New Study Results Published in the New England Journal of Medicine Show Dabigatran Etexilate Mesylate Reduces the Risk of Recurrent Venous Thromboembolism

Ridgefield, CT, February 20, 2013– New findings from two double-blind, randomized trials, RE-MEDY^SM and RE-SONATE®, show that dabigatran 150 mg twice daily reduces the risk of recurrent venous thromboembolism (VTE)*. The results were published today in the New England Journal of Medicine.

VTE is the third most common cardiovascular disorder after heart disease and stroke, and consists of two related conditions caused by blood clots: deep vein thrombosis (DVT) and pulmonary embolism (PE). DVT is when a blood clot develops in the deep veins of the leg or pelvis. The clot, or part of it, can break off from the site where it formed and travel through the veins (embolism). A PE can occur if the clot lodges in the arteries of the lungs.

There are an estimated 900,000 VTE events per year in the U.S., approximately one-third of which result in death from PE. Further, roughly one-third of people with VTE will have a recurrence within 10 years. The standard of care for patients with VTE is anticoagulation.

RE-MEDY demonstrated that treatment with dabigatran 150 mg twice daily was non-inferior to warfarin (p=0.01) in preventing recurrent VTE, including VTE-related death. RE-SONATE demonstrated dabigatran was superior to placebo for the prevention of first recurrent or fatal VTE with a risk reduction of 92 percent during the treatment period (p<0.001). Lower event rates were reported across all secondary efficacy endpoints for dabigatran over placebo.

“Patients who suffer one VTE event are at increased risk of suffering another, with the risk accumulating over time,” said Sam Schulman, M.D., Ph.D., FRCPC(C), lead study author and professor, Department of Medicine, McMaster University, Ontario, Canada. “We are encouraged to see that the RE-MEDY and RE-SONATE trials met their endpoints and we will continue to study the safety, efficacy and practical management of dabigatran.”

In the RE-MEDY trial, there were fewer major bleeding events in patients with a prior history of VTE receiving dabigatran compared with those receiving warfarin. There was also a significantly lower risk (46 percent) of major or clinically relevant bleeding events in this same set of patients.

In the RE-SONATE trial, the incidence of major bleeding was two patients in the dabigatran group versus zero patients in the placebo group. Combined rates of major or clinically relevant bleeding were significantly higher in patients receiving dabigatran as compared with those receiving placebo.

“Boehringer Ingelheim is continuously searching for new and innovative ways to improve the lives of patients and build upon the breadth of clinical data for our existing products,” said Sabine Luik, M.D., senior vice president, Medicine & Regulatory Affairs, U.S. Regional Medical Director, Boehringer Ingelheim Pharmaceuticals, Inc. “RE-MEDY and RE-SONATE are the result of our commitment to address the complex medical need of patients with recurrent VTE, a potentially life-threatening condition.”

Study Details

RE-MEDY

• Design: 2,856 patients randomized to dabigatran 150 mg (1,430 patients) or warfarin (1,426 patients) for an extended treatment period of six to 36 months
• Efficacy: dabigatran demonstrated non-inferiority compared to warfarin for the primary endpoint of recurrent or fatal VTE (26 patients,1.8 percent versus 18 patients, 1.3 percent, respectively; p=0.01)
• Safety: dabigatran showed a 46 percent lower risk of clinically relevant bleeding (including major bleeding) versus warfarin:
  • Significantly lower clinically relevant bleeding (including major bleeding) with dabigatran versus warfarin: 80 patients, 5.6 percent versus 145 patients, 10.2 percent (relative risk reduction 46 percent; p<0.001)
  • Trend toward lower risk of major bleeding alone: 13 patients, 0.9 percent versus 25 patients,1.8 percent (relative risk reduction 48 percent; p=0.06)
  • A higher rate of acute coronary syndrome (ACS) events was observed in the dabigatran group versus warfarin (13 patients, 0.9 percent versus three patients, 0.2 percent, respectively; p=0.02)

RE-SONATE

• Design: 1,343 patients randomized to dabigatran 150 mg (681 patients) or placebo (662 patients) for six months with extended follow-up to evaluate the long-term risk of recurrence (12 months after completion of study treatment)
• Efficacy: 92 percent risk reduction for recurrent or fatal VTE with dabigatran versus placebo (three patients, 0.4 percent versus 37 patients, 5.6 percent; p<0.001 for superiority)
• Safety: the incidence of major bleeding was two patients in the dabigatran group versus zero patients in the placebo group. A higher rate of major or clinically relevant bleeding in the dabigatran group versus no treatment was observed (36 patients, 5.3 percent versus 12 patients, 1.8 percent; p=0.001)

* Pradaxa® (dabigatran etexilate mesylate) capsules are not approved by the U.S. Food and Drug Administration for the prevention of recurrent VTE or the treatment of acute VTE.

About Pradaxa® (dabigatran etexilate mesylate) Capsules

Indications and Usage
Pradaxa® (dabigatran etexilate mesylate) capsules is indicated to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation.

IMPORTANT SAFETY INFORMATION ABOUT PRADAXA

CONTRAINDICATIONS
PRADAXA is contraindicated in patients with:

• Active pathological bleeding
• A known serious hypersensitivity reaction to PRADAXA (e.g., anaphylactic reaction or anaphylactic shock)
• A mechanical prosthetic heart valve 

WARNINGS & PRECAUTIONS 
Risk of Bleeding

PRADAXA increases the risk of bleeding and can cause significant and, sometimes, fatal bleeding. Promptly evaluate any signs or symptoms of blood loss (e.g., a drop in hemoglobin and/or hematocrit or hypotension). Discontinue PRADAXA in patients with active pathological bleeding.

Risk factors for bleeding include concomitant use of medications that increase the risk of bleeding (e.g., anti-platelet agents, heparin, fibrinolytic therapy, and chronic use of NSAIDs). PRADAXA’s anticoagulant activity and half-life are increased in patients with renal impairment. 

A specific reversal agent for dabigatran is not available. Hemodialysis can remove dabigatran; however clinical experience for hemodialysis as a treatment for bleeding is limited. Activated prothrombin complex concentrates, recombinant Factor VIIa, or concentrates of factors II, IX or X may be considered but their use has not been evaluated. Protamine sulfate and vitamin K are not expected to affect dabigatran anticoagulant activity. Consider administration of platelet concentrates where thrombocytopenia is present or long-acting antiplatelet drugs have been used. 

Thromboembolic and Bleeding Events in Patients with Prosthetic Heart Valves
The safety and efficacy of PRADAXA in patients with bileaflet mechanical prosthetic heart valves (recently implanted or implanted more than 3 months prior to enrollment) was evaluated in the phase 2 RE-ALIGN trial. RE-ALIGN was terminated early because of significantly more thromboembolic events (valve thrombosis, stroke, transient ischemic attack, and myocardial infarction) and an excess of major bleeding (predominantly post-operative pericardial effusions requiring intervention for hemodynamic compromise) for PRADAXA vs warfarin. Therefore, the use of PRADAXA is contraindicated in patients with mechanical prosthetic valves.

Use of PRADAXA for the prophylaxis of thromboembolic events in patients with atrial fibrillation and other forms of valvular heart disease, including bioprosthetic heart valve, has not been studied and is not recommended.

Temporary Discontinuation of PRADAXA
Discontinuing PRADAXA for active bleeding, elective surgery, or invasive procedures places patients at an increased risk of stroke. Minimize lapses in therapy.

Effect of P-gp Inducers & Inhibitors on Dabigatran Exposure
The concomitant use of PRADAXA with P-gp inducers (e.g., rifampin) reduces exposure to dabigatran and should generally be avoided. P-gp inhibition and impaired renal function are major independent factors in increased exposure to dabigatran. Concomitant use of P-gp inhibitors in patients with renal impairment is expected to increase exposure of dabigatran compared to either factor alone.

For patients with moderate renal impairment (CrCl 30-50 mL/min), consider reducing the dose of PRADAXA to 75 mg twice daily when dronedarone or systemic ketoconazole is coadministered with PRADAXA.

For patients with severe renal impairment (CrCl 15-30 mL/min), avoid concomitant use of PRADAXA and P-gp inhibitors.

ADVERSE REACTIONS
In the pivotal trial comparing PRADAXA to warfarin, the most frequent adverse reactions leading to discontinuation of PRADAXA were bleeding and gastrointestinal (GI) events. PRADAXA 150 mg resulted in a higher rate of major GI bleeds and any GI bleeds compared to warfarin. In patients ≥75 years of age, the risk of major bleeding may be greater with PRADAXA than with warfarin. Patients on PRADAXA 150 mg had an increased incidence of GI adverse reactions. These were commonly dyspepsia (including abdominal pain upper, abdominal pain, abdominal discomfort, and epigastric discomfort) and gastritis-like symptoms (including GERD, esophagitis, erosive gastritis, gastric hemorrhage, hemorrhagic gastritis, hemorrhagic erosive gastritis, and GI ulcer). Drug hypersensitivity reactions were reported in <0.1% of patients receiving PRADAXA.

Other Measures Evaluated
In the pivotal trial, a higher rate of clinical myocardial infarction was reported in patients who received PRADAXA (0.7 per 100 patient-years for 150 mg dose) than in those who received warfarin (0.6).

Click here for full PRADAXA prescribing information and medication guide.

About Boehringer Ingelheim Pharmaceuticals, Inc.
Boehringer Ingelheim Pharmaceuticals, Inc., based in Ridgefield, CT, is the largest U.S. subsidiary of Boehringer Ingelheim Corporation (Ridgefield, CT) and a member of the Boehringer Ingelheim group of companies.

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.

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PRADAXA^® is a registered trademark of Boehringer Ingelheim Pharma GmbH and Co. KG and used under license.

RE-MEDY^SM is a registered service mark of Boehringer Ingelheim International GmbH and used under license.

RE-SONATE^® is a registered trademark of Boehringer Ingelheim International GmbH and used under license.