Value through Innovation22 September 2014
25 June 2012

No significant difference in the risk of Acute Coronary Syndrome (including Myocardial Infarction) seen with Pradaxa® (dabigatran etexilate) compared to enoxaparin for VTE prevention after orthopaedic surgery

For Non-US, Non-UK & Non-Canadian Media Only

Ingelheim, Germany, 25 June 2012 – Findings from an analysis of four Phase III trials, comparing Pradaxa® to enoxaparin recently published in Thrombosis Research, support the positive safety profile of Pradaxa® for the prevention of venous thromboembolism (VTE) in patients undergoing total knee or hip arthroplasty. The results demonstrate that the risk of acute coronary syndrome (ACS) events was low and that there was no significant difference in between the two treatments. The analysis concluded that Pradaxa® does not elevate the risk of myocardial infarction (MI) compared to enoxaparin and is not associated with any clinically important 'rebound effect' in the post-treatment period.1

Prof. Bengt I. Eriksson, Senior Consultant at the Department of Orthopaedic Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden

Prof. Bengt I. Eriksson, Senior Consultant at the Department of Orthopaedic Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden

"These findings are encouraging for both physicians and patients," stated Prof. Bengt I. Eriksson, Senior Consultant at the Department of Orthopaedic Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden. "The evaluation provides reassurance for patients undergoing orthopaedic procedures with subsequent treatment with dabigatran etexilate for the prevention of VTE that the risk of ACS events is low and that there is no rebound effect after the discontinuation of the treatment."

These new findings were derived from four randomised, non-inferiority, Phase III trials conducted to investigate the efficacy and safety of Pradaxa® in patients being treated for the prevention of VTE undergoing total knee or hip arthroplasty. A total of 10,148 patients were randomised in the RE-MOBILIZE®2, RE-MODEL™3, RE-NOVATE®4, and
RE-NOVATE®5 II trials to Pradaxa® (150 mg or 220 mg once daily) or enoxaparin for 6–35 days, and followed for up to 90 days. ACS events were defined as unstable angina, myocardial infaction or sudden cardiac death. 1

Key results from the pooled analysis of the four trials showed:1

  • The incidence of treatment-emergent ACS events was low for Pradaxa® patients and similar to those seen with enoxaparin (220mg: 6 patients [0.16%] vs. 150mg: 14 patients [0.51%] and enoxaparin: 13 patients [0.35%])
  • No increased risk of myocardial infarction (MI) in patients treated with Pradaxa® compared to enoxaparin (220mg: 4 patients [0.11%] vs. 150mg: 14 patients [0.51%] and enoxaparin: 13 patients [0.35%])
  • Also in the post-treatment period, comparable rates of ACS events were seen in patients previously treated with Pradaxa® versus those previously treated with enoxaparin (220mg: 2 patients [0.06%] vs. 150mg: 1 patient [0.04%] and enoxaparin: 4 patients [0.11%]). The authors concluded that no evidence of a rebound effect was observed with Pradaxa®. *

The low incidence of MI with Pradaxa® was also observed in the landmark RE-LY® trial, which examined the role of Pradaxa® versus well-controlled warfarin in the prevention of stroke and systemic embolism in over 18,000 patients with atrial fibrillation.6-8 No statistically significant difference in rates of myocardial infarction was observed between the trial groups, with a low incidence rate reported for both doses of Pradaxa® and warfarin (Pradaxa® 110mg: 98/6015, Pradaxa® 150mg: 97/6075 and warfarin: 75/6022).7

Furthermore, the results from the RE-LY® trial have shown the substantial benefits Pradaxa® offers in terms of effective prevention of stroke and major reduction in intracranial bleeding. Pradaxa® 150mg bid provided an additional reduction in risk of stroke and systemic embolism by 35% compared to well-controlled warfarin (INR 2-3, median TTR 67%9).6,7 Pradaxa® 150mg bid is the only novel oral anticoagulant to have demonstrated in a major study a significant reduction of both ischaemic and haemorrhagic stroke in patients with non-valvular AF when compared to warfarin.6,7 Pradaxa®110mg bid, which is indicated for certain patients, was shown to be non-inferior to well-controlled warfarin for the prevention of stroke and systemic embolism in patients with non-valvular AF. Significantly lower life threatening and intracranial bleeding was provided with both doses of Pradaxa®, with significantly lower major bleeding events also seen with Pradaxa® 110mg bid 6,7

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.6,7

The effectiveness and favourable safety profile of Pradaxa® is well documented in an extensive clinical trial programme 2-7,9,10, passing independent regulatory scrutiny and approval worldwide. Clinical experience of Pradaxa® for stroke protection is already well established and continues to grow, equating to over 780,000 patient years in over 70 countries worldwide11 and exceeding clinical trial experience of all other novel oral anticoagulants.12

NOTES TO THE EDITORS

About AF and stroke
AF is the most common sustained heart rhythm condition,13 with one in four adults over the age of 40 14 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.14,15 Up to three million people worldwide suffer strokes related to AF each year.16-19 Strokes due to AF tend to be severe, with an increased likelihood of death (20%), and disability (60%).20 Many AF-related strokes can be prevented with appropriate antithrombotic therapy.21 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).22

About RE-MOBILIZE®, RE-MODEL™, RE-NOVATE® and RE-NOVATE® II
The four randomized, active-controlled, double-blind, non-inferiority, phase III studies investigated the efficacy and safety of dabigatran etexilate versus enoxaparin in the prevention of venous thromboembolism following major orthopaedic surgery (total knee or hip arthroplasty).1 The primary efficacy endpoint in each trial was a composite of VTE (venographic or symptomatic deep vein thrombosis and/or pulmonary embolism) and all-cause mortality during treatment.1

  • Results from RE-MODEL™ and RE-NOVATE® demonstrated that either dose of dabigatran etexilate (150 mg or 220 mg) was non-inferior to enoxaparin (40 mg once daily) in the prevention of major VTE following total knee and hip arthroplasty1
  • RE-NOVATE® II, which only evaluated the 220 mg once daily dose of dabigatran etexilate, reinforced the earlier findings from RE-NOVATE® and concluded dabigatran etexilate to be non-inferior to enoxaparin 40 mg once daily1
  • Results from the RE-MOBILIZE® study did not show non-inferiority for the primary end point1
  • There were no statistically significant differences in major bleeding rates observed between the compared treatments in all four trials, respectively1

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%9) open label warfarin.6,7 Patients were followed-up in the study for a median of 2 years with a minimum of 1 year follow-up.6,7

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: 6,7

  • 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) 23 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.

* Differences between groups were not statistically significant

References

1.Eriksson BI et al. Evaluation of the acute coronary syndrome safety profile of dabigatran etexilate in patients undergoing major orthopedic surgery. Thromb Res. 2012. http://dx.doi.org/10.1016/j.thromres.2012.05.014
2.RE-MOBILIZE Writing Committee. Oral thrombin inhibitor dabigatran etexilate vs North American enoxaparin regimen for prevention of venous thromboembolism after knee arthroplasty surgery. J Arthroplasty 2009; 24 (1), 1–9.
3.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 (11), 2178–85.
4.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 (9591), 949–56.
5.Eriksson BI, et al. Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty (RE-NOVATE II). Thromb Haemost 2011; 105 (4), 721–9.
6.Connolly SJ, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361:1139-51.
7.Connolly SJ, et al. Newly identified events in the RE-LY® trial. N Engl J Med 2010; 363(19):1875-6.
8.Hohnloser H, et al. Myocardial Ischemic Events in Patients with Atrial Fibrillation Treated with Dabigatran or Warfarin in the RE-LY Trial. Circulation 2012; 125:669–76.
9.Pradaxa, European Summary of Product Characteristics, 2012.
10.Schulman S, et al. Dabigatran etexilate versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009; 361:2342-52.&nbsp;
11.Data on file.
12.Eikelboom JW, et al. Does dabigatran improve stroke-prevention in atrial fibrillation? Reply to a rebuttal. J Thromb Haemost 2010; 8:1438–9.
13.Stewart S, et al. Cost of an emerging epidemic: an economic analysis of atrial fibrillation in the UK. Heart 2004; 90:286-92.
14.Lloyd-Jones DM, et al.&nbsp; Lifetime risk for development of atrial fibrillation: the Framingham Heart Study. Circulation 2004; 110:1042-6.&nbsp;
15.Fuster V, et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients with Atrial Fibrillation – executive summary. Circulation 2006; 114:700-52.
16.Global Atlas on Cardiovascular Disease Prevention and Control, World Health Organization in collaboration with the World Heart Federation and the World Stroke Organization 2011. Viewed May 2012 at http://www.world-heart-federation.org/fileadmin/user_upload/documents/Publications/Global_CVD_Atlas.pdf. 17.Atlas 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 .
18.Wolf PA, et al. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 1991: 22(8);983-8.
19.Marini 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.
20.Lin HJ, et al. Stroke severity in atrial fibrillation: the Framingham study. Stroke 1996; 27:1760-4.
21.Hart RG, et al. Meta-Analysis: antithrombotic therapy to prevvent stroke in patients who have non-valvular atrial fibrillation. Ann Intern Med 2007; 146:857-67.
22.Bruggenjurgen B, et al. The Impact of Atrial Fibrillation on the Cost of Stroke: The Berlin Acute Stroke Study. Value Health 2007; 10: 137–43.
23.Di Nisio M, et al. Direct Thrombin Inhibitors. N Engl J Med 2005; 353:1028-40.

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