Summary

• 5.9% of patients in ROCKET AF trial had peripheral artery disease (PAD), with 47.8% randomized to XARELTO and 52.2% randomized to warfarin.¹
  • Patients with and without PAD had similar rates of stroke or systemic embolism and major or non-major clinically relevant bleeding. Efficacy of XARELTO vs. warfarin for the prevention of stroke or systemic embolism was similar among patients with PAD and those without PAD. In patients with PAD compared with those without PAD, there was a higher risk of major or non-major clinically relevant bleeding with XARELTO when compared with warfarin.¹
• In the COMPASS study which evaluated patients with stable coronary artery disease (CAD) or PAD, patients with atrial fibrillation requiring treatment with anticoagulants were excluded. Atrial fibrillation was reported in 392/27,395 (1.4%) patients from the entire study population.²
  • Patients that developed atrial fibrillation 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.³
• In a retrospective analysis of claims data from January 2012 to December 2017, nonvalvular atrial fibrillation patients with comorbid CAD and/or PAD using XARELTO had a significant reduction, 32% (95% CI. 8-50), of major thrombotic vascular events (MTVEs) versus warfarin (4.21 vs. 7.15 events per 100 person years). There was no significant difference in major bleeding, intracranial hemorrhage, or gastrointestinal bleeding with XARELTO compared to warfarin.⁴
• Additional articles identified during a literature search are included in the REFERENCES section for your review.^{5, 6,7}

CLINICAL STUDIES

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 international normalized ratio [INR], 2.0 to 3.0) for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (AF) at moderate-to-high risk for stroke.⁸

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 non-major clinically relevant bleeding. The median duration of treatment exposure was 590 days; the median follow-up period was 707 days.⁸

Jones et al (2014)¹ conducted a substudy of the ROCKET AF trial to evaluate the efficacy and safety of XARELTO compared with warfarin in patients with and without PAD, which included intermittent claudication, amputation for arterial insufficiency, vascular reconstruction, bypass surgery, percutaneous intervention to the extremities, or previously documented abdominal aortic aneurysm.

• A total of 839 (5.9%) patients in ROCKET AF had a diagnosis of PAD at the time of entry into the study, with 401 (47.8%) randomized to XARELTO and 438 (52.2%) randomized to warfarin; 17% had undergone prior surgical revascularization for PAD and 14% had undergone prior peripheral angioplasty without stenting.
• Patients with PAD were older, more likely to be male, have a higher CHADS2 score, and more likely to have a prior diagnosis of HF, myocardial infarction (MI), DM, or chronic obstructive pulmonary disease.
• More patients with PAD vs. those without PAD were utilizing vitamin K antagonists, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta blockers, and diuretics at baseline. Greater use of daily aspirin (ASA), clopidogrel, and any anti-platelet agent (ASA, clopidogrel, or dipyridamole) was also noted in patients with PAD vs. those without PAD at 1 year and at the time of study medication discontinuation.
• Median exposure to study drug was 564 days in patients with PAD and 592 days in patients without PAD; median duration of follow-up was 730 days vs. 718 days, respectively.
• Median proportion of time in the therapeutic INR range was 59% among warfarin-treated patients with PAD vs. 58% among warfarin-treated patients without PAD.

Outcomes in Patients With and Without Peripheral Artery Disease¹

• The overall rate of stroke or systemic embolism was similar among patients with PAD compared with those without PAD (2.41 vs. 2.09 events/100 patient-years; adjusted HR, 1.04; 95% CI, 0.72–1.50; P=0.84).
• The overall rate of major or non-major clinically relevant bleeding was also similar among patients with PAD compared with those without PAD (17.81 vs. 14.54 events/100 patient-years; HR, 1.11; 95% CI, 0.96–1.28; P=0.17).

XARELTO vs. Warfarin in Patients With and Without Peripheral Artery Disease¹

• See Table: Treatment Comparisons for Efficacy and Safety Endpoints in Patients With and Without PAD.
• The primary efficacy outcome of stroke or systemic embolism in XARELTO- and warfarin-treated patients was similar in patients with PAD (2.61 vs. 2.23 events/100 patient-years, respectively; HR, 1.19; 95% CI, 0.63-2.22) and without PAD (1.93 vs. 2.25 events/100 patient-years, respectively; HR, 0.86; 95% CI, 0.73-1.02; P=0.34 for interaction).
• The relative risk for the primary safety outcome of major or non-major clinically relevant bleeding was significantly higher for XARELTO compared with warfarin in patients with PAD (21.02 vs. 15.12 events/100 patient-years, respectively; HR, 1.40; 95% CI, 1.061.86) than in those without PAD (14.59 vs. 14.48 events/100 patient-years, respectively; HR, 1.03; 95% CI, 0.95–1.11; P=0.037 for interaction).
• A non-statistically significant trend towards a higher risk of major bleeding was observed with XARELTO vs. warfarin in patients with PAD (HR, 1.76; 95% CI, 1.04–2.95) compared with those without PAD (HR, 1.03; 95% CI, 0.89–1.19; P=0.053 for interaction), as the result of bleeding events adjudicated as major due to drops in hemoglobin levels or transfusions of packed red blood cells. Two fatal and 5 intracranial bleeding events were observed in patients with PAD.

COMPASS

COMPASS (Cardiovascular OutcoMes for People Using Anticoagulation StrategieS) was a phase 3, event-driven, double-blind, randomized study designed to evaluate whether treatment with XARELTO 2.5 mg twice daily plus aspirin 100 mg once daily or XARELTO 5 mg BID alone is more effective than aspirin 100 mg once daily alone for prevention of MI, stroke, or cardiovascular (CV) death in patients with a history of stable atherosclerotic vascular disease (CAD or PAD). Patients with atrial fibrillation requiring anticoagulation were excluded.²

• The primary efficacy outcome was the composite of CV death, stroke, and MI and the principal safety outcome was modified ISTH major bleeding.²
• Atrial fibrillation was reported in 392/27,395 (1.4%) patients from the entire study population. Of these patients with atrial fibrillation, 26/392 experienced a stroke.²
• Patients that developed atrial fibrillation 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.³

Retrospective Studies

Coleman et al (2018) conducted an analysis of US Truven MarketScan administrative claims data from January 1, 2012 to December 31, 2017 to identify patients with NVAF and comorbid CAD and/or PAD.  The primary effectiveness endpoint was the composite of any MTVE including ischemic stroke, MI, or major adverse limb event including surgical and/or percutaneous lower limb revascularization or major amputation. The primary safety was any major bleeding.⁴

• A total of 3,257 patients using 15mg or 20mg XARELTO and 5,046 warfarin patients were eligible for inclusion in the study.  Approximately 45% of all the patients had PAD and 47% of patients had CAD, with 21% having both PAD and CAD.  Approximately 19% of the PAD patients had a prior major adverse limb event.
• The study followed individuals until an outcome occurrence, the index oral anticoagulant (OAC) was discontinued, insurance disenrollment or end of study date.  The median duration of available follow-up was 1.4 (0.6, 2.7) years and the time on index OAC was 112 (38, 260) days.  
• XARELTO significantly (32%, 95% CI, 8-50) reduced the risk of a MTVE compared with warfarin (rates = 4.21 vs 7.15 events per 100-person-years). There was no significant difference in major bleeding (HR, 1.13, 95% CI, 0.84–1.52) between the XARELTO and warfarin groups.  Details are presented in the table below.

• A subgroup analysis was conducted involving PAD, CAD and comorbid CAD/PAD and is presented in the table below.

• The main limitations of this study included:
  • Multiple biases including misclassification, selection or sampling bias and confounding by indication may impact a study’s internal validity.
  • The number of patients included was not determined based upon a sample size calculation and underpowering is possible.
  • The study used US commercial and Medicare advantage claims data and the results are generalizable to an insured US population with NVAF and concomitant CAD and/or PAD.
  • The use of aspirin could not be assessed and its impact on MTVE or major bleeding.
  • The study did not have access to vital sign or laboratory data to determine proper dosing of XARELTO or warfarin.
  • Residual confounding cannot be fully excluded due to the possibility of confounding from unobserved or unmeasured covariates.

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.