Apixaban Use in Obese Patients

A Review of the Pharmacokinetic, Interventional, and Observational Study Data

Michael J. Jamieson; Wonkyung Byon; Richard W. Dettloff; Matthew Crawford; Peter S. Gargalovic; Samira J. Merali; Joelle Onorato; Andres J. Quintero; Cristina Russ


Am J Cardiovasc Drugs. 2022;22(6):615-631. 

In This Article

Abstract and Introduction


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


Relatively little is known about the influence of extreme body weight on the clinical pharmacokinetics (PK), pharmacodynamics (PD), efficacy, and safety of drugs used in many disease states, including the direct oral anticoagulants (DOACs) in prothrombotic disorders such as nonvalvular atrial fibrillation (NVAF) and venous thromboembolism (VTE).

Overweight and obesity are frequently categorized according to the following body mass index (BMI) categories:[1–3]

  • Overweight: BMI 25 to < 30 kg/m2.

  • Class 1 obesity: BMI of 30 to < 35 kg/m2.

  • Class 2 obesity: BMI of 35 to < 40 kg/m2.

  • Class 3 obesity: BMI of ≥ 40 kg/m2 (also categorized as "severe" or "morbid" obesity).

The European Society of Cardiology further defines class 4 or "super-obesity" as BMI ≥ 50 kg/m2, and class 5 or "super-super or extreme obesity" as BMI ≥ 60 kg/m2.[4]

"Morbid" obesity is somewhat variously defined according to weight, ideal body weight, BMI alone, waist circumference, or weight-exacerbated comorbid conditions. For example, according to the University of Rochester, "An individual is considered morbidly obese if he or she is 100 pounds over his/her ideal body weight, has a BMI of ≥ 40 kg/m2, or ≥ 35 kg/m2 and experiencing obesity-related health conditions, such as high blood pressure or diabetes".[5] Diagnostic codes for severe obesity with multiple, largely BMI-based synonyms are available in the International Classification of Diseases 9 and 10 coding systems.[6]

The prevalence of both obesity and morbid obesity has been increasing sharply over the past decades.[7,8] Data from the US Centers for Disease Control show that from 1999 through 2018, the prevalence of obesity (BMI ≥ 30 kg/m2) and severe obesity (BMI ≥ 40 kg/m2) in adults (≥ 20 years) increased from 30.5 to 42.4% and from 4.7 to 9.2%, respectively.[7] In 2014, the average adult body weight in the United States was 88.8 kg (5th and 95th percentiles, 62.0 and 124.9 kg) for males and 76.4 kg (5th and 95th percentiles, 50.1 and 116.5 kg) for females.[9] It is estimated that 38% of the world's adult population will be overweight and another 20% will be obese by 2030.[10]

Although some studies have suggested that obesity may be associated with paradoxically improved survival and thrombotic outcomes in patients with NVAF,[11–15] obesity is nevertheless clearly recognized as a biologically plausible independent risk factor for developing NVAF.[11–13] In a longitudinal cohort study of 67,278 patients, half of whom were obese, after over 8 years of follow-up, obesity was strongly associated with a new diagnosis of NVAF after controlling for differences in age, gender, hypertension, and diabetes.[16] In addition, the contribution of obesity as an independent risk factor for stroke in patients with NVAF remains unclear.[17] Two observational studies have shown that there was an increased rate of stroke in obese patients with NVAF relative to those with normal body weight.[18,19] A separate observational study showed that there was an inverse relationship between BMI and stroke severity in patients with acute ischemic stroke and NVAF, with lower stroke severity in patients with higher body weights.[20]

As with NVAF,[21] some studies have also suggested an obesity–mortality paradox also exists in patients with VTE. Nevertheless, obesity is clearly associated with first VTE, is less clearly associated with recurrent VTE, and is recognized to interact with other risk factors for VTE.[22–24] Obesity is a risk factor in certain VTE risk assessment scores, including HERDOO2 for recurrent unprovoked VTE in women,[23,25] the Padua Prediction Score for hospitalized medical patients,[26] and the Khorana risk stratification score for cancer-associated VTE.[27] By contrast, however, obesity is not a recognized risk factor in other risk stratification models such as the Vienna Risk Model[22] and the DASH Prediction Score,[28] both for recurrent unprovoked VTE.

Consensus guidelines for anticoagulant therapy in NVAF or VTE have either discussed obesity obliquely or discouraged DOAC use in patients weighing > 120 kg, or with a BMI > 35–40 kg/m2. However, the recent 2021 International Society on Thrombosis and Haemostasis (ISTH) guidelines suggest that standard doses of apixaban or rivaroxaban, along with vitamin K antagonists (VKAs), weight-based low molecular weight heparin (LMWH), and fondaparinux, are among appropriate anticoagulation options regardless of high BMI and weight for the treatment of VTE and VTE prophylaxis after hip or knee replacement surgery.[29] Additionally, and in contrast to previous recommendations (2016),[30] the ISTH guidelines no longer suggest regularly monitoring peak or trough drug-specific DOAC levels because there are insufficient data to influence management decisions. The 2016 AC Forum Guidance on DOAC use for VTE treatment suggests avoiding DOACs in patients with VTE at extremes of body weight/BMI (e.g., weight < 50 kg or > 120 kg, or BMI ≥ 35 kg/m2) pending availability of more data.[31]

Other guidelines on VTE management do not provide clear guidance on use of DOACs in obese patients. For example, the 2021 update of the CHEST Guideline and Expert Panel Report on antithrombotic therapy for VTE disease states that certain clinical situations, such as extremes of weight, may favor use of VKAs over DOACs.[32] The American Society of Hematology 2021 guidelines for management of VTE in patients with cancer note that additional information is needed on the dosing of anticoagulation for obese patients.[33] For NVAF, the 2021 European Heart Rhythm Association practical guide on the use of DOACs in NVAF recommends using DOACs with caution or consideration of VKA use in patients with a BMI ≥ 40 kg/m2 or weight > 120 kg.[34] The 2019 focused update by the American Heart Association (AHA)/American College of Cardiology (ACC)/Heart Rhythm Society (HRS) does not make a specific recommendation, but suggests DOAC level measurements might be indicated for evaluation of drug absorption in patients > 120 kg or with a BMI > 35 kg/m2.[35 The recommendation to routinely check DOAC exposure levels in high body weight patients has recently been challenged.[36]

Regardless of consensus guidelines, DOACs continue to be used in the obese patient population. For example, a recently published study in an urban university setting reveals that DOACs were prescribed to patients with morbid obesity (weight > 120 kg or BMI > 40 kg/m2).[37] Data from the GLORIA-AF registry show not only that obesity in general is associated with increased oral anticoagulant (OAC) prescription rates in NVAF, but also suggest that moderate and severe obesity tend to favor the use of DOACs over warfarin.[38]

Apixaban is a selective inhibitor of activated coagulation factor Xa in the class of DOACs. Apixaban is approved for use in the United States to reduce the risk of stroke and systemic embolism (SE) in adult patients with NVAF, for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), for the reduction in the risk of recurrent DVT and PE following initial therapy, and for the prophylaxis of DVT, which may lead to PE, in patients who have undergone hip or knee replacement surgery.[39]

According to US product labeling of apixaban based on PK studies and subgroup analyses of the pivotal randomized controlled trials (RCTs), no dose adjustment is necessary for any single patient characteristic, including body weight alone.[40] The recommended dosage should be reduced from 5 to 2.5 mg orally twice daily (bid) only in patients with NVAF who have two or more of the following characteristics: age ≥ 80 years, body weight ≤ 60 kg, or serum creatinine ≥ 1.5 mg/dL (commonly referred to as the "ABC" [age, body weight, creatinine] criteria).[39] According to the European Summary of Product Characteristics, in patients with severe renal impairment (creatinine clearance 15–29 mL/min), the following additional recommendations apply: for the treatment of DVT, treatment of PE, and prevention of recurrent DVT and PE, apixaban is to be used with caution; for the prevention of stroke and SE in patients with NVAF, patients should receive the lower dose of apixaban 2.5 mg bid.[41]

Apixaban, like other DOACs, was developed with the advantage over warfarin that therapeutic drug monitoring is not required for use. However, clinical decisions (e.g., overdose and emergency surgery) may be better informed by knowledge of apixaban exposure. Although the chromogenic assay used to support apixaban clinical development reported anti-factor Xa activity in LMWH units, current assays are available using an apixaban-specific calibrator for which anti-factor Xa activity values are reported in apixaban concentration units, enabling a timely evaluation of apixaban exposure.[42] Predicted steady-state apixaban and anti-factor Xa activity levels are available for each indication and at each dose level. To the best of our knowledge, the HemosIL® Liquid Anti-Xa assay (Instrumentation Laboratory, Bedford, MA, USA) is the only apixaban assay currently approved by the US Food and Drug Administration for clinical practice.[43]

Exposure–response analyses of apixaban in NVAF and VTE studies have shown that there is no defined therapeutic exposure range or discernible threshold of apixaban concentration that would predict efficacy outcomes for a given individual.[42] For this reason, except in the above unique situations, measurement of apixaban concentration to guide dose selection is not recommended.

Concerns regarding dosing of DOACs in obese patients persist widely in the medical community, due to a perceived risk of decreased efficacy resulting from hypothetical sub-therapeutic exposure. To provide a comprehensive resource on use of apixaban in obese patients, we summarized all available PK and clinical outcomes data for apixaban across weight categories, from both pivotal RCTs and observational studies. This review represents the most complete summary of apixaban PK, PD and clinical outcome data to date, collectively demonstrating that the safety and efficacy of apixaban remain consistent across body weights using standard prescribing information (PI) dosing guidance.