Original Investigation
Clinical and Pharmacological Effects of Apixaban Dose Adjustment in the ARISTOTLE Trial

https://doi.org/10.1016/j.jacc.2019.12.060Get rights and content
Under an Elsevier user license
open archive

Abstract

Background

In the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial, patients with atrial fibrillation and ≥2 dose-adjustment criteria (age ≥80 years, weight ≤60 kg, or creatinine ≥1.5 mg/dl [133 μmol/l]) were randomized to receive apixaban 2.5 mg twice daily or warfarin.

Objectives

The purpose of this study was to describe the effects of apixaban dose adjustment on clinical and pharmacological outcomes.

Methods

Patients receiving the correct dose of study drug were included (n = 18,073). The effect of apixaban 2.5 mg twice daily versus warfarin on population pharmacokinetics, D-dimer, prothrombin fragment 1 + 2 (PF1+2), and clinical outcomes was compared with the standard dose (5 mg twice daily).

Results

Patients receiving apixaban 2.5 mg twice daily exhibited lower apixaban exposure (median area under the concentration time curve at a steady state 2,720 ng/ml vs. 3,599 ng/ml; p < 0.0001) than those receiving the standard dose. In patients with ≥2 dose-adjustment criteria, reductions in D-dimers (p interaction = 0.20) and PF1+2 (p interaction = 0.55) were consistent with those observed in the standard-dose population. Patients with ≥2 dose-adjustment criteria (n = 751) were at higher risk for stroke/systemic embolism, major bleeding, and all-cause death than the standard-dose population (0 or 1 dose-adjustment criterion, n = 17,322). The effect of apixaban 2.5 mg twice daily versus warfarin in the ≥2 dose-adjustment criteria population was consistent with the standard dose in the reductions in stroke or systemic embolism (p interaction = 0.26), major bleeding (p interaction = 0.25), and death (p interaction = 0.72).

Conclusions

Apixaban drug concentrations were lower in patients receiving 2.5 mg twice daily compared with 5 mg twice daily. However, the effects of apixaban dose adjustment to 2.5 mg versus warfarin were consistent for coagulation biomarkers and clinical outcomes, providing reassuring data on efficacy and safety. (Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation [ARISTOTLE]; NCT00412984)

Key Words

apixaban
atrial fibrillation
DOAC
dose adjustment
high bleeding risk
oral anticoagulation
stroke prevention

Abbreviations and Acronyms

AF
atrial fibrillation
AUCss
area under the concentration time curve at a steady state
DOACs
direct oral anticoagulants
INR
international normalized ratio
ISTH
International Society on Thrombosis and Haemostasis
PF1+2
prothrombin fragment 1 + 2
TTR
time in therapeutic range
VKA
vitamin K antagonist

Cited by (0)

The ARISTOTLE study was funded by Bristol-Myers Squibb and Pfizer. Dr. Zeitouni has received research grants from the Federation Française de Cardiologie and Institut Servier; and has received consulting fees from Bristol-Myers Squibb and Pfizer. Dr. Lopes has received research grants from Bristol-Myers Squibb, Pfizer, Amgen, GlaxoSmithKline, Medtronic PLC, Sanofi, and Merck; and has received consulting fees from Bristol-Myers Squibb, Pfizer, Boehringer Ingelheim, Bayer AG, Daiichi-Sankyo, and Portola. Dr. Christersson has received lecture fees from Bristol-Myers Squibb and Bayer; and has served on the Advisory Board of Boehringer Ingelheim and Novartis. Dr. Siegbahn has received institutional research grants from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, GlaxoSmithKline, and Roche Diagnostics; and has received consulting fees from Olink Proteomics. Dr. De Caterina has received fees, honoraria, and research funding from Sanofi, Boehringer Ingelheim, Bayer, Bristol-Myers Squibb/Pfizer, Daiichi-Sankyo, Novartis, Merck, and Portola; and has served as a consultant for Roche. Dr. Steg has received research grants from Amarin, Bayer, Sanofi, and Servier; and has received speaking/consulting fees from Amarin, Amgen, AstraZeneca, Bayer/Janssen, Boehringer Ingelheim, Bristol-Myers Squibb, Idorsia, Novartis, Novo Nordisk, Pfizer, Regeneron, Sanofi, and Servier. Dr. Granger has received research grants from Akros, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Janssen, Pfizer, Armetheon, AstraZeneca, U.S. Food and Drug Administration, GlaxoSmithKline, The Medicines Company, Medtronic Foundation, Medtronic Inc., and Novartis; and has received consulting fees from Bayer, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Celecor, Correvio, Daiichi-Sankyo, Espero, Janssen, Pfizer, Abbvie, Armetheon, AstraZeneca, Eli Lilly, Gilead, GlaxoSmithKline, Hoffmann-La Roche, The Medicines Company, National Institutes of Health, Novartis, Sirtex, Verseon, Apple, Medscape, Merck, Novo Nordisk, Roche Diagnostics, Rhoshan, and Rho Pharmaceuticals. Dr. Wallentin has received institutional research grants from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, GlaxoSmithKline, Roche Diagnostics, and Merck & Co; has received consulting fees from Abbott; and has 2 patents for GDF-15 with Roche Diagnostics (EP2047275B1 and US8951742B2). Dr. Alexander has received research grants from Bristol-Myers Squibb, Boehringer Ingelheim, AstraZeneca, CryoLife, CSL Behring, U.S. Food and Drug Administration, National Institutes of Health, Sanofi, and VoluMetrix; and has received consulting fees from Pfizer, Bristol-Myers Squibb, AbbVie Pharmaceuticals, CSL Behring, Novo Nordisk, Portola Pharmaceuticals, Quantum Genomics, Teikoku Pharmaceuticals, VA Cooperative Studies, and Zafgen. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Listen to this manuscript's audio summary by Editor-in-Chief Dr. Valentin Fuster on JACC.org.