Health Canada, the Canadian health authority, has approved PRADAX™ (dabigatran etexilate), 1 Boehringer Ingelheim's novel, oral direct thrombin inhibitor 2 for the prevention of stroke and systemic embolism in patients with atrial fibrillation (AF) in whom anticoagulation is appropriate, marking the second approval of this new oral anticoagulant following the recent marketing authorisation by the US Food and Drug Administration (FDA). The Health Canada approval makes PRADAX™ available to AF patients in Canada, 1 with the flexibility of two dosing regimens. While overall the 150 mg bid dose is recommended, the 110 mg bid dose is specifically available for elderly patients aged 80 years and above as well as for patients at high risk of bleeding.

The approval is based on findings from RE-LY®, the largest AF trial completed to date and is set to provide a breakthrough for stroke prevention in AF - a condition that affects 250,000 people in Canada alone. 3 The results demonstrated that dabigatran etexilate 150 mg significantly reduced the risk of stroke and systemic embolism by 35 percent beyond the reduction achieved with warfarin, the longtime standard of care, while the risk of major bleeding events was similar. Compared to well controlled warfarin, dabigatran etexilate 110 mg bid was associated with a similar reduction of stroke and systemic embolism but a lower rate of major bleeding. Importantly, both doses provided a reduction in intracranial and life-threatening bleeding, as well as in total bleeding, compared with warfarin. 4 Besides providing superior efficacy compared to warfarin, dabigatran etexilate does not require monitoring or related dose adjustments, is not affected by food, and no dose adjustment is required for many common co-medications in patients with AF.

"Dabigatran etexilate is a significant advance in medicine. We have been waiting a long time for an alternative to warfarin. For decades, we have had no other choice than to use warfarin in the majority of patients, a treatment that imposes challenging restrictions on people's quality of life," said Dr. Stuart Connolly co-principal investigator of RE-LY®, Director, Division of Cardiology at McMaster University and member of The Population Health Research Institute, Hamilton, Ontario. "It is really great to finally have a safer and more effective alternative for patients with AF, which is easier to use. The approval of dabigatran etexilate will transform the way we treat and manage patients with atrial fibrillation at risk of stroke."

Coinciding with the Health Canada approval of PRADAX™, the Canadian Cardiovascular Society (CCS) has released new guidelines on stroke prevention in atrial fibrillation, which contain guidance on the use of dabigatran etexilate. Based on the safety and efficacy profile of PRADAX™, the guidelines generally recommend its use over warfarin for overall stroke reduction, particularly the 150mg dose twice-daily. 5

Professor Klaus Dugi, Corporate Senior Vice President Medicine, Boehringer Ingelheim said, "The approvals of dabigatran etexilate for stroke prevention in AF in North America are good news for patients and physicians, who now have access to a novel agent that has the potential to change the treatment paradigm in this indication. The decision of Health Canada marks another important step towards our goal to make this treatment available to all patients with atrial fibrillation at risk of stroke. We are working with regulatory authorities worldwide to ensure this."

Notes

About RE-LY®

RE-LY® (Randomized Evaluation of Long term anticoagulant therapY) was a global, phase III, randomised trial of 18,113 patients enrolled in over 900 centres in 44 countries, investigating whether dabigatran etexilate (2 blinded doses) is as effective as well controlled warfarin with target INR of 2.0-3.0 for stroke prevention. Patients were followed-up in the study for a median of 2 years with a minimum of 1 year follow-up.

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: 4

- Significant reduction in the risk of stroke and systemic embolism - including haemorrhagic strokes with dabigatran etexilate 150 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 AF and stroke

AF is the most common heart rhythm condition, affecting around 1% of the total population, rising to 10% in people over the age of 80. 6 People with AF are at increased risk of blood clots, which raises stroke risk by five times. 7,8 Up to three million people worldwide suffer strokes related to AF each year, 9-11 which tend to be especially severe and disabling, with half of people dying within one year. 12 A total of 6.3 million people in the US, Japan, Germany, Italy, France, UK and Spain were living with AF in 2007 and this is expected to increase to 7.5 million by 2017 primarily due to the ageing population. 13 Strokes due to AF tend to be severe, with an increased likelihood of death (20%), and disability (60%), with resultant societal costs and burden to the healthcare system. 12 AF alone is associated with a cost of up to €13.5 billion across the European Union. 7

Well-controlled vitamin K antagonist (VKA) therapy (warfarin), currently used for the prevention of stroke in atrial fibrillation, is highly effective in reducing the risk of stroke by approximately two-thirds, 14 but is associated with an increased risk of bleeding as well as several limitations. Drug-drug and food interactions as well as the requirement for frequent monitoring result in only about 50% of eligible patients receiving VKA therapy 15 with fewer than half of these controlled within the therapeutic INR range. 16

About dabigatran etexilate

Dabigatran etexilate is at the forefront of a new generation of oral anticoagulants/direct thrombin inhibitors (DTIs) 2 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.

Dabigatran etexilate has already been approved in 75 countries under the trademark Pradaxa® (in Canada: Pradax®) for the primary prevention of venous thromboembolic events (blood clots) in adults who have undergone elective total hip or elective total knee replacement surgery.

Disclaimer

Dabigatran etexilate is only approved for clinical use in stroke risk reduction in non-valvular atrial fibrillation prevention in the US and the prevention of stroke, and systemic embolism in adults with atrial fibrillation in Canada. This information is provided for medical education purposes only.

About the dabigatran etexilate clinical trial programme

Boehringer Ingelheim's clinical trial program to evaluate the efficacy and safety of dabigatran etexilate encompasses studies in:

- Primary prevention of venous thromboembolism (VTE) in patients undergoing elective total hip and knee replacement surgeries
- Treatment of acute VTE
- Secondary prevention of VTE
- Secondary prevention of cardiac events in patients with acute coronary syndrome (ACS)
- Stroke prevention in atrial fibrillation (AF).

References

1. Health Canada¬† - PRADAX™ Prescribing Information

2. Di Nisio M, et al. Direct Thrombin Inhibitors. N Engl J Med 2005; 353:1028-40.The European Atrial Fibrillation Trial Study Group. Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack or minor stroke. Lancet 1993; 342:1255-1262.

3. Heart and Stroke Foundation of Canada. 2009 Stroke Report Card. See here ; (Accessed July 5, 2010)

4. Connolly SJ, et al. Dabigatran versus Warfarin in Patients with Atrial Fibrillation. N Engl J Med 2009; 361:1139-51.

5. Canadian Cardiovascular Society (CCS) Atrial Fibrillation Guidelines Symposium at Canadian Cardiovascular Congress (CCC) 2010, 25 October 2010, Montréal, Canada

6. Stewart S, Murphy N, Walker A, et al. Cost of an Emerging Epidemic: an Economic Analysis of Atrial Fibrillation in the UK. Heart 2004; 90:286-92.

7. Fuster V, Rydn LE, Cannom DS, et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients with Atrial Fibrillation - executive summary. Circulation 2006; 114:700-52.

8. Kannel WB, et al. Final Draft Status of the Epidemiology of Atrial Fibrillation. Med Clin North Am. 2008; 92(1): 17-ix.

9. Atlas of Heart Disease and Stroke, World Health Organization, September 2004. Viewed July 2009 here.

10. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 1991: 22(8);983-8.

11-. Marini C, De Santis F, Sacco S, et al. Contribution of atrial fibrillation to incidence and outcome of ischemic stroke: results from a population-based study. Stroke 2005; 36:1115-9.

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

13. Benyoucef S, Hughes M, Mehta N. Atrial Fibrillation. Decision Resources, December 2008.

14. Hart RG, Benavente O, McBride R, Pearce LA. Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: a meta-analysis. Ann Intern Med 1999; 131:492-501.

15. Hylek EM, DAntonio J, Evans-Molina C, et al. Translating the results of randomized trials into clinical practice. The challenge of warfarin candidacy among hospitalized elderly patients with atrial fibrillation. Stroke 2006; 37:1075-80.

16. Samsa GP, Matchar DB, Goldstein LB, et al. Quality of anticoagulation management among patients with atrial fibrillation: results of a review of medical records from 2 communities. Arch Intern Med 2000; 160:967-73.

Source:
Boehringer Ingelheim

View drug information on Pradaxa; Warfarin Sodium tablets.

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