SUMMARY  

• 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, international study designed to evaluate whether XARELTO 2.5 mg twice daily (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 cardiovascular (CV) and limb events in patients with symptomatic peripheral artery disease (PAD) undergoing lower extremity revascularization.¹

CLINICAL DATA

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

Definitions

The following definitions were used in the VOYAGER PAD trial:^2-4

• Myocardial Infarction (MI):
  • [Type 1, spontaneous; Type 2, ischemic imbalance] Detection of a rise and/or fall of cardiac biomarker values [preferably cardiac troponin (cTn)] with at least one value above the 99th percentile of the upper reference limit (URL) and with at least one of the following:
    • Symptoms of ischemia; New or presumed new, significant ST-segment–T wave (ST–T) changes or new left bundle branch block (LBBB); Development of pathological Q waves in the ECG; Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality; Identification of an intracoronary thrombus by angiography or autopsy [Type 1 only]
  • [Type 3] Cardiac death with symptoms suggestive of myocardial ischemia and presumed new ischemic ECG changes or new LBBB, but death occurred before cardiac biomarkers were obtained or before cardiac biomarker values would be increased.
  • [Type 4a] Percutaneous coronary intervention (PCI) related MI is defined as MI associated with, and occurring within 48 hours of PCI, with elevation of cardiac biomarker levels  (>5 x 99th percentile URL) in patients with normal baseline values (≤99th percentile URL); or a rise of cardiac biomarker levels values >20% if the baseline values are elevated and are stable or falling. In addition, at least one of the following:
    • Symptoms suggestive of myocardial ischemia (i.e., prolonged ischemia ≥ 20 minutes); new ischemic ECG changes or new LBBB; Angiographic loss of patency of a major coronary artery or a side branch or persistent slow flow or no flow or embolization; imaging demonstration of new loss of viable myocardium or new regional wall motion abnormality
  • [Type 4b] Stent thrombosis-associated with MI when detected by coronary angiography or autopsy in the setting of myocardial ischemia and with a rise and/or fall of cardiac biomarker values with at least one value above the 99th percentile URL.
  • [Type 4c] Stent restenosis-associated MI, as detected by coronary angiography or at autopsy, occurring >48 hours after PCI, without evidence of stent thrombosis but with symptoms suggestive of myocardial ischemia, and with elevation of cardiac biomarker values with at least one value above the 99th percentile URL.  The following criteria are also required:
    • Does not meet criteria for any other classification of MI
    • Presence of a ≥50% stenosis at the site of previous successful stent PCI or a complex lesion and no other obstructive CAD of greater severity following either initially successful stent deployment, or dilation of a coronary artery stenosis with balloon angioplasty to <50% stenosis.
  • [Type 5] Coronary artery bypass grafting (CABG)-related MI is defined as MI associated with, and occurring within 48 hours of CABG surgery, with elevation of cardiac biomarker values (>10 x 99th percentile URL) in patients with normal baseline cTn values (≤99th percentile URL). In addition, one of the following must also be present:
    • New pathological Q waves or new LBBB
    • Angiographic documented new graft or new native coronary artery occlusion
    • Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality
  • Operationally, if a site submits evidence consistent with a post-randomization silent or pathologic MI, these too will be adjudicated; One of the following in the absence of symptoms and/or biomarker evidence can be considered:
    • Development of new pathological Q waves in the ECG
    • Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality
    • Pathologic findings of an acute MI not otherwise meeting the above definitions
• Stroke
  • The new onset of focal or global neurological deficit caused by brain, spinal cord, or retinal vascular injury as a result of infarct or hemorrhage.  A stroke may be identified by the persistence of symptoms ≥24 hours, or by imaging, autopsy, or other evidence of infarct or hemorrhage.  Events adjudicated as a stroke will be classified as hemorrhagic, ischemic, or undetermined:
    • Hemorrhagic stroke (a component of the primary safety endpoint) will be diagnosed by appropriate clinical history and brain imaging (e.g. CT or MRI) that shows the presence of a blood mass (cerebral, intraventricular, or subarachnoid) consistent with the timing and localization of symptoms.  Microhemorrhages (<10mm) evident only on MRI are not considered to be hemorrhagic stroke.
    • Ischemic stroke (a component of the primary efficacy endpoint) will be diagnosed by appropriate clinical history; available brain imaging can demonstrate infarct lesion, edema, midline shift, or ventricular effacement consistent with the timing and localization of symptoms.
      • Hemorrhagic conversion of an ischemic infarction will be diagnosed by appropriate imaging that shows an ischemic infarction with localized confluent bleeding into necrotic tissue; this type of stroke will be categorized as ischemic.
      • Neurologic deficits that resolve with the administration of thrombolytic therapy (aborted stroke) will be adjudicated as ischemic stroke.
  • When, after acquisition of source documentation has been completed, the ICAC does not have sufficient information to distinguish between ischemic and hemorrhagic stroke, the stroke will be classified as ‘Undetermined.’
• CV death
  • Coronary Heart Disease death: death due to sudden cardiac death, MI, and the subset of death due to other cardiovascular causes that are secondary to a coronary revascularization procedure
    • Death due to cardiovascular causes occurring within 30 days after an acute MI, related to the immediate consequences of the MI, such as progressive heart failure or recalcitrant arrhythmia, will be considered CHD death.
  • Non-CHD death: death not attributable to the above CHD factors
• Acute Limb Ischemia
  • ALI is defined as clinical history of sudden significant worsening limb perfusion, requiring hospitalization and
    • a new pulse deficit with associated rest pain, pallor, paresthesia, or paralysis, and either:
      • confirmation of arterial obstruction by imaging, limb hemodynamics, intraoperative findings, or pathological evaluation; OR requiring thrombolysis, thrombectomy, or urgent revascularization.
• Major Amputation of Vascular Etiology
  • Major amputation of vascular etiology is operationally defined as above-the-ankle (or proximal-to-the-wrist in the upper extremity) amputation that is:
    • non-traumatic; and due to a vascular etiology, which includes worsening perfusion of the limb, but excludes foot sepsis, as the primary indication for amputation.
• Thrombolysis In Myocardial Infarction Study Group (TIMI) Major bleeding
  • Non-CABG-related Bleeding (any one of the following)
    • Any intracranial bleeding (excluding microhemorrhages <10 mm evident only on gradient-echo MRI); Clinically overt signs of hemorrhage associated with a drop in hemoglobin of ≥5 g/dL; if hemoglobin not available, drop in hematocrit ≥15%*; Fatal bleeding (bleeding that directly results in death within 7 days)
      • *Corrected for transfusion (1 U packed red blood cells or 1 U whole blood = 1 g/dL hemoglobin or 3% hematocrit change):
      • Δ Hgb = (Pre-Transfusion Hgb) – (Post-Transfusion Hgb) + (# transfused units)
      • Δ Hct = (Pre-Transfusion Hct) – (Post-Transfusion Hct) + (# transfused units x 3)
  • CABG-related Major Bleeding (any one of the following)
    • Fatal bleeding; Perioperative intracranial bleeding; Reoperation after closure of the sternotomy incision for the purpose of controlling bleeding; Transfusion of ≥5 units whole blood or red blood cells within a 48-hour period^† (cell saver products not counted); Chest tube output > 2L within a 24-hour period
• Non-major TIMI classifications
  • Minor Bleeding
    • Clinically overt bleeding (including imaging), associated with a drop in hemoglobin of 3 to <5 g/dL; if hemoglobin not available, drop in hematocrit 9 to <15%
      • Corrected for transfusion (1 U packed red blood cells or 1 U whole blood = 1 g/dL hemoglobin or 3% hematocrit change).
  • Medical Attention
    • Any clinically overt sign of hemorrhage that does not meet the definitions of major or minor bleeding above, that involves any one of the following:
      • Requiring intervention to stop the bleeding, including temporary or permanent changes to medications or study drug
      • Leading to prolonged hospitalization
      • Prompting evaluation (unscheduled visit to a healthcare professional with laboratory or imaging diagnostic testing)
  • Minimal Bleeding
    • Clinically overt bleeding (including imaging) that does not meet any of the above criteria, associated with a decrease in hemoglobin of <3 g/dL (decrease in hematocrit of <9%)
      • Corrected for transfusion (1 U packed red blood cells or 1 U whole blood=1 g/dL hemoglobin or 3% hematocrit change).
• Critical Limb Ischemia (CLI):
  • Patients with chronic ischemic rest pain, ulcers, or gangrene attributable to objectively proven arterial occlusive disease.  
  • Hemodynamics:  
    • Rest pain with ankle pressure 50 mm Hg or less and toe pressure 30 mm Hg or less
    • Tissue loss (ulcer or gangrene) 70 mm Hg or less and toe pressure 50 mm Hg or less
• Chronic Limb-Threatening Ischemia (CLTI):
  • A clinical syndrome defined by the presence of peripheral arterial disease and:
    • Rest pain
    • Ulceration of >2 weeks duration
    • Gangrene
  • Hemodynamics:
    • Rest pain with ankle pressure 50 mmHg or less and toe pressure 30 mmHg or less
    • Ulceration >2 weeks or any gangrene ankle pressure < 100 mmHg or toe pressure <60 mmHg

Study Outcomes

• Primary Efficacy Outcome: the composite of acute limb ischemia, major amputation of vascular etiology, myocardial infarction (MI), ischemic stroke, or CV death^2,4
• Principal Safety Outcome: Major bleeding according to TIMI classification^2,4
• Secondary Efficacy Outcomes:^2,4
  • ALI, major amputation of a vascular etiology, MI, ischemic stroke, or CHD death
  • Unplanned index limb revascularizations for recurrent limb ischemia
  • Vascular hospitalizations for a peripheral or coronary event of a thrombotic nature
  • ALI, major amputation of a vascular etiology, MI, ischemic stroke or all-cause mortality
  • ALI, major amputation of a vascular etiology, MI, all stroke or CV death
  • Death from any cause
  • VTE
• Secondary Safety Outcomes:^2,4
  • BARC major bleeding
  • ISTH major bleeding
• Exploratory Outcomes:^2,4
  • Subsequent limb revascularizations of a lower extremity that were not planned or considered as part of the initial treatment plan at the time of randomization
  • Above-ankle amputation of the index leg or major reintervention (eg, new bypass graft, jump/interposition graft revision, or thrombectomy/thrombolysis)
  • All-cause amputations
  • Patient reported outcomes using disease- and non–disease-specific questionnaires (EQ-5D and WIQ)
  • Serial changes in limb hemodynamics (ABI/TBI)

Inclusion Criteria

• 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 has provided written informed consent
• Patient understands and is 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 Criteria

• Patients undergoing revascularization for asymptomatic PAD or mild claudication without functional limitation
• Patients undergoing revascularization to treat asymptomatic or minimally symptomatic restenosis of a bypass graft or target lesion restenosis
• Prior revascularization on the index leg within 10 days of the qualifying revascularization
• Acute limb ischemia within 2 weeks prior to the qualifying revascularization
• Major tissue loss (defined as significant ulceration/gangrene proximal to the metatarsal heads) in either leg
• Clinical requirement for aspirin dose >100 mg daily
• Planned DAPT with clopidogrel for the qualifying revascularization procedure for >6 months
• Planned use of any additional antiplatelet agent other than clopidogrel and aspirin after the qualifying revascularization
• Clinical condition requiring systemic anticoagulation after the qualifying revascularization
• Any contraindication for aspirin or XARELTO
• 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, dependent of the investigator)
• Breast feeding

Study Design

• 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 daily.^2,4
• 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 procedures.^2,4
  • 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 end point events at study visits at 1, 3, and 6 months and then 6 months thereafter until the end of the trial.^2,4

Statistical Analyses

• All efficacy analyses were assessed on an intention-to-treat (ITT) basis in all randomized subjects, regardless of whether they received the trial treatment, in a time-to-event analysis from randomization to the first occurrence of any component of the outcome.^2,4
• Safety analyses were performed on the on-treatment analyses that included all patients who underwent randomization and had received at least one dose of trial medication; these analyses counted the first occurrence of the safety outcome from randomization through 2 days after permanent discontinuation of treatment.^2,4
• Event probabilities are expressed as Kaplan–Meier estimates of the cumulative incidence at 3 years after randomization.^2,4

Literature Search

A literature search of MEDLINE^® EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 13 December 2023.