Summary

• XARELTOis approved for the treatment of deep vein thrombosis (DVT), pulmonary embolism (PE), and reduction in the risk of recurrence of DVT and/or PE, in adult patients with creatinine clearance (CrCl) ≥15 mL/min.¹
• In patients with CrCl <30 mL/min, rivaroxaban exposure and pharmacodynamic effects are increased compared to patients with normal renal function. There are limited clinical data in patients with CrCl 15 to <30 mL/min; therefore, observe closely and promptly evaluate any signs or symptoms of blood loss in these patients. There are no clinical data in patients with CrCl <15 mL/min (including patients on dialysis); therefore, avoid the use of XARELTO in these patients. Discontinue XARELTO in patients who develop acute renal failure while on treatment.¹
• A pharmacokinetic (PK) and pharmacodynamic (PD) study demonstrated the administration of rivaroxaban is expected to result in similar serum concentrations of rivaroxaban in patients with moderate renal impairment and those with severe renal impairment or end-stage renal disease. Multiple daily dosing did not appear to result in clinically relevant accumulation.²
• PK/PD results from three Phase 1 studies demonstrated that decreasing renal function was associated with increased rivaroxaban exposure (AUC), and an increase in Factor Xa inhibition and prothrombin time prolongation. The increase in systemic exposure was comparable among subjects with moderate/severe renal impairment and ESRD, indicating a plateau in the AUC.^3-5
• In the EINSTEIN program, efficacy and safety measures were stratified by patient's renal function in each of the studies. Patients with a CrCl <30 mL/min were excluded from the EINSTEIN program.^6,7
• In the EINSTEIN-DVT and EINSTEIN-PE pooled analysis:
  • In key subgroups, including fragile patients (age, moderate or severe renal impairment, low body weight),  the efficacy and safety of XARELTO were similar compared with standard-therapy.⁸
  • In patients with CrCl <50 mL/min, the rate of recurrent venous thromboembolism (VTE) was 3.3% (11/332) in the XARELTO group and 3.4% (11/322) in the standard therapy group. For this subgroup, major bleeding occurred in 0.9% (3/329) patients treated with XARELTO, and 4.1% (13/320) of patients in the standard therapy group.⁸
• In a systemic review, pairwise and network meta-analysis comparing the efficacy and safety of DOACs in patients with VTE and different levels of renal function:
  • No significant difference was observed in recurrent VTE or VTE-related death, and bleeding events between any pairing of 2 oral anticoagulants in patients with CrCl of 30-50 mL/min and 50-80 mL/min.⁹
  • Apixaban 2.5 mg and 5 mg twice daily demonstrated a lower risk of bleeding than dabigatran 150 mg twice daily, XARELTO 10 and 20 mg once daily, warfarin, and aspirin in patients with VTE and CrCl >80 mL/min.⁹

Pharmacokinetic/Pharmacodynamic studies

De Vriese et al (2015)² investigated the PK/PD effects of rivaroxaban in patients without residual kidney function on maintenance hemodialysis therapy.

Study Design/Methods

Patients (N=18) received rivaroxaban 10 mg either 6 to 8 hours before a dialysis session (1 single dose), immediately after each of 3 consecutive dialysis sessions (3 total doses), or once daily in the morning for 7 days (7 total doses).

Results

• Mean area under the concentration-time curve (AUC_0-44) of rivaroxaban plasma concentrations after a single dose of 10 mg was 2072 µg/L/h, mean maximum concentration (C_max) was 172.6 µg/L, and mean terminal elimination half-life was 8.6 hours.
• Dialysis had no appreciable effect on rivaroxaban plasma concentrations. Mean trough concentration after multiple daily doses of 10 mg was 20.2 µg/L.
• Rivaroxaban was not eliminated by dialysis. No significant accumulation of rivaroxaban was observed after comparison of day 1 and day 7 PK parameters in patients on hemodialysis.
• The study concluded that rivaroxaban 10 mg in hemodialysis patients without residual kidney function resulted in drug exposure (AUC_0-44/48: 2072 µg/L/h; C_max: 172.6 µg/L) similar to that seen with 20 mg in healthy volunteers (AUC_0-44/48: 2294 µg/L/h; C_max: 294.4 µg/L).

CLINICAL STUDIES

Phase 1 Studies

Kubitza et al (2010)³ conducted a two-center, non-blinded cohort study that evaluated the PK/PD and safety of rivaroxaban in patients with impaired renal function.

Study Design/Methods

Patients (N=32) were assigned to one of four groups according to their measured CrCl rates: CrCrl ≥80 mL/min (healthy control), CrCl 50-79 mL/min (mild impairment), CrCl 30-49 mL/min (moderate impairment), and CrCl <30 mL/min (severe impairment). Rivaroxaban was given as a single oral dose of 10 mg (two 5 mg tablets) in the morning.

Results

• Decreased renal clearance led to an increase in rivaroxaban plasma concentrations.
• The AUC increased by 44%, 52%, and 64% in patients with mild, moderate, and severe renal impairment compared with healthy controls, respectively.
• The AUC for Factor Xa inhibition was 1.50-fold (90% CI 1.07, 2.10), 1.86-fold (90% CI 1.34, 2.59), and 2.0-fold (90% CI 1.44, 2.7) higher in mild, moderate, and severe renal impairment patients than in healthy patients, respectively.
• No serious adverse events were reported after rivaroxaban administration.

Dias et al (2016)⁴ conducted an open-label, single-dose, parallel-group study to evaluate the PK/PD of rivaroxaban both once before and once after dialysis in patients with ESRD and compare that to healthy control patients with CrCl ≥80 mL/min (n=8).

Study Design/Methods

In patients with ESRD (n=8), a 15 mg dose of rivaroxaban was administered 2 ± 0.5 h before a hemodialysis session and repeated 7–14 days later at 3 h after a 4-h hemodialysis session. The healthy control patients (n=8) received one 15 mg rivaroxaban dose and were matched for age, sex, and body mass index.

Results

• Compared to healthy patients, rivaroxaban AUC increased by approximately 56% following post-dialysis administration, reflecting a 35% decrease in overall drug clearance in ESRD patients.
• Pre-dialysis dosing resulted in only a 5% lowering of AUC. PD changes were generally concordant with the observed changes in plasma PK and were higher in ESRD patients compared to healthy patients.
• Two patients with ESRD experienced 4 adverse events including 2 episodes of nausea, 1 of gingivitis, and 1 of arterio-venous shunt thrombosis. None of the adverse events were deemed serious. No bleeding events occurred during the study.

Another study evaluated the PK/PD of rivaroxaban in patients with ESRD undergoing hemodialysis compared to matched healthy volunteers.⁵

Study Design/Methods

A total of 6 patients with ESRD received rivaroxaban 5 mg and 10 patients with ESRD received rivaroxaban 15 mg and were evaluated 3 hours before hemodialysis (ie, on-dialysis) and dialysis-free (off-dialysis) periods. In the healthy volunteer group, 6 and 10 patients received 5 mg and 15 mg oral doses of rivaroxaban, respectively.⁵

Results

• Patients with ESRD who received the 5 mg dose had an approximate 23% increase in AUC when compared with healthy controls.⁵
• Patients with ESRD who received the 15 mg dose after dialysis had an approximate 50% increase in AUC and an approximate 40% increase in AUC when rivaroxaban was dosed before dialysis.⁵

Phase 3 Studies

Treatment of DVT, PE, and Reduction in the Risk of Recurrence of DVT and of PE

The EINSTEIN program consisted of the EINSTEIN-DVT, EINSTEIN-PE, EINSTEIN-Extension, and EINSTEIN-CHOICE trials. All 4 trials were phase 3, randomized studies which excluded patients with a CrCl below 30 mL/min at screening. The principal safety outcome was clinically relevant bleeding, defined as the composite of major or clinically relevant non-major (CRNM) bleeding for EINSTEIN-DVT and EINSTEIN-PE, major bleeding for EINSTEIN-Extension, and ISTH major bleeding for EINSTEIN-CHOICE.

EINSTEIN-DVT

The EINSTEIN-DVT study compared oral XARELTO alone (15 mg twice daily for 3 weeks, followed by 20 mg once daily) with subcutaneous enoxaparin (1.0 mg/kg twice daily) followed by dose-adjusted oral vitamin K antagonist (VKA [warfarin or acenocoumaral]) in patients with confirmed symptomatic DVT without symptomatic PE. The primary efficacy outcome was symptomatic, recurrent VTE (a composite of DVT or nonfatal or fatal PE).⁶

EINSTEIN-PE

The EINSTEIN-PE study evaluated the efficacy and safety of oral XARELTO (15 mg twice daily for 3 weeks followed by 20 mg once daily) versus subcutaneous enoxaparin (1.0 mg/kg twice daily) followed by dose-adjusted oral VKA in patients with acute symptomatic PE with or without DVT. The primary efficacy outcome was symptomatic recurrent VTE, which was defined as a composite of fatal or nonfatal PE or DVT.⁸

EINSTEIN-Extension

The EINSTEIN-Extension study compared XARELTO 20 mg once daily to placebo in patients with confirmed symptomatic PE or DVT who have been treated for 6 to 12 months with XARELTO or VKA. The primary efficacy outcome was symptomatic, recurrent VTE (a composite of DVT or nonfatal or fatal PE).⁶

EINSTEIN-CHOICE

EINSTEIN CHOICE compared the efficacy and safety of two doses of XARELTO (20 mg and 10 mg, once-daily) with aspirin (100 mg, once-daily) in patients with VTE who had completed 6-12 months of anticoagulation therapy and for whom there was equipoise with respect to the need for ongoing anticoagulation. The primary efficacy outcome was symptomatic recurrent fatal or non-fatal VTE and the principal safety outcome was ISTH major bleeding.¹⁰

Baseline CrCl for the XARELTO group and enoxaparin/VKA group is presented in Table: Baseline Creatinine Clearance in the EINSTEIN Program.

Efficacy results stratified by renal function are displayed in Table: Relative Efficacy per Renal Function in the EINSTEIN Program.

Safety results for EINSTEIN-DVT and EINSTEIN-PE by renal function are displayed in Table: Primary Safety Outcome per Renal Function (Clinically Relevant Bleeding, Defined as the Composite of Major or CRNM Bleeding).

Safety results for EINSTEIN-Extension and EINSTEIN-CHOICE by renal function are displayed in Table: Primary Safety Outcome per Renal Function (Major Bleeding).

EINSTEIN-DVT and EINSTEIN-PE Pooled Analysis

A pre-specified pooled analysis of the EINSTEIN-DVT and EINSTEIN-PE studies was conducted to provide a more detailed analysis of the efficacy and safety of XARELTO in key clinical subgroups, including those defined as fragile patients. Both studies used the same protocol to ascertain outcomes.⁸

• In fragile patients (defined as having one or more of the following criteria: age >75 years, calculated CrCl <50 mL/min or low body weight (≤50kg)), the efficacy and safety of XARELTO were similar compared with standard-therapy.
  • 1573 patients were defined as fragile (19%) based on age (n=1279), moderate or severe renal impairment (n=649), or low body weight (n=107).
• Compared with nonfragile patients, rates of recurrent VTE were higher in fragile patients (XARELTO 2.7% vs 1.9%; enoxaparin/VKA 3.8% vs 1.9%, respectively), but the difference between treatment groups in the fragile and nonfragile populations was not significantly different.
• For major bleeding, there was a statistically significant difference in favor of XARELTO (1.3%) compared with standard therapy (4.5%) in fragile patients (HR 0.27; 95% CI, 0.13-0.54; absolute risk reduction, 3.2%; 95% CI, 1.6%-4.9%). The P value for the treatment group × fragility interaction was 0.011, suggesting heterogeneity. These differences were not observed in non-fragile patients.
• The effects on both recurrent VTE and bleeding were consistent across the individual subgroups that defined the fragile population.
• In patients with CrCl <50 mL/min, the rate of recurrent VTE was 3.3% (11/332) in the XARELTO group and 3.4% (11/322) in the standard therapy group. For this subgroup, major bleeding occurred in 0.9% (3/329) patients treated with XARELTO, and 4.1% (13/320) of patients in the standard therapy group.

Bauersachs et al (2014)

Bauersachs et al (2014)¹³ conducted a subgroup analysis of the EINSTEIN-DVT and EINSTEIN-PE pooled analysis to assess the rates of bleeding and recurrent VTE in patients with renal impairment treated with XARELTO or enoxaparin-VKA.

• Rates of recurrent VTE and bleeding in relation to renal function and treatment are listed in Table: Recurrent VTE and Bleeding in Relation to Renal Function and Treatment.

SYSTEMATIC REVIEW AND PAIRWISE NETWORK META-ANALYSIS

Su et al (2022)⁹ conducted a systemic review containing pairwise and Bayesian network meta-analysis of 10 randomized controlled trials (RCTs) to compare the efficacy and safety of DOACs in patients with VTE and different renal functions.

• Ten multicenter RCTs with 8 publications recruited a total of 37,298 patients (treatment of acute VTE=5 RCTs, n=26,269; extended treatment of VTE=5 RCTs, n=11,029).
• In a subgroup analysis, patients were categorized into 3 groups based on CrCl [(treatment of acute VTE trials: CrCl 30-50 mL/min, n=1759; CrCl 50-80 mL/min, n=11,882; CrCl> 80mL/min, n=12,628) and (extended treatment of VTE trials: CrCl 30-50 mL/min, n=555; CrCl 50-80 mL/min, n=2601; CrCl> 80mL/min, n=7873)].
• The DOACs in the trials included XARELTO, apixaban, dabigatran, and edoxaban.
• In the treatment of acute VTE trials, DOACs were compared with warfarin alone or enoxaparin, followed by warfarin. In the extended treatment of VTE trials, DOACs were compared with a placebo in 3 RCTs, aspirin in 1 RCT, and warfarin in 1 RCT.
• The efficacy outcomes were recurrent VTE and VTE-related death.
• The safety outcomes were major bleeding and clinically relevant non-major bleeding defined by individual studies.
• In patients with acute VTE, there was no significant difference in the use of DOACs vs warfarin for recurrent VTE or VTE-related death (OR, 0.96; 95% CI, 0.82-1.11). The risk of bleeding was significantly lower in the DOAC group compared with the warfarin group (OR, 0.76; 95% CI, 0.68-0.90).
• In the extended treatment of VTE, recurrent VTE or VTE-related death was significantly lower in DOAC patients compared with placebo or aspirin (OR, 0.23; 95% CI, 0.16-0.29).  The risk of bleeding events was significantly higher in the DOAC group than in the aspirin/placebo group (OR, 1.86; 95% CI, 1.04-3.33).
• There were no significant differences in the effects of DOACs on recurrent VTE or VTE-related death, and bleeding events among the different CrCl subgroups.
• Per Bayesian network meta-analysis, apixaban 2.5 mg and 5 mg twice daily were associated with a reduced bleeding risk compared to dabigatran 150 mg twice daily, XARELTO 10 and 20 mg once daily, warfarin, and aspirin in patients with CrCl>80 mL/min. Dabigatran 150 mg twice daily was superior to XARELTO 20 mg once daily in reducing bleeding events (OR, 0.61; 95% CI, 0.47 to 0.81) for patients with CrCl>80 mL/min. No significant differences were reported in recurrent VTE or VTE-related death, and bleeding events between any 2 oral anticoagulants in patients with CrCl of 30-50 mL/min and 50-80 mL/min.

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 21 November 2024.