Safety and Efficacy of Rivaroxaban and Apixaban in Patients with Increased Body Mass: a Systematic Review

Buck, Margaret M; Haddon, Alexa M; Paneccasio, Antonietta; Skoloda, Daniel J; Zimmerman, David E.; Guarascio, Anthony J.; Nemecek, Branden D.; Covvey, Jordan R.; Montepara, Courtney A.

doi:10.1007/s40261-021-01019-4

Cited by 9 publications

(7 citation statements)

References 41 publications

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“…The Willmann et al population PK analysis included body weight as a covariate for CL and V, but it was found that weight had a minor influence on rivaroxaban exposure. This finding has been supported by other studies that have evaluated rivaroxaban PK, safety, and efficacy in obese patients 8–10 . Despite these differences in the demographics, the covariate models for V and CL accounted for these covariates and enabled a model ignoring a study effect for V and CL to fit the data nearly as well as a model with study effects.…”

Section: Discussionsupporting

confidence: 63%

“…This finding has been supported by other studies that have evaluated rivaroxaban PK, safety, and efficacy in obese patients. [8][9][10] Despite these differences in the demographics, the covariate models for V and CL accounted for these covariates and enabled a model ignoring a study effect for V and CL to fit the data nearly as well as a model with study effects.…”

Section: Discussionmentioning

confidence: 99%

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Leveraging a Previously Published Population Pharmacokinetic Model to Predict Rivaroxaban Exposure in Real‐World Patients

Weiner

Powell

Patterson

et al. 2022

The Journal of Clinical Pharma

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Population pharmacokinetic (PK)/pharmacodynamic models are commonly used to inform drug dosing; however, often real‐world patients are not well represented in the clinical trial population. We sought to determine how well dosing recommended in the rivaroxaban drug label results in exposure for real‐world patients within a reference area under the concentration–time curve (AUC) range. To accomplish this, we assessed the utility of a prior published rivaroxaban population PK model to predict exposure in real‐world patients. We used the model to predict rivaroxaban exposure for 230 real‐world patients using 3 methods: (1) using patient phenotype information only, (2) using individual post hoc estimates of clearance from the prior model based on single PK samples of rivaroxaban collected at steady state without refitting of the prior model, and (3) using individual post hoc estimates of clearance from the prior model based on PK samples of rivaroxaban collected at steady state after refitting of the prior model. We compared the results across 3 software packages (NONMEM, Phoenix NLME, and Monolix). We found that while the average patient‐assigned dosing per the drug label will likely result in the AUC falling within the reference range, AUC for most individual patients will be outside the reference range. When comparing post hoc estimates, the average pairwise percentage differences were all <10% when comparing the software packages, but individual pairwise estimates varied as much as 50%. This study demonstrates the use of a prior published rivaroxaban population PK model to predict exposure in real‐world patients.

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Section: Discussionsupporting

confidence: 63%

Section: Discussionmentioning

confidence: 99%

Leveraging a Previously Published Population Pharmacokinetic Model to Predict Rivaroxaban Exposure in Real‐World Patients

Weiner

Powell

Patterson

et al. 2022

The Journal of Clinical Pharma

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“…55 All of the other systematic reviews involving patients with varying degrees of obesity found DOACs to yield similar or better outcomes compared with warfarin in terms of VTE and major bleeding events. [56][57][58][59][60][61][62][63] However, as exemplified by one of the more recent systematic reviews, 63 the certainty of evidence underlying outcome comparisons was typically defined as low or very low, as the majority of included studies were observational or post hoc analyses of randomized trials. Detailed information related to specific DOACs and dosing regimens was not provided likely due to the lack of such data in the studies under review.…”

Section: Systematic Reviewsmentioning

confidence: 99%

Dilemmas Related to Direct-Acting Oral Anticoagulant Administration in Patients With Extreme Obesity

Erstad

Barletta

2022

Ann Pharmacother

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Objective: The objective of the study was to discuss the controversies surrounding the use and dosing of direct-acting oral anticoagulants (DOACs) in obese patients recognizing the limitations of the existing evidence base that preclude strong recommendations. Data Sources: A literature search of MEDLINE was performed (2020 to end August 2022) subsequent to recent guidelines using the following search terms: direct acting anticoagulants, obesity, rivaroxaban, apixaban, edoxaban, dabigatran, dabigatran etexilate, and clinical practice guidelines. Study Selection and Data Abstraction: English-language studies and those conducted in adults were selected. Data Synthesis: The available randomized studies evaluating DOACs had relatively small numbers of patients with more extreme forms of obesity (body mass index [BMI] > 40 kg/m2) and none of the larger studies had a specific focus on dosing DOACs in obese patients. Recent guidelines by the International Society on Thrombosis and Haemostasis (ISTH) have specific recommendations for dosing DOACs in obesity. There are pharmacokinetic/pharmacodynamic and observational studies published before and after the ISTH guidelines with a focus on DOAC dosing in obese patients that generally support the recommendations in the guidelines, but most involved small numbers of patients usually with BMIs <45 kg/m2. Relevance to Patient Care and Clinical Practice: This review discusses DOAC dosing in obesity with important considerations for clinicians related to DOAC choice and dosing. Conclusions: Dosing alterations of DOACs do not appear to be necessary when used for either prophylaxis or treatment in patients with BMIs up to approximately 45 to 50 kg/m2, but research is needed for BMIs >50 kg/m2.

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“…Several systematic reviews and/or meta-analyses of DOAC use in obese patients with NVAF [ 13 , 62 – 65 ], VTE [ 66 – 68 ], or both [ 62 , 69 ] have been published. Detailed discussion of each is outside the scope of this article, but in general the analyses suggest that in obese and non-obese patient populations, there were no significant differences between apixaban and warfarin treatment for the outcomes of stroke, SE, recurrent VTE, or MB associated with apixaban versus warfarin use in obese versus non-obese patient populations.…”

Section: Introductionmentioning

confidence: 99%

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

Jamieson

Byon

Dettloff

et al. 2022

Am J Cardiovasc Drugs

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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/m 2 , 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 Video abstract Supplementary Information The online version contains supplementary material available at 10.1007/s40256-022-00524-x.

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Safety and Efficacy of Rivaroxaban and Apixaban in Patients with Increased Body Mass: a Systematic Review

Cited by 9 publications

References 41 publications

Leveraging a Previously Published Population Pharmacokinetic Model to Predict Rivaroxaban Exposure in Real‐World Patients

Leveraging a Previously Published Population Pharmacokinetic Model to Predict Rivaroxaban Exposure in Real‐World Patients

Dilemmas Related to Direct-Acting Oral Anticoagulant Administration in Patients With Extreme Obesity

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

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