SUMMARY

• In patients who receive XARELTO in combination with aspirin (ASA) for the reduction in the risk of major cardiovascular (CV) events (CV death, myocardial infarction [MI], and stroke), no dosage adjustment is needed based on creatinine clearance.¹
• 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 ASA 100 mg once daily or XARELTO 5 mg BID alone is more effective than ASA 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]).^2,3
  • Patients with advanced stable kidney disease (estimated glomerular filtration rate [eGFR] <15 mL/min/1.73 m²) were excluded.^2,3
  • Patients treated with XARELTO plus ASA had significantly better CV outcomes and more major bleeding events than those treated with ASA alone. Treatment with XARELTO alone did not result in better CV outcomes vs ASA alone and resulted in more major bleeding events.^1,3
  • The effects of XARELTO plus ASA vs ASA alone on the primary efficacy outcome and on major bleeding were consistent among eGFR subgroups, (<30 mL/min/1.73 m², 3050 mL/min/1.73 m², >50-80 mL/min/1.73 m², >80 mL/min/1.73 m²).^1,3,4
• A prespecified secondary analysis of the COMPASS study demonstrated that the primary efficacy outcome and major bleeding were more frequent in those with renal dysfunction. The primary efficacy outcome was lower with XARELTO plus ASA vs ASA alone, irrespective of eGFR. Major bleeding was higher with XARELTO plus ASA vs ASA alone, irrespective of glomerular filtration rate.⁵
• In a separate prespecified subanalysis of patients in the COMPASS study (N=27,395) which analyzed 7470 (~27%) patients with a history of PAD at baseline, the effects of XARELTO plus ASA vs ASA alone on the combined outcome of major adverse cardiovascular events (MACE) and major adverse limb events (MALE; including major amputation) were consistent in patients with eGFR <60 mL/min/1.73 m² vs ≥60 mL/min/1.73 m².⁶
• A prespecified, post hoc analysis of the VOYAGER PAD (Vascular Outcomes StudY of ASA alonG with Rivaroxaban in Endovascular or Surgical Limb Revascularization for PAD) study evaluated the impact of baseline renal function on the risk of major CV and limb outcomes and bleeding in patients with symptomatic PAD who had recently undergone lower-extremity revascularization. No heterogeneity by eGFR category was observed in major CV and limb events and thrombolysis in myocardial infarction (TIMI) major bleeding events.^7,8
• A post hoc subgroup analysis of the AFIRE (Atrial Fibrillation and Ischemic Events with Rivaroxaban in Patients with Stable Coronary Artery Disease) study evaluated the effects of kidney function on bleeding and thrombotic CV events, including recurrent bleeding, in patients with stable CAD with atrial fibrillation (AF) who were on XARELTO therapy.⁹
  • During the study period, up to 10 episodes of bleeding were observed per patient, and there were no differences in bleeding incidences between low (<50 mL/min) and high eGFR (≥50 mL/min) groups (P=0.546). The incidence of severe bleeding did not differ significantly between the high and low eGFR groups (P=0.096).

CLINICAL studies

COMPASS Study

COMPASS was a phase 3, event-driven, double-blind, double-dummy, randomized, multicenter study designed to evaluate whether treatment with XARELTO 2.5 mg BID plus ASA 100 mg once daily or XARELTO 5 mg BID alone is more effective than ASA 100 mg once daily alone for secondary prevention of MI, stroke, or CV death in patients with a history of stable atherosclerotic vascular disease (CAD or PAD).^2,3

Study Design/Methods

• A total of 27,395 patients were recruited from 602 centers in 33 countries between February 2013 and May 2016.
• Key inclusion criteria included: PAD; CAD with ≥1 of the following: age ≥65 years or <65 years and documented atherosclerosis or revascularization involving ≥2 vascular beds or ≥2 additional risk factors: current smoker, diabetes mellitus (DM), renal dysfunction (eGFR <60 mL/min/1.73 m²), heart failure (HF), or nonlacunar ischemic stroke ≥1 month ago.
• Key exclusion criteria included: Advanced stable kidney disease (eGFR <15 mL/min/1.73 m²); high bleeding risk; 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 (DAPT), other non-ASA antiplatelet therapy, or oral anticoagulant therapy; systemic treatment with strong inhibitors of both CYP3A4 and P-glycoprotein or strong inducers of CYP3A4.
• Dosing interventions were as follows (patients stratified according to center and use of proton-pump inhibitor [PPI] therapy at time of randomization):
  • XARELTO 2.5 mg BID and ASA 100 mg once daily.
  • XARELTO 5 mg BID and placebo once daily.
  • Placebo BID and ASA 100 mg once daily.
• Patients who were not already receiving a PPI were randomized in a 1:1 ratio to receive pantoprazole 40 mg once daily or placebo for prevention of upper gastrointestinal (GI) complications, including bleeding, ulceration, obstruction, or perforation.
• Primary efficacy outcome: the composite of MI, stroke, or CV death.
• Primary safety outcome (based on modified International Society on Thrombosis and Hemostasis [ISTH] criteria): major bleeding including fatal bleeding, symptomatic bleeding into 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).

Results

Baseline Characteristics

• Mean age was 68.2 years, 22.0% of patients were female, 90.6% had a history of CAD, 27.3% had a history of PAD, ~75% had hypertension, ~38% had DM, and ~71% were on an angiotensin-converting enzyme (ACE) inhibitor or angiotensin-receptor blocker (ARB).
• Less than 1% of patients had an eGFR of <30 mL/min/1.73 m², ~22% had an eGFR between 30 to <60 mL/min/1.73 m², and ~77% had an eGFR of ≥60 mL/min/1.73 m².

Efficacy/Safety

• The primary efficacy outcome occurred in significantly fewer patients in the XARELTO plus ASA group vs the ASA alone group (4.1% of patients vs 5.4% of patients, respectively; hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.66-0.86; P<0.001); a significant difference was not observed between the XARELTO alone group and the ASA alone group (4.9% of patients vs 5.4% of patients, respectively; HR, 0.90; 95% CI, 0.79-1.03; P=0.12).³
• Major bleeding occurred in more patients treated with XARELTO plus ASA (288 [3.1%] patients vs 170 [1.9%] patients, respectively; HR, 1.70; 95% CI, 1.40-2.05; P<0.001) and XARELTO alone (255 [2.8%] patients vs 170 [1.9%] patients, respectively; HR, 1.51; 95% CI, 1.25-1.84; P<0.001) than in those treated with ASA alone.³
• The effects of XARELTO plus ASA as compared with ASA alone on the primary efficacy outcome and on major bleeding were consistent between eGFR subgroups (<30, 30-50, >50-80, and 80 mL/min).¹ See Table: Subgroup Analysis of Primary Efficacy Outcome and Major Bleeding by Renal Function.

Fox et al (2019)⁵ conducted a prespecified secondary analysis evaluating the efficacy and safety of XARELTO and ASA vs ASA alone in patients with and without renal dysfunction in the COMPASS study with stable CAD or PAD. The primary efficacy and safety outcomes of the overall COMPASS study have been described above.

Results

Baseline Characteristics

• A total of 21,111 patients had a baseline eGFR ≥ 60 mL/min/1.73 m² and 6276 had an eGFR of <60 mL/min/1.73 m².
• The baseline characteristics of the reduced eGFR group (<60 mL/min/1.73 m²) compared to the ≥60 mL/min/1.73 m² group tended to be older with a greater incidence of DM, hypertension, PAD, stroke, and a greater use of diuretics and calciumchannel blockers. The prevalence of CAD, prior misuse of ACE inhibitors, ARBs, beta-blockers, lipidlowering agents, nonsteroidal anti-inflammatory drugs, and PPIs were similar.

Efficacy/Safety

• Patients with renal dysfunction observed higher rates of the primary efficacy outcome (CV death, MI, or stroke) compared to patients with no renal dysfunction. This rate was inversely related to eGFR.
• The efficacy outcomes were consistently lower for the XARELTO plus ASA patients compared to the ASA alone group across the two eGFR populations (<60 mL/min/1.73 m² and ≥60 mL/min/1.73 m²) except for hemorrhagic stroke. The efficacy outcomes by renal outcomes are listed in the Table: Efficacy Outcomes by Renal Dysfunction
• Patients with greater renal dysfunction (eGFR <30 mL/min/1.73 m²; n=243) observed a similar HR for the primary efficacy outcome (HR, 0.73; 95% CI, 0.28-1.91).

• The rate of major bleeding was higher among both reduced renal function groups (XARELTO plus ASA and the ASA alone).
• The increase in major bleeding (XARELTO plus ASA vs ASA alone) was consistent for the patients with a decreased eGFR (<60 mL/min/1.73 m²) compared to the normal eGFR patients (≥60 mL/min/1.73 m²).
• The safety outcomes by renal dysfunction are listed in Table: Safety Outcomes by Renal Dysfunction.

• The net clinical benefits outcomes are listed below in Table: Net Clinical Benefit Outcomes by Renal Dysfunction

Anand et al (2018)⁶ conducted a prespecified subanalysis of patients in the COMPASS study that had stable PAD (n=7470).

Study Design/Methods

• The primary efficacy outcome and safety outcomes of the overall COMPASS study have been described above.
• Additional prespecified outcomes for PAD (subanalysis): acute limb ischemia, chronic limb ischemia, and amputation.
• Additional key composite outcomes for PAD (subanalysis): MALE (development of acute or chronic limb ischemia over course of follow-up, including additional major amputations due to a vascular event that was not acute or chronic limb ischemia), the composite of MACE and MALE, and the composite of MACE and MALE, including major amputations.

Results

• Baseline characteristics: mean age 67.8 years, 66% of patients with CAD, ~79% with hypertension, ~44% with DM, and ~70% on an ACE inhibitor or an ARB.
• The number of patients with an eGFR <60 mL/min/1.73 m² were as follows for each of the treatment arms:
  • XARELTO 2.5 mg BID and ASA 100 mg once daily (n=2492): 688 (27.6%).
  • XARELTO 5 mg BID (n=2474): 681 (27.5%).
  • ASA 100 mg once daily (n=2504): 706 (28.2%).

Efficacy/Safety

• Provisions to address multiple testing for subgroups, such as PAD, were not specified and therefore any HRs, corresponding CIs, and P values reported for subgroup analyses cannot be interpreted as statistically significant.⁴
• The effects of XARELTO plus ASA vs ASA alone on the combined outcome of MACE and MALE (including major amputation) were consistent in patients with eGFR <60 mL/min/1.73 m² vs ≥60 mL/min/1.73 m² (interaction P value=0.99).
  • eGFR <60 mL/min/1.73 m²: XARELTO plus ASA, 60 events/688 patients (9%); ASA alone, 86 events/706 patients (12%); HR, 0.69; 95% CI, 0.49-0.96.
  • eGFR ≥60 mL/min/1.73 m²: XARELTO plus ASA, 97 events/1803 patients (5%); ASA alone, 139 events/1798 patients (8%); HR, 0.69; 95% CI, 0.53-0.89.

Darmon et al (2019)¹⁰ evaluated the risk of ischemic and bleeding events in the presence of >1 enrichment criterion in COMPASS-eligible patients from the REACH (REduction of Atherothrombosis for Continued Health) registry.

Anand et al (2024)¹¹ evaluated ischemic and bleeding outcomes in the post-approval XATOA (Xarelto plus Acetylsalicylic acid: Treatment patterns and outcomes in patients with atherosclerosis) registry study of patients with CAD and/or PAD.

In both these studies, the associated risk of ischemic and bleeding events in patients with stable CAD, PAD, or both who also had renal impairment (eGFR < 60 mL/min/1.73 m²) was higher compared to those with no renal impairment.^10,11

VOYAGER PAD

VOYAGER PAD was a phase 3, multicenter, randomized, placebo-controlled, double-blind, international study designed to evaluate whether XARELTO 2.5 mg BID plus ASA 100 mg once daily is more effective than ASA 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.⁷

Study Design/Methods

• A total of 6564 patients were recruited from 542 centers in 34 countries between August 2015 and January 2018.
• Dosing interventions were as follows:
  • XARELTO 2.5 mg BID and ASA 100 mg once daily.
  • Placebo BID and ASA 100 mg once daily.
• Eligible participants with symptomatic PAD underwent successful revascularization for a lesion distal to the external iliac artery within the last 10 days.
• Patients were stratified according to the type of index procedure underwent (endovascular vs surgical) and according to clopidogrel use or nonuse within the group of patients who underwent an endovascular procedure.
• Key inclusion criteria: Age 50 or older; moderate to severe PAD; abnormal anklebrachial index (ABI) <0.80 or toe-brachial index (TBI) <0.60 without prior history of limb revascularization; abnormal ABI ≤0.85 or TBI <0.65 with prior history of limb revascularization.
• Key exclusion criteria: Patients without functional limitation of the index leg; prior revascularization on the index leg within 10 days of the qualifying revascularization; patients with major tissue loss; patients requiring treatment with ASA >100 mg; planned DAPT use for >6 months after revascularization procedure.
  • Additional exclusion criteria included: any condition requiring dialysis or renal replacement therapy, or a renal impairment at screening assessed with an eGFR <15 mL/min/1.73 m².¹²
  • If a patient's eGFR was <30 mL/min/1.73 m² prior to the procedure, it must have remained to be >15 mL/min/1.73 m² 72 hours after the procedure to enroll and randomize the patient.¹²
• The median follow-up period was 28 months.
• Primary efficacy outcome: the composite of acute limb ischemia, major amputation of vascular etiology, MI, ischemic stroke, or CV death.
• Principal safety outcome: Major bleeding according to TIMI classification.

Results

Baseline Characteristics

• Median age was 67 years; ~26.0% of patients were female; ~81% of patients were Caucasian.
• Baseline medical history: 40% had DM; ~20% had an eGFR less than 60 mL/min/1.73m²; ~35.0% were current smokers; ~31.0% had a history of symptomatic CAD; ~11.0% had a MI; median ABI was 0.56; ~6.0% had a prior amputation; ~96.0% had a history of claudication.
• Qualifying revascularization: ~65.0% had an endovascular procedure; ~35.0% treated surgically; ~36.0% had a history of a prior lower extremity revascularization.
• Baseline medication: ~80.0% used a statin; ~63.0% were on an ACE inhibitor or ARB
• Approximately 51% of patients were given clopidogrel at randomization.

Outcomes

• The primary efficacy outcome occurred in fewer patients in the XARELTO-plus-ASA group than in the ASA-alone group (508 patients [17.3%] vs 584 patients [19.9%]; HR, 0.85; 95% CI, 0.76 to 0.96; P=0.009) based on Kaplan-Meier estimates of the cumulative incidence at 3 years.⁷
• The principal safety outcome occurred in more patients in the XARELTO-plus-ASA group than in the ASA-alone group (62 patients [2.65%] vs 44 patients [1.87%]; HR, 1.43; 95% CI, 0.97 to 2.10; P=0.07) based on Kaplan-Meier estimates of the cumulative incidence at 3 years.⁷
• The effects of XARELTO plus ASA as compared with ASA alone on the primary efficacy outcome and the primary safety outcome between eGFR subgroups (<60 and ≥60 mL/min/1.73m²) are displayed in Table: Primary Efficacy and Safety Outcomes by Renal Dysfunction

Hsia et al (2021)⁸ conducted a prespecified, post hoc analysis evaluating the impact of baseline renal function on the risk of major CV and limb outcomes and major bleeding in patients in the VOYAGER PAD study.

Study Design/Methods

• Primary efficacy outcome was composite of acute limb ischemia, major amputation, MI, ischemic stroke, or CV death.
• Primary safety outcome and inclusion/exclusion criteria were consistent with those of the main VOYAGER PAD study.

Results

Baseline Characteristics

• Of the 6319 patients with baseline eGFR assessments, 6.6% and 14.4% had an eGFR of <45 mL/min/1.73 m² and 45 to <60 mL/min/1.73 m², respectively.
• In patients with eGFR <45 mL/min/1.73 m² vs 45 to <60 mL/min/1.73 m², the median age was 74 vs 72 years, 40.9% vs 36.4% were female, 94.5% vs 89.8% had hypertension, 61.1% vs 48.7% had DM, 63.0% vs 65.5% had hyperlipidemia, and 19.0% vs 22.5% were smokers, respectively.

Efficacy/Safety

• Improvement in limb outcomes following peripheral vascularization was observed in the XARELTO group across all eGFR categories.
  • No heterogeneity by eGFR category was observed in the reduction of primary endpoint events.
• See Table: Reduction in Major Limb Events With XARELTO.

• More bleeding events were observed in the XARELTO group in patients with eGFR <45 mL/min/1.73 m² than in other eGFR categories;no heterogeneity by eGFR category was observed.
• See Table: MACE + MALE and TIMI Major Bleeding by eGFR category.
• No excess intracerebral or fatal hemorrhage was observed in the XARELTO group.

AFIRE Study

AFIRE was a multicenter, randomized, open-label, parallel group study to evaluate whether monotherapy with XARELTO is noninferior to combination therapy with XARELTO plus an antiplatelet agent in patients with stable CAD and AF, more than 1 year after revascularization, or in those with angiographically confirmed CAD not requiring revascularization.¹³

Matsui et al (2022)⁹ conducted a post hoc subgroup analysis of the AFIRE study to evaluate the effects of kidney function on bleeding and thrombotic CV events, including recurrent bleeding, in patients with stable CAD with AF who were on XARELTO therapy.

Study Design/Methods

• The following outcomes were evaluated according to renal function: Bleeding events, including recurrent bleeding, and ischemic CV events, including MI, unstable angina requiring revascularization, ischemic stroke, systemic embolism, and death due to any cause.
• The overall median follow-up time was 36 months.

Results

Baseline Characteristics

• A total of 2092 patients were included, of whom, 1386 (66.3%) were in the high eGFR group (≥50 mL/min) with a mean eGFR of 74.3±21.8 mL/min, and 706 (33.7%) patients were in the low eGFR (<50 mL/min) group with a mean eGFR of 38.7±7.9 mL/min.
• The mean CHADS₂ (congestive HF, hypertension, age ≥75, diabetes, stroke [doubled]) score was 2.3 (standard deviation [SD], 1.1) in the high eGFR group and 2.9 (SD, 1.2) in the low eGFR group.
• Compared to the low eGFR group, the high eGFR group had younger patients (80.3±5.8 vs 71.4±7.6 years, P<0.001), respectively, and more male patients (66.0% vs 85.6%, P<.001), respectively.
• Compared to the high eGFR group, the low eGFR group showed higher rates of kidney dysfunction (0.3% vs 1.8%, P< 0.001), respectively.

Outcomes

• During the study period, up to 10 episodes of bleeding were observed per patient, and there were no differences in bleeding incidences between the low and high eGFR groups (P=0.546), and the incidence of severe bleeding did not differ significantly between the high and low eGFR groups (P=0.096), see Table: Outcome Events According to eGFR.

• By the end of the first year, cumulative episodes of bleeding per 100 patients were 5.4 and 6.2 in the high and low eGFR groups, respectively (difference, 0.8 per 100 patients).
  • After 1 year, the difference increased persistently, 1.3 and 1.7 per 100 patients at 2 and 3 years, respectively.
• By the end of the first year, the cumulative number of bleeding and ischemic CV events per 100 patients were 6.4 and 7.8 in the high and low eGFR groups, respectively (difference, 1.4 per 100 patients).
  • After 1 year, the difference increased persistently, 2.3 and 2.9 per 100 patients at 2 and 3 years, respectively.
• The bleeding rate per 100 person-years (PY) was 11.3 in the high eGFR group and 15.3 in the low eGFR group, with a rate ratio of 0.738 (95% CI, 0.615-0.886, P=0.0009) for recurrent bleeding.
  • In the same composite outcome settings, the recurrent bleeding event analysis revealed larger differences than the time-to-first event analysis.
• After adjustments, the HR for the first bleeding event in the high eGFR group was 0.875 (95% CI, 0.701-1.090; P=0.234), and for the first composite events (bleeding events, ischemic CV events, and death), the HR was 0.723 (95% CI, 0.603-0.867; P=0.000), see Table: Comparison of the Effect of eGFR Difference Among Different Endpoints

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 12 July 2024.