SUMMARY

• A risk stratification study of the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial identified subsets of patients with higher risk of recurrent vascular events, using 2 methods.¹
  • The REduction of Atherothrombosis for Continued Health (REACH) scoring method identified patients as higher risk if they had an incidence risk score ≥13, ie, history of ≥2 vascular beds affected, history of heart failure (HF), or a lower estimated glomerular filtration rate (eGFR). The Classification and Regression Trees (CART) analysis identified patients as higher-risk if they had a history of ≥2 vascular beds affected, a history of HF, or a history of diabetes mellitus (DM).
  • Each of these two methods (REACH and CART) identified higher-risk patient groups who had a 2-fold higher 30-month incidence risk compared with the patient subsets that did not have high risk features.
  • The combination of XARELTO and aspirin, in patients identified to be at a higher risk for recurring vascular events, reduced serious vascular event incidence with a nonsignificant increase in severe bleeding.
• Patients from the REACH registry, that were also COMPASS-eligible, were categorized by certain enrichment criteria (ie, DM, age >65 years, asymptomatic carotid stenosis >70%, peripheral artery disease [PAD], history of HF, renal impairment [eGFR<60mL/min], current smoking status and history of ischemic stroke). The presence of any of the COMPASS enrichment criteria resulted in a consistent increase in ischemic and bleeding risk. However, the presence of multiple enrichment criteria was associated with a greater absolute increase in ischemic than in bleeding risk, and this subset may be good candidates for treatment with low-dose XARELTO plus aspirin.²
• A post-hoc analysis study assessed whether CHA₂DS₂-VASc (congestive heart failure [CHF], hypertension, age ≥75 years [doubled], diabetes, stroke/transient ischemic attack (TIA)/thromboembolism [doubled], vascular disease [prior MI, PAD, or aortic plaque], age 65–75 years, and sex category [female]) and CHADS₂ (CHF, hypertension, age ≥75 years, diabetes, stroke/TIA [doubled]) scores were calculated based on validated criteria scores can identify vascular patients at highest risk of recurrent events and to examine the effects of XARELTO plus aspirin compared to aspirin alone.³
  • The effects of XARELTO plus aspirin compared with aspirin alone were consistent across CHA2DS₂-VASc and CHADS₂ score categories for major adverse cardiovascular events (MACE), bleeding and net clinical benefit, with greatest reduction in MACE observed in patients treated for 30 months with highest CHADS₂ score (3-6).
• A subgroup analysis of COMPASS trial assessed the predictive value of interarm differences (IAD) in blood pressure and the effects of treatment with the combination of XARELTO 2.5 mg twice daily plus aspirin 100 mg once daily vs aspirin 100 mg once daily according to IAD in patients with coronary artery disease (CAD) or PAD.⁴
  • Compared with aspirin alone, the combination of XARELTO 2.5 mg plus aspirin decreased the composite of MACE or major adverse limb events (MALE) events in both the IAD <15 mm Hg group (hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.65-0.85) and the IAD ≥15 mm Hg group (HR, 0.65; 95% CI, 0.44-0.96; P interaction, 0.53).
  • Compared with aspirin alone, the combination of XARELTO plus aspirin showed similar increase in bleeding risk irrespective of the IAD <15 mm Hg group (HR, 1.73; 95% CI, 1.41-2.11) and the IAD ≥15 mm Hg group (HR, 1.51; 95% CI, 0.85-2.67; P interaction, 0.68).
• A population-based cohort study using the CANHEART (Cardiovascular Health in Ambulatory Care Research Team) registry compared the 5-year MACE and major bleeding rates stratified by the COMPASS eligibility and clinical risk factors in patients with CAD or PAD.⁵
  • An increasing rate of MACE was associated with an increased number of comorbidities, and presence of more risk factors was associated with moderate increase in major bleeding events.
• A registry-based study was conducted to assess risk differences in patients with a history of myocardial infarction (MI) with or without COMPASS-like features.⁶
• Additional citations are included under the references section for review.^7-10

CLINICAL DATA

Anand et al (2019)¹

COMPASS was a multicenter, double-blind, randomized, placebo-controlled trial that enrolled 27,395 high risk patients with a clinical history of CAD and/or PAD, and compared the combination of XARELTO 2.5 mg twice daily and aspirin 100 mg once daily or XARELTO 5 mg twice daily to aspirin alone. A risk stratification study was conducted, based on the XARELTO with aspirin and aspirin only arms of the COMPASS trial (n = 18,278), using 2 distinct methods to identify subsets of patients at higher risk of recurrent vascular events.

Study Design/Methods

• The REACH registry risk score and CART were used to classify patients by vascular risk. A slightly modified REACH scoring algorithm was used, which included sex, age, smoking, DM, low body mass index, number of vascular beds affected, cardiovascular (CV) events in the past year, HF, atrial fibrillation (AF), lipid-lowering therapy, any antiplatelet therapy use, low eGFR and low, intermediate, or high-risk regions. The adaptations to the original scoring algorithm included replacing use of “statin therapy” and “aspirin use” at baseline with “lipidlowering therapy” and “any antiplatelet therapy use” at baseline, respectively. Individuals with AF were excluded and thus given a zero for this criterion. The maximum REACH risk score in the COMPASS population is 27; and the median value is 12. Patients were categorized as low-risk if their score was below 13 and high-risk if their score was ≥13. The CART survival analysis method was used to identify independent groups of highrisk individuals in the aspirin-treated patients of the COMPASS trial. This method used a series of algorithms to divide the population into subgroups that are separated with respect to the incidence risks over time.
• The REACH scoring method identified patients as higher-risk if they had an incidence risk score ≥13, ie, history of ≥2 vascular beds affected, history of HF, or a lower eGFR. The CART analysis identified patients as higher-risk if they had a history of ≥2 vascular beds affected, a history of HF, or a history of DM. Each of these two methods (REACH and CART) identified higher-risk patient groups who had a 2-fold higher 30-month incidence risk compared with patient subsets that did not have high risk features. Patients who did not have high risk features had an incidence risk of ≥5% over 30 months.
• The primary outcome was the composite of CV death, MI, and stroke and other vascular outcomes including acute limb ischemia (ALI) and vascular amputation. The primary safety outcome was severe bleeding, pre-defined as bleeding that was fatal or symptomatic into a critical organ. The net clinical benefit outcome was the composite of CV death, stroke, MI, ALI, vascular amputation, fatal bleeding, or symptomatic bleeding into a critical organ.

Results

• In the aspirin-treated patients the incidence risk of CV death, MI, stroke, ALI or vascular amputation after 30 months is 8.0%, whereas for patients with a REACH score ≥13, the Kaplan-Meier incidence risk is 11.6% over 30 months, which is 2-fold higher than those with a REACH score below the median of 12 (5.4%).¹
• The combination of XARELTO and aspirin reduced the incidence of the composite of CV death, MI, stroke, ALI or vascular amputation compared to aspirin alone (4.48% vs 5.96%; HR,0.75; 95% CI, 0.66-0.85). The 30-month incidence rates by risk subgroup are presented in Table: 30-Month Incidence and Treatment Impact of XARELTO and Aspirin on MACE, ALI, Total Vascular Amputation
• The rate of severe bleeding with XARELTO and aspirin compared to aspirin alone was not significantly increased (0.85% vs 0.64%; HR, 1.34; 95% CI, 0.95-1.88). The 30month incidence rates by risk subgroup are presented in Table: 30-Month Incidence and Treatment Impact on Severe Bleeding (Fatal or Critical Organ)

Darmon (2019)²identified “COMPASS-eligible” patients from the REACH registry of stable atherothrombotic patients to evaluate the bleeding and ischemic risks according to the presence of ≥1 enrichment criterion. REACH was a large prospective, observational, international registry enrolling patients >4-45 years of age with established vascular disease (CAD, PAD, or cerebrovascular disease) or with ≥3 atherosclerotic risk factors.

Study Design/Methods

• The “COMPASS-eligible” population was selected from the overall REACH cohort if they had CAD and/or PAD and criteria required for COMPASS eligibility were evaluable. First, the main exclusion criteria, then the inclusion criteria from the COMPASS trial were applied.
• The exclusion criteria for COMPASS were: high bleeding risk evaluated using the REACH bleeding risk score, severe renal failure (eGFR <15 ml/min), need for dual antiplatelet therapy for an acute coronary syndrome <12 months prior, oral anticoagulant therapy, and history of ischemic stroke in the past year.
• The inclusion criteria for COMPASS were: PAD patients (regardless of age), CAD patients age >65 years; CAD patients age <65 years with ≥1 additional risk factor (i.e., documented atherosclerosis or documented prior revascularization involving ≥2 vascular beds) or with ≥2 additional risk factors (i.e., current smoker, DM, HF, eGFR <60 mL/min, or nonlacunar ischemic stroke >1 year). Patients with CAD age <65 years with no enrichment criteria were not eligible for COMPASS and constituted the “COMPASS no enrichment criteria population”.

Results

• The REACH registry population included 65,531 patients, 31,873 of which had PAD and/or CAD and complete data, allowing evaluation. Among these, 16,875 patients were COMPASS-eligible. DM (41%), age >65 years (81.5%), asymptomatic carotid stenosis >70% (8.7%), PAD (33.7%), history of HF (13.3%), renal impairment (eGFR<60ml/min; 40.2%), current smoking status (13.8%) and history of ischemic stroke (11.1%) were the clinically relevant subgroups based on the COMPASS enrichment criteria at inclusion.
• The primary ischemic outcome was a composite of CV death, MI, or stroke at 4 years. The secondary outcome was the 4-year rate of serious bleeding, defined as any bleeding requiring transfusion, hospitalization for transfusion, or hemorrhagic stroke. The 4-year rates of the primary and secondary outcomes are presented in Table: 4-Year Rates of the Primary Ischemic and Secondary Bleeding Outcomes According to Presence of Enrichment Criteria, Compared With the Overall COMPASS-Eligible Population
• The 4-year rate of CV death, MI, or stroke was 14.9% (95% CI, 14.2%-15.6%) for the overall COMPASS-eligible population and 7.7% (95% CI, 6.9%-8.6%) in the COMPASS “no enrichment criteria population”. Each enrichment criterion was associated with a significant increase in the rate of the ischemic outcome. In multivariable analysis, each enrichment criterion (e.g., age >65 years, current smoker, DM, history of ischemic stroke, HF, chronic kidney disease, PAD) was associated with a higher risk of CV death, MI or stroke, except for asymptomatic carotid stenosis, see Table: Multivariable Analysis for the Predictions of Combined Ischemic Endpoint and Serious Bleeding.
• The 4-year rate of serious bleeding was 2.2% (95% CI, 2.0%-2.4%) in the COMPASS- eligible population and 0.8% (95% CI, 0.6%-1.1%) in the “COMPASS no enrichment criteria population”. Patients with a history of PAD or current smokers were not associated with a significant increase in the rate of serious bleeding while all other enrichment criteria were associated with a significant increase in the 4-year rate of serious bleeding. In multivariable analysis, age >65, DM, history of HF, chronic kidney disease and PAD were associated with a higher risk of serious bleeding. Multivariable analysis of the enrichment criteria is presented in Table: Multivariable Analysis for the Predictions of Combined Ischemic Endpoint and Serious Bleeding
• Increase in the number of enrichment criteria was associated with a dramatic increase in the rate of CV death, MI or stroke and a more modest increase in serious bleeding. There was an ~5% increase in risk of CV death, MI or stroke with the addition of each enrichment criterion, until patients accumulated ≥4. In contrast, there was no significant increase in serious bleeding for patients with ≤3 criteria. Only the presence of ≥4 enrichment criteria led to an increase in the rate of serious bleeding. The number of enrichment criteria associated with ischemic and bleeding risk are presented in Table: Association of Multiple Enrichment Criteria With Ischemic and Bleeding Risks Among COMPASS-Eligible Patients

Sen et al (2021)³ conducted a post-hoc analysis from the COMPASS trial (n=18,278) to evaluate the CHA₂DS₂-VASc and CHADS₂ scores to identify patients with chronic atherosclerotic disease at highest risk for MACE and to examine the effects of XARELTO plus aspirin compared to aspirin alone on clinical outcomes and net clinical benefit according to risk score.

Study Design/Methods

• The CHA₂DS₂-VASc and CHADS₂ scores were calculated based on validated criteria. CHA₂DS₂-VASc scores were assessed by individual scores from 1 to 9 and grouped score category: 1–2, 3, 4, 5, and 6–9. Similarly, CHADS₂ scores were calculated as individual scores from 0 to 6 and grouped score category: 0, 1, 2, 3–6.
• The pre-specified primary outcome was MACE, defined as a composite of MI, stroke and CV death, and the secondary outcomes included all-cause mortality, and the composite of MACE and MALE.
• The safety outcomes included major bleeding (modified International Society on Thrombosis and Hemostasis (ISTH) criteria, which included fatal bleeding, symptomatic bleeding into critical area or organ, bleeding into surgical site that led to reoperation and/or bleeding that led to presentation to an acute care facility or hospitalization), and serious bleeding (fatal or symptomatic bleeding into critical organ). The net-clinical-benefit outcome was the composite of MI, stroke, CV death, fatal bleeding, or symptomatic bleeding into a critical organ.

Results

• Risk of MACE was 3 times greater in patients with a high CHA₂DS₂-VASc score (6-9) compared to low scores (1-2) (HR, 3.39; 95% CI, 2.54-4.51, P< 0.0001). Risk of MACE was almost 4 times greater in patients with a high CHADS₂ score (3–6) compared to low score (0) (HR, 3.75; 95% CI, 2.96–4.76; P <0.0001).
• The event rate of individual secondary outcomes increased with higher CHA₂DS₂-VASc and CHADS₂ scores (P <0.001) (see Table: Univariate Proportional Hazards Analyses of CV Outcomes by CHA₂DS₂-VASc and CHADS₂ Scores as Continuous Variables). Netclinicalbenefit outcome was 3.4 or 3.7 times greater in higher CHA₂DS₂-VASc or CHADS₂ scores compared to lower scores (P<0.0001, both).
• The incidence of MACE, composite of MACE and MALE, and net-clinical-benefit were consistently lower in patients treated with XARELTO plus aspirin compared to aspirin alone across all risk scores. The largest significant MACE risk reduction from XARELTO plus aspirin occurred in patients treated for 30 months with CHADS₂ score of 3 or above (HR, 0.67; 95% CI, 0.53-0.86, P=0.0012). Absolute benefit of reduction in MACE and MALE were seen in all score categories with largest risk reduction in highest CHA₂DS₂-VASc or CHADS₂ scores, see Table: Treatment Effects of Combination Therapy With XARELTO Plus Aspirin Compared With Aspirin Alone Over Mean Follow-up of 30 Months.

Qadura et al (2023)⁴ conducted a subgroup analysis of the COMPASS trial to evaluate the predictive value of IAD in blood pressure and the effects of treatment with the combination of XARELTO 2.5 mg twice daily plus aspirin 100 mg once daily vs aspirin 100 mg once daily according to IAD in patients with CAD or PAD.

Study Design/Methods

• The systolic blood pressures were measured in both arms at enrollment in the COMPASS trial. The primary analysis was based on systolic IAD of ≥15 mm Hg between the right and left arms.
• The primary outcome was MACE, defined as a composite of MI, ischemic stroke, and CV death.
• The secondary outcome was MALE, defined as a composite of acute or chronic limb ischemia leading to an intervention or major vascular amputation.
• The main safety outcome was major bleeding (modified ISTH criteria), which included fatal bleeding, symptomatic bleeding into a critical organ, bleeding into a surgical site requiring reoperation and bleeding that led to hospitalization.

Results

• A total of 24,539 patients had IAD <15 mm Hg with a mean age of 68.2 (standard deviation [SD], 8.0) years and 2776 patients had IAD ≥15 mm Hg with a mean age of 68.8 (SD, 7.4) years.
• The proportion of female patients was 5366 (21.9%) in the IAD <15 mm Hg group and 618 (22.3%) in the IAD ≥15 mm Hg group.
• Compared with aspirin alone, the combination of XARELTO 2.5 mg plus aspirin decreased the MACE events in both the IAD <15 mm Hg group (HR, 0.76; 95% CI, 0.66-0.87) and the IAD ≥15 mm Hg group (HR, 0.69; 95% CI, 0.461.03; P interaction, 0.67), see Table: Efficacy Outcomes in Patients With IAD <15 mm Hg and IAD ≥15 mm Hg.
• Compared with aspirin alone, the combination of XARELTO plus aspirin showed similar increase in bleeding risk irrespective of the IAD <15 mm Hg group (HR, 1.73; 95% CI, 1.41-2.11) and the IAD ≥15 mm Hg group (HR, 1.51; 95% CI, 0.85-2.67; P interaction, 0.68), see Table: Safety Outcomes in Patients With IAD <15 mm Hg and IAD ≥15 mm Hg.

Sheth et al (2022)⁵ conducted a population-based cohort study using the CANHEART (Cardiovascular Health in Ambulatory Care Research Team) registry to compare the 5-year MACE and major bleeding rates stratified by the COMPASS eligibility and clinical risk factors.

Study Design/Methods

• Community-dwelling patients aged ≥40 years on January 1, 2011, who were eligible for the Ontario health insurance plan between 2006 and 2010 and who met the COMPASS trial inclusion criteria for either CAD or PAD, were included.
• Patients who met the CAD/PAD criteria but did not meet any exclusion criteria were classified as: “COMPASS eligible” and thereby eligible for XARELTO therapy for secondary prevention; patients who met exclusion criteria were classified as “COMPASS ineligible”; and those who could not be categorized into eligible and ineligible groups were classified as “COMPASS indeterminate”.
• The primary outcome was a composite of CV death, MI, and stroke, and secondary outcomes were CV death, MI, stroke, all-cause death, HF, and major bleeding.

Results

• A total of 137,895 patients were COMPASS eligible; of them, 14,616 (10.6%), 47,949 (34.8%), 46,316 (33.6%), 22,139 (16.1%), and 6875 (5.0%) patients had 0, 1, 2, 3, and 4 risk factors, respectively.
• The mean age of COMPASS eligible patients was 65.8 (SD, 11.0) years and 35,798 (26.0%) patients were females.
• An increasing rate of MACE was associated with an increased number of comorbidities, and presence of more risk factors was associated with moderate increase in major bleeding events.
• The rates of the composite of CV death, MI or stroke was 2.19 per 100 PY.
• For event rates and estimated absolute risk reduction (ARR) in COMPASS eligible patients, see Table: Observed Event Rates and Estimated ARR in COMPASS Eligible Patients at 5 Years.

• For outcomes based on risk factors, see Table: Outcomes of COMPASS-Eligible Patients Stratified by Number of Risk Factors.

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 26 August 2024.