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 myocardial infarction (MI), stroke, or cardiovascular (CV) death in patients with a history of stable atherosclerotic vascular disease (coronary artery disease [CAD] or peripheral artery disease [PAD]).¹
• Mean follow-up duration of the COMPASS study was 23 months.¹
• The primary outcome occurred in fewer patients in the XARELTO plus-aspirin-group than in the aspirin-alone group (379 patients [4.1%] vs 496 patients [5.4%]; hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.66-0.86; P<0.001; z=-4.126), but major bleeding events occurred in more patients in the XARELTO-plus-aspirin group (288 patients [3.1%] vs 170 patients [1.9%]; HR, 1.70; 95% CI, 1.40-2.05; P<0.001).¹
• The primary outcome did not occur in significantly fewer patients in the XARELTO-alone group than in the aspirin-alone group (448 patients [4.9%] vs 496 patients [5.4%]; HR, 0.90; CI, 0.79-1.03; P=0.12; z=-1.575), but major bleeding events occurred in more patients in the XARELTO-alone group (255 patients [2.8%] vs 170 patients [1.9%]; HR, 1.51; 95% CI, 1.25-1.84; P<0.001).¹
• The effects of XARELTO plus aspirin as compared with aspirin alone on the primary outcome and on major bleeding were consistent among subgroups according to age, demographics, body weight, renal function, and history of CV risk factors.¹
• Net clinical benefit (NCB) (composite of CV death, stroke, MI, fatal bleeding, or symptomatic bleeding into a critical organ) occurred in 4.7% of patients treated with XARELTO plus aspirin and in 5.9% of patients treated with aspirin alone (P<0.001).¹ In a prespecified analysis, the NCB was consistent across high-risk subgroups including patients with polyvascular disease (>2 vascular beds affected with atherosclerosis), impaired renal function (estimated glomerular filtration rate [eGFR] <60 mL/min), heart failure (HF), presence of diabetes mellitus (DM), or a combination of these risk factors; as well as patients aged ≥65 years.²
• An analysis of the COMPASS study was conducted to evaluate the effect of early discontinuation of combination therapy with XARELTO (2.5 mg BID) and aspirin (100 mg once daily) and switching to nonstudy aspirin (75-100 mg once daily) on CV outcomes in patients with chronic CAD or PAD. Patients originally randomized to combination therapy compared with those randomized to aspirin monotherapy had similar rates of MI, stroke, or CV death (P=0.56), MI (P=0.11), and CV death (P=0.25) and higher rates of stroke (P=0.03).³
• A prespecified subanalysis of 7470 (~27%) patients with a history of PAD at baseline and a prespecified subanalysis of 24,824 (~91%) patients with a history of CAD at baseline were conducted. The safety and efficacy of XARELTO plus aspirin vs aspirin alone were consistent with the overall COMPASS study results.^4,5
  • In a subset of patients with symptomatic lower extremity PAD, the risk of major adverse cardiovascular events (MACE), major adverse limb events, including major amputation (MALE), or both was lower among patients who received both XARELTO and aspirin versus aspirin alone. The risk of major bleeding was higher among this patient group receiving both XARELTO and aspirin versus aspirin alone.⁶
• Of the 27,395 patients enrolled in the COMPASS study, 1488 were randomized within 4-14 days following coronary artery bypass graft (CABG) surgery and were included in the COMPASS CABG subanalysis. In this prespecified subanalysis, there was no reduction in the risk of graft occlusion with XARELTO plus aspirin or XARELTO alone vs aspirin alone. Reduction in the risk of MACE with XARELTO plus aspirin vs aspirin alone was consistent with results seen in non-CABG patients. There was no increase in major bleeding with XARELTO plus aspirin vs aspirin alone.⁷
• COMPASS MIND (MRI and Neurocognitive Deterioration substudy of COMPASS), which was conducted in a subset of COMPASS patients (n=1905), examined the effect of antithrombotic treatment (XARELTO plus aspirin or XARELTO alone vs aspirin alone) on magnetic resonance imaging (MRI) outcomes (incident covert brain infarcts), cognitive and functional outcomes, and biomarkers and genetics. Approximately 92% of patients underwent a baseline MRI scan, 90.3% had a history of CAD, and 28.5% had a history of PAD. Study results are pending.⁸
• A subgroup analysis of the COMPASS study was conducted for patients with or without HF. The effects of XARELTO plus aspirin as compared with aspirin alone on the primary efficacy and on major bleeding were consistent between patients with or without HF.⁹
• A detailed analysis of stroke outcomes in the COMPASS study found that patients treated with XARELTO plus aspirin experienced fewer strokes and fatal/disabling strokes vs those treated with aspirin alone. Compared with aspirin alone, the combination of XARELTO plus aspirin did not increase the risk of hemorrhagic stroke. Prior stroke was the strongest predictor of incident stroke. In an additional subanalysis of ischemic stroke subtypes as defined by Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria, ischemic or uncertain strokes occurred significantly less frequently in groups treated with low-dose XARELTO plus aspirin (HR, 0.51; 95% CI, 0.38-0.68; P<.001) and in groups treated with XARELTO alone (HR, 0.69; 95% CI, 0.53-0.90; P=0.006) compared with aspirin alone. There were significant differences in groups treated with XARELTO plus aspirin compared with aspirin alone in incidence of cardioembolic stroke (HR, 0.40; 95% CI, 0.20-0.78; P=0.005) and stroke of undetermined cause (HR, 0.49; 95% CI, 0.32-0.74; P>0.001).^10,11
• COMPASS PCI was a prespecified subanalysis of 16,560 COMPASS participants who had stable CAD with (n=9862) or without (n=6698) prior percutaneous coronary intervention (PCI) assigned to low-dose XARELTO and aspirin or aspirin only. The safety and efficacy of XARELTO plus aspirin vs aspirin alone were consistent with the overall COMPASS study results, regardless of prior history of PCI.¹²
• A non-prespecified subanalysis evaluated the efficacy and safety of dual pathway inhibition (DPI) treatment in 14,670 COMPASS study patients with chronic coronary syndrome according to baseline risk classified by CHADS-P₂ A₂ RC score. All-cause death and MACE were reduced by DPI without increasing bleeding events. Similar absolute NCB and mortality reduction were observed in patients at low/moderate risk and at high risk.¹³
• A prespecified subgroup analysis of the COMPASS study was conducted for patients with or without DM. The effects of XARELTO plus aspirin as compared with aspirin alone on the primary efficacy outcome and on major bleeding were consistent between patients with or without DM. When evaluating the absolute risk reduction for the primary efficacy outcome, patients with DM had a greater absolute benefit (HR, 0.74; 95% CI, 0.61-0.90; absolute risk reduction [ARR], 2.3%) compared to those without (HR, 0.77; 95% CI, 0.64-0.93; ARR, 1.4%) over 3 years (Gail-Simon qualitative P_interaction<0.0001).¹⁴
• A subgroup analysis of the COMPASS study was conducted among male and female participants assigned to low-dose XARELTO plus aspirin or aspirin alone. Another subanalysis was conducted on the same subset of patients by comparing baseline modified REACH score (excluding female gender) to the median REACH score recorded in the overall COMPASS trial population. The effects of XARELTO plus aspirin as compared with aspirin alone on the primary efficacy and on major bleeding were consistent between male and female patients. Effects were consistent among male and female participants receiving XARELTO plus aspirin as compared with aspirin alone for patients whose modified REACH score was greater than or less than or equal to the median COMPASS trial REACH score of 12.¹⁵
• A sub-analysis of the COMPASS trial compared the efficacy and safety outcomes of XARELTO plus ASA with those of ASA monotherapy between Asian and non-Asian patients with chronic CAD/PAD. The primary efficacy composite of MI, stroke, or CV death was less common with XARELTO + ASA vs ASA monotherapy in the Asian (risk reduction, 36%; HR, 0.64; 95% CI, 0.45-0.90) and non-Asian (risk reduction, 22%; HR, 0.78; 95% CI, 0.67-0.90) groups, respectively [P (for interaction) =0.29]. Major bleeding was more common with XARELTO plus ASA vs ASA monotherapy in the Asian (>2-fold; HR, 2.24; 95% CI, 1.40–3.58) and non-Asian (1.6-fold; HR:1.60; 95% CI: 1.30–1.97) groups, respectively [P (heterogeneity) =0.20].¹⁶
• A post hoc analysis of the COMPASS trial evaluated the recurrent and total (first and recurrent) MACE, bleeding outcomes, and NCB outcomes in patients with chronic CAD or PAD. As an intention-to-treat analysis, the XARELTO + ASA group compared to the ASA monotherapy group reduced the total MACE relative risk by 25% (P<0.0001).¹⁷
• A subgroup analysis of the COMPASS study was conducted among patients with an interarm blood pressure difference (IAD)<15 mmHg or IAD≥15 mmHg comparing the composite of MACE, the composite of MALE, the composite of MACE or MALE and the effects XARELTO + ASA or ASA monotherapy treatment groups would have on these outcomes.¹⁸
  • The composite of MACE or MALE events in the XARELTO + ASA group compared to the ASA monotherapy group was reduced in both the IAD<15 mmHg and the IAD≥15 mmHg groups.
  • Both the ASA monotherapy and XARELTO + ASA groups had similar increases in bleeding risk, regardless of the IAD group (IAD<15 mmHg: HR 1.73, [95% CI: 1.41-2.11]; IAD≥15 mmHg: HR 1.51, [95% CI: 0.85-2.67], P [interaction] = 0.68).
• COMPASS LTOLE (Long Term Open Label Extension) was a long-term open-label continuation of the COMPASS trial which examined the safety and efficacy of XARELTO 2.5 mg BID in combination with aspirin 75 or 100 mg once daily for a median of 374 additional days. During this extension, the incidence rates for efficacy and bleeding for XARELTO plus aspirin were consistent with the overall COMPASS study results.¹⁹
• An additional citation identified during a literature related to the mortality benefit of XARELTO plus aspirin in patients with chronic coronary or PAD is included in the REFERENCES section for your review.²⁰

BACKGROUND

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 MACE endpoint reached its prespecified criteria for superiority.^1,21

CLINICAL DATA

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 (CAD or PAD).^1,22

Study Design/Methods

• A total of 27,395 patients were recruited from 602 centers in 33 countries between February 2013 and May 2016.
• 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 4-14 days following CABG surgery) entered a run-in phase during which they received XARELTO-matched placebo BID and aspirin 100 mg once daily.
• CAD was defined as previous MI or history of angina with multivessel disease, or multivessel revascularization. PAD was defined as claudication with objective evidence of arterial disease, previous amputation or revascularization, previous carotid revascularization, or asymptomatic carotid disease with ≥50% stenosis.²²
• Key inclusion criteria: 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), DM, renal dysfunction with eGFR <60 mL/min, HF, or nonlacunar ischemic stroke ≥1 month ago.
• Key exclusion criteria: 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, other non-aspirin antiplatelet therapy, or oral anticoagulant therapy; eGFR <15 mL/min; or systemic treatment with strong inhibitors of both CYP3A4 and P-glycoprotein or strong inducers of Cytochrome P450 3A4 (CYP3A4). Patients with atrial fibrillation requiring anticoagulation were also excluded.
• Primary efficacy outcome: the composite of MI, stroke, or CV death
• Primary safety outcome (based on modified ISTH criteria): the composite of fatal bleeding, symptomatic bleeding in 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)
• Primary outcome for pantoprazole randomization: the composite of overt bleeding of GI origin confirmed by endoscopy or radiography, overt upper GI bleeding of unknown origin, bleeding of presumed occult GI origin with documented decrease in hemoglobin of 2 g/dL from baseline, symptomatic gastroduodenal ulcer, GI pain with underlying multiple gastroduodenal erosions, and obstruction or perforation

Results

• A total of 1448 patients were randomized within 4-14 days following CABG surgery and 17,603 were randomized to pantoprazole or placebo.

Baseline Characteristics¹

• Mean age was 68.2 years, 22.0% of patients were female
• Race/Ethnicity: 4.2% Chinese, 19.3% Hispanic, 62.2% White/Caucasian, 1.1% South Asian, 10.3% Other Asian, 1.0% Black/African American, and 2.0% Other²³
• Baseline medical history: 90.6% had CAD, 27.3% had PAD, 3.8% had a history of stroke
• Baseline medications: ~90.0% used lipid-lowering agents (the specific type of lipid-lowering agent/statin use was not recorded at baseline), >70.0% used an angiotensin-converting-enzyme inhibitor or angiotensin-receptor blocker
• Baseline measurements: mean blood pressure was 136/78 mmHg and mean total cholesterol level was 162 mg/dL. Less than 1% of patients had an eGFR <30 mL/min, ~22% of patients had an eGFR between 30 to ≤60 mL/min, and the remainder had an eGFR ≥60 mL/min.

Outcomes

• The primary efficacy outcome occurred in fewer patients in the XARELTO-plus-aspirin group than in the aspirin-alone group (379 patients [4.1%] vs 496 patients [5.4%]; HR, 0.76; 95% CI, 0.66-0.86; P<0.001; z=-4.126).¹ This translates into a 24% relative risk reduction in the composite of CV death, stroke, or MI with XARELTO (2.5 mg BID) plus aspirin versus aspirin alone.¹
• Major bleeding events occurred in more patients in the XARELTO-plus-aspirin group (288 patients [3.1%] vs 170 patients [1.9%]; HR, 1.70; 95% CI, 1.40-2.05; P<0.001), equating to a 70% higher rate of major bleeding with XARELTO plus aspirin compared to aspirin alone.¹
• The primary efficacy outcome did not occur in significantly fewer patients in the XARELTO-alone (5 mg BID) group than in the aspirin-alone group (448 patients [4.9%] vs 496 patients [5.4%]; HR, 0.90; 95% CI, 0.79-1.03; P=0.12; z=-1.575).¹
• Major bleeding events occurred in more patients in the XARELTO-alone group than in the aspirin-alone group (255 patients [2.8%] vs 170 patients [1.9%]; HR, 1.51; 95% CI, 1.25-1.84; P<0.001).¹
• The threshold P value used for statistical significance of secondary efficacy outcomes was 0.0025 per the COMPASS study statistical analysis plan. For outcomes that did not meet this threshold, statistical significance cannot be claimed.
• The relative risk of the net-clinical-benefit outcome was reduced by 20% with XARELTO plus aspirin than with aspirin alone (4.7% vs 5.9%).
• Follow-up for the comparison of pantoprazole vs placebo, in which 17,598 patients were included, is currently ongoing. Thus, results are not available at this time.
• For efficacy and safety outcomes, see Tables: Primary Efficacy Outcome, Secondary Efficacy Outcomes, Other Efficacy Outcomes, and Safety Outcomes.
• The effects of XARELTO plus aspirin as compared with aspirin alone on the primary outcome and on major bleeding were consistent among subgroups according to age, sex, geographic region, race/ethnicity, weight, renal function, and history of CV risk factors.¹

CAD and PAD Subgroup Analyses

Connolly et al (2018)⁵ conducted a prespecified subanalysis of patients (n=24,824 [~91%]) in the COMPASS study that had stable CAD. Anand et al (2018)⁴ conducted a prespecified subanalysis of patients (n=7470 [~27%]) in the COMPASS study that had stable PAD. Efficacy data is also available for patients with CAD and PAD (18.0%) within the US Prescribing Information.²⁴

• The effects of XARELTO plus aspirin vs aspirin alone on the primary efficacy and safety outcomes in the CAD and PAD subgroups were consistent with overall COMPASS study results, as shown in the following: Table: Primary Outcomes in CAD Subgroup, Table: Outcomes in PAD Subgroup Table: Primary Efficacy Outcome in CAD and PAD subgroup.
• Provisions to address multiple testing for subgroups were not specified and therefore, any HRs, corresponding CIs, and P values reported for subgroup analyses cannot be interpreted as statistically significant.²⁵

Kaplovitch et al (2020)⁶ conducted a secondary analysis of a subset of PAD patients (N=7470) from the COMPASS trial, focusing on patients with symptomatic lower extremity (LE) PAD (N=4129). Symptomatic LE-PAD included patients with a history of aortofemoral bypass surgery, limb bypass surgery, or percutaneous transluminal angioplasty revascularization of the iliac or infrainguinal arteries; limb or foot amputation for arterial vascular disease; or intermittent claudication with an ankle brachial index of less than 0.90 or a peripheral artery stenosis (>50%). Patients were further classified by symptom severity at baseline utilizing the Fontaine classification and by high-risk limb presentation (incidence risk of MACE or MALE greater than 10% over 30 months) or high-risk comorbidities (polyvascular disease [vascular disease in 2 or more vascular beds]; history of diabetes; history of HF; and kidney insufficiency, defined as estimated glomerular filtration rate <60 mL/min).

• The primary outcome measures were the incidence risk of the composite measures of MACE, MALE (including major amputation), MACE or MALE (including major amputation), and a composite of MI, ischemic stroke, CV death, acute limb ischemia, or major amputation in patients receiving low-dose XARELTO plus aspirin vs aspirin alone. Safety outcomes included the 30-month incidence risk of the modified ISTH major bleeding, and severe bleeding, defined as fatal or critical organ bleeding. The NCB comprised of the composite of MACE or MALE, including major amputation, and fatal or critical organ bleeding was also calculated.
• In patients with high-risk limb presentation, the incidence risk of MACE or MALE, including amputation was highest among patients with a prior amputation (22.6%, n=54), followed by patients with Fontaine III or IV symptoms (17.6%, n=15), and patients with previous lower limb revascularization (11.8%, n=142). In patients with any high-risk comorbidity, the 30-month Kaplan-Meier incidence risk of MACE or MALE, including amputation, was highest among patients with kidney insufficiency (14.1%, n=118), followed by patients with HF (13.5%, n=67), patients with diabetes (13.4%, n=199), and patients with polyvascular disease (12.8%, n=222). Patients with both high-risk limb presentation and a high-risk comorbidity had the highest incidence of MACE or MALE, including amputation (14.7%, n=189). In patients with neither high-risk limb presentation nor a high-risk comorbidity, the incidence risk of MACE or MALE, including amputation was 3.1% (n=8).
• The incidence risk of major bleeding and fatal or critical organ bleeding was higher among patients with any high-risk limb presentation (1.0% [n=17] and 4.7% [n=67] for fatal or critical organ bleeding and modified ISTH major bleeding, respectively) and in patients with a high-risk comorbidity (1.2% [n=30] and 4.0% [n=92] for fatal or critical organ bleeding and modified ISTH major bleeding, respectively) compared to patients with neither high-risk limb presentation nor high-risk comorbidity (0.4% [n=1] and 2.0% [n=4] for fatal or critical organ bleeding and modified ISTH major bleeding, respectively).
• The results of the treatment outcomes among patients with LE-PAD in compass receiving low-dose XARELTO plus aspirin vs aspirin alone are described in table: Outcomes in Symptomatic Lower Extremity PAD Subgroup.⁶

Hori et al (2022)¹⁶ conducted a subgroup analysis of the COMPASS trial evaluating the risk of MI, stroke, or CV death and safety of XARELTO + ASA compared to ASA monotherapy between Asian and non-Asian patients with chronic CAD/PAD.

Results

Baseline characteristics

• The trial consisted of 27,395 patients that included 4269 Asian and 23,126 non-Asian patients.
  • Patients were considered Asian if they identified as South Asian, Chinese, Japanese, Malay, or Other Asian. All other races were analyzed as non-Asian.
  • The average age in Asian and non-Asian patients was 67.1 and 68.4, respectively.
  • The female sex accounted for 21% and 22.1% in Asian and non-Asian patients, respectively.
  • Baseline CAD and PAD, respectively, were reported in 3878 (90.8%) and 801 (18.8%) of patients in the Asian group and 20,946 (90.6%) and 6669 (28.8%) in the non-Asian group.

Efficacy

• The outcome of CV death, stroke or MI was less common in XARELTO + ASA vs ASA monotherapy in the Asian (risk reduction, 36%; HR, 0.64; 95% CI: 0.45-0.90) and non-Asian groups (risk reduction, 22%; HR, 0.78; 95% CI: 0.67-0.90), respectively with a P-value for interaction of 0.29.
• For primary efficacy outcomes, see Table: Primary Efficacy and Safety Outcomes in the COMPASS trial sub-analysis.

Safety

• The outcome of modified ISTH major bleeding was more common with XARELTO + ASA vs ASA monotherapy in the Asian (>2-fold; HR, 2.24; 95% CI: 1.40–3.58) and non-Asian (1.6-fold; HR: 1.60; 95% CI: 1.30–1.97) groups, respectively [P (heterogeneity)=0.20].
• For primary safety outcomes, see Table: Primary Efficacy and Safety Outcomes in the COMPASS trial sub-analysis.

Branch et al (2023)¹⁷ conducted a post hoc analysis of the COMPASS trial evaluating the recurrent and total (first and recurrent) MACE, bleeding outcomes, and NCB outcomes in patients with chronic CAD or PAD.

• Severe bleeding was defined as symptomatic bleeding into a critical organ or fatal bleeding.
• The total MACE and bleeding events were compiled to determine the number of total events over an average 1.9 year follow-up.

Results

Baseline characteristics

• Overall, of the 174 patients (0.6%) with ≥2 primary MACE events, the average age was 70.5±8.2 years old, 42 patients (24.1%) were female, 161 patients (92.5%) had CAD, and 55 patients (31.6%) had PAD.  
• Compared to patients with no primary MACE event, patients with 1 or ≥ 2 events were more likely to be older, hypertensive, have a low eGFR, a history of HF or diabetes, a prior CV event, or CAD.

Efficacy

• Patients treated with XARELTO + ASA (n=432) or XARELTO monotherapy (n=508) were less likely to experience a MACE outcome compared to patients treated with ASA monotherapy (n=574). The number of recurrent (>1) events were 53, 52, and 77 for the XARELTO + ASA, XARELTO monotherapy, and ASA monotherapy groups, respectively.
• As an intention-to-treat analysis, compared to the ASA monotherapy group, the XARELTO + ASA group reduced the total MACE relative risk by 25% (P<0.0001). There was no significant reduction in the total number of MACE events in the XARELTO monotherapy group.
• In the XARELTO + ASA group, the absolute risk reductions for total MACE events were lower compared with those with only 1 event (1.6%, NNT_2y 63 vs. 1.3% NNT_2y 77, respectively). No significant difference was observed in the XARELTO and ASA monotherapy groups.
• For efficacy outcomes, see Table: MACE and Bleeding Outcomes

Safety

• Compared to patients in the ASA monotherapy group, patients in the XARELTO + ASA group had a higher number of first and total major bleeding events. There was no significant difference in total severe bleeding events between randomized groups.
• For safety outcomes, see Table: MACE and Bleeding Outcomes

Net Clinical Benefit

• The total number of NCB events was 496 (5.4%) and 616 (6.7%) in the XARELTO + ASA and ASA monotherapy groups, respectively. Compared to the ASA monotherapy group, the XARELTO + ASA group had a 20% improvement in the total number of NCB events (HR 0.80, 95% CI 0.70–0.91; P=0.001).
• For NCB outcomes, see Table: Net Clinical Benefit for Total Events.

Qadura et al (2023)¹⁸ a subgroup analysis of the COMPASS study was conducted among patients with an IAD<15 mmHg or IAD≥15 mmHg comparing the composite of MACE, the composite of MALE, the composite of MACE or MALE and the effects XARELTO + ASA or ASA monotherapy treatment groups would have on these outcomes.

• Out of the 27,395 patients enrolled in the COMPASS trial, 80 patients were excluded from this study because their IAD was not assessed.

Results

Baseline Characteristics

• A total of 24,359 patients from the COMPASS study had an IAD<15 mmHg (mean age 68.2±8.0 years; 21.9% females) while the remaining 2776 patients had an IAD≥15 mmHg (mean age 68.8±8.0 years; 22.3% females).
• Compared to patients with IAD<15 mmHg, patients with IAD≥15 mmHg had significantly higher body-mass index (28.3±4.7 vs 28.9±4.9 kg/m²), systolic blood pressure (135±17 mmHg vs 139±18), and former tobacco use (46.1% vs 51.0%), respectively.
• PAD was more common in patients with an IAD≥15 mmHg while CAD, MI, and HF were more common in patients with IAD<15 mmHg.

Efficacy

• The composite of MACE or MALE events in the XARELTO + ASA group compared to the ASA monotherapy group was reduced in both the IAD<15 mmHg (HR 0.74 [95% CI: 0.65–0.85]) and the IAD≥15 mmHg groups (HR 0.65 [95% CI: 0.44–0.96, P [interaction] = 0.53).
• Compared to ASA monotherapy, XARELTO + ASA had reduced events in the MACE group (IAD≥15 mm Hg: HR 0.69 [95% CI: 0.46–1.03]; IAD<15 mmHg: HR 0.76 [95% CI: 0.66-0.87], P [interaction]= 0.67) and the MALE group (IAD≥15 mmHg: HR 0.23 [95% CI: 0.05-1.1], IAD<15 mmHg: HR 0.57 [95% CI: 0.37-0.88], P [interaction] = 0.29).
• For efficacy outcomes, see Table: Effects of XARELTO + ASA Compared to ASA Monotherapy on the Efficacy Outcome in Patients with IAD<15 mmHg and IAD≥15 mmHg.

Safety

• The ASA monotherapy and XARELTO + ASA groups had similar increases in bleeding risk, regardless of the IAD group (IAD<15 mmHg: HR 1.73, [95% CI: 1.41-2.11]; IAD≥15 mmHg: HR 1.51, [95% CI: 0.85-2.67], P [interaction] = 0.68).
• No significant difference was observed between patients in the IAD<15 mmHg and IAD≥15 mmHg groups.
• For safety outcomes, see Table: Safety Outcomes of XARELTO + ASA Compared to ASA Monotherapy on the Efficacy Outcome in Patients with IAD<15 mmHg and IAD≥15 mmHg.
• Among patients with PAD and CAD, those in the IAD<15 mmHg group compared to the IAD≥15 mmHg group, both experienced similar major bleeding events.

NCB in High-Risk Subgroups

Steffel et al (2020)² conducted a prespecified analysis to assess the NCB of adding low-dose XARELTO plus aspirin vs aspirin monotherapy in patients with chronic vascular disease in the COMPASS study population (intention-to-treat [ITT]) in specific high-risk subgroups.

• The predefined NCB outcome was the composite of CV death, stroke, MI, fatal bleeding, or symptomatic bleeding into a critical organ (including intraarticular, intramuscular with compartment syndrome, intraspinal, intracranial, intraocular, respiratory, pericardial, liver, pancreas, retroperitoneal, adrenal gland or kidney; or bleeding into the surgical site requiring reoperation).
• High-risk subgroups of the COMPASS study population included patients with polyvascular disease (>2 vascular beds affected with atherosclerosis), impaired renal function (eGFR <60mL/min), HF, presence of DM, or a combination of these risk factors. An additional subgroup included in this analysis was conducted in patients aged <65 years of age and >65 years of age.
• There were several baseline differences in patients experiencing an NCB vs. those who had not. Patients experiencing an NCB were more likely to have had hypertension, DM, a previous stroke, HF, PAD, and more significant renal impairment (eGFR <30mL/min, 30 to <60mL/min, and less likely to have an eGFR >60mL/min).
• In the overall study population, significantly fewer NCB events occurred in the low-dose XARELTO plus aspirin group compared to the aspirin monotherapy group (HR: 0.80; 95% CI: 0.70-0.91; P=0.0005).
• The NCB was consistent across prespecified high-risk subgroups and in patients aged <65 years of age or >65 years of age. See table: Net Clinical Benefit in High-risk COMPASS Subgroups.²

NCB in High-Risk Subgroups

Effects of Switching From XARELTO and Aspirin Combination Therapy to Aspirin Monotherapy

Dagenais et al (2021)³ conducted an analysis of the COMPASS study to evaluate the effect of early discontinuation of combination therapy with XARELTO (2.5 mg BID) and aspirin (100 mg once daily) and switching to nonstudy aspirin (75-100 mg once daily) on CV outcomes in patients with chronic CAD or PAD.

• Of the 18,278 patients randomized to XARELTO and aspirin combination therapy or aspirin monotherapy in the COMPASS study, 14,068 had switched to nonstudy aspirin, of whom 7027 patients belonged to the group originally randomized to combination therapy and 7041 to the group originally randomized to aspirin monotherapy. Overall, 3123 (22.2%) patients were female, and the mean age was 67.9 years. There were no significant differences in the clinical characteristics between the 2 study groups; however, 399 patients in the combination group were also on a nonsteroid antiinflammatory drug compared with 346 in the aspirin group (P=0.04).
• Patients who continued to take XARELTO and aspirin combination therapy until early discontinuation and transitioned to nonstudy aspirin were followed until the last contact for a median of 1.02 years (interquartile range [IQR], 0.74-1.11).
  • The composite outcome of MI, stroke, or CV death was observed in 240 patients (MI, n=95; stroke, n=66; CV death, n=102). Acute limb ischemia, limb amputation due to a vascular cause, and major bleeding occurred in 15, 9, and 52 patients, respectively.
    • Patients originally randomized to combination therapy compared with those randomized to aspirin monotherapy had similar rates of MI, stroke, or CV death (2.1/100 patient-years [PY] vs 2.0/100 PY; HR, 1.08; 95% CI, 0.84-1.39; P=0.56), MI (0.7/100 PY vs 0.9/100 PY; HR, 0.72; 95% CI, 0.48-1.08; P=0.11), and CV death (1/100 PY vs 0.8/100 PY; HR, 1.26; 95% CI, 0.85-1.86; P=0.25) and higher rates of stroke (0.7/100 PY vs 0.4/100 PY; HR, 1.74; 95% CI, 1.05-2.87; P=0.03). There were no differences in major bleeding between the 2 groups (0.4/100 PY vs 0.5/100 PY; HR, 0.85; 95% CI, 0.49-1.47; P=0.56).
  • During the first 6 months after switching to nonstudy aspirin, the composite outcome of MI, stroke, or CV death was observed in 115 patients (MI, n=46; stroke, n=33; CV death, n=47). Acute limb ischemia, limb amputation due to a vascular cause, and venous thromboembolism occurred in 12, 7, and 13 patients, respectively.
    • For patients who were originally randomized to combination therapy compared with those who were randomized to aspirin monotherapy, MI, stroke, or CV death rates were 2.1/100 PY vs 1.9/100 PY (HR, 1.12; 95% CI, 0.78-1.62), MI rates were 0.7/100 PY vs 1/100 PY (HR, 0.70; 95% CI, 0.391.26), and CV death rates were 0.8/100 PY vs 0.8/100 PY (HR, 0.95; 95% CI, 0.54-1.68). Higher rates of stroke (0.9/100 PY vs 0.2/100 PY; HR, 3.69; 95% CI, 1.60-8.51) were observed in patients on combination therapy vs those on aspirin monotherapy.

COMPASS CABG

Lamy et al (2019)⁷ conducted a prespecified subanalysis of patients in the COMPASS study that were randomized within 4-14 days following CABG surgery (n=1488). The study evaluated whether treatment with XARELTO plus aspirin (n=502) or XARELTO alone (n=483) is more effective than aspirin alone (n=463) for prevention of graft occlusion (primary outcome) and MACE (composite of CV death, stroke, or MI) in patients who have undergone recent CABG surgery.

• Approximately 78.1% of patients who were enrolled 4-14 days following CABG surgery had triple vessel disease; 75.3% underwent on-pump surgery and 24.4% underwent off-pump surgery.
• There was no risk reduction of graft occlusion with XARELTO plus aspirin (9.1%; HR, 1.13; 95% CI, 0.82-1.57; P=0.45) or XARELTO alone (7.8%; HR, 0.95; 95% CI, 0.67-1.33; P=0.75) compared to aspirin alone (8.0%).
• Incidence of MACE was 2.4% (HR, 0.69; 95% CI, 0.33-1.47; P=0.34), 3.3% (HR, 0.99; 95% CI, 0.50-1.99; P=0.98), and 3.5% in the XARELTO-plus-aspirin group, XARELTO-alone group, and aspirin-alone group, respectively.
  • Reduction in the risk of MACE with XARELTO plus aspirin vs aspirin alone was consistent with the results observed in non-CABG patients.
• Incidence of major bleeding ≤30 days after CABG surgery was 2 (0.4%), 1 (0.2%), and 5 (1.1%) for the XARELTO-plus-aspirin group, XARELTO-alone group, and aspirin-alone group, respectively. While the incidence of major bleeding >30 days after CABG surgery was 12 (2.4%), 19 (3.9%), and 8 (1.7%) for the XARELTO-plus-aspirin group, XARELTO-alone group, and aspirin-alone group, respectively.

COMPASS MIND

Sharma et al (2018)⁸ conducted a prespecified subanalysis of COMPASS patients (n=1905) to examine the effect of antithrombotic treatment (XARELTO plus aspirin or XARELTO alone vs aspirin alone) on MRI outcomes (incident covert brain infarcts), cognitive and functional outcomes, and biomarkers and genetics.

• COMPASS study patients were eligible for inclusion in COMPASS MIND if they had no contraindications to MRI and provided additional informed consent for the subanalysis.
• COMPASS MIND recruited COMPASS study patients across 86 sites in 16 countries.
• The primary outcome was incident covert brain infarcts (detected on imaging in the absence of an adjudicated stroke, consistent with the location of the infarct) detected by blinded comparison of baseline and end-of-study MRI.
• T1-weighted, T2-weighted, T2*-weighted, and FLAIR images were obtained close to randomization and near study drug termination; biomarker and genetic samples at randomization and 1 month; and cognitive and functional assessment at randomization, after 2 years, and at study end.
• A baseline MRI was completed in 1760/1905 (~92%) patients.
• Mean age of patients was 71.2 years (vs 68.2 years in COMPASS), 23.9% of patients were female, 90.3% had a history of CAD, 28.5% had a history of PAD, 2.5% had prior transient ischemic attack, and 4.5% had a history of stroke.
• Brain infarcts were present in 34.8% of patients, 29.3% had cerebral microbleeds, and 93.0% had white matter hyperintensities.
• The median Montreal Cognitive Assessment score was 26, similar to that seen in the overall COMPASS population.
• Study results are pending.

COMPASS HF

Branch (2019)⁹ conducted a subanalysis of COMPASS patients to evaluate XARELTO 2.5 mg BID plus aspirin 100 mg once daily compared with aspirin alone in patients chronic CAD and PAD with or without HF.

• The COMPASS study excluded patients with severe HF with known left ventricular ejection fraction <30% or New York Heart Association (NYHA) class III or IV symptoms.
• Of the 27,395 patients within the overall COMPASS study, 5902 had HF at baseline. Of those patients with HF, 36% had NYHA Class I HF, 64% had Class II HF, and 0.1% had Class III HF.
• Patients in COMPASS with HF vs patients without HF in COMPASS on average were younger (65.5 years vs 69.0 years), were more likely to have hypertension (84.7% vs 72.7%), diabetes (41.1% vs 36.8%), and were more likely to have had a previous MI (76.8% vs 58.1%).
• The effects of XARELTO plus aspirin as compared with aspirin alone on the primary efficacy and on major bleeding were consistent between patients with or without HF. See Table: COMPASS HF Subgroup Analysis.

Stroke Outcomes in COMPASS

Sharma et al (2019)¹⁰ evaluated stroke outcomes in the COMPASS study and reported detailed information on stroke (including disability), independent predictors of stroke, and the effects of low-dose XARELTO plus aspirin vs aspirin alone according to risk status.

• The COMPASS study excluded patients who required anticoagulation, had a stroke within 1 month, had a history of lacunar stroke, or had a history of intracerebral hemorrhage.
• Stroke was defined as the presence of acute focal neurological deficit of vascular origin, with signs/symptoms lasting ≥24 hours or until death. Strokes were classified as ischemic, hemorrhagic (consisting of primary intracerebral/intraparenchymal brain hemorrhage or subarachnoid hemorrhage), or uncertain type (in the absence of relevant brain imaging/autopsy).
• Of the 27,395 patients that were randomized, 291 (1%) had ischemic/uncertain strokes and 52 (0.2%) had hemorrhagic strokes. Mortality occurred within 30 days of stroke in 43 patients and did not differ significantly by treatment group.
• During a mean follow-up of 23 months, the XARELTO-plus-aspirin group experienced fewer strokes vs the aspirin-alone group (83 [0.5%/year] vs 142 [0.8%/year]; HR, 0.58; 95% CI, 0.44-0.76; P<0.0001). There was no significant difference in annual incidence of stroke between the XARELTO-alone group and the aspirin-alone group (117 [0.7%/year] vs 142 [0.8%/year]; HR, 0.82; 95% CI, 0.65-1.05; P=0.12).  
• The combination of XARELTO plus aspirin reduced the number of ischemic/uncertain strokes by almost a half compared to aspirin alone (68 [0.4%/year] vs 132 [0.8%/year]; HR, 0.51; 95% CI, 0.38-0.68; P<0.0001). XARELTO alone also reduced ischemic/uncertain strokes vs aspirin alone (91 [0.5%/year] vs 132 [0.8%/year]; HR, 0.69; 95% CI, 0.53-0.90; P=0.006).
• Both XARELTO plus aspirin and XARELTO alone were associated with reduction in hemorrhagic transformation of ischemic stroke vs aspirin alone, occurring in 5 patients in the XARELTO-plus-aspirin group (HR, 0.35; 95% CI, 0.13-0.99), in 5 patients in the XARELTO-alone group (HR, 0.36; 95% CI, 0.13-0.99), and in 14 patients in the aspirin-alone group.
• A significant increase in hemorrhagic strokes was observed with XARELTO alone when compared with aspirin alone (27 vs 10; HR, 2.70; 95% CI, 1.31-5.58; P=0.005), but not with XARELTO plus aspirin vs aspirin alone (15 vs 10; HR, 1.49; 95% CI, 0.67-3.31; P=0.33).
• XARELTO plus aspirin was associated with a decrease in fatal and disabling strokes (32 [0.2%/year]) vs aspirin alone (55 [0.3%/year; HR: 0.58; 95% CI: 0.37-0.89; P=0.01). Patients treated with XARELTO alone had a similar rate of fatal and disabling strokes vs those treated with aspirin alone (52 [0.3%/year] vs 55 [0.3%/year]; HR: 0.95; 95% CI: 0.65-1.38; P=0.77).
• Independent predictors of stroke included prior stroke, hypertension, systolic blood pressure at baseline, age, DM, and Asian ethnicity. Of these, prior stroke was the strongest predictor of incident stroke (HR, 3.63; 95% CI, 2.65-4.97; P<0.0001) and was associated with a 3.4%/year rate of stroke recurrence on aspirin.
• Major bleeding was not significantly increased in patients with prior stroke vs those without a history of prior stroke (1.5% vs 1.4%, respectively; HR, 1.06; 95% CI, 0.72–1.56; P=0.76; interaction P=0.19).
• The effect of XARELTO plus aspirin vs aspirin alone was consistent across subgroups with high stroke risk, including those with prior stroke.

Perera et al (2019)¹¹ conducted a subanalysis of COMPASS patients to evaluate the effect of low-dose XARELTO plus aspirin and of XARELTO alone compared with aspirin alone on different subtypes of ischemic stroke as defined by the TOAST criteria.

• All first ischemic strokes (those that were confirmed as ischemic by results of neuroimaging or autopsy) and uncertain strokes (those presumed likely to be ischemic based on clinical features) that occurred until the first formal interim analysis were included in the analysis.
• A total of 291 ischemic or uncertain strokes occurred during the study according to the TOAST criteria; 59 (20.3%) were cardioembolic, 54 (18.6%) were secondary to carotid stenosis greater than 50%, 21 (7.2%) were lacunar strokes secondary to small vessel disease, 42 (14.4%) had a negative evaluation and met the criteria for embolic stroke of undetermined source (ESUS), 108 (37.1%) had an incomplete evaluation, and 5 (1.7%) had 2 or more potential causes.
• Overall, ischemic or uncertain strokes occurred significantly less frequently in groups treated with low-dose XARELTO plus aspirin (HR, 0.51; 95% CI, 0.38-0.68; P<.001) and in groups treated with XARELTO alone (HR, 0.69; 95% CI, 0.53-0.90; P=0.006) compared with aspirin alone. There were significant differences in groups treated with XARELTO plus aspirin compared with aspirin alone in incidence of cardioembolic stroke (HR, 0.40; 95% CI, 0.20-0.78; P=0.005) and stroke of undetermined cause (HR, 0.49; 95% CI, 0.32-0.74; P>0.001), including ESUS (HR, 0.30; 95% CI, 0.12-0.74; P=0.006) and strokes that had an incomplete evaluation (HR, 0.60; 95% CI, 0.37-0.96; P=0.03).
• The effects of XARELTO plus aspirin or XARELTO alone as compared with aspirin alone on stroke subtypes are presented in Table: COMPASS Stroke Subtype Analysis.¹¹

COMPASS DM

Bhatt et al (2020)¹⁴ conducted a prespecified analysis of COMPASS patients (N=18278) to evaluate efficacy and safety outcomes in patients with and without DM at randomization being treated with low-dose XARELTO plus aspirin or aspirin alone.

• Of the 18278 patients randomized to the combination of XARELTO and aspirin or aspirin alone in the COMPASS Study, 6922 had DM at baseline and 11356 did not. There were several significant differences between baseline characteristics in the DM and non-DM groups.
• There was a consistent relative risk reduction for the benefit of dual antithrombotic therapy versus aspirin alone in patients with and without DM for the primary efficacy end point (CV death, stroke, or MI), stroke, ischemic or uncertain stroke, and the totality of ischemic events, including CV death, stroke, MI, major adverse limb events, or major vascular amputation. Effects were consistent across all other efficacy, safety and NCB outcomes, including an increased risk of major bleeding in both patients with and without DM.
• There was a statistically significant difference in ARR among patients with DM (HR, 0.74; 95% CI, 0.61-0.90; ARR 2.3%) compared to those without (HR, 0.77; 95% CI, 0.64-0.93; ARR, 1.4%) over 3 years for the primary efficacy endpoint (Gail-Simon qualitative P_interaction<0.0001).
• There was a numerically greater absolute NCB (CV death, MI, stroke, fatal bleeding, or symptomatic bleeding into critical organ) in patients with DM (HR, 0.78; 95% CI, 0.65-0.94; ARR, 2.7%) compared to those without (HR, 0.81; 95% CI, 0.68-0.97; ARR, 1.0%) over 3 years (Gail-Simon qualitative P_interaction=0.001).
• Results were consistent in those with DM treated with diabetes medications versus those with DM not receiving diabetes medications at baseline. Consistent results were seen among patients with DM with or without a history of ischemic events (MI, unstable angina, stroke, transient ischemic attack) and with or without a history of revascularization (PCI, CABG, peripheral artery intervention, peripheral artery bypass surgery).

COMPASS-PCI

Bainey et al (2020)¹² conducted a prespecified subgroup analysis of COMPASS Study patients (N=16560) to evaluate the efficacy and safety of DPI (or low-dose XARELTO plus aspirin) in patients who had stable CAD (chronic coronary syndrome) with or without previous PCI [PCI, N=9862; no PCI, N=6698].

• Baseline characteristics among PCI participants and non-PCI participants receiving DPI or aspirin alone were well-balanced. Patients who had PCI were more likely to have had a previous MI (74.8% vs. 59.6%) and have lower rates of PAD (17.6% vs 23.3%). There was no difference in baseline characteristics among participants with single-vessel or multivessel PCI.
• All analyses were conducted on an intention-to-treat population.
• There was a consistent relative risk reduction in the primary outcome, a composite of the first occurrence of CV death, MI, or stroke, regardless of previous PCI (PCI: HR,
• 0.74; 95% CI, 0.61-0.88; no PCI: HR, 0.76; 95% CI, 0.61-0.94; P-interaction=0.85). There was no heterogeneity between previous single-vessel PCI and previous multivessel PCI with DPI vs. aspirin alone (P-interaction=0.31) or between bare-metal and drug-eluting stents (P-interaction=0.95).  
• Effects were consistent among subgroups for secondary outcomes including all-cause mortality and the individual end points of the primary composite, and definite or probable stent thrombosis. Relative risk reductions were observed for all-cause death, CV mortality, and stroke. See table: COMPASS PCI Subgroup Analysis¹²
• DPI vs aspirin alone did not impact the rate of definite stent thrombosis (0.6% vs 0.6%; HR, 1.06; 95% CI, 0.0.64-1.75; P-interaction=0.40 between previous single-vessel or multivessel PCI) or probable stent thrombosis (0.2% vs 0.2%; HR, 1.30; 95% CI, 0.63-2.67; P-interaction=0.72 between previous single-vessel or multivessel PCI) in those with previous PCI.
• There was a consistent relative increase in the primary safety outcome, modified ISTH major bleeding defined as: fatal bleeding or symptomatic bleeding in a critical organ or bleeding into the surgical site requiring reoperation or bleeding leading to hospitalization (PCI: HR, 1.72; 95% CI, 1.34-2.21; no PCI: HR, 1.58; 95% CI, 1.15-2.17; P-interaction=0.68).
• Effects were consistent across all other bleeding events, including a relative increase in minor bleed (PCI: HR, 1.71; 95% CI, 1.48-1.98; no PCI: HR, 1.78; 95% CI, 1.47-2.16; P-interaction=0.74). See table: COMPASS PCI Subgroup Analysis¹²
• The lower risk of the net-clinical benefit outcome, a composite of CV death, MI, stroke, fatal bleeding, or symptomatic bleeding into a critical organ, was consistent across subgroups (PCI: HR, 0.78; 95% CI, 0.65-0.93; no PCI: HR, 0.79; 95% CI, 0.65-0.98; P-interaction=0.98).

Würtz et al (2024)¹³ conducted a non-prespecified subgroup analysis of COMPASS study patients with chronic coronary syndrome (N=14,670) to evaluate the efficacy and safety of DPI treatment or aspirin alone. Patients were stratified according to baseline cardiovascular risk using the CHADS-P₂A₂ RC score. Patients were classified as low/moderate risk (CHADS-P₂ A₂ RC score: 0-3, n=7194, mean±SD age: 67.0±7.12 years) or high risk (CHADS-P₂ A₂ RC score ≥4, n=7476, mean±SD age: 69.7±8.14 years). Patients with a history of previous stroke were excluded. Cardiovascular death, MI, or stroke were primary efficacy outcomes, whereas fatal or critical organ bleeding were primary safety outcomes.

• DPI was associated with reduced relative risks of MACE and all-cause mortality in both low/moderate risk and high risk patients compared to aspirin monotherapy but did not significantly increase the risk of fatal/critical bleeding in either group.
• DPI showed a similar level of benefit in both low/moderate-risk patients and high-risk patients when comparing the 30-month risk difference for combined ischemic and bleeding outcomes.
• Results of the treatment effect by CHADS-P₂ A₂ RC risk group and COMPASS treatment regimen are mentioned in the table Treatment Effect by CHADS-P₂ A₂ RC Risk Group and COMPASS Treatment Regimen.

Outcomes in COMPASS by Sex

Liang et al (2019)¹⁵ conducted a subanalysis of COMPASS patients (N=18,278) to evaluate efficacy, safety, and NCB outcomes in patients by sex (M/F) being treated with low-dose XARELTO and aspirin or aspirin alone, as well as a subanalysis by modified REACH score in patients whose risk score was greater or less than or equal to the median value of 12 in the COMPASS trial population.

• The original REACH score is comprised of sex, age, smoking, diabetes, low body mass index, number of vascular beds affected, CV events in the past year, HF, atrial fibrillation, statin therapy, aspirin therapy, and low eGFR, and groups countries into regions defined as low, intermediate, or high risk. The modified REACH score includes the following amendments: ‘statin therapy’ was replaced with ‘lipid-lowering therapy’, individuals with atrial fibrillation were excluded in the COMPASS trial, aspirin therapy was replaced with ‘any antiplatelet therapy use’; countries in COMPASS were grouped into three risk regions for the outcome of CV death, MI, stroke and then divided into high-, intermediate-, and low-risk regions, patients with an eGFR <60mL/min were given a +2.0 score. The maximum REACH score in the COMPASS population is 27. The median modified REACH score in the COMPASS population was 12. The original REACH score includes female sex, a further modification was the exclusion of female sex for this analysis.
• Of the 18,278 patients in the COMPASS trial randomized to receive the combination of low-dose XARELTO and aspirin or aspirin alone, 4048 were women (22.1%) and 14,230 were men (77.9%). At baseline, women were more likely to be older, more likely to have not used tobacco, had a higher prevalence of hypertension or diabetes, a lower incidence of previous MI, lower prevalence of CAD, higher prevalence of PAD, a higher prevalence of decreased renal function (<60mL/min), less likely to be white, more likely to be on a diuretic, and less likely to be on a lipid-lowering agent compared to men.
• Upon completion of follow-up, 15.9% of women and 16.7% of men in the combination arm permanently discontinued treatment. In the aspirin-only arm, 16.2% of women and 15.6% of men permanently discontinued therapy. The mean follow-up time among women was 22.5 months in women and 23.2 months in men.
• Incidence rates of efficacy, safety, and NCB outcomes were consistent among men and women.
• The effect of combination of XARELTO and aspirin compared to aspirin alone were consistent among women compared to men for the primary efficacy outcome, an expanded composite outcome which included events in the primary outcome in addition to acute limb ischemia or vascular amputation, as well as the individual components of the primary efficacy outcome (CV death, stroke, MI) and death from any cause. Relative risk reductions were recorded for the primary efficacy outcome in women (3.8% vs 5.2%; HR, 0.72; 95% CI, 0.54-0.97) and men (4.2% vs 5.5%; HR, 0.76; 95% CI, 0.66-0.89), the expanded composite outcome in women (4.0% vs 5.3%; HR, 0.73; 95% CI, 0.55-0.97) and men (4.5% vs 5.9%; HR, 0.75; 95% CI, 0.65-0.87), and the individual component of stroke in women (0.8% vs 1.9%; HR, 0.39; 95% CI, 0.22-0.71) and men (0.9% vs 1.5%; HR, 0.65; 95% CI, 0.48-0.88).
• The effect of combination of XARELTO and aspirin compared to aspirin alone were consistent among women compared to men for all safety outcomes NCB. Relative risk increases were recorded for major bleeding in women (3.1% vs 1.4%; HR, 2.22; 95% CI, 1.42-3.46) and men (3.2% vs 2.0%; HR, 1.60; 95% CI, 1.29-1.97), major bleeding at the gastrointestinal site in women (1.7% vs 0.6%; HR, 2.98; 95% CI, 1.51-5.89) and men (1.5% vs 0.8%; HR, 1.98; 95% CI, 1.43-2.75), and any bleeding in women (11.0% vs 6.2%; HR, 1.81; 95% CI, 1.46-2.26) and men (12.0% vs 7.3%; HR, 1.69; 95% CI, 1.52-1.89). A consistent relative decrease in the NCB outcome was recorded in women (4.3% vs 5.6%; HR, 0.74; 95% CI, 0.56-0.98) and men (4.8% v. 5.9%; HR, 0.81; 95% CI, 0.71-0.94).
• Effects were consistent among men and women for the primary outcome and major bleeding in patients with a modified reach score >12 or <12.

COMPASS LTOLE

Eikelboom et al (2022)¹⁹ conducted a long-term open-label extension of the COMPASS trial to assess the efficacy (composite of stroke, MI, or CV death) and safety (modified ISTH major bleeding defined as: fatal bleeding or symptomatic bleeding in a critical organ or bleeding into the surgical site requiring reoperation or bleeding leading to hospitalization) of XARELTO 2.5 mg twice a day in combination with aspirin 75 or 100 mg once a day in patients with CAD and/or PAD.

• A total of 12,964 participants who continued to meet the inclusion criteria for COMPASS were eligible to participate in COMPASS LTOLE. Participants would continue treatment until combination product was approved by regulatory authorities in their country for the treatment of CAD or PAD or for a maximum of 3 years form the start of LTOLE.
• Participants were followed every 6 months to evaluate adherence and safety and to collect clinical outcomes including stroke, MI, and mortality.
• Overall, 353 participants experienced a primary outcome (composite of stroke, MI, or CV death) event during LTOLE, with a rate of 2.35 (95% CI, 2.11-2.61) per 100 PY. Stroke, MI, and CV death had an independent incidence rate of 0.62 (95% CI, 0.50-0.76), 1.02 (95% CI, 0.86-1.19), and 1.10 (95% CI, 0.94-1.28) per 100 PY, respectively.
  • In comparison to the COMPASS trial treatment arm of XARELTO and aspirin, 379 patients experienced a primary outcome (composite of stroke, MI, or CV death) event rate of 2.18 (95% CI, 1.97-2.41) per 100 PY. Stroke, MI, and CV death had independent incidence rates of 0.47 (95% CI, 0.38-0.59), 1.02 (95% CI, 0.88-1.18), and 0.91 (95% CI, 0.77-1.06) per 100 PY, respectively.
• One hundred fifty-two participants experienced major bleeding during LTOLE, with an incidence rate of 1.01 (95% CI, 0.86-1.19) per 100 PY, whereas 370 participants experienced minor bleeding, with an incidence rate of 2.49 (95% CI, 2.24-2.75) per 100 PY.
  • In comparison to the COMPASS trial treatment arm of XARELTO and aspirin, 288 participants experienced major bleeding with an incidence rate of 1.67 (95% CI, 1.48- 1.87) per 100 PY and 838 participants experienced minor bleeding with an incidence rate of 5.11 (95% CI, 4.77-5.47) per 100 PY.

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 17 June 2024.