Summary

• 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) 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 major cardiovascular events (myocardial infarction [MI], stroke, or cardiovascular [CV] death) in patients with a history of stable atherosclerotic vascular disease.¹

BACKGROUND

The steering committee of COMPASS, consisting of Population Health Research Institute (PHRI) investigators, the National Leaders, and sponsor representatives, was responsible for the development of the study protocol and for the conduct and oversight of the study. Institutional review boards and health authorities from all participating countries approved the study protocol, and written informed consent was obtained from all study participants.²

The inclusion and exclusion criteria were derived in partnership with an academic research organization in order to identify patients with stable atherosclerotic vascular disease who could potentially benefit from XARELTO or XARELTO in combination with aspirin.³

The COMPASS study was terminated earlier than planned based on the recommendation of the study’s independent Data Monitoring and Safety Committee, as the primary endpoint (composite of MI, stroke or CV death) reached its prespecified criteria for superiority.^1,4

Additional information and the study protocol may be found on clinicaltrials.gov by using the following link here.⁵

CLINICAL STUDY - COMPASS

COMPASS was a phase 3, event-driven, double-blind, randomized study designed to evaluate whether treatment with XARELTO 2.5 mg BID 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 CV death in patients with a history of stable atherosclerotic vascular disease (coronary artery disease [CAD] or peripheral artery disease [PAD]). In an additional randomized comparison, pantoprazole is being compared with placebo in patients participating in the COMPASS trial that were not receiving a proton-pump inhibitor (PPI) prior to randomization.^1,2

Definitions

The following definitions were used in the COMPASS trial:^1,2,6

• Coronary artery disease:
  • MI within the last 20 years, or
  • Multi-vessel coronary disease with symptoms or with history of stable or unstable angina
    • Multi-vessel coronary disease refers to stenosis of greater than or equal to 50% in 2 or more coronary arteries, confirmed by invasive coronary angiography, or non-invasive imaging or stress studies suggestive of significant ischemia in two or more coronary territories; or in one coronary territory if at least one other territory has been revascularized.
  • Multi-vessel percutaneous coronary intervention (PCI), or
  • Multi-vessel coronary artery bypass graft (CABG) surgery
• Peripheral arterial disease:
  • Previous aorto-femoral bypass surgery, limb bypass surgery, or percutaneous transluminal angioplasty revascularization of the iliac, or infra-inguinal arteries, or
  • Previous limb or foot amputation for arterial vascular disease, or
  • History of intermittent claudication and one or more of the following:
    • An ankle/arm blood pressure (ABI) ratio <0.90, or
    • Significant peripheral artery stenosis (≥50%) documented by angiography, or by duplex ultrasound or angiography.
  • Previous carotid revascularization or asymptomatic carotid artery stenosis ≥50% as diagnosed by duplex ultrasound or angiography.
• Modified International Society of Thrombosis and Haemostasis (ISTH) major bleeding:
  • Composite of:
    • Fatal bleeding
    • Symptomatic bleeding into a critical organ
    • Bleeding into a surgical site requiring reoperation OR
    • Bleeding that led to hospitalization (including presentation to an acute care facility without an overnight stay)
  • This modified definition of ISTH major bleeding was used for the COMPASS trial in response to regulators. It differed from the ISTH definition of major bleeding in that it did not take into account whether bleeding was associated with a decrease in the hemoglobin level or with blood transfusion, and it included any bleeding that led to hospitalization with or without an overnight stay.

Study Outcomes^1,2,6

• Primary efficacy outcome: composite of MI, stroke, or CV death
• Primary safety outcome: modified ISTH major bleeding
• Secondary efficacy outcomes:
  • Composite of coronary heart disease (CHD) death, MI, ischemic stroke, or acute limb ischemia (ALI)
  • Composite of CV death, MI, ischemic stroke, or ALI
  • All-cause mortality
• Key additional outcomes:
  • Individual components of the primary and secondary outcomes
  • Cardiovascular hospitalizations
  • All-cause hospitalizations
  • Revascularization
  • Stent thrombosis
  • Limb amputation

Inclusion Criteria^2,6

• Willing and able to provide written informed consent
• Meet criteria for CAD and/or PAD (previously defined)
• Subjects with CAD must also meet at least one of the following:
  • Age ≥ 65 years, or
  • Age < 65 years and documented atherosclerosis or revascularization involving at least 2 vascular beds or at least 2 additional risk factors:
    • Current smoker (within one year of randomization)
    • Diabetes mellitus
    • Renal dysfunction with estimated glomerular filtration rate <60 mL/min
    • Heart failure
    • Non-lacunar ischemic stroke ≥1 month ago

Exclusion Criteria^2,6,7

• High risk of bleeding
• Stroke within one month or any history of hemorrhagic or lacunar stroke
• Severe heart failure with known ejection fraction <30% or New York Heart Association (NYHA) class III or IV symptoms
• Estimated glomerular filtration rate <15 mL/min
• Need for dual antiplatelet therapy, other non-aspirin antiplatelet therapy, or oral anticoagulant therapy
• Known non-CV disease that is associated with poor prognosis (eg, metastatic cancer) or that increases the risk of an adverse reaction to study interventions
• History of hypersensitivity or known contraindication for XARELTO, aspirin, pantoprazole, or excipients, if applicable
• Systemic treatment with strong inhibitors of both CYP3A4 and p-glycoprotein (eg, systemic azole antimycotics, such as ketoconazole, and human immunodeficiency virus [HIV]-protease inhibitors, such as ritonavir), or strong inducers of CYP3A4, (eg, rifampicin, rifabutin, phenobarbital, phenytoin, and carbamazepine)
• Any known hepatic disease associated with coagulopathy
• Subjects who are pregnant, breastfeeding, or are of childbearing potential, and sexually active and not practicing an effective method of birth control
• Previous assignment to treatment during this study
• Concomitant participation in another study with an investigational drug
• Known contraindication to any study procedures
• Additional exclusion for the pantoprazole randomization: Need for continuous treatment with a PPI

Study Design^1,2

• Eligible participants entered a 30-day run-in phase during which they received XARELTO-matched placebo BID and aspirin 100 mg once daily. Patients within the COMPASS trial who had undergone CABG surgery within 4-14 days of randomization did not undergo the run-in phase, because thrombotic graft occlusion is most common during the first few weeks after surgery and a run-in would delay the start of the therapy.
• At screening, body weight, blood pressure, height, waist circumference, hip circumference, heart rate, and ankle-brachial blood pressure index were collected, and reassessed at 2 years follow-up and at final follow-up visits for each participant. Laboratory tests for serum creatinine and total cholesterol were collected during the screening/run-in phase or at randomization. No other laboratory results were systematically collected at baseline for the COMPASS trial.⁷
• Patients who adhered to the assigned regimen during the run-in phase (defined as at least 80% adherence to treatment), and who did not have adverse events, as well as those enrolled within 4-14 days following CABG surgery, were randomized in a 1:1:1 ratio to one of the following treatment arms:
  • 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.

Study Dose Modifications

• Based on the study protocol, subjects who developed a need for non-study antiplatelet therapy during the course of the COMPASS trial, such as aspirin plus clopidogrel (eg, subjects who experienced an acute coronary syndrome, those who underwent a PCI with stent insertion) were to discontinue study XARELTO/XARELTO placebo. Study XARELTO/XARELTO placebo was to be restarted once dual antiplatelet therapy (DAPT) was stopped.
• Subjects who were to remain on long-term DAPT may have commenced on “interim study XARELTO/XARELTO placebo” once any non-study anticoagulant therapy was stopped. The “interim study XARELTO/XARELTO placebo” was a XARELTO dose of 2.5 mg twice daily, even if the subject was randomized to the XARELTO 5 mg twice daily arm. Subjects on placebo were to have remained on placebo. All subjects were to resume originally allocated study XARELTO/XARELTO placebo once non-study DAPT was stopped and the subjects were not being treated with non-study anticoagulants.
• Subjects who developed a need for anticoagulant therapy (eg, thromboprophylaxis in subjects undergoing major orthopedic surgery, acute venous thromboembolism, atrial fibrillation, mechanical aortic valve replacement) were to have interrupted study XARELTO/XARELTO placebo. Study XARELTO/XARELTO placebo should have been restarted in subjects who no longer had a need for non-study anticoagulant therapy (eg, after completion of anticoagulant thromboprophylaxis or anticoagulant treatment for venous thromboembolism).

Statistical Analyses^1,6

• To provide a power of 90% to detect a 20% lower relative risk reduction in each of the comparisons of XARELTO versus aspirin, at least 2200 participants were to have a confirmed primary efficacy outcome (ie, CV death, MI, or stroke).
• An independent data and safety monitoring committee monitored the study and had guidelines for stopping for efficacy and safety. Two formal interim analyses were planned for efficacy, after 50% and 75% of the primary efficacy events had occurred.
• Comparisons were conducted between the two XARELTO arms versus the aspirin only arm following the intent-to-treat principle.
• To adjust for multiplicity, primary and secondary outcomes evaluated were analyzed using a mixture gatekeeping procedure based on the Hochberg test to control the familywise error rate of 5%. A strategy for formal testing of secondary outcomes at the interim analysis was not prespecified.
• Kaplan-Meier estimates of cumulative risk were used. Hazard ratios and corresponding 95% confidence intervals were obtained from stratified Cox proportional-hazards models.
• P values reported were two-sided. The threshold P value used for statistical significance was 0.0025. For outcomes that did not meet this threshold, statistical significance cannot be claimed.
• Early termination of the study was not anticipated; therefore, there was no formal testing for secondary outcomes prespecified at the interim analysis.

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 11 November 2024.