New ARISTOTLE Data ‘Reassuring’ on Lower Apixaban Dose

In A-fib patients selected using established dose-reduction criteria, the 2.5-mg twice daily dose of apixaban (Eliquis; Bristol-Myers Squibb) provides protection against stroke and death versus warfarin that is consistent with the effects of the standard 5.0-mg twice daily dose in the rest of the patients, despite reduced exposure to the drug in the blood, data from ARISTOTLE indicate.

The two doses of apixaban also provided comparable reductions in major bleeding relative to warfarin in their respective groups, lead author Michel Zeitouni, MD (Duke Clinical Research Institute, Durham, NC), told TCTMD. “Those are very important reassuring data on efficacy and safety,” he said.

It definitely tells you that you should not use apixaban 2.5 mg twice daily in individuals who don’t have the criteria for it. Michel Zeitouni

Zeitouni stressed, however, that because drug exposure was about 25% lower in patients who met criteria for and received the lower apixaban dose, “it definitely tells you that you should not use apixaban 2.5 mg twice daily in individuals who don’t have the criteria for it.”

The fear, explained senior author John Alexander, MD (Duke Clinical Research Institute), is that lowering the dose in an attempt to minimize bleeding risk in patients without established dose-reduction criteria, clinicians will also lose some of the protection from stroke.

“Even in people who do meet the dose-reduction criteria, [the 2.5-mg dose] results in lower concentrations of apixaban, and based on what we know about apixaban’s clearance, those concentrations can only be lower in people who don’t meet the dose-reduction criteria,” Alexander told TCTMD.

He added that this analysis, published in the March 17, 2020, issue of the Journal of the American College of Cardiology, cannot inform use of the lower dose in a broader population of A-fib patients. “It gives us another platform to talk about [that question] but doesn’t directly address it and shouldn’t reassure people about using the lower dose in people who don’t meet the criteria,” he advised.

Pharmacological and Clinical Effects

The main results of the ARISTOTLE trial showed that relative to warfarin, apixaban led to a 21% reduction in stroke or systemic embolism, a 31% reduction in major bleeding, and an 11% reduction in all-cause mortality in patients with A-fib. Most apixaban-treated patients received the standard dose of 5.0 mg twice daily, but those who had at least two of three characteristics expected to be associated with increased exposure to the drug (age 80 or older, weight 60 kg or less, and creatinine 1.5 mg/dL or greater) received a half dose.

Although only about 4% of trial participants qualified for the 2.5-mg dose, the reduced dose is used much more widely now in practice (20% to 60% of apixaban-treated patients). In that context, it’s useful to have more information about the lower dose, Alexander said.

This analysis included only those patients who received the appropriate dose of study drug (n = 18,073). Of those, 4.2% met dose-reduction criteria.

Among apixaban-treated patients, those who appropriately received the reduced dose had lower median drug exposure (area under the concentration time curve at a steady state 2,720 vs 3,599 ng/mL; P < 0.0001).

Despite that, the relative effect of apixaban versus warfarin in terms of reducing the coagulation biomarkers D-dimer and prothrombin fragment 1+2 was similar in both dose groups.

For clinical outcomes, patients who met criteria for dose reduction had higher risks of stroke/systemic embolism, major bleeding, and all-cause death compared with those who could receive a standard apixaban dose, regardless of which anticoagulant they were randomized to receive. But the relative impact of apixaban versus warfarin did not differ by dose for stroke or systemic embolism, major bleeding, or mortality (P for interaction = NS for all).

“The consistent safety and efficacy outcomes suggest a relatively wide therapeutic window for apixaban, also reflected in the consistent effect on coagulation biomarkers,” the authors write in their paper.

More Study on Reduced Dose in Wider Population Needed

In an accompanying editorial, John Eikelboom, MBBS (Population Health Research Institute and McMaster University, Hamilton, Canada), and colleagues note that the lower 2.5-mg dose of apixaban is used much more widely in everyday practice than it was in ARISTOTLE and AVERROES, the latter of which compared apixaban and aspirin in A-fib patients who were unsuitable for warfarin. Both employed the same dose-reduction criteria for apixaban.

“The data reported by Zeitouni et al will be welcomed by clinicians, but an important knowledge gap remains concerning the appropriateness of the unexpectedly frequent use of apixaban 2.5 mg twice daily in clinical practice. . . . One of the possible reasons for the frequent use of apixaban 2.5 mg twice daily in the community might be that clinicians are increasingly anticoagulating atrial fibrillation patients who would not have been eligible for inclusion in the trials, and in an attempt to mitigate bleeding risk are choosing the lower dose of apixaban even when they do not meet the trial criteria for dose reduction.”

Though the data from the current paper should be reassuring to clinicians who treat patients who would have been eligible for ARISTOTLTE according to the dosing criteria, “we urgently need additional data on the optimal dosing of apixaban in patients with atrial fibrillation who have clinical characteristics that may place them at very high risk of drug overexposure and bleeding, and which would have excluded them from the ARISTOTLE and AVERROES trial,” Eikelboom and colleagues write. “It remains possible that such patients are best treated with the lower dose of apixaban, even if they do not meet the criteria for dose reduction used in the trials. Until we have more data, clinicians will have to apply clinical judgment when treating these patients.”

Alexander agreed that the right dose for patients who would not have been included in the large A-fib trials is not clear, noting that many treatment decisions in practice involve extrapolating data from trials to different populations or settings. He said he tends to start patients on apixaban 5.0 mg twice daily even if they are older and frail because of its established superiority over warfarin in terms of risks of stroke/systemic embolism and major bleeding.