Value through Innovation12 February 2016
18 April 2012

Dabigatran etexilate (Pradaxa®) associated with significantly lower rates of fatal and traumatic intracranial haemorrhage compared with Warfarin

Ingelheim, Germany, 18 April 2012 – A new analysis of the 18,113 patient, RE-LY® trial highlights significantly lower rates of both fatal and traumatic intracranial haemorrhage (ICH) in patients treated with dabigatran etexilate (Pradaxa®) 110mg and 150mg bid compared to those treated with well-controlled warfarin.1 As part of the primary safety endpoint, the analysis evaluated 154 intracranial haemorrhages that occurred in153 patients during the trial, including bleeding sites, rates, risk factors, associated trauma, and outcomes. Results of this safety analysis were recently published online in Stroke: The Journal of the American Heart Association.

Intracranial haemorrhage is mostly seen in older patients with atrial fibrillation (AF), and is one of the most devastating complications of anticoagulation therapy. Intracranial haemorrhage, which comprises intracerebral haemorrhage, subdural haematoma and subarachnoid haemorrhage,1 is responsible for the majority of disability and death from bleeding related to treatment with the long time standard of care warfarin.2

In the RE-LY® trial, Pradaxa® 110mg bid and Pradaxa® 150mg significantly reduced the rate of ICH by 70% and 59% respectively, compared to well-controlled warfarin.3,4 This new detailed analysis of 154 intracranial haemorrhages across treatment groups in the RE-LY® trial showed:

  • Pradaxa® 110mg bid and 150mg bid were both associated with significantly fewer fatal (110mg: 11 vs. 32, P<0.001 / 150mg: 13 vs. 32, P<0.001) ICH events compared to well-controlled warfarin1
  • In a combined analysis, Pradaxa® 110mg & 150mg bid were associated with significantly fewer traumatic (11 vs. 24, P<0.05) ICH events compared to well-controlled warfarin1
  • When ICH did occur, the prognosis was similar across all treatment groups1
  • In an historic comparison, the rates of ICH seen with both doses of Pradaxa® in RE-LY were similarly low as the rate seen in patients with AF receiving antiplatelet therapy.1,5

"The risk of intracranial haemorrhage is a key factor when healthcare professionals are reviewing the benefit-risk profile of anticoagulation therapy, and this analysis highlights that both dosing regimens of Pradaxa® are safer than warfarin in this respect," said Hans-Christoph Diener, M.D., Ph.D., Professor and Chairman, Department of Neurology, University Duisburg-Essen, Germany.

Dr. Stuart Connolly, Director, Division of Cardiology at McMaster University and member of The Population Health Research Institute, Hamilton, Ontario commented, "Intracranial haemorrhage is one of the most feared complications of anticoagulation therapy. In our hospital, we see patients frequently presenting with intracranial haemorrhage as a result of warfarin and unfortunately, this complication is associated with a high mortality rate. These data show us that not only is Pradaxa® associated with lower rates of intracranial haemorrhage overall, but that fatal and traumatic intracranial bleeding is also reduced, highlighting the favourable safety profile of Pradaxa®."

The analysis showed that in RE-LY®, patients who experienced an ICH were, on average, older (mean age 75 [with ICH] vs. 71.5 [without ICH] P<0.001), associated with a higher frequency of previous history of stroke or TIA (P=0.001), used aspirin concomitantly more often (P=0.001), and had lower estimated creatinine clearance levels (P<0.001) compared with other study participants.Differences were consistent across treatment arms.1 A history of falling was not an independent risk factor for ICH amongst patients in the RE-LY® trial.1

In the landmark RE-LY® trial, Pradaxa® 150mg bid significantly reduced the risk of stroke and systemic embolism by 35% compared to well-controlled warfarin (median time in therapeutic range (TTR) 67%6), providing significantly superior stroke prevention in non-valvular atrial fibrillation (AF).3,4 Pradaxa 110mg bid was shown to be non-inferior to well-controlled warfarin for the prevention of stroke and systemic embolism in patients with non-valvular AF. Pradaxa® 150mg bid is the only novel oral anticoagulant shown to significantly reduce both ischaemic and haemorrhagic stroke in patients with non-valvular AF compared to well-controlled warfarin.3,4

RE-LY® was a PROBE trial (prospective, randomized, open-label with blinded endpoint evaluation), comparing two fixed doses of the oral direct thrombin inhibitor dabigatran etexilate (110mg and 150mg bid) each administered in a blinded manner, with open label warfarin.3


About AF and stroke
AF is the most common sustained heart rhythm condition,7 with one in four adults over the age of 408 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.8,9 Up to three million people worldwide suffer strokes related to AF each year.10-13 Strokes due to AF tend to be severe, with an increased likelihood of death (20%), and disability (60%).14 Many AF-related strokes can be prevented with appropriate antithrombotic therapy.15 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).16

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%6) 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.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, dabigatran etexilate showed in the trial:3,4

  • 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)17 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.

Updated information on the corporation’s annual results in 2011 will be available on April 24th, 2012.

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 or Canada.

1Hart RG, et al. Intracranial hemorrhage in atrial fibrillation patients during anticoagulation with Warfarin or Dabigatran: The RE-LY Trial. Stroke 2012; 112: 1-18.
2Fang MC, et al. Death and disability from warfarin-associated intracranial and extracranial hemorrhages. Am J Med. 2007; 120:700 –705.
3Connolly SJ, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361:1139-51.
4Connolly SJ, et al. Newly identified events in the RE-LY trial. N Engl J Med 2010; 363(19):1875-76.
5Hart RG, et al. Avoiding Central Nervous System Bleeding During Antithrombotic Therapy: Recent Data and Ideas. Stroke 2005; 36:1588-1593.
6FDA Advisory Committee Briefing Document, September 2010, Committee/UCM226009.pdf
7Stewart 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.
8Lloyd-Jones DM, Wang TJ, Leip EP, et al. Lifetime risk for development of atrial fibrillation: the Framingham Heart Study. Circulation 2004; 110:1042-6.
9Fuster 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.
10Kannel WB, et al. Final Draft Status of the Epidemiology of Atrial Fibrillation. Med Clin North Am. 2008; 92(1): 17–40.
11Atlas of Heart Disease and Stroke, World Health Organization, September 2004. Viewed Dec 2010 at cvd_atlas_15_burden_stroke.pdf .
12Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 1991: 22(8);983-8.
13Marini C, De Santis F, Sacco S, et al. Contribution of atrial fibrillation to incidence and outcome of ischaemic stroke: results from a population-based study. Stroke 2005; 36:1115-9.
14Lin HJ, Wolf PA, Kelly-Hayes M, et al. Stroke severity in atrial fibrillation: the Framingham study. Stroke 1996; 27:1760-4.
15Hart 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.
16Bruggenjurgen B et al. The Impact of Atrial Fibrillation on the Cost of Stroke: The Berlin Acute Stroke Study. Value Health 2007; 10: 137–43.
17Di Nisio M, et al. Direct Thrombin Inhibitors. N Engl J Med 2005; 353:1028-40.

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