New Sub-Analysis of RE-LY Trial Examines Pradaxa in Patients with Atrial Fibrillation Undergoing Cardioversion

Ridgefield, CT, January 5, 2011 – Results of a post-hoc analysis of the RE-LY ^® trial among patients with non-valvular atrial fibrillation (NVAF) undergoing cardioversion, a treatment to convert an abnormal heartbeat back to normal sinus rhythm, were published online on Jan. 3 in Circulation. ¹ Stroke and systemic embolism and major bleeding episodes within 30 days of the cardioversion were the major outcome measures. The analysis reported that rates of stroke and systemic embolism and major bleeding were low and comparable to warfarin in cardioverted patients receiving Pradaxa ^® (dabigatran etexilate mesylate) 150mg capsules, ¹ an oral anticoagulant recently approved by the U.S. Food and Drug Administration (FDA) to reduce the risk of stroke and systemic embolism in patients with NVAF. ²

In RE-LY, a total of 1,983 cardioversions were performed in 1,270 patients, with similar numbers in each treatment group (647 in the dabigatran 110mg* group, 672 in the PRADAXA 150mg group and 664 in the warfarin group). ¹ Rates of stroke and systemic embolism within 30 days of cardioversion were low and did not differ significantly between treatment arms (0.77%, 0.3% and 0.6%, respectively; dabigatran 110mg vs. warfarin, p=0.71; PRADAXA 150mg vs. warfarin, p=0.45), ¹ though the RE-LY trial and this subgroup analysis were not powered to demonstrate statistical significance. Similarly, major bleeding within 30 days of cardioversion was infrequent and comparable between treatment groups (1.7%, 0.6% and 0.6%, respectively). ¹

“Cardioversion is one treatment option for patients with atrial fibrillation and requires anticoagulation both prior to and following treatment in order to reduce the risk of stroke,” said Rangadham Nagarakanti, MD, Louisiana State University School of Medicine. “It’s helpful to know that patients on PRADAXA who underwent cardioversion had low rates of stroke and systemic embolism and bleeding similar to warfarin.”

In the RE-LY trial, an imaging technique known as transesophageal echocardiography (TEE) was encouraged prior to cardioversion to identify existing clots in the left atrium of the heart, which would suggest an increased risk of stroke or embolism associated with cardioversion. ¹ TEE was performed prior to cardioversion in more patients on dabigatran 110mg and PRADAXA 150mg than warfarin (25.5%, 24.1%, 13.3%, respectively). ¹ Rates of stroke and systemic embolism were similar across all treatment arms for those who underwent TEE-guided cardioversions (0.61, 0.00 and 1.14%, respectively; dabigatran 110mg vs. warfarin, p=0.65; PRADAXA 150mg vs. warfarin, p=0.17) and those who did not undergo TEE (0.83, 0.39 and 0.52%, respectively; dabigatran 110mg vs. warfarin, p=0.54; PRADAXA 150mg vs. warfarin, p=0.75). ¹

“Physicians have expressed excitement about the recent approval of PRADAXA to reduce the risk of stroke for patients with atrial fibrillation,” said Paul Reilly, PhD, clinical program director, Boehringer Ingelheim Pharmaceuticals, Inc. “Boehringer Ingelheim remains committed to publishing data analyses from RE-LY to help inform physicians about the clinical implications for patients taking PRADAXA.”

PRADAXA is the first oral anticoagulant to be approved in the U.S. in more than 50 years. PRADAXA is now available in more than 35,000 pharmacies nationwide. PRADAXA 75mg is also available for patients who have severe renal impairment

About RE-LY ^®

RE-LY ^® was a global, Phase III, randomized trial of 18,113 patients ² enrolled in 951 centers in 44 countries, ³ investigating whether PRADAXA (two blinded doses) was as effective as well-controlled warfarin – INR 2.0 - 3.0 – (open label) for stroke prevention. ² 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 dysfunction, age > 75 years, age > 65 years with either diabetes mellitus, history of coronary artery disease, or hypertension) ² were enrolled in the study for two years with a minimum follow-up period of one year. ⁴ RE-LY enrolled a comparable number of patients in each stroke risk group, ⁵ providing a broad representation of patients with NVAF.

The RE-LY ^® trial utilized the established PROBE (prospective, randomized, open-label, blinded endpoint evaluation) clinical trial protocol, ⁴ which has been used in the previous trials of anticoagulation for stroke prevention in patients with AFib. ⁴ A PROBE design may reflect the differences in the management of warfarin and PRADAXA in clinical practice. ⁴

The primary endpoint of the trial was incidence of stroke (including hemorrhagic) and systemic embolism. ⁴ 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. ⁴

In the RE-LY ^® trial, all clinical outcomes were adjudicated in a blinded manner to minimize bias in assessment of outcomes for each treatment. ⁴

About Atrial Fibrillation and Stroke

Atrial fibrillation, characterized by an irregular heartbeat, can cause blood clots to form in the heart that can travel to the brain and cause a stroke. ⁶ An estimated 2.3 million Americans are living with atrial fibrillation, ⁷ and the prevalence is expected to increase to 5.6 million by 2050. ⁷ A large managed care database study showed that NVAF represents approximately 95 percent of all atrial fibrillation cases in the U.S. ⁷ Atrial fibrillation increases the risk of stroke nearly five times ⁷ and is associated with up to 15 percent of all strokes in the U.S. ⁸ Atrial fibrillation imposes a substantial economic burden to the healthcare system, ⁹ specifically the high costs associated with stroke. ¹⁰

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 events. PRADAXA 150 mg resulted in a higher rate of major gastrointestinal (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

The risk of myocardial infarction was numerically greater in patients who received PRADAXA 150 mg than in those who received warfarin.

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

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 142 affiliates in 50 countries and more than 41,500 employees. Since it was founded in 1885, the family-owned company has been committed to researching, developing, manufacturing and marketing novel products of high therapeutic value for human and veterinary medicine.

In 2009, Boehringer Ingelheim posted net sales of US $17.7 billion (12.7 billion euro) while spending 21% of net sales in its largest business segment, Prescription Medicines, on research and development.

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