Boehringer Ingelheim today announced that it had discontinued a phase 2 trial of its anticoagulant drug dabigatran (Pradaxa) in patients with mechanical heart valves. As reported here in October, the company had previously terminated one arm of the study after an interim review of the data by the trial’s Data Safety Monitoring Board
The RE-ALIGN trial was an open-label, 12-week randomized comparison of warfarin and dabigatran in 400 patients who received a mechanical valve. The first arm randomized patients during their initial hospital stay. The second arm randomized patients more than 3 months after their surgery.
Despite the recent advent of novel oral anticoagulants, the much-maligned warfarin remains the only current option available for patients who have received a mechanical valve. Now the first trial to explore this indication for one of the newer oral anticoagulants has been stopped.
In October Boehringer told members of its speakers bureau that the post-surgery arm of the trial had been terminated due to “lower than projected plasma levels of dabigatran in this population, and an imbalance in reports of thromboembolic events (primarily strokes).” At that time the company said the second arm of the trial would continue.
Dabigatran has been approved in Europe, but not in the United States, for venous thromboemoblism (VTE) prevention after knee and hip replacement surgery. Rivaroxaban (Xarelto) has been approved for both VTE prevention in the United States and Europe. To date there have been no head-to-head comparisons of the newer anticoagulants.
According to a recent study in Circulation: Cardiovascular Quality and Outcomes dabigatran now has about 19% of the oral anticoagulant market, mostly for the approved treatment of AF “but increasingly for off-label indications” as well. A recent letter in the Journal of the American College of Cardiology provided information about the off-label use of dabigatran in two mechanical valve patients. Both patients developed thrombosis after switching to dabigatran from warfarin. The authors noted that “while there is a wealth of data and clinical experience on dosing and therapeutic response to warfarin in this context, these data are unavailable for dabigatran.” Although newer anticoagulants “hold tremendous promise for mechanical valve anticoagulation… there is a need for dose-finding studies and clinical trials to demonstrate safety and efficacy in this setting.”
Here is the press release from Boehringer:
Boehringer Ingelheim discontinues Phase II trial in patients with artificial heart valves
For Non-US, Non-UK & Non-Canadian Media Only
Ingelheim, Germany, 11 December 2012 – Boehringer Ingelheim has taken the voluntary decision to discontinue treatment with the oral anticoagulant dabigatran etexilate in a phase II clinical trial in patients with artificial heart valves. The company based its decision on interim results from the phase II RE-ALIGNTM trial which suggested that the investigated dosing regimen did not achieve the desired results in this patient population.
“Despite the trial not having delivered the desired interim results, we believe that we have provided data to contribute to the better understanding of this particular patient group and indication. It also underlines the urgent need for new advancements in anticoagulation for patients with artificial heart valves.” commented Professor Klaus Dugi, Corporate Senior Vice President Medicine Boehringer Ingelheim.
“Other studies with dabigatran etexilate are continuing and dabigatran remains one of the best investigated anticoagulants, having been studied in the RE-VOLUTION program with more than 40.000 patients involved.”
The decision on the RE-ALIGN® clinical research project does not alter the positive benefit/risk profile of Pradaxa® in the already approved and established indications in preventing strokes and systemic embolism in patients with non-valvular atrial fibrillation as well as in preventing venous thromboembolism following elective knee- or hip-replacement-surgery.1
Dabigatran etexilate is not approved and not recommended for use in patients with prosthetic (artificial) heart valves. The presence of an artificial heart valve in patients is a clinical condition that is distinct from those for which dabigatran is an approved treatment. In view of the interim trial results, the company is currently in discussions with the relevant regulatory authorities to reinforce the product label text accordingly and to discuss appropriate communication to physicians and relevant health care providers.
The effectiveness and safety profile of dabigatran etexilate in its licensed indications is proven and well documented in an extensive clinical trial programme,1-6 which led to world-wide regulatory approvals in over 80 countries to date.7
The long term benefit of the treatment has just recently been demonstrated in a long-term clinical trial in the prevention of stroke and systemic embolism in patients with atrial fibrillations, providing data from over four years of clinical treatment.8 The positive benefit-risk-profile of dabigatran was also recently reconfirmed by the European Medicines Agency9 and the U.S. Food and Drug administration (FDA).10Clinical experience with dabigatran continues to grow and equates to over one million patient-years in all licensed indications11 and exceeding that of all other novel oral anticoagulants.12
Boehringer Ingelheim remains in continuous communication with all regulatory and clinical trial authorities to ensure patient safety, which is of the utmost importance to the company.
NOTES TO THE EDITORS
Stroke Prevention in Atrial Fibrillation
AF is the most common sustained heart rhythm condition, with one in four adults over the age of 40 developing the condition in their lifetime.13,14 People with AF are more likely to experience blood clots, which increases the risk of stroke by five-fold.15,16 Up to three million people worldwide suffer strokes related to AF each year.17,18 Strokes due to AF tend to be severe, with an increased likelihood of death (20%), and disability (60%).19
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.20 Appropriate anticoagulation therapy can help to prevent many types of AF-related strokes and improve overall patient outcomes.21
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.22,23 Given AF-related strokes tend to be more severe, this results in higher direct medical patient costs annually.24 The total societal burden of AF reaches €13.5 billion per year in the European Union alone.13
About dabigatran etexilate
Dabigatran etexilate is at the forefront of a new generation of oral anticoagulants/direct thrombin inhibitors (DTIs)25 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.
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.
1Pradaxa®, European Summary of Product Characteristics, 2012.
2Connolly SJ, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361:1139-51.
3Connolly SJ, et al. Newly identified events in the RE-LY trial. N Engl J Med 2010; 363(19):1875-6.
4Schulman S, et al. Dabigatran etexilate versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009; 361:2342-52.
5Eriksson 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.
6Eriksson BI, et al. Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial. Lancet 2007; 370: 949–56.
7Boehringer Ingelheim data on file.
8Connolly 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.
9European 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
10Food 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
11Boehringer Ingelheim data on file.
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17Global Atlas on Cardiovascular Disease Prevention and Control, World Health Organization in collaboration with the World Heart Federation and the World Stroke Organization 2011. Viewed May 2012 at http://www.world-heart-federation.org/fileadmin/user_upload/documents/Publications/Global_CVD_Atlas.pdf.
18Atlas 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
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20Andersen KK, et al. Hemorrhagic and ischemic strokes compared: stroke severity, mortality, and risk factors. Stroke 2009; 40:2068-72.
21Hart RG, et al. Meta-analysis: Antithrombotic Therapy to Prevent Stroke in Patients Who Have Nonvalvular Atrial Fibrillation Ann Intern Med. 2007;146:857-67.
22Coyne KS, et al. Assessing the direct costs of treating nonvalvular atrial fibrillation in the United States. Value Health 2006; 9:348-56.
23Ringborg 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.
24Brüggenjürgen B, et al. The impact of atrial fibrillation on the cost of stroke: the Berlin acute stroke study. Value Health 2007;10:137-43.
25Di Nisio M, et al. Direct thrombin inhibitors. N Engl J Med 2005; 353:1028-40.