XARELTO®: VOYAGER clinical trial in patients with PAD post LER1,2

VOYAGER: The ONLY successful trial resulting in an indication for PAD post LER*1,2

voyager_sd

TRIAL DESIGN‡1,2

VOYAGER PAD (Vascular Outcomes Study of ASA Along With Rivaroxaban in Endovascular or Surgical Limb Revascularization for PAD) was a phase 3, multicenter, randomized, placebo-controlled, double-blind, event-driven, international study designed to evaluate whether XARELTO® 2.5 mg twice daily (BID) plus aspirin (ASA) 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 cardiovascular (CV) and limb events in patients with symptomatic PAD who have recently undergone LER.2

  • Eligible subjects were randomized in a 1:1 ratio to receive either XARELTO® 2.5 mg BID or placebo BID, with all subjects receiving standard background therapy of aspirin 100 mg daily2,3
  • Randomization was stratified by type of procedure and use of clopidogrel into the following 3 groups: surgical, endovascular with clopidogrel, or endovascular without clopidogrel. Subjects receiving both surgical and endovascular techniques were stratified as endovascular procedures2,3
    • Patients were eligible after a successful revascularization procedure performed for symptoms within the previous 10 days
  • Subjects were assessed for adverse events and potential study endpoint events at study visits 1, 3, and 6 months and then 6 months thereafter until the end of the trial2,3
  • The median age of patients enrolled in VOYAGER was 67 years. Risk factors were common among both treatment arms: 40% of patients suffered from diabetes mellitus; 20% had an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m² of BSA; 35% were active smokers at randomization; 31% had known coronary disease; and 11% had previous myocardial infarction (MI)2
Voyager procedural characteristics
  • A majority of patients enrolled in VOYAGER had a past history of claudication and a median ABI of 0.56. Of the patients who underwent a revascularization, 65% had an endovascular procedure and 35% had been treated surgically
  • Patients were eligible after a successful revascularization procedure performed within the previous 10 days for symptoms of peripheral artery disease

Inclusion Criteria2,3

  • Age 50 years
  • Documented moderate to severe symptomatic lower extremity atherosclerotic PAD, evidenced by all of the following:
    • Functional limitation in walking activity, rest pain, or ischemic ulceration
    • Imaging evidence within the past 12 months of PAD distal to the external iliac artery
    • Abnormal hemodynamics with either:
      • ABI 0.80 or TBI 0.60 for patients with no prior history of revascularization
      • ABI 0.85 or TBI 0.65 for patients with prior history of revascularization
    • Technically successful peripheral revascularization distal to the external iliac artery within the last 10 days prior to randomization
    • Patient or legal representative provided written informed consent
    • Patient understood and was willing and able to comply with study instructions and follow-up
    • Negative serum pregnancy test result and agreement to use adequate contraception (women of childbearing potential only)

Exclusion Criteria2,3

  • Patients undergoing revascularization for asymptomatic PAD or mild claudication without functional limitation of the index leg
  • Patients undergoing revascularization of the index leg to treat an asymptomatic or minimally symptomatic restenosis of a bypass graft or target lesion restenosis
  • Acute limb ischemia (ALI) within 2 weeks prior to the qualifying revascularization
  • Patients requiring treatment with ASA at doses >100 mg
  • Prior revascularization on the index leg within 10 days of the qualifying revascularization
  • Planned dual antiplatelet therapy (DAPT) use for the qualifying revascularization procedure of clopidogrel in addition to aspirin for >6 months after the qualifying revascularization procedure; it is strongly recommended that any course of clopidogrel is kept to the minimum necessary in accordance with local standard of care and international practice guidelines (typically 30 days, or up to 60 days for some drug-coated products or devices) and is only allowed for up to 6 months for complex procedures or devices in the investigator's opinion that require longer use
  • Planned use of any additional antiplatelet agent other than clopidogrel and ASA after the qualifying revascularization procedure
  • Clinical condition requiring systemic anticoagulation after the qualifying revascularization
  • Any contraindication for aspirin or rivaroxaban
  • Systemic treatment with strong inhibitors of both cytochrome P450 isoenzyme 3A4 and p-glycoprotein anticipated after randomization or during the study
  • Active or recent (within 6 months) condition considered to pose a significant risk for major bleeding
  • Hepatic disease associated with coagulopathy or bleeding risk
  • Requirement for dialysis or renal replacement therapy, or renal impairment assessed by an eGFR <15 mL/min/1.73 m2
  • Acute coronary syndrome within 30 days prior to randomization
  • Major trauma or accidents within 30 days prior to randomization
  • Any medically documented history of intracranial hemorrhage, stroke, or transient ischemic attack
  • Active malignancy (excluding local basal or squamous cell carcinoma)
  • Poorly controlled diabetes or severe uncontrolled hypertension
  • Life expectancy <1 year
  • Previous assignment to study drug during this study
  • Previous or concomitant participation in another clinical study with investigational product(s)
  • Close affiliation with the investigational site (eg, relative or dependent of the investigator)
  • Breast feeding

ABI = ankle-brachial index; ACEi = angiotensin-converting enzyme inhibitor; ALI = acute limb ischemia; ARB = angiotensin II receptor blocker; BARC = Bleeding Academic Research Consortium; BSA = body surface area; CHD = coronary heart disease; eGFR = estimated glomerular filtration rate; ISTH = International Society on Thrombosis and Haemostasis; IQR = interquartile range; LER = lower extremity revascularization; PAD = peripheral artery disease; Q6 = every 6 months; TBI = traumatic brachial injury; TIMI = Thrombolysis in Myocardial Infarction; WIQ = Walking Impairment Questionnaire.

*Including patients after recent LER due to symptomatic PAD.
Patients on placebo received aspirin 100 mg once daily.
Treatment schedule: XARELTO® 2.5 mg twice daily versus placebo; all patients received aspirin 100 mg once daily as background therapy.