SUMMARY

• In patients taking XARELTO to reduce the risk of stroke and systemic embolism in nonvalvular atrial fibrillation (NVAF) with a creatinine clearance (CrCl) ≤50 mL/min, the recommended dose is 15 mg orally once daily with the evening meal. Periodically assess renal function as clinically indicated (ie, more frequently in situations in which renal function may decline) and adjust therapy accordingly. Consider dose adjustment or discontinuation of XARELTO in patients who develop acute renal failure while on XARELTO.¹
• In a prespecified secondary analysis of ROCKET AF and J-ROCKET AF, efficacy and safety results in patients with moderate renal impairment (CrCl 30-49 mL/min) were consistent with those of patients with CrCl >50 mL/min and the overall trial.^2,3
• In a subset analysis of patients with worsening renal function (WRF), XARELTO was associated with lower rates of stroke/systemic embolism compared to warfarin. There was no difference in the composite of major + nonmajor clinically relevant bleeding with XARELTO versus warfarin.^4,5
• In the Valkyrie Study evaluating patients with atrial fibrillation (AF) on hemodialysis, there was no difference in the progression of vascular calcification (VC) over 18 months in patients treated with vitamin K antagonists (VKAs), XARELTO, and XARELTO +vitamin K2.⁶
  • A follow-up analysis comprising of patients who completed the Valkyrie Study and continued their assigned treatment for at least an additional 18 months found that XARELTO significantly reduced the composite outcome of fatal and nonfatal cardiovascular (CV) events, compared with VKA.⁷
• In a meta-analysis, XARELTO showed superiority in the reduction of stroke or systemic embolic (S/SE) events with similar major bleeding events compared with warfarin in patients with AF and renal impairment.⁸
• In a pharmacokinetic (PK) and pharmacodynamic (PD) analysis of ROCKET AF, increasing XARELTO plasma concentrations elevated prothrombin time and prothrombinase-induced clotting time in a near-linear relationship and reduced factor Xa activity.⁹
• 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 chronic kidney disease (CKD), incidence rate of ischemic stroke events among XARELTO and apixaban users were comparable. XARELTO was associated with a higher rate of major bleeding compared to apixaban.¹⁰
• In an observational, postmarketing safety study of XARELTO users with NVAF, the cohort of patients with renal disease experienced a higher rate of major bleeding than the cohort of patients without renal disease.¹¹
• An additional study identified during literature search is included under the REFRENCES section for your review.¹²

CLINICAL STUDIES

ROCKET-AF

Fox et al (2011)² conducted a prespecified secondary analysis of ROCKET AF to assess the risk and benefits of XARELTO 15 mg once daily compared to warfarin in patients with moderate renal impairment (CrCl 30-49 mL/min).

• A total of 2950 of 14,263 patients (20.7%) had moderate renal impairment at baseline. These patients had a median age of 79 and mean CHADS2 (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, stroke [double weight]) score of 3.7.
• Patients with moderate renal impairment had higher rates of stroke, systemic embolism and bleeding than those with normal renal function, irrespective of study treatment.
• Results are presented in Table: Efficacy Outcomes in the Per-Protocol Population.
• Treatment effect in patients with moderate renal impairment were consistent with those seen in patients with CrCl >50 mL/min and consistent with the overall trial results. These findings were similar in the intention-to-treat analysis.

• Patients with moderate renal impairment had higher rates of major and clinically relevant nonmajor bleeding than those patients with a CrCl ≥50 mL/min, irrespective of treatment (see Table: Bleeding Outcomes in Safety Population). There was no significant increase in major and clinically relevant nonmajor bleeding or in individual bleeding outcomes in patients treated with XARELTO 15 mg compared with warfarin.
• In patients with moderate renal impairment, gastrointestinal (GI) bleeding was more frequent with XARELTO vs warfarin (4.1% vs 2.6%; P=0.02), while critical organ bleeding and fatal bleeding were less frequent with XARELTO vs warfarin.

During the ROCKET AF trial, 4.8% and 4.3% of patients with a baseline CrCl >50 mL/min in the safety population developed moderate renal impairment (CrCl 30 to 49 mL/min) while on XARELTO and warfarin, respectively (with a median duration of treatment exposure of 590 days).¹³

• This population includes all patients with 2 consecutive on-study CrCl readings <50 mL/min.
• Based on the study protocol, the medication doses were not adjusted with the decline in CrCl (<50 mL/min) but were discontinued if CrCl decreased to <25 mL/min on 2 consecutive occasions.

A post hoc analysis of this population found a statistically significant difference in the rate of stroke and non-central nervous system (CNS) systemic embolism between treatment groups but similar rates of major or nonmajor clinically relevant bleeding. See Table: Clinical Outcomes in Patients With Baseline CrCl ≥50 mL/min With 2 Consecutive On-Treatment CrCl Readings <50 mL/min.

Fordyce et al (2015)^4,5 evaluated the differences in clinical outcomes and treatment efficacy between XARELTO and warfarin in patients with stable renal function (SRF) and WRF from ROCKET AF.

• WRF was defined as a decrease of ≥20% in CrCl from the screening visit. SRF included all other patients. Patients with a baseline CrCl < 30 mL/min were excluded from ROCKET AF.
• CrCl was measured a minimum of 4 times: at screening, 24 weeks, 52 weeks, and at end of study (or early discontinuation).
  • Study drug dose was assigned based on CrCl during the screening visit: 20 mg daily or 15 mg daily with CrCl 30–49 mL/min at baseline.
  • Patients with CrCl < 25 mL/min on 2 consecutive measurements were required to discontinue study drug. There were no other dose adjustments postbaseline for changing CrCl.
• There was no difference in the primary efficacy outcome (stroke or non-CNS embolism) or primary safety endpoint (International Society on Thrombosis and Haemostasis [ISTH] major or nonmajor clinically relevant bleeding) between patients with SRF compared to those with WRF.
• WRF patients had an increase in vascular death, the composite endpoint of stroke, systemic embolism, vascular death, or myocardial infarction and all-cause mortality.
• See Table: Results Based on SRF and WRF.

• Patients with WRF on XARELTO had a reduction in stroke or systemic embolism compared to patients with WRF on warfarin (P=0.050 for interaction). See Table: Results Based on Renal Function and Treatment Assignment.
• There was no difference in patients with WRF and SRF taking XARELTO or warfarin for major or clinically relevant nonmajor bleeding or intracerebral hemorrhage (P=0.61 and P=0.67 for interaction,  respectively).
• Patients with WRF on XARELTO had a greater incidence of hemoglobin fall ≥2 g/dL, that was also not seen in SRF patients (P=0.047 for interaction).

• In patients receiving warfarin, a greater increase in events was seen with the greater CrCl decrease from screening. In patients receiving XARELTO, the rates of events were similar irrespective of CrCl decrease.

J-ROCKET AF

Hori et al (2013)³ conducted a subanalysis of the J-ROCKET AF study to assess the safety and efficacy of dose-adjusted XARELTO (10 mg once daily) compared with warfarin in Japanese patients with moderate renal impairment (CrCl, 30-49 mL/min).

• J-ROCKET AF was conducted with Japanese-specific dosing because of the altered PK effects in Japanese patients.
• A total of 284 of 1278 patients in the safety group (22.2%) had moderate renal impairment at baseline. These patients were older (median age, 78 years), had higher CHADS₂ scores (mean score, 3.52-3.56), were more likely to be female (25.5%-33.6%), and had lower median body weight (56.0-56.1 kg) compared to those with normal renal function.
• The subanalysis showed that irrespective of study treatment, Patients with moderate renal impairment had higher rates of the principal composite efficacy endpoint (stroke, non-CNS systemic embolism) and the primary safety endpoint than patients with preserved renal function.

De Vriese et al (2020)⁶conducted an investigator driven, randomized, prospective, open-label interventional trial to investigate vitamin K’s effect on the status of VC progression in patients on hemodialysis with AF treated with VKAs or who qualified for anticoagulation (The Valkyrie Study).

• The study included 132 adults from February 2015 to July 2017 on chronic hemodialysis with nonvalvular AF, who had a 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 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 international normalized ratio 2-3, XARELTO 10 mg daily, or XARELTO 10 mg daily plus vitamin K2 2000 µg three times weekly after dialysis for 18 months.
• The primary outcomes included a 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 XARELTO 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.
• Fifty-five patients did not complete the study due to death (n=47) or withdrawal of consent (n=8).  
• 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 XARELTO group and XARELTO + 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 XARELTO 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, XARELTO group remained stable, and XARELTO + vitamin K2 group decreased.
• There was no significant difference between treatment groups for longitudinal changes in calcification.
• 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.

De Vriese et al (2021)⁷ conducted a follow-up analysis comprising of patients who completed the Valkyrie Study and continued their treatments for at least an additional 18 months.

• The primary efficacy endpoint was a composite of fatal and nonfatal stroke, CV, and other vascular events.
• Secondary efficacy endpoints were individual components of the composite outcome and all-cause death. Safety endpoints were life-threatening, major, and minor bleeding.
• All patients who completed the Valkyrie Study were eligible for the extension. Twenty-five percent (33/132 patients) prematurely discontinued treatment, mainly due to a consequence of bleeding events (VKA group, 31.8% [14/44]; pooled XARELTO groups, 21.6% [19/88 patients]; P=0.21).
• The median (interquartile range) follow-up was 1.88 (1.01-3.38) years.
• The primary endpoints occurred for 35 patients (63.8 per 100 person-years) in the VKA group, 23 patients (26.2 per 100 person-years) in the XARELTO group, and 17 patients (21.4 per 100 person-years) in the XARELTO and vitamin K2 group.
• The estimated competing risk-adjusted HRs in comparison to the VKA group of the primary endpoint were 0.41 (95% confidence interval [CI], 0.25-0.68; P=0.0006) in the XARELTO group and 0.34 (95% CI, 0.19-0.61; P=0.0003) in the XARELTO +vitamin K2 group.
• There was no difference in death from any cause, (VKA, 33.7 per 100 person-years; XARELTO, 28.3 per 100 person-years, and XARELTO +vitamin K2, 30.2 per 100 person-years; P=0.66), but symptomatic limb ischemia showed a lower frequency with XARELTO than VKA (VKA, 20 patients; XARELTO, 10 patients; and XARELTO + vitamin K2, 9 patients; P=0.02).
• After adjustment for competing risk of death, hazard ratio (HR) for life-threatening and major bleeding compared with the VKA group was 0.39 (95% CI, 0.17-0.90; P=0.03) in the XARELTO group, 0.48 (95% CI, 0.22-1.08; P=0.08) in the XARELTO and vitamin K2 group, and 0.44 (95% CI, 0.23-0.85; P=0.02) in the pooled XARELTO groups.

Meta-analysis

Wang et al (2021)⁸ conducted a meta-analysis to evaluate the efficacy and safety of direct oral anticoagulants (DOACs) (apixaban, XARELTO, and edoxaban) and warfarin in AF or venous thromboembolism (VTE) patients with renal impairment.

• Studies that included adult patients with CKD and AF or VTE who received DOACs and/or warfarin therapy were evaluated.
• Fifteen studies (AF=11 studies; VTE=4 studies) were included in the analysis (82,931 patients: 76,957 patients with AF and 5974 patients with VTE).
• In the AF group, 29,509 patients had a CrCl of 50-79 mL/min, 12,062 patients had a CrCl of 30-49 mL/min, and 29,945 patients had a CrCl <30 mL/min. Patients taking XARELTO in the AF group included 3626 with a CrCl of 50-79 mL/min, 1575 with a CrCl of 30-49 mL/min, and 2921 with a CrCl of <30 mL/min.
• The efficacy outcome was S/SE events for AF patients and recurrent VTE or VTE-related deaths for VTE patients. The safety outcome was major bleeding events defined by ISTH for both AF and VTE patients.
• For the efficacy outcome in AF patients, XARELTO showed superior S/SE protection compared with warfarin (Relative risk [RR], 0.74; 95% CI, 0.62-0.88).
• For the safety outcome in AF patients, XARELTO showed similar event rates for major bleeding events compared with warfarin (RR, 0.86; 95% CI, 0.74-1.01). Major bleeding rates for XARELTO vs. warfarin were reported in patients with CrCl 50-79 mL/min (RR, 0.99; 95% CI, 0.81-1.20), 30-49 mL/min (RR, 0.96; 95% CI, 0.74-1.25), and <30 mL/min (RR, 0.79; 95% CI, 0.61-1.02).
• In a subgroup analysis of AF patients, XARELTO was associated with a lower incidence of S/SE compared to warfarin in patients with CrCl 50-79 mL/min (RR, 0.74; 95% CI, 0.57-0.95) and CrCl<30 mL/min (RR, 0.69; 95% CI, 0.50-0.95). Event rates for S/SE were similar between XARELTO and warfarin in patients with CrCl 30-49 mL/min (RR, 0.81; 95% CI, 0.56-1.16).

PK AND PD STUDIES

Girgis et al (2014)⁹ reported findings from prespecified PK and PD modeling analyses, based on matched data obtained from a subset of XARELTO-treated patients in the ROCKET AF trial (N=161; n=25 with moderate renal impairment [CrCl 30-49 mL/min]).

• The dataset contained 801 PK samples (moderate renal impairment, n=114), 786 prothrombin time samples, 742 prothrombinase-induced clotting time samples, and 799 factor Xa activity samples.

Results

PK Model

• XARELTO PK were described by an oral 1-compartment model with first-order absorption.
• Patient covariates that influenced PK included age and renal function (expressed as serum creatinine), which affected apparent oral clearance, and lean body mass and age, which affected apparent volume of distribution. See Table: Final Parameter Estimates From the Population PK Model in Patients With AF, Original DVT Population PK Model, and ACS Population PK Model Showing Typical (Population) Values (% SE).
  • Parameter estimates for the AF population were similar to those reported for the deep vein thrombosis population (dataset: 870 patients and 4634 PK samples).
  • Differences in parameters estimates between the AF and the acute coronary syndrome population (dataset: 1347 patients and 6644 PK samples) may have been due to differing patient demographics, dissimilar covariate distributions, and/or influences of the underlying disease state on the PK of XARELTO.

Dosing Regimens

• Dose modification for patients with moderate renal impairment was confirmed.
• Population-stimulated ratios (patients with moderate renal impairment:patients with mild renal impairment or normal renal function) of the means of maximum plasma concentration (C_max) and area under the concentration vs time curve from time 0 to 24 hours (AUC_0-24h) fell within a prespecified statistic test range of 0.70-1.43.
• See Table: XARELTO Exposure Individual Parameter Estimates at Steady State: C_max and AUC_0-24h.

Population PK/PD Model Results

• Factor Xa activity was negatively correlated with increasing plasma XARELTO concentration.
  • Age had a moderate effect on baseline parameter of the factor Xa activity model; factor Xa activity values varied approximately 30% for the age range included in the study population.
• There was a near-linear relationship between XARELTO concentration and prothrombin time and prothrombinase-induced clotting time values.
  • Inhibitory effects were observed through 24 hours postdose.

RETROSPECTIVE STUDIES

Fu et al (2024)¹⁰ 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 propensity score matching (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 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 patient-years (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).

Patel et al (2018)¹¹ conducted a retrospective, observational, postmarketing safety study to compare the incidence and pattern of major bleeding between XARELTO users with NVAF and renal disease and XARELTO users with NVAF and no renal disease.

• Electronic medical records from January 2013 to June 2015 within the US Department of Defense Military Health System were analyzed to identify XARELTO users with NVAF, major bleeding-related hospitalizations, and renal disease (defined through diagnostic codes present within the 6 months prior to bleeding date for major bleeding cases and end of study participation for nonmajor bleeding patients).
• Major bleeding, the primary outcome, included GI bleeding, hemorrhagic strokes, other intracranial bleeds, genitourinary bleeding, and bleeding at other sites.
  • Events were included if they occurred during XARELTO treatment and during the 7 days following treatment discontinuation.
  • Patients were evaluated for major bleeding throughout the study until censored at the earliest occurrence of any 1 of 4 events: a major bleeding event, death, loss of Military Health System eligibility, or end of study interval.
• A total of 44,793 XARELTO users with NVAF were identified; renal disease was present in 15.5% (n=6921) of these patients, of which 4.5% (n=312) experienced major bleeding.
• CKD (83.3%) and acute kidney failure (32.0%) comprised the primary renal disease diagnoses.
• Among patients who experienced major bleeding, mean age was similar between those with and without renal disease (78.3 vs 78.8 years, respectively), and 60.3% vs 48.7% of patients were male in the renal disease and nonrenal disease cohorts, respectively.
• A higher prevalence of comorbidities (including hypertension and coronary heart disease) was observed in patients with renal disease vs those without renal disease, along with a higher CHA₂DS₂-VASc score among patients with major bleeding (mean [standard deviation]: 5.1 [1.4] vs 4.4 [1.5], respectively).
• The most common XARELTO dose among patients who had renal disease and experienced major bleeding was 15 mg (51.6% of patients), followed by 20 mg (44.6% of patients).
• Patients with renal disease had a higher rate of major bleeding vs those without renal disease (4.52/100 person-years [95% CI, 4.05-5.05] vs 2.54/100 person-years [95% CI, 2.38-2.70], respectively).
  • GI bleeding was the most common site of major bleeding, regardless of renal disease status (with renal disease, 87.5%; without renal disease, 85.9%).
• Those with renal disease and those without renal disease had the same rate of fatal bleeding (0.09/100 person-years) and a case fatality rate of 1.9% vs 3.6%, respectively.
  • Patients with renal disease were older at the time of death vs those without renal disease (mean [standard deviation]: 80.5 [6.3] years vs 79.6 [8.1] years, respectively).

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 28 October 2024.