Apixaban Use in Obese Patients: A Review of the Pharmacokinetic, Interventional, and Observational Study Data

Abstract

Relatively little is known about the influence of extreme body weight on the pharmacokinetics (PK), pharmacodynamics (PD), efficacy, and safety of drugs used in many disease states. While direct oral anticoagulants (DOACs) have an advantage over warfarin in that they do not require routine drug monitoring, some may regard this convenience as less compelling in obese patients. Some consensus guidelines discourage using DOACs in patients weighing > 120 kg or with a body mass index > 35-40 kg/m², given a sparsity of available data in this population and the concern that fixed dosing in obese patients might lead to decreased drug exposure and lower efficacy. Per the prescribing information, apixaban does not require dose adjustment in patients weighing above a certain threshold (e.g., ≥ 120 kg). Data from healthy volunteers and patients with nonvalvular atrial fibrillation (NVAF) or venous thromboembolism (VTE) have shown that increased body weight has a modest effect on apixaban's PK. However, the paucity of exposure data in individuals > 120 kg and the lack of guideline consensus on DOAC use in obese patients continue to raise concerns about potential decreased drug exposure at extreme weight. This article is the first to comprehensively review the available PK data in obese individuals without NVAF or VTE, and PK, PD, efficacy, effectiveness, and safety data for apixaban in obese patients with either NVAF or VTE, including subgroup analyses across randomized controlled trials and observational (real-world) studies. These data suggest that obesity does not substantially influence the efficacy, effectiveness, or safety of apixaban in these patients. Trial Registration ARISTOTLE: NCT00412984; AVERROES: NCT00496769; AMPLIFY: NCT00643201; AMPLIFY-EXT: NCT00633893; ADVANCE-1: NCT00371683; ADVANCE-2: NCT00452530; ADVANCE-3: NCT00423319 Apixaban Use in Obese Patients: A Review of the Pharmacokinetic, Interventional, and Observational Study Data (MP4 161.22 MB).

Fig. 1

Relationship between body weight and apixaban exposure in 2804 patients with NVAF receiving apixaban 5 mg bid in the ARISTOTLE trial. Triangles = female (n = 915); circles = male (n = 1889). AUC area under the concentration–time curve, bid twice daily, NVAF nonvalvular atrial fibrillation

Fig. 2

Predicted steady-state daily AUC by baseline body weight category in participants in the AMPLIFY trial [59]. Boxes = 25th to 75th percentiles; whiskers = 5th to 95th percentiles; numbers inside boxes = median values; circles = individual predicted values. AUC area under the concentration–time curve. Reproduced from Cohen AT, Pan S, Byon W, et al. Efficacy, Safety, and Exposure of Apixaban in Patients with High Body Weight or Obesity and Venous Thromboembolism: Insights from AMPLIFY. Adv Ther. 2021;38:3003–18 [59], https://link.springer.com/article/10.1007/s12325-021-01716-8, under Creative Commons license 4.0 (CC BY-NC-4.0)

Fig. 3

Efficacy and safety outcomes for apixaban vs warfarin, with weight as a continuous variable, in patients with NVAF in the ARISTOTLE trial [70]. A Stroke or SE; B all-cause death; C myocardial infarction; D ISTH major bleeding. ISTH International Society on Thrombosis and Haemostasis, NVAF nonvalvular atrial fibrillation, SE systemic embolism. Reproduced with permission from: Hohnsloser SH et al. Efficacy and Safety of Apixaban Versus Warfarin in Patients With Atrial Fibrillation and Extremes in Body Weight. Circulation. 2019;139(20):2292–2300 [70]; https://www.ahajournals.org/journal/circ

Fig. 4

Body weight categories vs relative risk of A stroke or SE and B ISTH MB in patients with NVAF in the ARISTOTLE trial [70]. ISTH International Society on Thrombosis and Haemostasis, MB major bleeding, NVAF nonvalvular atrial fibrillation, SE systemic embolism

Fig. 5

Recurrent VTE or VTE-related death and MB in 5384 participants in the AMPLIFY trial, during the treatment period, by baseline body weight category [59]. CI confidence interval, CRNM major or clinically relevant non-major, ISTH International Society on Thrombosis and Haemostasis, MB major bleeding, N number of participants, n number of events, NE not estimable, RR relative risk, VTE venous thromboembolism. Reproduced from Cohen AT, Pan S, Byon W, et al. Efficacy, Safety, and Exposure of Apixaban in Patients with High Body Weight or Obesity and Venous Thromboembolism: Insights from AMPLIFY. Adv Ther. 2021;38:3003–3018 [59], https://link.springer.com/article/10.1007/s12325-021-01716-8, under Creative Commons license 4.0 (CC BY-NC-4.0)

Fig. 6

Incidence rates and hazard ratios for stroke or SE and MB among DOACs vs warfarin in obese patients with a diagnosis code for BMI ≥ 30 kg/m². BMI body mass index, CI confidence interval, DOAC direct oral anticoagulant, GI gastrointestinal, ICH intracranial hemorrhage, MB major bleeding, NOAC non–vitamin K antagonist oral anticoagulant, ref reference, SE systemic embolism. Reproduced from Deitelzweig S, Keshishian A, Kang A, et al. Effectiveness and Safety of Oral Anticoagulants among NVAF Patients with Obesity: Insights from the ARISTOPHANES Study. J Clin Med. 2020;9:1633 [89], under Creative Commons license 4.0 (CC BY-4.0)

Fig. 7

Evaluation of recurrent VTE, MB, and CRNM bleeding among patients with VTE who initiated apixaban or warfarin, stratified by body weight category [90]. CRNM clinically relevant non-major, CI confidence interval, IR incidence rate, MB major bleeding, VTE venous thromboembolism. Reproduced from Cohen A, Sah J, Lee T, et al. Effectiveness and Safety of Apixaban vs. Warfarin in Venous Thromboembolism Patients with Obesity and Morbid Obesity. J Clin Med. 2021;10:200 [90], under Creative Commons license 4.0 (CC BY-4.0)