SUMMARY OF PRESCRIBING INFORMATION

• In adult patients who receive XARELTO for reduction of stroke and systemic embolism in nonvalvular atrial fibrillation (AF)¹¹:
  • The recommended dose of XARELTO for patients with creatinine clearance (CrCl) ≤50 mL/min is 15 mg taken orally once daily with the evening meal.¹¹ Periodically assess renal function as clinically indicated and adjust therapy accordingly. Consider dose adjustment or discontinuation of XARELTO in patients who develop acute renal failure while on XARELTO.
  • For patients with end-stage renal disease (ESRD) on dialysis: Clinical efficacy and safety studies with XARELTO did not enroll patients with ESRD on dialysis. In patients with ESRD maintained on intermittent hemodialysis, administration of XARELTO 15 mg once daily will result in concentrations of rivaroxaban and pharmacodynamic (PD) activity similar to those observed in the ROCKET AF study. It is not known whether these concentrations will lead to similar stroke reduction and bleeding risk in patients with ESRD on dialysis as was seen in ROCKET AF.
• In adult patients who receive XARELTO in combination with aspirin for reduction in the risk of major cardiovascular (CV) events (CV death, myocardial infarction [MI], and stroke)¹¹:
  • The recommended dose is XARELTO 2.5 mg twice daily plus aspirin (75-100 mg) once daily. No dosage adjustment is needed based on CrCl.
  • In patients with ESRD on dialysis: No clinical outcome data is available for the use of XARELTO with aspirin in patients with ESRD on dialysis since these patients were not enrolled in the COMPASS study. In patients with ESRD maintained on intermittent hemodialysis, administration of XARELTO 2.5 mg twice daily will result in concentrations of rivaroxaban and PD activity similar to those observed in moderate renal impaired patients in COMPASS. It is not known whether these concentrations will lead to similar CV risk reduction and bleeding risk in patients with ESRD on dialysis as was seen in COMPASS.
• For treatment of deep vein thrombosis (DVT), pulmonary embolism (PE), and for the reduction in the risk of recurrence of DVT and of PE in adult patients: Avoid the use of XARELTO in patients with CrCl <15 mL/min.¹¹
• For the prophylaxis of DVT following hip or knee replacement surgery in adult patients: Avoid the use of XARELTO in patients with CrCl <15 mL/min.¹¹
• For the prophylaxis of venous thromboembolism (VTE) in adult acutely ill medical patients at risk for thromboembolic complications not at high risk of bleeding: Avoid the use of XARELTO in patients with CrCl <15 mL/min.¹¹

PK AND PD STUDIES

Dias et al (2016)¹ conducted an open-label, single-dose, single-center, parallel-group study to assess the PK and PD of XARELTO in patients with ESRD who were stable on maintenance hemodialysis for at least 3 months.

• The primary objectives of the study were to characterize the PK and PD of a single 15-mg dose before and after dialysis, and compare it to the PK/PD profile of healthy subjects with a CrCl >80 ml/min.
• Secondary objectives included assessing the fraction of XARELTO removed by hemodialysis, the PD of XARELTO in subjects with ESRD, and the safety and tolerability of XARELTO in ESRD patients.
• Sixteen male patients (8 with ESRD and 8 healthy) were recruited. Group matching was applied to the healthy group to ensure a similar patient population with respect to gender, age, and body mass index.
• The study consisted of a 21-day screening period followed by 2 treatment periods for the ESRD group and 1 treatment period for the healthy group. Blood samples were collected prior to and 72 hours following XARELTO administration. XARELTO concentrations were measured from urine samples from both groups and from the dialysate fluid in the ESRD group.
• Treatment period 1 (ESRD group): single 15-mg XARELTO dose administered 2 (±0.5) hours before starting a 4-hour hemodialysis session (predialysis), followed by a washout period of 7-14 days
• Treatment period 2 (ESRD group): single 15-mg XARELTO dose administered 3 hours after completion of a 4-hour dialysis session (postdialysis)
• Treatment period 1 (healthy group): single 15-mg XARELTO dose

Please see the table below for XARELTO PK data in ESRD compared with normal renal function.

• XARELTO was found to be highly protein-bound in both treatment groups.
• Patients with ESRD who were given XARELTO postdialysis had increased systemic exposure, with a 56% increase in AUC compared with healthy control subjects. This reflects an approximate 35% decrease in overall clearance due to ESRD.
• This is similar to the increases in exposure previously shown in another study for patients with moderate renal impairment (52% increase in AUC) or severe renal impairment (64% increase in AUC).¹²
  • XARELTO administration prior to a 4-hour dialysis session resulted in a 5% lowering of plasma AUC compared with postdialysis administration, which reflects the minimal impact of dialysis on the PK of XARELTO. This is generally consistent with the high protein binding of XARELTO (86% - 89%).
  • Maximum plasma concentration and AUC were lower when XARELTO was administered predialysis compared with postdialysis.
  • Changes in PD parameters, such as prothrombin time, factor Xa inhibition, and anti-Xa activity, were generally consistent with the PK changes and were higher in ESRD vs healthy subjects.

De Vriese et al (2015)² performed a study to evaluate the PK and PD of XARELTO in maintenance hemodialysis patients.

Study Design/Methods

• Eighteen adult patients who were dialyzed 3 times weekly for at least 3 months without residual renal function were included.
• Intervention 1: evaluate XARELTO concentrations and response following a single 10-mg dose administration immediately after 3 consecutive dialysis sessions in 12 patients
• Intervention 2: evaluate the effect of dialysis on XARELTO concentrations and response following a single 10-mg dose in the morning when dialysis was scheduled in the afternoon, or in the previous evening when dialysis was scheduled in the morning; dialysis was scheduled 6-8 hours following the XARELTO dose
• Intervention 3: evaluate XARELTO concentrations following a dose of 10 mg once daily in the morning in 6 patients over 7 days
• Safety and tolerability were also assessed.

Results

• Intervention 1 (n=12):
  • Mean area under the concentration-time curve from 0 to 44 hours (AUC_0-44) following a single oral dose of XARELTO was 2072 (range, 1141-4946) µg/L/hour with coefficient of variation (CV) of 54.7%.
  • Mean maximum plasma concentration (C_max) was 172.6 (range, 103-394) µg/L with CV of 45.5%.
  • Mean terminal elimination half-life (t_1/2) was 8.6 (range, 5.0-12.4) hours with CV of 27.3%.
• Intervention 2 (n=12):
  • Dialysis had no appreciable effect on concentrations of XARELTO. Mean concentration of XARELTO in dialysate was 5.4±5.4 (standard deviation) ng/mL.
• Intervention 3 (n=6):
  • Day 1
    • Mean area under the concentration-time curve from 0 to 24 hours (AUC_0-24) after XARELTO 10 mg was 1449 (range, 766-2851) µg/L/hour with CV of 47.6%.
    • Mean C_max was 152.8 (range, 122-239) µg/L with CV of 30.7%.
    • Mean t_1/2 was 6.6 (range, 4.2-12.4) hours with CV of 48.4%.
  • Day 7
    • Mean AUC_0-24 after XARELTO 10 mg was 1851 (range, 1174-2806) µg/L/hour with CV of 38.3%.
    • Mean C_max was 192.0 (range, 134-304) µg/L with CV of 31.7%.
    • Mean t_1/2 was 7.3 (range, 4.3-11.8) hours with CV of 39.4%.
    • Following multiple 10-mg doses, trough plasma concentration (C_trough) was 20.2 (range, 4.1-93.4) µg/L.
• There were no serious side effects associated with XARELTO administration and no patient-reported side effects.

RANDOMIZED STUDY

De Vriese et al (2020)³conducted an investigator driven, randomized, prospective, open-label interventional trial to investigate vitamin K’s effect on the status of vascular calcification (VC) progression in patients on hemodialysis with atrial fibrillation (AF) treated with vitamin K antagonists (VKAs) or who qualified for anticoagulation. “The Valkyrie Study”.

Study Design/Methods

• The study included 132 adults from February 2015 to July 2017 on chronic hemodialysis with nonvalvular AF, who had a CHA2DS2-VASc score of ≥2, and who were candidates for anticoagulation therapy or who were already receiving VKAs.
• Patients were randomized 1:1:1 to VKA with a target INR 2-3, rivaroxaban 10 mg daily, or rivaroxaban 10 mg daily plus vitamin K2 2000 µg three times weekly after dialysis for 18 months.
• The primary outcomes included change of coronary artery calcification, thoracic aorta calcification, and pulse wave velocity (PWV) over 18 months vs baseline.
  • Calcification scores were used to assess the effect of VKA and rivaroxaban on CV risk.
    • Calcium scores were calculated by the Agatston method and volume method.
  • Arterial stiffness was quantified by PWV.
  • Dephosphorylation uncarboxylated MGP (dp-ucMGP) was used as the biomarker for vascular vitamin K stores.
• Data collected for the primary outcomes occurred at baseline, 6, 12, and 18 months.

Results

• Baseline demographic, clinical, biochemical characteristics, and maintenance medications were not different between the groups.
• Baseline calcification scores, hemodynamic parameters, and PWV were not significantly different among the treatment arms.
• 55 patients did not complete the study, (n=47, death; n=8, withdrawal of consent)
• The change in dp-ucMGP levels were significantly different (P<0.001) across treatment arms over time.
  • Levels increased significantly in the VKA group (P=0.03).
  • Levels decreased significantly in the rivaroxaban group and rivaroxaban + vitamin K2 group, (P=0.04 and P=0.04, respectively).
  • There were significantly larger decreases in dp-ucMGP when vitamin K2 was added to rivaroxaban therapy (P=0.004).
• A subgroup analysis of warfarin naïve (n=34, 25.8%) patients also saw a significant change in dp-ucMGP levels over time across treatment arms (P<0.01).
  • VKA group increased, rivaroxaban group remained stable, and rivaroxaban + vitamin K2 group decreased.
• There was no significant difference between treatment groups for longitudinal changes in calcification.
• The proportion of patients with an annualized percentage change in Agatston calcification scores ≥15% for the sum of coronary arteries and for the thoracic aorta were not different among all treatment groups after 18 months.
• The proportion of patients with an annualized percentage change in volume scores ≥15% for the sum of coronary arteries and for the thoracic aorta were not different among all treatment groups after 18 months.
• Changes in PWV were not significantly different across treatment groups over time (P=0.56).
• Secondary efficacy outcomes were also evaluated and are referenced within the Table: Secondary Efficacy Outcomes.

• There were no adverse events related to the use of vitamin K2 three times weekly after dialysis.
• 36 of 132 patients experienced a life-threatening or major bleeding episode.
• When compared with the VKA group, the total number of combined life-threatening and major bleeding episodes were statistically lower in both rivaroxaban groups. Please refer to Table: Bleeding Outcomes.
• Exploratory analysis of bleeding rates found significantly fewer major bleedings and combined life-threatening and major bleedings in the combined rivaroxaban groups vs VKA.

De Vriese et al (2021)⁴ conducted a follow-up analysis of efficacy and safety comprising of patients who completed the Valkyrie Study and continued their treatment assignment for at least an additional 18 months.

• The primary efficacy outcome was a composite of fatal cardiovascular disease, nonfatal stroke, cardiac events, and other vascular events.
• Secondary efficacy outcomes were individual components of the composite outcome and all cause death.
• The primary composite outcome occurred for 35 patients in the VKA group, 23 in the XARELTO group, and 17 in the XARELTO + vitamin K2 group. The estimated competing risk–adjusted hazard ratios (HRs) were 0.41 (95% confidence interval [CI], 0.25-0.68; P=0.0006) for the XARELTO vs VKA group and 0.34 (95% CI, 0.19-0.61; P=0.0003) for the XARELTO + vitamin K2 vs VKA group.
• There was no significant difference between treatment arms for all cause death, cardiac death, and risk of stroke. Symptomatic limb ischemia occurred significantly less frequently in the XARELTO group, compared with VKA (P=0.02)
• After adjustment for the competing risk of death, the HRs for life-threatening and major bleeding were 0.39 (95% CI, 0.17-0.90; P=0.03) for the XARELTO vs VKA group, and 0.48 (95% CI, 0.22-1.08; P=0.08) for the XARELTO + vitamin K2 vs VKA group.

real-world evidence

Chan et al (2015)⁵ 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) and 67.8% received the reduced dose (15 mg once daily).
• 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 with warfarin.
• When analyzed by dose, dialysis patients prescribed the full dose of XARELTO 20 mg (which is not recommended in this patient population¹¹) 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 impairment¹¹).
• 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.

Coleman et al (2019)⁶ conducted a retrospective study to evaluate the effectiveness and safety of XARELTO vs warfarin in nonvalvular atrial fibrillation patients with stage 4 or 5 chronic kidney disease or undergoing hemodialysis in routine practice. Data using Truven MarketScan data, from January 2012 through December 2017, was used to identify oral anticoagulant (OAC)-naïve nonvalvular atrial fibrillation patients with stage 4 or 5 chronic kidney disease or undergoing hemodialysis and with ≥12-months of insurance coverage before OAC initiation.

• Patients were followed until a stroke/systemic embolism 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 inverse probability-of-treatment weights 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 <20mg/day) and 4848 warfarin users were included.
• Eighty-eight percent of included patients had stage 5 chronic kidney disease or were undergoing hemodialysis.
• XARELTO did not significantly reduce stroke/systemic embolism (HR, 0.55; 95% CI, 0.27-1.10) or ischemic stroke (HR, 0.67; 95% CI, 0.30-1.50) alone, but was associated with a significant 32% (95% CI, 1-53) reduction in major bleeding risk vs warfarin.

Miao et al (2020)⁷ conducted a retrospective study to evaluate the effectiveness and safety of rivaroxaban vs apixaban in AF 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.

• The study included adults with ≥12 months of continuous medical and prescription insurance coverage prior to OAC initiation, who were OAC-naïve during the 12 months prior to the first qualifying rivaroxaban or apixaban dispensing, had ≥2-inpatient or outpatient codes in any position for atrial fibrillation without codes suggesting valvular heart disease and had comorbid ESRD or 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 was major bleeding. It was identified using a validated algorithm for detecting bleeding-related hospitalizations.
• All patients were followed until outcome occurrence, insurance disenrollment, or end-of-claims data availability.
• The study identified 787 rivaroxaban (28.8% received a dose <20 mg/d) and 1836 apixaban (28.9% received a dose <10 mg/d) users. Median (25, 75% range) CHA2DS2VASc score was 3 (2, 4). Duration of 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 rivaroxaban and apixaban users (P>0.57 for all).
  • In the XARELTO vs apixaban groups, the event rates per 100 person-years (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.
• 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).

SYSTEMATIC REVIEW AND META-ANALYSIS

Abdullah, et al (2021)⁸ conducted a systematic review and meta-analysis, using an electronic database search of studies evaluating direct oral anticoagulants in patients with atrial fibrillation and concomitant end stage renal disease (databases were last accessed in December 2019). Eight articles were identified for quantitative analysis (6 for apixaban and 3 for XARELTO). The three XARELTO studies included 2196 patients on XARELTO and 15,705 on warfarin.

• In the pooled analysis of XARELTO compared with warfarin, there was no significant difference in the risk of major bleeding (HR, 0.95; 95% CI, 0.50–1.81; P=0.88) or stroke events (HR, 1.39; 95% CI, 0.59–3.29; P=0.45).

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, Derwent^® (and/or other resources, including internal/external databases) was conducted on 19 November 2024.