Dabigatran 110 mg Similar in Benefit to 150 mg in Weighted Analysis

Shelley Wood

June 12, 2013

HAMILTON, Ontario — Reigniting a smoldering debate, a new analysis based largely on data from the RE-LY trial has found similar overall benefits to the higher and lower doses of dabigatran (Pradaxa, Boehringer Ingelheim) studied in that trial [1].

European, Canadian, and Australian regulators all approved both the 110-mg and 150-mg twice-daily doses studied in RE-LY, while the FDA approved only the higher dose. (The FDA also approved a 75-mg dose for patients with severe renal impairment, although this dose was not studied in RELY.) As Dr John W Eikelboom (McMaster University, Hamilton, ON) and colleagues note in their paper, the FDA's controversial decision was based on the view that the reduction in bleeding seen with the lower dose was "clearly less significant for patients" than the reduction in stroke seen with the higher dose; the FDA also was "unable to find any population for whom the availability of a lower dose would improve dabigatran's benefit/risk profile."

In their new analysis, published online in the Journal of the American College of Cardiology, investigators assigned a "weight" to each of the key outcomes (ischemic stroke, non–CNS systemic embolism, hemorrhagic stroke, subdural bleeding, major extracranial bleeding) seen in these nonvalvular atrial fibrillation patients. Eikelboom et al previously used this method of "weighting" events in an analysis of the ACTIVE A trial. They also combined events from ACTIVE and RE-LY to increase the number of each type of adverse event to get a more precise estimate of the "weight" related to safety and efficacy. Using this methodology, ischemic and bleeding events were integrated as "ischemic-stroke equivalents."

In the analysis, both doses of dabigatran were associated with a lower risk of ischemic-stroke equivalents than warfarin, and no significant differences were seen between the two dabigatran doses. This remained the case even when deaths were included in the weighted calculations and when the data were broken down by age, presence of heart failure, diabetes, or other factors.

An analysis looking at CHADS2 score found a "nominally significant" interaction, suggesting that the lower dose of dabigatran had increased benefit, compared with the higher dose, in patients with a CHADS2 score of >3, while the higher vs lower dose was better in patients with scores <3. A similar finding was seen using the CHA2DS2-VASc scoring system.

Eikelboom et al acknowledge that other approaches have been used to weigh the net benefits of antithrombotic therapy, reaching different conclusions. Those, however, have tended to assign a lesser weight to bleeding. The FDA's decision not to approve the 110-mg dose reflected its conclusion that extracranial bleeding was "relatively unimportant, especially compared with stroke," they write.

To heartwire , however, Eikelboom pointed out that "patients differ in their values and preferences. According to a study led by Devereaux and colleagues involving patients with AF, most patients were much more concerned about stroke than bleeding, but some were just as concerned about having a serious bleed as having a stroke."

The authors write that the disparity in the approval decisions taken by different public agencies caused "considerable uncertainty for clinicians." This paper, Eikelboom said, was published in the hopes of helping doctors and patients make the best treatment decisions.

"The FDA has a very tough job, and it is not our task to tell them what to do," he told heartwire . "We simply try to present the data in a form that best helps clinicians and patients to make treatment decisions.

"What our data show is that on average, patients randomly assigned dabigatran 110 mg [twice daily] achieve the same net benefit as those assigned 150 mg [twice daily]."

In clinical practice, doctors do not "randomly" assign patients to receive the lower vs the higher dose, he reminded heartwire . "It is reasonable to expect that if the dose is tailored according to patient characteristics, patients may do even better than if they are randomly assigned to one of the two doses."

Eikelboom has received grant support/honoraria/consulting fees from Boehringer Ingelheim. Disclosures for the coautho

HAMILTON, Ontario — Reigniting a smoldering debate, a new analysis based largely on data from the RE-LY trial has found similar overall benefits to the higher and lower doses of dabigatran (Pradaxa, Boehringer Ingelheim) studied in that trial [1].

European, Canadian, and Australian regulators all approved both the 110-mg and 150-mg twice-daily doses studied in RE-LY, while the FDA approved only the higher dose. (The FDA also approved a 75-mg dose for patients with severe renal impairment, although this dose was not studied in RELY.) As Dr John W Eikelboom (McMaster University, Hamilton, ON) and colleagues note in their paper, the FDA's controversial decision was based on the view that the reduction in bleeding seen with the lower dose was "clearly less significant for patients" than the reduction in stroke seen with the higher dose; the FDA also was "unable to find any population for whom the availability of a lower dose would improve dabigatran's benefit/risk profile."

In their new analysis, published online in the Journal of the American College of Cardiology, investigators assigned a "weight" to each of the key outcomes (ischemic stroke, non–CNS systemic embolism, hemorrhagic stroke, subdural bleeding, major extracranial bleeding) seen in these nonvalvular atrial fibrillation patients. Eikelboom et al previously used this method of "weighting" events in an analysis of the ACTIVE A trial. They also combined events from ACTIVE and RE-LY to increase the number of each type of adverse event to get a more precise estimate of the "weight" related to safety and efficacy. Using this methodology, ischemic and bleeding events were integrated as "ischemic-stroke equivalents."

In the analysis, both doses of dabigatran were associated with a lower risk of ischemic-stroke equivalents than warfarin, and no significant differences were seen between the two dabigatran doses. This remained the case even when deaths were included in the weighted calculations and when the data were broken down by age, presence of heart failure, diabetes, or other factors.

An analysis looking at CHADS2 score found a "nominally significant" interaction, suggesting that the lower dose of dabigatran had increased benefit, compared with the higher dose, in patients with a CHADS2 score of >3, while the higher vs lower dose was better in patients with scores <3. A similar finding was seen using the CHA2DS2-VASc scoring system.

Eikelboom et al acknowledge that other approaches have been used to weigh the net benefits of antithrombotic therapy, reaching different conclusions. Those, however, have tended to assign a lesser weight to bleeding. The FDA's decision not to approve the 110-mg dose reflected its conclusion that extracranial bleeding was "relatively unimportant, especially compared with stroke," they write.

To heartwire , however, Eikelboom pointed out that "patients differ in their values and preferences. According to a study led by Devereaux and colleagues involving patients with AF, most patients were much more concerned about stroke than bleeding, but some were just as concerned about having a serious bleed as having a stroke."

The authors write that the disparity in the approval decisions taken by different public agencies caused "considerable uncertainty for clinicians." This paper, Eikelboom said, was published in the hopes of helping doctors and patients make the best treatment decisions.

"The FDA has a very tough job, and it is not our task to tell them what to do," he told heartwire . "We simply try to present the data in a form that best helps clinicians and patients to make treatment decisions.

"What our data show is that on average, patients randomly assigned dabigatran 110 mg [twice daily] achieve the same net benefit as those assigned 150 mg [twice daily]."

In clinical practice, doctors do not "randomly" assign patients to receive the lower vs the higher dose, he reminded heartwire . "It is reasonable to expect that if the dose is tailored according to patient characteristics, patients may do even better than if they are randomly assigned to one of the two doses."

Eikelboom has received grant support/honoraria/consulting fees from Boehringer Ingelheim. Disclosures for the coauthors are listed in the paper.

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