New Sub-Analysis Evaluates Outcomes Associated with Lower Intracranial Hemorrhage Rates for Pradaxa® –

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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.