, New Orleans, Louisiana, USA.
2. Schulman S, et al. Influence Of Active Cancer On The Efficacy and Safety Of Dabigatran Versus Warfarin For The Treatment Of Acute Venous Thromboembolism: A Pooled Analysis From RE-Cover and RE-Cover II. Poster presentation #582 on Monday 9 December 2013 at American Society of Hematology Annual Meeting and Exposition, New Orleans, Louisiana, USA.
3. Schulman S, et al. Influence Of Renal Function On The Efficacy and Safety Of Dabigatran Versus Warfarin For The Treatment Of Acute Venous Thromboembolism: A Pooled Analysis From RE-Cover and RE-Cover II. Poster presentation #212 on Monday 9 December 2013 at American Society of Hematology Annual Meeting and Exposition, New Orleans, Louisiana, USA.
4. Schulman S, et al. Influence Of Age On The Efficacy and Safety Of Dabigatran Versus Warfarin For The Treatment Of Acute Venous Thromboembolism: A Pooled Analysis Of RE-Cover and RE-Cover II. Poster presentation #2375 on Sunday 8 December 2013 at American Society of Hematology Annual Meeting and Exposition, New Orleans, Louisiana, USA.
5. Schulman S. et al. Dabigatran versus warfarin in the Treatment of Acute Venous Thromboembolism. N Engl J Med. 2009;361:2342–52.
6. Schulman S, et al. Safety of dabigatran versus warfarin for acute venous thromboembolism: pooled analyses of RE-COVER and RE-COVER II. Oral presentation. Presented on July 3, 2013 at the 2013 Congress of the International Society on Thrombosis and Haemostasis.
7. Pradaxa European Summary of Product Characteristics, 2013
8. Ezekowitz M, et al. RE-LY and RELY-ABLE: Long-term Follow-up of Patients With Nonvalvular. Atrial Fibrillation Receiving Dabigatran Etexilate for Up to 6.7 Years. Oral presentation #10684 on Monday 18 November 2013 at the American Heart Association’s Scientific Sessions, Dallas, Texas, USA.
9. Boehringer Ingelheim data on file.
10. Schulman S, et al. Extended use of dabigatran, warfarin or placebo in venous thromboembolism. N Engl J Med. 2013;368:709-18
11. Eriksson BI. et al. Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial. The Lancet. 2007;370:949–56.
12. Eriksson BI. et al. Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty (RE-NOVATE II*). A randomised, doubleblind, non-inferiority trial. J Thromb Haemost. 2011;105(4):721-9.
13. Eriksson BI. et al. Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial. J Thromb Haemost. 2007;5:2178–85.
14. Ginsberg JS. et al. Oral thrombin inhibitor dabigatran etexilate vs North American enoxaparin regimen for prevention of venous thromboembolism after knee arthroplasty surgery. J Arthoplasty. 2009;24(1)1–9.
15. Stangier J. Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate. Clin Pharmacokinet. 2008;47(5):285–95.
16. Di Nisio M. et al. Direct thrombin inhibitors. N Engl J Med. 2005;353:1028–40.
17. Stangier J, et al. Pharmacokinetic Profile of the Oral Direct Thrombin Inhibitor Dabagitran Etexilate in Healthy Volunteers and Patients Undergoing Total Hip Replacement. J Clin Pharmacol. 2005;45:555–63.
18. Centers for Disease Control. Are you at risk for deep vein thrombosis? Available at: www.cdc.gov/Features/Thrombosis/index.html.
19. Goldhaber SZ. Pulmonary embolism thrombolysis: a clarion call for international collaboration. J Am Coll Cardiol. 1992;19:246-247.
20. Prandoni P. et al. The risk of recurrent venous thromboembolism after discontinuing anticoagulation in patients with acute proximal deep vein thrombosis or pulmonary embolism. A prospective cohort study in 1,626 patients. Haematologica. 2007;92(02):199–205.
21. Weitz JL. Emerging anticoagulants for the treatment of venous thromboembolism. J Thromb Haemost. 2006;96(3):274-84

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