Patients with atrial fibrillation who require surgery benefit from a shorter treatment interruption on dabigatran etexilate (Pradaxa) compared to warfarin

Burlington, ON - June 26, 2012 – Findings published in Circulation demonstrate that treatment with PRADAX® (dabigatran etexilate) allows a substantially shorter interruption of oral anticoagulation therapy compared to warfarin in patients with atrial fibrillation (AF)1 who require surgery or invasive procedures. Treatment with PRADAX® allows patients to undergo procedures more quickly and decreases the time of reduced protection against stroke. Additionally, the study found that discontinuing PRADAX® within 48 hours of surgery or invasive procedures was associated with a lower risk of peri-operative bleeding compared to similar discontinuation times with warfarin.1

The new analysis of the RE-LY® trial highlights that significantly more patients treated with PRADAX® were able to undergo surgery or invasive procedures within 48 hours of stopping therapy, compared to patients taking warfarin (46% for dabigatran 110mg bid / 150mg bid / vs. 11% for warfarin, p < 0.001)1. This is primarily due to the specific pharmacokinetic characteristics of PRADAX® including a shorter terminal elimination half-life (12-14 hours vs. the effective half-life of approx. 40 hours for warfarin2,3) and much faster on-and off-set of anticoagulant effect offered by this novel oral anticoagulant treatment.

Overall, similar rates of bleeding and thrombotic events were observed in patients treated with PRADAX® and warfarin who were undergoing surgery or invasive procedures, including those requiring urgent or major surgery.1

Dr. Jeff Healey, McMaster University, Hamilton, Canada, commented, “Surgical or invasive procedures are commonly required in patients with atrial fibrillation taking anticoagulant medications. This analysis provides reassurance that dabigatran is as safe as warfarin with regards to perioperative bleeding and thromboembolic events in patients undergoing surgery or invasive procedures, irrespective of whether interventions were minor or major. In addition, nearly half of all patients using dabigatran were able to have their procedure performed within 48 hours of the discontinuation of treatment with the anticoagulant, ensuring a shorter interruption of protection from thromboembolic complications than with warfarin, while still ensuring adequate haemostasis at the time of surgery.”

In the RE-LY® trial, 4,591 patients underwent at least one surgical procedure, which represented 24.7% of patients receiving PRADAX® 110mg bid, 25.4% receiving PRADAX® 150mg bid and 25.9% receiving warfarin. The most common reasons for surgical procedures were pacemaker/defibrillator insertion (10.3%), dental procedures (10.0%), and diagnostic procedures (10.0%). Key results from the analysis showed:1

• There was no significant difference in the rates of peri-procedural major bleeding with either dose of PRADAX® compared to warfarin (110mg bid: RR=0.83, 95% CI: 0.59-1.17, p=0.28/150mg bid: RR=1.09, 95% CI: 0.80-1.49, p=0.58)1
• Statistically lower rates of major bleeding were seen with both doses of PRADAX® compared to warfarin when surgery was performed within a 48 hour period:
o 24-48 hrs interruption: 110mg bid: RR= 0.35, 95% CI: 0.16-0.80, p= 0.01/150mg bid: RR=0.36, 95% CI: 0.16-0.82, p=0.011
o < 24 hrs interruption: 110mg bid: RR=0.18, 95% CI: 0.07-0.50, p<0.001/150mg bid: RR=0.44, 95% CI: 0.21-0.92, p=0.0271
• The incidence of stroke and all other thromboembolic complications, including cardiovascular death, systemic embolism, myocardial infarction or pulmonary embolism were low and not significantly different between treatment groups1.
• The advantage of PRADAX® with regard to the incidence of haemorrhagic stroke was again confirmed in the present analysis where four peri-operative haemorrhagic strokes were seen within the well-controlled warfarin group versus none with either dose of PRADAX® (p<0.05 for both doses of PRADAX® compared to warfarin).1
In the analysis, recommendations developed during the RE-LY® study to establish the optimal timing of discontinuation of PRADAX® prior to invasive procedures were reviewed. The recommendations take into account the bleeding risk of the surgery itself and renal function of the patient, due to PRADAX® being 80% renally excreted4. The analysis reconfirmed the application of these recommendations, which are reflected in the labelling information and provide specific guidance on the discontinuation time for PRADAX® in patients at varying degrees of renal impairment based on a standard or high risk of bleeding associated with the planned surgery or intervention.

The effectiveness and favourable safety profile of PRADAX® have been proven within an extensive clinical trial program,2, 4-8 passing independent regulatory scrutiny and approval worldwide.
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About AF and stroke in Canada

Atrial fibrillation is an irregular heart rhythm known as an arrhythmia. 9 While AF is rare in people under 40, its prevalence increases with age. 9 In fact, after the age of 55, the incidence of AF doubles with each decade of life.10

Atrial fibrillation affects up to 350,000 Canadians.9 People with AF are three to five times more at risk of having a stroke than those without the condition.9 After age 60, one-third of all strokes are caused by AF.9 Strokes due to AF tend to be more severe and can cause greater disability11 and for those who survive a stroke, the disabilities can be significant, including: paralysis; loss of speech and understanding; effects on the memory, thought and emotional processes.12

About RE-LY®
The RE-LY® (Randomized Evaluation of Long term anticoagulant therapY) was a global, Phase III, randomized trial of 18,113 patients13, enrolled in over 950 centres in 44 countries, including 52 centres in Canada and 1,150 Canadian patients,13 investigating whether dabigatran etexilate (two blinded doses) was as effective as well-
controlled warfarin – INR 2.0 - 3.0 – (open label) for stroke prevention.14
Patients with non-valvular AF and at least one other risk factor for stroke (i.e., previous ischemic stroke, transient ischemic attack, or systemic embolism, left ventricular dysfunction, symptomatic heart failure, ≥ 75 years, ≥ 65 with either diabetes mellitus, history of coronary artery disease, or hypertension requiring treatment)14 were enrolled in the study for two years with a minimum follow-up period of one year.14
The RE-LY® trial utilized the established PROBE (prospective, randomized, open-label, blinded endpoint evaluation) clinical trial protocol,14 which has been used in the majority of previous trials of anticoagulation for stroke prevention in patients with AF. A PROBE design is more reflective of the differences in the management of warfarin and dabigatran in clinical practice and it is reflective of the standard of care for patients.
In the RE-LY® trial, all clinical outcomes were adjudicated in a blinded manner to minimize bias in assessment of outcomes for each treatment.14 Gastrointestinal bleeding and dyspepsia occurred more frequently with dabigatran than with warfarin.4

About dabigatran etexilate (PRADAX®)

Clinical experience with PRADAX® is already well established and continues to grow, equating to over 700,000 patient years in over 70 countries worldwide13 and exceeding clinical trial and real-life experience of all other novel oral anticoagulants in the class.15

PRADAX® is a novel, reversible oral direct thrombin inhibitor. It provides its anticoagulant effect by selectively blocking the activity of thrombin, the central enzyme in clot formation.13,16

The Canadian approval of PRADAX® for stroke prevention in atrial fibrillation is based on data from the landmark RE-LY® Trial (Randomized Evaluation of Long term anticoagulant therapY) published last year in the New England Journal of Medicine.4 The study population included patients with high, moderate, and low risk of stroke. PRADAX® was proven to be more effective than warfarin at preventing strokes, with comparable safety.4
Specifically, PRADAX® 150 mg twice daily significantly reduced the risk of stroke and systemic embolism by 35 per cent versus warfarin, (p=0.0001) without increasing the risk of major bleeding, and reducing the risk of intracranial bleeding by 59 per cent (p<0.0001).4 The efficacy and safety benefits of PRADAX® occurred without any evidence of hepatotoxicity.4 The adverse event reported in the RE-LY® trial that was significantly more common with dabigatran etexilate than with warfarin were gastrointestinal (GI) disorders, such as abdominal pain, diarrhea, dyspepsia and nausea.2 In patients with atrial fibrillation treated for the prevention of stroke and systemic embolism, the co-administration of oral anti-platelet (including aspirin and clopidogrel) and NSAID therapies increases the risk of bleeding, by about two-fold.2 This higher rate of bleeding events by ASA or clopidogrel co-medication was, however, also observed for warfarin. Close clinical surveillance (looking for signs of bleeding or anaemia) is recommended throughout the treatment.2

Health Canada has approved the 150mg dose of PRADAX® to be taken twice-daily for prevention of stroke and systemic embolism in patients with atrial fibrillation in whom anti-coagulation is appropriate. The 110mg dose has been recommended for use in patients 80 years of age or older and may be considered for patients at higher risk of bleeding.2

About Boehringer Ingelheim (Canada) Ltd.
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 products 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 endeavours.

In 2011, Boehringer Ingelheim posted net sales of 13.2 billion euro while spending almost 24% of net sales in its largest business segment Prescription Medicines on research and development.

The Canadian headquarters of Boehringer Ingelheim was established in 1972 in Burlington, Ontario, Canada and the Research and Development Centre is located in Laval, Québec, Canada. Boehringer Ingelheim (Canada) Ltd. is home to more than 750 employees including 170 scientists across the country.

For more information please visit www.boehringer-ingelheim.ca


References
1. Healey JS, et al. Peri-Procedural Bleeding and Thromboembolic Events with Dabigatran Compared to Warfarin: Results from the RE-LY randomized trial. Circulation 2012; published online on 14 June 2012; DOI: 10.1161/CIRCULATIONAHA.111.090464
2. PRADAX® Product Monograph. January 27, 2012.
3. Coumadin Product Monograph. March 10, 2011
4. Connolly SJ, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361:1139-51.
5. Connolly SJ, et al. Newly identified events in the RE-LY® trial. N Engl J Med 2010; 363(19):1875-6.
6. Schulman S, et al. Dabigatran etexilate versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009; 361:2342-52.
7. Eriksson BI, et al. Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial. J Thromb Haemost 2007; 5:2178–85.
8. Eriksson BI, et al. Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial. Lancet 2007; 370: 949–56.
9. http://www.heartandstroke.on.ca/site/c.pvI3IeNWJwE/b.3581877/k.A37/Stroke__Heart_disease__atrial_fibrillation.htm Last accessed June 15, 2012
10. http://www.heartandstroke.on.ca/site/c.pvI3IeNWJwE/b.3581729/k.359A/Statistics.htm Last accessed June 15, 2012
11. Kimura, K, Minematsu K, et al. Atrial fibrillation as a predictive factor for severe stroke and early death in 15,831 patients with actue ischaemic stroke. J Neurol Neurosurg Psychiatry 2005;76:679–683.
12. National Institute of Disorders and Stroke http://www.ninds.nih.gov/disorders/stroke/poststrokerehab.htm: July 2011 Last accessed June 15, 2012.
13. Data on file at Boehringer Ingelheim.
14. Ezekowitz MD, et al. Rationale and Design of RE-LY®: Randomized Evaluation of Long-Term Anticoagulation Therapy, Warfarin, Compared with Dabigatran. American Heart Journal 2009; 157:805-810.
15. Eikelboom JW, et al. Does dabigatran improve stroke-prevention in atrial fibrillation? Reply to a rebuttal. J Thromb Haemost 2010; 8:1438–9.
16. Van Ryn J, Hauel, N, Waldmann L. et al. Dabigatran inhibits both clot-bound and fluid-phase thrombin in vitro: comparison to heparin and hirudin. 2008 ATVB Oral Presentations (P570). Arterioscler Thromb Vasc Biol 2008; 28:el36-7.
 

Posted: June 2012

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