Concomitant Use of XARELTO with Calcium Channel Blockers

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 (CYP)3A inhibitors unless the potential benefit justifies the potential risk.¹
• A post hoc analysis examined patients on XARELTO and warfarin based on the use of non-dihydropyridine (non-DHP) calcium channel blockers (CCBs) at baseline in the ROCKET-AF study.²
  • CCB use was not associated with an increased risk of stroke or non-central nervous system (non-CNS) embolism (P=0.11) or the composite outcome of clinically relevant nonmajor (CRNM) or major bleeding (P=0.087).
  • CCB use was associated with an increase in the risk for major bleeding (P=0.0091) and intracranial hemorrhage (P=0.001).
  • No significant difference was observed in the primary efficacy (stroke or non-CNS embolism; P=0.38) or primary safety outcome (CRNM bleeding or major bleeding; P=0.14) between XARELTO and warfarin with CCB use.
• A retrospective, case-cohort study assessed major and CRNM bleeding outcomes in patients with nonvalvular atrial fibrillation (NVAF) on concomitant XARELTO and diltiazem vs XARELTO without diltiazem. This study found that coadministration of XARELTO and diltiazem was not associated in an increased rate of bleeding events vs XARELTO without diltiazem.³
• A retrospective cohort study found that patients receiving XARELTO or apixaban with a combined P-gp and moderate CYP3A4 inhibitor (amiodarone, dronedarone, diltiazem, verapamil) experienced increased bleeding risk compared to those without this drug-drug interaction (DDI).⁴
• A nested case-control study assessed the risk of serious bleeding in patients with atrial fibrillation (AF) and deep vein thrombosis (DVT)/pulmonary embolism (PE) on concomitant direct acting oral anticoagulants (DOACs) and different classes of interacting medications. The study concluded that the concomitant prescription of verapamil and XARELTO increased the risk of serious bleeding (P=0.031); however, concomitant prescription of amlodipine and XARELTO did not display similar results (P=0.217).⁵
• A nationwide cohort study conducted in Belgium evaluated the impact of P-gp- and CYP3A4-interacting drugs on clinical outcomes in patients with AF who were treated with non-vitamin K antagonist oral anticoagulants (NOACs). The co-administration of P-gp/CYP3A4 inhibitors was associated with a significantly increased risk of major bleeding in patients taking edoxaban (adjusted hazard ratio [aHR], 1.24; 95% confidence interval [CI], 1.06-1.45), XARELTO (aHR, 1.25; 95% CI, 1.16-1.34), and apixaban (aHR, 1.27; 95% CI, 1.16-1.39) but not in those taking dabigatran (aHR, 1.07; 95% CI, 0.94-1.23), when compared with patients who did not use non-pharmacokinetically interacting drugs.⁶
• A longitudinal cohort study showed no statistically significant differences in clinically relevant bleeding, all-cause mortality, gastrointestinal (GI) bleeding, or intracranial hemorrhage outcomes between patients receiving a concurrent DOAC (including XARELTO) with verapamil/diltiazem (P-gp/CYP3A4 inhibitor) and those receiving a concurrent DOAC with metoprolol (noninhibitor).⁷
• A real-world study evaluated the risk of bleeding associated with the concomitant use of DOACs (XARELTO, apixaban, or dabigatran) with diltiazem in adult patients with AF. XARELTO users who were exposed to diltiazem had a doubled risk of major bleeding compared to XARELTO users who were not exposed to diltiazem, with an unadjusted incidence rate of 4.1 per 100 patient-years (PY) in the diltiazem exposed group and 1.8 per 100 PY in the diltiazem unexposed group.⁸
• A comparative retrospective cohort study using TriNetX data evaluated the risk of GI bleeding associated with factor Xa inhibitors (XARELTO or apixaban) and dabigatran when coadministered with diltiazem or metoprolol in adults aged ≥18 years.⁹
  • GI bleeding risk assessed was as follows:
    • Cohort A: 6.3% in patients receiving diltiazem with apixaban or XARELTO versus 5.7% in those receiving metoprolol (risk ratio [RR], 1.09; 95% CI, 1.074-1.111; P<0.0001).
    • Cohort B: Among patients receiving metoprolol, 5.4% with apixaban versus 6.4% with XARELTO (RR, 0.85; 95% CI, 0.838-0.868; P<0.0001).
    • Cohort C: Among patients receiving diltiazem, 7.3% with XARELTO versus 5.8% with apixaban (RR, 1.23; 95% CI, 1.194-1.265; P<0.0001).
    • Cohort D: 7.4% in patients receiving diltiazem with dabigatran versus 6.71% in those receiving metoprolol (RR, 1.097; 95% CI, 1.038-1.16; P=0.0011).
• In the EINSTEIN-DVT study, there were 188/1731 (10.9%) patients on CCBs in the XARELTO treatment group and 215/1718 (12.5%) on CCBs in the enoxaparin/vitamin K antagonist (VKA) treatment group.¹⁰
• In the EINSTEIN-PE study, there were 391/2419 (16.2%) patients on CCBs in the XARELTO treatment group and 376/2413 (15.6%) on CCBs in the enoxaparin/VKA treatment group.¹¹
• In the EINSTEIN-EXTENSION study, there were 64/602 (10.6%) patients on CCBs in the XARELTO treatment group and 80/594 (13.5%) on CCBs in the placebo group.¹²
• In the COMPASS (Cardiovascular OutcoMes for People Using Anticoagulation StrategieS) study, there were 2413/9152 (26.4%) patients in the XARELTO plus aspirin group, 2374/9117 (26.0%) patients in the XARELTO alone group, and 2482/9126 (27.2%) patients in the aspirin alone group taking a CCB at baseline.¹³
• In ATLAS ACS-2 TIMI-51, at baseline, there were 820 (15.8%) patients in the XARELTO 2.5 mg twice daily group that had taken a CCB prior to the first dose of study drug.¹⁴
• Additional studies pertaining to concomitant use of CCBs (ie, diltiazem and verapamil) with XARELTO have been included in the REFERENCES section for your review.^15-28

PRODUCT LABELING

Drug Interactions

Rivaroxaban is a substrate of CYP3A4/5, CYP2J2, and the P-gp and adenosine triphosphate (ATP)-binding cassette G2 (ABCG2) transporters.¹

Interaction with Combined P-gp and Moderate CYP3A Inhibitors in Patients with Renal Impairment

XARELTO should not be used in patients with CrCl 15 to <80 mL/min who are receiving concomitant combined P-gp and moderate CYP3A inhibitors unless the potential benefit justifies the potential risk.¹

CLINICAL STUDIES

Stroke Prevention in NVAF

Phase 3 Study

The ROCKET AF trial was a phase 3, randomized, double-blind, double-dummy, active-controlled, parallel-group, multicenter, event-driven, noninferiority study to evaluate the efficacy and safety of oral fixed-dose XARELTO and dose-adjusted warfarin for the prevention of stroke and systemic embolism (SE) in patients with NVAF at moderate-to-high risk for stroke.²⁹

A post hoc analysis of the ROCKET AF trial examined patient characteristics and compared outcomes between patients on XARELTO and warfarin based on the use of CCBs.²

• Of the 14,264 randomized patients in ROCKET AF, 1308 patients (9.2%) were taking a CCB. Eight hundred (61.1%) patients received diltiazem, 506 (38.7%) patients received verapamil, and 2 patients (0.2%) received gallopamil.
• Patients taking a CCB were more likely to be female (45% vs 39%), have diabetes (43% vs 40%), and have a medical history of chronic obstructive pulmonary disease (21% vs 9%), while they were less likely to have a medical history of heart failure (49% vs 64%), myocardial infarction (MI; 14% vs 18%), and had a lower mean CHADS₂ (congestive heart failure, hypertension, age ≥75, diabetes, stroke [doubled]) score (3.3 vs 3.5) compared to those not taking a CCB.
• In both treatment groups, CCB use was not associated with a significant increase in the risk for the primary efficacy outcome of stroke or non-CNS SE (P=0.11) or the primary safety composite outcome of major or CRNM bleeding (P=0.087).
  • CCB use was associated with an increase in the risk for major bleeding (aHR, 1.50; 95% CI, 1.11-2.04; P=0.0091) and intracranial hemorrhage (aHR, 2.84; 95% CI, 1.53-5.29; P=0.001).
• No significant differences were observed in the primary efficacy (stroke or non-CNS embolism; adjusted interaction P=0.38) or primary safety composite outcome (CRNM bleeding or major bleeding; adjusted interaction P=0.14) between XARELTO and warfarin with CCB use. Detailed results are presented in Table: Efficacy and Safety Outcomes of XARELTO vs Warfarin According to CCB Use.

• An additional analysis assessed the association of CCB use across subgroups of renal function for the primary safety composite outcome of CRNM bleeding or major bleeding events. The renal subgroups were classified as no chronic kidney disease (CrCl >80 mL/min), mild chronic kidney disease (CrCl 50-80 mL/min), and moderate chronic kidney disease (CrCl 30-40 mL/min). In patients taking a CCB, no difference was observed in the treatment effect of XARELTO vs warfarin across renal function subgroups (interaction P=0.76).

Observational Studies

Bartlett et al (2019)³ conducted a single-center, retrospective, case-cohort study to assess major and CRNM bleeding outcomes in adult patients with NVAF who were prescribed concomitant XARELTO and diltiazem vs XARELTO without diltiazem for at least 30 days.

• Between January 1, 2013 and September 1, 2017, patients 18 years and older with NVAF taking XARELTO with diltiazem (case) were matched to patients taking XARELTO without diltiazem (control).
• Cases and controls were identified using an electronic medical record of a health-system.
• A total of 143 cases and 143 controls were included in the analysis. The median duration of treatment and follow-up was 12.4 months and 16.5 months for cases and controls, respectively.
• The primary outcome of the composite major and CRNM bleeding, occurred in 23.1% (33/143) of subjects in the XARELTO plus diltiazem treatment group and 28.0% (40/143) of subjects in the XARELTO without diltiazem treatment group (P=0.34), respectively.
• Major or CRNM bleeding resulting in permanent discontinuation of XARELTO, occurred in 6.3% (9/143) of subjects in the case cohort and 5.6% (8/143) of subjects in the control cohort (P=0.80).
• GI/rectal bleeding and hematuria were the most frequently reported bleeding events in both groups.

Kabutoya et al (2020)³⁰ conducted a single-arm study involving patients with hypertension and AF treated with XARELTO and antihypertensives to evaluate changes in anticoagulant activity and blood pressure.

• The study enrolled 72 NVAF patients from December 1, 2014 to August 31, 2017 at 22 institutions in Japan.
• Patients were administered XARELTO (10-15 mg) once daily continuously over 8 weeks (study period I). For subjects who exhibited uncontrolled morning hypertension (home systolic blood pressure [SBP] ≥125 mmHg) at the end of study period I (at 8 weeks), nifedipine controlled-release (20-40 mg) was added at bedtime and XARELTO was continued an additional 8 weeks (period II).
• A total of 50 patients entered period II and had nifedipine added to their regimen.
• An abnormal increase in prothrombin fragment 1 + 2 (F1 + 2) reflects an increase in coagulation activity and results in thrombosis, but an abnormal decrease confers a risk of bleeding.
• The combination of XARELTO and nifedipine, achieved F1 + 2 lower than twice the upper limit in all patients, and the high optimal range of F1 + 2 was achieved at 12 weeks.
• Rates of negative D-dimer were significantly increased by combination therapy with XARELTO and nifedipine.
• Home morning SBP and diastolic blood pressure (DBP) were lower at 12 and 16 weeks compared with week 8 results.
  • Morning SBP at 12 weeks: 119.9±12.1 vs 133.5±10.5 mmHg, P<0.001.
  • Morning DBP at 12 weeks: 75.0±11.3 vs 83.1±10.5 mmHg, P<0.001.
  • Morning SBP at 16 weeks: 118.5±11.0 vs 133.5±10.5 mmHg, P<0.001.
  • Morning DBP at 16 weeks: 74.2±9.8 vs 83.1±10.5 mmHg, P<0.001.

Hanigan et al (2020)⁴ conducted a real-world, single-center, retrospective cohort study to compare the occurrence of bleeding in patients taking XARELTO or apixaban with and without a combined P-gp and moderate CYP3A4 inhibitor.

• Patients were eligible for inclusion if they were ≥18 years of age and received XARELTO or apixaban for AF for a minimum duration of 3 months between January 1, 2012 to December 31, 2016.
• Patients with concomitant use of a combined P-gp and moderate CYP3A4 inhibitor (amiodarone, dronedarone, diltiazem, verapamil, or erythromycin) for ≥3 months were included in the DDI group. These patients must have had XARELTO or apixaban initiated after or no longer than 2 weeks before starting the combined P-gp and moderate CYP3A4 inhibitor. Those without this interaction were included in the control group.
• The primary outcome was the composite of major, CRNM, and minor bleeding, as defined by the International Society on Thrombosis and Hemostasis.
• A total of 712 patients were screened for inclusion in the DDI group, with 226 patients meeting criteria. A total of 977 patients were screened for inclusion in the control group, with 400 patients meeting criteria.
  • There were significant differences between groups in the incidence of prior stroke or transient ischemic attack (TIA), diabetes, vascular disease, liver disease, alcohol consumption, anemia, and surgery or trauma in the prior 6 months. CHA₂DS₂-VASc (congestive heart failure, hypertension, age ≥75 [doubled], diabetes, stroke [doubled], vascular disease, age 65 to 74 and sex category [female]) score and aspirin use also significantly differed.
  • Following propensity matching, 213 patients with similar baseline characteristics were included in each group.
• Mean age was 68 years, mean CHA₂DS₂-VASc score was 3.0, and median duration of follow-up was 1.45 years.
• The primary outcome of any bleed occurred in 26.4% of patients in the DDI group and in 18.4% of patients in the control group (HR, 1.8; 95% CI, 1.19-2.73; P=0.006).
  • Major bleeding occurred in 2.3% of patients in the DDI group and 1.9% of patients in the control group; CRNM bleeding occurred in 15% and 10.3% of patients, respectively; and minor bleeding occurred in 8.9% and 5.2% of patients, respectively (P=not significant).
  • There was no difference in bleeding rates based on the type of combined P-gp and moderate CYP3A4 inhibitor.

Pham et al (2020)³¹ conducted a retrospective, comparative effectiveness, active comparator cohort study to assess the risk of bleeding among patients with concomitant use of DOACs and verapamil or diltiazem vs concomitant use of DOACs and amlodipine or metoprolol.

• The study utilized data from the IBM Watson MarketScan Databases, including the Commercial Claims and Medicare Supplemental Database, and included patients with NVAF who had received an index prescription of XARELTO, dabigatran, or apixaban between October 19, 2010 and June 30, 2015 (with final follow-up on October 1, 2015).
  • The analysis was limited to patients with normal kidney function who had received treatment with standard doses of DOACs (XARELTO 20 mg once daily, dabigatran 150 mg twice daily, and apixaban 5 mg twice daily).
• Patients were excluded if they had received a prescription for any of the study drugs (DOACs or antihypertensives) during the baseline period. Patients with >1 DOAC dispensed on the index date, as well as those with a diagnosis of mitral valve disease, heart valve repair or replacement, or joint replacement during the baseline period, were also excluded.
• Data were analyzed between January 1, 2019 and July 15, 2019.
• Study outcomes included major bleeding, moderate bleeding, and minor bleeding.
• Of the 48,442 patients with NVAF that received new DOAC therapy between 2010 and 2015, 1764 received DOACs with verapamil or diltiazem compared with 3105 that received amlodipine, and 1793 received DOACs with verapamil or diltiazem compared with 3224 that received metoprolol.
  • Approximately 60% of the cohorts were <65 years of age and male, which differed by treatment group.
• XARELTO and apixaban were not associated with increased rates of bleeding in patients receiving verapamil or diltiazem compared with those receiving amlodipine or metoprolol.
• Dabigatran was associated with a 52% higher overall bleeding rate (HR, 1.52; 95% CI, 1.05-2.20) when combined with verapamil or diltiazem vs amlodipine and 43% higher rate (HR, 1.43; 95% CI, 1.02-2.00) when combined with verapamil or diltiazem vs metoprolol.
  • Bleeding rates for dabigatran with verapamil or diltiazem were higher for other bleeding types, including overall GI bleeding, minor bleeding, and minor GI bleeding.
• Similar results were observed with sensitivity analyses; 50 to 100% increased hazard rates with dabigatran and no significant results for XARELTO or apixaban.

Gronich et al (2021)⁵ conducted a nested case-control study to determine the risk of serious bleeding with concomitant prescription of DOACs, including XARELTO, and different classes of interacting medications, including CCBs, in patients with AF and DVT/PE.

• Overall, 89,284 patients were included in the study, of whom 79,302 were diagnosed with AF and 9982 with recent DVT/PE, 46,428 (52%) were female, and 27,914 (31.3%) received XARELTO.
• Of the 89,284 patients with AF and DVT/PE, 29,764 controls were matched with 1587 cases of serious bleeding by age, sex, DOAC type, indication for DOAC, length of follow-up, and year of DOAC initiation.
• Concomitant prescription of verapamil and XARELTO increased the risk of serious bleeding (adjusted odds ratio [OR], 2.18; 95% CI, 1.07-4.40; P=0.031); however, concomitant prescription of amlodipine and XARELTO did not display similar results (adjusted OR, 0.76; 95% CI, 0.49-1.18; P=0.217).

Grymonprez et al (2023)⁶ conducted a nationwide cohort study to evaluate the impact of p-gp and CYP3A4-interacting drugs on clinical outcomes in NOAC-treated patients with NVAF. Outcomes evaluated in the study included stroke or SE, stroke alone, all-cause mortality, major bleeding, intracranial bleeding, and GI bleeding. A 3:1 propensity score matching was used to balance differences in baseline characteristics among NOACs.

• The study utilized data from 2 Belgian databases, the InterMutualistic Agency and the Minimal Hospital Dataset and included patients age ≥45 years with at least 1 year of coverage by Belgian health insurance funds who received an index prescription for a NOAC between January 1, 2013 to January 1, 2019.
  • Patients with a prescription for an OAC filled within 1 year of the index date, recent total hip/knee replacement surgery, recent VTE, moderate-severe mitral stenosis, mechanical prosthetic heart valve, CKD stage V or dialysis were excluded.
• Of the 193,072 NOAC-treated patients with NVAF, 46,194 (23.9%) concomitantly used a P-gp/CYP3A4 inhibitor, 2903 (1.5%) used an inducer, and 957 (0.5%) used a combination of both an inhibitor and an inducer at the time a NOAC was prescribed. Of the patients concomitantly using a P-gp/3A4 inhibitor, 5023 (10.9%) were on diltiazem and 1345 (2.9%) were on verapamil.³²
• Subgroup analysis after stratifying by type of NOAC demonstrated a significantly higher major bleeding risk in patients using edoxaban (aHR, 1.24; 95% CI, 1.06-1.45), XARELTO (aHR, 1.25; 95% CI, 1.16-1.34), and apixaban (aHR, 1.27; 95% CI, 1.16-1.39) but not in those using dabigatran (aHR 1.07; 95% CI, 0.94-1.23) concomitantly with P-gp/CYP3A4 inhibitors, when compared with patients using drugs that did not interact pharmacokinetically.
• Of note, following propensity score matching, 58.0% of dabigatran users concurrently using P-gp/CYP3A4 inhibitors used a lower dose of NOAC, compared with 40.7%, 31.8%, and 34.3% of XARELTO, apixaban, and edoxaban users, respectively.
• Subgroup analysis was not provided for patients expressly prescribed XARELTO who were on diltiazem or verapamil.

Teshima et al (2023)⁷ conducted a longitudinal cohort study to evaluate the concurrent use of DOACs and non-DHP CCBs within the real-world setting. The primary outcome was the occurrence of clinically relevant bleeding; all-cause mortality, GI bleeding, and intracranial hemorrhage were secondary outcomes. Clinically significant bleeding was defined as either major or non-major bleeding that resulted in hospitalization or an emergency department visit.

• The study included adult patients from 3 US health care delivery systems who concomitantly received a DOAC (dabigatran, apixaban, or XARELTO) and diltiazem or verapamil (CYP3A4-/P-gp-inhibiting group), or a DOAC and metoprolol (noninhibitor group).
  • Patients were excluded if they had a mechanical heart valve, mitral stenosis or were pregnant or were taking a CYP3A4/P-gp inhibitor.
• A total of 63,881 patients were included in the study. Among these patients, 2845 patients who were concomitantly receiving a non-DHP CCB were on apixaban, 18,673 were on dabigatran and 1077 were on XARELTO while 5397 patients who were concomitantly receiving metoprolol were on apixaban, 33,384 were on dabigatran and 2505 were on XARELTO. The study outcomes are summarized in Table: Unadjusted and Adjusted Study Outcomes in Patients Receiving XARELTO and a Non-DHP CCB or Metoprolol.

Xu et al (2022)⁸ conducted a real-world study to evaluate the risk of bleeding associated with the concomitant use of DOACs with diltiazem and to evaluate whether the bleeding risk differed by chronic kidney disease (CKD) status in adult patients (>18 years old) with AF who received XARELTO, apixaban, or dabigatran between January 1, 2010, and February 1, 2019.

• A total of 4544 patients with AF were identified, of whom 1583 received XARELTO.
• Index date was defined as the date of the first prescription of DOACs and required at least 1 year of prior engagement with Geisinger system and at least one outpatient serum creatinine measurement within the year before the index date for inclusion.
• The mean age was 72 (standard deviation [SD], 12) and 70 (SD, 12) years in the diltiazem exposed and diltiazem unexposed groups, respectively.
• The median duration of follow-up from DOAC initiation was 182 (interquartile interval [IQI], 33-540) days.
• A total of 2021 (44.5%) were female patients, of whom 1674 (43.3%) and 347 (50.9%) were in the diltiazem exposed and diltiazem unexposed groups, respectively.
• The mean estimated glomerular filtration rate (eGFR) was 69 mL/min and 71 mL/min in the diltiazem exposed and diltiazem unexposed groups, respectively.
• For XARLETO users, the unadjusted incidence rate of any bleeding was 8.7 vs 4.3 events per 100 PY in diltiazem exposed group vs diltiazem unexposed group (unadjusted rate difference, 4.4; 95% CI, 1.0-7.8), and the risk of bleeding remained significant after controlling for potential cofounders (aHR, 1.90; 95% CI, 1.20-3.01).
• Compared with diltiazem unexposed group, patients in the diltiazem exposed group had a doubled risk of major bleeding. See Table: Risk of Any Bleeding-Related Hospitalization and Major Bleeding Associated with Concomitant Use of Diltiazem and XARELTO.
• In XARELTO users (n=1583), the risk of any bleeding related hospitalization was consistent in both patients with CKD (eGFR <60 mL/min per 1.73 m²) and without CKD (eGFR ≥60 mL/min per 1.73 m²) (P value for interaction = 0.638).
• In XARELTO users (n=1583), the risk of major bleeding was consistent in both patients with CKD (eGFR <60 mL/min per 1.73 m²) and without CKD (eGFR ≥60 mL/min per 1.73 m²) (P value for interaction = 0.843).

Seylani et al (2024)⁹ conducted a comparative retrospective cohort study evaluating the risk of GI bleeding associated with factor Xa inhibitors (XARELTO or apixaban) and dabigatran when coadministered with diltiazem or metoprolol in adults aged ≥18 years.

• The study utilized deidentified patient data from the TriNetX global network, which includes over 147 million patients across 120 healthcare systems.
  • Patients were categorized into the following 4 cohorts:
    • Cohort A: diltiazem vs metoprolol with apixaban or XARELTO
    • Cohort B: metoprolol with apixaban vs XARELTO
    • Cohort C: diltiazem with apixaban vs XARELTO
    • Cohort D: diltiazem vs metoprolol with dabigatran
  • Propensity score matching was applied to balance baseline characteristics, including age, sex, ethnicity, and comorbidities.
• GI bleeding risk assessed was as follows:
  • Cohort A: 6.3% in patients receiving diltiazem with apixaban or XARELTO versus 5.7% in those receiving metoprolol (RR, 1.09; 95% CI, 1.074-1.111; P<0.0001).
  • Cohort B: Among patients receiving metoprolol, 5.4% with apixaban versus 6.4% with XARELTO (RR, 0.85; 95% CI, 0.838-0.868; P<0.0001).
  • Cohort C: Among patients receiving diltiazem, 7.3% with XARELTO versus 5.8% with apixaban (RR, 1.23; 95% CI, 1.194-1.265; P<0.0001).
  • Cohort D: 7.4% in patients receiving diltiazem with dabigatran versus 6.71% in those receiving metoprolol (RR, 1.097; 95% CI, 1.038-1.16; P=0.0011).

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

The EINSTEIN program consists of 3 randomized trials of XARELTO:

1. The Acute DVT Study (EINSTEIN-DVT) - Treatment of acute DVT.
2. The Acute PE Study (EINSTEIN-PE) - Treatment of acute PE.
3. The Continued Treatment Study (EINSTEIN-Extension) - For the continued treatment in patients who have received treatment for either acute DVT or PE.

EINSTEIN-DVT

The Acute DVT Study (EINSTEIN-DVT) was a phase 3, randomized, open-label, event-driven, noninferiority trial that 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 VKA (warfarin or acenocoumarol) in patients with confirmed symptomatic DVT without symptomatic PE.³³

After randomization, in the intent-to-treat (ITT) population, there were 188/1731 (10.9%) patients on CCBs in the XARELTO group and 215/1718 (12.5%) on CCBs in the enoxaparin/VKA treatment group.¹⁰

EINSTEIN-PE

The Acute PE Study (EINSTEIN-PE) was a phase 3, randomized, open-label, event-driven, noninferiority study evaluating the efficacy and safety of oral XARELTO (15 mg twice daily for 3 weeks followed by 20 mg once daily) vs subcutaneous enoxaparin (1.0 mg/kg twice daily) followed by dose-adjusted oral VKA in patients with acute symptomatic PE with or without DVT.³⁴

In the ITT population, there were 391/2419 (16.2%) patients on CCBs in the XARELTO group and 376/2413 (15.6%) on CCBs in the enoxaparin/VKA treatment group.¹¹

EINSTEIN-Extension

The Continued Treatment Study (EINSTEIN-Extension) was a phase 3, randomized, double-blind, event-driven superiority study comparing XARELTO 20 mg once daily with placebo in patients with confirmed symptomatic PE or DVT who have been treated for 6-12 months with XARELTO or VKA.³³

In the ITT population, there were 64/602 (10.6%) patients on CCBs in the XARELTO treatment group and 80/594 (13.5%) on CCBs in the placebo group.¹²

In the EINSTEIN program, no post hoc analyses of safety and efficacy measures were performed for this subgroup of patients to identify potential pharmacodynamic (PD) drug interactions between XARELTO and CCBs.

Risk Reduction of Major Cardiovascular Events in Stable Coronary Artery Disease and Peripheral Artery Disease

The COMPASS study was a phase 3, event-driven, double-blind, randomized, controlled study designed to determine whether treatment with XARELTO 2.5 mg twice daily plus aspirin 100 mg once daily or XARELTO 5 mg twice daily alone is more effective than aspirin 100 mg once daily alone for prevention of MI, stroke, or cardiovascular death in patients with stable coronary artery disease (CAD) or peripheral artery disease (PAD).¹³

• A total of 27,395 patients were enrolled in the study with a mean age of 68.2 years.
• At baseline, there were 2413/9152 (26.4%) patients in the XARELTO plus aspirin group, 2374/9117 (26.0%) patients in the XARELTO alone group, and 2482/9126 (27.2%) patients in the aspirin alone group that were taking a CCB.

No post hoc analyses of safety and efficacy measures were performed for this subgroup of patients to identify potential PD drug interactions between XARELTO and CCBs.

Acute Coronary Syndrome

ATLAS ACS-2 TIMI-51 was a randomized, placebo-controlled, multicenter, event-driven trial to determine whether XARELTO (2.5 mg twice daily or 5 mg twice daily), when added to standard care, is safe and reduces the risk of the composite of cardiovascular death, MI, or stroke in subjects with acute coronary syndrome (ACS) compared with placebo. Low-dose aspirin (75-100 mg/day) was administered throughout the study to all patients. Patients were stratified by the investigator’s intention to administer a thienopyridine or not at the time of enrollment. Over 90% of patients received background therapy with a thienopyridine during the study.¹⁴

At baseline, there were 820 (15.8%) patients in the XARELTO 2.5 mg twice daily group and 764 (14.8%) patients in the placebo group that had taken a CCB prior to the first dose of study drug.¹⁴

No post hoc analyses of safety and efficacy measures were performed for this subgroup of patients to identify potential PD drug interactions between XARELTO and CCBs.

PHARMACOKINETICS/PHARMACODYNAMICS Study

Kim et al (2019)³⁵ evaluated the effects of verapamil and diltiazem on the pharmacokinetics (PK) and PD of rivaroxaban in rats.

• A total of 15 Sprague Dawley rats were randomized into 3 groups: a control group, a verapamil-treated group, and a diltiazem-treated group, each consisting of 5 rats.
• Rivaroxaban (2 mg/kg) was administrated in the presence or absence of either verapamil (25 mg/kg) or diltiazem (30 mg/kg). All drugs were suspended in corn oil and administered orally.
• Rivaroxaban plasma concentrations and prothrombin time were measured following oral administration of rivaroxaban in the presence or absence of either verapamil or diltiazem.
• A PK/PD modeling approach was used to analyze the data and determine the impact of concurrent drugs.
• Compared with the control group, verapamil, a strong P-gp/CYP inhibitor, was shown to significantly increase the systemic exposure of rivaroxaban (maximum plasma concentration [C_max] increased by 2.9-fold [P<0.01], area under the plasma concentration-time curve from zero to infinity [AUC_inf] increased by 2.8-fold [P<0.001], and clearance decreased by 63%), which was likely due to the inhibition of efflux transportation rather than metabolism. Prothrombin time was also prolonged in a proportional manner with verapamil, likely due to the increment of the systemic exposure of rivaroxaban.
• Overall, diltiazem, a moderate inhibitor, did not have a significant effect on the systemic exposure of rivaroxaban (significantly increased C_max, but no statistical difference in AUC_inf and clearance).

Cherniaeva et al (2024)³⁶ conducted a cross-sectional study to evaluate DDIs between XARELTO and P-gp inhibitors (using verapamil as an example), considering CYP3A4 (rs35599367) and CYP3A5 (rs776746) gene polymorphisms in patients with NVAF aged ≥80 years.

• The study included 128 Caucasian patients (median age, 87.5 years; 75% women) treated with once daily XARELTO (15 mg/day in 86.7% of patients and 20 mg/day in 13.3% of patients) for ischemic stroke prophylaxis between January 2019 and February 2020. The minimum steady-state concentration of rivaroxaban (C_min,ss); C_min,ss standardized to the daily drug dose (C_min,ss/D); plasma prothrombin time; and adverse drug reactions (ADRs) as CRNM bleeding, were assessed.
• For the CYP3A4 (rs35599367) polymorphism, most patients had the wild-type CC genotype (96.1%), but 3.9% of patients had the heterozygous ST genotype; no patients with a homozygous mutant TT genotype were identified. Patients were comparable in terms of sex, age, comorbidities, and the number of drugs used. No significant differences were observed between patients with the CC and ST genotypes in C_min,ss, C_min,ss/D, prothrombin time, or CRNM bleeding associated with rivaroxaban (P>0.05).
• Results of separate analyses of PK profiles of carriers with CC and CT genotypes, considering concomitant therapy with CCBs, are provided in Table: Effects of a Drugs with Potential Drug-Drug Interactions (Depending on the CYP3A4 [rs35599367] Gene Polymorphism) on Various Parameters. These analyses included evaluation of coadministration of rivaroxaban with amlodipine and verapamil.

• For the CYP3A5 (rs776746) polymorphism, most patients had the wild-type GG genotype (85.9%), but 12.5% of patients had the heterozygous GA genotype and 1.6% of patients had the homozygous mutant AA genotype; GA and AA carriers were combined for further analysis (14.1%). Patients were comparable in terms of sex, age, comorbidities, and the number of drugs used. No significant differences were observed between GG and GA + AA genotype carriers in C_min,ss, C_min,ss/D, prothrombin time, or CRNM bleeding associated with rivaroxaban (P>0.05).
• Results of separate analyses of PK profiles of carriers with GG and GA + AA genotypes, considering concomitant therapy with CCBs, are provided in Table: Effects of Drugs with Potential Drug-Drug Interactions (Depending on the CYP3A5 [rs776746] Gene Polymorphism) on Various Parameters. These analyses included evaluation of coadministration of rivaroxaban with amlodipine and verapamil.

Huang et al (2024)³⁷ developed and characterized Cyp3a1/2 and multidrug resistance (Mdr)1a/b quadruple gene knockout (qKO) rats to investigate DDIs between rivaroxaban and verapamil and to support prediction of drug metabolism and disposition in preclinical research.

• Male wild type (WT), Mdr1a/b knockout (KO), Cyp3a1/2 KO, and qKO rats were randomized into the following 3 groups (n=6 each): rivaroxaban + control (R + C), verapamil + control (V + C), and rivaroxaban + verapamil (R + V).
• Prior to the experiment, all rats were made to fast for 12 hours, while free access to water was maintained. Verapamil was prepared as a solution in normal saline at a concentration of 2 mg/mL, whereas rivaroxaban was formulated as a suspension in 0.5% (w/v) sodium carboxymethyl cellulose (CMC-Na) at 0.4 mg/mL. Both drugs were administered orally at a dosing volume of 5 mL/kg, and control groups received an equivalent volume of blank solvents.
• PK evaluation of verapamil was performed in WT, Mdr1a/b KO, Cyp3a1/2 KO, and qKO rats to further confirm the absence of CYP3A1/2 and P-gp activity. Verapamil (10 mg/kg) was used as a substrate.
  • Compared with WT rats, qKO rats exhibited a notable increase in C_max and AUC_0-t by 96.6% and 150.5%, respectively.
  • Furthermore, the half-life (t_1/2), time to reach C_max (T_max), and mean residence time (MRT) were prolonged by 203.8%, 54.6%, and 50.0%, respectively.
  • Clearance/bioavailability (CL/F) decreased by 64.5%, consistent with findings in Mdr1a/b KO and Cyp3a1/2 KO rats, indicating loss of CYP3A1/2 and P-gp function, respectively, in qKO rats.
• PK of rivaroxaban was assessed in WT, Mdr1a/b KO, Cyp3a1/2 KO, and qKO rats to evaluate the impact of CYP3A1/2 and P-gp deficiency.
  • Compared with WT rats, qKO rats showed no change in t_1/2 or MRT but showed an increase in T_max, C_max, and AUC_0-t, with C_max and AUC_0-t rising by 135.7% and 162.4%, respectively.
  • In contrast, CL/F and apparent volume of distribution at steady state (V_ss/F) decreased by 59.4% and 55.6%, respectively.
  • The ratio of the area under the concentration-time curve (AUC) in qKO rats to that in Mdr1a/b KO rats and Cyp3a1/2 KO rats was 1.53 and 1.37, respectively, indicating greater involvement of CYP3A in the in vivo PK of rivaroxaban compared with P-gp.
  • Similar trends were also observed in Mdr1a/b KO and Cyp3a1/2 KO rats, suggesting that both Cyp3a1/2 and P-gp contribute to the metabolism and disposition of rivaroxaban in vivo.
• Cyp3a1/2- and P-gp-mediated PK interactions between rivaroxaban and verapamil were evaluated using WT rats to assess the potential for DDIs. See Table: Pharmacokinetic Parameters of Rivaroxaban in WT, Mdr1a/b KO, Cyp3a1/2 KO, and qKO Rats.

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 7 May 2026.