Value through Innovation23 April 2014
18 June 2012

AF patients who require surgery benefit from a shorter treatment interruption on dabigatran etexilate (Pradaxa®) compared to warfarin

Ingelheim, Germany, 18 June, 2012 –Findings published in Circulation demonstrate that Pradaxa® (dabigatran etexilate) is associated with a substantially shorter interruption of oral anticoagulation therapy compared to warfarin in patients with atrial fibrillation (AF)1 who require surgery, allowing patients to undergo procedures more quickly and reducing the time of reduced protection against stroke. Additionally, the study found that discontinuing Pradaxa® within 48 hours of surgery 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 Pradaxa® were able to undergo surgery within 48 hours of stopping therapy, compared to patients taking warfarin (46% for dabigatran 150mg bid/110mg bid vs. 11% for warfarin, p < 0.001)1. This is primarily due to the specific pharmacokinetic characteristics of Pradaxa® including a short half life (12-17 hours vs. approx. 36 hours for warfarin)2 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 Pradaxa® 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 peri-operative 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 Pradaxa® 110mg bid, 25.4% receiving Pradaxa® 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 Pradaxa® 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)
  • Substantially lower rates of major bleeding were seen with both doses of Pradaxa® compared to warfarin when surgery was performed within a 48 hour period:
    • 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=0.01
    • < 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=0.027
  • 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 groups
  • The advantage of Pradaxa® 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 Pradaxa® (p<0.05 for both doses of Pradaxa® compared to warfarin).

In the analysis, recommendations developed during the RE-LY® study to establish the optimal timing of discontinuation of Pradaxa® 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 Pradaxa® being 80% renally excreted. The analysis reconfirmed the application of these recommendations, which are reflected in the labelling information such as the European Summary of Product Characteristics, and provide specific guidance on the discontinuation time for Pradaxa® in patients at varying degrees of renal impairment based on a standard or high risk of bleeding associated with the planned surgery or intervention.

"Emergency surgery is a frightening proposition for any patient taking an anticoagulant given the increased risk of bleeding encountered," commented Eve Knight Co-Founder and Chief Executive of AntiCoagulation Europe (ACE). "This data is encouraging for patients as it demonstrates that with Pradaxa® shorter therapy interruptions with no increase in bleeding risk are possible."

The effectiveness and favourable safety profile of Pradaxa® have been proven within an extensive clinical trial programme,3 -8 passing independent regulatory scrutiny and approval worldwide. Clinical experience of Pradaxa® is already well established and continues to grow, equating to over 700,000 patient years in over 70 countries worldwide9 and exceeding clinical trial and real-life experience of all other novel oral anticoagulants in the class.10

 
NOTES TO THE EDITORS

About AF and stroke
AF is the most common sustained heart rhythm condition,11 with one in four adults over the age of 4012 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.12,13 Up to three million people worldwide suffer strokes related to AF each year.14-17 Strokes due to AF tend to be severe, with an increased likelihood of death (20%), and disability (60%).18 Many AF-related strokes can be prevented with appropriate antithrombotic therapy.19 AF-related strokes currently represent a significant cost to healthcare systems across Europe. Given AF-related strokes tend to be more severe this results in direct medical patient costs which are higher than non AF-related strokes annually (€11,799 vs €8,817 P < 0.001).20

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 (110mg and 150mg bid) each administered in a blinded manner, with well controlled (INR 2.0-3.0, median TTR 67%3) open label warfarin.4,5 Patients were followed-up in the study for a median of 2 years with a minimum of 1 year follow-up.4
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: 4,5

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


About dabigatran etexilate
Dabigatran etexilate is at the forefront of a new generation of oral anticoagulants/direct thrombin inhibitors (DTIs)21 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.

About the dabigatran etexilate clinical trial programme
Boehringer Ingelheim’s clinical trial programme 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 surgery
  • Treatment of acute VTE
  • Secondary prevention of VTE
  • Stroke prevention in AF
  • Prevention of thromboembolism after heart valve replacement.

Boehringer Ingelheim
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.

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 endeavors.

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.

Please be advised
This release is from Boehringer Ingelheim Corporate Headquarters in Germany. Please be aware that there may be national differences between countries regarding specific medical information, including licensed uses. Please take account of this when referring to the information provided in this document. This press release is not intended for distribution within the USA, UK or Canada.

References
1Healey 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
2Eriksson BI et al. Evaluation of the acute coronary syndrome safety profile of dabigatran etexilate in patients undergoing major orthopedic surgery. Thromb Res. 2012. doi:10.1016/j.thromres.2012.05.014
3Pradaxa®, European Summary of Product Characteristics, 2012.
4Connolly SJ, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361:1139-51.
5Connolly SJ, et al. Newly identified events in the RE-LY® trial. N Engl J Med 2010; 363(19):1875-6.
6Schulman S, et al. Dabigatran etexilate versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009; 361:2342-52.&nbsp;
7Eriksson 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.
8Eriksson 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.
9Data on file.
10Eikelboom JW, et al. Does dabigatran improve stroke-prevention in atrial fibrillation? Reply to a rebuttal. J Thromb Haemost 2010; 8:1438–9.
11Stewart S, et al. Cost of an emerging epidemic: an economic analysis of atrial fibrillation in the UK. Heart 2004; 90:286-92.
12Lloyd-Jones DM, et al.&nbsp; Lifetime risk for development of atrial fibrillation: the Framingham Heart Study. Circulation 2004; 110:1042-6.&nbsp;
13Fuster V, et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients with Atrial Fibrillation – executive summary. Circulation 2006; 114:700-52.
14Kannel WB, et al. Final Draft Status of the Epidemiology of Atrial Fibrillation. Med Clin North Am. 2008; 92(1): 17–40.
15Atlas of Heart Disease and Stroke, World Health Organization, September 2004. Viewed Dec 2010 at www.who.int/cardiovascular_diseases/en/ cvd_atlas_15_burden_stroke.pdf .
16Wolf PA, et al. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 1991: 22(8);983-8.
17Marini 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.
18Lin HJ, et al. Stroke severity in atrial fibrillation: the Framingham study. Stroke 1996; 27:1760-4.
19Hart RG, et al. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have non-valvular atrial fibrillation. Ann Intern Med 2007; 146:857-67.
20Bruggenjurgen B, et al. The Impact of Atrial Fibrillation on the Cost of Stroke: The Berlin Acute Stroke Study. Value Health 2007; 10: 137–43.
21Di Nisio M, et al. Direct Thrombin Inhibitors. N Eng J Med 2005; 353:1028-40.

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