Summary

• Patients with preexisting, significant liver disease were excluded from the ROCKET-AF¹, EINSTEIN program^2,3, RECORD program⁴, ATLAS ACS 2-TIMI 51⁵, MAGELLAN⁶, and MARINER⁷ studies. Patients with hepatic disease associated with coagulopathy were excluded from the COMPASS⁸ study.
• No specific information regarding the temporal relationship between initiation of XARELTO therapy and elevation of liver enzymes was noted in any of the publications that described the results of phase 3 clinical studies.
• ROCKET-AF: Increased serum levels of hepatic enzymes were observed, with comparable frequencies, in both the XARELTO (0.47% of patients) and warfarin (0.50% of patients) groups (alanine aminotransferase [ALT] >3x upper limit of normal [ULN] and total bilirubin >2x ULN, either on the same day or within 30 days); hazard ratio (HR), 0.96; 95% confidence interval (CI), 0.59-1.54.¹
• EINSTEIN: Concurrent rates of ALT >3x ULN and bilirubin >2x ULN were similar in both the XARELTO and enoxaparin/vitamin K antagonist (VKA) groups in EINSTEIN-DVT (XARELTO, 0.1%; enoxaparin/VKA, 0.2%), EINSTEIN-PE (XARELTO, 0.2%; enoxaparin/VKA, 0.2%), and EINSTEIN-Extension (XARELTO, 0%; enoxaparin/VKA, 0%).^9,2
• RECORD: Overall, rates of ALT elevation >3x ULN were lower in patients receiving XARELTO than in patients receiving enoxaparin (2.5% vs 3.7%, respectively), and the incidence of concurrent ALT >3x ULN and bilirubin >2x ULN levels was similar between the XARELTO and enoxaparin groups (0.1% vs 0.1%, respectively) across the 4 RECORD studies.⁴
• ATLAS ACS 2-TIMI 51: A similar rate of increased ALT levels (0.2%) was observed across all treatment groups (XARELTO 2.5 mg twice daily [BID], XARELTO 5 mg BID, and placebo).¹⁰
• MAGELLAN: Concurrent rates of ALT >3x ULN and bilirubin >2x ULN were observed in 7/3364 patients (0.2%) in the XARELTO group and in 7/3382 patients (0.2%) in the enoxaparin group.⁶
• A cohort study of new oral anticoagulant (OAC) users with nonvalvular atrial fibrillation (NVAF), found an increased risk of hospitalized acute liver injury (ALI) in XARELTO users when compared to VKA users (adjusted HR, 1.41; 95% CI, 1.05–1.91). Patients with a history of liver disease or chronic alcoholism showed a higher incidence of ALI compared to patients with no history of liver disease.¹¹
• A prospective study of a claims database found that among patients with NVAF, direct oral anticoagulants (DOACs) were associated with lower risk of hospitalization secondary to liver injury compared with warfarin.¹²
• Several case reports have been published describing drug-induced liver injuries in patients that underwent XARELTO therapy. The onset of signs and symptoms of liver injury occurred within a range of 2 to 586 days, and all but 4 patients recovered upon discontinuation of XARELTO.^13-21
• Additional citations identified during a literature search are included in the REFERENCES section for your review.^22-26

PRODUCT LABELING

Please refer to the following sections of the enclosed XARELTO full Prescribing Information that are relevant to your inquiry: WARNINGS AND PRECAUTIONS - Use in Patients with Hepatic Impairment, USE IN SPECIFIC POPULATIONS - Hepatic Impairment, and ADVERSE REACTIONS - Postmarketing Experience.²⁷

CLINICAL STUDIES

ROCKET-AF and EINSTEIN Program Studies

A summary of the incidence rates of elevations in hepatic enzymes and liver failure from the ROCKET-AF and EINSTEIN program studies are presented in Table: Incidence of Hepatotoxicity (Safety Population) - Summary of ROCKET-AF, EINSTEIN-DVT, EINSTEIN-PE, and EINSTEIN-Extension Studies.

Patients were excluded from the ROCKET-AF and EINSTEIN studies if they had known significant liver disease (eg, acute clinical hepatitis, chronic active hepatitis, cirrhosis) or ALT >3x ULN.

RECORD Studies

The incidence of relevant hepatic elevations in the pooled RECORD 1-4 studies is presented in Table: Liver Function Tests (LFTs) in RECORD 1-4 Pooled Analysis (Total Treatment Duration Pooled Population).⁴

• In patients receiving XARELTO, all elevations of ALT levels, with or without concomitant elevations of bilirubin levels, had resolved by the end of the follow-up period.^28-31
• Patients with preexisting significant liver disease were excluded from all 4 RECORD clinical studies.
• The total treatment duration pool focused on events that occurred during the planned treatment period for double-blind study medication for each RECORD study. Events were counted until day 42 for RECORD1 and 2 (including events that occurred during the placebo period of RECORD2) and until day 17 for RECORD3 and 4 (with day 1 defined as the day of surgery).

ATLAS ACS 2-TIMI 51

In ATLAS ACS 2-TIMI 51, increased ALT levels occurred in 0.9%, 0.8%, and 1.0% of patients treated with XARELTO 2.5 mg BID, XARELTO 5 mg BID, and placebo, respectively.³² Additionally, among patients treated with XARELTO or placebo, clinical and laboratory liver abnormalities were comparable, including concurrent ALT levels >3x ULN and total bilirubin levels >2x ULN, which occurred in 0.2% of patients in each treatment group.¹⁰

MAGELLAN

In MAGELLAN, ALT levels >3x ULN and concurrent bilirubin levels >2x ULN occurred in 7 of 3364 patients (0.2%) in the XARELTO group and in 7 of 3382 patients (0.2%) in the enoxaparin group. Levels were not available for approximately 16% of patients.⁶

STUDY CHARACTERISTICS

Stroke Prevention in NVAF

The ROCKET-AF study¹ was a multicenter, event-driven, noninferiority study designed to evaluate the efficacy and safety of XARELTO (20 mg once daily with the evening meal in patients with creatinine clearance [CrCl] >50 mL/min and 15 mg once daily with the evening meal in patients with CrCl 30 to <50 mL/min) vs warfarin (titrated to international normalized ratio of 2.0 to 3.0) for the prevention of stroke and systemic embolism in patients with NVAF at moderate-to-high risk for stroke. The median duration of treatment exposure was 590 days; the median follow-up period was 707 days.

Treatment of Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), and Reduction in the Risk of Recurrence of DVT and of PE

The EINSTEIN program consisted of 3 phase 3, randomized studies of XARELTO:

1. Acute DVT Study (EINSTEIN-DVT) - open-label, event-driven, noninferiority study that compared oral XARELTO alone (15 mg BID for 3 weeks, followed by 20 mg once daily) with subcutaneous (SC) enoxaparin (1.0 mg/kg BID) followed by dose-adjusted oral VKA (warfarin or acenocoumarol) in patients with confirmed, symptomatic DVT without symptomatic PE.³
2. Acute PE Study (EINSTEIN-PE) - open-label, event-driven, noninferiority study evaluating the efficacy and safety of oral XARELTO (15 mg BID for 3 weeks, followed by 20 mg once daily) vs SC enoxaparin (1.0 mg/kg BID) followed by dose-adjusted oral VKA in patients with acute, symptomatic PE, with or without DVT.²
3. The Continued Treatment Study (EINSTEIN-Extension) - continued treatment in patients who have received treatment for either acute DVT or PE. The Continued Treatment Study was a phase 3, double-blind, event-driven, superiority study comparing 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.

Prophylaxis of DVT Following Hip or Knee Replacement Surgery

The RECORD clinical development program, a comprehensive program of 4 phase 3 studies with over 12,000 patients, studied XARELTO for the prophylaxis of VTE in patients undergoing knee (RECORD 3 and 4) or hip (RECORD 1 and 2) replacement surgery. The data from the RECORD program were submitted to the Food and Drug Administration (FDA). XARELTO was approved on July 1, 2011, by the FDA for the indication studied in the RECORD program.

In the RECORD 4 study, patients received either oral XARELTO 10 mg once daily, beginning at least 6-8 hours after surgery, or subcutaneous enoxaparin 30 mg every 12 hours, starting 12-24 hours after surgery. Data from RECORD 4 are not included in the approved product labeling for XARELTO.

Since the publication of RECORD 4 findings, the sponsor company conducted a verification of the data for all patients in this clinical trial. With respect to study findings, additional adverse events/serious adverse events were identified; however, the distribution of those was balanced between study groups. In the company’s view, verification findings did not appreciably change the conclusions of the study. Thus, the RECORD 4 findings reported in the publication remain consistent with the overall results from the total RECORD program.^28-31

Acute Coronary Syndrome (ACS)

ATLAS-ACS 2-TIMI 51 was a randomized, multicenter, double-blind, event-driven study designed to determine whether XARELTO, when added to standard of care, was safe and reduced the risk of the composite of cardiovascular death, myocardial infarction, or stroke in patients with ACS, compared with placebo.¹⁰ Standard medical therapy included low-dose aspirin. Randomization was stratified by the investigator's intent to administer a thienopyridine (clopidogrel or ticlopidine) at the time of enrollment. The mean duration of treatment with the study medication was 13.1 months.

• Exclusion criteria included patients with known significant liver disease (eg, acute hepatitis, chronic active hepatitis, cirrhosis) or LFT abnormalities confirmed with repeat testing, which would require study drug discontinuation (eg, ALT >5x ULN or ALT >3x ULN plus total bilirubin >2x ULN).³³

Prophylaxis of VTE in Medically Ill Patients Requiring Hospitalization

The MAGELLAN study was an international, randomized, double-blind study designed to evaluate the efficacy and safety of once-daily oral XARELTO compared to standard-duration, once-daily, SC enoxaparin, and to evaluate the role of extended-duration XARELTO (up to 39 days) for the prevention of VTE in acutely ill medical patients who required hospitalization.^{6, 34}

• Exclusion criteria included patients with known significant liver disease (eg, acute hepatitis, chronic active hepatitis, cirrhosis) or LFT abnormalities (confirmed with repeat testing), which would require study medication discontinuation (ie, ALT >5x ULN or ALT >3x ULN plus total bilirubin >2x ULN and the ratio of direct-to-total bilirubin ≥50%).³⁴

REAL-WORLD EVIDENCE

Maura et al (2020)¹¹ conducted a propensity-weighted nationwide cohort (Régime general of the French national healthcare database) study from January 2011 to December 2016 in patients with NVAF starting OACs to assess the risk of serious ALI. The risk was compared between each non-vitamin K antagonist oral anticoagulant (NOACs; dabigatran, XARELTO, apixaban) and vitamin K antagonist (VKA; fluindione, warfarin and acenocoumarol) in patients with no prior liver disease, prior liver disease, and also in those with a history of chronic alcoholism. Patients were excluded if they had been treated for other non-NVAF OAC indications (i.e. patients with a history of DVT/PE or who had undergone limb orthopaedic procedures during the six-week pre-index period), a history of prosthetic heart valve, chronic rheumatic heart disease, contraindications to OAC therapy, currently or recently treated for cancer or treated for HIV infection.

• The main outcome was serious ALI determined by hospitalization for a liver transplant or presented with non-chronic toxic liver disease, non-chronic hepatic failure, nonspecific reactive hepatitis, unspecified inflammatory liver disease or unspecified jaundice.
• An additional outcome assessed the potential role of differential anticoagulation blood monitoring in the early detection of ALI. Elevation of transaminases were considered when patients presented with consecutive reimbursements for serum transaminase assays on at least 3 different dates over a 30-day period during follow-up.
• A total of 434,015 new OAC patients had no prior liver disease. A majority of the NOAC patients were on XARELTO (n=99,408) followed by apixaban (n=62,503) and dabigatran (51,737), compared to 220,367 patients on a VKA.
  • Compared to VKA, XARELTO users were at an increased risk of hospitalized ALI (adjusted HR, 1.41; 95% CI, 1.05–1.91). Dabigatran (adjusted HR, 1.17; 95% CI, 0.79–1.75) and apixaban (adjusted HR, 0.82; 95% CI, 0.53–1.25), compared to VKA, demonstrated no increased risk in hospitalized ALI.
  • Both XARELTO (adjusted HR, 0.97; 95% CI, 0.93–1.01) and apixaban (adjusted HR, 1.01; 95% CI, 0.96–1.06), compared to VKA, demonstrated no association in transaminase elevation. A reduced risk of transaminase elevation was observed in dabigatran patients versus VKA patients (adjusted HR, 0.85; 95% CI, 0.81-0.90).
• In patients with prior liver disease and a history of chronic alcoholism, the incidence of ALI was higher in both groups compared to patients with no prior liver disease.
• There was no difference in patients with prior liver disease treated with dabigatran compared to VKA and the risk of ALI (adjusted HR, 1.33; 95% CI, 0.72–2.45). XARELTO and apixaban patients were at a lower risk of ALI compared to warfarin in patients with prior liver disease (adjusted HR, 0.49; 95% CI, 0.25–0.96 and adjusted HR, 0.14; 95% CI, 0.03–0.80, respectively).
• A history of chronic alcoholism was noted in 13,173 OAC patients. Patients treated with dabigatran (n=1317), compared to VKA (n=7779), with a history of chronic alcoholism were at an increased risk of ALI (adjusted HR, 2.88; 95% CI, 1.74–4.76). There was no difference in the risk of ALI in patients treated with XARELTO compared to VKA with a history of chronic alcoholism (adjusted HR, 0.61; 95% CI, 0.29-1.26). Apixaban patients were at a lower risk of ALI compared to VKA patients (adjusted HR, 0.14; 95% CI 0.03–0.80).

Alonso et al (2017)¹² evaluated the risk of hospitalization related to liver injury in patients with NVAF following initiation of DOACs or warfarin. Predictors of hospitalization secondary to liver injury were also assessed in this population.

• Prospective study evaluating 113,717 patients with NVAF included in the MarketScan Commercial and Medicare Supplemental databases, with an initial prescription for an oral anticoagulant after November 4, 2011, followed through December 31, 2014.
• Of the 113,717 patients, 50% were initiated on warfarin, 27% were initiated on XARELTO, 15% were initiated on dabigatran, and 8% were initiated on apixaban.
• The primary outcome was hospitalization secondary to liver injury that was potentially related to drug hepatotoxicity.
• Mean age was 70 years and 39% of patients were female. The percentage of patients with liver disease at baseline by anticoagulant was as follows: 5.4%, 4.7%, 4.6%, and 4.5% for warfarin, XARELTO, dabigatran, and apixaban, respectively.
  • Compared with patients initiated on DOACs, those initiated on warfarin were older, were more likely to be female, had higher CHA₂DS₂-VASc and HAS-BLED scores, and had greater prevalence of most comorbidities.
• A total of 960 hospitalizations secondary to liver injury were identified during a mean follow-up of 14 months.
• Rates of liver injury-related hospitalization per 1000 person-years by anticoagulant were as follows: warfarin, 9.0; XARELTO, 6.6; apixaban, 5.6; and dabigatran, 4.0.
  • Liver injury-related hospitalization rates were lower in patients on DOACs vs warfarin: HR, 0.57 (95% CI, 0.46-0.71), HR, 0.88 (95% CI, 0.75-1.03), and HR, 0.70 (95% CI, 0.50-0.97) for those initiated on dabigatran, XARELTO, and apixaban, respectively.
  • Those initiated on XARELTO experienced a 56% increase in risk of liver injury-related hospitalization (HR, 1.56; 95% CI, 1.22-1.99) vs those initiated on dabigatran.
• Significant predictors of hospitalization secondary to liver injury included: type of anticoagulant; prior liver, gallbladder, or kidney disease; cancer; anemia; heart failure; and alcoholism.

CASE REPORTS

Several case reports have been published that discuss hepatic events in patients treated with XARELTO.^13-21,35,36 Various data collected from the case reports are:

• Liver biopsy to confirm liver injury.^13-15,18,20
• Serology testing or other imaging to rule out other causes besides drug-induced liver injury.^13-21
• Observation of elevated LFTs.^13-21,35,36
• Onset was 5 to 62 days in the majority of patients^{13-15,17,19,35} followed by 4 months²⁰, and 180 days (6 months).¹⁶ The onset of hepatic injury was not recorded for two patients.^18,21
• Discontinuation of XARELTO therapy.^13-21,35,36
• Recovery of patients that experienced XARELTO-induced liver injury.^13-16,18-21
• Death
  • Supplemental information regarding these deaths; paralytic ileus¹⁴, multiorgan failure¹⁷, encephalopathy/multiorgan failure³⁵, and liver failure³⁶ are described below in the table: Case Reports

LITERATURE SEARCH

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