New Sub-Analysis Evaluates Outcomes Associated with Lower Intracranial Hemorrhage Rates for Pradaxa^® (dabigatran etexilate mesylate) Versus Warfarin in the RE-LY^® Trial

Ridgefield, CT, April 18, 2012 – A new retrospective sub-analysis of the 18,113 patient RE-LY^® trial showed lower rates of intracranial hemorrhage (ICH), including both fatal and traumatic ICH, for Pradaxa^® (dabigatran etexilate mesylate) capsules 150mg taken twice daily compared with warfarin. Results of the sub-analysis recently were published online in Stroke: The Journal of the American Heart Association.

Intracranial hemorrhage can be a devastating complication of anticoagulation, particularly in older patients with atrial fibrillation. In the RE-LY trial, ICH consisted of intracerebral hemorrhage, subdural hematoma and subarachnoid hemorrhage. Intracranial hemorrhage is responsible for the majority of disability and death from treatment-related bleeding.

As previously reported in the pivotal RE-LY trial, the rate of ICH was 59 percent lower with PRADAXA 150mg (n=38) compared with warfarin (n=90). In this new RE-LY sub-analysis, 153 patients experienced 154 ICHs. The sub-analysis showed fewer fatal (13 vs. 32) and traumatic (11 vs. 24) ICH events in patients treated with PRADAXA 150mg compared to warfarin.

"These data further our understanding of the risk profile of PRADAXA compared to warfarin, showing a lower rate of both fatal and traumatic ICH with PRADAXA 150mg in patients with non-valvular atrial fibrillation, including those who were older," said Paul A. Reilly, Ph.D., clinical program director, Boehringer Ingelheim Pharmaceuticals, Inc. and an author of the sub-analysis.

The sub-analysis showed that in RE-LY, patients who experienced an ICH were, on average, older (mean age 75 [with ICH] vs. 71.5 [without ICH]) with a history of stroke or transient ischemic attack (TIA), used aspirin concomitantly, experienced less heart failure and had lower estimated creatinine clearance levels compared with study participants who did not experience an ICH. These differences were consistent across treatment arms. A history of falling was not an independent risk factor for ICH among RE-LY participants.

"Understanding the risk of ICH is a critical factor when prescribing anticoagulation therapy," said John Smith, M.D., Ph.D., senior vice president for clinical development and medical affairs, Boehringer Ingelheim Pharmaceuticals, Inc. "The sub-analysis highlights important information for physicians on independent predictors of ICH, including age, prior history of stroke or TIA and aspirin use."

In RE-LY, PRADAXA 150mg taken twice daily significantly reduced stroke and systemic embolism by 35 percent beyond the reduction achieved with warfarin dosed to target INR 2.0 to 3.0 (median TTR 67%). PRADAXA 150mg also was shown to significantly reduce both ischemic and hemorrhagic stroke compared to warfarin in patients with non-valvular atrial fibrillation (NVAF). Effects of PRADAXA compared to warfarin were more apparent in patients with lower levels of INR control.

Additional Sub-Analysis Results
The rate of ICH at all sites (intracerebral, subdural and subarachnoid) was lower for PRADAXA 150mg versus warfarin (includes both spontaneous and traumatic ICH):

• The rate of intracerebral hemorrhage was lower with PRADAXA 150mg (0.09%/year, n=11) compared with warfarin (0.39%/year, n=46; RR=0.23; 95% CI, 0.12–0.45)
• The rate of subdural hematoma was lower with PRADAXA 150mg (0.20%/year, n=24) compared with warfarin (0.31%/year, n=36; RR=0.65; 95% CI, 0.39–1.1)
• The rate of subarachnoid hemorrhage was lower with PRADAXA 150mg (0.02%/year, n=2) compared with warfarin (0.06%/year, n=8; RR=0.24; 95% CI, 0.05–1.2)

For patients who experienced a spontaneous or traumatic ICH, mortality outcomes were similar between PRADAXA 150mg (35 percent) and warfarin (36 percent) across sites (intracerebral, subdural and subarachnoid).

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 well-controlled warfarin – INR 2.0 - 3.0 – (open label) 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 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 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 hemorrhagic) and systemic embolism. The primary safety endpoint was major bleeding, defined as a reduction in the hemoglobin level of at least 20 g/L, 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) 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. 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
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.

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