Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI) announced plans to launch RE-ALIGN™, a global, Phase II trial evaluating the safety and pharmacokinetics of dabigatran etexilate in 400 patients who have mechanical heart valves.(1) The 12-week study will compare three doses of dabigatran etexilate (150mg bid, 220mg bid and 300mg bid) to warfarin in patients with both aortic valve replacements and mitral valve replacements.(1) A RE-ALIGN extension study will evaluate the ongoing safety of dabigatran etexilate in this patient population for up to 84 months.(1)

Mechanical heart valves are used to treat heart valve disease, which occurs when one or more valves in the heart does not function properly.(2) An estimated 2.5 percent of the American population has heart valve disease.(3) Approximately 100,000 patients undergo heart valve replacement in the U.S. each year,(4) 55 percent of which are mechanical heart valves.(5) Patients with mechanical heart valves require lifelong anticoagulation to help prevent blood clots from forming on or around the valve.(6) A meta-analysis of 46 studies involving patients with mechanical heart valves found the annual incidence of thromboembolism for those who are untreated to be 8.6 percent.(7)

"Boehringer Ingelheim is committed to ongoing research that will expand our understanding of dabigatran etexilate as a treatment option for patients with a variety of cardiovascular and thromboembolic conditions," said John Smith, MD, PhD, senior vice president for clinical development and medical affairs, Boehringer Ingelheim Pharmaceuticals, Inc. "We are proud to announce the launch of RE-ALIGN and plans for a RE-ALIGN extension study, to assess dabigatran etexilate as a potential treatment option to reduce stroke risk in patients with mechanical heart valves."

Dabigatran etexilate was approved by the FDA in October 2010 as the first oral anticoagulant in more than 50 years to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF) and is sold under the brand name Pradaxa®.(8) In the first eight months after approval, nearly 300,000 patients in the U.S. were prescribed PRADAXA.(9)

"PRADAXA has almost a full year of clinical use for the reduction of stroke risk in patients with non-valvular atrial fibrillation," said Chris Barrett, senior vice president, marketing, Boehringer Ingelheim Pharmaceuticals, Inc. "We continue to see a steady growth in the number of patients treated with PRADAXA and are proud of the widespread formulary coverage that has been achieved, providing access to 90 percent of covered lives in the U.S."

Findings from the Phase III RE-LY® trial showed that PRADAXA 150mg taken twice daily significantly reduced stroke and systemic embolism by 35 percent beyond the reduction achieved with warfarin (dosed to international normalized ratio (INR) 2.0 to 3.0, mean time in therapeutic range = 64.4 percent)(8) in patients with NVAF.(8) Effects of PRADAXA were more apparent in patients with lower levels of INR control.(8) Dabigatran is recommended in an update to atrial fibrillation treatment guidelines.

About RE-LY

RE-LY was a global, Phase III, randomized trial of 18,113 patients(8) enrolled in 951 centers in 44 countries,(10) investigating whether dabigatran etexilate (two blinded doses) was as effective as well-controlled warfarin - INR 2.0 - 3.0 - (open label) for stroke prevention.(8) Patients with non-valvular AFib and at least one other risk factor for stroke (i.e., previous ischemic stroke, transient ischemic attack, or systemic embolism, left ventricular dysfunction, age greater than or equal to 75 years, age greater than or equal to 65 years with either diabetes mellitus, history of coronary artery disease, or hypertension) were enrolled in the study for two years(8) with a minimum follow-up period of one year.(11)

The RE-LY trial utilized the established PROBE (prospective, randomized, open-label, blinded endpoint evaluation) clinical trial protocol,(11) which has been used in the previous trials of anticoagulation for stroke prevention in patients with AFib.(11) A PROBE design may reflect the differences in the management of warfarin and dabigatran in clinical practice.(11)

The primary endpoint of the trial was incidence of stroke (including hemorrhagic) and systemic embolism.(11) 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.(11)

In the RE-LY trial, all clinical outcomes were adjudicated in a blinded manner to minimize bias in assessment of outcomes for each treatment.(11)

About Pradaxa® (dabigatran etexilate) Capsules

Indications and Usage

PRADAXA 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 AND PRECAUTIONS

Risk of Bleeding

PRADAXA increases the risk of bleeding and can cause significant and, sometimes, fatal bleeding.

Risk factors for bleeding include:

-- Medications that increase the risk of bleeding in general (e.g., anti-platelet agents, heparin, fibrinolytic therapy, and chronic use of NSAIDs).

-- Labor and delivery

Promptly evaluate any signs or symptoms of blood loss, such as a drop in hemoglobin and/or hematocrit or hypotension. Discontinue PRADAXA in patients with active pathological bleeding.

Temporary Discontinuation of PRADAXA

Discontinuing PRADAXA for active bleeding, elective surgery, or invasive procedures places patients at an increased risk of stroke. Lapses in therapy should be avoided, and if PRADAXA must be temporarily discontinued for any reason, therapy should be restarted as soon as possible.

Effect of P-gp Inducers and Inhibitors on PRADAXA Exposure

The concomitant use of PRADAXA with P-gp inducers (e.g., rifampin) reduces dabigatran exposure and should generally be avoided. P-gp inhibitors ketoconazole, verapamil, amiodarone, quinidine, and clarithromycin, do not require dose adjustments. These results should not be extrapolated to other 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 greater than or equal to 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