Use of XARELTO in Carotid or Coronary Artery Disease and Nonvalvular Atrial Fibrillation

SUMMARY

• In the ROCKET AF trial, 4.2% of patients had carotid artery disease (CD), with 49% randomized to XARELTO.¹
  • Patients with and without CD had similar rates of stroke or systemic embolism and major or non-major clinically relevant (NMCR) bleeding.¹
  • Efficacy measures of stroke or systemic embolism and safety measures of major or NMCR relevant bleeding were not significantly different between XARELTO and warfarin among patients with CD vs those without CD.¹
• A subanalysis of the ROCKET AF trial reported there were 36.5% of patients taking aspirin at baseline, with 30.6% of those patients having coronary artery disease (CAD).²
• In COMPASS, patients with atrial fibrillation (AF) requiring treatment with anticoagulants were excluded. AF occurred in 365 (1.5%) patients with CAD in the trial.³
  • Patients that developed AF during the study were required to interrupt treatment with XARELTO and XARELTO placebo to receive anticoagulant treatment until they no longer had a need for non-study anticoagulant treatment. Aspirin and aspirin placebo were interrupted for anticoagulant treatment at the discretion of the investigator.⁴
• The Atrial Fibrillation and Ischemic Events with Rivaroxaban in Patients with Stable Coronary Artery Disease (AFIRE)⁵ trial was a randomized, multicenter, open-label, non-inferiority trial in Japanese adults with nonvalvular atrial fibrillation (NVAF) and stable CAD.
  • This trial showed non-inferiority of XARELTO alone compared to combination XARELTO plus a P2Y₁₂ inhibitor for the primary composite efficacy endpoint. In analyses which were not prespecified, XARELTO alone showed superiority for both the primary efficacy and safety endpoints.
• The EXPAND (Evaluation of Effectiveness and Safety of Xa Inhibitor for the Prevention of Stroke and Systemic Embolism in a Nationwide Cohort of Japanese Patients Diagnosed as NVAF) study was a multicenter, prospective, observational cohort study that assessed the efficacy and safety of XARELTO in patients with NVAF in routine clinical practice.⁶
  • A subanalysis of the EXPAND study evaluated the risks and benefits of XARELTO alone vs XARELTO plus single antiplatelet therapy (APT) in patients with NVAF and stable cardiovascular (CV) disease, including CAD, ischemic stroke (including transient ischemic attack [TIA]), and peripheral artery disease (PAD).
    • Efficacy outcomes, including stroke plus systemic embolism, stroke plus systemic embolism plus myocardial infarction (MI) plus CV death, and all-cause death, did not differ significantly between the APT (+) and APT (-) groups.
    • In the PAD subcohort, rates of stroke plus systemic embolism and stroke plus systemic embolism plus MI plus CV death were comparable between the treatment groups. However, the all-cause death rate was higher in the APT (+) group than in the APT (-) group (5.59 vs 1.33 events/100 person-years; adjusted hazard ratio [aHR], 4.43; 95% CI, 1.05-18.71; P=0.043).
• A retrospective, observational study compared effectiveness, safety, and cost outcomes in patients with NVAF and CAD and/or PAD prescribed apixaban vs XARELTO.⁷
  • Patients on XARELTO had a higher risk of stroke/systemic embolism and major bleeding compared to apixaban.
• Lopes et al (2018)⁸ completed a retrospective, observational study in which XARELTO was compared to warfarin using propensity score matching in patients with NVAF and CAD and/or PAD.
  • Compared to warfarin, stroke/systemic embolism, all-cause mortality (ACM), stroke/MI/ACM, and stroke/MI/ACM/revascularization occurred at a lower rate in the XARELTO group.
  • However, patients in the XARELTO group experienced a significantly higher rate of major bleeding compared to warfarin.
• Coleman et al (2020)⁹ completed a retrospective claims analysis consisting of commercial and Medicare supplemental databases. The study identified oral anticoagulant naïve NVAF patients with comorbid CAD and/or PAD receiving XARELTO (15-20 mg once daily) or warfarin.
  • Among patients with NVAF and comorbid CAD and/or PAD, XARELTO use was associated with a reduced risk of major thrombotic vascular events (MTVEs) vs warfarin.
  • There was no significant difference in major bleeding risk between the XARELTO and warfarin cohorts.

CLINICAL STUDIES

Use in Carotid Artery Disease and Nonvalvular Atrial Fibrillation (NVAF)

ROCKET-AF

The ROCKET AF trial was a randomized, double-blind, double-dummy, active-controlled, parallel-group, multi-center, event-driven, non-inferiority study designed to evaluate the efficacy and safety of fixed-dose oral XARELTO 20 mg once daily (15 mg for patients with creatinine clearance [CrCl] 30-49 mL/min) vs dose-adjusted warfarin (target international normalized ratio [INR]: 2 to 3) for the prevention of stroke and systemic embolism in patients with NVAF at moderate-to-high risk for stroke.¹⁰

The primary efficacy endpoint was the composite of stroke (ischemic or hemorrhagic) and systemic embolism. The primary safety endpoint was the composite of major or NMCR bleeding. The median duration of treatment exposure was 590 days; the median follow-up period was 707 days.¹⁰

Kochar et al (2018)¹ conducted a post-hoc subgroup analysis of the ROCKET AF trial to evaluate the efficacy and safety of XARELTO compared with warfarin in patients with and without CD.

• CD was defined as patients with a history of carotid occlusive disease or history of carotid revascularization (carotid stenting or carotid endarterectomy).
• A total of 593 (4.2%) patients in ROCKET AF had a diagnosis of CD, with 293 (49%) randomized to XARELTO. Of CD patients, 27% (n=158) had prior carotid endarterectomy, 8% (n=49) had prior carotid artery stenting, and 2% (n=9) had both prior carotid enterectomy and angioplasty/stenting.
• Patients with CD were older, had higher average CHADS₂ scores, and had higher rates of several comorbidities, including prior MI, transient ischemic attack, prior stroke, and non-central nervous system embolism, compared to patients without CD.

Outcomes in Patients With and Without Carotid Artery Disease

• The overall rate of stroke or systemic embolism was similar among patients with CD vs those without CD (2.95 vs 2.24 events/100 patient-years [PY]; aHR: 0.99, 95% CI: 0.66-1.48; P=0.96).
• The overall rate of major or NMCR bleeding was similar among patients with CD compared with those without CD (18.02 vs 14.58 events/100 PY; (aHR, 1.04; 95% CI, 0.88-1.24; P=0.62).

XARELTO vs Warfarin in Patients With and Without Carotid Artery Disease

• The primary efficacy outcome of stroke or system embolism in XARELTO- and warfarin-treated patients was not statistically significant in patients with CD vs without CD (P=0.25).
• The relative risk for the primary safety outcome of major or NMCR bleeding in XARELTO- and warfarin-treated patients was similar in patients with CD vs without CD (P=0.64).
• The analysis of patients with CD in the ROCKET AF trial was not prespecified.
• See Table: Treatment Comparisons for Efficacy and Safety Endpoints in Patients With and Without CD for detailed information.

Use in CAD and NVAF

COMPASS

The COMPASS trial was a phase 3, event-driven, double-blind, randomized, controlled study that compared treatment with XARELTO (2.5 mg twice daily) plus aspirin (100 mg once daily) vs aspirin (100 mg once daily) with a XARELTO-matched placebo twice daily or XARELTO alone (5 mg twice daily) with an aspirin-matched placebo once daily vs aspirin (100 mg once daily) with a XARELTO-matched placebo twice daily in patients with stable CAD or PAD. Patients with AF requiring anticoagulation were excluded.^3,11

The primary efficacy outcome was the composite of CV death, stroke, and MI and the principal safety outcome was major bleeding.¹¹

Connolly et al (2018)³ conducted a pre-specified subgroup analysis of 24,824 patients with CAD from the COMPASS trial.

• CAD was defined as: MI within 20 years, multi-vessel CAD, history of stable or unstable angina, previous multi-vessel percutaneous coronary intervention (PCI), or previous multi-vessel coronary artery bypass graft surgery (CABG).
  • Patients with CAD were also included if they had CABG surgery within 4 to 14 days, with ≥24 hours since removal of chest tubes, and ≥12 hours after last receiving an anticoagulant.
• AF occurred in 365 (1.5%) patients during the trial, spread evenly across treatment groups.
• In patients that developed AF, strokes occurred in 7% (5/74), 8% (8/105), and 7% (9/130) of patients in the XARELTO plus aspirin group, XARELTO alone group, and the aspirin alone group, respectfully.
• Patients that developed AF during the study were required to interrupt treatment with XARELTO and XARELTO placebo to receive anticoagulant treatment until they no longer had a need for non-study anticoagulant treatment. Aspirin and aspirin placebo were interrupted for anticoagulant treatment at the discretion of the investigator.⁴
• The effects of XARELTO plus aspirin vs aspirin alone on the primary composite outcome of CV death, stroke, or MI and safety outcome of modified International Society on Thrombosis and Haemostasis (ISTH) major bleeding were consistent with the overall COMPASS study results.

ROCKET-AF

The ROCKET AF trial was a randomized, double-blind, double-dummy, active-controlled, parallel-group, multi-center, event-driven, non-inferiority study designed to evaluate the efficacy and safety of fixed-dose oral XARELTO 20 mg once daily (15 mg for patients with creatinine clearance 30-49 mL/min) vs dose-adjusted warfarin (target INR: 2 to 3) for the prevention of stroke and systemic embolism in patients with NVAF at moderate-to-high risk for stroke.¹⁰

The primary efficacy endpoint was the composite of stroke (ischemic or hemorrhagic) and systemic embolism. The primary safety endpoint was the composite of major or NMCR bleeding. The median duration of treatment exposure was 590 days; the median follow-up period was 707 days.¹⁰

Shah et al (2016)² conducted a subgroup analysis of patients who received aspirin at baseline in the ROCKET AF study in order to investigate the relationship between aspirin use and clinical outcomes, particularly in those with CAD.

• CAD was defined as a history of MI, PCI, or CABG surgery.
• Of the 14,264 patients in ROCKET AF, 5205 (36.5%) reported taking aspirin at baseline (mean daily dose of 99.2 mg). Of those, 30.6% had known CAD.
• Those receiving aspirin at baseline had significantly higher rates of prior MI (22% vs 14%; P<0.0001) and congestive heart failure (68% vs 59%; P<0.0001).
• A significant interaction between baseline aspirin use and CAD was observed in all-cause death (P=0.009) and vascular death (P=0.041). For patients without CAD and continued aspirin use, the interaction only remained significant for all-cause death (P=0.027).
• Regardless of CAD diagnosis, there was an increased risk of major or NMCR bleeding in patients taking baseline aspirin. See Table: Efficacy and Safety Endpoints in Patients With And Without CAD for detailed results.
• In patients with CAD and baseline aspirin use, the cause of death was vascular in nature in 70.8% of deaths, as compared with 67.3% of deaths in patients with CAD not taking baseline aspirin.

AFIRE

The AFIRE⁵ trial was a randomized, multicenter, open-label, non-inferiority trial in Japanese adults with NVAF and stable CAD. Patients were required to have a CHADS₂ score ≥ 1 and had either history of PCI ≥1 year prior to enrollment, history of angiographically confirmed CAD not requiring revascularization, or history of CABG ≥1 year before enrollment.

• Patients were assigned 1:1 to XARELTO 15 mg once daily (dose reduced to 10 mg daily with CrCl 15-49 mL/min) or a combination of XARELTO plus an antiplatelet agent (aspirin or a P2Y₁₂ inhibitor, based on physician choice).
• The primary efficacy endpoint was the composite of stroke, systemic embolism, MI, unstable angina requiring revascularization, or death from any cause. The primary safety endpoint was major bleeding.
• The secondary endpoints included individual components of the composite, as well as any bleeding events.

Results

A total of 2240 patients were enrolled with a mean age 74 years, 79% male, majority had previous PCI, median CHADS₂ score 2. In the combination therapy group, ~70% received aspirin. The study was terminated early due to higher risk of death from any cause in the

combination therapy group in July 2018. Median treatment duration was 23 months (interquartile range [IQR] of 15.8-31); median follow-up 24.1 months (IQR, 17.3-31.5).

This trial showed non-inferiority of XARELTO alone compared to combination XARELTO plus a P2Y₁₂ inhibitor for the primary composite efficacy endpoint. In analyses which were not prespecified, XARELTO alone showed superiority for both the primary efficacy and safety endpoints. See Table: AFIRE Efficacy and Safety Results.

• Results were similar across all prespecified subgroups.

EXPAND

The EXPAND study (N=7141) was a multicenter, prospective, observational cohort study conducted in Japanese patients with NVAF to assess the efficacy and safety of XARELTO in routine clinical practice. Eligible patients were ≥20 years of age with NVAF and had initiated XARELTO 10 mg/day or 15 mg/day (approved doses in Japan). Patients receiving XARELTO with or without concomitant APT at treatment initiation were included.⁶

Kaikita et al (2025) conducted a subanalysis of the EXPAND study to assess the risks and benefits of XARELTO alone vs XARELTO plus single APT in 2030 patients with stable CV disease, including CAD, ischemic stroke, or PAD.

• The analysis population comprised an ALL cohort (n=2030) and 3 subcohorts: CAD (n=886), STROKE (n=1231), and PAD (n=160). Patients in the ALL cohort and each subcohort were further categorized into APT (-) and APT (+) groups. Age was generally similar between the APT (+) and APT (-) groups across the subcohorts. However, in the CAD subcohort, the mean (SD) age differed significantly between the APT (+) and APT (-) groups (73.4 [7.9] years vs 74.7 [8.0] years, respectively; P=0.013).

Results

• In the ALL cohort and the CAD and STROKE subcohorts, no significant differences were observed between the APT (+) and APT (-) groups in the efficacy outcomes of stroke plus systemic embolism, stroke plus systemic embolism plus MI plus CV death, and
  all-cause death.
• In the PAD subcohort, no significant differences were reported between the APT (+) and APT (-) groups for stroke plus systemic embolism or stroke plus systemic embolism plus MI plus CV death.
• However, the all-cause death rate was higher in the APT (+) group (5.59 events/100 person-years) than in the APT (-) group (1.33 events/100 person-years), with an aHR of 4.43 (95% CI, 1.05-18.71; P=0.043). See Table: Events, Rates, aHRs, and 95% CIs for the Efficacy and Safety Outcomes With Concomitant Use of APT.⁶

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 06 July 2026.