Short-Term Outcomes of Apixaban Versus Warfarin in Patients With Atrial Fibrillation: Is Body Weight an Important Consideration?

Atrial fibrillation (AF) is associated with increased risk of stroke and mortality. Prevention of thromboembolism is the foundation of managing this common disease.¹ The nonvitamin K antagonist oral anticoagulants (NOACs) have supplanted use of traditional vitamin K antagonists, such as warfarin, offering superior efficacy, convenience, and a better safety profile.² However, dosing recommendations for NOACs vary based on criteria that consider age, renal function, and several comorbidities—but is excess weight an important consideration before prescribing a NOAC?

Obesity is a multifaceted condition of increasing prevalence, particularly in the Western world. It is also an important risk factor in the development and maintenance of AF.³ Obesity affects drug pharmacokinetics including the volume of distribution (especially lipophilic drugs), drug clearance, and potentially, effectiveness. Weight may affect the safety and efficacy of anticoagulants. Previous studies evaluating vitamin K antagonists have proven that obese patients require larger doses and prolonged lead-in periods to achieve therapeutic levels.⁴ Safety and efficacy data on the use of NOACs in the extremes of weight are sparse. Recent International Society on Thrombosis and Haemostasis guidelines caution against use of NOACs in patients weighing >120 kg.⁵ Furthermore, the potential advantage of a fixed-dosing regimen with NOACS may be problematic in those at extremes of weight with concern of under- or overdosing leading to increased thromboembolic or bleeding risk.

Therefore, the work from Hohnloser et al in the current issue of Circulation is timely.⁶ This post hoc analysis of the double-blind, double-dummy ARISTOTLE trial (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) randomized patients with AF to apixaban or warfarin anticoagulation. Available data from 18 139 patients were stratified by body weight (≤60 kg, 61–120 kg, and >120 kg) and analyzed using Cox regression to determine the efficacy and safety of apixaban in relation to warfarin according to body weight over a 2-year follow-up.⁶ Apixaban was efficacious and safe across the spectrum of weight, including extremes of weight.⁶ Relative benefits of apixaban over warfarin were consistent across all weight groups.⁶ However, warfarin was associated with a higher relative risk of International Society on Thrombosis and Haemostasis major bleeding in the lower weight range as opposed to the higher weight categories compared with apixaban.⁶ Among overweight patients (>120 kg), the absolute risk of major bleeding was lower than in lower weight categories, with the relative risk between apixaban and warfarin being comparable (hazard ratio, 0.47; 95% CI, 0.37–1.50). The authors concluded that apixaban is appropriate for patients with AF irrespective of body weight.⁶ This study is thus reassuring in view of today’s predilection toward obesity in the Western world. Data from this large study (n=18 139) also apply to ethnic groups in Latin America and Asia. They also provide us with helpful information on a low-weight population that was not covered extensively in a previous meta-analysis.⁷

Nonetheless, limitations should be recognized. This is a retrospective subgroup analysis. Weight, not a static measure, was assessed only at baseline. Variability in weight or body mass index (BMI) is relevant in relation to development of AF and its sequelae.⁸ Furthermore, BMI and obesity are not equivalent to a specific weight. Far extremes of body weight were not considered. When assessing those >140 kg, there may have been a trend toward more thromboembolic events and less bleeding with apixaban, but this population evaluated was very small. Thus, these data do not guide the clinician with the morbidly obese AF patient weighing >140 kg.

There was a significant variation in age composition, sex dominance, region of enrollment, and presence of comorbidities between the weight groups that may contribute to differences seen. There were also significant differences in concomitant medications among the 3 weight groups. Patients with low body weight had more comorbidities, had higher mean CHA₂DS₂–VASc scores and were found to have the largest difference in safety between apixaban and warfarin.⁶ Much has yet to be learned for those atrial fibrillation patients who are massively obese or vanishingly frail in regards to proper oral anticoagulation.

The conclusion is that apixaban is safe in extremes of body weight; it appears superior to warfarin in both low- and high-weight individuals, and this is reassuring. These results support evidence from a post hoc analysis of the ROCKET-AF trial (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) that found rivaroxaban and warfarin had similar efficacy for stroke prevention in all subgroups of obese patients.⁹ This study also demonstrated important differences in stroke and bleeding outcomes based on BMI. Anticoagulated AF patients with BMI ≥30 kg/m² had significantly lower risk of stroke than AF patients with a normal BMI (18.5–24.99 kg/m²).⁹ Moreover, in the AMPLIFY study(Apixaban for the Initial Management of Pulmonary Embolism and Deep-Vein Thrombosis as First-Line Therapy) of patients with acute venous thromboembolism, randomization to apixaban as opposed to subcutaneous enoxaparin, followed by warfarin reduced bleeding risk in the obese patient subgroup. Thus, both studies are suggesting a paradox that high BMI is protective against stroke and bleeding risk in anticoagulated AF patients.¹⁰ This “obesity paradox” has been reviewed systematically.⁷ Post hoc analysis of other large trials, such as the ENGAGE AF-TIMI 48 trial (Effective aNticoaGulation with factor xA next GEneration in Atrial Fibrillation–Thrombolysis In Myocardial Infarction study 48) and RE-LY (Randomized Evaluation of Long Term Anticoagulant Therapy), comparing edoxaban and dabigatran, respectively, with warfarin in obese patients have shown no significant effect of weight on safety and efficacy.^11–13 The data from post hoc analyses are summarized in Table 1.

The 2018 European Heart Rhythm Association Practical Guide on the use of NOACs in patients appreciates the uncertainty of NOAC use in individuals at the extremes of the weight spectrum as they have been underrepresented in the clinical trials.¹⁴ It advises use of vitamin K antagonists in patients weighing <50 kg and those weighing >120 kg (or BMI ≥40 kg/m²) in line with recommendations from the International Society on Thrombosis and Haemostasis.¹⁴ If NOAC use is considered in such individuals, then assessment of plasma trough levels may be considered in such patients.¹⁴

While the results from Hohnloser et al are promising and provide reassurance regarding apixaban use up to a weight of 140 kg, careful risk stratification and frequent reassessment are prudent in AF patients with extremes of weight. As the prevalence of obesity and morbid obesity increases, data on safety and efficacy of NOACs become even more important. Until data based on well-designed large, prospective, randomized, controlled trials become available, for patients at extremes in body weight, data from studies like those from Hohnloser et al remain critically important.