Summary

• VOYAGER PAD (Vascular Outcomes Study of ASA alonG with Rivaroxaban in Endovascular or Surgical Limb Revascularization for peripheral artery disease [PAD]) was a phase 3, multicenter, randomized, placebo-controlled, double-blind, international study designed to evaluate whether XARELTO 2.5 mg BID plus aspirin 100 mg once daily is more effective than aspirin 100 mg once daily alone for the risk reduction of major atherothrombotic vascular outcomes consisting of both CV and limb events in patients with symptomatic PAD undergoing lower-extremity revascularization.¹
  • The primary efficacy outcome occurred in fewer patients in the XARELTO-plus-aspirin group than in the aspirin-alone group (508 patients [17.3%] vs 584 patients [19.9%]; hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.76-0.96; P=0.009) based on Kaplan-Meier estimates of the cumulative incidence at 3 years.
  • The principal safety outcome occurred in more patients in the XARELTO-plus-aspirin group than in the aspirin-alone group (62 patients [2.65%] vs 44 patients [1.87%]; HR, 1.43; 95% CI, 0.97-2.10; P=0.07) based on Kaplan-Meier estimates of the cumulative incidence at 3 years.
  • A prespecified subanalysis of 4379 (66.7%) patients who underwent endovascular revascularization was performed. Compared to the aspirin-alone group, the primary outcome occurred in fewer patients in the XARELTO-plus-aspirin group, but it did not reach statistical significance. A significant reduction in major adverse limb events (MALE) and acute limb ischemia occurred in the XARELTO-plus-aspirin group. No heterogeneity was noted with concomitant clopidogrel use or when comparing patients receiving endovascular revascularization to surgically treated patients.²
• 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 (BID) and aspirin 100 mg once daily or XARELTO 5 mg BID alone is more effective than aspirin 100 mg once daily alone for prevention of myocardial infarction (MI), stroke, or cardiovascular (CV) death in 27,395 patients with a history of stable atherosclerotic vascular disease (coronary artery disease [CAD] or PAD).³
  • A prespecified subanalysis of 7470 (~27%) patients with a history of PAD at baseline was conducted. The effects of XARELTO plus aspirin vs aspirin alone on the primary composite outcome of CV death, stroke, or MI and the safety outcome of modified International Society on Thrombosis and Haemostasis (ISTH) major bleeding were consistent with the overall COMPASS study results.⁴
    • The primary outcome occurred in 126 (5%) of 2492 patients who received XARELTO plus aspirin and in 174 (7%) of 2504 patients who received aspirin alone (HR, 0.72; 95% CI, 0.57-0.90; P=0.0047).
    • The XARELTO plus aspirin group had increased major bleeding compared with the aspirin alone group (77 [3%] of 2492 patients vs 48 [2%] of 2504 patients; HR, 1.61; 95% CI, 1.12–2.31; P=0.0089).
    • MALE were lower in the XARELTO plus aspirin group compared with the aspirin alone group (30 [1%] of 2492 patients vs 56 [2%] of 2504 patients; HR, 0.54; 95% CI, 0.35-0.84, P=0·0054).
    • Major amputations were fewer in the XARELTO plus aspirin group when compared with the aspirin alone group (HR, 0.30; 95% CI, 0.11-0.80).
    • For every 1000 patients treated, 27 major adverse cardiovascular events (MACE) or MALE including major amputation would be prevented, and 1 fatal and 1 critical organ bleed would be caused over a 21-month period.
  • Results were consistent in a prespecified subgroup of 6391 (~23%) patients with lower-extremity PAD at baseline. Compared with aspirin alone, the combination of XARELTO 2.5 mg BID plus aspirin reduced the risk of MALE, total vascular amputation, major vascular amputation, and vascular intervention and increased the risk of major bleeding.⁵
  • Results were consistent in a subset of 4129 (15%) patients with symptomatic lower-extremity PAD. Compared to aspirin alone, the combination of XARETO 2.5 mg BID plus aspirin reduced the risk of MACE, MALE (including major amputation), or both and increased the risk of major bleeding.⁶
• COMPASS LTOLE (Long Term Open Label Extension) was a long-term open-label extension of the COMPASS trial that assessed the safety and efficacy of XARELTO 2.5 mg BID plus aspirin 75 or 100 mg once daily in patients with CAD and/or PAD.⁷
  • The primary efficacy outcome (composite of stroke, MI, or CV death) occurred in 115 patients with PAD at a rate of 2.85 (95% CI, 2.35-2.42) per 100 patient-years (PY), and in 72 patients with CAD plus PAD at a rate of 2.93 (95% CI, 2.29-3.69) per 100 PY.
• An analysis was conducted to determine high-risk patients among patients with CAD and/or PAD selected to receive low-dose XARELTO and aspirin in a prospective, postapproval registry study called XATOA (Xarelto plus Acetylsalicylic acid: Treatment Patterns and Outcomes in Patients with Atherosclerosis).⁸
  • The cumulative incidence risk of primary outcomes (MACE or MALE) was the highest among patients with polyvascular disease at 13.58% over 24 months. The incidence risk was 9.16 per 100 PY in patients with polyvascular disease vs 2.48 per 100 PY in patients without polyvascular disease.
• XARELTO is not indicated for the reduction of symptoms related to PAD, such as intermittent claudication. The COMPASS study did not evaluate the efficacy of XARELTO alone or XARELTO in combination with aspirin for the reduction of intermittent claudication symptoms.³
• Additional references identified during the literature search are included in the REFERENCES section for your review.^9-14

CLINICAL STUDIES

VOYAGER PAD

VOYAGER PAD was a phase 3, multicenter, randomized, placebo-controlled, double-blind, international study designed to evaluate whether XARELTO 2.5 mg BID plus aspirin 100 mg once daily is more effective than aspirin 100 mg once daily alone for the risk reduction of major atherothrombotic vascular outcomes consisting of both CV and limb events in patients with symptomatic PAD undergoing lower-extremity revascularization.¹

Study Design/Methods

• A total of 6,564 patients were recruited from 542 centers in 34 countries between August 2015 and January 2018.
• Dosing interventions were as follows:
  • XARELTO 2.5 mg BID and aspirin 100 mg once daily
  • Placebo BID and aspirin 100 mg once daily
• Eligible participants with symptomatic PAD underwent successful revascularization for a lesion distal to the external iliac artery within the last 10 days
• Patients were stratified according to the type of index procedure underwent (endovascular vs. surgical) and according to clopidogrel use or nonuse within the group of patients who underwent an endovascular procedure
• Key Inclusion Criteria: Age 50 or older; moderate to severe PAD; abnormal ABI <0.80 or toe-brachial index (TBI) <0.60 without prior history of limb revascularization; abnormal ABI ≤0.85 or TBI <0.65 with prior history of limb revascularization
• Key Exclusion Criteria: Patients without functional limitation of the index leg; prior revascularization on the index leg within 10 days of the qualifying revascularization; patients with major tissue loss; patients requiring treatment with aspirin >100 mg; planned DAPT use for >6 months after revascularization procedure
• The median follow-up period was 28 months
• Primary Efficacy Outcome: the composite of ALI, major amputation of vascular etiology, MI, ischemic stroke, or CV death
• Principal Safety Outcome: Major bleeding according to Thrombolysis in Myocardial Infarction (TIMI) classification

Results

Baseline Characteristics

• Median age was 67 years; ~26.0% of patients were female; ~81% of patients were Caucasian
• Baseline medical history: 40% had diabetes mellitus; ~20% had an eGFR less than 60 mL/min/1.73m²; ~35.0% were current smokers; ~31.0% had a history of symptomatic CAD; ~11.0% had a MI; median ABI was 0.56; ~6.0% had a prior amputation; ~96.0% had a history of claudication
• Qualifying revascularization: ~65.0% had an endovascular procedure; ~35.0% treated surgically; ~36.0% had a history of a prior lower-extremity revascularization
• Baseline medication: ~80.0% used a statin; ~63.0% were on an angiotensin-converting-enzyme inhibitor or angiotensin-receptor blocker
• Approximately 51% of patients were given clopidogrel at randomization.

Outcomes

For efficacy and safety outcomes, see Tables: Efficacy Outcomes and Safety Outcomes.

COMPASS

COMPASS was a phase 3, event-driven, double-blind, randomized study designed to evaluate whether treatment with XARELTO 2.5 mg BID and 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 CV death in 27,395 patients with a history of stable atherosclerotic vascular disease (CAD or PAD).³

Study Design/Methods

• A total of 27,395 patients were recruited from 602 centers in 33 countries between February 2013 and May 2016.
• Key inclusion criteria included: PAD; CAD with ≥1 of the following: age ≥65 years or age <65 years and documented atherosclerosis or revascularization involving ≥2 vascular beds or ≥2 additional risk factors: current smoker (within 1 year of randomization), diabetes mellitus, renal dysfunction with estimated glomerular filtration rate (eGFR) <60 mL/min, heart failure (HF), or nonlacunar ischemic stroke ≥1 month ago.
• Key exclusion criteria included: stroke within 1 month or any history of hemorrhagic or lacunar stroke; severe HF with known ejection fraction <30% of New York Heart Association class III or IV symptoms; need for dual antiplatelet therapy (DAPT), other nonaspirin antiplatelet therapy, or oral anticoagulant therapy; eGFR <15 mL/min; systemic treatment with strong inhibitors of both cytochrome P (CYP)3A4 and P-glycoprotein or strong inducers of CYP3A4. Patients with atrial fibrillation (AF) requiring anticoagulation were also excluded.
• CAD was defined as previous MI or history of angina with multivessel disease, or multivessel revascularization.¹⁵
• Dosing interventions were as follows:
  • XARELTO 2.5 mg BID and aspirin 100 mg once daily
  • XARELTO 5 mg BID and placebo once daily
  • Placebo BID and aspirin 100 mg once daily
• Patients who were not already receiving a proton pump inhibitor were randomized, using a partial factorial design, to receive pantoprazole 40 mg once daily or placebo for prevention of upper gastrointestinal (GI) complications.
• Eligible participants (except those who underwent randomization 4 to 14 days after coronary artery bypass graft [CABG] surgery) entered a run-in phase during which they received a XARELTO-matched placebo BID and aspirin at a dose of 100 mg once daily.
• Primary efficacy outcome: the composite of MI, stroke, or CV death
• Primary safety outcome (based on modified ISTH criteria): major bleeding, including fatal bleeding, symptomatic bleeding into a critical organ, bleeding into a surgical site requiring reoperation, and bleeding leading to hospitalization (including presentation to an acute care facility without overnight stay)

Results

Baseline Characteristics

• Mean age was 68.2 years, 22.0% of patients were female, 90.6% had a history of CAD, and 27.3% had a history of PAD.
• Vital status was available for 27,331 (99.8%) patients up to February 6, 2017; the mean duration of follow-up for these patients was 21 months (maximum duration of 47 months).²

Efficacy/Safety

• For efficacy and safety outcomes, see Table: Primary Efficacy and Safety Outcomes in Overall COMPASS Patients.

Extension of COMPASS⁷

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 09 July 2024.