Real-world Evidence: Use of XARELTO in Renal Insufficiency - Atrial Fibrillation

SUMMARY

• In a prospective, observational study (LATTEE) of patients with atrial fibrillation (AF) or atrial flutter (AFL; N=2790) treated with different anticoagulant regimens depending on their renal function, left atrial thrombus (LAT) prevalence was higher in those treated with an inappropriate dose of XARELTO vs those treated with an appropriate dose (n=944; 15% vs 3.9%; P<0.001).^1,2
• In a single-center, prospective, observational study that compared bleeding risks with or without the combined use of XARELTO or edoxaban with amiodarone in patients with AF (N=910), XARELTO-treated patients with reduced kidney function had a significantly higher bleeding risk compared with edoxaban-treated patients (hazard ratio [HR], 2.186; 95% confidence interval [CI], 1.016-4.702; P=0.045).³
• In a multicenter, prospective, observational, noninterventional, single-arm study (XARENAL; N=888) that evaluated the safety of XARELTO in patients with nonvalvular atrial fibrillation (NVAF) and renal impairment (creatinine clearance [CrCl], 15-49 mL/min), the incidence of major bleeding (MB) was 5.6% and that of fatal bleeding was 0.5%. Mean (standard deviation [SD]) change in the estimated glomerular filtration rate (eGFR) from baseline was 2.22 (26.47) mL/min/1.73 m² per year.⁴
• In a 24-month prospective study that evaluated the efficacy and safety of direct oral anticoagulants (DOACs) in elderly patients with AF and stage 4 chronic kidney disease (CKD; N=436; XARELTO, n=292; warfarin, n=144), no significant difference was found in the incidence of ischemic events between XARELTO- and warfarin-treated patients.⁵
• In a study with an 18-month follow-up that evaluated the dynamics of efficacy and safety of XARELTO use in patients with NVAF and a glomerular filtration rate (GFR) of 15 to 29 mL/min/1.73 m² (N=109; XARELTO, n=73; warfarin, n=36),no significant difference was found in the incidence of any acute cerebrovascular event, myocardial infarction (MI), and all-cause mortality between XARELTO- and warfarin-treated patients.⁶
• In a prospective, multicenter study that compared the treatment outcomes associated with XARELTO vs warfarin in patients with CKD, the incidence of major adverse cardiac and cerebral events (MACCEs) in XARELTO-treated patients was noninferior to that in warfarin-treated patients after propensity score matching (PSM). The incidence rate of net adverse clinical events (NACEs) was significantly lower in XARELTO-treated vs warfarin-treated patients after PSM (19.6% vs 31.0%; HR, 0.63; 95% CI, 0.40-0.98; P=0.043).⁷
• In a prospective, noninterventional, multicenter observational study (XAIENT) that compared the efficacy and safety of a high-dose XARELTO regimen (HDRR; 20/15 mg) and a low-dose XARELTO regimen (LDRR; 15/10 mg) in patients with AF (N=1039), a subgroup analysis based on CrCl found no significant differences in the incidence of MB or stroke.⁸
• In a prospective, single-center study that compared the bleeding risk between XARELTO and amiodarone and XARELTO alone and evaluated the relationship of renal function with XARELTO dosage and the bleeding risk, patients with stage 2, 3, 4, or 5 CKD (eGFR <90 mL/min/1.73 m²) had a significantly higher risk of bleeding with XARELTO and amiodarone vs XARELTO alone (26.6% vs 10.7%; HR, 2.698; 95% CI, 1.419-5.127; P=0.002).⁹
• In a real-world, retrospective cohort study that estimated the risk of using oral anticoagulant (OAC) treatments based on a composite of cardiac and renal outcomes and renal outcomes of interest in patients with NVAF (N=2198), an off-label XARELTO dose was associated with a significantly higher risk of the composite of cardiac and renal events (HR, 1.269; 95% CI, 1.017-1.585; P=0.0353) and a ≥30% decline in eGFR (HR, 1.346; 95% CI, 1.073-1.689; P=0.0103). Effects of the standard XARELTO dose on all outcomes did not differ significantly from those of warfarin.¹⁰
• In a prospective, observational registry of adult patients with NVAF and advanced CKD with eGFR 15 to 49 mL/min/1.73m², XARELTO treatment was associated with greater net clinical benefit (lower event rates for stroke and other thromboembolic events, MB, and all-cause mortality) compared with vitamin K antagonists (VKAs).¹¹ Additionally, a reduction in adverse kidney outcomes was observed in patients treated with XARELTO.¹²
• In a multicenter, retrospective cohort study that compared renal outcomes of warfarin and non-VKA oral anticoagulant (NOAC) treatment in patients with NVAF (N=1456; XARELTO, n=249), XARELTO-treated patients had a lower risk of eGFR decline vs warfarin-treated patients (adjusted hazard ratio [aHR], 0.83; 95% CI, 0.50-1.37; P=0.456).¹³
• In a multicenter, retrospective study that evaluated the efficacy and safety of OACs in patients with NVAF and end-stage renal disease (ESRD; N=933; XARELTO, n=39), at a median follow-up of 3.0 years, clinical outcomes (incidence of stroke and systemic embolism [SE], MB, intracranial hemorrhage [ICH], gastrointestinal bleeding [GIB], and all-cause mortality) did not differ significantly between XARELTO and apixaban.^14,15
• In a retrospective study that assessed the relationship between the presence of bleeding in patients aged 65 to 97 years with stage C3-4 CKD and AF and the level of renal damage markers in the urine (N=266), a statistically significant association was found between the presence of bleeding and the urine levels of renal damage markers neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1).¹⁶
• In a 1- and 3-year PSM analysis that compared the outcomes associated with XARELTO vs warfarin treatment in patients with ESRD and AF (n=240 in each group), at 1 year, patients in the XARELTO group had lower incidence of ischemic stroke (IS; 8.3% vs 17.5%), MB events (14.2% vs 22.5%), and thromboembolic events (16.7% vs 28.3%) compared with patients in the warfarin group (P<0.001); the trend persisted at 3 years.¹⁷
• In a retrospective study that compared the efficacy and safety of OACs in subgroups of patients with NVAF at high risk for GIB (N=314,184), including patients with stage 3 or 4 CKD (n=18,703), XARELTO was associated with a lower risk of MB leading to hospitalization compared with VKAs in patients with stage 3-4 CKD (HR, 0.62; 95% CI, 0.49-0.78; P<0.0001).¹⁸
• In a new user, active-comparator cohort study that compared the fracture risk for select DOACs, including XARELTO, in patients with AF and stage 3-5 CKD (XARELTO, n=4268), XARELTO was associated with a minor decrease in the fracture risk compared with warfarin.¹⁹
• In a study that compared the efficacy of factor Xa NOACs and phenprocoumon in patients with NVAF and concomitant renal impairment, XARELTO was associated with a lower risk of kidney failure compared with phenprocoumon (aHR, 0.27; 95% CI, 0.16-0.43); the risk was more pronounced in this population than in the general population.²⁰
• In a retrospective cohort study that evaluated the efficacy and safety of DOACs, including XARELTO, in patients with stage 4-5 CKD (N=2382; XARELTO, n=342), XARELTO was associated with an event rate of 8.9% for a composite ischemic stroke/systemic embolism (ISSE) event (subdistribution hazard ratio [SHR], 1.09; 95% CI, 0.88-1.34; P=0.448) and of 17.8% for a composite bleeding event (SHR, 0.82; 95% CI, 0.72-0.95; P=0.007) at the end of follow-up.²¹
• In a retrospective cohort study that compared outcomes associated with XARELTO vs warfarin treatment in patients with ESRD and AF (n=2381 for each group), XARELTO-treated patients had a lower risk of experiencing a composite outcome (infarct, ICH, and mortality; relative risk [RR], 0.823; 95% CI, 0.765-0.885), mortality (RR, 0.830; 95% CI, 0.775-0.888), GI hemorrhage (RR, 0.566; 95% CI, 0.439-0.730), and cardiac arrest (RR, 0.696; 95% CI, 0.531-0.911).²²
• In a retrospective cohort study evaluating the effectiveness and safety of newly prescribed warfarin or XARELTO vs apixaban in patients with AF and advanced, non-dialysis dependent CKD, the incidence rate of IS events among XARELTO and apixaban users, respectively, was 10.5 (95% CI, 6.3-16.4) and 14.3 (95% CI, 9.9-20.0) per 1000 person-years (PYs) (after PSM, HR was 0.71; 95% CI, 0.40-1.24). Corresponding incidence rate of MB was 96.1 (95% CI, 82.3-111.7) vs 52.8 (95% CI, 43.9-63.0) per 1000 PYs, respectively (HR, 1.69; 95% CI, 1.33-2.15).²³
• In a retrospective cohort study comparing the risks for MB, stroke/SE, and death associated with different OACs in patients with AF and severe CKD, there were no significant differences in the risks of stroke/SE (HR, 1.23; 95% CI, 0.76-1.98) and death (HR, 1.20; 95% CI, 0.82-1.76) between XARELTO and warfarin. A higher risk of MB was seen with the use of XARELTO compared with warfarin (HR, 1.65; 95% CI, 1.10-2.48).²⁴
• In another retrospective cohort study evaluating the effectiveness and safety of DOACs vs warfarin in patients with AF and advanced kidney disease (AKD), warfarin showed a higher risk of stroke/SE (aHR, 0.74; 95% CI, 0.13-4.33) compared with XARELTO. The risk of MB was similar in both groups (aHR, 1.79; 95% CI, 0.39-8.25).²⁵
• In a retrospective study conducted in patients with  NVAF and ESRD undergoing/not undergoing hemodialysis, XARELTO- and apixaban-treated patients had similar risks of stroke/SE, IS, and MB (P>0.57 for all). In the XARELTO vs apixaban groups, the event rates per 100 PYs for stroke/SE, IS, and MB were 1.27 vs 1.26 (HR, 1.18; 95% CI, 0.53-2.63), 1.01 vs 1.03 (HR, 1.12; 95% CI, 0.45-2.76), and 3.73 vs 3.49 (HR, 1; 95% CI, 0.63-1.58), respectively.²⁶
• In a retrospective cohort study comparing the risks of ISSE and MB in patients with NVAF and stage 4-5 CKD treated with XARELTO or warfarin, no statistically significant difference in the risk of ISSE or MB was found between XARELTO- and warfarin-treated patients. HRs for XARELTO compared to warfarin were 0.93 (95% CI, 0.46-1.90; P=0.85) for the risk of ISSE and 0.91 (95% CI, 0.65-1.28; P=0.60) for MB.²⁷
• In an observational, retrospective study using data from the United States International Business Machines (US IBM) Watson MarketScan Commercial Claims and Medicare Supplemental Database, NVAF patients with stage 3 or 4 CKD who were treated with XARELTO had a 47% reduced risk for worsened kidney function (composite of progression to stage 5 CKD, kidney failure, or the need for dialysis), compared with patients treated with warfarin (HR, 0.53; 95% CI, 0.35-0.78).²⁸
• In a retrospective study that evaluated the rates of stroke, bleeding, and death in patients with NVAF with or without renal insufficiency taking XARELTO, patients with CrCl <50 mL/min/1.73 m² vs CrCl ≥50 mL/min/1.73m² had a higher risk of death (17.5% vs 7.6%; P=0.001) and stroke (9.2% vs 2.3%; P=0.001) but not MB (7% vs 6.4%; P=nonsignificant [NS]).²⁹
• In a retrospective analysis, which evaluated effectiveness and safety of XARELTO vs warfarin in NVAF patients with stage 4 or 5 CKD or undergoing hemodialysis, XARELTO was not associated with a significant reduction in ISSE (HR, 0.55; 95% CI, 0.27-1.10) or IS alone (HR, 0.67; 95% CI, 0.30-1.50) compared to warfarin, but was associated with a significant (32%; HR, 0.68; 95% CI, 0.47-0.99) reduction in MB risk.³⁰
• Two real-world studies in patients with NVAF and renal impairment found that treatment with XARELTO was associated with lower rates of IS than treatment with warfarin, but there was no difference between the 2 treatments in the incidence of MB.^31,32
• A retrospective analysis surveyed an ESRD population to describe the prescribing patterns of dabigatran and XARELTO in chronic hemodialysis patients with AF from October 2010 to October 2014. Results showed a higher rate of MB (defined as a hemorrhagic event resulting in hospitalization or death) with XARELTO (rate ratio, 1.38; 95% CI, 1.03-1.83) and dabigatran (RR, 1.48; 95% CI, 1.21-1.81) compared with warfarin. When analyzed by dose, dialysis patients prescribed the full dose of XARELTO 20 mg (which is not recommended in this patient population³³) had a higher risk of MB than patients who were prescribed the lower dose of XARELTO 15 mg (which is recommended for patients with renal impairment³³).³⁴
• Additional citations identified during a literature search are included in the REFERENCES section for your review.^35-45

REAL-WORLD EVIDENCE

LATTEE Study¹

Gawalko et al (2026)^1,2 conducted a prospective observational study (LATTEE; NCT03591627) that compared LAT prevalence in patients with AF treated with different anticoagulant regimens depending on their renal function (stratified by CrCl). The study enrolled consecutive hospitalized patients diagnosed with AF or AFL upon hospital admission or during hospitalization in whom transesophageal echocardiography (TEE) was performed. The primary outcome measure was the prevalence of LAT in patients with AF/AFL in whom TEE was performed before AF/AFL cardioversion.

• Overall, the study included 2790 patients who had CrCl data available. Of these, 2480 (89%) and 310 (11%) patients had a CrCl of ≥50 mL/min and <50 mL/min, respectively. Of those with CrCl <50 mL/min, 43 (14%) and 267 (86%) patients had a CrCl of 30 to <50 mL/min and <30 mL/min, respectively.
• The mean (interquartile range [IQR]) patient age was 66 (59-72) years in the CrCl ≥50 mL/min group and 75 (69-81) years in the CrCl <50 mL/min group (P<0.001).
• The prevalence of LAT in patients with CrCl ≥50 mL/min, CrCl 30 to <50 mL/min, and CrCl <30 mL/min was 6.7% (167/2480), 16% (44/267), and 19% (8/43), respectively (P=0.008 for the intergroup comparison).
• Of 944 XARELTO-treated patients, 84% were treated with an appropriate dose. LAT prevalence was higher in patients treated with an inappropriate dose of XARELTO vs those treated with an appropriate dose (15% vs 3.9%; P<0.001).

Wang et al (2026)³ conducted a single-center, prospective observational study to compare the bleeding risk associated with XARELTO, edoxaban, and the combination of either with amiodarone in patients with AF. The study included patients diagnosed with nonpermanent AF from July 2022 to December 2023.

• The primary endpoint was the time to the first occurrence of the composite of MB, clinically relevant nonmajor (CRNM) bleeding, and minor bleeding, as defined by the International Society on Thrombosis and Hemostasis (ISTH).
• Secondary endpoints included stroke, recurrence of AF, and discontinuation of anticoagulant therapy or amiodarone due to adverse drug reactions.
• The study included 910 patients with AF (XARELTO, n=298; edoxaban, n=151; XARELTO plus amiodarone, n=321; edoxaban plus amiodarone, n=140). The mean (SD) follow-up duration in the overall cohort was 81.7 (22.8) days and was similar across the treatment groups.
• Among patients receiving XARELTO monotherapy, 37 (12.4%), 125 (41.9%), and 136 (45.6%) patients were prescribed daily doses of 10 mg, 15 mg, and 20 mg, respectively. In the combination therapy groups, XARELTO was administered at doses of 10 mg in 13 (4.0%) patients, 15 mg in 127 (39.6%) patients, and 20 mg in 181 (56.4%) patients.
• After PSM, no significant differences were found between the XARELTO and edoxaban groups in baseline characteristics (P>0.05).
• In subgroup analyses following kidney function-based PSM, when renal function was stratified using an eGFR cutoff of 90 mL/min/1.73 m², XARELTO did not increase the bleeding risk vs edoxaban after combination therapy with amiodarone in patients with normal kidney function.  
  • However, in patients with reduced kidney function, those treated with XARELTO had a significantly higher bleeding risk compared with those treated with edoxaban (HR, 2.186; 95% CI, 1.016-4.702; P=0.045).
  • Using an alternative stratification method in which renal function was classified using an eGFR cutoff of 60 mL/min/1.73 m², after concomitant use of amiodarone, no statistically significant difference in the bleeding risk was observed between XARELTO and edoxaban in patients with preserved renal function (P=0.130) or impaired renal function (P=0.081), although a numerically higher bleeding risk was observed in the XARELTO group among patients with impaired renal function.

XARENAL Study⁴

Oh et al (2025)⁴ conducted a multicenter, prospective, observational, noninterventional, single-arm study (XARENAL) to evaluate the safety of XARELTO in patients with NVAF with renal impairment (CrCl, 15-49 mL/min).

The primary outcome was the incidence of MB events per ISTH criteria. Secondary outcomes included the incidence of adverse events (AEs), serious adverse events (SAEs), all-cause mortality, and change in renal function using determined by eGFR calculated using the Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) formula.

The study included adult patients (≥19 years old) diagnosed with NVAF and moderate to severe renal impairment who required rivaroxaban for stroke and non-central nervous system SE prevention per physician’s decision. Patients with XARELTO contraindication according to the local label, those participating in other interventional studies, those with planned treatment with other anticoagulants, and those expecting renal replacement therapy within the next 3 months were excluded.

The study included 888 patients in the full analysis set. The mean (SD) patient age was 77.8 (6.7) years, and 55.4% of patients were male. The mean (SD) baseline CrCl was 37.0 (8.5) mL/min, and the mean (SD) baseline eGFR was 45.2 (13.0) mL/min/1.73 m². The primary and secondary outcomes are listed in Table: Primary and Secondary Outcomes.

• AEs reported in the study included mediastinal disorders (16.8%; eg, dyspnea or cough), gastrointestinal [GI] disorders (11.9%; eg, constipation), cardiac disorders (10.5%; eg, palpitation), and general condition disorders (9.7%).
• In additional analyses, patients were categorized into the severe renal impairment group (CrCl, 15-29 mL/min; n=175) and the moderate renal impairment group (CrCl, 30-49 mL/min; n=713). MB was reported in 15 (8.6%) and 35 (4.9%) patients in the severe and moderate groups, respectively. Fatal bleeding occurred in 1 (0.6%) and 3 (0.4%) patients in the severe and moderate groups, respectively.

Igamberdieva et al (2025)⁵ conducted a 24-month study to evaluate the efficacy and safety of DOACs in elderly patients with AF and stage 4 CKD (N=436; XARELTO, n=292; warfarin, n=144; warfarin dose adjusted by the international normalized ratio [INR]).

• The study included patients with various forms of AF and a GFR of 15 to 29 mL/min/1.73 m².
• The mean patient age was 79 years in the XARELTO group and 80 years in the warfarin group (P=0.38).
• The average risk of thromboembolic complications according to CHA₂DS₂-VASc was 4.6 in the XARELTO group and 4.7 in the warfarin group (P=0.58).
• The risk of hemorrhagic complication according to HAS-BLED was 3.0 in the XARELTO group and 3.1 in the warfarin group (P=0.6). Clinical outcomes are listed in Table: Clinical Outcomes.

Igamberdieva et al (2024)⁶ conducted a study to evaluate the dynamics of the efficacy and safety of XARELTO use in patients with NVAF and a GFR of 15 to 29 mL/min/1.73 m².

Overall, 109 patients were randomized 2:1 to receive XARELTO 15 mg (n=73) or warfarin (n=36). The average follow-up period was 18 months.

• Differences in the incidence of any acute cerebrovascular accident, MI, and all-cause mortality were not significant between the warfarin group (1.4%, 6.9%, and 6.8%, respectively) and the XARELTO group (5.6%, 2.8%, and 8.3%, respectively; P=0.25, 0.66, and 0.78, respectively).
• Warfarin-treated vs XARELTO-treated patients were significantly more likely to develop minor bleeding (61.1% vs 36.9%; P=0.01) and all clinically significant bleeding (27.7% vs 10.9%; P=0.03), based on the ISTH scale.
• The all-cause readmission rate was 43% in the XARELTO group and 48% in the warfarin group (P=0.57). Among these patients, 36.9% and 40.7%, respectively, were hospitalized for emergency reasons (P=0.96).

Ozaki et al (2024)⁷ conducted a prospective multicenter study to compare the outcomes associated with XARELTO vs warfarin treatment in patients with CKD. The primary efficacy endpoint was the incidence of MACCEs, and the primary safety endpoint was the incidence of Bleeding Academic Research Consortium (BARC) type 3 and 5 bleeding. Another safety endpoint was the rate of NACE, which was defined as the composite of all-cause mortality and MB.

• Both crude and PSM analyses were performed; 493 patients were included, of whom 66.3% had CKD.
• XARELTO was associated with a lower MB risk vs warfarin (6.5% vs 12.6%; HR, 0.50; 95% CI, 0.27-0.91; P=0.025) in the crude analyses, but this difference was not significant in the PSM analyses (5.7% vs 10.8%; HR, 0.53; 95% CI, 0.24-1.19; P=0.12).
• The NACE rate was significantly lower with XARELTO vs warfarin in both the crude (19.0% vs 35.7%; HR, 0.50; 95% CI, 0.35-0.72; P=0.0002) and PSM (19.6% vs 31.0%; HR, 0.63; 95% CI, 0.40-0.98; P=0.043) analyses.

Kim et al (2024)⁸ conducted a prospective, noninterventional, multicenter observational study (XAIENT) to compare the safety and efficacy of HDRR (20/15 mg) and LDRR (15/10 mg) in patients with AF.

• The study included patients aged >65 years with NVAF who were indicated to receive oral anticoagulation for stroke prevention (CHA₂DS₂-VASc score of >2) and were prescribed any dose of XARELTO during the period from October 2019 to April 2021. Patients who had a history of mechanical valve surgery or moderate to severe mitral stenosis were excluded.
• Clinical endpoints included MB; IS; and a composite of IS, MB ,or all-cause mortality. The study included 1093 patients (HDRR, n=493; LDRR, n=598).
• The mean (SD) follow-up duration was 517 (228) days. The mean (SD) age was 72.8 (5.8) years, and 686 (62.9%) participants were men.
• In a CrCl-based subgroup analysis for the composite outcome, there were no significant differences between the subgroups. In patients with CrCl ≥50 mL/min, HDRR was associated with a similar incidence of MB, stroke, and the composite outcome compared with LDRR.

Wang et al (2024)⁹ conducted a prospective single-center study to compare the risk of bleeding with XARELTO vs amiodarone in patients newly diagnosed with AF and evaluate the relationship of renal function with XARELTO dosage and bleeding risk. The study included patients newly diagnosed with nonpermanent AF from January 2022 to September 2022.

• The primary endpoint was the time to the first occurrence of the composite of major, CRNM, and minor bleeding as defined by ISTH.
• The secondary endpoint was the association of renal function with the XARELTO dose and bleeding risk. The study included 481 patients (XARELTO, n=285; XARELTO plus amiodarone, n=196).
• After PSM, the risk of bleeding was significantly higher in XARELTO plus amiodarone-treated patients vs XARELTO-treated patients (26.6% vs 10.7%; HR, 2.698; 95% CI, 1.419-5.127; P=0.002) with stage 2, 3, 4, or 5 CKD (eGFR <90 mL/min/1.73 m²).
• For patients with stage 1 CKD (eGFR ≥90 mL/min/1.73 m²), XARELTO plus amiodarone vs XARELTO alone increased the risk of bleeding, but the difference was not statistically significant (23.3% vs 9.1%; HR, 2.879; 95% CI, 0.743-11.154; P=0.172).

Wang et al (2024)¹⁰ conducted a real-world, retrospective cohort study to estimate the risk of using OAC treatments based on a composite of cardiac and renal outcomes and renal outcomes of interest in patients with NVAF.

• Data were collected from the Taipei Medical University Clinical Research Database.
• The primary outcome was a composite of cardiac and renal outcomes: ≥30% decline in eGFR, renal failure (RF), and cardiovascular death. The renal outcomes of interest were a ≥30% decline in eGFR, doubling of the serum creatinine level, acute kidney injury (AKI) incidence, and RF incidence.
• The study included 2198 patients with AF; baseline characteristics of the patients were matched after weighting across different treatment groups (warfarin, n=599; XARELTO, n=1066; edoxaban, n=290; dabigatran, n=248).
• The crude incidence rate of the composite of cardiac and renal events was 25.7, 37.6, 30.1, and 19.3 per 100 PYs in patients treated with warfarin, XARELTO, edoxaban, and dabigatran, respectively.
• XARELTO and edoxaban were associated with a higher risk of ≥30% decline in eGFR compared with warfarin in the original cohort (HR, 1.04 [95% CI, 0.861-1.260] and 1.20 [95% CI, 0.920-1.571], respectively) but not in the weighted cohort.
• None of the 3 DOACs were associated with a significantly lower risk of AKI or RF.
• An off-label XARELTO dose was associated with a significantly higher risk of the composite of cardiac and renal events (HR, 1.269; 95% CI, 1.017-1.585; P=0.0353) and ≥30% decline in eGFR (HR, 1.346; 95% CI, 1.073-1.689; P=0.0103).
• Effects of the standard XARELTO dose on all outcomes did not differ significantly from those of warfarin.

XARENO Study^11,46

The XARENO Study is a prospective, observational registry conducted at various sites within Europe. The study was designed to compare the clinical impact of XARELTO with VKA treatment in adult patients with NVAF and advanced CKD (eGFR 15-49 mL/min/1.73m²). Patients were treated with either XARELTO 15 mg once daily (OD) or VKA, at the discretion of the attending physician. Patients who did not receive anticoagulation were also enrolled for exploratory analysis.

Exclusion criteria included current or expected renal-replacement therapy, and chronic treatment with parenteral anticoagulants or DOACs other than XARELTO. Antiplatelet therapy was allowed at the discretion of the attending physician.

The minimum follow-up for this analysis was 12 months. Primary outcomes included progression of CKD and net clinical benefit (stroke and other thromboembolic events, MB, and all-cause mortality). In the intention-to-treat group, there were 766 patients who received XARELTO and 695 patients who received VKA. A PSM analysis was used to evaluate XARELTO (n=397) vs VKA (n=410).

• Net clinical benefit occurred in 12.9% (51/397) of patients in the XARELTO group and 18.3% (75/410) in the VKA group (incidence rate ratio [IRR], 0.68; 95% CI, 0.47-0.96, P=0.03).¹¹
• In the PSM analysis, baseline eGFR was similar in both groups and numerically higher in the XARELTO group after follow-up (difference 1.0 mL/min/1.73m², 95% CI, -0.48-2.51, P=0.18).¹¹

A total of 764 XARELTO patients compared to 691 VKA patients from the XARENO study were evaluated for the possibility of XARELTO to preserve kidney function. Adverse kidney outcomes and net clinical benefit were analyzed using propensity score-overlap weighted Cox regression.¹²

A reduction in adverse kidney outcomes and all-cause mortality was associated with XARELTO. Event rates per 100 patient-years in XARELTO compared to VKA, respectively, included:

• Adverse kidney outcome, 8.3 compared to 12.7 (HR, 0.62; 95% CI, 0.43-0.88)
  • Chronic kidney replacement therapy, 1.5 compared to 3.6 (HR, 0.39; 95% CI, 0.17-0.89)
  • eGFR <15 mL/minute/1.73 m², 6.5 compared to 12.1 (HR, 0.51; 95% CI, 0.35-0.76)
  • AKI, 2.8 compared to 3.6 (HR, 0.74; 95% CI, 0.40-1.34)
• Net clinical benefit, 13.8 compared to 13.6 (HR, 0.97; 95% CI, 0.72-1.31)
• All-cause death, 17.6 compared to 21.9 (HR, 0.76; 95% CI, 0.59-0.98)

Tongkate et al (2026)¹³ conducted a multicenter, retrospective cohort study to compare renal outcomes of warfarin and NOAC treatment in patients with NVAF.

• The study included adult patients (aged ≥18 years) who were newly prescribed OACs (warfarin, dabigatran, rivaroxaban, apixaban, or edoxaban) and were being treated for at least 3 months with regular follow-up at the study site.
• Patients with mechanical valve replacement or moderate to severe mitral stenosis, those with eGFR ≤15 mL/min/1.73 m² or those requiring dialysis, those with moderate to severe hepatic impairment (Child-Pugh B or Child-Pugh C), those who were pregnant or lactating, and those with an absence of serum creatinine (SCr) or eGFR at baseline before the initiation of OACs were excluded.
• The primary outcome was a ≥30% decline in eGFR. Secondary outcomes included the doubling of SCr and AKI.
• The study included 1456 patients (warfarin, n=761; dabigatran, n=181; XARELTO, n=249; apixaban, n=217; edoxaban, n=48).
• In terms of the primary outcome, XARELTO-treated patients showed a lower risk of eGFR decline compared with warfarin-treated patients (aHR, 0.83; 95% CI, 0.50-1.37; P=0.456).
• Regarding the secondary outcomes, after inverse probability of treatment weighting (IPTW) and multivariable adjustment, NOACs were associated with no significant reduction in the doubling of SCr (aHR, 0.64; 95% CI, 0.24-1.72; P=0.373) and AKI (aHR, 0.69; 95% CI, 0.41-1.17; P=0.169) compared with warfarin.

Yang et al (2026)¹⁴ conducted a multicenter retrospective study to evaluate the efficacy and safety of OACs in patients with NVAF and ESRD.

• Primary efficacy outcomes were ISSE events. The primary safety outcome was MB, defined according to ISTH criteria as fatal bleeding, symptomatic bleeding in a critical organ, or bleeding that reduced hemoglobin by ≥2 g/dL or required transfusion of ≥2 units of whole blood or red cells.
• The secondary efficacy outcome was all-cause mortality; secondary safety outcomes were ICH and GIB.
• The study included 933 patients (no anticoagulation, n=604; warfarin, n=197; apixaban, n=73; XARELTO, n=39; edoxaban, n=18; dabigatran, n=2). Overall, 79% of DOAC users (n=104) received low-dose regimens.
• The median (IQR) follow-up was 3.0 years (0.8-8.6).
• Clinical outcomes did not differ significantly between apixaban and XARELTO. The clinical outcomes are listed in Table: Primary and Secondary Outcomes.

Igamberdieva et al (2025)¹⁶ conducted a retrospective study to assess the relationship between the presence of bleeding in patients with stage C3-4 CKD and AF receiving XARELTO and the level of renal damage markers in the urine.

• The study included 266 patients aged 65 to 97 years (AF and CKD C3a, n=140; AF and CKD C3b and C4, n=126).
• According to the risk of bleeding, patients were assigned to group 1 (≥1 point; n=92; average age, 80.7 years) or group 2 (0 points; n=174; average age, 78.2 years).
• Among bleeding events, Of the bleeding, bruises were common, with events reported in 52 patients (19%). Other bleeding events included the following: nosebleeds, 22 patients (8.3%); bleeding from minor wounds, 12 patients (4.3%); muscle hematomas, 6 patients (2.2%); bleeding from the oral cavity, 6 patients (2.2%); and hemorrhoidal bleeding, 2 patients (0.75%).
• Urine NGAL and KIM-1 levels in patients with AF and CKD in group 1 (5.6 ng/mL and 0.69 ng/mL, respectively) were statistically significantly higher than those in patients in group 2 (4.2 ng/mL [P=0.039] and 0.39 ng/mL [P=0.019], respectively).

Issa et al (2025)¹⁷ conducted 1- and 3-year PSM analyses to compare outcomes associated with XARELTO vs warfarin treatment in patients with ESRD and AF. Data were derived from the TriNetX health research network database. The study compared the incidence of IS, MB events, and thromboembolic events.

• The study identified 17,510 patients from the database. After PSM, 240 patients each were included in the XARELTO and warfarin groups.
• At 1 year, patients in the XARELTO vs warfarin group had a lower incidence of IS (8.3% vs 17.5%), MB events (14.2% vs 22.5%), and thromboembolic events (16.7% vs 28.3%) (P<0.001 for all).
• These trends persisted at 3 years, with a lower incidence of IS (8.3% vs 19.6%), MB events (14.6% vs 28.8%), and thromboembolic events (17.5% vs 34.2%) in the XARELTO vs warfarin group (P<0.001).

Lip et al (2024)¹⁸ conducted a retrospective study to compare the efficacy and safety of OACs (XARELTO, apixaban, dabigatran, or VKAs) in subgroups of patients with NVAF at high risk for GIB, including patients with stage 3-4 CKD, using data from the French national health data system.

• Adult patients (aged ≥18 years) were included if they were diagnosed with NVAF with a high risk of GIB, were anticoagulant treatment naïve, or were newly initiated on anticoagulant treatment (index anticoagulant: XARELTO, apixaban, dabigatran, or VKAs) during the period from January 1, 2016, to December 31, 2019.
• Primary efficacy outcomes included the risk of stroke (ischemic or hemorrhagic) or SE, overall and separately. Primary safety outcomes included the risk of MB leading to hospitalization, overall and by site (GIB, ICH, and other).
• The study included 314,184 patients, of whom 18,703 (6.0%) had renal impairment (CKD stage 3 or 4).
• In patients with stage 3-4 CKD, XARELTO was associated with a lower risk of MB leading to hospitalization compared with VKAs (HR, 0.62; 95% CI, 0.49-0.78; P<0.0001).
• The GIB risk in XARELTO-treated patients was similar to that in VKA-treated patients (HR, 0.81; 95% CI, 0.57-1.16; P=0.26), whereas the ICH risk was lower in XARELTO-treated patients than in VKA-treated patients (HR, 0.31; 95% CI, 0.17-0.55; P<0.0001); similarly, the risk of other bleeds was also lower with XARELTO vs VKAs (HR, 0.64; 95% CI, 0.45-0.90; P=0.0096).
• XARELTO-treated patients had a similar risk of stroke/SE compared with VKA-treated patients (HR, 0.87; 95% CI, 0.63-1.19; P=0.38).
• Among patients with CKD stage 3 or 4, the risk of MB was lower with apixaban vs XARELTO (HR, 0.76; 95% CI, 0.58-1.00; P=0.0495).
• Apixaban was associated with a lower risk of GIB vs rivaroxaban (HR, 0.64; 95% CI, 0.41-0.98; P=0.0394) and a similar risk of ICH vs rivaroxaban (HR, 1.52; 95% CI, 0.80-2.92; P=0.20). Risks of other bleeding (HR, 0.71; 95% CI, 0.47-1.07; P=0.10) and stroke/SE (HR, 0.81; 95% CI, 0.57-1.15; P=0.23) were similar between apixaban and rivaroxaban.

Khan et al (2025)¹⁹ conducted a cohort study to quantify the comparative risk of fracture for select DOACs, including XARELTO, vs warfarin in patients with moderate to advanced CKD (stages 3-5) and AF.

• The study used data from Optum’s deidentified Clinformatics Data Mart Database for the period between January 1, 2013, and December 31, 2020.
• After 1:1 PSM, the study included 14,370 DOAC and warfarin initiators each, with 4268 XARELTO initiators (29.7%).
• The mean (SD) age at anticoagulant initiation was 77 (8) years, and 45% of patients were female in the matched population.
• XARELTO was associated with a minor decrease in the fracture risk compared with warfarin based on point estimates.
• For all-cause mortality, no statistically significant association was indicated for apixaban or XARELTO initiation vs warfarin initiation.

Kreutz et al (2024)²⁰ conducted a study (RELOADED) to compare the efficacy of factor Xa NOACs and phenprocoumon in patients with NVAF. The primary effectiveness outcome was ISSE as a combined endpoint; the primary safety outcome was ICH. The study included 64,920 participants (phenprocoumon, n=23,552 [36.3%]; XARELTO, n=22,339 [34.4%]; apixaban, n=16,201 [25.0%]; edoxaban, n=2828 [4.4%]).

• Of the total patient population, 17,842 (27.5%) patients had concomitant renal impairment (phenprocoumon, n=7289; XARELTO, n=5121; apixaban, n=4750; edoxaban, n=682).
• In the renal impairment population, both XARELTO and apixaban were associated with a lower risk of kidney failure compared with phenprocoumon (aHR, 0.27 [95% CI, 0.16-0.43] and 0.43 [95% CI, 0.29-0.63], respectively); the risk in this population was more pronounced than in the general population.

Lin et al (2024)²¹ conducted a retrospective cohort study to evaluate the efficacy and safety of DOACs, including XARELTO, in patients with stage 4 or 5 CKD.

• The study included data from the Chang Gung Research Database for patients with AF who received either VKA or DOACs for the first time from outpatient clinics between 2012 and 2021. Primary efficacy outcomes included IS, SE, and a composite of ISSE, and safety outcomes included MB, GIB, hemorrhagic stroke, and a composite of bleeding events.
• The study included 2382 patients with NVAF and stage 4-5 CKD receiving OACs (DOACs, n=1047; VKAs, n=1335). Of the patients receiving DOACs, 342 patients used XARELTO.
• At the 1-year follow-up, XARELTO was associated with an event rate of 4.7% for a composite ISSE event (SHR, 1.21; 95% CI, 0.90-1.64; P=0.213) and 9.7% for a composite bleeding event (SHR, 0.81; 95% CI, 0.66-0.98; P=0.031).
• At the 2-year follow-up, XARELTO was associated with an event rate of 5.6% for a composite ISSE event (SHR, 1.001; 95% CI, 0.77-1.31; P=0.992) and 13.9% for a composite bleeding event (SHR, 0.86; 95% CI, 0.73-1.02; P=0.077).
• At the end of follow-up, XARELTO was associated with an event rate of 8.9% for a composite ISSE event (SHR, 1.09; 95% CI, 0.88-1.34; P=0.448) and 17.8% for a composite bleeding event (SHR, 0.82; 95% CI, 0.72-0.95; P=0.007).

Somerville et al (2024)²² conducted a retrospective PSM cohort study to compare outcomes associated with XARELTO vs warfarin treatment in patients with ESRD and AF. Data were derived from the TriNetX Global Collaborative Network, which includes 114 healthcare organizations, for the period from 2011 to 2024. The study compared the incidence of IS, ICH, cardiac arrest, mortality, GI hemorrhage, SE, thrombosis, and other cardiac arrhythmias.

• The study identified 2391 patients in the XARELTO group and 25,092 patients in the warfarin group; from these, 2381 patients were included in each group after PSM.
• The mean age was 72.9 years, and 59.8% of patients were male.
• XARELTO-treated patients had a lower risk of experiencing a composite outcome (infarct, ICH, and mortality; RR, 0.823; 95% CI, 0.765-0.885), mortality (RR, 0.830; 95% CI, 0.775-0.888), GI hemorrhage (RR, 0.566; 95% CI, 0.439-0.730), and cardiac arrest (RR, 0.696; 95% CI, 0.531-0.911) compared with warfarin-treated patients.
• No significant difference in risk was found between the treatment groups for IS (RR, 1.024; 95% CI, 0.744-1.408), ICH (RR, 0.587; 95% CI, 0.270-1.280), SE (RR, 0.828; 95% CI, 0.512-1.339), or other cardiac arrhythmias (RR, 0.973; 95% CI, 0.804-1.179).

Fu et al (2024)²³ conducted a retrospective cohort study to assess the effectiveness and safety of newly prescribed warfarin or XARELTO vs apixaban in patients with AF and advanced, non-dialysis dependent CKD. Data were derived using 2 large US health insurance databases, Optum’s deidentified Clinformatics Data Mart database and Medicare fee-for-service Parts A (inpatient), B (outpatient), and D (pharmacy claims) between January 1, 2013, and March 31, 2022. The primary effectiveness outcome was the time to first IS, and the primary safety outcome was the time to first hospitalization with MB, including GI, intracranial, and extracranial bleeding.

• Two cohorts of patients (warfarin vs apixaban and XARELTO vs apixaban) were created using 1:1 PSM. Only results specific to XARELTO vs apixaban are discussed below.
  • Baseline characteristics:
    • XARELTO: n=2860; mean age, 78.4 years; 52.2% were female; 41.1% had CKD stage 3; mean CHA₂DS₂-VASc (congestive heart failure [CHF], hypertension, age ≥75 years [doubled], diabetes, stroke/transient ischemic attack (TIA)/thromboembolism [doubled], vascular disease [prior MI, PAD, or aortic plaque]) score was 5.29; mean HAS-BLED (Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly, Drugs/alcohol concomitantly) score was 2.85.
    • Apixaban: n=2860; mean age, 78.5 years; 52.1% were female; 42.0% had CKD stage 3; mean CHA₂DS₂-VASc score was 5.32; mean HAS-BLED score was 2.85.
• The incidence rate of IS events among XARELTO and apixaban users was 10.5 (95% CI, 6.3-16.4) and 14.3 (95% CI, 9.9-20.0) per 1000 PYs, respectively; HR was 0.71 (95% CI, 0.40-1.24).
• Patients experienced a higher rate of MB when initiated on XARELTO vs apixaban, with an incidence rate of 96.1 (95% CI, 82.3-111.7) and 52.8 (95% CI, 43.9-63.0) per 1000 PYs, respectively; HR was 1.69 (95% CI, 1.33-2.15).
• At the 2-year follow-up, the absolute risk for IS was 1.5% (95% CI, 0.8-2.8) vs 2.2% (95% CI, 1.5-3.3) with XARELTO vs apixaban, with an absolute risk difference of -0.7% (95% CI, -2.0 to 0.6).
• At the 2-year follow-up, the corresponding absolute risk for MB was 11.2% (95% CI, 9.3-13.4) with XARELTO vs 7.7% (95% CI, 6.2-9.5) with apixaban, with an absolute risk difference of 3.5% (95% CI, 0.9-6.1).

Xu et al (2024)²⁴ conducted a retrospective cohort study to compare the risks for MB, stroke/SE, and death associated with different OACs in patients with AF and severe CKD. Data were derived using deidentified electronic health record (EHR) data from 51 health systems participating in the Optum Labs Data Warehouse, including healthcare encounters, medication prescriptions, and laboratory measurements between November 4, 2011, and December 31, 2021.

• Inclusion criteria: adult patients with AF and nondialysis-dependent CKD stage 4/5 (eGFR <30 mL/min per 1.73 m²) who initiated warfarin or DOAC.
• Primary outcomes were hospitalization with a primary diagnosis of IS or SE, MB (defined as bleeding at anatomic sites, including intracranial, GI, retroperitoneal, intraspinal, intraocular, pericardial, or intraarticular sites), and all-cause death.
• Covariates across treatment groups were balanced using IPTW.
• Post weighing, baseline characteristics in the XARELTO and warfarin cohorts were as follows:
  • XARELTO (n=610): mean age, 75.2 years; 46.2% were female; mean CHA₂DS₂-VASc score was 4.4; mean HAS-BLED score was 3.8.
  • Warfarin (n=3436): mean age, 75.5 years; 49.3% were female; mean CHA₂DS₂-VASc score was 4.5; mean HAS-BLED score was 3.8.
• There were no significant differences between XARELTO and warfarin in the risks of
  • Stroke/systemic embolism (incidence rate [IR], 2.7 vs 2.2 per 100 PYs); SHR, 1.23 (95% CI, 0.76-1.98).
  • Death (IR, 5.2 vs 4.3 per 100 PYs; HR, 1.20; 95% CI, 0.82-1.76).
• Use of XARELTO was associated with a higher risk of MB compared with use of warfarin
  • IR, 4.9 vs 2.9 per 100 PYs; SHR, 1.65 (95% CI, 1.10-2.48).

Hsu et al (2023)²⁵ conducted a retrospective cohort study to assess the effectiveness and safety of DOACs vs warfarin in patients with AF and AKD. Data were derived from Big Data Center, Taipei Veterans General Hospital, between July 1, 2011, and December 31, 2020.

• Primary outcomes were hospital admissions due to stroke/systemic embolism and MB. MB was defined as hemorrhagic events that led to hospitalization.
• Covariates across treatment groups were balanced using IPTW.
• A total of 1011 patients with AF and eGFR <30 mL/min were recruited. After weighting, baseline characteristics were as follows:
  • DOACs (n=503): mean age, 83.1 years; 42.7% were women; 91.3% had eGFR of 15-29 mL/min; 8.7% had eGFR <15 mL/min, including dialysis; mean CHA₂DS₂-VASc score was 4.5; mean HAS-BLED score was 3.3.
  • Warfarin (n=508): mean age, 82.5 years; 43.6% were women; 90.7% had eGFR of 15-29 mL/min; 9.4% had eGFR <15 mL/min, including dialysis; mean CHA₂DS₂-VASc score was 4.6; mean HAS-BLED score was 3.4.
• After IPTW, in a DOAC specific subanalysis, outcomes specific to XARELTO (n=257) compared with warfarin (n=202) were as follows:
  • Stroke/SE (3 vs 5 patients), aHR 0.74 (95% CI, 0.13-4.33).
  • MB (6 patients in each group), aHR 1.79 (95% CI, 0.39-8.25).

Miao et al (2020)²⁶ conducted a retrospective study to evaluate the effectiveness and safety of XARELTO vs apixaban in NVAF patients with ESRD and/or receiving dialysis in routine practice. The study performed claims database analysis using US IBM MarketScan data from January 1, 2014, to December 31, 2017. MarketScan captured enrollment records, demographics, International Classification of Diseases, Tenth-Revision (ICD-10) diagnosis codes (and cross-walked International Classification of Diseases, Ninth Revision [ICD-9] codes), procedure codes, admission and discharge dates, outpatient medical services data, and prescription dispensing records.

• Patients were included if they were adults with ≥12 months of continuous medical and prescription insurance coverage prior to OAC initiation, were OAC-naïve 12 months prior to the first qualifying XARELTO or apixaban dispensing, had ≥2-inpatient or outpatient codes in any position for AF without codes suggesting valvular heart disease and had comorbid ESRD or were receiving dialysis.
• The primary effectiveness outcome was the composite of stroke and systemic embolism (SSE), including ischemic or hemorrhagic stroke or systemic embolism.
• The primary safety outcome, MB, was identified using a validated algorithm that detects bleeding-related hospitalizations.
• All patients were followed until outcome occurrence, insurance disenrollment, or end-of-claims data availability.
• There were 787 XARELTO (28.8% received a dose <20 mg/d) and 1836 apixaban (28.9% received a dose <10 mg/d) patients. The median (25, 75% range) CHA₂DS₂-VASc score was 3 (2, 4). The available follow-up was 0.87 (range: 0.38-1.56) years, and time on index OAC was 119 (range: 31-289) days. A total of 1493 (56.9%) of the patients discontinued index OAC during follow-up.
• The analysis did not identify a difference in the relative hazard of SSE, IS, MB, or any MB subtype between XARELTO and apixaban users (P>0.57 for all).
  • In the XARELTO vs apixaban group, the event rate per 100 PYs for SSE, IS, and MB was 1.27 vs 1.26 (HR, 1.18; 95% CI, 0.53-2.63), 1.01 vs 1.03 (HR, 1.12; 95% CI, 0.45-2.76), and 3.73 vs 3.49 (HR, 1; 95% CI, 0.63-1.58), respectively.
• Upon subgroup analysis, no statistical interactions were observed for any subgroup for either the SSE or MB outcome (P-interaction ≥0.23 for all).

Weir et al (2020)²⁷ conducted a retrospective cohort study comparing the risks of ISSE and MB in patients with NVAF and stage 4-5 CKD treated with XARELTO or warfarin. Claims from the Optum^® Deidentified EHR Database between November 2011 and June 2018 were used to identify NVAF patients who initiated XARELTO or warfarin, with a minimum of 6 months of EHR activity prior to treatment initiation. Stage IV and V CKD was identified using ICD diagnosis codes and was confirmed based on CrCl <30 mL/min, estimated from serum creatinine using the Cockcroft-Gault equation and/or evidence of dialysis. Patients were excluded if they had a history of kidney transplant, evidence of another indication for anticoagulant use, prior OAC use during the baseline period or experienced an ISSE or major bleed on the index date or 30 days prior.

• Patients were followed from the index date until the earliest of the following: first postindex outcome event or censoring due to cessation of EHR activity, mortality, reaching the database cutoff date (September 30, 2018), death, or reaching the maximum duration of follow-up (2 years postindex).
• PSM was used to balance XARELTO- and warfarin-treated patients on 112 measured baseline covariates. All outcome analyses were match-weighted to account for k:1 PSM variable-ratio of warfarin users to XARELTO users. Outcomes were analyzed as time-to-event data using Kaplan-Meier survival estimators and Cox regression.
• A total of 781 XARELTO-treated patients and 1536 warfarin-treated patients were included.
• Mean duration of follow-up was 389 days for XARELTO-treated patients and 370 days for warfarin-treated patients.
• The risk of ISSE in XARELTO-treated patients was similar to the risk observed in warfarin-treated patients (HR, 0.93; 95% CI, 0.46-1.90; P=0.85).
• The risk of MB was also comparable between XARELTO-treated patients and warfarin-treated patients (HR, 0.91; 95% CI, 0.65-1.28; P=0.60). Differences in MB rates between XARELTO-treated patients and warfarin-treated patients were not statistically significant when analyzed by bleeding site: GIB (HR, 1.14; 95% CI, 0.77-1.69; P=0.52); intracranial bleeding (HR, 0.60; 95% CI, 0.22-1.68; P=0.33); and other MB site (HR, 0.64; 95% CI, 0.30-1.36; P=0.24).
• No statistically significant differences were found in the additional secondary analyses (ie, on-treatment, Modification of Diet in Renal Disease-defined CKD severity) or the subgroup analyses (ie, age, gender, CKD severity, diabetes status, obesity status, CV disease status, and antiplatelet exposure).

Vaitsiakhovich et al (2019)²⁸ conducted an observational, retrospective study in NVAF patients with stage 3 or 4 CKD, who were treated with XARELTO 15 mg (reduced dose) or warfarin from the US IBM Watson MarketScan Commercial Claims and Medicare Supplemental Database (2012-2017). A main study outcome was the composite of progression to stage 5 CKD, kidney failure, or the need for dialysis. Other outcomes included a composite of IS and ICH, IS alone, and MB.

A total of 7368 patients (warfarin, n=5903; XARELTO, n=1465) were included in the cohort. At baseline, most patients were male (n=4440, 60.3%), and the median age was 79 (Interquartile range [IQR] 71-84) years. The median CHA₂DS₂-VASc score was 4.43 (IQR 3.40-5.62). Across the cohort, a total of 53.0% (n=3903) had diabetes. Patients were followed for a median of 115 days (IQR 51-271) with warfarin and 119 days (IQR 33-304) with XARELTO.

• XARELTO was associated a 47% reduced risk for worsened kidney function (composite of progression to stage 5 CKD, kidney failure, or the need for dialysis), compared with warfarin (HR, 0.53; 95% CI, 0.35-0.78). In a subgroup of patients with type 2 diabetes (warfarin, n=3159; XARELTO, n=746) XARELTO was associated with a 50% reduction in the risk of worsening kidney function compared to warfarin (HR, 0.50; 95% CI, 0.30-0.83).
• XARELTO was associated with a reduced risk of the composite of IS and ICH compared to warfarin (HR, 0.61; 95% CI, 0.30-1.24).
• XARELTO was associated with a reduced risk of IS alone compared to warfarin (HR, 0.77; 95% CI, 0.33-1.82).
• There was no significant difference in Cunningham bleeding-related hospitalizations for XARELTO vs warfarin (HR, 1.14; 95% CI, 0.83-1.58).

Caro et al (2019)²⁹ conducted a retrospective study to evaluate the rates of stroke, bleeding, and death in NVAF patients taking XARELTO in clinical practice for stroke or systemic embolism prevention between December 2012 and December 2015. Analyses based on subgroups, including renal insufficiency, CrCl <50 mL/min/1.73m² (n=180) vs CrCl ≥50 mL/min/1.73m² (n=552), were performed.

• Patients with CrCl <50 mL/min/1.73m² vs. CrCl ≥50 mL/min/1.73m², respectively, were older (82.5±5.7 years vs 74±9.3 years, P<0.001), more frequently female (66.4% vs 50.2%, P=0.001), had a greater thromboembolic and bleeding risk (CHA₂DS₂-VASc 4.8±1.3 vs 3.6±1.4, P<0.001; HAS-BLED 2.7±0.8 vs 2.2±0.9, P<0.001), and had increased vascular disease (prior stroke or transient ischemic attack [23.8% vs 15.3%, P=0.023], heart failure [28.7% vs 10.3%, P<0.001], ischemic heart disease [16.8% vs 10.5%, P=0.035], and peripheral artery disease [6.3% vs 1.8%, P=0.018]).
• XARELTO 15 mg and 20 mg were appropriately prescribed in 74.8% vs 39.6% and 25.2% vs 60.4% of patients with CrCl <50 mL/min/1.73m² vs CrCl ≥50 mL/min/1.73m², respectively.
• Patients with CrCl <50 mL/min/1.73m² vs CrCl ≥50 mL/min/1.73m², respectively, had a higher risk of death (17.5% vs 7.6; P=0.001) and stroke (9.2% vs 2.3%; P=0.001) but not MB (7% vs 6.4%; P=NS).

Coleman et al (2019)³⁰ conducted a retrospective study to evaluate the effectiveness and safety of XARELTO vs warfarin in NVAF patients with stage 4 or 5 CKD or undergoing hemodialysis in routine practice. Truven MarketScan data from January 2012 through December 2017 was used to identify OAC-naïve NVAF patients with stage 4 or 5 CKD or undergoing hemodialysis and with ≥12 months of insurance coverage before OAC initiation.

• Patients were followed until an ISSE or MB event, OAC discontinuation/switch, insurance disenrollment, or end of data availability. HRs and 95% CIs comparing the OAC cohorts were calculated using Cox regression.
• Differences in baseline covariates between the XARELTO and warfarin cohorts were adjusted using IPTW based on propensity scores calculated using generalized boosted models and 10,000 regression trees (absolute standardized differences <0.1 achieved for all covariates after adjustment).
• A total of 1896 XARELTO (38.7% received a dose <20 mg/day) and 4848 warfarin users were included.
• Eighty-eight percent of included patients had stage 5 CKD or were undergoing hemodialysis.
• XARELTO did not significantly reduce ISSE (HR, 0.55; 95% CI, 0.27-1.10) or IS alone (HR, 0.67; 95% CI, 0.30-1.50) but was associated with a significant (32%; HR, 0.68; 95% CI, 0.47-0.99) reduction in MB risk vs warfarin.

Weir et al (2018)³² conducted a retrospective study using data from the Incidental Medical services (IMS) Health Real-World Data Adjudicated Claims database from May 2011 through June 2015 to identify adult patients with NVAF who had been treated with XARELTO or warfarin for ≥6 months. There were 39,872 XARELTO-treated patients and 48,637 warfarin-treated patients who were stratified based on their renal function. Renal impairment was identified by relevant ICD-9-Clinical Modification (CM) diagnosis codes (XARELTO, n=3572 and warfarin, n=8230) and by estimated creatinine clearance (eCrCl) values <60 mL/min (XARELTO, n=66 and warfarin, n=208). Outcomes were the rates of IS, thromboembolic events (venous thromboembolism, MI, or IS), and MB events (identified by Cunningham algorithm).

• When renal function was categorized by diagnostic codes:
  • The rate of IS was lower in patients treated with XARELTO than in those treated with warfarin, both for the overall population (HR, 0.79; P=0.0008) and for the subgroup of patients with renal impairment (HR, 0.55; P=0.0004).
  • The rate of thromboembolic events was lower in patients treated with XARELTO than in those treated with warfarin, both for the overall population (HR, 0.63; P<0.0001) and for the patients with renal impairment (HR, 0.62; P<0.0001).
  • MB occurred significantly less frequently in patients treated with XARELTO vs warfarin (HR, 0.91; P=0.0405) in the overall population. There were similar bleeding rates in patients treated with XARELTO and warfarin in the subgroup of patients with renal impairment.
• When renal function was categorized by eCrCl values:
  • The rates of IS, thromboembolic events, and MB were not significantly different between the XARELTO and warfarin groups for either the overall population or for the subgroup with renal impairment (eCrCl <60 mL/min).

Weir et al (2017)³¹ conducted a retrospective cohort study to assess the impact of renal function on IS and MB rates in patients with NVAF in the real-world setting (outside a clinical trial). Medical claims and EHRs were retrieved retrospectively from Optum’s Integrated Claims-Clinical de-identified dataset from May 2011 to August 2014. Stroke was identified in the claims database as a primary diagnosis of IS during a hospitalization (using ICD-9 codes). MB was identified using the Cunningham criteria, which identify bleeding events based on a primary diagnosis ICD-9-CM code using a validated algorithm and includes GI, genitourinary, cerebral, and other relevant bleeding sites. Patients with NVAF treated with warfarin (2468) or XARELTO (1290) were selected. Each treatment cohort was stratified by baseline eCrCl levels. Confounding adjustments were made using IPTW. Incidence rates and HRs of IS and MB events were calculated for both cohorts.

• Among the overall population, patients treated with XARELTO had an IS incidence rate of 1.9 per 100 PYs, while patients treated with warfarin had a rate of 4.2 per 100 PYs (HR, 0.41; 95% CI, 0.21-0.80; P=0.009).
• XARELTO-treated patients with eCrCl ≤50 mL/min (n=229) had an IS rate of 0.8 per 100 PYs, while the rate for the warfarin cohort (N=647) was 6.0 per 100 PYs (HR, 0.09; 95% CI, 0.01-0.72; P=0.02).
• For other renal function levels (ie, eCrCl 50-80 and ≥80 mL/min), IS rates were numerically lower for XARELTO vs warfarin, but HRs indicated no statistically significant differences between the treatment groups.
• The overall MB rate was 7.3 per 100 PYs for XARELTO and 7.4 per 100 PYs for warfarin (IPTW-weighted HR, 1.04; 95% CI, 0.72-1.51; P=0.83).
• The weighted HR (95% CI) for the CrCl ≤50 mL/min, >50 to <80 mL/min, and ≥80 mL/min groups was 1.20 (0.66-2.20), 1.26 (0.75-2.12), and 0.73 (0.33-1.63), respectively.
• Bleeding events did not differ significantly between cohorts stratified by renal function.

Chan et al (2015)³⁴ conducted a retrospective analysis to describe the prescribing patterns of dabigatran and XARELTO in chronic hemodialysis patients with AF. Rates of bleeding, stroke, and arterial embolism among dialysis patients taking warfarin, dabigatran, or XARELTO were also compared.

• Data for the study were derived from the Fresenius Medical Care North America ESRD database for the period of October 2010 (Food and Drug Administration [FDA] approval date for dabigatran) to October 2014.
• Among the 316,859 chronic hemodialysis patients assessed within the October 2010 to October 2014 period, 29,977 (9.5%) were identified as having AF.
• Among these patients, the first XARELTO prescription occurred 161 days after FDA approval of XARELTO for stroke prevention in AF. The first record of dabigatran prescription occurred 45 days after drug approval. Since that time, dabigatran and XARELTO use has steadily risen in the AF-ESRD population, with 5.9% of anticoagulated dialysis patients being started on dabigatran (3.1%) or XARELTO (2.8%).
• A total of 244 patients were started on XARELTO and 281 patients were started on dabigatran. For XARELTO, 32.1% of patients received the full dose (20 mg OD) and 67.8% received the reduced dose (15 mg OD).
• In covariate-adjusted Poisson regression, XARELTO (RR, 1.38; 95% CI, 1.03-1.83; P=0.04) and dabigatran (RR, 1.48; 95% CI, 1.21-1.81; P=0.0001) were associated with a higher risk of MB (defined as a hemorrhagic event resulting in hospitalization or death) compared with warfarin.
• When analyzed by dose, dialysis patients prescribed the full dose of XARELTO 20 mg (which is not recommended in this patient population³³) had a higher risk of MB compared with patients who were prescribed the lower dose of XARELTO 15 mg (which is the recommended dose for patients with renal impairment³³).
• The risk of hemorrhagic death was larger with XARELTO (RR, 1.71; 95% CI, 0.94-3.12; P=0.07) and with dabigatran (RR, 1.78; 95% CI, 1.18-2.68; P=0.006) relative to warfarin. Similar associations were observed with minor bleeding.
• Significant differences in stroke and arterial embolism could not be detected between groups as there were limited events in the study.

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 07 August 2026.