RE-LY^® Sub-Analysis Suggests Similar Safety and Efficacy With Pradaxa^® (dabigatran etexilate mesylate) Versus Warfarin in NVAF Patients With and Without Diabetes

Comparison of Dabigatran versus Warfarin in Diabetic Patients with Atrial Fibrillation: Results from the RE-LY Trial (Lead Author: H. Darius) [Abstract No. 15937, 3:00 p.m. - 4:30 p.m.]

Ridgefield, CT, November 4, 2012 – Boehringer Ingelheim Pharmaceuticals, Inc. presented study results from a new retrospective sub-analysis of the RE-LY^® trial that indicated patients with non-valvular atrial fibrillation (NVAF) who also have diabetes experienced similar safety and efficacy with Pradaxa^® (dabigatran etexilate mesylate) 150mg or dabigatran 110mg* relative to warfarin, in comparison to patients with NVAF who do not have diabetes. This data was presented today during the American Heart Association’s Scientific Sessions 2012.

Diabetes affects 25.8 million Americans. It is one of the most common conditions associated with atrial fibrillation (AFib), and patients with both conditions have up to double the risk of experiencing a stroke compared to those with only AFib.

“These results are encouraging, as they indicate PRADAXA 150mg twice daily is effective in this higher risk NVAF patient population, a group in need of effective treatments,” said Paul Reilly, PhD, clinical program director, Boehringer Ingelheim Pharmaceuticals, Inc.

Of the 18,113 patients in the RE-LY trial, 4,221 patients (23 percent) had diabetes when the trial began. This sub-analysis examined patient characteristics and outcomes of patients with NVAF, comparing those with and without diabetes, and the relative efficacy of PRADAXA 150mg twice daily or dabigatran 110mg twice daily versus warfarin, using an interaction p-value.

The results show that patients with diabetes in the RE-LY study had a higher prevalence of additional cardiovascular diseases (e.g., hypertension), and for diabetic patients with NVAF randomized to warfarin, INR was not as well-controlled. Despite this, the sub-analysis indicates that patients with NVAF and diabetes, compared to patients with NVAF without diabetes, derive similar relative outcomes from PRADAXA 150mg or dabigatran 110mg compared to warfarin.

“It is common for patients with atrial fibrillation to have co-morbidities, such as diabetes,” said Harald Darius, MD, PhD, Vivantes Berlin-Neukölln Medical Center, Germany. “These findings are important and relevant since nearly one out of four patients with NVAF in the RE-LY study also had diabetes.”

The sub-analysis found that patients with diabetes were younger (70.9 vs. 71.7 years, p<0.01) and more likely to have other cardiovascular diseases, including hypertension (86.6 percent vs. 76.5 percent, p<0.01), coronary artery disease (37.4 percent vs. 24.9 percent, p<0.01) and peripheral vascular disease (5.6 percent vs. 3.2 percent, p<0.01). Compared to RE-LY patients without diabetes, those with diabetes had a higher risk of strokes and major bleeds, except intracranial bleeding.

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 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 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 2 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 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, such as a drop in hemoglobin and/or hematocrit or hypotension. Discontinue PRADAXA in patients with active pathological bleeding.
• Risk factors for bleeding include 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. Dabigatran can be dialyzed (removal of about 60% of drug over 2-3 hours) but data supporting this 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.

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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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.