Value through Innovation28 July 2014
14 November 2011

New RE-LY® sub-analyses demonstrate safety and efficacy of Pradaxa® (dabigatran etexilate) in patients with heart failure & those undergoing surgery

• Pradaxa® 150mg bid reduced the risk of stroke in atrial fibrillation patients with symptomatic heart failure (sHF) compared to well-controlled warfarin1
• Rates of major bleeding in patients with sHF taking Pradaxa® are consistent with results seen in the RE-LY® trial, with significantly lower rates of intracranial bleeds1-3
• Pradaxa® was not associated with an increased risk of peri-operative bleeding compared to well-controlled warfarin, even among patients having emergency or major surgery.4

Orlando, U.S., 14 November 2011 – A new post hoc sub-analysis of the RE-LY® trial found Pradaxa® (dabigatran etexilate) 150mg bid significantly reduced the risk of stroke compared to well-controlled warfarin (median time in therapeutic range (TTR) 67.3%5) in patients with non-valvular atrial fibrillation (AF) and symptomatic heart failure (sHF). Importantly, the benefit for Pradaxa® compared to well-controlled warfarin with regard to major bleeding was maintained, irrespective of sHF.1 The results were presented today at the American Heart Association (AHA) Scientific Sessions 2011.

The landmark RE-LY® trial 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. The trial was 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%5) open label warfarin.2

Heart failure is a serious condition that occurs when the heart is unable to pump enough blood to meet the body’s needs. Up to 45% of patients with heart failure present with AF, which results in an increased risk of stroke and mortality above that seen in AF alone.6 Heart failure can also increase the risk of bleeding in patients using anticoagulation therapy.7

Dr. Stuart Connolly, Director, Division of Cardiology at McMaster University and member of The Population Health Research Institute, Hamilton, Canada

Dr. Stuart Connolly, Director, Division of Cardiology at McMaster University and member of The Population Health Research Institute, Hamilton, Canada

Dr. Stuart Connolly, Director, Division of Cardiology at McMaster University and member of The Population Health Research Institute, Hamilton, Canada, commented, "This post hoc sub-analysis shows that AF patients with symptomatic heart failure benefit from treatment with Pradaxa® consistently with the overall results of the RE-LY® trial. Pradaxa®150mg bid significantly reduced the risk of stroke and intracranial bleeds compared to well-controlled warfarin, with similar rates of major bleeds. This is an important clinical finding given patients with symptomatic heart failure and AF are at high risk of suffering a stroke, and require effective and safe anticoagulation to prevent these potentially disabling and fatal events."

Main findings from the post hoc RE-LY® sub-analysis were:1

  • Pradaxa® 150mg bid reduced the risk of stroke in AF patients with or without sHF compared to well-controlled warfarin (HR = 0.75 vs. 0.61; p-value for interaction = 0.66)
  • Rates of intracranial bleeding were significantly lower with both doses of Pradaxa® compared to well-controlled warfarin, irrespective of whether patients had sHF or not (Pradaxa® 110mg bid: HR=0.34 vs. 0.28, Pradaxa® 150mg bid: HR = 0.39 vs. 0.42; p-value for interaction = 0.80)
  • Annual rates of stroke or systemic embolism were higher overall for patients with sHF (Pradaxa® 110mg bid: 1.90%, Pradaxa® 150mg bid: 1.44%, warfarin: 1.92%) than those without sHF (Pradaxa® 110mg bid: 1.41%, Pradaxa®150mg bid: 1.00%, warfarin: 1.64%)
  • There were no significant interactions for major bleeding events between patients with sHF and those without – i.e. no signal for an increase in major bleeding events was detected in patients with sHF (Pradaxa® 110mg bid: HR=0.83 vs. 0.79, Pradaxa® 150mg bid: HR = 0.79 vs. 0.99; p-value for interaction = 0.21).

A second sub-analysis presented at the AHA Scientific Sessions 2011 assessed the risk of bleeding with Pradaxa® compared to well-controlled warfarin in patients undergoing surgery (n = 4,615). The analysis showed that there was no increased risk of peri-operative bleeding with both doses of Pradaxa® compared to well-controlled warfarin, even among patients having emergency or major surgery.4

Key findings were:4

  • There was no significant difference in the risk of bleeding, including major (RR = 1.08; p = 0.64), minor (RR = 1.15; p = 0.25), fatal (RR = 1.01; p = 0.99), bleeding requiring re-operation (RR = 1.39; p = 0.32) and bleeding requiring red blood cell transfusion (RR = 0.85; p = 0.37), between patients receiving Pradaxa® 150mg bid compared to warfarin.
  • Emergency surgery was associated with more major bleeds across all treatment groups compared to those having elective surgery (Pradaxa® 110mg: 17.5% vs. 2.7%, Pradaxa® 150mg: 17.4% vs. 3.8%, warfarin: 21.7% vs. 3.3%; p<0.001 for all).
  • Major bleeding was more common for major compared to minor surgery with both doses of Pradaxa® compared to warfarin (Pradaxa® 110mg: 6.3% vs. 1.9%, Pradaxa® 150mg: 6.4% vs. 3.2%, warfarin: 8.0% vs. 1.8%; p<0.01 for all). However, there were no significant differences between treatment arms.

Dr. Jeff Healey, McMaster University, Hamilton, Canada, commented, "This sub-study highlights that patients taking Pradaxa® who require surgery or invasive procedures have no increased risk of bleeding complications compared to patients treated with warfarin, even when these procedures are major or are performed on an emergency basis.This is important as one-quarter of RE-LY® patients underwent an invasive procedure or surgery over a two-year period. Patients receiving Pradaxa® required a shorter period of interruption of their anticoagulation."

Pradaxa® has been approved for the prevention of stroke in AF in more than 50 countries worldwide (including the U.S., Canada, Japan and the member states of European Union).5,8-11 Since the first launch of Pradaxa® in this new indication in October 2010, more than 450,000 patients have already been prescribed the novel oral anticoagulant.12-14

NOTES TO EDITORS

About AF and stroke
AF is the most common sustained heart rhythm condition,15 with one in four adults over the age of 4016 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.16,17 Up to three million people worldwide suffer strokes related to AF each year.18-21 Strokes due to AF tend to be severe, with an increased likelihood of death (20%), and disability (60%).22 Many AF-related strokes can be prevented with appropriate antithrombotic therapy.23 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).24

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%1) open label warfarin.3,4 Patients were followed-up in the study for a median of 2 years with a minimum of 1 year follow-up.2,3

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 (median TTR 67.3%5), the following results were seen with Pradaxa® in the landmark RE-LY® trial:2,3

  • Pradaxa® 150mg bid significantly reduced the risk of stroke and systemic embolism by 35%, providing clinically important stroke prevention in non-valvular AF
  • Pradaxa® 150mg bid significantly reduced both ischaemic (RRR 25%) and haemorrhagic stroke (RRR 74%)
  • Pradaxa® 110mg bid showed similar rates of stroke and systemic embolism as well-controlled warfarin
  • Both doses of Pradaxa® significantly reduced intracranial and life threatening bleeding compared to warfarin
  • Pradaxa® 110mg bid also significantly reduced major bleeds.

About dabigatran etexilate
Dabigatran etexilate is at the forefront of a new generation of oral anticoagulants/direct thrombin inhibitors (DTIs)25 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 42,000 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 2010, Boehringer Ingelheim posted net sales of about 12.6 billion euro while spending almost 24% of net sales in its largest business segment Prescription Medicines on research and development.

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, Canada or UK.

References
1Ferreira J, et al. Dabigatran compared with warfarin in patients with atrial fibrillation and symptomatic heart failure: a subgroup analysis of the RE-LY trial. Presented at the American Heart Association Scientific Sessions 2011, 14 November 2011.
2Connolly SJ, et al. Dabigatran versus Warfarin in Patients with Atrial Fibrillation. N Engl J Med 2009;361:1139-51.
3Connolly SJ, et al. Newly identified events in the RE-LY® trial. N Engl J Med 2010; 63(19):1875-6.
4Healey J, et al. The risk of peri-operative bleeding with warfarin compared to two doses of dabigatran: results from the RE-LY trial. Presented at the American Heart Association Scientific Sessions 2011, 14 November 2011.
5Pradaxa®, Summary of Product Characteristics, August 2011. Europe.
6Savelieva I, et al. Atrial fibrillation and heart failure: natural history and pharmacological treatment. Europace 2004;5:S5-S19.
7Hughes M, et al. Risk factors for anticoagulation-related bleeding complications in patients with atrial fibrillation: a systematic review. Q J Med 2007;100:599–607.
8U.S. Food and Drug Administration – Pradaxa® Prescribing Information.Oct 19th, 2010.
9Health Canada – PRADAX™ Product Monograph. Oct 26th, 2010.
10Prazaxa® product information, January 2011, Japan.
11Pradaxa®, Australian Product information, April, 2011.
12Data on file. Boehringer Ingelheim Pharmaceuticals U.S., Inc.
13Data on file. Boehringer Ingelheim Pharmaceuticals Canada, Inc.
14Data on file. Boehringer Ingelheim Pharmaceuticals Japan, Inc.
15Stewart S, et al. Cost of an emerging epidemic: an economic analysis of atrial fibrillation in the UK. Heart 2004;90:286-92.
16Lloyd-Jones DM, et al. Lifetime risk for development of atrial fibrillation: the Framingham Heart Study. Circulation 2004;110:1042-6.
17Fuster V, et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients with Atrial Fibrillation – executive summary. Circulation 2006;114:700-52.
18Kannel WB, et al. Final Draft Status of the Epidemiology of Atrial Fibrillation. Med Clin North Am. 2008;92(1):17–40.
19Atlas 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 .
20Wolf PA, et al. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 1991;22(8):983-8.
21Marini 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.
22Lin HJ, et al. Stroke severity in atrial fibrillation: the Framingham study. Stroke 1996;27:1760-4.
23Hart 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.
24Bruggenjurgen B, et al. The Impact of Atrial Fibrillation on the Cost of Stroke: The Berlin Acute Stroke Study. Value Health 2007;10:137–43.
25Di Nisio M, et al. Direct Thrombin Inhibitors. N Engl J Med 2005;353:1028-40.

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