RIDGEFIELD, Conn., Dec. 8, 2012 /PRNewswire/ -- Boehringer Ingelheim Pharmaceuticals, Inc. today announced results from two new post-hoc sub-analyses comparing the clinical management and outcomes of patients who experienced major bleeding while treated with dabigatran or warfarin. These findings from the RE-LY® trial and four other Phase III trials report outcomes after a major bleed on dabigatran, despite the lack of a specific reversal agent, may be better than after a warfarin-associated bleed. The sub-analyses also indicate that the overall medical resources used to manage bleeding were not greater with dabigatran. These data were presented today at the 54th Annual Meeting of the American Society of Hematology in Atlanta, Ga.

"Bleeding, especially major bleeding, is a well-recognized concern with all blood thinners. The sub-analyses report that major bleeding outcomes with dabigatran, using standard clinical support measures, appeared to be better than warfarin and required no greater use of medical resources," said Sam Schulman, M.D., Ph.D., FRCPC(C), professor, Department of Medicine, McMaster University, Ontario, Canada.

The data consist of two retrospective sub-analyses that reviewed the use of resources and hospital length of stay after major bleeds in patients treated with dabigatran or warfarin.

• A sub-analysis of the RE-LY trial examined patients with non-valvular atrial fibrillation (NVAF) treated with dabigatran 110mg* and 150mg.
• A pooled sub-analysis assessed reports of 1,034 major bleeds (627 dabigatran, 407 warfarin) in five Phase III studies, including the RE-LY trial, in patients with NVAF and four other Phase III dabigatran trials in patients with acute treatment and secondary prevention of venous thromboembolism (VTE). This analysis is based on a case narrative analysis and included only centrally adjudicated (meaning confirmed by an independent team or group) major bleeding events within three days of the last dose. 

In the sub-analysis of the RE-LY study alone, the rate of major bleeds requiring surgery was lower for patients on dabigatran than warfarin (12.1 percent and 15 percent, respectively). While dabigatran and warfarin patients were hospitalized at the same rates and length of stay was the same, time spent in the intensive care unit (ICU) and coronary care unit (CCU) was less for patients on dabigatran than on warfarin (1.6 nights and 2.7 nights, respectively).

Management of bleeding events for dabigatran or warfarin was based on current standards of clinical care, including: blood transfusion, fresh frozen plasma, vitamin K, prothrombin complex concentrate and recombinant factor VIIa. In the RE-LY sub-analysis alone, patients on dabigatran were more frequently treated with blood transfusions than those on warfarin (59.2 percent and 49.9 percent, respectively). Patients on dabigatran were less frequently treated with fresh frozen plasma than those on warfarin (19.8 percent and 30.2 percent, respectively).

More patients in the dabigatran group were older than the warfarin group (mean age of 75.3 and 71.8, respectively), had lower median creatinine clearance (53 mL/min and 62 mL/min, respectively) and were using aspirin (30.9 percent and 24.6 percent, respectively) or non-steroidal anti-inflammatory drugs (NSAIDs) (12.9 percent and 8.4 percent, respectively).

About Pradaxa
The efficacy and safety of Pradaxa® (dabigatran etexilate mesylate) capsules was established in the RE-LY trial, one of the largest stroke prevention clinical studies ever conducted in patients with NVAF. PRADAXA 150mg twice daily is the only treatment compared to warfarin to demonstrate superior reduction in ischemic and hemorrhagic stroke. Nearly nine out of 10 strokes caused by atrial fibrillation (AFib) are ischemic strokes. In RE-LY, PRADAXA was proven to be 36 percent better than warfarin at reducing the risk of stroke in patients with NVAF. PRADAXA 150mg twice daily also showed a 59 percent lower rate of intracranial bleeding in the RE-LY trial, compared to warfarin.

About RE-LY®
RE-LY was a global, Phase III, randomized trial of 18,113 patients enrolled in 951 centers in 44 countries, investigating whether dabigatran etexilate (two blinded doses) was as effective as open label warfarin – INR 2.0 - 3.0 – for stroke prevention. Patients with NVAF and at least one other risk factor for stroke (i.e., previous ischemic stroke, transient ischemic attack, or systemic embolism, left ventricular ejection fraction <40 percent, symptomatic heart failure, New York Heart Association Class > 2, age > 75 years, age > 65 years with either diabetes mellitus, history of coronary artery disease, or hypertension) were enrolled in the study for two years with a minimum follow-up period of one year.

The RE-LY trial utilized the established PROBE (prospective, randomized, open-label, blinded endpoint evaluation) clinical trial protocol, which has been used in the previous trials of anticoagulation for stroke prevention in patients with AFib. A PROBE design may reflect the differences in the management of warfarin and dabigatran in clinical practice.

The primary endpoint of the trial was incidence of stroke (including ischemic and hemorrhagic) and systemic embolism. The primary safety endpoint was major bleeding, defined as a reduction in the hemoglobin level of at least 2.0 g/dL, transfusion of at least two units of blood, or symptomatic bleeding in a critical area or organ. Other safety endpoints included bleeding events (major and minor), intracerebral hemorrhage, other intracranial hemorrhage, elevations in liver transaminases, bilirubin and hepatic dysfunction and other adverse events.

In the RE-LY trial, all clinical outcomes were adjudicated in a blinded manner to assess outcomes for each treatment.

*Although studied in the RE-LY trial, dabigatran 110mg is not approved by the U.S. FDA.

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 and patients with a known serious hypersensitivity reaction (e.g., anaphylactic reaction or anaphylactic shock) to PRADAXA.

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.

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.

Patients with Prosthetic Heart Valves
The safety and efficacy of PRADAXA has not been studied in patients with prosthetic heart valves. Use of PRADAXA is not recommended in these patients.

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).

For full PRADAXA prescribing information, please visit www.pradaxa.com or contact Boehringer Ingelheim's Medical and Technical Information Unit at 1-800-542-6257.

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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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In 2011, Boehringer Ingelheim achieved net sales of about $17.1 billion (13.2 billion euro). R&D expenditure in the business area Prescription Medicines corresponds to 23.5% of its net sales.

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

RE-LY® is a registered service mark of Boehringer Ingelheim International GmbH and used under license.

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