In patients with atrial fibrillation, the risk for major bleeding is lower with apixaban (Eliquis) than with warfarin (Coumadin), regardless of age, body weight, or serum creatinine level, a secondary analysis of the pivotal ARISTOTLE trial showed.
The 22.8% of patients assigned to receive the most common, 5-mg twice daily dose of apixaban who had one dose-reduction criterion -- advanced age, low body weight, or renal dysfunction -- were at higher risk. They had higher rates of stroke or systemic embolism (HR 1.47; 95% CI 1.20-1.81) and major bleeding (HR 1.89; 95% CI 1.62-2.20) compared with the 79.6% of participants with no dose-reduction criteria.
But the stroke or systemic embolism risk reduction was similar to warfarin in patients with one dose-reduction criterion (HR 0.94; 95% CI 0.66-1.32) and those with no dose-reduction criterion (HR 0.77; 95% CI 0.62-0.97; P=0.36 for interaction), John H. Alexander, MD, of Duke Clinical Research Institute in Durham, N.C., and colleagues reported online in JAMA Cardiology.
Likewise, the benefit on major bleeding versus warfarin was similar with one dose-reduction criterion (HR 0.68; 95% CI 0.53-0.87) and no dose-reduction criterion (HR 0.72; 95% CI 0.60-0.86; P=0.71 for interaction).
"The 5 mg twice daily dose of apixaban is safe, efficacious, and in the absence of additional data on the efficacy and safety of reduced apixaban doses compared with warfarin, should be the preferred dose of apixaban for patients with one dose- reduction criterion," the researchers wrote.
Jeffrey I. Weitz, MD, and John W. Eikelboom, MD, of McMaster University in Hamilton, Ontario, agreed in an accompanying editorial.
"Until more is known, the 2.5 mg twice daily dose should only be prescribed for patients with atrial fibrillation [AF] with at least two of the three dose-reduction criteria," they wrote, adding, "it is essential that apixaban and the other direct oral anticoagulants be given at the right dose for the right patient."
"Education is urgently needed to translate this information into practice because the inappropriate use of the lower dose of apixaban may place patients at risk for stroke," they wrote. They added that the success of educational efforts can be tracked by monitoring prescription trends.
In the study, researchers looked at a subgroup of patients with only one of three dose-reduction criteria -- an age of 80 years or older, a body weight of 60 kg or less, and a creatinine level of 1.5 mg/dL or higher -- receiving the 5-mg twice daily dose of apixaban vs warfarin in the the double-blind ARISTOTLE trial, which included 18,201 patients with AF and at least one additional risk factor for stroke or systemic embolism.
Although most of the patients randomized to apixaban in the trial received the 5 mg twice daily dose, patients with two or three dose-reduction criteria at baseline were assigned the reduced 2.5 mg twice daily dose. Those patients were excluded from the secondary analysis. Warfarin was dose adjusted to achieve a target international normalized ratio (INR) of 2.0 to 3.0.
Even for the oldest, slimmest patients with the most compromised renal function, the 5-mg twice daily dose of apixaban was associated with substantially less bleeding than warfarin, Alexander and colleagues noted.
Patterns for each dose-reduction criterion were similar across the spectrum of age, body weight, creatinine level, and creatinine clearance, the researchers said.
They pointed out that while anticoagulation alternatives to warfarin hold the promise of more effective and safer stroke prevention, quality improvement programs must ensure that patients with AF receive "the correct dose on the basis of available evidence from clinical trials."
The researchers acknowledged that data from the ARISTOTLE trial population may not be generalizable to other populations of patients with AF and that no study has been conducted comparing the efficacy of the 5 versus 2.5 mg twice daily doses of apixaban in any population of patients with AF.
"The effect of the 2.5 mg twice daily dose of apixaban on stroke or bleeding in patients without two or more dose-reduction criteria is unknown," they said.
The study was supported by Bristol-Myers Squibb and Pfizer.
Alexander reported relationships with Boehringer Ingelheim, Bristol-Myers Squibb, CSL Behring, Pfizer, Tenax Therapeutics, Regado Biosciences, Bayer, Bristol-Myers Squibb, CSL Behring, Daiichi Sankyo, GlaxoSmithKline, Janssen, Pfizer, Inc., Portola, and Somahlution. The other study authors also reported relationships with industry.
Weitz reported relationships with Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, Daiichi-Sankyo, Ionis Pharmaceuticals, Janssen Pharmaceuticals, Merck, and Portola.
Eikelboom reported relationships with AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, Daiichi-Sankyo, Eli Lilly, GlaxoSmithKline, Janssen Pharmaceuticals, and Sanofi Aventis.
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