SUMMARY  

• XARELTO should not be used in patients with creatinine clearance (CrCl) 15 to <80 mL/min who are receiving concomitant combined P-glycoprotein (P-gp) and moderate cytochrome P450 3A4 (CYP3A4) inhibitors, unless the potential benefit justifies the potential risk.¹
• A post hoc analysis of the ROCKET AF study showed that the primary efficacy and safety endpoints were similar between patients on baseline digoxin and those that were not.²
• A post hoc analysis of the ROCKET AF study demonstrated that efficacy and safety results between XARELTO and warfarin were consistent in patients with amiodarone use and without antiarrhythmic use.³
• In a phase 1 clinical study evaluating the safety of XARELTO in combination with digoxin, there were no clinically relevant pharmacokinetic (PK) or pharmacodynamic (PD) interactions between XARELTO and digoxin. Digoxin had minimal effects on XARELTO-induced inhibition of factor Xa activity and prolongation of clotting time.⁴
• Another study evaluated whether there are significant clinical consequences of combining XARELTO with dronedarone in patients with nonvalvular atrial fibrillation (NVAF). At follow-up (9.1 ± 6.7 months), approximately 25% of patients experienced atrial fibrillation (AF) recurrence; there were no thromboembolic or major bleeding events.⁵
• A single-center, prospective, observational study evaluated the risk of bleeding associated with administration of the combination of XARELTO and amiodarone in patients with AF. The primary endpoint (time to the first occurrence of the composite of major, clinically relevant nonmajor bleeding [CRNMB], and minor bleeding) occurred in 26.0% of patients in the combination group and in 10.4% of patients taking XARELTO only (hazard ratio [HR], 2.76; 95% confidence interval [CI], 1.55-4.93; P<0.001).⁶
• Additional retrospective cohort studies evaluating the combined use of XARELTO with antiarrhythmics (including amiodarone, dronedarone, and propafenone) vs XARELTO alone and/or comparing different XARELTO-antiarrhythmic combinations are summarized in the REAL-WORLD EVIDENCE section below.^7-13
• Additional citations identified during a literature search has been included in the REFERENCES section for your review.^14-20

CLINICAL DATA

Post Hoc Analyses

Washam et al (2015)² conducted a retrospective post hoc analysis of patients from ROCKET AF on the basis of digoxin use at baseline and during the study. The objective of the study was to investigate the association of digoxin with all-cause mortality, vascular death, and sudden death.

• Of the 14,171 randomly assigned patients in ROCKET AF, digoxin was used at baseline in 5239 (37%).
• Patients given digoxin were more likely to be female (42% vs 38%) and have a history of heart failure (HF) (73% vs 56%), diabetes (43% vs 38%), and persistent AF (88% vs 77%; P<0.0001 for each comparison).
• Digoxin was associated with increased all-cause mortality (5.41 vs 4.30 events per 100 patient-years [PY]; HR, 1.17; 95% CI, 1.04-1.32; P=0.0093), vascular death (3.55 vs 2.69 events per 100 PY; HR, 1.19; 95% CI, 1.031.39; P=0.0201), and sudden death (1.68 vs 1.12 events per 100 PY; HR, 1.36; 95% CI, 1.08-1.70; P=0.0076).

Steinberg et al (2014)³ conducted a post hoc analysis of the ROCKET AF trial to assess the clinical outcomes associated with concomitant use of XARELTO and antiarrhythmic medications.

• All patients randomized in ROCKET AF (intention-to-treat) were included in this analysis. A total of 1681 (11.8%) patients were treated with antiarrhythmic medications, with 1144 (8%) receiving amiodarone and 537 (3.8%) receiving other antiarrhythmic medications; clinical outcomes were compared between XARELTO and warfarin only in the subset of patients receiving amiodarone.
• More patients taking amiodarone at baseline had HF than those patients not taking antiarrhythmic medication at baseline (71% vs 63%), fewer had prior vitamin K antagonist use (53% vs 63%), and fewer used digitalis (24% vs 41%).
• There were no significant differences between the XARELTO and warfarin treatment groups in terms of amiodarone dose. The most common amiodarone daily dose was 200 to 300 mg daily (>70% of patients in both groups); this was followed by amiodarone 100 to 150 mg daily (14% receiving XARELTO and 12% receiving warfarin).
• Except for myocardial infarction (MI), efficacy and safety outcomes were not significantly different between patients treated with amiodarone and those not taking any antiarrhythmic medication at baseline. Patients treated with amiodarone had an increased risk of incident MI compared to patients not taking any antiarrhythmic (HR, 1.76; 95% CI, 1.11-2.77; P=0.02).
• There were no significant tests for interaction between treatment assignment and antiarrhythmic use. There was also no significant interaction between use of XARELTO vs warfarin and renal dysfunction for the primary outcome in patients taking amiodarone.

Phase 1 Study

Kubitza et al (2012)⁴ conducted 2 randomized, phase 1 clinical studies in healthy male subjects to assess the PK, PD, and safety of XARELTO in combination with digoxin or atorvastatin. The digoxin-XARELTO interaction study was a 2-way crossover study.

Digoxin-XARELTO Interaction Study

• On Day 0, subjects were administered a single dose of XARELTO 20 mg.
• On Day 2, subjects were administered digoxin 0.375 mg once daily for a period of 28 days.
• Subjects were randomized to receive a single dose of XARELTO 20 mg on day 6 (group A) or day 20 (group B), followed by XARELTO 20 mg twice daily for 9 days (group A, days 7-15; group B, days 21-29).
• Nineteen subjects were included in the safety analysis.
• The most frequent adverse event was headache, occurring in 8 subjects receiving the steady state XARELTO-digoxin combination and in 2 subjects receiving steady state digoxin alone.
• XARELTO had no effect on vital signs or electrocardiogram parameters.

Other Clinical Studies

Escobar et al (2017)⁵ evaluated whether there are significant clinical consequences of combining XARELTO with dronedarone in patients with NVAF. Of the 23 patients with paroxysmal AF (age 60.9 ± 9.1 years) that were included in the study, approximately 75% were treated with XARELTO 20 mg once daily and all were treated with dronedarone 400 mg twice daily, except for 1 patient who was treated with dronedarone 200 mg twice daily. One patient required dronedarone withdrawal due to drug intolerance. At follow-up (9.1 ± 6.7 months), approximately 25% of patients experienced AF recurrence; there were no thromboembolic or major bleeding events.

Real-World evidence

Prospective Studies

Wang et al (2024)⁶ conducted a single-center, prospective, observational study to evaluate the risk of bleeding associated with administration of the combination of XARELTO and amiodarone in patients with AF.

• Primary endpoint: time to the first occurrence of the composite of major, clinically relevant nonmajor bleeding (CRNMB), and minor bleeding (defined according to International Society on Thrombosis and Haemostasis criteria).
• Three adjustments were made to account for the between-group differences: propensity score matching (PSM), inverse probability of treatment weighting (IPTW), and stabilized IPTW.
• There were 481 patients included in the final analysis.
• After PSM (1:1 ratio):
  • XARELTO group (n=154): mean age, 63.97 years; 68.8% of patients were male.
  • Combination group (n=154): mean age, 64.40 years; 68.2% of patients were male.
• After PSM, the primary outcome was observed in 26.0% of patients in the combination group and in 10.4% of patients in the XARELTO group (HR, 2.76; 95% CI, 1.55-4.93; P<0.001).
  • Major bleeding: 1 patient in XARELTO group vs 0 patients in combination group (P=1.000).
  • CRNMB risk: 4.5% in XARELTO group vs 13.0% in combination group (P=0.014).
  • Minor bleeding: 5.2% in XARELTO group vs 13.0% in combination group (P=0.028).
• In the IPTW and stabilized IPTW, the bleeding risk was also higher in the combination group compared to XARELTO (HR, 2.17; 95% CI, 1.32-3.56; P=0.002).
• Patients with stage 2-5 chronic kidney disease (estimated glomerular filtration rate <90 mL/min/1.73 m²) had a significantly higher risk of bleeding with the combination of XARELTO and amiodarone than with XARELTO alone (26.6% vs 10.7%; HR, 2.698; 95% CI, 1.419-5.127; P=0.002).

Retrospective Studies

Ray et al (2023)¹⁰ conducted a retrospective cohort study using Medicare insurance database to compare the outcomes of amiodarone vs flecainide or sotalol in 91,590 patients (≥65 years old) with AF who were on XARELTO or apixaban between January 1, 2012, and November 30, 2018.

• The mean age of patients was 76.3 years and 52.5% were females, 41.7% received XARELTO, and 79.6% were receiving the standard anticoagulant dose.
• In patients with a HASBLED score of ≤2, the number of bleeding-related hospitalizations (major hemorrhagic events-intracranial [fatal or nonfatal] bleeding or fatal extracranial bleeding within 30 days of bleeding onset and nonfatal extracranial bleeding) was 144 (2369 PY) and 63 (2536 PY) in the XARELTO plus amiodarone and XARELTO plus flecainide or sotalol groups, respectively (rate difference [RD], 24.1 per 1000 PY; 95% CI, 12.0-36.2).
• In patients with a HASBLED score of >2, the number of bleeding-related hospitalizations was 612 (5067 PY) and 168 (3120 PY) in the XARELTO plus amiodarone and XARELTO plus flecainide or sotalol groups, respectively (RD, 29.7 per 1000 PY; 95% CI, 16.043.4).

Chiou et al (2022)⁷ designed a subsequent study to Chiou et al (2021) to compare the safety and effectiveness between XARELTO alone and with concomitant antiarrhythmic drugs (amiodarone, propafenone and dronedarone) when propensity score matched for baseline characteristics.

• After PSM (1:1 ratio), there were 738 patients treated with XARELTO alone compared to 739 patients treated with concomitant antiarrhythmic drugs and XARELTO for at least 28 days. No significant differences were identified among the covariates.
• Using multivariate Cox regression analysis, no statistically significant differences were found between both groups regarding the safety endpoint, defined as major, critical site, minor, and fatal bleeding (HR, 1.11; 95% CI, 0.82-1.49; P=0.503), effectiveness endpoint, defined as stroke or systemic thromboembolism (HR, 0.90; 95% CI, 0.52-1.56; P=0.709), and MACE (HR, 1.06; 95% CI, 0.70-1.61; P=0.779).
• Concomitant use of XARELTO and antiarrhythmic drugs was associated with a significantly lower risk of systemic thromboembolism when compared to XARELTO only (HR, 0.35; 95% CI, 0.14-0.89; P=0.027) and a significantly increased risk of HF readmission (HR, 1.61; 95% CI, 1.15-2.25; P=0.006) along with a lower rate of all-cause death (HR, 0.73; 95% CI, 0.50-1.07; P=0.105).

Zhang et al (2022)⁹ conducted an observational study at the Affiliated Hospital of Qingdao University in China to compare the bleeding risk between concomitant administration of XARELTO and amiodarone or dronedarone after catheter ablation (CA).

• A total of 100 patients with persistent or paroxysmal NVAF were identified between December 2019 and November 2020 and had undergone CA. After PSM, 41 patients were included in the amiodarone and XARELTO arm and 41 patients in the dronedarone and XARELTO arm. Both groups received XARELTO 15 mg daily for at least 3 months after CA.
• After PSM, there were no statistically significant differences in baseline characteristics.
• During 3-month follow-up, the dronedarone and XARELTO group had a significantly higher rate of clinically relevant non-major bleeding compared to the amiodarone and XARELTO group (26.8% vs 7.3%, P=0.02). There were no major bleeding events in either group.

Gandhi et al (2021)¹³ conducted a retrospective cohort study utilizing the Commercial Claims and the Medicare Supplemental databases of the Truven Health MarketScan United States claims database between January 2007 and September 2017 to examine the association between concomitant use of dronedarone and NOACs, including XARELTO, in adult patients (≥18 years) with AF.

• A total of 2395 patients received concomitant exposure to XARELTO and dronedarone compared to 57,300 XARELTO only patients.
• When adjusted for covariates, concomitant use of XARELTO and dronedarone was associated with a higher risk of overall bleeding (adjusted HR [aHR], 1.31; 95% CI, 1.01-1.69; P=0.04), gastrointestinal (GI) bleeding (aHR, 1.39; 95% CI, 0.98-1.95; P=0.06), and bleeding at other sites, excluding GI bleeding and intracranial hemorrhage (ICH) (aHR, 1.27; 95% CI, 0.86-1.87; P=0.23) compared to XARELTO alone. There was no increased incidence of ICH associated with concomitant use of XARELTO and dronedarone (aHR, 0.75; 95% CI, 0.24-2.36; P=0.63).
• There was a statistically significant increased risk of overall bleeding observed in the first 6 months of concomitant use of XARELTO and dronedarone compared to XARELTO only (aHR, 1.42; 95% CI, 1.06-1.91; P=0.02), but this trend was not observed after day 183.

Chiou et al (2021)¹² investigated patient electronic medical records from a hospital system in four cities in Taiwan, to conduct a multicenter, retrospective cohort study assessing the risk of concomitant use of XARELTO and antiarrhythmic drugs.

Study Design/Methods

• Inclusion Criteria:
  • Patients with a diagnosis of nonpermanent AF and who had undergone XARELTO treatment for a period of ≥1 month between December 2011 and November 2016 were enrolled.
• Exclusion Criteria:
  • Permanent AF diagnosis.
  • Use of strong CYP3A4 or P-gp inhibitors (rifampicin, human immunodeficiency virus [HIV] protease inhibitors, itraconazole, ketoconazole, and voriconazole).
• Concomitant antiarrhythmic groups were defined as those using amiodarone, dronedarone, or propafenone, at the same time as XARELTO for more than 28 days throughout the course of the study.
• Bleeding (both major and minor bleeding) was the safety endpoint evaluated.
• A composite of stroke (ischemic and hemorrhagic) and systemic thromboembolism was considered the effectiveness endpoint.
• MACE encompassed any combination of cardiovascular death, MI, ischemic stroke, systemic thromboembolism, or hemorrhagic stroke.

Results

• A total of 1777 patients were separated into 4 groups, XARELTO alone (n=1205), concomitant amiodarone (n=177), dronedarone (n=231), and propafenone (n=164).
• The average dose of XARELTO was lowest in the dronedarone group (12.3 mg, P=0.146) followed by amiodarone group (14.2 mg), XARELTO alone (14.6 mg), and the propafenone group (15.4 mg).
• Cumulative incidence of the safety (P=0.892), effectiveness (P=0.336), and MACE (P=0.674) endpoints were similar between the 4 groups, calculated using the Gray test.
• The effectiveness endpoints and bleeding and clinical events among the 4 groups are provided in Table: Bleeding and Clinical Events of Patients with Atrial Fibrillation Receiving XARELTO Combined with Other Medications.

• The analysis of the primary effectiveness, primary safety, MACE, and all-cause death are provided in Table: Multivariate Cox Regression Analyses for Effectiveness, Safety, MACE and All-Cause Death Outcomes in Patients with AF Receiving XARELTO Combined with Other Medication.
  • The addition of antiarrhythmic drugs was not associated with an increased risk for patients with nonpermanent AF when compared with the use of XARELTO alone.  

Lin et al (2021)⁸ conducted a retrospective cohort study to assess effectiveness and safety outcomes in patients with nonpermanent AF on dronedarone and antithrombotic therapy, including XARELTO dosed at 10 mg daily.

• Patients with nonpermanent AF on dronedarone for more than 3 months were screened between January 2009 and February 2016 in Taiwan.
• Of the 689 patients enrolled in the study, 93 were included in the dronedarone with concomitant XARELTO 10 mg group.
• During the follow-up period, there were no reports of effectiveness endpoints (new ischemic stroke or ICH), MACE, fatal bleeding, critical site bleeding, and non-GI bleeding safety endpoints reported in the XARELTO group.
• Of the 3 GI bleeding events reported in the XARELTO group, 2 resulted in a safety endpoint leading to a hemoglobin drop of ≥2 g/dL or transfusion ≥2 units of packed red blood cells.

Chang et al (2017)¹¹ conducted a retrospective cohort study to assess the association between concurrent use of NOACs and commonly prescribed medications and risk of major bleeding in patients with NVAF.

Study Design/Methods

• The study utilized data from the Taiwan National Health Insurance database and included patients with NVAF who were prescribed at least 1 NOAC (dabigatran, XARELTO, or apixaban) from January 1, 2012, through December 31, 2016.
• Patients were excluded if they had mitral stenosis or prosthetic valves.
• Each calendar year was divided into 4 quarters for each patient and each year after the first NOAC prescription. The analytic unit was 1 person-quarter; person-quarters exposed to NOACs with or without concurrent medications were identified.
• Major bleeding risks associated with use of NOACs and 12 concurrent medications were compared with major bleeding risks associated with use of NOACs alone. The 12 concurrent medications (listed below) were selected due to potential drug-drug interactions with NOACs and included antiarrhythmic agents:
  • P-gp competitors (digoxin, verapamil, diltiazem, amiodarone, and cyclosporine)
  • CYP3A4 inhibitors (fluconazole and ketoconazole, itraconazole, voriconazole, or posaconazole)
  • Both P-gp competitors and CYP3A4 inhibitors (atorvastatin, erythromycin or clarithromycin, and dronedarone) OR
  • CYP3A4 inducers (rifampin and phenytoin)
• The primary outcome was major bleeding and the secondary outcome was site-specific bleeding.
• Covariates included patient demographics, comorbidities, relevant medications, and health care utilization.

Results

• Of the 279,734 patients with NVAF, 91,330 received NOACs.
• Mean age was 74.7 years and 55.8% of patients were male.
• Of the 91,330 patients that were analyzed, approximately 59.1% received XARELTO.
• A significant increase in adjusted incidence rate of major bleeding per 1000 PY was observed with concomitant use of NOACs and amiodarone (52.04) vs use of NOACs alone (38.09; difference of 13.94; 99% CI, 9.76-18.13; P<0.01).
  • Compared with XARELTO use alone, the adjusted incidence rate difference of major bleeding for XARELTO combined with amiodarone was 15.41 (99% CI, 9.43-21.39; P<0.01).
• In contrast, the adjusted incidence rate of major bleeding was significantly lower for concurrent use of digoxin with NOACs (45.69) compared to the rate observed with use of NOACs alone (50.14; difference of -4.46; 99% CI, -8.45 to -0.47; P<0.01).
  • Compared with XARELTO use alone, the adjusted incidence rate difference of major bleeding for XARELTO combined with digoxin was -2.06 (99% CI: -7.95 to 3.82).
• The adjusted incidence rates of major bleeding were not significantly different between concurrent use of verapamil, diltiazem, and dronedarone with NOACs (57.26, 51.91, and 34.67, respectively) and use of NOACs alone (50.90 [difference of 6.35; 99% CI, -3.37 to 16.07], 55.38 [difference of -3.47; 99% CI, -7.69 to 0.75], and 38.83 [difference of 4.20; 99% CI, -12.11 to 3.72], respectively).
  • Compared with XARELTO use alone, the adjusted incidence rate differences of major bleeding for XARELTO combined with verapamil, diltiazem, and dronedarone were 9.08 (99% CI, -4.71 to 22.87), 1.70 (99% CI, -4.46 to 7.86), and -3.02 (99% CI, 13.02 to 6.98), respectively.
• Several Letters to the Editor commented on this study.^21-25 Chang et al (2018)²⁶ responded with context for some of the study design questions, and insight that NOAC drug levels may be only 1 of many mechanisms contributing to complex drug-drug interactions.

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 04 October 2024.