SUMMARY

• In a prospective, observational registry of adult patients with non-valvular atrial fibrillation (NVAF) and advanced chronic kidney disease (CKD) with estimated glomerular filtration rate [eGFR] 15-49 mL/min/1.73m², XARELTO treatment was associated with greater net clinical benefit (lower event rates for stroke and other thromboembolic events, major bleeding, and all-cause mortality) compared to vitamin K antagonist (VKA).¹ Additionally, a reduction in adverse kidney outcomes was observed in patients treated with XARELTO.²
• In a retrospective cohort study evaluating the effectiveness and safety of newly prescribed warfarin or XARELTO vs apixaban in patients with atrial fibrillation (AF) and advanced, non-dialysis dependent CKD, incidence rate of ischemic stroke events among XARELTO and apixaban users respectively were 10.5 (95% CI, 6.3-16.4) and 14.3 (95% CI, 9.9-20.0) per 1000 person-years (PYs) (after propensity score matching [PSM], hazard ratio (HR) was 0.71; 95% CI, 0.40-1.24). Corresponding incidence rate of major bleeding 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).³
• In a retrospective cohort study comparing the risks for major bleeding, stroke/systemic embolism, and death associated with different oral anticoagulants (OACs) in patients with AF and severe CKD, there were no significant differences in the risks of stroke/systemic embolism (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 major bleeding was seen with the use of XARELTO compared with warfarin (HR, 1.65; 95% CI, 1.10–2.48).⁴
• In another retrospective cohort study evaluating the effectiveness and safety of direct oral anticoagulants (DOACs) vs warfarin in patients with AF and advanced kidney disease (AKD), warfarin showed a higher risk of stroke/ systemic embolism (SE) (aHR 0.74; 95% CI, 0.13-4.33) compared to XARELTO. The risk of major bleeding was similar in both groups (aHR 1.79; 95% CI, 0.39-8.25).⁵
• In a retrospective study conducted in NVAF patients with ESRD and/or hemodialysis, XARELTO and apixaban patients had similar risks of stroke/SE, ischemic stroke, and major bleeding (P>0.57 for all). In the XARELTO vs apixaban groups, the event rates per 100 PYs for stroke/SE, ischemic stroke, and major bleeding 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.⁶
• In a retrospective cohort study comparing the risks of ischemic stroke/systemic embolism (ISSE) and major bleeding in patients with NVAF and stage 4-5 CKD treated with XARELTO or warfarin, no statistically significant difference in the risk of ISSE or major bleeding 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 major bleeding.⁷
• 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).⁸
• In a retrospective study that evaluated the rates of stroke, bleeding, and death in NVAF patients with or without renal insufficiency taking XARELTO, patients with creatinine clearance (CrCl) <50 mL/min/1.73 m² 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 major bleeding (7% vs 6.4%, P=nonsignificant [NS]).⁹
• 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 ischemic stroke 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 major bleeding risk.¹⁰
• Two real-world studies in patients with NVAF and renal impairment found that treatment with XARELTO was associated with lower rates of ischemic stroke than treatment with warfarin, but there was no difference between the 2 treatments in the incidence of major bleeding.^11,12
• A retrospective analysis surveyed an end-stage renal disease (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 major bleeding (defined as a hemorrhagic event resulting in hospitalization or death) with XARELTO (rate ratio [RR], 1.38; 95% confidence interval [CI], 1.03-1.83) and dabigatran (RR, 1.48; 95% CI, 1.21-1.81) compared to warfarin. When analyzed by dose, dialysis patients prescribed the full dose of XARELTO 20 mg (which is not recommended in this patient population¹³) had a higher risk of major bleeding than patients who were prescribed the lower dose of XARELTO 15 mg (which is recommended for patients with renal impairment¹³).¹⁴
• Additional citations identified during a literature search are included in the REFERENCES section for your review.^15-25

REAL-WORLD EVIDENCE

XARENO Study^1,26

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 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, major bleeding, and all-cause mortality). In the intention-to-treat group, there were 766 patients who received XARELTO and 695 patients who received VKA. A propensity score matched analysis (PSMA) was used to evaluate XARELTO (n=397) versus 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).¹
• In the PSMA, 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).¹

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.²

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)
  • Acute kidney injury, 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)

Fu et al (2024)³ 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 was 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. Primary effectiveness outcome was time to first ischemic stroke, and the primary safety outcome was time to first hospitalization with major bleeding, including gastrointestinal, 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.
• Incidence rates of ischemic stroke events among XARELTO and apixaban users were 10.5 (95% CI, 6.3-16.4) and 14.3 (95% CI, 9.9-20.0) per 1000 PYs, respectively; HR 0.71 (95% CI, 0.40-1.24).
• Patients who initiated XARELTO had higher rates of major bleeding compared with apixaban, with incidence rates of 96.1 (95% CI, 82.3-111.7) and 52.8 (95% CI, 43.9-63.0) per 1000 PYs, respectively; HR 1.69 (95% CI, 1.33-2.15).
• At 2 years follow-up, the absolute risks for ischemic stroke were 1.5% (95% CI, 0.8-2.8) vs 2.2% (95% CI, 1.5-3.3) with XARELTO and apixaban respectively, with an absolute risk difference of -0.7% (95% CI, -2.0 to 0.6).
• At 2 years follow up, corresponding absolute risks for major bleeding were 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)⁴ conducted a retrospective cohort study to compare the risks for major bleeding, stroke/systemic embolism, and death associated with different OACs in patients with AF and severe CKD. Data were derived using deidentified electronic health record 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 primary diagnosis of ischemic stroke or systemic embolism, major bleeding (defined as bleeding at anatomic sites, including intracranial, gastrointestinal, retroperitoneal, intraspinal, intraocular, pericardial, or intraarticular sites), and all-cause death.
• Covariates across treatment groups were balanced using inverse probability of treatment weighting (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); subdistribution HR, 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 major bleeding compared with use of warfarin
  • IR, 4.9 vs 2.9 per 100 PYs; subdistribution HR, 1.65 (95% CI, 1.10-2.48).

Hsu et al (2023)⁵ conducted a retrospective cohort study to assess the effectiveness and safety of DOACs vs warfarin in patients with AF and AKD. Data was 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 major bleeding. Major bleeding 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).
  • Major bleeding (6 patients in each group), aHR 1.79 (95% CI, 0.39-8.25).

Miao et al (2020)⁶ 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 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, major bleeding, 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.
• Analysis did not identify difference in the relative hazard of SSE, ischemic stroke, major bleeding, or any major bleeding subtype between XARELTO and apixaban users (P>0.57 for all).
  • In the XARELTO vs apixaban groups, the event rates per 100 PYs for SSE, ischemic stroke, and major bleeding 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.
• Upon subgroup analysis, no statistical interactions were observed for any subgroup for either the SSE or major bleeding outcome (P-interaction ≥0.23 for all).

Weir et al (2020)⁷ conducted a retrospective cohort study comparing the risks of ISSE and major bleeding in patients with NVAF and stage 4-5 CKD treated with XARELTO or warfarin. Claims from the Optum^® Deidentified electronic health records (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 index date until the earliest of the following: first postindex outcome event or censoring due to cessation of EHR activity, mortality, reaching the database cut-off date (September 30, 2018), death, or reaching the maximum duration of follow-up (2 years postindex).
• Propensity score matching (PSM) was used to balance XARELTO and warfarin 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 major bleeding 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 major bleeding rates between XARELTO-treated patients and warfarin-treated patients were not statistically significant when analyzed by bleeding site: gastrointestinal bleeding (HR, 1.14; 95% CI, 0.77-1.69; P=0.52); intracranial bleeding (HR, 0.60; 95% CI, 0.221.68; P=0.33); and other major bleeding 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)⁸ 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 ischemic stroke and intracranial hemorrhage, ischemic stroke alone, and major bleeding.

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, 0.300.83).
• XARELTO was associated with a reduced risk for the composite of ischemic stroke and intracranial hemorrhage compared to warfarin (HR, 0.61; 95% CI, 0.30-1.24).
• XARELTO was associated with a reduced risk of ischemic stroke 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)⁹ 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 major bleeding (7% vs 6.4%, P=NS).

Coleman et al (2019)¹⁰ 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 major bleeding 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 ischemic stroke 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 major bleeding risk vs warfarin.

Weir et al (2018)¹² 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 warfarintreated 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 eCrCl values <60 mL/min (XARELTO, n=66 and warfarin, n=208). Outcomes were the rates of ischemic stroke, thromboembolic events (venous thromboembolism, myocardial infarction, or ischemic stroke), and major bleeding events (identified by Cunningham algorithm).

• When renal function was categorized by diagnostic codes:
  • The rate of ischemic stroke 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).
  • Major bleeding occurred significantly less frequently in patients treated with XARELTO rather than warfarin (HR, 0.91; P=0.0405) for 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 ischemic stroke, thromboembolic events, and major bleeding 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)¹¹ conducted a retrospective cohort study to assess the impact of renal function on ischemic stroke and major bleeding rates in NVAF patients 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 ischemic stroke during a hospitalization (using International Classification of Disease, Ninth Revision [ICD-9] codes). Major bleeding was identified using the Cunningham criteria, which identifies bleeding events based on a primary diagnosis ICD9CM code using a validated algorithm and includes gastrointestinal, 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 estimated creatinine clearance (eCrCl) levels. Confounding adjustments were made using IPTW. Incidence rates and HRs of ischemic stroke and major bleeding events were calculated for both cohorts.

• Among the overall population, patients treated with XARELTO had an ischemic stroke 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 patients with an eCrCl ≤50 mL/min (N=229) had an ischemic stroke 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), ischemic stroke rates were numerically lower for XARELTO vs warfarin, but HRs indicated no statistically significant differences between the treatment groups.
• Overall major bleeding rates were 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).
• Weighted HRs (95% CI) for CrCl ≤50 mL/min, >50 - <80 mL/min, and ≥80 mL/min groups were 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)¹⁴ 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 once-daily [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 major bleeding (defined as a hemorrhagic event resulting in hospitalization or death) compared to warfarin.
• When analyzed by dose, dialysis patients prescribed the full dose of XARELTO 20 mg (which is not recommended in this patient population¹³) had a higher risk of major bleeding than patients who were prescribed the lower dose of XARELTO 15 mg (which is the recommended dose for patients with renal impairment¹³).
• 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 03 September 2024.