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Kamis, 21 Februari 2013

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


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

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®* trial 2,3 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.5
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)
“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="" font="" size="1">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

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

1 Hori 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.
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 Hu D, Sun Y. Epidemiology, risk factors for stroke, and management of atrial fibrillation in China. JACC 2008; 52:865–8
5 World 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.
6 Healey 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.
7 Pradaxa European Summary of Product Characteristics, 2012
8 Stewart S, et al. Cost of an emerging epidemic: an economic analysis of atrial fibrillation in the UK. Heart. 2004;90:286-92.
9 Lloyd-Jones DM, et al. Lifetime risk for development of atrial fibrillation: the Framingham Heart Study. Circulation. 2004;110:1042-6.
10 Fuster V, et al. ACC/AHA/ESC 2006 Guidelines for the management of patients with atrial fibrillation – executive summary. Circulation. 2006;114:700-52.
11 Global 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.
12 Atlas 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.
13 Wolf PA, et al. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke. 1991;22:983-8.
14 Marini 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.
15 Gladstone DJ, et al. Potentially Preventable Strokes in High-Risk Patients With Atrial Fibrillation Who Are Not Adequately Anticoagulated. Stroke. 2009;40:235-240.
16 Paolucci S, et al. Functional outcome of ischemic and hemorrhagic stroke patients after inpatient rehabilitation. Stroke. 2003;34:2861−5.
17 Petrea RE, et al. Gender differences in stroke incidence and poststroke disability in the Framingham Heart Study. Stroke. 2009;40:1032-7.
18 Meschia JF, et al. Genetic susceptibility to ischemic stroke. Nat Rev Neurol. 2011;7:369−78.
19 Andersen KK, et al. Hemorrhagic and ischemic strokes compared: stroke severity, mortality, and risk factors. Stroke. 2009; 40:2068−72.
20 Roger 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.
21 Hart RG, et al. Meta-analysis: Antithrombotic Therapy to Prevent Stroke in Patients Who Have Nonvalvular Atrial Fibrillation Ann Intern Med. 2007;146:857-67.
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 Di 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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