Key points

Introduction

Although direct oral anticoagulants (DOACs) have been approved for the treatment of venous thromboembolism (VTE) and atrial fibrillation (AF) in the United States based on phase III randomized controlled trials (RCTs) that have directly compared with vitamin K antagonists (VKAs), questions remain about their applicability and safety in selected populations that were less represented in the trials. With rare exceptions, DOACs have been studied and approved using a “one-dose-fits-all” model, without the need for routine measurement of anticoagulant effect. Although this simplicity is attractive, in some situations, the absence of an evidence based dose adjustment algorithm can be problematic. In this article, we review the currently available evidence relevant to the use of DOACs in patients with extremes of body weight, advanced age, renal impairment, cancer, and antiphospholipid antibody syndrome (APS). When presenting data derived from individual or pooled subgroup analyses, both the interaction effects and the sample sizes within these subgroups are important. In Table 1 we present the names of the major phase III VTE and AF trials, their relevant dosing, as well as the sample size for each subgroup. In this review, we will focus on the US Food and Drug Administration (FDA)–approved dosing when more than 1 dose has been studied for a particular DOAC.

Introduction

Although direct oral anticoagulants (DOACs) have been approved for the treatment of venous thromboembolism (VTE) and atrial fibrillation (AF) in the United States based on phase III randomized controlled trials (RCTs) that have directly compared with vitamin K antagonists (VKAs), questions remain about their applicability and safety in selected populations that were less represented in the trials. With rare exceptions, DOACs have been studied and approved using a “one-dose-fits-all” model, without the need for routine measurement of anticoagulant effect. Although this simplicity is attractive, in some situations, the absence of an evidence based dose adjustment algorithm can be problematic. In this article, we review the currently available evidence relevant to the use of DOACs in patients with extremes of body weight, advanced age, renal impairment, cancer, and antiphospholipid antibody syndrome (APS). When presenting data derived from individual or pooled subgroup analyses, both the interaction effects and the sample sizes within these subgroups are important. In Table 1 we present the names of the major phase III VTE and AF trials, their relevant dosing, as well as the sample size for each subgroup. In this review, we will focus on the US Food and Drug Administration (FDA)–approved dosing when more than 1 dose has been studied for a particular DOAC.

Patients at extremes of body weight

Patients with extreme body weight are common in clinical practice. Obesity is an independent risk factor for both VTE and AF. Alternatively, patients with low body weight may have higher risk of bleeding with all forms of anticoagulation. Pharmacokinetic and pharmacodynamic studies in healthy subjects suggest that overall DOAC exposure for patients at extremes of body weight (<50 or >120 kg) is not substantially different from the exposure in patients who weigh between 50 and 120 kg. However, few patients with weight 50 kg or less or greater than 120 kg were included in phase III RCTs. While there is a metaanalysis comparing the efficacy and risks of DOACs versus VKA using data from the VTE (not AF) trials, the authors compared “clinically relevant” rather than “major bleeding” risks as a clinical outcome and there was significant variation of the definition of “high” and “low” body weight depending on the individual trial. In this section, we review data from subgroups of phase III AF and VTE trials to compare the rates of thrombosis and major bleeding for DOACs versus VKA in patients with extremes of body weight ( Table 2 ).

According to the package insert, dabigatran trough concentration is 20% lower in subjects with a body weight of greater than 100 kg. In a pooled analysis of the Efficacy and Safety of Dabigatran Compared to Warfarin for 6 Month Treatment of Acute Symptomatic Venous Thromboembolism (RE-COVER) studies (see Table 1 ), dabigatran 150 mg versus warfarin had a consistent treatment effect on primary efficacy in both high (>100 kg) and low (≤50 kg) body weight subgroups (nonsignificant interactions). Of note, there were only 57 patients with weight 50 kg or less and the number of patients with weight greater than 120 kg was not reported; thus, these results must be applied to these subgroups with caution. Major bleeding was not reported as a subgroup outcome. In the Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial, subgroup analysis for dabigatran 150 mg versus warfarin based on weight was also consistent with the primary trial for both improved primary efficacy and noninferior major bleeding (nonsignificant interactions). This result was confirmed by a recently published subgroup analysis where no significant interaction was observed for the relative effect of dabigatran versus warfarin on stroke or bleeding rates when patients were stratified into top 10% and bottom 10% of body mass index (BMI).

When given to healthy volunteers, the area under the curve (AUC) for rivaroxaban was not significantly different ( P = .21) for healthy subjects who weighed 50 kg or less or more than 120 kg when compared with those who weighed 70 to 80 kg. In a pooled analysis of the 2 Oral Direct Factor Xa Inhibitor Rivaroxaban in Patients With Acute Symptomatic Deep Vein Thrombosis (EINSTEIN) VTE studies, there were only 107 patients with body weight of 50 kg or less. In this low body weight subgroup, there were not sufficient numbers to detect a difference in primary efficacy or major bleeding (nonsignificant interactions). Both EINSTEIN studies analyzed weight greater than 90 kg in the subgroups. In this high body weight subgroup, there was no difference in primary efficacy (nonsignificant interactions) and major bleeding was not reported. In the Efficacy and safety of rivaroxaban compared with warfarin among elderly patients with nonvalvular atrial fibrillation in the rivaroxaban once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation (ROCKET-AF) trial, body weight subgroup used a different cutoff of 70 kg or less and greater than 90 kg. There was no obvious difference in primary efficacy outcomes (nonsignificant interactions). Major bleeding was not reported in the weight-based subgroup analysis.

In pharmacokinetic studies of healthy volunteers, apixaban has a 20% higher AUC in subjects who weigh less than 50 kg and 23% lower AUC in those whose weight is greater than 120 kg compared with the reference group whose weight is 65 to 85 kg. In the Apixaban for the Initial Management of Pulmonary Embolism and Deep-Vein Thrombosis as First-Line Therapy (AMPLIFY) trial, the subgroup analysis based on patients with high (>100 kg) or low (≤60 kg) body weight showed an effect consistent with the overall trial: no difference in recurrent VTE or death but significantly less major bleeding in the apixaban group in comparison with the VKA group (nonsignificant interactions). In the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial, apixaban was dose-reduced for patients with weight 60 kg or less when another risk factor was present (creatinine ≥1.5 mg/dL or age ≥80 y). The subgroup analysis based on low body weight showed results consistent with the overall trial, which demonstrated both significantly decreased stroke/systemic embolism as well as significantly decreased major bleeding (nonsignificant interactions) for apixaban versus VKA. In a recent subgroup analysis, 6.5% of the patients studied were found to have BMI >= 40. There was a significant interaction (interaction P = .02) between BMI categories and effects of apixaban versus warfarin concerning major bleeding, where apixaban use in patients with higher BMI (>30) was associated with less reduction in bleeding risk (hazard ratio [HR], 0.84; 0.67–1.07) when compared with patients with normal BMI (HR, 0.73, 0.57–0.92) or low BMI (HR, 0.51, 0.39–0.67).

The pharmacokinetics of edoxaban dosing have been studied in several phase II dose-finding studies in patients with AF. In a study of 536 Japanese AF patients, Yamashita and associates found that minimum concentration of edoxaban was higher in those with weight less than 60 kg across all doses of the drug. In a study of 235 Asian AF patients, Chung and colleagues confirmed that low body weight (≤60 kg) was associated with a higher minimum concentration of edoxaban and a higher incidence of bleeding. Consequently, subsequent phase III trials of edoxaban incorporated a “low-dose” edoxaban regimen (one-half dose of study drug) in patients with a weight of 60 kg or less. In the Evaluation of Efficacy and Safety of (LMW) Heparin/Edoxaban Versus (LMW) Heparin/Warfarin in Subjects With Symptomatic Deep-Vein Thrombosis and or Pulmonary Embolism (HOKUSAI-VTE) subgroup analysis with both high (>100 kg) and low (≤60 kg) body weights, edoxaban 60 mg had a consistent noninferior primary efficacy treatment effect compared with VKA (nonsignificant interactions). Major bleeding was not reported in subgroups defined by weight. In the Global Study to Assess the Safety and Effectiveness of Edoxaban (DU-176b) vs Standard Practice of Dosing With Warfarin in Patients With Atrial Fibrillation (ENGAGE AF-TIMI 48) study, edoxaban 60 mg was noninferior to VKA for prevention of stroke/systemic embolism and had significantly lower rates of major bleeding. Although there was further reduction in major bleeding in the dose-reduced groups (which included patients with low body weight), specific subgroup analysis on body weight was not reported.

In conclusion, there are sufficient data to show that, for major bleeding, apixaban 5 mg twice daily is superior to VKA in lower body weight subgroups (after necessary adjustment for age and estimated creatinine clearance [eCrCl]) and dabigatran 150 mg twice daily is noninferior to VKA in both high and low body weight subgroups. However, for the other 2 DOACs, more high-quality data are needed to exclude a possible effect of extreme body weight on the relative risk for major bleeding compared with VKA. DOACs (when used according to their labelling) seem to be noninferior or superior to VKA for primary efficacy in both VTE and AF, even in patients weighing less than 50 kg or more than 100 kg. However, to the best of our knowledge, very few patients who weighed more than 120 kg were enrolled in the large phase III RCTs and there is likely a weight above which the anticoagulant effect of any DOAC would be insufficient. Thus, more information about the efficacy and safety of FDA-approved doses of DOACs in extremely obese patients is needed.