Value through Innovation31 October 2014
12 September 2012

Asian populations with atrial fibrillation (AF) benefit from better stroke prevention with Pradaxa® (dabigatran etexilate) compared to warfarin

Ingelheim, Germany, 12 September, 2012 – New findings presented today at the 2nd Asia Pacific Stroke Conference in Tokyo, Japan, have confirmed that in Asian populations, Pradaxa® (dabigatran etexilate) offers considerable benefits for the management of patients with atrial fibrillation (AF) from this region.1 The new sub-analysis of the RE-LY®* trial2,3 demonstrates consistently superior efficacy of Pradaxa® (150 mg) compared to warfarin for this particular patient group. Pradaxa® (150 mg) also shows larger risk reductions in the rate of haemorrhagic stroke and systemic embolism (SE) iin addition to providing greater reductions in major and total bleeding.1


There is a vast and increasing number of Asian people living with atrial fibrillation, with over 8 million people being treated for the condition in China alone.4 In the Asia-Pacific region, it is reported that over 5.1 million people suffer a first-ever AF-related stroke each year, with this number expected to rise dramatically as the population ages.


Regional and ethnical differences are known to account for variances in treatment responses and can ultimately affect patient outcomes.6 The sub-group analysis involved 2,782 patients with AF from ten Asian countries, which represented approximately 15% of the 18,113 patients involved within the RE-LY® trial.2,3 Key findings from the sub-group analysis included:

  • Benefits were consistent across both Asian and non-Asian groups with Pradaxa® 150mg bid showing larger risk reductions in stroke and SE compared to warfarin (rates of stroke/SE in Asia were 1.39% per year on Pradaxa® 150 mg bid, 2.50% per year on Pradaxa® 110 mg bid and as high as 3.06% per year on warfarin).
  • In Asian patients, both doses of Pradaxa® (150 mg and 110 mg bid) were associated with significantly lower rates of major bleeding events compared to warfarin (2.17% per year on Pradaxa® 150 mg bid, 2.22% per year on Pradaxa® 110 mg bid, and 3.82% per year on warfarin). A significant interaction (P=0.008) was seen between treatment and region when comparing Pradaxa® 150 mg bid vs. warfarin in Asian patients (HR 0.57, 95%CI 0.38-0.84) with that in non-Asian patients (HR 1.00, 95%CI 0.87-1.16)
  • Similarly, both doses of Pradaxa® were associated with significantly lower rates of total bleeding vs. warfarin. This benefit was even greater in Asian patients:
    • For Pradaxa® 110 mg bid vs. warfarin HR=0.48, 95%CI 0.40-0.56 for Asians and HR= 0.85, 95%CI 0.79-0.91 for non-Asians
    • For Pradaxa® 150 mg bid vs. warfarin HR= 0.60, 95%CI 0.51-0.70 for Asians and HR= 0.98, 95%CI 0.91-1.04 for non-Asians; (P<0.0001 before and after age adjustment)
Professor Gregory Lip, Professor of cardiovascular medicine at University of Birmingham Centre for Cardiovascular Sciences, UK

Professor Gregory Lip, Professor of cardiovascular medicine at University of Birmingham Centre for Cardiovascular Sciences, UK

"The findings of this study reaffirm the efficacy and safety of dabigatran etexilate for the treatment of people living with atrial fibrillation around the world," commented Professor Gregory Lip, Professor of cardiovascular medicine at University of Birmingham Centre for Cardiovascular Sciences, UK, on the findings. "This analysis provides doctors who are practicing in this region with further guidance and support for the use of this oral anticoagulant and the benefits that it can deliver to patients."


The sub-analysis also highlighted that there are known variances between populations especially when considering the time a patient is within the therapeutic range or the rates of intracranial haemorrhages. Asian patients with AF spent less time within the therapeutic range than non-Asian patients (mean 55% versus 66%) . This puts Asian patients at increased risk of stroke and systemic embolism. The rate of haemorrhagic stroke on warfarin treated patients was subsequently more than two-fold higher in Asian than in non-Asian patients (HR 2.4, 95% CI 1.3-4.7; p<0.05)1. These findings may also be important for countries with a high Asian sub-population like United States of America or the United Kingdom. The benefits of Pradaxa® now seen for the Asian population are consistent with the overall conclusions from the RE-LY® trial. Pradaxa® 150 mg bid is the only novel oral anticoagulant, study of which has shown a significant reduction of ischaemic strokes in patients with non-valvular AF compared to warfarin, offering a relative risk reduction of 25%.2,3 In RE-LY®, a PROBE trial (prospective, randomized, open-label with blinded endpoint evaluation) Pradaxa® 150 mg bid provided a 35% reduction in the overall risk of stroke and systemic embolism versus well-controlled warfarin (INR 2-3, median TTR 67%7).2,3** Pradaxa® 110 mg bid, which is indicated for certain patients, was shown to be non-inferior compared to well-controlled warfarin for the prevention of stroke and systemic embolism.2,3

In the overall trial, both doses of Pradaxa® were associated with significantly lower total, intracranial and life-threatening bleeding compared to well-controlled warfarin, and Pradaxa® 110 mg bid additionally demonstrated significantly lower major bleeding versus warfarin.2,3

NOTES TO THE EDITORS
Stroke Prevention in Atrial FibrillationAF is the most common sustained heart rhythm condition,8 with one in four adults over the age of 409 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.9,10 Up to three million people worldwide suffer strokes related to AF each year.11-14 Strokes due to AF tend to be severe, with an increased likelihood of death (20%), and disability (60%).15


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.16-20 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-related stroke reaches €13.5 billion per year in the European Union alone.10


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 (110 mg and 150 mg bid) each administered in a blinded manner, with well-controlled (INR 2.0-3.0, median TTR 67%7) open label warfarin.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).Compared to well controlled warfarin, dabigatran etexilate showed in the trial: 2,3

  • Significant reduction in the risk of stroke and systemic embolism – including haemorrhagic strokes with dabigatran etexilate 150 mg bid
  • Similar rates of stroke/systemic embolism with dabigatran etexilate 110 mg bid
  • Significantly lower major bleeding events with dabigatran etexilate 110 mg bid
  • Significantly lower life threatening and intracranial bleeding with both doses
  • Significant reduction in vascular mortality with dabigatran etexilate 150 mg bid.

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.


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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.


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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.


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References
1Hori M, et al. Efficacy and safety of dabigatran versus warfarin in patients with atrial fibrillation: Analysis in Asian population in RE-LY trial. Presented at the 2nd Asia Pacific Stroke Conference, Japan, 11th September 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;363:1875-6.
4Hu D, Sun Y. Epidemiology, risk factors for stroke, and management of atrial fibrillation in China. JACC 2008; 52:865–8
5World Health Organization. The global burden of disease: 2004 update. 2008. Viewed September 2012 at http://www.who.int/healthinfo/global_burden_disease/GBD_report_2004update_full.pdf.
6Healey JS, et al. Global Variations in the 1-Year Rates of Death and Stroke in 15,340 Patients Presenting to the Emergency Department with Atrial Fibrillation in 47 Countries: The RE-LY AF Registry. Presented at the European Society of Cardiology Congress 2012, 29th August 2012.
7Pradaxa European Summary of Product Characteristics, 2012
8Stewart S, et al. Cost of an emerging epidemic: an economic analysis of atrial fibrillation in the UK. Heart. 2004;90:286-92.
9Lloyd-Jones DM, et al. Lifetime risk for development of atrial fibrillation: the Framingham Heart Study. Circulation. 2004;110:1042-6.
10Fuster V, et al. ACC/AHA/ESC 2006 Guidelines for the management of patients with atrial fibrillation – executive summary. Circulation. 2006;114:700-52.
11Global 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.
12Atlas of Heart Disease and Stroke, World Health Organization, September 2004. Viewed Dec 2010 at http://www.who.int/cardiovascular_diseases/en/cvd_atlas_15_burden_stroke.pdf.
13Wolf PA, et al. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke. 1991;22:983-8.
14Marini C, et al. Contribution of atrial fibrillation to incidence and outcome of ischaemic stroke: results from a population-based study. Stroke. 2005;36:1115-9.
15Gladstone DJ, et al. Potentially Preventable Strokes in High-Risk Patients With Atrial Fibrillation Who Are Not Adequately Anticoagulated. Stroke. 2009;40:235-240.
16Paolucci S, et al. Functional outcome of ischemic and hemorrhagic stroke patients after inpatient rehabilitation. Stroke. 2003;34:2861−5.
17Petrea RE, et al. Gender differences in stroke incidence and poststroke disability in the Framingham Heart Study. Stroke. 2009;40:1032-7.
18Meschia JF, et al. Genetic susceptibility to ischemic stroke. Nat Rev Neurol. 2011;7:369−78.
19Andersen KK, et al. Hemorrhagic and ischemic strokes compared: stroke severity, mortality, and risk factors. Stroke. 2009; 40:2068−72.
20Roger VL, et al. AHA Statistical Update. Heart Disease and Stroke Statistics—2011 Update. A Report From the American Heart Association. Circulation 2011; 123:e18−e209.
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.

*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 (110mg and 150mg bid) each administered in a blinded manner, with open label warfarin.2,3

**In an intention-to-treat (ITT) analysis. The ITT analysis represents the highest standard for analysing superiority in non-inferiority trials.

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