A post-hoc analysis of five Phase III trials compared the management and outcomes of a major bleeding event in patients taking Pradaxa® (dabigatran etexilate) with major bleeding events in patients taking warfarin. The results are now published online in Circulation. The analysis showed that the 30-day mortality (death within one month) related to a major bleeding event was significantly lower with Pradaxa® than with warfarin in atrial fibrillation patients requiring long-term treatment in the RE-LY® trial. In addition, Pradaxa® treated patients could leave the Intensive Care Unit faster than warfarin treated patients.
When major bleeding did occur in the trials analysed, the patients were managed using standard strategies and treatment options currently available in the clinical setting, both for Pradaxa® and warfarin.(4) This better outcome in case of a major bleed, even in the absence of a specific antidote, provides crucial support for the positive benefit-risk profile of Pradaxa®.
"We found that atrial fibrillation patients, who had a major bleed during therapy, actually had better outcomes if they took dabigatran than if they took warfarin," said Prof. Sam Schulman, Division of Hematology and Thromboembolism, McMaster University, Hamilton, Canada. "It is reassuring to see that existing standard strategies, such as stopping the drug and replacing blood, work just as well with dabigatran treatment as they do with warfarin treatment – if not even better."
The analysis also found that patients who had a major bleeding event during Pradaxa® treatment were usually at higher baseline risk compared to patients with major bleeding events on warfarin - Pradaxa® patients were older, had worse renal function and more often used concomitant treatment with aspirin or non-steroid anti-inflammatory agents.(4)
The pooled post-hoc analysis featured data from five large long-term Phase III trials including the pivotal RE-LY® trial comparing Pradaxa® with warfarin for stroke prevention in non-valvular atrial fibrillation and trials in acute treatment / secondary prevention of venous thromboembolism (VTE). The trials had durations of six to 36 months and included 27,419 patients. Key results are:(4)
- Lower 30-day mortality in case of a first major bleed in the combined Pradaxa® treatment group compared to the warfarin group in atrial fibrillation patients (odds ratio 0.56, p=0.009)
- When outcomes for all indications were combined and adjusted, the data showed a strong trend to lower mortality for Pradaxa® compared to warfarin (odds ratio 0.66, p=0.051)
- One day shorter stay in the intensive care unit required for Pradaxa® patients (mean 1.6 nights) compared with warfarin patients (mean 2.7 nights; p=0.01)
- Most major bleeds were managed mainly with supportive care using standard clinical measures. The most common measures used were blood transfusions and plasma transfusions.
"These findings provide important and reassuring insights for both physicians and patients", commented Professor Klaus Dugi, Corporate Senior Vice President Medicine, Boehringer Ingelheim. "They demonstrate that even in the absence of a specific antidote, when existing standard strategies are used, patients can expect a better outcome with Pradaxa® than with warfarin should a major bleed 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).(5,6) The most recent FDA update reports the results of a Mini-Sentinel assessment that indicated 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®.(6)
Pradaxa® is already widely approved for stroke prevention in atrial fibrillation and for primary prevention of VTE following total hip replacement or total knee replacement surgery.7 The extensive in-market experience of over 2 million patient-years in all licensed indications puts Pradaxa® first among the novel oral anticoagulants.(8)
About Pradaxa® (dabigatran etexilate)
Pradaxa® is approved in over 100 countries worldwide.(8) It is licensed for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation and for the primary prevention of venous thromboembolism in patients undergoing total hip replacement or total knee replacement surgery.(7)
Pradaxa®, a direct thrombin inhibitor (DTI),(9) was the first of a new generation of direct oral anticoagulants 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 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.
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 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.
1. Marini C, et al. From a Population-Based Study Contribution of Atrial Fibrillation to Incidence and Outcome of Ischemic Stroke: Results From a Population-Based Study. Stroke. 2005;36:1115-9.
2. 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 Syst Rev. 2005;(3):CD001927.
3. Levine MN, et al. Hemorrhagic complications of anticoagulant treatment. Chest. 2001;119(1,Suppl.):108S–21S.
4. Majeed A, et al. Management and outcomes of major bleeding during treatment with dabigatran or warfarin. Circulation. 2013; published online before print September 30 2013, doi:10.1161/CIRCULATIONAHA.113.00233
5. European Medicines Agency Press release - 25 May 2012: EMA/337406/2012. European Medicines Agency updates patient and prescriber information for Pradaxa. http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2012/05/news_detail_001518.jsp&mid=WC0b01ac058004d5c1 Last accessed 7 October 2013.
6. FDA Drug Safety Communication: Update on the risk for serious bleeding events with the anticoagulant Pradaxa (dabigatran) - 2 November 2012 http://www.fda.gov/Drugs/drugsafety/ucm326580.htm Last accessed 7 October2013.
7. Pradaxa® European Summary of Product Characteristics, 2013
8. Boehringer Ingelheim data on file.
9. Di Nisio M, et al. Direct thrombin inhibitors. N Engl J Med. 2005;353:1028-40.