SUMMARY

• No clinical data are available for adult patients with severe hepatic impairment. Avoid the use of XARELTOin adult patients with moderate (Child-Pugh B) or severe (ChildPugh C) hepatic impairment or with any hepatic disease associated with coagulopathy.¹
• No clinical data are available in pediatric patients with hepatic impairment.¹
• In adult patients with moderate hepatic impairment, total body clearance of XARELTO was decreased, which led to increased exposure to XARELTO, more pronounced inhibition of factor Xa activity, and prolongation of prothrombin time (PT).^2-4
• There were no clinically relevant differences in the pharmacokinetics (PK) and pharmacodynamics (PD) of XARELTO between adult patients with mild hepatic impairment and those with normal liver function.^{3, 4}
• The physiologically based pharmacokinetic (PBPK) study showed an increase in the area under the curve (AUC) of XARELTO in adult patients with severe hepatic impairment and a minor effect in AUC and maximum plasma concentration (C_max) of XARELTO in adult patients with mild and moderate hepatic impairment.⁵
• A real-world, retrospective cohort study assessed the safety and effectiveness of direct oral anticoagulants (DOACs) vs warfarin and between DOACs in patients with atrial fibrillation (AF) and chronic liver disease.⁶
  • The risk of hospitalization for ischemic stroke/systemic embolism (SE) was not significantly different with XARELTO vs warfarin (hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.47-1.21), but was significantly lower with apixaban vs warfarin (HR, 0.40; 95% CI, 0.19-0.82) and not significantly different with XARELTO vs apixaban (HR, 1.73; 95% CI, 0.91-3.29).
  • The risk of hospitalization for major bleeding was lower with XARELTO vs warfarin (HR, 0.79; 95% CI, 0.621.0) and apixaban vs warfarin (HR, 0.60; 95% CI, 0.460.78) and higher with XARELTO vs apixaban (HR, 1.59; 95% CI, 1.182.14).
• A retrospective cohort study compared the safety and efficacy of DOACs (apixaban, XARELTO, dabigatran, or edoxaban) and traditional anticoagulants (warfarin, or enoxaparin) in patients with moderate Child-Turcotte-Pugh (CTP) B or C cirrhosis.⁷
  • Bleeding events occurred in 36% vs 22% in the DOAC group vs the traditional anticoagulant group (P=0.149).
  • Thromboembolic events were reported in 4% vs 0% in the DOAC group vs the traditional anticoagulant group (P=0.55).
• A prospective study in patients with nonvalvular atrial fibrillation (NVAF) who received their first prescription for an anticoagulant found that the risk of liver injury was lower in patients on XARELTO compared with those on warfarin.⁸

CLINICAL Pharmacology

Hepatic Impairment

Adult Population

The safety and PK of single-dose XARELTO (10 mg) were evaluated in a study in healthy subjects (n=16) and subjects with varying degrees of hepatic impairment. No patients with severe hepatic impairment (Child-Pugh C) were studied. Compared to healthy subjects with normal liver function, significant increases in XARELTO exposure were observed in subjects with moderate hepatic impairment (Child-Pugh B). Increases in PD effects were also observed.¹

In a PK study, compared to healthy subjects with normal liver function, AUC increases of 127% were observed in subjects with moderate hepatic impairment (ChildPugh B). The safety or PK of XARELTO in patients with severe hepatic impairment (ChildPugh C) has not been evaluated. Avoid the use of XARELTO in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy.¹

Pediatric Population

No clinical data are available in pediatric patients with hepatic impairment.

Clinical Data

Adult Population

Kubitza et al (2013)² conducted a single-center, nonrandomized, parallel-group, noncontrolled, nonblinded study that evaluated the effects of mild (Child-Pugh A; n=8) and moderate (Child-Pugh B; n=8) hepatic impairment, compared to no hepatic impairment in healthy adult patients (n=16), on the PK and PD of a single, 10 mg XARELTO dose.

• Venous blood samples were collected for PK assessments prior to and 0.5, 1, 2, 3, 4, 6, 8, 12, 15, 24, 36, 48, and 72 hours following XARELTO administration. Urine was collected at specified intervals for 48 hours after XARELTO administration. For PD assessments, blood samples were collected prior to and 1, 2, 3, 4, 6, 8, 12, 15, 24, 48, and 72 hours after XARELTO administration. Safety and tolerability were also evaluated.
• Demographic characteristics were similar across groups.
• In patients with mild hepatic impairment, AUC was increased slightly and the C_max was relatively unaffected compared with healthy patients. In patients with moderate hepatic impairment, AUC was increased by 2.27-fold, and C_max was increased by 1.27-fold, compared with healthy patients. The terminal half-life (t_1/2) was prolonged by approximately 2 hours in patients with mild and moderate hepatic impairment compared with healthy controls.
• Table: PK Parameters of 10 mg XARELTO in Healthy Patients and Patients With Mild and Moderate Hepatic Impairment provides PK parameters of patients included in the study. Analysis of variance (ANOVA) showed that AUC was significantly increased in patients with moderate hepatic impairment compared with healthy controls (P<0.0004). There was a significant effect of hepatic impairment on unbound XARELTO plasma concentrations (P<0.0001).

• Patients with moderate hepatic impairment had lower baseline factor Xa activity (median: 0.63 U/mL) compared with patients with mild hepatic impairment (median 0.84 U/mL) and healthy patients (median 0.87 U/mL).
• Compared with healthy patients, those with moderate hepatic impairment had an increased AUC between XARELTO administration (0) and tn (AUC_0-tn) and maximum effect (E_max; least squares [LS] means ratios 2.59 and 1.24, respectively). The difference between healthy patients and those with mild hepatic impairment was not significantly different. Based on the results of ANOVA, the differences between patients with moderate hepatic impairment and healthy patients and those with mild hepatic impairment were statistically significant for AUC_0–tn (P<0.01) and E_max (P<0.05).
• Healthy patients and those with mild hepatic impairment had similar baseline PT values, but values were higher in patients with moderate hepatic impairment. Following the administration of XARELTO 10 mg, PT prolongation was similar in patients with mild hepatic impairment and in healthy patients but was more pronounced in those with moderate hepatic impairment.
• Based on the results of ANOVA, the difference between patients with moderate hepatic impairment and healthy patients was statistically significant for AUC_0–tn (P<0.0004) and E_max (P<0.0001).
• For HepTest^® and activated partial thromboplastin time, the effect of impaired hepatic function was similar to the effect described for PT.
• The majority of the 11 reported treatment-emergent adverse events (AEs) were mild and resolved by the time the trial was completed. Four AEs (all headaches) were considered possibly related to study medication. There were no relevant changes in electrocardiogram (ECG) parameters or vital signs, and no there were no clinically relevant changes in laboratory values attributable to XARELTO.

Halabi et al (2007)^{3, 4} conducted a nonrandomized, nonblinded study evaluating the effect of mild or moderate hepatic impairment on the pharmacology of a single, 10 mg dose of XARELTO (N=32).

• Adult patients with mild hepatic impairment showed no clinically relevant differences from those with normal liver function in exposure.
• The t_1/2 was prolonged (~10 hours) in patients with mild or moderate hepatic impairment compared to those with normal liver function (8 hours).
• In patients with moderate hepatic impairment, total body clearance of XARELTO was lower (2.8 L/hour) than that of normal patients (6.6 L/hour).
• The resulting increased plasma levels of XARELTO (AUC: normal hepatic function, 1516 μg·hour/L; moderate hepatic impairment, 3510 μg·hour/L) led to moderate increases in inhibition of factor Xa and prolongation of PT. C_max of XARELTO was slightly more increased in patients with moderate hepatic impairment (279 μg/L) than in those with normal liver function (214 μg/L).
• The effect of severe hepatic impairment on the pharmacology of XARELTO was not studied. XARELTO was well-tolerated by all patients and AEs resolved by the end of the study.

Willmann et al (2020)⁵ conducted a PBPK study that evaluated the PK behavior of XARELTO in clinical situations, including hepatic impairment (N=1000 virtual adult patients).

• Virtual patients received a single, 10-mg dose of XARELTO in fasted state.
• Patients with severe hepatic impairment showed an increase in the AUC of XARELTO.
• In patients with moderate hepatic impairment, the predicted AUC and C_max were lower than the observed values (AUC ratio, 1.46 [CI, 0.75-2.97] vs 2.27 [CI, 1.68-3.07]; C_max ratio, 1.14 [CI, 0.63-2.00] vs 1.27 [CI, 0.99-1.63]).
• In patients with mild hepatic impairment, the predicted AUC and C_max were consistent with the observed values (AUC ratio, 1.17 [CI, 0.58-2.25] vs 1.15 [CI, 0.85-1.57]; C_max ratio, 1.04 [CI, 0.57-1.83] vs 0.97 [CI, 0.75-1.25]).

Sasso et al (2019)⁹ conducted a study on anticoagulation in patients with cirrhosis in which some adult patients were taking XARELTO.

Lawal et al (2023)⁶ conducted a real-world, retrospective cohort study using United States (US) administrative claims data from the Optum Clinformatics Data Mart Database to assess the safety and effectiveness of DOACs (XARELTO, apixaban, dabigatran, or edoxaban) vs warfarin and between DOACs in patients with AF and chronic liver disease between January 2011 and December 2017.

• The primary outcomes were hospitalization for ischemic stroke/SE and major bleeding.
• The secondary outcomes were all-cause death, major gastrointestinal (GI) bleeding, ischemic stroke/SE and all-cause death, ischemic stroke/SE and major bleeding, and net adverse clinical event (NACE; a composite of the effectiveness and safety events).
• Inclusion criteria consisted of age ≥18 years with both AF and chronic liver disease and treated with DOACs or warfarin.
• Exclusion criteria consisted of hospitalization for ischemic stroke, SE, or major bleeding within 4 weeks before the index date. Additionally, patients with conditions requiring a specific class of oral anticoagulant treatment over another (e.g., mechanical prosthetic heart valve for warfarin), contraindications to long-term oral anticoagulation, or alternative indications for oral anticoagulants besides AF were excluded from the study.
• A total of 10,209 patients were included in the study (DOAC, n=5788 [XARELTO, n=2211; apixaban, n=2721; dabigatran, n=851; edoxaban, n=5]; warfarin, n=4421).
• Due to the small sample size of dabigatran and edoxaban users, the analyses were limited to XARELTO vs warfarin, apixaban vs warfarin, and XARELTO vs apixaban.
• The risk of hospitalization for ischemic stroke/SE was not significantly different with XARELTO vs warfarin (HR, 0.76; 95% CI, 0.47-1.21), but was significantly lower with apixaban vs warfarin (HR, 0.40; 95% CI, 0.19-0.82) and not significantly different with XARELTO vs apixaban (HR, 1.73; 95% CI, 0.91-3.29).
• The risk of hospitalization for major bleeding was lower with XARELTO vs warfarin (HR, 0.79; 95% CI, 0.62-1.0) and apixaban vs warfarin (HR, 0.60; 95% CI, 0.46-0.78) and higher with XARELTO vs apixaban (HR, 1.59; 95% CI, 1.18-2.14).
• The incidence rates and HRs of the primary and secondary outcomes with DOACs (XARELTO and apixaban) vs warfarin and between DOACs (XARELTO and apixaban) after inverse probability treatment weighing are presented in the Table: Clinical Outcomes With DOACs vs Warfarin and Between DOACs.

Oldham et al (2022)⁷ conducted a retrospective, single-center cohort study to compare the safety and efficacy between DOAC (apixaban, XARELTO, dabigatran, or edoxaban) and traditional anticoagulants (warfarin, or enoxaparin) in patients with moderate CTP B or C cirrhosis between January 2017 and September 2019.

• The primary efficacy and safety outcomes were defined as the incidence of thromboembolic events and the incidence of bleeding events, respectively, in the DOAC population as compared with the traditional population. Patients were followed until the first event or until discontinuation of anticoagulation therapy.
• Inclusion criteria consisted of age ≥18 years, CTP B or C at the time of anticoagulant prescription, and documentation of follow-up at ≥3 months, or documentation of a bleeding or thrombotic event within 3 months of anticoagulation therapy initiation.
• Exclusion criteria consisted of failure to initiate the anticoagulant after it was prescribed, discontinuation of the anticoagulant within 3 months of initiation for reasons other than bleeding or thrombotic events, use of prophylactic enoxaparin dosing, or liver transplantation.
• A total of 101 patients were included in the study (DOAC, n=69 [apixaban, n=57; XARELTO, n=10; dabigatran, n=2] and traditional anticoagulants, n=32 [warfarin, n=31; enoxaparin, n=1]).
• CTP scores were higher in the DOAC group (DOAC group, 9±2; traditional group, 8±1; P=0.019). Of those patients, XARELTO patients were CTP B (n=9) and CTP C (n=1).
• Model for end-stage liver disease (MELD) scores were significantly higher in the traditional anticoagulant group (DOAC group, 15±5; traditional group, 19±5, P=0.001).
• Bleeding events occurred in 25 patients (36%) of the DOAC group and 7 patients (22%) of the traditional group (P=0.149). Within the DOAC group, bleeding events were reported in 22 patients (39%) on apixaban and 3 patients (30%) on XARELTO.
• Thromboembolic events were reported in 3 patients (4%) in the DOAC group. All these events occurred in patients on therapeutic anticoagulation for a thromboembolism, apixaban 5 mg twice daily. No thromboembolic events were observed in the traditional group (P=0.55).

Alonso et al (2017)⁸ studied adult patients with NVAF from the MarketScan^® Commercial and Medicare Supplemental databases who received their first prescription for an anticoagulant between November 2011 and December 2014.

• Analysis was restricted to NVAF (without mitral valve disorder or stenosis) by International Classification of Diseases, Ninth Revision (ICD-9) codes for inpatient or outpatient claims.
• Patients were required to be enrolled for at least 90 days; mean follow-up 14 months.
• After adjustment for age and sex, compared to warfarin, the risk of liver injury was 26% lower in initiators of XARELTO. Associations were similar when considering DOAC usage and adjustment for comorbidities and CHA2DS2-VASc and HAS-BLED scores.

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 09 December 2023.