SUMMARY

• In a multicenter, retrospective, observational study comparing direct oral anticoagulants (DOACs) in patients with acute venous thromboembolism (VTE), no differences were observed between XARELTO and apixaban in either body mass index (BMI) group (≥40 kg/m² or <40 kg/m²).¹
  • When comparing XARELTO vs apixaban in the BMI ≥40 kg/m² group, VTE recurrence was observed in 2 (5.3%) vs 3 (2.4%) patients and major bleeding (MB) was observed in 1 (2.6%) vs 4 (3.1%) patients.
• A retrospective, hospital-based cohort study in admitted patients that evaluated the association between body weight and adverse clinical outcomes in patients treated with DOACs showed that²:
  • Mortality rates were higher with XARELTO vs apixaban in overweight (BMI 25-29.9 kg/m²) and obese (BMI 30-39.9 kg/m²) patients (P=0.001).
  • Mortality rates were higher with apixaban vs XARELTO in morbidly obese (BMI ≥40 kg/m²) patients (P=0.001).
• A retrospective chart review at an outpatient clinic comparing XARELTO and apixaban in patients with obesity and nonvalvular atrial fibrillation (NVAF) found³:
  • No difference in the primary efficacy outcome, which was the composite of stroke, transient ischemic attack (TIA), myocardial infarction (MI), or presence of arterial thrombosis.
  • No difference in clinically relevant nonmajor bleeding (CRNMB) and MB events.
• A single-center, retrospective observational study of obese and morbidly obese patients with NVAF and/or atrial flutter and concurrent heart failure (HF) found⁴:
  • In patients receiving XARELTO vs apixaban, the incidence of ischemic stroke was 7 (2.9%) vs 6 (5.9%) in obese patients and 9 (9.3%) and 2 (3.7%) in morbidly obese patients, respectively.
  • In patients receiving XARELTO vs apixaban, the incidence of safety events was 61 (25.6%) vs 7 (6.9%) in obese patients and 15 (15.5%) vs 6 (11.1%) in morbidly obese patients, respectively.
• In an analysis of a cohort of patients with atrial fibrillation (AF) from the Veterans Health Administration system, there was a significantly higher ischemic stroke risk with apixaban vs XARELTO in obese patients (≥120 kg). In patients with morbid obesity (BMI >40 kg/m²), there were no differences in the risk of ischemic stroke between apixaban and XARELTO.⁵
• In a retrospective observational study in NVAF patients with obesity (BMI ≥30 kg/m²), XARELTO and apixaban were associated with a lower risk of stroke/systemic embolism (SE) vs warfarin. XARELTO was associated with a similar risk of MB compared to warfarin. Compared to XARELTO, apixaban was associated with a lower risk of stroke/SE and MB.⁶
• In a single-center, retrospective analysis evaluating XARELTO and apixaban in comparison with warfarin in morbidly obese patients (BMI ≥40 kg/m²), the incidence of recurrent thromboembolism in the VTE group and incidence of stroke in the AF group was low and similar among all cohorts. In the VTE group, incidence of MB was also similar between the cohorts.⁷
• Additional citations have been included in the REFERENCES section for your review.^8-14

REAL-WORLD Data

Sperry et al (2024)¹ conducted a multicenter, retrospective, observational study using electronic medical records to compare the effectiveness and safety of DOACs including XARELTO and apixaban in high BMI (≥40 kg/m²)vs low BMI (<40 kg/m²) patients with acute VTE from January 1, 2013, to December 31, 2021. The primary efficacy outcome was the recurrence of VTE within 12 months of the index event (or within 1 month of anticoagulation discontinuation). The primary safety outcome was the occurrence of MB. The primary efficacy and safety outcomes were also compared between XARELTO and apixaban.

• A total of 485 patients were included, of whom 165 were included in the high BMI group and 320 were included in the low BMI group.
• Among the 165 patients with high BMI, 38 were treated with XARELTO and 127 were treated with apixaban.
  • A total of 38 (23%) patients were further categorized under BMI ≥50 kg/m², and 8 (4.8%) patients were categorized under BMI ≥60 kg/m².
  • The median BMI was 44.4 kg/m² (quartile [Q]1-Q3, 42.1-49.6).
  • The median age was 57 years (Q1-Q3, 46-66).
• Among the 320 patients with low BMI, 73 were treated with XARELTO and 246 were treated with apixaban.
  • The median BMI was 28.9 kg/m² (Q1-Q3, 24.8-33.5).
  • The median age was 63 years (Q1-Q3, 51-72).
• When comparing any patient receiving apixaban vs XARELTO, no differences were observed with respect to VTE recurrence (2.9% vs 6.3%; unadjusted odds ratio [OR], 0.45; 95% confidence interval [CI], 0.16-1.41) and MB (4.0% vs 4.5%; unadjusted OR, 0.89; 95% CI, 0.30-3.20).
• No differences were observed when specifically comparing apixaban vs XARELTO among the different BMI categories. See Table: Efficacy and Safety Outcomes in Patients Treated With XARELTO vs Apixaban.

Nwanosike et al (2024)² conducted a retrospective, hospital-based cohort study using data from electronic health records to evaluate the association between body weight and adverse clinical outcomes in patients treated with DOACs, including XARELTO and apixaban, admitted between May 1, 2017, and October 31, 2021. The primary outcomes were CRNMB, all-cause mortality, ischemic stroke, and any thromboembolic event.

• The primary objective was to compare outcomes among patients in different weight categories. Outcomes were also compared between different DOACs.
• A total of 97,413 patients were included, of whom 13,849 were treated with XARELTO and 82,073 were treated with apixaban.
  • The mean (standard deviation [SD]) BMI was 27.2 (7.2) kg/m².
    • Underweight (BMI <18.5 kg/m²) group included 5525 (5.7%) patients.
    • Normal weight (BMI 18.5-24.9 kg/m²) group included 37,316 (38.3%) patients.
    • Overweight (BMI 25-29.9 kg/m²) group included 27,140 (27.9%) patients.
    • Obese (BMI 30-39.9 kg/m²) group included 23,157 (23.8%) patients.
    • Morbidly obese (BMI ≥40 kg/m²) group included 4275 (4.4%) patients.
• Overall, patients treated with XARELTO had higher mortality rates than those treated with apixaban (P<0.001).
• When evaluating outcomes among the BMI categories, mortality rates were higher with XARELTO vs apixaban in obese and overweight patients (P=0.001), whereas mortality rates were higher with apixaban vs XARELTO in morbidly obese patients (P=0.001).

Burnham et al (2023)³ conducted a retrospective chart review to compare the safety and effectiveness between XARELTO and apixaban in obese (≥30 kg/m²) and morbidly obese (≥40 kg/m²) patients with NVAF at a single outpatient cardiovascular clinic from October 2014 to January 2021. The primary efficacy endpoint was the composite rate of stroke, TIA, MI, or presence of atrial thrombosis. The primary safety endpoints were CRNMB and MB events. All-cause mortality was a secondary exploratory outcome.

• Of the 333 patients treated with DOACs, 121 and 212 were treated with XARELTO and apixaban, respectively.
• Baseline characteristics were similar between the 2 groups, with the exception of higher HAS-BLED scores and higher proportion of patients who drank alcohol and had a bleeding history in the apixaban group, and a higher proportion of patients with kidney disease in the XARELTO group.
• The mean (SD) BMI was 38.3 (7.5) kg/m² and 37.2 (6.9) kg/m² for the XARELTO and apixaban groups, respectively.
• A total of 32 (26.4%) patients in the XARELTO group and 61 (28.8%) patients in the apixaban group were morbidly obese.
• There was no observed difference between XARELTO vs apixaban for the primary efficacy and safety outcomes. The secondary exploratory outcome of all-cause mortality rate was higher with apixaban vs XARELTO (3.8% vs 0%; P=0.03). See Table: Primary Efficacy and Safety Outcomes in Patients Treated With XARELTO vs Apixaban.

Chugh et al (2023)⁴ conducted a single-center, retrospective observational study using inpatient records from Montefiore Medical Center to compare the efficacy and safety of apixaban, dabigatran, and XARELTO in obese (BMI ≥30 and <40 kg/m²) and morbidly obese (BMI ≥40 kg/m²) patients (≥18 years age) with NVAF and/or atrial flutter and concurrent HF from January 2011 to September 2015. The primary efficacy outcome was the first inpatient admission for ischemic stroke or SE, and the primary safety outcome was the first admission for a bleeding event, including intracranial hemorrhage (ICH), gastrointestinal (GI) hemorrhage, or bleeding from other sites.

• A total of 883 patients were included, of whom 614 were obese and 269 were morbidly obese.
• Among obese patients receiving XARELTO (n=238) vs apixaban (n=101):
  • The median age was 70 years (IQR, 62-79) vs 78.4 years (IQR, 67.6-87.1).
  • The median Charlson score was 3 (IQR, 2-5) vs 6 (IQR, 5-8).
  • The prevalence of chronic kidney disease (CKD) was 72 (30.3%) vs 42 (41.6%).
  • The prevalence of prior cerebrovascular disease was 21 (8.8%) vs 20 (19.8%).
• Among morbidly obese patients receiving XARELTO (n=97) vs apixaban (n=54):
  • The median age was 62 years (IQR, 55-71) vs 67.4 years (IQR, 58-76.1).
  • The median Charlson score was 3 (IQR, 2-5) vs 5 (IQR, 37).
  • The prevalence of CKD was 24 (24.7%) vs 24 (44.4%).
  • The prevalence of prior cerebrovascular disease was 5 (5.2%) vs 5 (9.3%).
• In obese patients, the composite of ischemic stroke and SE was significantly higher in patients who were on dabigatran than in those who were on XARELTO and apixaban (P=0.02). See Table: Efficacy and Safety Outcomes in Obese Patients.
• All-cause mortality was 16.7%, 6.7%, and 5.9% in patients with obesity on dabigatran, XARELTO, or apixaban (P=0.0003), respectively.

• In morbidly obese patients, there was no significant difference in efficacy outcomes in patients who were on dabigatran, XARELTO, or apixaban (P=0.44). See Table: Efficacy and Safety Outcomes in Morbidly Obese Patients.
• All-cause mortality was 16.1%, 6.2%, and 7.4% in patients with morbid obesity who were on dabigatran, XARELTO, or apixaban (P=0.044), respectively.

• In unadjusted cox regression analysis, apixaban was safer than XARELTO (hazard ratio [HR], 0.29; 95% CI, 0.12-0.67; P=0.004). This association remained consistent after adjusting for age, gender, Charlson Comorbidity index, history of previous cerebrovascular accident, use of digoxin, reduced DOACs dose, CKD, and the usage of antiplatelet, non-steroidal anti-inflammatory drugs, and amiodarone. See Table: Univariate and Multivariate Analysis in Apixaban vs XARELTO Cohort.

Briasoulis et al (2021)⁵ conducted a retrospective study to analyze a cohort of obese (≥120 kg) and morbidly obese (BMI >40 kg/m²) patients diagnosed with AF from the Veterans Health Administration system who initiated XARELTO (15 or 20 mg once daily), apixaban (2.5 or 5 mg twice daily), dabigatran (150 mg twice daily), or warfarin between 2013 and 2018. The clinical endpoints included ischemic stroke, any MB, GI bleeding, intracranial bleeding, acute MI, and HF.

• A total of 28,011 veterans were included in the study (4309 on XARELTO, 6052 on apixaban, 4233 on dabigatran, and 13,417 on warfarin). Prior to applying inverse probability of treatment weighting (IPTW), patients on apixaban were older with higher rates of renal failure, peripheral vascular disease, previous stroke and MI compared with dabigatran and XARELTO. After applying IPTW, all standardized differences in demographics, comorbid conditions, and medications use among oral anticoagulant groups were <10%.
• There was a significantly higher ischemic stroke risk with apixaban vs XARELTO (P<0.001). MB risk was significantly lower with apixaban than XARELTO (P<0.001). See Table: Outcomes of Obese Patients (>120 kg) With AF Treated with Apixaban or XARELTO.
• Among the patients with BMI >40 kg/m², 2340 were on XARELTO, 3414 were on apixaban, 2405 were on dabigatran, and 8267 were on warfarin.
• In the outcomes in IPTW analysis in patients with BMI >40 kg/m², there were no differences in the risk of ischemic stroke across DOAC groups. MB risk was similar between apixaban and XARELTO (P=0.25). See Table: Outcomes of Obese Patients (BMI >40 kg/m²) with AF Treated With Apixaban or XARELTO.

Deitelzweig et al (2020)⁶ conducted a retrospective observational study in NVAF patients diagnosed with obesity (BMI ≥30 kg/m²) and who started XARELTO, apixaban, dabigatran, or warfarin between January 2013 to September 2015 with data pooled from Centers for Medicare & Medicaid Services (CMS) Medicare and 4 United States (US) commercial claims databases. Outcome measures included time to first stroke/SE, including ischemic stroke, hemorrhagic stroke, and SE and the time to first MB.

• Propensity score matching was done between the non-vitamin K oral anticoagulant (NOAC) and warfarin cohorts and between the NOAC cohorts and these results were pooled for analysis. After propensity score matching, all demographic and clinical characteristics were well balanced between pairs.
• A total of 88,461 NVAF patients with obesity were identified. Patients were matched 1:1 in each dataset: XARELTO-warfarin (22,053), apixaban-warfarin (18,181), dabigatranwarfarin (6646), XARELTO-dabigatran (7103), XARELTO-apixaban (20,431), and apixaban-dabigatran (6884).
• Patients who were prescribed XARELTO and apixaban had a lower risk of stroke/SE compared to warfarin patients (XARELTO: HR, 0.84; 95% CI, 0.72-0.98; apixaban: HR, 0.63; 95% CI, 0.49-0.82).
• XARELTO had a similar risk of MB (HR, 1.02, 95% CI, 0.90-1.17) compared to warfarin. Apixaban (HR, 0.54; 95% CI, 0.49-0.61) was associated with a lower risk of MB compared with warfarin.
• Compared to XARELTO, apixaban was associated with a lower risk of stroke/SE (HR, 0.78; 95% CI, 0.64-0.94) and MB (HR, 0.52; 95% CI, 0.47-0.59).
• A second subgroup analysis was also conducted among patients with morbid obesity (BMI ≥40 kg/m²).
  • After another propensity score matching (PSM), patients in each dataset included: XARELTO-warfarin (8055), apixaban-warfarin (6310), dabigatran-warfarin (2342), XARELTO-dabigatran (2617), XARELTO-apixaban (7180), and apixaban-dabigatran (2373).
  • There was no significant difference between apixaban and XARELTO for stroke/SE (HR, 0.93, 95% CI, 0.68-1.26, P=0.618).
  • Apixaban had a lower risk of MB compared to XARELTO (4.0 incidence per 100person years vs 7.9 incidence per 100 person-years, respectively; HR, 0.47, 95% CI, 0.39-0.56, P=0.086).

Kushnir et al (2019)⁷ conducted a single-center, retrospective analysis to investigate the efficacy and safety of XARELTO and apixaban in comparison with warfarin in morbidly obese patients. Adult patients with a BMI ≥40 kg/m² who were started on XARELTO, apixaban, or warfarin for AF or VTE were included based on chart data from Montefiore Medical Center between March 2013 and March 2017. Outcomes included recurrent VTE, ischemic stroke, and bleeding from the first prescription date to the earliest of a thrombotic event, discontinuation of medication, death, or end of study period.

• A total of 795 patients (VTE, n=366; AF, n=429) were included in the study (XARELTO, n=326; apixaban, n=150, warfarin: n=319). In the total sample, BMI ranged from 40 to 88 kg/m².
• The incidence of recurrent VTE in the VTE group was low and similar among the XARELTO, apixaban, and warfarin cohorts. The incidence of MB was also similar between the cohorts. See Table: Outcomes in Patients With VTE by Anticoagulant (BMI ≥40 kg/m²)
• In patients with AF, incidence of stroke was low and similar among the XARELTO, apixaban, and warfarin cohorts. See Table: Outcomes in Patients With Atrial Fibrillation by Anticoagulant (BMI ≥40 kg/m²)

• In a subgroup analysis in patients with VTE and a BMI ≥50 kg/m², no patients in the XARELTO (0/30) and apixaban (0/10) group had recurrent VTE. No patients experienced MB and 6/30 patients experienced composite bleeding in the XARELTO group. MB and composite bleeding occurred in 0/10 patients in the apixaban group.
• In a subgroup analysis in patients with AF and a BMI ≥50 kg/m², strokes occurred in none of the 37 patients on XARELTO and 1 of the 19 patients on apixaban. The incidence of MB and composite bleeding in patients on XARELTO was 2/37 and 6/37, respectively. The incidence of MB and composite bleeding with apixaban was 1/19 for both.

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 15 April 2024.