ARISTOTLE Analysis: Don’t Shy Away From Standard Apixaban Dose in Certain High-Risk Patients

Patients with A-fib and only one of the three dose-reduction criteria used in the ARISTOTLE trial—age 80 years or older, body weight 60 kg or less, and creatinine level 1.5 mg/dL or higher—have higher event rates but derive the same benefits from the standard 5-mg twice daily dose of apixaban relative to warfarin as those with none of those characteristics, a secondary analysis of the trial shows.

That means that use of the reduced 2.5-mg dose should remain confined to patients meeting at least two of those three criteria, as was done in the trial, lead author John Alexander, MD (Duke Clinical Research Institute, Durham, NC), told TCTMD.

“The standard dose of apixaban is safe in people with one dose-reduction criterion and—as is labeled in the package insert—should be the dose that’s used in [those patients],” he said.

Further research using real-world data should focus on who is getting each dose of all of the direct-acting oral anticoagulants (DOACs)—apixaban (Eliquis; Bristol-Myers Squibb), dabigatran (Pradaxa; Boehringer Ingelheim), rivaroxaban (Xarelto; Janssen Pharmaceuticals), and edoxaban (Savaysa; Daiichi Sankyo)—to determine whether these agents are being prescribed appropriately in everyday practice and whether using lower doses has an impact on outcomes, he added.

Alexander pointed out that about 25% of apixaban prescriptions written in the United States are for the lower dose, and that in some parts of the world that figure can reach 50%. Only about 4.5% of patients in the 18,201-patient ARISTOTLE trial had two or three dose-reduction criteria, he noted.

He said that he suspects much of that use of the lower dose is driven by concerns about bleeding, particularly in patients who are older and have low body weight or renal insufficiency.

In this secondary analysis of ARISTOTLE, published online July 27, 2016, ahead of print in JAMA Cardiology, the investigators explored whether the full 5.0-mg twice daily dose of apixaban is safe and effective in patients with just one of those characteristics, which are all associated with greater exposure to the drug. The main results of the trial, published in August 2011, showed that apixaban reduced stroke or systemic embolism, all-cause death, hemorrhagic stroke, and major bleeding compared with warfarin.

After excluding patients with at least two dose-reduction criteria, there were 17,322 patients included in the new analysis (23% with one criterion and 77% with none).

Compared with patients meeting none of the dose-reduction criteria, those with one of the characteristics had higher rates of several outcomes, including stroke or systemic embolism, ischemic stroke, major bleeding, intracranial hemorrhage, and all-cause and cardiovascular death (HRs ranging from 1.47 to 2.01).

The safety and efficacy of apixaban relative to warfarin did not differ based on the presence of a dose-reduction criterion for any of the outcomes, however (P = NS for all interactions). The results were consistent across ranges of age, body weight, creatinine level, and creatinine clearance.

The findings indicate that apixaban should be used as it was in the trial, the authors say.

“No data currently exist on the effect of the 2.5-mg twice daily dose of apixaban on clinical outcomes in patients with [A-fib] without two or more dose-reduction criteria,” the authors write. “In the absence of data to the contrary, we can reasonably presume that . . . lower rates of bleeding and higher rates of stroke would be seen.”

“Therefore, limiting the use of the 2.5-mg twice daily dose of apixaban to patients who meet two or more of the three dose-reduction criteria used in the ARISTOTLE trial seems most appropriate,” they say.

Asked whether a price differential between the two doses might be one factor driving the proportion of patients prescribed the reduced dose, Alexander thought it unlikely. He noted, though, that there is a lot of complexity around drug costs, particularly among various markets internationally.

“In general,” he said, “the 2.5-mg and 5.0-mg tabs cost about the same for a month’s supply. . . . Cost is highly unlikely to be the reason for the use of the lower dose.”



Alexander JH, Anderson U, Lopes RD, et al. Apixaban 5 mg twice daily and clinical outcomes in patients with atrial fibrillation and advanced age, low body weight, or high creatinine. JAMA Cardiol. 2016;Epub ahead of print.


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Todd Neale is the Associate News Editor for TCTMD and a Senior Medical Journalist. He got his start in journalism at …

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  • The study was supported by Bristol-Myers Squibb and Pfizer.
  • Alexander reports receiving institutional research grants from Boehringer Ingelheim, Bristol-Myers Squibb, CSL Behring, Pfizer, Tenax Therapeutics, and Regado Biosciences and consulting fees from Bayer, Bristol-Myers Squibb, CSL Behring, Daiichi Sankyo, GlaxoSmithKline, Janssen, Pfizer, Portola, and Somahlution.