New Subanalyses of RE-LY^® Trial Evaluate PRADAXA in Subsets of Patients with Non-Valvular Atrial Fibrillation

Ridgefield, CT, November 14, 2011 – A new retrospective subanalysis of the RE-LY^® trial found Pradaxa^® (dabigatran etexilate mesylate) capsules 150mg twice daily reduced the risk of stroke and systemic embolism compared to warfarin in patients with non-valvular atrial fibrillation (NVAF) irrespective of the presence of symptomatic heart failure (sHF), with no significant interaction for major bleeding events.¹ The results were presented today at the American Heart Association’s Scientific Sessions 2011.

Heart failure is a serious condition that occurs when the heart is unable to pump enough blood to meet the body's needs.² Up to 30 percent of heart failure patients have atrial fibrillation (AFib),³ and heart failure can increase the risk of stroke for patients with AFib.⁴ Heart failure also can increase the risk of bleeding in anticoagulated patients.⁵

"Since heart failure and AFib frequently coexist, this subanalysis is particularly important to physicians who treat patients with non-valvular atrial fibrillation," said Paul Reilly, PhD, clinical program director, Boehringer Ingelheim Pharmaceuticals, Inc. "These findings add to the growing body of data about the use of PRADAXA in this patient population."

The subanalysis assessed the effects of PRADAXA 150mg twice daily compared to warfarin in a prespecified subset of patients with previous sHF (n = 4,904).¹ The analysis found that while annual event rates of stroke or systemic embolism were higher overall for patients with sHF at baseline (PRADAXA 150mg: 1.44%; warfarin: 1.92%) than those without sHF (PRADAXA 150mg: 1.00%; warfarin: 1.64%), PRADAXA 150mg twice daily reduced the risk of stroke compared to warfarin for both groups of patients (HR = 0.75 for patients with sHF; HR = 0.61 for patients without sHF; p-value for interaction = 0.39).¹

Annual event rates for major bleeding were lower with PRADAXA 150mg twice daily than warfarin in patients with sHF at baseline (PRADAXA 150mg: 3.10%; warfarin: 3.90%) and those without sHF (PRADAXA 150mg: 3.39%; warfarin: 3.45%).¹ There was no significant interaction for major bleeding events between the two subgroups of patients (HR = 0.79 for patients with sHF; 0.99 for patients without sHF; p-value for interaction = 0.74).¹ Additionally, annual rates of intracranial bleeding were lower with PRADAXA 150mg twice daily than warfarin in patients with sHF at baseline (PRADAXA 150mg: 0.26%; warfarin: 0.65%) and those without sHF (PRADAXA 150mg: 0.34%; warfarin: 0.80%).¹ There was no significant interaction for intracranial bleeding events between the two subgroups of patients (HR = 0.39 for patients with sHF; 0.42 for patients without sHF; p-value for interaction = 0.72).¹

"It is important that we continue to analyze the data from RE-LY to better understand the use of PRADAXA in different types of non-valvular atrial fibrillation patients," said John Smith, MD, PhD, senior vice president for clinical development and medical affairs, Boehringer Ingelheim Pharmaceuticals, Inc. "Boehringer Ingelheim is committed to informing physicians about the clinical implications for patients taking PRADAXA through data analyses such as these."

PRADAXA was approved by the U.S. Food and Drug Administration in October 2010 to reduce the risk of stroke and systemic embolism in patients with NVAF.⁶ PRADAXA has been shown to reduce both ischemic and hemorrhagic stroke compared to warfarin in patients with NVAF.⁶ In the first eleven months after approval, more than 420,000 patients in the U.S. were prescribed PRADAXA.⁷ Dabigatran is recommended in a 2011 update to atrial fibrillation treatment guidelines.

Additional RE-LY Subanalysis Presented at AHA
A second subanalysis assessed the risk of peri-operative bleeding with PRADAXA 150mg twice daily compared to warfarin in patients undergoing surgery (n = 4,615).⁸ In the analysis, the peri-operative phase was defined as seven days before until 30 days following the procedure.⁸ The analysis found no significant difference in the risk of bleeding, including major (RR = 1.08; p = 0.64), minor (RR = 1.15; p = 0.25), fatal (RR = 1.01; p = 0.99), bleeding requiring re-operation (RR = 1.39; p = 0.32) and bleeding requiring red blood cell transfusion (RR = 0.85; p = 0.37), between patients receiving PRADAXA 150mg twice daily compared to warfarin.⁸ The analysis also found that patients in all treatment arms who had emergency surgery were at much higher risk of major bleeding than those undergoing elective surgery (PRADAXA 150mg: 17.4% vs. 3.8%; warfarin: 21.7% vs. 3.3%; p<0.001 for all); however, there was no significant difference between treatment arms for either type of surgery.⁸ Additionally, in all treatment arms, major bleeding was more common for major compared to minor surgery (PRADAXA 150mg: 6.4% vs. 3.2%; warfarin: 8.0% vs. 1.8%; p<0.01 for all), with no significant difference between treatment arms.⁸

About RE-LY
RE-LY was a global, Phase III, randomized trial of 18,113 patients⁶ enrolled in 951 centers in 44 countries,⁹ investigating whether dabigatran etexilate (two blinded doses) was as effective as well-controlled warfarin – INR 2.0 - 3.0 – (open label) for stroke prevention.⁶ 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 > 75 years, age > 65 years with either diabetes mellitus, history of coronary artery disease, or hypertension) were enrolled in the study for two years⁶ with a minimum follow-up period of one year.¹⁰  

The RE-LY trial utilized the established PROBE (prospective, randomized, open-label, blinded endpoint evaluation) clinical trial protocol,¹⁰ which has been used in the previous trials of anticoagulation for stroke prevention in patients with AFib.¹⁰ A PROBE design may reflect the differences in the management of warfarin and dabigatran in clinical practice.¹⁰

The primary endpoint of the trial was incidence of stroke (including hemorrhagic) and systemic embolism.¹⁰ 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.¹⁰

In the RE-LY trial, all clinical outcomes were adjudicated in a blinded manner to assess outcomes for each treatment.¹⁰

About Pradaxa^® (dabigatran etexilate) 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 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. Consider evaluation of renal function. 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 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), concomitant use of PRADAXA and P-gp inhibitors should be avoided.  

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
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 and medication guide, please visit www.pradaxa.com or contact Boehringer Ingelheim's Drug Information Unit at 1-800-542-6257.

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