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This information is intended for US healthcare professionals to access current scientific information about J&J Innovative Medicine products. It is prepared by Medical Information and is not intended for promotional purposes, nor to provide medical advice.

XARELTO® (rivaroxaban)

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Use of XARELTO in Patients with Class III Obesity (BMI≥40 kg/m2)

Last Updated: 08/27/2024

Summary

Large, randomized, controlled trials that investigate the efficacy and safety of XARELTO specifically in obese patients have not been conducted.
The use of XARELTO is not contraindicated in patients with extremes in body weight. There are no specific dosing recommendations based on body weight in the XARELTO prescribing information.¹
A post hoc, observational analysis of the RECORD clinical trial program was conducted to compare postoperative (up to 6-8 weeks) rates of efficacy and safety events in morbidly obese patients (BMI, ≥40 kg/m²; n=445) with normal weight (BMI, <25 kg/m²; n=3008), overweight (BMI, 25-29 kg/m²; n=4916), and obese (BMI, 30-39 kg/m²; n=3986) patients. No significant differences in efficacy and bleeding rates were found between the groups.²
Multiple retrospective studies that evaluated the effectiveness and safety of XARELTO in Class III obese patients have been summarized below.³^-¹⁷

BACKGROUND

Large randomized controlled trials that specifically investigated the efficacy and safety of XARELTO in obese patients have not been conducted.
The use of XARELTO is not contraindicated in patients with extremes in body weight. There are no specific dosing recommendations based on body weight in the XARELTO prescribing information.¹
XARELTO is a reasonable option in patients with obesity, including class III obesity (defined as BMI >40 kg/m2), as noted within the 2023 ACC/AHA/ACCP/HRS guidelines for the diagnosis and management of atrial fibrillation and the 2021 ISTH guidelines for the use of DOACs in patients with obesity for treatment and prevention of venous thromboembolism.¹⁸^,¹⁹
- 2023 ACC/AHA/ACCP/HRS guidelines provide a moderate strength recommendation based on moderate-quality, nonrandomized evidence, though do not specifically provide a suggestion regarding dose.¹⁸
- 2021 ISTH guidelines provide a weak recommendation based on limited literature for using standard doses of XARELTO, regardless of BMI and weight.¹⁹

CLINICAL DATA

The RECORD Program

The RECORD clinical development program, a comprehensive program of 4 phase 3 studies with over 12,000 patients, studied XARELTO for the prophylaxis of VTE in patients undergoing knee (RECORD 3 and 4) or hip (RECORD 1 and 2) replacement surgery. The data from the RECORD program were submitted to the Food and Drug Administration (FDA). XARELTOwas approved on July 1, 2011, by the FDA for the indication studied in the RECORD program.

In the RECORD 4 study, patients received either oral XARELTO 10 mg once daily, beginning at least 6-8 hours after surgery, or subcutaneous enoxaparin 30 mg every 12 hours, starting 12-24 hours after surgery. Data from RECORD 4 are not included in the approved product labeling for XARELTO.

Since the publication of RECORD 4 findings, the sponsor company conducted a verification of the data for all patients in this clinical trial. With respect to study findings, additional adverse events/serious adverse events were identified; however, the distribution of those was balanced between study groups. In the company’s view, verification findings did not appreciably change the conclusions of the study. Thus, the RECORD 4 findings reported in the publication remain consistent with the overall results from the total RECORD program.²⁰^-²³

Friedman et al (2013)² conducted a post hoc, observational analysis of the RECORD clinical trial program to compare postoperative (up to 6-8 weeks) rates of efficacy events (asymptomatic deep vein thrombosis [DVT], symptomatic DVT, symptomatic pulmonary embolism) and safety events (bleeding events, adverse events, wound complications) in Class III obese patients (BMI, ≥40 kg/m²; n=445) with those in normal-weight (BMI, <25 kg/m²; n=3008), overweight (BMI, 25-29 kg/m²; n=4916), and obese (BMI, 30-39 kg/m²; n=3986) patients combined.

An adjusted analysis was performed to remove the influence of demographic or baseline data on outcomes:
- There were no significant differences in the efficacy and bleeding event rates between Class III obese patients and patients in the other BMI groups combined.
- Serious adverse events occurred more commonly in Class III obese patients compared with patients in the other BMI groups combined (P=0.0014). These included device-related infection (0.67%), femur fracture (0.67%), hypoxia (0.45%), increased alanine aminotransferase (0.45%), infective arthritis (0.45%), nausea (0.45%), vomiting (0.45%), and wound dehiscence (0.45%).
- Wound inflammation and infection, infections excluding the surgical site, and respiratory tract and lung infections were significantly higher in Class III obese patients compared with other BMI groups combined (P=0.0021, P=0.0015, and P=0.0391, respectively).

Real-world STUDIES

Multiple real-world studies have been conducted to evaluate the safety and efficacy of XARELTO in Class III obese patients ³^-¹⁷. See Table: Real-World Studies of XARELTO in Class III Obese Populations.

Real-World Studies of XARELTO in Class III (BMI≥40 kg/m²) Obese Populations

Author (Year) Study Design BMI (kg/m²)	Methods			Outcomes
Author (Year) Study Design BMI (kg/m²)	Indication	Number of Patients on XARELTO with a BMI≥40 kg/m²/Number of patients in study with BMI≥40 kg/m²	Comparator	Outcomes
Dobry et al (2024)³ Retrospective cohort study Mean BMI in: DOAC: 44.1±7.7 Warfarin: 45.4±8.8 Subgroup analysis of patients with a BMI>50 (average BMI: 51.8)	NVAF	674/2070 Study included warfarin (1396), apixaban (1086), XARELTO (674); total N=3156. Only reporting XARELTO vs. warfarin outcomes (N=2070) Subgroup analysis (BMI>50 kg/m²): 558/1049 (No patients in the apixaban group had a BMI>50 kg/m²)	Warfarin	Primary outcome^a: Stroke or systemic embolism (XARELTO vs warfarin OR): 0.93 (95% CI, 0.51-1.69); P=0.82 Major bleeding^b (XARELTO vs warfarin OR): 1.22 (95% CI, 0.73-2.05); P=0.44 Secondary outcome^a: CRNMB^c (XARELTO vs warfarin OR): 1.31 (95% CI, 0.74-2.31); P=0.35 Subgroup analysis outcome: XARELTO vs warfarin Stroke or systemic embolism (2.5% vs 3.3%, P=0.47) Major bleeding^b (2.2% vs 3.7%, P=0.14) CRNMB^c (2.3% vs 3.3%, P=0.36)
Chin-Hon et al (2023)⁴ Retrospective review Average BMI is not mentioned	VTE or AF	22/107	Warfarin, apixaban, and dabigatran	Primary outcome^d: Rate of bleeding^b (XARELTO vs warfarin vs apixaban vs dabigatran): 9.09% vs 8.33% vs 23.53 % vs 12.5% (P=0.34) Secondary outcome: Rate of VTE (XARELTO vs warfarin vs apixaban vs dabigatran): 13.64% vs 0% vs 0% vs 12.5% (P=0.01) Rate of ischemic stroke was 0% in all groups.
Chugh et al (2023)⁵ Retrospective, observational study Mean BMI in XARELTO: 45.7 Apixaban: 46.1 Dabigatran: 45.3	AF and HF	97/269	Apixaban and dabigatran	Primary outcome^a: First inpatient admission for ischemic stroke or SE: Apixaban vs XARELTO: HR, 0.22 (95% CI, 0.035-1.44); P=0.23 Dabigatran vs XARELTO: HR, 0.26 (95% CI, 0.086-0.78); P=0.016 First inpatient admission for bleeding event^e: XARELTO vs apixaban: HR, 0.55 (95% CI, 0.19-1.60); P=0.27 Dabigatran vs XARELTO: HR, 0.95 (95% CI, 0.47-1.92); P=0.89
Weaver et al (2022)⁶ Retrospective cohort study Mean BMI±SD in XARELTO: 44.8±7.8 Warfarin: 47.1±10.4 Subgroup analysis of patients with a BMI>50 (Mean BMI was 53.4 kg/m²)	Acute VTE	487/1272 Subgroup analysis (BMI>50 kg/m²): 159/494	Warfarin	Primary outcome^a: Recurrent VTE (XARELTO vs warfarin): HR, 0.69 (95% CI, 0.42-1.08); P=0.12 Major bleeding^b (XARELTO vs warfarin): HR, 1.21 (95% CI, 0.62-2.34); P=0.58 Secondary outcome^a: CRNMB^c (XARELTO vs warfarin): 1.8% vs 3.1%; P=0.21 All-cause mortality (XARELTO vs warfarin): 1.2% vs 2.3%; P=0.21 Subgroup analysis outcome: There were no significant differences observed in VTE recurrence, major bleeding^b, CRNMB^c, and all-cause mortality in this population.
Navarro et al (2021)⁷ Retrospective study Mean BMI±SD: 43.4±6.5	NVAF	54/135	Apixaban and dabigatran	Primary outcome: Ischemic stroke/TIA (XARELTO vs apixaban vs dabigatran): 0% vs 2.4% vs 2.6%; P=0.25 Major bleeding^b (XARELTO vs apixaban vs dabigatran): 7.4% vs 4.8% vs 2.6%; P=0.34 Mortality (XARELTO vs apixaban vs dabigatran): 5.6% vs 16.7% vs 5.1%; P=0.27
Briasoulis et al (2021)⁸ Retrospective study Average BMI not mentioned	AF	2340/16,426	Apixaban, dabigatran, and warfarin	Ischemic stroke^a: Apixaban vs XARELTO: HR, 0.85 (95% CI, 0.65-1.11) Dabigatran vs XARELTO: HR, 0.85 (95% CI, 0.65-1.1) Warfarin vs XARELTO: HR, 1.1 (95% CI, 0.84-1.41) Major bleeding^a,f: Apixaban vs XARELTO: HR, 1.08 (95% CI, 0.94-1.25); P=0.25 Dabigatran vs XARELTO: HR, 0.8 (95% CI, 0.69-0.93); P=0.005 XARELTO vs Warfarin: HR, 0.66 (95% CI, 0.58-0.75); P<0.01
Costa et al (2021)⁹ Retrospective cohort study Average BMI not mentioned	Acute VTE	1697/3394	Warfarin	Primary outcome^a: Risk of recurrent VTE (XARELTO vs warfarin): HR, 0.57 (95% CI, 0.42-0.77); P=0.61 Risk of major bleeding^g (XARELTO vs warfarin): HR, 0.74 (95% CI, 0.43-1.30); P=0.58
Berger et al (2021)²⁴ Retrospective cohort study Average BMI not mentioned	NVAF	3792/5886	Warfarin	Primary outcome^a: Risk of stroke/SE (XARELTO vs warfarin): HR, 0.66 (95% CI, 0.48-0.91); P=0.01 Risk of major bleeding^g (XARELTO vs warfarin): HR, 0.72 (95% CI, 0.55-0.95); P=0.02
Costa et al (2020)¹¹ Retrospective cohort study Average BMI not mentioned	NVAF	9161/18,322	Warfarin	Primary outcome^a: Risk of stroke/SE (XARELTO vs warfarin): HR, 0.87 (95% CI, 0.68-1.12) Risk of major bleeding^g (XARELTO vs warfarin): HR, 0.75; (95% CI, 0.64-0.89) Secondary outcome^a: Risk of ischemic stroke (XARELTO vs warfarin): HR, 0.96 (95% CI, 0.74-1.24) Risk of ICH (XARELTO vs warfarin): HR, 0.39 (95% CI, 0.21-0.72) Risk of extracranial hemorrhage (XARELTO vs warfarin): HR, 0.81 (95% CI, 0.68-0.96)
Perales et al (2020)¹² Retrospective chart review Median (IQR) BMI in XARELTO: 45 (41-51) Warfarin: 44 (41-50)	NVAF and VTE	84/176	Warfarin	Primary outcome: Clinical failure^h (XARELTO vs warfarin): 5% vs 13%; P=0.06 Secondary outcome: VTE recurrence (XARELTO vs warfarin): 2% vs 4%; P=0.68 Mortality (XARELTO vs warfarin): 2% vs 9%; P=0.06 Major bleeding^b or CRNMB^c (XARELTO vs warfarin): 8% vs 2%; P=0.06
Peterson et al (2019)¹³ Retrospective cohort study Average BMI not mentioned	AF	3563/7126	Warfarin	Primary outcome^a: Risk of ischemic stroke/systemic embolism (XARELTO vs warfarin): OR, 0.88 (95% CI, 0.60-1.28); P=0.50 Secondary outcome^a: Risk of major bleeding^g (XARELTO vs warfarin): OR, 0.80 (95% CI, 0.59-1.08); P=0.14
Kushnir et al (2019)¹⁴^,¹⁵ Retrospective cohort study Median (IQR) BMI in VTE: 44.7 (41·3-50.1) AF: 44·4 (41·6-49·4)	AF/VTE	VTE: 152/366 AF: 174/429	Apixaban and warfarin	VTE groupⁱ: Recurrent VTE (apixaban vs XARELTO vs warfarin): 2.1% vs 2% vs 1.2%; P=0.74 Major bleeding^b (apixaban vs XARELTO vs warfarin): 2.1% vs 1.3% vs 2.4%; P=0.77 AF groupⁱ: Embolic stroke (apixaban vs XARELTO vs warfarin): 1% vs 2.3% vs 1.3%; P=0.71 Major bleeding^b (apixaban vs XARELTO vs warfarin): 2.9% vs 2.9% vs 7.9%; P=0.06
Spyropoulos et al (2019)¹⁶ Retrospective cohort study Average BMI not mentioned	VTE	2890/5780	Warfarin	On-treatment analysis^a: Primary outcome: Risk of recurrent VTE (XARELTO vs warfarin): OR, 1.02 (95% CI, 0.87-1.20); P=0.83 Secondary outcome: Risk of major bleeding^g (XARELTO vs warfarin): OR, 0.75 (95% CI, 0.47-1.19); P=0.22 ITT analysis^a: Primary outcome: Risk of recurrent VTE (XARELTO vs warfarin): OR, 0.99 (95% CI, 0.85-1.14); P=0.84 Secondary outcome: Risk of major bleeding^g (XARELTO vs warfarin): OR, 0.66 (95% CI, 0.45-0.98); P=0.04
Kalani et al (2019)¹⁷ Retrospective cohort study Average BMI in DOACs: 46.7 Warfarin: 45.8	NVAF, postoperative thromboprophylaxis, or DVT/PE treatment and/or reduction in risk for recurrence	33/123 Study included apixaban (46), dabigatran (11), XARELTO (33), and warfarin (90); total N=180. Only reporting XARELTO vs. warfarin outcomes (N=123)	Warfarin	Primary Outcomes: No XARELTO-specific results reported Secondary Outcome: Ischemic stroke (XARELTO vs warfarin): 3% vs 3.3% Major bleeding^b (XARELTO vs warfarin): 3% vs 3.3%
Abbreviations: AF, atrial fibrillation; CI, confidence interval; CRNMB, clinically relevant non-major bleeding; DVT, deep vein thrombosis; HR, hazard ratio; ICH, intracranial hemorrhage; IQR, interquartile range; ITT, intent-to-treat; NVAF, nonvalvular atrial fibrillation; OR, odds ratio; PE, pulmonary embolism; SE, systemic embolism; TIA, transient ischemic attack; VTE, venous thromboembolism.^aResults were adjusted to try to control for potential confounding factors.^bMajor bleeding was defined according to International Society on Thrombosis and Hemostasis (ISTH) criteria: fatal bleeding, bleeding in a critical area, or bleeding causing a decrease in the hemoglobin level of ≥2 g/dL or transfusion of ≥2 units PRBC.^cCRNMB was defined according to the ISTH criteria: any sign of symptom of bleeding (not classified as major) that required medical intervention, led to hospitalization or increased level of care, or promoted a face-to-face intervention.^dPrimary outcome was occurrence of thrombosis or ischemic stroke. The primary safety endpoint compared rates of bleeding. No patients developed an ischemic stroke.^eThe primary safety endpoint was the patient’s first inpatient admission for a bleeding event, including intracranial hemorrhage (ICH), gastrointestinal (GI) hemorrhage, or bleeding from other sites.^fMajor bleeding was identified by ICD-9-CM/ICD-10 diagnosis on inpatients claims for acute stays.^gMajor bleeding was defined using validated claims-based algorithm by Cunningham et al.^hClinical failure during anticoagulation therapy was defined as VTE recurrence, stroke incidence, or mortality, within the first 12 months of therapy initiation.ⁱStudy tried to compensate for a potential bias in anticoagulation choice by adjusting significant associations in the unadjusted analyses (for CHADS-VASc score for AF patients and age/Charlson score for all patients).

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 09 April 2024.

References

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1	XARELTO (rivaroxaban) [Prescribing Information]. Titusville, NJ: Janssen Pharmaceuticals, Inc;https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/XARELTO-pi.pdf
2	Friedman RJ, Hess S, Berkowitz SD, et al. Complication rates after hip or knee arthroplasty in morbidly obese patients. Clin Orthop Relat Res. 2013;471(10):3358-3366.
3	Dobry P, McGrew K, Yun I, et al. Factor Xa inhibitors versus warfarin in patients with morbid obesity and atrial fibrillation. [published online ahead of print March 20, 2024]. Eur J Clin Pharmacol. 2024. doi:10.1007/s00228-024-03672-y.
4	Chin-Hon J, Davenport L, Huang J, et al. Safety and efficacy of oral anticoagulants in extreme weights. Thromb Res. 2023;231:1-6.
5	Chugh Y, Gupta K, Krishna HB, et al. Safety and efficacy of apixaban, dabigatran and rivaroxaban in obese and morbidly obese patients with heart failure and atrial fibrillation: a real‐world analysis. Pacing Clin Electrophysiol. 2023;46(1):50-58.
6	Weaver P, Ng TH, Breeden T, et al. Management of venous thromboembolism in morbid obesity with rivaroxaban or warfarin. Ann Pharmacother. 2022;56(12):1315-1324.
7	Navarro-Almenzar B, Cerezo-Manchado JJ, García-Candel F. Real life behaviour of direct oral anticoagulants in patients with nonvalvular atrial fibrillation and morbid obesity. Int J Cardiol Heart Vasc. 2021;37:100913.
8	Briasoulis A, Mentias A, Mazur A, et al. Comparative effectiveness and safety of direct oral anticoagulants in obese patients with atrial fibrillation. Cardiovasc Drug Ther. 2021;35(2):261-272.
9	Costa OS, Beyer-Westendorf J, Ashton V, et al. Effectiveness and safety of rivaroxaban versus warfarin in obese patients with acute venous thromboembolism: analysis of electronic health record data. J Thromb Thrombolysis. 2021;51(2):349-358.
10	Berger JS, Laliberté F, Kharat A, et al. Real-world effectiveness and safety of rivaroxaban versus warfarin among non-valvular atrial fibrillation patients with obesity in a US population. Curr Med Res Opin. 2021;37(6):881-890.
11	Costa OS, Beyer-Westendorf J, Ashton V, et al. Effectiveness and safety of rivaroxaban versus warfarin in obese nonvalvular atrial fibrillation patients: analysis of electronic health record data. Curr Med Res Opin. 2020;36(7):1081-1088.
12	Perales I, Agustin KS, DeAngelo J, et al. Rivaroxaban versus warfarin for stroke prevention and venous thromboembolism treatment in extreme obesity and high body weight. Ann Pharmacother. 2020;54(4):344-350.
13	Peterson ED, Ashton V, Chen YW, et al. Comparative effectiveness, safety, and costs of rivaroxaban and warfarin among morbidly obese patients with atrial fibrillation. Am Heart J. 2019;212:113-119.
14	Kushnir M, Choi Y, Eisenberg R, et al. Efficacy and safety of direct oral factor Xa inhibitors compared with warfarin in patients with morbid obesity: a single-centre, retrospective analysis of chart data. Lancet Haematol. 2019;6(7):e359-e365.
15	Kushnir M, Choi Y, Eisenberg R, et al. Supplement to: Efficacy and safety of direct oral factor Xa inhibitors compared with warfarin in patients with morbid obesity: a single-centre, retrospective analysis of chart data. Lancet Haematol. 2019;6(7):e359-e365.
16	Spyropoulos AC, Ashton V, Chen YW, et al. Rivaroxaban versus warfarin treatment among morbidly obese patients with venous thromboembolism: comparative effectiveness, safety, and costs. Thromb Res. 2019;182:159-166.
17	Kalani C, Awudi E, Alexander T, et al. Evaluation of the efficacy of direct oral anticoagulants (DOACs) in comparison to warfarin in morbidly obese patients. Hosp Pract. 2019;47(4):181-185.
18	Joglar JA, Chung MK, Armbruster AL, et al. 2023 ACC/AHA/ACCP/HRS guideline for the diagnosis and management of atrial fibrillation: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2024;149(1):e1-e156.
19	Martin KA, Beyer‐Westendorf J, Davidson BL, et al. Use of direct oral anticoagulants in patients with obesity for treatment and prevention of venous thromboembolism: updated communication from the ISTH SSC Subcommittee on Control of Anticoagulation. J Thromb Haemost. 2021;19(8):1874-1882.
20	Eriksson BI, Borris LC, Friedman RJ, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med. 2008;358(26):2765-2775.
21	Kakkar A, Brenner B, Dahl O, et al. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double blind, randomized controlled trial. Lancet. 2008;372(9632):31-39.
22	Lassen MR, Ageno W, Borris LC, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med. 2008;358(26):2776-2786.
23	Turpie AGG, Lassen MR, Davidson BL, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. Lancet. 2009;373(9676):1673-1680.
24	Berger J, Laliberté F, Kharat A, et al. Supplement to: Real-world effectiveness and safety of rivaroxaban versus warfarin among non-valvular atrial fibrillation patients with obesity in a US population. Curr Med Res Opin. 2021;37(6):881-890.