Value through Innovation30 August 2014
28 August 2011

Pradaxa® (dabigatran etexilate, 150mg bid) shows significant reduction in the risk of stroke over warfarin in patients with atrial fibrillation taking antiplatelet or other concomitant therapies

Paris, France, 28 August 2011 – New data from two RE-LY® trial sub-group analyses show that dabigatran etexilate 150mg bid consistently reduces the risk of stroke in atrial fibrillation (AF) compared to well-controlled warfarin, irrespective of whether patients use antiplatelet1 or other concomitant therapies, such as the anti-arrhythmics amiodarone or verapamil.2 The relative benefits of dabigatran etexilate over well-controlled warfarin in the overall results of RE-LY®3,4 were consistent across patients using these concomitant treatments .1,2 The data was presented at the European Society of Cardiology (ESC) Congress 2011, in Paris, France.

Dabigatran etexilate 150mg bid is the only novel oral anticoagulant approved for stroke prevention in AF shown superior to well-controlled warfarin (median TTR 67%5,6) in an intention to treat analysis.3,4 These groundbreaking results were demonstrated in RE-LY®, a PROBE trial (prospective, randomized, open-label with blinded endpoint evaluation), comparing two fixed doses of the oral direct thrombin inhibitor dabigatran etexilate (110mg and 150mg bid) each administered in a blinded manner, with open label warfarin. 3,7

The new findings are significant because the long time standard of care warfarin is known to interact with numerous medications, including many common co-medications metabolised via the Cytochtrome P450 pathway. In addition, approximately one in five patients with AF are being prescribed antiplatelet therapy alongside warfarin for conditions such as coronary artery disease, acute coronary syndrome, or recent coronary artery stenting.8 The safety of antiplatelet therapy in combination with anticoagulants has been a physician concern, with the combination shown to increase major bleeding over the use of anticoagulation alone.8

The present antiplatelet analysis assessed the combined use of aspirin and/ or clopidogrel in 8,507 patients taking either dabigatran etexilate (150mg bid or 110mg bid) or well-controlled warfarin.1 The second analysis evaluated interactions with dabigatran etexilate and the use of P-glycoprotein inhibitors such as amiodarone, verapamil and diltiazem.2 Results showed:

  • As seen in the overall RE-LY® trial, dabigatran etexilate 150mg bid maintained its efficacy benefits over well-controlled warfarin for the prevention of stroke and systemic embolism (SEE) in AF patients using antiplatelet therapy (HR=0.76, 95% CI=0.58-0.99), with similar rates of major bleeding events compared to warfarin (HR=0.94; 95% CI=0.79-1.12) and non-significant p-values for interaction indicating consistency of this sub-group compared to the overall RE-LY® trial 1
  • Dabigatran etexilate 110mg bid remained as effective as well-controlled warfarin in preventing stroke/SEE in patients in AF using antiplatelet therapy (HR=0.93, 95%CI=0.72-1.20, p-value for interaction = ns), with reduction in major bleeding events (HR=0.84, 95% CI=0.70-1.00, p-value for interaction = ns)1
  • Concomitant antiplatelet use increased the risk of major bleeding (HR=1.60, 95% CI=1.41-1.81) in all treatment arms, with no difference between patients treated with dabigatran etexilate or warfarin1
  • Use of P-glycoprotein inhibitors*, such as amiodarone, verapamil and diltiazem, in combination with dabigatran etexilate did not alter the overall benefits of dabigatran etexilate for stroke prevention, major bleeding or intracranial hemorrhage relative to well-controlled warfarin.2
Prof. Antonio Dans, Department of Medicine, University of the Philippines College of Medicine

Prof. Antonio Dans, Department of Medicine, University of the Philippines College of Medicine

Prof. Antonio Dans, Department of Medicine, University of the Philippines College of Medicine said, "Even though combining antiplatelets with an anticoagulant bears the risk of increased bleeding, it is often required in AF patients with coronary artery disease. The new results are thus an important finding for clinical practice, because they show that the benefits of dabigatran etexilate over warfarin for the prevention of stroke in AF remain unchanged when patients use concomitant antiplatelet therapy."

Dabigatran etexilate was recently approved for stroke prevention in AF in the EU following previous approvals in the US, Canada, Japan, Australia and many other countries across five continents.6,9-12

NOTES TO EDITORS

About AF and stroke
AF is the most common sustained heart rhythm condition,13 with one in four adults over the age of 4014 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.14,15 Up to three million people worldwide suffer strokes related to AF each year.16-19 Strokes due to AF tend to be severe, with an increased likelihood of death (20%), and disability (60%).20 Many AF-related strokes can be prevented with appropriate antithrombotic therapy.21 AF-related strokes currently represent a significant cost to healthcare systems across Europe. Given AF-related strokes tend to be more severe this results in direct medical patient costs which are higher than non AF-related strokes annually (€11,799 vs €8,817 P < 0.001).22

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 well controlled (INR 2.0-3.0, median TTR 67%) open label warfarin.3-5 Patients were followed-up in the study for a median of 2 years with a minimum of 1 year follow-up.10,11

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:3,4

  • Significant reduction in the risk of stroke and systemic embolism – including haemorrhagic 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.

About dabigatran etexilate

Dabigatran etexilate is at the forefront of a new generation of oral anticoagulants/direct thrombin inhibitors (DTIs)23 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 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.

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 2010, Boehringer Ingelheim posted net sales of about 12.6 billion euro while spending almost 24% of net sales in its largest business segment Prescription Medicines on research and development.

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 or Canada.

References
1Dans A, et al. Concomitant use of antiplatelet therapy with dabigatran or warfarin in the Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY®) trial. Presented at the European Society of Cardiology Congress 2011, 28th August 2011.
2Reilly P, et al. Concomitant use of P-glycoprotein inhibitors with dabigatran or warfarin in the Randomized Evaluation of Long-term anticoagulation therapY (RE-LY) trial. Presented at the European Society of Cardiology Congress 2011, 28th August 2011.
3Connolly SJ, et al. Dabigatran versus Warfarin in Patients with Atrial Fibrillation. N Engl J Med 2009; 361:1139-51.
4Connolly SJ, Ezekowitz MD, Yusuf S, Reilly PA, Wallentin L: Newly identified events in the RE-LY® trial. N Engl J Med 2010; 363(19): 1875-1876.
5FDA Advisory Committee Briefing Document, September 2010, http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/CardiovascularandRenalDrugsAdvisory Committee/UCM226009.pdf.
6Pradaxa®, Summary of Product Characteristics, August 2011. Europe.
7Ezekowitz MD, et al. Rationale and Design of RE-LY®: Randomized Evaluation of Long-Term Anticoagulation Therapy, Warfarin, Compared with Dabigatran. American Heart Journal 2009; 157:805-810.
8Shireman TI, et al. Combined anticoagulant–antiplatelet use and major bleeding events in elderly atrial fibrillation patients. Stroke 2004 35:2362-2367.
9U.S. Food and Drug Administration – Pradaxa® Prescribing Information.Oct 19th, 2010.
10Health Canada – PRADAX™ Product Monograph. Oct 26th, 2010.
11Prazaxa® product information, January 2011, Japan.
12Pradaxa®, Australian Product information, approved April 29th, 2011.
13Stewart S, Murphy N, Walker A, et al. Cost of an emerging epidemic: an economic analysis of atrial fibrillation in the UK. Heart 2004; 90:286-92.
14Lloyd-Jones DM, Wang TJ, Leip EP, et al. Lifetime risk for development of atrial fibrillation: the Framingham Heart Study. Circulation 2004; 110:1042-6.
15Fuster V, Rydn LE, Cannom DS, et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients with Atrial Fibrillation – executive summary. Circulation 2006; 114:700-52.
16Kannel WB, et al. Final Draft Status of the Epidemiology of Atrial Fibrillation. Med Clin North Am. 2008; 92(1): 17–40.
17Atlas of Heart Disease and Stroke, World Health Organization, September 2004. Viewed Dec 2010 at www.who.int/cardiovascular_diseases/en/cvd_atlas_15_burden_stroke.pdf .
18Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 1991: 22(8);983-8.
19Marini C, De Santis F, Sacco S, et al. Contribution of atrial fibrillation to incidence and outcome of ischaemic stroke: results from a population-based study. Stroke 2005; 36:1115-9.
20Lin HJ, Wolf PA, Kelly-Hayes M, et al. Stroke severity in atrial fibrillation: the Framingham study. Stroke 1996; 27:1760-4.
21Hart RG, Pearce LA, Aguilar MI, et al. Meta-Analysis: antithrombotic therapy to prevent stroke in patients who have non-valvular atrial fibrillation. Ann Intern Med 2007; 146:857-67.
22Bruggenjurgen B et al. The Impact of Atrial Fibrillation on the Cost of Stroke: The Berlin Acute Stroke Study. Value Health 2007; 10: 137–43.
23Di Nisio M, et al. Direct Thrombin Inhibitors. N Engl J Med 2005; 353:1028-40.

*P-glycoprotein inhibitors work to inhibit the P-glycoprotein transporter which is a membrane-associated protein that transports various substrates across cell membranes of the body, thereby affecting the bioavailability of drugs

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    Boehringer Ingelheim

    Media & PR
    Dr Reinhard Malin
    Binger Strasse 173
    55216 Ingelheim am Rhein

    GERMANY

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