New findings from two studies support substantial benefit of Pradaxa®

Boehringer IngelheimToday, the New England Journal of Medicine published findings from the RE-MEDYTM and RE-SONATETM trials investigating Pradaxa® (dabigatran etexilate) in the long-term prevention of deep vein thrombosis (DVT) or pulmonary embolism (PE). The results demonstrate that Pradaxa® 150 mg twice daily is an effective option with a favourable safety profile for the extended prevention of recurrence of these venous blood clots (known as venous thromboembolism or VTE) after a first event.*

Pradaxa® is the only novel oral anticoagulant which in its clinical trials vs. warfarin has shown lower rates of clinically relevant bleeding (including major bleeding) in patients with either DVT or PE.(1,2,3)

In the RE-SONATETM trial, Pradaxa® reduced the risk of recurrent events of deep vein thrombosis or pulmonary embolism by 92% compared with placebo.(1) In the RE-MEDYTM trial, Pradaxa® compared to warfarin showed a 46% lower risk of clinically relevant bleeding (including major bleeding) while the protection from recurrent VTE was similar to warfarin.(1)

Additional follow-up data from the RE-SONATETM trial presented at the American Society for Hematology (ASH) Congress 2012 showed that the treatment benefit of Pradaxa® for prevention of recurrent DVT and PE is maintained when a one-year-period after the end of the treatment is included in the analysis.(4) DVT and PE are venous thrombotic events triggered by a blood clot blocking blood vessels.(5,6) Venous thromboembolism is estimated to be the third most common cardiovascular disorder after coronary heart disease and stroke.(7) Over 750,000 venous thrombotic events are estimated to occur annually in six major European countries (France, Germany, Italy, Spain, Sweden, UK) (8) and over 900,000 events occur annually in the US.(9) Data has shown that the risk of recurrent VTE can increase cumulatively in patients who are not treated with standard therapy from 11% after one year to up to 40% after 10 years.(10) Therefore, long-term preventive treatment may be of benefit.

"The new results from RE-MEDY and RE-SONATE suggest dabigatran is a good option to prevent deep vein thrombosis and pulmonary embolism from happening again after an initial event," says Professor Sam Schulman, Division of Hematology and Thromboembolism, Department of Medicine, McMaster University, Canada. "They reinforce the efficacy and favourable safety profile of dabigatran seen in the RE-COVER trials, where dabigatran showed similar efficacy and a significant reduction in clinically relevant bleeding versus warfarin in the treatment of acute venous thromboembolism."

Details on RE-MEDYTM and RE-SONATETM
The new findings were derived from two double-blind randomised studies - RE-MEDYTM and RE-SONATETM - investigating Pradaxa® in the long-term prophylaxis of recurrence after an initial DVT or PE. Enrolled patients had completed at least three months of acute treatment. In RE-MEDYTM, 2,856 patients were randomised and received Pradaxa® or warfarin for an extended treatment period of up to 36 months. In RE-SONATETM, 1,343 patients were randomised and received Pradaxa® or placebo for six months, extended follow-up to evaluate the long-term risk of recurrence took place 12 months after completion of study treatment.

Key results from the two double-blind randomised trials show:(1)

Efficacy (1)

  • RE-SONATE TM: 92% risk reduction for recurrent DVT or PE with Pradaxa® vs. placebo: 0.4% vs. 5.6% (P<0.001 for superiority)
  • RE-MEDY TM: Pradaxa® demonstrated comparable efficacy to warfarin with a low frequency of recurrent DVT or PE: 1.8% vs. 1.3% (P=0.01 for non-inferiority)

Safety (1)

  • Low overall bleeding rates seen with Pradaxa® in both trials with major bleeds occurring in two patients in RE-SONATE TM and 13 patients in RE-MEDY TM out of over 2,000 patients receiving Pradaxa®
  • RE-MEDY TM: Pradaxa® showed a 46% lower risk of clinically relevant bleeding (including major bleeding) vs. warfarin:
    • Significantly lower clinically relevant bleeding (including major bleeding) with Pradaxa® vs. warfarin: 5.6% vs. 10.2% (relative risk reduction 46%, P<0.001)
    • Trend towards lower risk of major bleeding alone: 0.9% vs. 1.8% (relative risk reduction 48%, P=0.06)
  • RE-SONATE TM:
    • Number of patients with a major bleed: 2 patients with Pradaxa® vs. 0 patient with placebo
    • Higher rate of major or clinically relevant bleeding vs. placebo (5.3% vs. 1.8%; P= 0.001)
  • In RE-SONATE TM, comparable rates of acute coronary syndrome (ACS) were observed in Pradaxa® and placebo (0.1% vs. 0.2%), while in RE-MEDYTM, a higher rate of ACS events was observed in the Pradaxa® group (13 patients, 0.9%) vs. warfarin (3 patients, 0.2%)

The efficacy and safety profile of Pradaxa® in its licensed indications to prevent stroke and systemic embolism in patients with atrial fibrillation (AF) and to prevent venous blood clots following elective hip- or knee-replacement surgery is well documented in an extensive clinical trial programme (11-16), which led to worldwide regulatory approvals in over 80 countries to date.(17) Clinical experience with Pradaxa® continues to grow and equates to over 1.3 million patient-years in all licensed indications to date.(17)

Pradaxa® is currently not approved for the acute treatment or secondary prevention of DVT and PE.

About venous thromboembolism
Venous thromboembolism (VTE) refers to two different conditions: deep vein thrombosis (DVT) and its potentially fatal acute complication, pulmonary embolism (PE).(5) A venous thrombosis is a blood clot (thrombus) that forms within a vein. Most often, it develops in the deep veins of the leg or pelvis and is known as deep vein thrombosis. An embolism occurs if the clot, or a part of it, breaks off from the site of formation and travels through the circulatory system. If the clot lodges in the lung a potentially fatal condition, pulmonary embolism, occurs.(6)

VTE is estimated to be the third most common cardiovascular disorder after coronary heart disease and stroke.(7) Over 750,000 venous thrombotic events are estimated to occur annually in six major EU countries (France, Germany, Italy, Spain, Sweden, UK) (8), and over 900,000 events occur annually in the US.(9) Figures for the six European countries show that venous thrombotic events kill more people than AIDS, breast cancer, prostate cancer, and traffic accidents combined.(8)

In addition, up to 60% of people with DVT develop post thrombotic syndrome (PTS) with two years, and 4% of people with PE develop chronic thromboembolic pulmonary hypertension.(17,18,19)

Given its prevalence, associated morbidity, mortality and chronic complications, VTE is a costly condition, which puts a significant burden on healthcare systems worldwide. Annual costs are estimated to be more than €3.07 billion in Europe for total direct costs associated with VTE (5) and up to $15.5 billion in the US for VTE diagnosis and treatment.(20)

About dabigatran etexilate
Dabigatran etexilate is at the forefront of a new generation of oral anticoagulants known as 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.(22) 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.

Currently, Pradaxa® (dabigatran etexilate) is approved for the primary prevention of venous thromboembolism after total knee and hip replacement surgery and for the prevention of stroke and systemic embolism in patients with atrial fibrillation with one or more risk factors (previous stroke, transient ischemic attack, or systemic embolism (SEE); left ventricular ejection fraction <40%; symptomatic heart failure, ≥New York Heart Association (NYHA) Class 2; age ≥75 years; age ≥65 years associated with one of the following: diabetes mellitus, coronary artery disease, or hypertension).

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 in patients undergoing elective total hip and knee replacement surgery
  • Treatment of acute venous thromboembolism
  • Secondary prevention of venous thromboembolism
  • Stroke prevention in atrial fibrillation

About 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 with social responsibility. 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.

1. Schulman S, et al. Extended Use of Dabigatran, Warfarin or Placebo in Venous Thromboembolism. N Engl J Med. 2013;368:709-18.
2. Schulman S, et al. Dabigatran versus Warfarin in the Treatment of Acute Venous Thomboembolism. N Engl J Med. 2009;361:2342-52.
3. Schulman S, et al. A Randomized Trial of Dabigatran Versus Warfarin in the Treament of Acute Venous Thromboembolism (RE-COVER II). 2011;118: Oral presentation from Session 332: Antithrombotic Therapy 1. Presented on 12 December at the American Society of Hematology (ASH) Annual Meeting 2011.
4. Schulman S, et al. Benefit of Extended Maintenance Therapy for Venous Thromboembolism with Dabigatran Etexilate is Maintained over 1 Year of Post-Treatment Follow-up. Poster 21 from Session 332: Antithrombotic Therapy 1. Presented on 8 December at the American Society of Hematology (ASH) Annual Meeting 2012.
5. Coalition to Prevent VTE. The Burden of VTE. Available at: http://www.coalitiontopreventvte.org/INDEX_CFM/T/THE_BURDEN_OF_VTE/OBJECTID/866876ED_1422_16B3_78D29387FBC3/VID/9E7D3566_C09F_296A_6111019937AE/CONTAINERID/666415AA_C09F_296A_61DB66942768/DISPLAYMETHOD/DISPLAY_ARTICLE.HTM Last accessed January 2013
6. Centers for Disease Control. Are You at Risk for Deep Vein Thrombosis? Available at: www.cdc.gov/Features/Thrombosis/index.html Last accessed January 2013
7. Goldhaber, SZ. Pulmonary Embolism Thrombolysis: A Clarion Call for International Collaboration. JACC. 1992:19:246 - 7
8. Cohen AT, et al. Venous thromboembolism (VTE) in Europe. Thromb Haemost. 2007;98:756–64.
9. Roger VL, et al. Heart Disease and Stroke Statistics—2012 Update: A Report from the American Heart Association. Circulation. 2012;125(1):e2-e220
10. Prandoni P, et al.The risk of recurrent venous thromboembolism after discontinuing anticoagulation in patients with acute proximal deep vein thrombosis or pulmonary embolism. A prospective cohort in 1,626 patients. haematologica. 2007;92:199-205.
11. Pradaxa®, European Summary of Product Characteristics, 2013.
12. Connolly SJ, et al. Dabigatran versus Warfarin in Patients with Atrial Fibrillation. N Engl J Med. 2009;361:1139-51.
13. Connolly SJ, et al. Newly Identified Events in the RE-LY Trial. N Engl J Med. 2010;363:1875-6.
14. 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.
15. 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.
16. Eriksson BI, et al. Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty (RE-NOVATE II). Thromb Haemost. 2011;105:721-29.
17. Boehringer Ingelheim. Data on file.
18. Ashrani AA, Heit JA. Incidence and cost burden of post-thrombotic syndrome. J Thromb Thrombolysis 2009;28:465-76.
19. Pengo V, et al. Incidence of Chronic Thromboembolic Pulmonary Hypertension after Pulmonary Embolism. NEJM. 2004;350:2257-64.
20. Medscape. Anticoagulation Therapy for Venous Thromboembolism. Medscape General Medicine. 2004;6,(3)5.
21. Di Nisio M, et al. Direct Thrombin Inhibitors. N Engl J Med. 2005;353(10):1028-40.
22. Sorbera LA, et al. Dabigatran/Dabigatran etexilate. Drugs Future. 2005; 30(9):877-885.

* Important Notice: Pradaxa® (dabigatran etexilate) is currently not approved for the acute treatment or secondary prevention of deep vein thrombosis and pulmonary embolism.

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