The new results support that Pradaxa® can also be beneficial for patients with multiple co-morbidities and further reinforce the consistent efficacy and safety profile of Pradaxa® that was shown in the main trial and various previous RE-LY® sub-analyses in several other patient subgroups, including patients with type 2 diabetes.(4-8)
"Atrial fibrillation and heart failure frequently coexist and are known to worsen patient prognoses. Heart failure is a specific risk factor for stroke in atrial fibrillation patients, therefore these patients especially need anticoagulant treatment," said Dr. Jorge Ferreira, Cardiologist, Hospital Santa Cruz, Lisbon, Portugal. "However, anticoagulation with a vitamin-K-antagonist in these patients is often associated with poor INR control. This results in more challenging management and impacts the overall efficacy and safety of VKA treatment."
From a total of 18,113 patients with non-valvular AF participating in the landmark RE-LY® trial, 4,904 patients (27%) had previous symptomatic HF.(2,3) In the sub-analysis comparing the main outcomes of stroke and systemic embolism as well as major bleeding between patients with and without previous symptomatic heart failure, the results were consistent with no statistically significant differences (p-values for interaction) between the two patient groups.(1) These results show that Pradaxa® is a valuable treatment alternative for patients who suffer from both atrial fibrillation and heart failure.
"These new results from RE-LY® highlight the value of Pradaxa® also for those atrial fibrillation patients that are traditionally considered difficult to treat and have multiple co-morbidities," commented Professor Klaus Dugi, Corporate Senior Vice President Medicine, Boehringer Ingelheim.
Pradaxa® 150mg bid is the only novel oral anticoagulant, study of which has shown a significant reduction in the incidence of ischaemic strokes in patients with non-valvular AF compared to warfarin (67% median time in therapeutic range9), offering a relative risk reduction of 25%.2,3 Nine out of ten strokes in AF patients are ischemic strokes,(10) 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.(11)
Furthermore in the main RE-LY® trial, Pradaxa® 150mg twice daily provided a 36% reduction in the overall risk of stroke versus warfarin, demonstrating superior protection.(2,3) Pradaxa® 110mg twice daily, indicated for certain patients, was as effective as warfarin for the prevention of stroke and systemic embolism.(2,3) Both doses of Pradaxa® were associated with significantly lower total, intracranial and life-threatening bleeding compared to warfarin.(2,3) Pradaxa® 150mg twice daily showed a similar risk of major bleeds versus warfarin while Pradaxa® 110mg twice daily demonstrated a significantly lower risk.(2,3) The RE-LY® trial was performed in PROBE design, i.e. prospective, randomized, open-label with blinded endpoint evaluation.
Pradaxa® is already widely approved for the prevention of stroke and systemic embolism in patient with non-valvular atrial fibrillation and for primary prevention of VTE following total hip replacement or total knee replacement surgery.(9) Over 1.6 million patient years of experience in all licensed indications in over 100 countries support Pradaxa® as the leading novel oral anticoagulant.(12)
About Pradaxa® (dabigatran etexilate)
Pradaxa® is approved in over 100 countries worldwide.(12) 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.(9)
Pradaxa®, a direct thrombin inhibitor (DTI),13 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.
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 twice daily) each administered in a blinded manner, with open label warfarin (INR 2.0-3.0, median TTR 67%9).(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).(2,3)
Compared to warfarin, dabigatran etexilate showed in the trial:(2,3)
- Significant reduction in the risk of stroke and systemic embolism - including ischaemic strokes with dabigatran etexilate 150mg twice daily
- Similar rates of stroke/systemic embolism with dabigatran etexilate 110mg twice daily (110mg indicated for certain patients)
- Significantly lower major bleeding events with dabigatran etexilate 110mg twice daily
- Significantly lower life threatening and intracranial bleeding with both doses
- Significant reduction in vascular mortality with dabigatran etexilate 150mg twice daily.
About the new RE-LY® sub-analysis
From a total of 18,113 patients with non-valvular AF participating in the landmark RE-LY® trial, 4,904 patients (27%) had previous symptomatic HF.(2,3) Despite the challenges of VKA therapy in these patients, the heart failure patients included in the RE-LY® trial spent 63.8% of their time within the therapeutic range (INR 2.0-3.0).(1) In the sub-analysis, the results were consistent between patients with and without HF, showing that Pradaxa® is a valuable treatment alternative for patients with AF and HF:(1)
- Annual rates of stroke and systemic embolism were 1.44% per year for Pradaxa® 150mg twice daily and 1.90% per year for Pradaxa® 110mg twice daily versus 1.92% per year for warfarin
- Annual rates of major bleeding were 3.10% per year for Pradaxa® 150mg twice daily and 3.26% per year for Pradaxa® 110mg twice daily versus 3.90% per year for warfarin
- Rates of intracranial haemorrhage, one of the most devastating complications of anticoagulation,14 were 0.26% per year for Pradaxa® 150mg twice daily and 0.22% per year for Pradaxa® 110mg twice daily versus 0.65% per year for warfarin
Stroke Prevention in Atrial Fibrillation (AF)
AF is the most common sustained heart rhythm condition,(15) with one in four adults over the age of 4015 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.(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 and frequently leading to severe debilitation.(10) Appropriate anticoagulation therapy can help to prevent many types of AF-related strokes and improve overall patient outcomes.(20) Pradaxa® 150mg twice daily is the only novel oral anticoagulant, for which its pivotal trial vs. warfarin has shown a statistically significant and clinically relevant reduction of both ischaemic and haemorrhagic strokes.(2,3) Additionally, treatment with Pradaxa® is associated with substantially lower rates of both fatal and non-fatal intracranial haemorrhage, one of the most devastating complications of anticoagulation therapy.(14,21)
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-related stroke reaches €13.5 billion per year in the European Union alone.(25)
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. Ferreira J, et al. Dabigatran compared with warfarin in patients with atrial fibrillation and symptomatic heart failure: a subgroup analysis of the RE-LY trial. Eur J of Heart Failure. 2013; doi 10.1093/eurjhf/hft111.
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. Diener HC, et al. Dabigatran compared with warfarin in patients with atrial fibrillation and previous transient ischaemic attack or stroke: a subgroup analysis of the RE-LY trial. Lancet Neurology. 2010;9:1157–1163.
5. Wallentin L, et al. Efficacy and safety of dabigatran compared with warfarin at different levels of international normalised ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial. Lancet. 2010;376:975–983.
6. Eikelboom JW, et al. Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) trial. Circulation. 2011;123:2363–2372.
7. Oldgren J, et al. Risks for stroke, bleeding, and death in patients with atrial fibrillation receiving dabigatran or warfarin in relation to the CHADS2 score: a subgroup analysis of the RE-LY trial. Ann Intern Med. 2012;155:660–668.
8. Darius H, et al. Comparison of Dabigatran versus Warfarin in Diabetic Patients with Atrial Fibrillation: Results from the RE-LY Trial. Presented at the American Heart Association's Scientific Sessions 2012, Los Angeles, USA. Abstract No. 15937.
9. Pradaxa European Summary of Product Characteristics, 2013
10. Andersen KK, et al. Hemorrhagic and ischemic strokes compared: stroke severity, mortality, and risk factors. Stroke. 2009;40:2068−72.
11. NHLBI website. “What is Stroke?” Available at: http://www.nhlbi.nih.gov/health/health-topics/topics/stroke. Accessed on: October 10, 2012.
12. Boehringer Ingelheim data on file.
13. Di Nisio M, et al. Direct thrombin inhibitors. N Engl J Med 2005; 353:1028-40.
14. Hart RG, et al. Intracranial hemorrhage in atrial fibrillation patients during anticoagulation with Warfarin or Dabigatran: The RE-LY® Trial. Stroke. 2012;43(6):1511-1517.
15. Lloyd-Jones DM, et al. Lifetime risk for development of atrial fibrillation: the Framingham Heart Study. Circulation. 2004;110:1042-6.
16. Camm JA, et al. 2012 focused update of the ESC guidelines for the management of atrial fibrillation. Eur Heart J. 2012;33:2719-47.
17. Camm JA, et al. Guidelines for the management of atrial fibrillation. European Heart Journal .2010;31:2369–2429.
18. 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
19. Gladstone DJ, et al. Potentially Preventable Strokes in High-Risk Patients With Atrial Fibrillation Who Are Not Adequately Anticoagulated. Stroke. 2009;40:235-240.
20. 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.
21. Fang MC, et al. Death and disability from warfarin-associated intracranial and extracranial hemorrhages. Am J Med. 2007; 120:700 –705.
22. Coyne KS, et al. Assessing the direct costs of treating nonvalvular atrial fibrillation in the United States. Value Health 2006; 9:348-56.
23. 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.
24. 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.
25. Fuster V, et al. ACC/AHA/ESC 2006 Guidelines for the management of patients with atrial fibrillation – executive summary. Circulation. 2006;114:700-52.
*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 bid and 150 mg bid) each administered in a blinded manner, with open label warfarin.(2,3)