Interim Results from RELY-ABLE®, the RE-LY® Extension Study, Provide Additional Clinical Evidence for the Safety of Pradaxa® (dabigatran etexilate mesylate)
RIDGEFIELD, Conn., Nov. 7, 2012 -- Boehringer Ingelheim Pharmaceuticals, Inc. today announced interim results from the RELY-ABLE® trial, a long-term extension of the RE-LY® study. During more than two years of randomized follow-up, key safety outcomes such as major bleeding, total bleeding and life threatening bleeding were similar to the results of the dabigatran 110mg* and 150mg arms of the pivotal RE-LY trial that evaluated Pradaxa® (dabigatran etexilate mesylate) capsules in patients with non-valvular atrial fibrillation (NVAF). There were no new safety findings identified in the interim study results. These data were presented today at the American Heart Association's Scientific Sessions 2012.
The RELY-ABLE trial evaluated the safety of PRADAXA 150mg BID over a longer term and provides an additional two years of randomized follow-up in over 2,900 NVAF patients. The median duration of treatment with dabigatran in the interim analysis was 4.3 years. To date, PRADAXA is the only treatment in the new class of oral anticoagulants to have more than four years of randomized follow-up in patients with NVAF.
Rates of major bleeding were 2.99 percent per year with dabigatran 110mg twice daily and 3.74 percent per year with PRADAXA 150mg twice daily (HR .79, 95% CI: 0.65-0.96). Major gastrointestinal bleeding occurred at rates of 1.56 percent per year with dabigatran 110mg twice daily and 1.52 percent per year with PRADAXA 150mg twice daily (HR 1.01, 95% CI: 0.40-1.46).
"Boehringer Ingelheim is committed to continuing to add to the scientific body of evidence for PRADAXA," said Paul Reilly, PhD, Clinical Program Director, Boehringer Ingelheim Pharmaceuticals, Inc. "We are very pleased to present the interim results of RELY-ABLE as they add important clinical data to the safety profile of PRADAXA over a longer period of time."
Approved in October 2010, 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. Clinical experience with PRADAXA continues to grow with more than 4.4 million prescriptions for PRADAXA 150mg and 75mg written for more than 700,000 NVAF patients in the U.S. since its approval.
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. PRADAXA 150mg twice daily is the only treatment compared to warfarin to demonstrate superior reduction in ischemic and hemorrhagic stroke. Nearly nine out of 10 strokes caused by atrial fibrillation (AFib) are ischemic strokes. In RE-LY, PRADAXA was proven 36 percent better than warfarin at reducing the risk of stroke in patients with NVAF. PRADAXA 150mg twice daily also showed a 59 percent lower rate of intracranial bleeding in the RE-LY trial, compared to warfarin.
"It is important to remember that patients with AFib are five times as likely to have a stroke than those without, which means anticoagulation treatment over the long term may be necessary," said Stuart Connolly, MD, FRCPC, professor, Department of Medicine, McMaster University, Ontario, Canada. "These interim findings, along with the ongoing study of PRADAXA, are critical to understanding the use of this important treatment over the longer term."
RELY-ABLE involved 5,851 patients across 35 countries taking dabigatran who continued on from the 12,091 patients in the original RE-LY study. Enrolled patients continued to receive the same double-blind dose with 2,937 patients on PRADAXA 150mg and 2,914 patients on dabigatran 110mg. Patients randomized to warfarin (n=6,022) in RE-LY were not eligible for RELY-ABLE.
In the RELY-ABLE trial efficacy outcomes were evaluated as secondary endpoints. Rates of ischemic or unspecified stroke were 1.15 percent per year with dabigatran 110mg and 1.01 percent per year with PRADAXA 150mg (HR 1.14, 95% CI: 0.82-1.60). Rates of hemorrhagic stroke were low and similar in the two treatment arms at 0.14 percent per year with dabigatran 110mg and 0.13 percent per year with PRADAXA 150mg (HR 1.13, 95% CI: 0.43-2.92). Net clinical benefits rates, which comprised the composite of stroke, systemic embolic events, pulmonary emboli, myocardial infarction, all-cause death and major bleeds, were also similar in both doses (HR 0.93, 95% CI: 0.82-1.06).
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
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.
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® and RELY-ABLE® are registered service marks of Boehringer Ingelheim International GmbH and used under license.
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