Time to Revisit Dabigatran Dose in the United States?

Megan Brooks

May 31, 2011 — The lower dose of dabigatran (Pradaxa; Boehringer Ingelheim), tested but not approved in the United States for stroke prevention in patients with atrial fibrillation, may be best after all for patients older than 75 years, a new analysis suggests.

"Important new data" from the RE-LY trial "strongly support" the need to make the 110-mg dose of dabigatran available in the United States "so it can be considered in elderly patients," lead study author John W. Eikelboom, MBBS, of McMaster University, Hamilton, Ontario, Canada, told Medscape Medical News.

In a report published online May 16 in Circulation, Dr. Eikelboom and the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trialists publish "previously unreported" safety results for both the 110-mg and 150-mg dose of dabigatran vs warfarin for different types of major bleeding and in key subgroups, most notably individuals older than 75 years.

A key finding in the new analysis, they say, is an increased risk for extracranial bleeding with dabigatran, 150 mg twice daily, in patients 75 years and older.

A RE-LY Refresher

The RE-LY trial enrolled more than 18,000 patients with atrial fibrillation at risk for stroke to receive dabigatran, 110 mg or 150 mg twice daily, or warfarin at a dose adjusted to an international normalized ratio of 2.0 to 3.0 for a median of 2 years.

The trial was conducted in 976 centers in 44 countries and was funded by Boehringer Ingelheim. The results were published in 2009 in the New England Journal of Medicine and reported by Medscape Medical News at that time.

The trial showed that dabigatran, 110 mg twice daily, compared with warfarin was associated with a similar risk for stroke and a lower risk for major bleeding and that dabigatran, 150 mg twice daily, was associated with a lower risk for stroke and a similar risk for major bleeding.

"The effects of both doses of dabigatran in stroke prevention were consistent irrespective of patient baseline characteristics, suggesting the efficacy results can be applied widely," Dr. Eikelboom and colleagues note in the Circulation article.

Largely on the basis of these findings, the US Food and Drug Administration (FDA) in October 2010 approved dabigatran for the prevention of stroke and systemic embolism in patients with AF. The agency approved 2 doses: 150 mg twice daily and, for a small subset of patients with severe renal impairment, 75 mg twice daily, which was not studied in RE-LY. In Canada, both the 110-mg and 150-mg doses are approved.

The failure of the FDA to approve the 110-mg dose fueled heated debate, which continues today.

J. David Spence, MD, of the University of Western Ontario, London, Canada, who was not involved in the RE-LY trial, called the FDA decision to approve the 75-mg dose "very strange."

In October 2010, at the time of the FDA decision, he noted that the problem with the RE-LY study is that it did not use dose adjustment; "it compared 2 doses to which patients were randomized [and] the 150-mg dose performed better on average, but patients don't come in averages; they come one at a time."

More recently, in a perspective published online April 13, 2011, in the New England Journal of Medicine, 3 FDA officers offered a fuller explanation of that decision.

"There were certainly reasons why we might have approved both doses," B. Nhi Beasley, Ellis F. Unger, and Robert Temple, all from the FDA Center for Drug Evaluation and Research, concede. "Ultimately, the FDA's decision to approve only the 150-mg strength was based on our inability to identify any subgroup in which use of the lower dose would not represent a substantial disadvantage."

In an interview with heartwire, sister publication to Medscape Medical News, RE-LY principal investigator Stuart J. Connolly, MD, from McMaster University, Hamilton, Ontario, disagreed, calling the FDA perspective an "apology" for a bad decision.

"I just think that they're wrong; they should have approved the lower dose. I don't think what they're saying is incorrect — they couldn't find a subgroup in the RE-LY study — but I do think that there are patients where the 110-mg dose makes perfect sense."

'Significant Treatment-by-Age Interaction'

In the new analysis of bleeding reported now in Circulation, dabigatran, 110 mg twice daily, compared with warfarin was associated with a lower risk for major bleeding (2.87% vs 3.57%; P = .002), whereas dabigatran, 150 mg twice daily, was associated with a similar risk for major bleeding (3.31% vs 3.57%; P = .32).

However, Dr. Eikelboom and colleagues say they found a "significant treatment-by-age interaction."

"In the under 75s," Dr. Eikelboom told Medscape Medical News, "both doses of dabigatran compared with warfarin are associated with reduced bleeding, but in the over 75s the lower dose of dabigatran (110 mg [twice daily]) is associated with a similar risk of bleeding compared with warfarin and the higher dose (150 mg [twice daily]) is associated with a higher risk of bleeding compared with warfarin."

Table 1. Risk for Major Bleeding (per Year) With Warfarin and Dabigatran by Age

"Importantly," Dr. Eikelboom said, "this change in the risk of bleeding with dabigatran compared with warfarin affects extracranial bleeding but not intracranial bleeding, which is the most feared complication of warfarin treatment. Both doses of dabigatran compared with warfarin have lower rates of intracranial bleeding irrespective of age," he noted.

Table 2. Risk of Extracranial and Intracranial Bleeding (Per Year) by Age

New Data Support a Second Look

Dr. Eikelboom said he believes that these new data "support the need for both doses of dabigatran to be made available in the US. The 150-mg dose will be the dose of choice in the under 75s but in older patients clinicians will want to consider the 110-mg dose to reduce the risk of extracranial bleeding."

The new analyses, Dr. Eikelboom added, indicate that "the safety advantages of dabigatran compared with warfarin are less evident with increasing age."

Dr. Spence agrees that these new data "provide a rationale for considering the 110-mg dose in patients above age 75. That dose would probably also be preferable for patients with impaired renal function (for example, an estimated glomerular filtration rate less than 50 or so)."

The RE-LY study was funded by Boehringer Ingelheim. Dr. Eikelboom has received grant support, honoraria, or consulting fees from Boehringer Ingelheim, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Regado Biosciences, and sanofi-aventis. A complete list of disclosures for the RE-LY study team can be found with the Circulation article. Dr. Spence is the principle investigator in the ARISTOTLE trial with apixaban and has been a consultant to Boehringer Ingelheim.

Circulation. 2011;123:2363-2372. Published online May 16, 2011. Abstract