New Long-Term Data Published in Circulation Reinforce Safety Profile of Pradaxa^® (dabigatran etexilate mesylate)

Ridgefield, CT, June 14, 2013 – Boehringer Ingelheim Pharmaceuticals, Inc. today announced results from the RELY-ABLE^® trial, a long-term extension of the pivotal RE-LY^® study of Pradaxa^® (dabigatran etexilate mesylate) capsules in patients with non-valvular atrial fibrillation (NVAF). PRADAXA is the first treatment among the new generation of oral anticoagulants (OACs) to be evaluated in a large set of NVAF patients for more than four years. The encouraging long-term safety results, published online today in the American Heart Association’s journal Circulation, add to the growing body of data reinforcing PRADAXA as an important treatment option for patients with NVAF.

The RELY-ABLE trial was designed to evaluate the long-term safety of ongoing PRADAXA therapy in patients with NVAF, following RE-LY. Accordingly, patients enrolled in RELY-ABLE continued PRADAXA therapy, as dosed in RE-LY, for an additional 2.3 years, bringing the mean duration of treatment to 4.3 years. A total of 5,851 patients participated in the extension study: 2,937 received PRADAXA 150mg twice daily and 2,914 received dabigatran 110mg twice daily.*

“Before RELY-ABLE, little was known about the long-term effects of PRADAXA in patients with NVAF,” said Stuart Connolly, MD, FRCPC, professor, Department of Medicine, McMaster University, Ontario, Canada. “The long-term data from RELY-ABLE provide additional safety information for a large group of patients continuing the same dose of PRADAXA.”

Rates of major bleeding, the primary endpoint, were 3.74 percent (n=238) per year with PRADAXA 150mg and 2.99 percent (n=190) per year with dabigatran 110mg (HR 1.26, 95% CI: 1.04-1.53). Major gastrointestinal bleeding occurred at rates of 1.54 percent (n=98) per year with PRADAXA 150mg and 1.56 percent (n=99) per year with dabigatran 110mg.

Secondary endpoints included other key safety outcomes, such as total bleeding and life-threatening bleeding, and showed similar results as RE-LY, with no new safety findings.

“We are pleased that the RELY-ABLE findings add to the growing body of safety data supporting PRADAXA as an important treatment option for patients with NVAF,” said Sabine Luik, MD, senior vice president, medicine & regulatory affairs, U.S. regional medical director, Boehringer Ingelheim Pharmaceuticals, Inc. “Boehringer Ingelheim is a science-based company that is proud to bring innovative products, like PRADAXA, to patients and the medical community and we believe these data will be useful to prescribers.”

Additional findings include:

• Rates of stroke or systemic embolism, on dabigatran 150mg and 110mg, were 1.46 percent (n=93) and 1.60 percent (n=102) per year in RELY-ABLE, respectively (HR 0.91, 95% CI: 0.69-1.20).
• Rates of ischemic stroke or unspecified stroke were 1.15 percent (n=73) and 1.24 percent  (n=79) per year on dabigatran 150mg and 110mg, respectively (HR 0.92, 95% CI: 0.67-1.27).
• Rates of hemorrhagic stroke were similar in the two treatment arms and were very low at 0.13 percent (n=8) and 0.14 percent (n=9) per year on dabigatran 150mg and 110mg, respectively (HR 0.89, 95% CI: 0.34-2.30).
• Rates of myocardial infarction were also low and similar between the two groups at 0.69 percent (n=44) and 0.72 percent (n=46) per year on dabigatran 150mg and 110mg, respectively (HR 0.96, 95% CI: 0.63-1.45).
• Dyspeptic symptoms were reported in 5.3 percent (n=156) and 4.8 percent (n=141) of patients on dabigatran 150mg and 110mg, respectively during the RELY-ABLE follow-up.
• Total mortality rate was 3.02 percent (n=192) and 3.10 percent (n=197) per year in patients on dabigatran 150mg and 110mg, respectively (HR 0.97, 95% CI: 0.80-1.19).
• During RELY-ABLE, serious adverse events occurred in 36.3 percent (n=1,067) and 33.7 percent (n=982) of patients on dabigatran 150mg and 110mg, respectively.

The rates of stroke or systemic embolism were slightly higher in RELY-ABLE than RE-LY partly due to the fact that there was no event adjudication. In RE-LY, adjudication either confirmed reported events or rejected them.

Data from RELY-ABLE contribute to the evidence supporting the safety profile of PRADAXA, including the most recent analyses of real-world safety data from the FDA Mini-Sentinel initiative.

PRADAXA was the first oral anticoagulant approved by the U.S. Food and Drug Administration in more than 50 years to reduce the risk of stroke and systemic embolism in patients with NVAF. PRADAXA 150mg twice daily is the only medication among the new generation of OACs to demonstrate superior reduction of ischemic stroke compared to warfarin. Nearly nine out of 10 strokes caused by atrial fibrillation (AFib) are ischemic strokes.

Prescribing experience with PRADAXA continues to grow with more than 5.5 million prescriptions for PRADAXA 150mg and 75mg filled for more than 775,000 NVAF patients in the U.S. since its approval in October of 2010.

About RELY-ABLE^®
RELY-ABLE was a global, extension trial of 5,851 dabigatran-treated patients across 35 countries who continued on from the 12,091 patients in the original RE-LY study.

There were some limitations to the RELY-ABLE trial. Only half of the patients continued from RE-LY to RELY-ABLE. Patients were eligible if they did not prematurely discontinue PRADAXA therapy. Also, it was at the investigator’s discretion to determine if it was clinically appropriate for patients to continue receiving long-term OAC treatment. Patients randomized to warfarin (n=6,022) in RE-LY were not eligible for RELY-ABLE.

Also, there was no event adjudication, meaning confirmation by an independent team or group, in RELY-ABLE, whereas there was event adjudication in RE-LY. Lastly, patients enrolled in RELY-ABLE were different from those in RE-LY and may have been at lower risk of events.

About RE-LY^®
The efficacy and safety of PRADAXA was established in the RE-LY trial, one of the largest stroke prevention clinical studies ever conducted in patients with NVAF. 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 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, liver function and other adverse events.

In RE-LY, PRADAXA 150mg twice daily significantly reduced the risk of stroke and systemic embolism by 35 percent more than warfarin (based on incidences of 2.2 percent for PRADAXA 150mg vs. 3.4 percent for warfarin), with a similar rate of major bleeding events. PRADAXA 150mg twice daily also showed a 59 percent lower rate of intracranial bleeding and a superior 25 percent reduction of ischemic stroke in the RE-LY trial, compared to warfarin

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^® (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

WARNING: DISCONTINUING PRADAXA IN PATIENTS WITHOUT ADEQUATE CONTINUOUS ANTICOAGULATION INCREASES RISK OF STROKE. Discontinuing PRADAXA places patients at an increased risk of thrombotic events. If anticoagulation with PRADAXA must be discontinued for a reason other than pathological bleeding, consider coverage with another anticoagulant.

CONTRAINDICATIONS
PRADAXA is contraindicated in patients with:

-          active pathological bleeding;
-          known serious hypersensitivity reaction (e.g., anaphylactic reaction or anaphylactic shock) to
           PRADAXA;
-          mechanical prosthetic heart valve

WARNINGS & PRECAUTIONS

Increased Risk of Stroke with Discontinuation of PRADAXA
Discontinuing PRADAXA in absence of adequate alternative anticoagulation increases the risk of thrombotic events. If PRADAXA must be discontinued for a reason other than pathological bleeding, consider coverage with another anticoagulant.

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 (e.g., a drop in hemoglobin and/or hematocrit or hypotension). Discontinue PRADAXA in patients with active pathological bleeding.
• Risk factors for bleeding include concomitant use of 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. Hemodialysis can remove dabigatran; however clinical experience for hemodialysis as a treatment for bleeding 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. 

Thromboembolic and Bleeding Events in Patients with Prosthetic Heart Valves
The safety and efficacy of PRADAXA in patients with bileaflet mechanical prosthetic heart valves (recently implanted or implanted more than 3 months prior to enrollment) was evaluated in the phase 2 RE-ALIGN trial. RE-ALIGN was terminated early because of significantly more thromboembolic events (valve thrombosis, stroke, transient ischemic attack, and myocardial infarction) and an excess of major bleeding (predominantly post-operative pericardial effusions requiring intervention for hemodynamic compromise) for PRADAXA vs warfarin. Therefore, the use of PRADAXA is contraindicated in patients with mechanical prosthetic valves.

Use of PRADAXA for the prophylaxis of thromboembolic events in patients with AFib in the setting of other forms of valvular heart disease, including bioprosthetic heart valve, has not been studied and is not recommended.

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 higher rates 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).

Click here for full Prescribing Information, including Boxed WARNING, and Medication Guide.

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RE-LY^® and RELY-ABLE^® are registered service marks of Boehringer Ingelheim International GmbH and used under license.