Long-term Data For Pradaxa(R) (dabigatran Etexilate) For Stroke Prevention In Atrial Fibrillation (AF)

Main Category: Stroke
Also Included In: Cardiovascular / Cardiology;  Heart Disease
Article Date: 12 Nov 2008 - 2:00 PST

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Long-term data for Pradaxa® (dabigatran etexilate) in the prevention of thromboembolic events in patients with recurrent, persistent and chronic AF was presented today at the 80th American Heart Association annual congress.1 PETRO-Ex is an open-label extension of the Prevention of Embolic and Thrombotic Events Study in Patients with AF Randomised to dabigatran (PETRO),2 and included 361 patients from 53 centres in Denmark, The Netherlands, Sweden and the United States, with AF and at least one other stroke risk factor receiving dabigatran etexilate. Patients have been followed for an average of 29 months, with the maximum follow-up being 51 months, marking the longest mean follow-up of any new oral anticoagulant.

The PETRO and PETRO-Ex studies showed that thromboembolic event rates were low with dabigatran etexilate doses of 150 and 300 mg twice daily (b.i.d.). Major bleeding was more frequent with the 300 mg b.i.d. dose. No significant liver function abnormalities were noted for dabigatran etexilate. The balance between stroke and bleeding risk is the subject of the ongoing Boehringer Ingelheim Phase III RE-LY® (Randomized Evaluation of Long Term Anticoagulant Therapy) trial, the largest stroke prevention in AF trial to date.

Patient recruitment for the global, multi-centre, randomised RE-LY® study was completed in December 2007. RE-LY® is intended to confirm the safety and efficacy of dabigatran etexilate in preventing stroke for patients and results are expected in 2009. This study is comparing two blinded doses of dabigatran etexilate with open-label warfarin in 18,113 patients with non-valvular AF and at least one other major risk factor for stroke. Primary outcomes of the study will measure the incidence of stroke and systemic embolism. Secondary outcome measures include all death associated with stroke, systemic embolism, pulmonary embolism, acute myocardial infarction and vascular deaths.

Dr Michael Ezekowitz from Lankenau Institute for Medical Research, Wynnewood, PA, USA who participated in the PETRO study and is Co-Principal Investigator of the RE-LY® study said:

"An oral therapy with a reliable and predictable anticoagulant effect without the need for coagulation monitoring and without any long-term safety concerns will be a major advance in stroke prevention and we look forward to the results of RE-LY which is evaluating dabigatran etexilate in the largest AF stroke prevention trial so far."

Significance of AF

AF affects 2.3 million people in the United States, and 4.5 million in the EU.3 It is the most common heart rhythm disorder and is a major risk factor for stroke.3 The incidence of AF increases with age and nearly 6% of individuals over the age of 65 are affected.4 Patients with AF are at risk of developing clots due to the irregular beating of the heart. AF increases the chance of stroke five-fold.5

The consequences of stroke can be devastating, therefore a primary aim of therapy is to decrease the risk of arterial thrombus formation and thromboembolism.6 Long-term anticoagulation therapy with VKAs such as warfarin is recommended for individuals with AF who are considered at moderate to high risk of stroke.3 These risk factors include age over 75 years, a history of a previous stroke or transient ischaemic attack, hypertension, diabetes or heart failure.3 Although anticoagulation therapy with warfarin has been shown to reduce the incidence of stroke by 61%,3 only half of eligible patients are estimated to receive appropriate treatment due to a variety of barriers in administration and use of VKAs.7

Management of warfarin therapy is complex, and failure to monitor patients adequately is associated with risk.6 Warfarin has a narrow therapeutic window, a slow onset and offset of action and is associated with an unpredictable dose response.8,9 It also interacts with many common foods, drugs and alcohol which alter its therapeutic effect, putting patients at risk of either a bleeding or thrombotic event.8 Therefore, it requires careful individualised dosing and frequent monitoring.

Dabigatran etexilate is an oral direct thrombin inhibitor. The new treatment has been launched in 19 countries this year for the primary prevention of venous thromboembolic events in adults who have undergone elective total hip or elective total knee replacement. Within this indication it is given as a once daily, fixed oral dose with no requirements for coagulation monitoring.10

Dr Andreas Barner, Vice-Chairman of the Board of Boehringer Ingelheim and responsible for Research, Development and Medicine said: "Landmark trials such as RE-LY demonstrate Boehringer Ingelheim's commitment to improving future treatment options for patients. Pradaxa is the most advanced novel oral anticoagulant in clinical development for stroke prevention in atrial fibrillation and our ongoing extensive RE-VOLUTION clinical trial programme is investigating Pradaxa across several further therapeutic areas."

Boehringer Ingelheim continues to evaluate the efficacy and safety of dabigatran etexilate within the global RE-VOLUTION™ clinical trial programme which involves over 38,000 patients. Efficacy and safety is being assessed for:

• Stroke prevention in AF in the RE-LY® trial - results are expected in 2009
• Treatment of acute VTE â€" results expected in 2009 from the RE-COVER™ trial
• Secondary prevention of VTE in the RE-MEDY™ and RE-SONATE™ trials
• Prevention of cardiac events in patients with acute coronary syndrome in the RE-DEEM™ trial

RE-LY® methodology

RE-LY® is an ongoing global, multi-centre, non-inferiority, randomised trial comparing two blinded doses of dabigatran etexilate with open label warfarin (INR 2.0-3.0) in patients with non-valvular AF and at least one other major risk factor for stroke. The median treatment duration is two years with a minimum of 1 year follow-up.

Primary outcomes of the trial will measure the incidence of stroke (including haemorrhagic) and systemic embolism. Secondary outcome measures include all death, incidence of stroke (including haemorrhagic), systemic embolism, pulmonary embolism, acute myocardial infarction, and vascular deaths (including deaths from bleeding).

Recruitment of 18,113 patients was completed in December 2007 and results are expected in 2009.

The trial is led by Dr Salim Yusuf, Professor of Epidemiology and Cardiology, Population Health Research Institute McMaster University, Hamilton, Canada; Dr Lars Wallentin, Professor of Cardiology and Director of the Uppsala University, Sweden; Dr Michael Ezekowitz, Vice President and Professor, Lankenau Institute for Medical Research, Wynnewood, PA, USA; Dr Stuart Connolly, Professor of Medicine and Director, Division of Cardiology at McMaster University, Hamilton, Canada.

Please be advised

This release is from the Corporate Headquarters of Boehringer Ingelheim and is intended for international markets. This being the case, please be aware that there may be some differences between countries regarding specific medical information including licensed uses. Please take account of this when referring to the material.

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 135 affiliates in 47 countries and 39,800 employees. Since it was founded in 1885, the family-owned company has been committed to researching, developing, manufacturing and marketing novel products of high therapeutic value for human and veterinary medicine.

In 2007, Boehringer Ingelheim posted net sales of 10.9 billion euro while spending one fifth of net sales in its largest business segment Prescription Medicines on research and development. http://www.boehringer-ingelheim.com

References

1. Nagarakanti R, Ezekowitz MD, Parcham-Azad K, et al. Long-term Open Label Extension of the Prevention of Embolic and Thrombotic Events Study in Patients with Atrial Fibrillation Randomized to Dabigatran (PETROâ€"Ex study). Poster presentation at the 80th Congress of the American Heart Association in New Orleans, USA, November 2008

2. Ezekowitz MD, Reilly PA, Nehmiz G, et al. Dabigatran with or without concomitant aspirin compared with warfarin alone inpatients with nonvalvular atrial fibrillation (PETRO Study). Am J Cardiol. 2007;100(9):1419-26

3. Fuster V, Rydén LE, Cannom DS, et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients with Atrial Fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation. 2006;114:257-354

4. Feinberg WM, Blackshear JL, Laupacis, et al. Prevalence, age distribution, and gender of patients with atrial fibrillation: analysis and implications. Arch Intern Med. 1995;155:469-473

5. Lin HJ, Wolf PA, Kelly-Hayes M, et al. Stroke severity in atrial fibrillation: the Framingham study. Stroke. 1996;27: 1760-4

6. Walker AM, Bennet D. Epidemiology and outcomes in patients with atrial fibrillation in the United States. Heart Rhythm 2008;5:1365-72

7. Connolly SJ. Anticoagulation for patients with atrial fibrillation and risk factors for stroke. BMJ. 2000;320:1219-20

8. Hirsh J, Dalen J, Anderson DR, et al. Oral anticoagulants. Mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest. 2001 Jan;119(1 Suppl):8S-21S

9. Thom T; Haase N; Rosamond W, et al. Heart Disease and Stroke Statistics-2006 Update. A Report From the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2006;113:e85-e151

10. Pradaxa, Summary of Product Characteristics, 2008

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