Dabigatran 150 Mg Twice Daily Effective in All Types of AF

April 12, 2011

April 11, 2011 (New Orleans, Louisiana) — Treatment with the 150-mg twice daily dose of dabigatran etexilate (Pradaxa, Boehringer Ingelheim) is equally safe and effective in patients with permanent, persistent, and paroxysmal atrial fibrillation, according to a new subgroup analysis of the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) trial. The results were presented at the American College of Cardiology (ACC) 2011 Scientific Sessions last week.

Like the overall results from the 18 000-patient study, dabigatran 150 mg twice daily was more effective than warfarin for reducing the risk of stroke or systemic embolism, with a comparable risk of bleeding, compared with the older anticoagulant. Investigators did observe slightly different responses among patients treated with the 110-mg twice-daily dose, however, with dabigatran most effective in patients with paroxysmal atrial fibrillation and less so in patients with permanent atrial fibrillation.

"We had no a priori evidence to say that paroxysmal or persistent atrial-fibrillation patients would respond differently," lead investigator Dr Greg Flaker (University of Missouri, Columbia) told heartwire . "In the patients treated with the 150-mg dose twice a day, everything lined up exactly with the main results of the trial. [We saw] that big impact on stroke reduction, and bleeding risks were about the same. The 110-mg dose was a little bit different. The bleeding was, as you would expect, less compared with warfarin, but the point estimates for stroke were a little different."

Among patients with permanent atrial fibrillation treated with the lower dose of dabigatran, the hazard ratio for the risk of stroke/systemic embolism was 1.13 (95% CI 0.81–1.57), while there was a significant 40% relative reduction in risk among paroxysmal-AF patients treated with dabigatran 110 mg twice daily.

"What is this due to? Is there something about permanent or paroxysmal patients that they respond differently to dabigatran?" asked Flaker. "We have no biologic mechanism for this, and we're in the process of doing sensitivity analyses. Maybe we don't characterize patients with paroxysmal atrial fibrillation accurately."

To heartwire , Flaker said the data should be cautiously interpreted with regard to the lack of efficacy among the permanent atrial fibrillation patients treated with the lower dose of dabigatran, noting it could be a play of chance. The researchers are in the process of analyzing the data based on patient ECGs as well as hospital records showing cardioversion to assess safety and effectiveness based on the atrial-fibrillation type.

On the whole, Flaker stressed that these results confirm the findings from the overall RE-LY trial and that the 110 mg dose is not available in the US. Instead of the 110-mg dose of dabigatran, the Food and Drug Administration approved a 75-mg twice daily dose, which is available for patients with a creatinine clearance between 15 and 30 mL/min. In Canada, where the 110-mg dose is available, physicians should select this dose on the basis of other risk factors, and not on the type of atrial fibrillation, said Flaker.

The Costs of Switching Anticoagulants

In another study, investigators analyzed patient eligibility for switching anticoagulants in RE-LY and RECOVER, a trial comparing dabigatran with warfarin in the treatment of acute venous thromboembolism, and found that 93% of patients were eligible to make the change to dabigatran. Led by Dr Julie Atay (Brigham and Women's Hospital, Boston, MA), the main rationale for the study was to assess the cost implications of substituting dabigatran for warfarin among patients with atrial fibrillation and venous thromboembolism enrolled in a large anticoagulation management service.

They observed that for 1774 patients who qualified for warfarin, the annual projected costs of anticoagulation management were $1 385 494, made up largely of labor and laboratory work. If all these patients were transitioned to dabigatran, the costs of labor and laboratory work would be eliminated, but the substantial drug costs significantly increase the price of patient management. For these 1774 patients to be treated with dabigatran, the cost of patient management increases to $4 371 136.

"When we did this analysis, we thought it might be the other way, or it might be equivalent," said Atay. "We were actually surprised to see that the drug costs of dabigatran did outweigh the therapeutic costs of warfarin management."

In February, as reported by heartwire , dabigatran entered the US atrial-fibrillation management guidelines as an alternative to warfarin for preventing strokes and thromboembolism. The drug received the highest class I recommendation, based primarily on its showing in the randomized RE-LY trial, according to the document posted online February 14, 2011 as an addendum to a guidelines update published jointly in late December by the American College of Cardiology, American Heart Association, and Heart Rhythm Society.

The RE-LY trial was sponsored by Boehringer-Ingelheim.