https://orcid.org/0000-0001-7077-283X
Abstract
To determine the characteristics of patients with coronary artery disease (CAD), peripheral artery disease (PAD), or both, initiating dual pathway inhibition (DPI) using rivaroxaban 2.5 mg twice daily plus aspirin, and to report their clinical outcomes and bleeding rates in clinical practice compared to the COMPASS randomized trial, which provided the basis for using DPI in this patient population.
XATOA is a prospective registry of 5532 patients: of which, 72.7% had CAD, 58.9% had PAD, and 31.6% had both. The mean age of patients was 68 years and 25.5% were women. The mean follow-up period was 15 months. The most frequently reported reason for initiating DPI was the presence of existing, worsening or newly diagnosed risk characteristics (n = 4753, 85.9%). Before initiating DPI, 75.3% received a single antiplatelet and 18.3% received various antiplatelet combinations. The incidence of major adverse cardiovascular events (MACE), major adverse limb events (MALE) and acute or severe limb ischaemia was 2.26, 3.57, and 1.54 per 100 patient-years, respectively, among the 5532 patients in XATOA. Corresponding rates in COMPASS were 2.18, 0.19, and 0.12 per 100 patient-years, respectively. Major bleeding rates were 0.95 and 1.67 per 100 patient-years in XATOA and COMPASS, respectively.
High-risk vascular patients are prioritized for DPI in clinical practice, and rates of MACE are similar to COMPASS, but MALE rates are higher in XATOA, consistent with the greater proportion of PAD patients. Major bleeding rates were lower in XATOA. The findings provide support for favourable net clinical benefit of DPI in high-risk vascular patients.
The characteristics of patients initiated on dual pathway inhibition (DPI: rivaroxaban 2.5 mg twice daily plus aspirin) have not previously been defined in clinical practice and the XATOA registry findings demonstrate patient outcomes are consistent with those of the COMPASS trial, despite geographic differences in recruitment and the higher proportion of PAD patients.
Introduction
Patients with coronary artery disease (CAD) and/or peripheral artery disease (PAD) are at elevated risk of future atherosclerotic events despite evidence-based recommendations for secondary prevention measures. Current guidelines recommend consideration of additional antithrombotic therapy in certain patients with CAD or PAD to mitigate the risk of cardiovascular events including stroke, myocardial infarction, ischaemic limb events, and cardiovascular death.1–7
The COMPASS trial assessed the efficacy and safety of dual pathway inhibition (DPI) with rivaroxaban 2.5 mg twice daily (bid) plus aspirin or rivaroxaban 5 mg bid versus aspirin alone for the prevention of atherothrombotic events in patients with CAD, PAD, or both.8–11 In a population receiving a high standard of risk factor management, DPI significantly reduced the risk of cardiovascular events (including limb events) compared with aspirin alone, at a cost of increased risk of International Society on Thrombosis and Haemostasis (ISTH) major bleeding, but not intracranial or fatal bleeding.8–11 Rivaroxaban 5 mg bid did not significantly reduce the risk of cardiovascular events and increased the risk of bleeding events versus aspirin alone.10
DPI has now been approved widely by healthcare regulatory authorities (such as the European Medicines Agency) for use in patients with increased vascular risk and CAD, PAD, or both. Several clinical guidelines recommend its use in this setting (e.g. Class IIa recommendation by European Society of Cardiology guidelines for the diagnosis and management of chronic coronary syndromes).1–7 In some countries, a broader population of patients is approved for DPI compared with the COMPASS trial population.12,13 However, it is unknown which types of patients with CAD or PAD are prioritized for DPI use in clinical practice. Additionally, the rates of bleeding and clinical events in clinical practice in patients receiving DPI outside of the context of a randomized trial are unknown.
The proportion of patients meeting the qualifying criteria for COMPASS and the characteristics of such COMPASS-eligible patients have been examined in some prior studies.14–17 However, XATOA differs importantly as patients were initiated on DPI in clinical practice. Clinicians initiating a new antithrombotic regimen may judge risks versus potential benefits differently from the selection criteria of the COMPASS trial.
To address this topic, the international, multicentre, prospective, single-arm XATOA registry study (NCT03746275) enrolled and prospectively followed patients receiving DPI in routine clinical practice.18 Treatment patterns and clinical characteristics, as well as adjudicated ischaemic and bleeding outcomes, were investigated.18 This pre-specified analysis reports the main results of XATOA for the overall population and compares them with those reported from the COMPASS trial.
The aim of XATOA was to determine the characteristics of patients with CAD, PAD, or both receiving DPI using rivaroxaban 2.5 mg bid plus aspirin, and to report their clinical outcomes and bleeding rates in clinical practice compared with those in the COMPASS randomized trial.
Methods
The design and methods of the XATOA study have been reported previously.18 In brief, XATOA is an international, multicentre, prospective, single-arm registry study in adults (aged ≥18 years) with CAD, PAD, or both. Enrolled patients received DPI based on a clinical practice decision. Patients starting DPI within 4 weeks prior to enrolment were included in the registry. All patients met all enrolment criteria and provided informed consent.
Patient population and follow-up
Patients aged ≥18 years with chronic CAD, PAD, or both were eligible in countries where DPI was in clinical use and had regulatory approval. Patients with contraindications according to the locally approved indication for DPI, those receiving chronic anticoagulation therapy, and those participating in an interventional trial were excluded. All treatment decisions were at the discretion of the responsible clinician, including the use of concomitant therapies. Clinicians were asked to consider patients consecutively to minimize the risk of selection bias. The population was limited to patients in countries where DPI was both approved by local healthcare authorities and in clinical use. The countries included in XATOA were intended to represent a population of patients worldwide where DPI was a possible treatment option at the time of this study. Similarly, centres were selected to be representative of patients in each country, as well as factors such as types of healthcare providers, type and size of practice, and geography. The minimum criteria for site selection were availability of suitable patients; availability of data for determining exposures, outcomes, and all other variables relevant to the study objectives; number of patients planned to be included per site experience with electronic data capturing where applicable; and representativeness.
The follow-up period was at least 12 months after enrolment and follow-up visits took place according to routine practice. Patients could withdraw from the XATOA study at any time and substitute patients were not recruited following premature treatment discontinuation. After permanent discontinuation, survival status within 30 days of the end-of-study observation was documented by the treating clinician. An electronic data-capturing system was used for data collection. Data collection took place at baseline and at routine clinical follow-up visits throughout the study. The study complied with the relevant local laws and regulations pertaining to observational studies and data protection.
Study outcomes
The primary objective of the study was to describe clinical characteristics of patients selected for DPI with CAD, PAD, or both, in clinical practice. The clinical outcomes of interest included major adverse cardiovascular events (MACE), defined as the composite of cardiovascular death, myocardial infarction (MI), or stroke; consistent with an analysis of the COMPASS trial,19 major adverse limb events (MALE) defined as the composite of acute or severe limb ischaemia (leading to an intervention), chronic limb ischaemia (leading to an intervention), and major amputation (amputation above the forefoot). The safety outcome was ISTH major bleeding, defined as the composite of fatal and/or symptomatic bleeding into a critical organ and/or associated with a ≥2 g/dL reduction in haemoglobin and/or requiring a transfusion of ≥2 units of packed red blood cells or whole blood. Non-major bleeding was defined according to the ISTH criteria (all bleeding events that do not meet the definition of ISTH major bleeding). Outcome definitions were harmonized with those of the COMPASS trial to allow comparisons of the data (Supplementary material online, Table S1). Adverse events that occurred within 30 days after the last rivaroxaban or aspirin dose were also documented and reported. Clinical events were centrally adjudicated by an independent external adjudication committee.
Statistical analysis
The full analysis set consisted of all patients who received at least one dose of DPI and the safety analysis set was defined as patients who received at least one dose of rivaroxaban. Treatment-emergent events were defined as events arising or worsening within 2 days after permanent treatment discontinuation. Clinical outcomes were assessed using incidence proportions, cumulative incidences, and incidence rates with 95% confidence intervals (Clopper–Pearson formula). All statistical analyses were descriptive and exploratory as XATOA was a single-arm prospective study. To allow the description of treatment patterns and estimation with adequate precision of clinical outcomes in the overall population, as well as by country and in the main subgroups as per the aim of the study, the inclusion of 5000–6500 patients from at least 300 sites was planned. Incidence proportions of 1%, 5%, and 10% and a study size of 5000 patients would yield corresponding 95% confidence intervals of 0.6%, 1.2%, and 1.7%, respectively. The corresponding characteristics and outcomes of patients in the COMPASS study are presented for reference.8–10 In XATOA, clinical outcomes were collected through adverse event reporting, whereas clinical events in COMPASS were captured separately. Annualized rates of clinical outcomes and bleeding events are presented.
The COMPASS trial10,20
The design and results of the COMPASS trial have been published previously.10,20 COMPASS was a phase III, double-blind, randomized controlled trial investigating the efficacy and safety of rivaroxaban 2.5 mg bid plus aspirin or rivaroxaban 5 mg bid versus aspirin in patients with chronic CAD or PAD.10,20 Key inclusion criteria were PAD, or CAD and ≥one of the following: age ≥65 years, or age <65 years and atherosclerosis in ≥2 vascular beds or ≥2 additional risk factors (smoking, diabetes, estimated glomerular filtration rate <60 mL/min/1.73 m2, heart failure or non-lacunar ischaemic stroke ≥1 month previously). Key exclusion criteria included stroke within 1 month previously, any haemorrhagic or lacunar stroke, severe heart failure with known ejection fraction <30% or NYHA class III or IV symptoms, a need for dual antiplatelet therapy (DAPT), other non-aspirin antiplatelet therapy or oral anticoagulation, or estimated glomerular filtration rate <15 mL/min/1.73 m2.10,20
Results
Patient disposition and follow-up
From November 2018 to May 2020, 6389 patients were screened. Of these, 581 patients were excluded and 5808 were enrolled. Reasons for exclusion are summarized in Figure 1 and Supplementary material online, Table S2. A total of 5615 patients received at least one dose of rivaroxaban and were included in the safety analysis set. The full analysis set consisted of 5532 patients who received at least one dose of DPI with rivaroxaban and aspirin. Of the patients in the full analysis set, 4022 (72.7%) had CAD, 3258 (58.9%) had PAD, and 1748 (31.6%) had both CAD and PAD. The mean observation period in the full analysis set was 15 ± 6 months and 79.1% (n = 4374) were followed up for more than 12 months.
Patient disposition in XATOA. aPatients could have more than one reason for exclusion or non-inclusion from the study. CAD, coronary artery disease; FAS, full analysis set; GCP, good clinical practice; PAD, peripheral artery disease; SAS, safety analysis set.
Baseline characteristics
Patients were mostly enrolled from outpatient clinics (n = 3344, 60.4%) and the remainder (n = 2188, 39.6%) from hospitals. A total of 2944 (53.2%) patients were enrolled in cardiology clinics, 815 (14.7%) in vascular medicine clinics, 743 (13.4%) in vascular surgery or other surgery clinics, 684 (12.4%) in internal medicine clinics, and 346 (6.3%) in general medicine clinics.
Baseline characteristics, including laboratory values of patients in XATOA, are shown in Table 1, Supplementary material online, Table S3, and Figure 2. Patients had a mean age of 68 years, and 25.5% were female. Common co-morbidities included hypertension (80.5%), diabetes (37.0%), and prior MI (36.4%). A total of 24.3% were smokers. In XATOA, study sites were asked to capture all available haemoglobin and creatinine values, and this resulted in 76.0% of patients with at least one haemoglobin test and 78.8% with at least one serum creatinine test (Table 1). Prior MI was reported in 36.4% of patients, prior acute coronary syndrome (ACS) in 13.5%, and prior percutaneous coronary intervention (PCI) in 41.5%. In these patients, the mean time between the event and the initial study visit was 100, 48, and 70 months, respectively.
Regions enrolling patients in XATOA and COMPASS.10
Baseline characteristics in XATOA and COMPASS
| XATOA (N = 5532) | COMPASS (N = 27 395)10 | |
|---|---|---|
| Demographics | ||
| Age, years, mean ± SD | 68.0 ± 9.6 | 68.2 ± 0.02 |
| Female sex | 1413 (25.5) | 6020 (22.0) |
| Race (self-reported) | ||
| White | 4773 (86.3) | 17 027 (62.2) |
| Black | 13 (0.2) | 262 (1.0) |
| Asian | 335 (6.1) | 4269 (15.6) |
| Other | 119 (2.2) | 5837 (21.3) |
| Regionsa | ||
| North America/Canada | 853 (15.4) | 3918 (14.3) |
| Latin America/South America | 311 (5.6) | 6144 (22.4) |
| Middle East, Western Europe, Australia, or South Africa | 3358 (60.7) | 8555 (31.2) |
| Eastern Europe | 866 (15.7) | 4823 (17.6) |
| Asia Pacific | 144 (2.6) | 3955 (14.4) |
| Clinical characteristics | ||
| BMI, kg/m2, mean ± SD | 28.2 ± 4.9 | 28.3 ± 0.02 |
| Tobacco use | 1343 (24.3)b | 5867 (21.4) |
| Family history of vascular disease | ||
| Yes | 1636 (29.6) | Not currently available |
| No | 3805 (68.8) | Not currently available |
| Missing | 91 (1.6) | Not currently available |
| Serum creatinine value available at baseline | 1516 (27.4) | Not reported |
| Serum creatinine, mg/dL, mean ± SD | 1.03 ± 0.43 | 1.03 ± 0.61 |
| eGFR (CKD-EPI), mL/min/1.73 m2 | 1516 (27.4) | 27 387 (100.0) |
| eGFR (CKD-EPI), mL/min/1.73 m2, mean ± SD | 73.31 ± 20.01 | 73.8 ± 17.9 |
| Co-morbidities | ||
| Myocardial infarction | 2015 (36.4) | 17 028 (62.2) |
| Heart failure | 921 (16.6) | 5902 (21.5) |
| Stroke | 319 (5.8) | 1032 (3.8) |
| Intermittent claudication | 1916 (34.6) | 3829 (14.0) |
| Diabetes | 2130 (38.5) | 10 341 (37.7) |
| Hypertension | 4454 (80.5) | 20 632 (75.3) |
| eGFR (CKD-EPI) <60 mL/min/1.73 m2 | 407 (26.8)c | 6276 (22.9)d |
| Prior interventions and revascularizations | ||
| PCI | 2295 (41.5) | 14 862 (54.3)e |
| CABG | 1048 (18.9) | 6471 (23.6) |
| Peripheral arterial intervention | 1692 (30.6) | 2045 (7.5)f |
| Lower-extremity amputation | 129 (2.3) | 335 (1.2) |
| Carotid intervention | 277 (5.0) | Not reported separately |
| Cerebrovascular intervention | 32 (0.6) | Not reported separately |
| Other | 199 (3.6) | Not reported separately |
| Prior medications of interest | ||
| Antidiabetic medications | 1615 (29.2) | 9890 (36.1) |
| Lipid-lowering agents | 4538 (82.0) | 25 727 (93.9) |
| Beta-blockers | 3286 (59.4) | 20 682 (75.5) |
| ACE inhibitors/ARBs | 3868 (69.9) | 21 628 (78.9) |
| ARN inhibitors | 63 (1.1) | Not reported |
| Mineralocorticoid receptor antagonists | 415 (7.5) | Not reported |
| Diuretics | 1372 (24.8) | 10 383 (37.9) |
| Proton pump inhibitors | 1437 (26.0) | 10 869 (39.7)g |
| XATOA (N = 5532) | COMPASS (N = 27 395)10 | |
|---|---|---|
| Demographics | ||
| Age, years, mean ± SD | 68.0 ± 9.6 | 68.2 ± 0.02 |
| Female sex | 1413 (25.5) | 6020 (22.0) |
| Race (self-reported) | ||
| White | 4773 (86.3) | 17 027 (62.2) |
| Black | 13 (0.2) | 262 (1.0) |
| Asian | 335 (6.1) | 4269 (15.6) |
| Other | 119 (2.2) | 5837 (21.3) |
| Regionsa | ||
| North America/Canada | 853 (15.4) | 3918 (14.3) |
| Latin America/South America | 311 (5.6) | 6144 (22.4) |
| Middle East, Western Europe, Australia, or South Africa | 3358 (60.7) | 8555 (31.2) |
| Eastern Europe | 866 (15.7) | 4823 (17.6) |
| Asia Pacific | 144 (2.6) | 3955 (14.4) |
| Clinical characteristics | ||
| BMI, kg/m2, mean ± SD | 28.2 ± 4.9 | 28.3 ± 0.02 |
| Tobacco use | 1343 (24.3)b | 5867 (21.4) |
| Family history of vascular disease | ||
| Yes | 1636 (29.6) | Not currently available |
| No | 3805 (68.8) | Not currently available |
| Missing | 91 (1.6) | Not currently available |
| Serum creatinine value available at baseline | 1516 (27.4) | Not reported |
| Serum creatinine, mg/dL, mean ± SD | 1.03 ± 0.43 | 1.03 ± 0.61 |
| eGFR (CKD-EPI), mL/min/1.73 m2 | 1516 (27.4) | 27 387 (100.0) |
| eGFR (CKD-EPI), mL/min/1.73 m2, mean ± SD | 73.31 ± 20.01 | 73.8 ± 17.9 |
| Co-morbidities | ||
| Myocardial infarction | 2015 (36.4) | 17 028 (62.2) |
| Heart failure | 921 (16.6) | 5902 (21.5) |
| Stroke | 319 (5.8) | 1032 (3.8) |
| Intermittent claudication | 1916 (34.6) | 3829 (14.0) |
| Diabetes | 2130 (38.5) | 10 341 (37.7) |
| Hypertension | 4454 (80.5) | 20 632 (75.3) |
| eGFR (CKD-EPI) <60 mL/min/1.73 m2 | 407 (26.8)c | 6276 (22.9)d |
| Prior interventions and revascularizations | ||
| PCI | 2295 (41.5) | 14 862 (54.3)e |
| CABG | 1048 (18.9) | 6471 (23.6) |
| Peripheral arterial intervention | 1692 (30.6) | 2045 (7.5)f |
| Lower-extremity amputation | 129 (2.3) | 335 (1.2) |
| Carotid intervention | 277 (5.0) | Not reported separately |
| Cerebrovascular intervention | 32 (0.6) | Not reported separately |
| Other | 199 (3.6) | Not reported separately |
| Prior medications of interest | ||
| Antidiabetic medications | 1615 (29.2) | 9890 (36.1) |
| Lipid-lowering agents | 4538 (82.0) | 25 727 (93.9) |
| Beta-blockers | 3286 (59.4) | 20 682 (75.5) |
| ACE inhibitors/ARBs | 3868 (69.9) | 21 628 (78.9) |
| ARN inhibitors | 63 (1.1) | Not reported |
| Mineralocorticoid receptor antagonists | 415 (7.5) | Not reported |
| Diuretics | 1372 (24.8) | 10 383 (37.9) |
| Proton pump inhibitors | 1437 (26.0) | 10 869 (39.7)g |
ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; ARN, angiotensin receptor–neprilysin; BMI, body mass index; CABG, coronary artery bypass grafting; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; eGFR, estimated glomerular filtration rate; PCI, percutaneous coronary intervention; SD, standard deviation.
Values are n (%) unless otherwise indicated.
aCountries are shown in Figure 2 and Supplementary material online, Table S2.
bCurrent smoking in XATOA.
cBased on laboratory values collected before inclusion in XATOA and shown as a proportion of patients with available values at baseline.
deGFR 15–<60 mL/min/1.73 m2.
eIncludes percutaneous transluminal coronary angioplasty and atherectomy.
fIncludes peripheral artery bypass surgery and peripheral percutaneous transluminal angioplasty.
gEligible patients (n = 17 598) who were not receiving a proton pump inhibitor at baseline were randomized to a proton pump inhibitor versus placebo.
Baseline characteristics in XATOA and COMPASS
| XATOA (N = 5532) | COMPASS (N = 27 395)10 | |
|---|---|---|
| Demographics | ||
| Age, years, mean ± SD | 68.0 ± 9.6 | 68.2 ± 0.02 |
| Female sex | 1413 (25.5) | 6020 (22.0) |
| Race (self-reported) | ||
| White | 4773 (86.3) | 17 027 (62.2) |
| Black | 13 (0.2) | 262 (1.0) |
| Asian | 335 (6.1) | 4269 (15.6) |
| Other | 119 (2.2) | 5837 (21.3) |
| Regionsa | ||
| North America/Canada | 853 (15.4) | 3918 (14.3) |
| Latin America/South America | 311 (5.6) | 6144 (22.4) |
| Middle East, Western Europe, Australia, or South Africa | 3358 (60.7) | 8555 (31.2) |
| Eastern Europe | 866 (15.7) | 4823 (17.6) |
| Asia Pacific | 144 (2.6) | 3955 (14.4) |
| Clinical characteristics | ||
| BMI, kg/m2, mean ± SD | 28.2 ± 4.9 | 28.3 ± 0.02 |
| Tobacco use | 1343 (24.3)b | 5867 (21.4) |
| Family history of vascular disease | ||
| Yes | 1636 (29.6) | Not currently available |
| No | 3805 (68.8) | Not currently available |
| Missing | 91 (1.6) | Not currently available |
| Serum creatinine value available at baseline | 1516 (27.4) | Not reported |
| Serum creatinine, mg/dL, mean ± SD | 1.03 ± 0.43 | 1.03 ± 0.61 |
| eGFR (CKD-EPI), mL/min/1.73 m2 | 1516 (27.4) | 27 387 (100.0) |
| eGFR (CKD-EPI), mL/min/1.73 m2, mean ± SD | 73.31 ± 20.01 | 73.8 ± 17.9 |
| Co-morbidities | ||
| Myocardial infarction | 2015 (36.4) | 17 028 (62.2) |
| Heart failure | 921 (16.6) | 5902 (21.5) |
| Stroke | 319 (5.8) | 1032 (3.8) |
| Intermittent claudication | 1916 (34.6) | 3829 (14.0) |
| Diabetes | 2130 (38.5) | 10 341 (37.7) |
| Hypertension | 4454 (80.5) | 20 632 (75.3) |
| eGFR (CKD-EPI) <60 mL/min/1.73 m2 | 407 (26.8)c | 6276 (22.9)d |
| Prior interventions and revascularizations | ||
| PCI | 2295 (41.5) | 14 862 (54.3)e |
| CABG | 1048 (18.9) | 6471 (23.6) |
| Peripheral arterial intervention | 1692 (30.6) | 2045 (7.5)f |
| Lower-extremity amputation | 129 (2.3) | 335 (1.2) |
| Carotid intervention | 277 (5.0) | Not reported separately |
| Cerebrovascular intervention | 32 (0.6) | Not reported separately |
| Other | 199 (3.6) | Not reported separately |
| Prior medications of interest | ||
| Antidiabetic medications | 1615 (29.2) | 9890 (36.1) |
| Lipid-lowering agents | 4538 (82.0) | 25 727 (93.9) |
| Beta-blockers | 3286 (59.4) | 20 682 (75.5) |
| ACE inhibitors/ARBs | 3868 (69.9) | 21 628 (78.9) |
| ARN inhibitors | 63 (1.1) | Not reported |
| Mineralocorticoid receptor antagonists | 415 (7.5) | Not reported |
| Diuretics | 1372 (24.8) | 10 383 (37.9) |
| Proton pump inhibitors | 1437 (26.0) | 10 869 (39.7)g |
| XATOA (N = 5532) | COMPASS (N = 27 395)10 | |
|---|---|---|
| Demographics | ||
| Age, years, mean ± SD | 68.0 ± 9.6 | 68.2 ± 0.02 |
| Female sex | 1413 (25.5) | 6020 (22.0) |
| Race (self-reported) | ||
| White | 4773 (86.3) | 17 027 (62.2) |
| Black | 13 (0.2) | 262 (1.0) |
| Asian | 335 (6.1) | 4269 (15.6) |
| Other | 119 (2.2) | 5837 (21.3) |
| Regionsa | ||
| North America/Canada | 853 (15.4) | 3918 (14.3) |
| Latin America/South America | 311 (5.6) | 6144 (22.4) |
| Middle East, Western Europe, Australia, or South Africa | 3358 (60.7) | 8555 (31.2) |
| Eastern Europe | 866 (15.7) | 4823 (17.6) |
| Asia Pacific | 144 (2.6) | 3955 (14.4) |
| Clinical characteristics | ||
| BMI, kg/m2, mean ± SD | 28.2 ± 4.9 | 28.3 ± 0.02 |
| Tobacco use | 1343 (24.3)b | 5867 (21.4) |
| Family history of vascular disease | ||
| Yes | 1636 (29.6) | Not currently available |
| No | 3805 (68.8) | Not currently available |
| Missing | 91 (1.6) | Not currently available |
| Serum creatinine value available at baseline | 1516 (27.4) | Not reported |
| Serum creatinine, mg/dL, mean ± SD | 1.03 ± 0.43 | 1.03 ± 0.61 |
| eGFR (CKD-EPI), mL/min/1.73 m2 | 1516 (27.4) | 27 387 (100.0) |
| eGFR (CKD-EPI), mL/min/1.73 m2, mean ± SD | 73.31 ± 20.01 | 73.8 ± 17.9 |
| Co-morbidities | ||
| Myocardial infarction | 2015 (36.4) | 17 028 (62.2) |
| Heart failure | 921 (16.6) | 5902 (21.5) |
| Stroke | 319 (5.8) | 1032 (3.8) |
| Intermittent claudication | 1916 (34.6) | 3829 (14.0) |
| Diabetes | 2130 (38.5) | 10 341 (37.7) |
| Hypertension | 4454 (80.5) | 20 632 (75.3) |
| eGFR (CKD-EPI) <60 mL/min/1.73 m2 | 407 (26.8)c | 6276 (22.9)d |
| Prior interventions and revascularizations | ||
| PCI | 2295 (41.5) | 14 862 (54.3)e |
| CABG | 1048 (18.9) | 6471 (23.6) |
| Peripheral arterial intervention | 1692 (30.6) | 2045 (7.5)f |
| Lower-extremity amputation | 129 (2.3) | 335 (1.2) |
| Carotid intervention | 277 (5.0) | Not reported separately |
| Cerebrovascular intervention | 32 (0.6) | Not reported separately |
| Other | 199 (3.6) | Not reported separately |
| Prior medications of interest | ||
| Antidiabetic medications | 1615 (29.2) | 9890 (36.1) |
| Lipid-lowering agents | 4538 (82.0) | 25 727 (93.9) |
| Beta-blockers | 3286 (59.4) | 20 682 (75.5) |
| ACE inhibitors/ARBs | 3868 (69.9) | 21 628 (78.9) |
| ARN inhibitors | 63 (1.1) | Not reported |
| Mineralocorticoid receptor antagonists | 415 (7.5) | Not reported |
| Diuretics | 1372 (24.8) | 10 383 (37.9) |
| Proton pump inhibitors | 1437 (26.0) | 10 869 (39.7)g |
ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; ARN, angiotensin receptor–neprilysin; BMI, body mass index; CABG, coronary artery bypass grafting; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; eGFR, estimated glomerular filtration rate; PCI, percutaneous coronary intervention; SD, standard deviation.
Values are n (%) unless otherwise indicated.
aCountries are shown in Figure 2 and Supplementary material online, Table S2.
bCurrent smoking in XATOA.
cBased on laboratory values collected before inclusion in XATOA and shown as a proportion of patients with available values at baseline.
deGFR 15–<60 mL/min/1.73 m2.
eIncludes percutaneous transluminal coronary angioplasty and atherectomy.
fIncludes peripheral artery bypass surgery and peripheral percutaneous transluminal angioplasty.
gEligible patients (n = 17 598) who were not receiving a proton pump inhibitor at baseline were randomized to a proton pump inhibitor versus placebo.
The use of secondary prevention treatments is shown in Table 1. More than two-thirds of patients were receiving standard secondary prevention therapies including antiplatelet agents, statins, and angiotensin-converting enzyme inhibitors /angiotensin receptor blockers, prior to enrolment. Secondary prevention therapies were used more frequently in CAD than in PAD patients. The most common type of antithrombotic therapy in XATOA patients prior to enrolment was aspirin only (n = 3910, 70.7%), followed by DAPT with aspirin and another antiplatelet agent (n = 900, 16.3%; Figure 3).
Antithrombotic regimens in XATOA before initiation of DPI (A) Antithrombotic regimens. (B) Antiplatelet therapy. Values are n (%) unless indicated otherwise. Other regimen: only anticoagulant (excluding antiplatelet agents), aspirin plus antiplatelet, aspirin plus anticoagulant, aspirin plus antiplatelet plus antithrombotic, antithrombotic plus antiplatelet, two antithrombotic agents, aspirin plus two antithrombotic agents, two antiplatelet agents, or aspirin plus two antiplatelet agents. DPI, dual pathway inhibition; SAPT, single antiplatelet therapy.
Study treatment and indications for initiating DPI
The most frequent reason reported for initiating DPI was existing, worsening, or newly diagnosed vascular risk characteristics (n = 4753, 85.9%). Clinicians defined high cardiovascular risk as the reason for initiating DPI in 70.7% of patients (including at least one of the following: history of hypertension, diabetes, hyperlipidaemia, chronic renal dysfunction, smoking, family history of vascular disease, age >65 years, or high body mass index). A total of 794 patients (14.4%) were initiated on DPI following the completion of DAPT. Clinical features leading to DPI initiation are shown in Table 2.
Reasons and risk features leading to DPI initiation in the XATOA registry
| Reason | Number (%) (N = 5532) |
|---|---|
| Risk features (existing, worsening, or newly diagnosed) | 4753 (85.9) |
| High cardiovascular risk profilea | 3913 (70.7) |
| CAD | 3266 (59.0) |
| CAD, 1 vessel affected | 818 (14.8) |
| CAD, 2 or 3 vessels affected | 2292 (41.4) |
| MI | 1269 (22.9) |
| ACS | 350 (6.3) |
| PCI | 1126 (20.4) |
| CABG | 647 (11.7) |
| Lower-limb PAD | 2467 (44.6) |
| PAD, lower extremities | 2375 (42.9) |
| PAD, otherb | 88 (1.6) |
| ABI <0.9 | 612 (11.1) |
| Peripheral arterial intervention | 847 (15.3) |
| Symptomatic lower-extremity PADc | 1090 (19.7) |
| Polyvascular disease (≥2 vascular beds affected) | 863 (15.6) |
| Carotid lesiond | 829 (15.0) |
| Other cardiovascular conditionse | 502 (9.1) |
| High stroke riskf | 389 (7.0) |
| Other non-cardiovascular conditionsg | 229 (4.1) |
| End of DAPT | 794 (14.4) |
| Missing | 2 (<0.1) |
| Reason | Number (%) (N = 5532) |
|---|---|
| Risk features (existing, worsening, or newly diagnosed) | 4753 (85.9) |
| High cardiovascular risk profilea | 3913 (70.7) |
| CAD | 3266 (59.0) |
| CAD, 1 vessel affected | 818 (14.8) |
| CAD, 2 or 3 vessels affected | 2292 (41.4) |
| MI | 1269 (22.9) |
| ACS | 350 (6.3) |
| PCI | 1126 (20.4) |
| CABG | 647 (11.7) |
| Lower-limb PAD | 2467 (44.6) |
| PAD, lower extremities | 2375 (42.9) |
| PAD, otherb | 88 (1.6) |
| ABI <0.9 | 612 (11.1) |
| Peripheral arterial intervention | 847 (15.3) |
| Symptomatic lower-extremity PADc | 1090 (19.7) |
| Polyvascular disease (≥2 vascular beds affected) | 863 (15.6) |
| Carotid lesiond | 829 (15.0) |
| Other cardiovascular conditionse | 502 (9.1) |
| High stroke riskf | 389 (7.0) |
| Other non-cardiovascular conditionsg | 229 (4.1) |
| End of DAPT | 794 (14.4) |
| Missing | 2 (<0.1) |
Values are n (%). Responses were chosen by the investigators from a prespecified list. Multiple responses were permitted.
ABI, ankle–brachial index; ACS, acute coronary syndrome; CABG, coronary artery bypass grafting; CAD, coronary artery disease; DAPT, dual antiplatelet therapy; DPI, dual pathway inhibition; MI, myocardial infarction; PAD, peripheral artery disease; PCI, percutaneous coronary intervention.
aAt least one of the following: history of hypertension, diabetes, hyperlipidaemia, chronic renal dysfunction, smoking, family history of vascular disease, age >65 years, or high body mass index.
bNot lower-limb or carotid.
cIntermittent claudication or lower-extremity amputation.
dPAD: carotid disease, carotid intervention, or cerebrovascular interventions.
eAtrial fibrillation or chronic heart failure.
fPrior transient ischaemic attack or stroke.
gLiver cirrhosis, cancer, or other conditions.
Reasons and risk features leading to DPI initiation in the XATOA registry
| Reason | Number (%) (N = 5532) |
|---|---|
| Risk features (existing, worsening, or newly diagnosed) | 4753 (85.9) |
| High cardiovascular risk profilea | 3913 (70.7) |
| CAD | 3266 (59.0) |
| CAD, 1 vessel affected | 818 (14.8) |
| CAD, 2 or 3 vessels affected | 2292 (41.4) |
| MI | 1269 (22.9) |
| ACS | 350 (6.3) |
| PCI | 1126 (20.4) |
| CABG | 647 (11.7) |
| Lower-limb PAD | 2467 (44.6) |
| PAD, lower extremities | 2375 (42.9) |
| PAD, otherb | 88 (1.6) |
| ABI <0.9 | 612 (11.1) |
| Peripheral arterial intervention | 847 (15.3) |
| Symptomatic lower-extremity PADc | 1090 (19.7) |
| Polyvascular disease (≥2 vascular beds affected) | 863 (15.6) |
| Carotid lesiond | 829 (15.0) |
| Other cardiovascular conditionse | 502 (9.1) |
| High stroke riskf | 389 (7.0) |
| Other non-cardiovascular conditionsg | 229 (4.1) |
| End of DAPT | 794 (14.4) |
| Missing | 2 (<0.1) |
| Reason | Number (%) (N = 5532) |
|---|---|
| Risk features (existing, worsening, or newly diagnosed) | 4753 (85.9) |
| High cardiovascular risk profilea | 3913 (70.7) |
| CAD | 3266 (59.0) |
| CAD, 1 vessel affected | 818 (14.8) |
| CAD, 2 or 3 vessels affected | 2292 (41.4) |
| MI | 1269 (22.9) |
| ACS | 350 (6.3) |
| PCI | 1126 (20.4) |
| CABG | 647 (11.7) |
| Lower-limb PAD | 2467 (44.6) |
| PAD, lower extremities | 2375 (42.9) |
| PAD, otherb | 88 (1.6) |
| ABI <0.9 | 612 (11.1) |
| Peripheral arterial intervention | 847 (15.3) |
| Symptomatic lower-extremity PADc | 1090 (19.7) |
| Polyvascular disease (≥2 vascular beds affected) | 863 (15.6) |
| Carotid lesiond | 829 (15.0) |
| Other cardiovascular conditionse | 502 (9.1) |
| High stroke riskf | 389 (7.0) |
| Other non-cardiovascular conditionsg | 229 (4.1) |
| End of DAPT | 794 (14.4) |
| Missing | 2 (<0.1) |
Values are n (%). Responses were chosen by the investigators from a prespecified list. Multiple responses were permitted.
ABI, ankle–brachial index; ACS, acute coronary syndrome; CABG, coronary artery bypass grafting; CAD, coronary artery disease; DAPT, dual antiplatelet therapy; DPI, dual pathway inhibition; MI, myocardial infarction; PAD, peripheral artery disease; PCI, percutaneous coronary intervention.
aAt least one of the following: history of hypertension, diabetes, hyperlipidaemia, chronic renal dysfunction, smoking, family history of vascular disease, age >65 years, or high body mass index.
bNot lower-limb or carotid.
cIntermittent claudication or lower-extremity amputation.
dPAD: carotid disease, carotid intervention, or cerebrovascular interventions.
eAtrial fibrillation or chronic heart failure.
fPrior transient ischaemic attack or stroke.
gLiver cirrhosis, cancer, or other conditions.
The initial daily dose of rivaroxaban was 2.5 mg twice daily in 5523 (99.8%) patients and 2.5 mg once daily in 9 (0.2%) patients. The mean duration of rivaroxaban treatment was 446.4 ± 198.0 days and the mean duration of aspirin treatment was 457.8 ± 186.0 days.
The majority of patients (88.2%) did not receive additional antiplatelet agents during the study, although 9.3% received DAPT.
Clinical events
Clinical outcomes occurred in 425 (7.7%) patients (Figures 4 and 5). The incidence of MACE, MALE and acute or severe limb ischaemia was 2.26, 3.57, and 1.54 per 100 patient-years, respectively. Other thrombotic events, such as transient ischaemic attack, amputation, pulmonary embolism, and deep vein thrombosis were very infrequent (rates less than 0.3 per 100 patient-years). ISTH major bleeding occurred at a rate of 0.95 per 100 patient-years and non-major bleeding at a rate of 4.43 per 100 patient-years. Events accrued at a consistent rate during the follow-up period as reflected by the consistent slopes of the event curves (Figure 5).
Incidence rates of clinical events in XATOA and in the DPI arm of COMPASS. Event rates in (A) XATOA and (B) COMPASS for corresponding outcomes. Bleeding in XATOA is shown for the safety analysis set (N = 5615). ALI, acute limb ischaemia; CI, confidence interval; CV, cardiovascular; DPI, dual pathway inhibition; DVT, deep vein thrombosis; IR, incidence rate; MACE, major adverse cardiovascular events; MALE, major adverse limb events; MI, myocardial infarction; PE, pulmonary embolism; TIA, transient ischaemic attack. aIncidence rate defined as the number of patients with a specific event divided by the total follow-up time over all patients. For patients who had an event, the exposure time was truncated at the time of the first occurrence of the event (or at rivaroxaban treatment start where the date of the event was missing). bIncidence rate estimated as the number of patients with incident events divided by the cumulative at-risk time in the reference population, where a subject was no longer at risk once an incident event occurred.
Cumulative incidences of clinical events in XATOA and the DPI arm of COMPASS.8,10(A) MACE. (B) MI. (C) Stroke. (D) CV death. (E) Acute/severe limb ischaemia. (F) Major bleeding. Event rates in XATOA and COMPASS are not exactly comparable. *A plot for ALI is not available for COMPASS. The most closely matched values available are shown. Major bleeding in XATOA is shown for the safety analysis set (N = 5615). ALI, acute limb ischaemia; CI, confidence interval; CV, cardiovascular; DPI, dual pathway inhibition; MACE, major adverse cardiovascular events; MI, myocardial infarction.
In COMPASS, the rate of MALE was 0.19 per 100 patient-years. Rates of MACE and acute limb ischaemia were 2.18 and 0.12 per 100 patient-years, respectively. The rate of major bleeding was 1.7 per 100 patient-years while the rate of non-major bleeding was 5.11 per 100 patient-years.
In XATOA, a total of 150 patients (2.7%) had died by the end of follow-up. A total of 242 (4.3%) patients had unknown survival status and 217 patients (3.9%) did not have follow-up data. Adjudicated treatment-emergent cardiovascular causes of death occurred in 64.1% and non-cardiovascular causes of death in 35.9% of patients. The incidence rate of all-cause death was 1.95 per 100 patient-years.
Any treatment-emergent adverse events related to rivaroxaban occurred in 473 (8.4%) patients and serious adverse events related to rivaroxaban occurred in 108 (1.9%) patients (Supplementary material online, Table S4). All-cause fatal adverse events occurred in 110 (2.0%) patients, and COVID-19 occurred in 68 (1.2%) patients, with a fatal outcome in 8 (0.1%) patients (Supplementary material online, Table S4).
Discussion
The findings of XATOA in the context of data from the COMPASS trial10
XATOA is the first prospective registry study to provide insights into which patients are being selected for treatment with DPI in clinical practice. The majority of patients were only on aspirin prior to enrolment. The main reason for initiating DPI was high or deteriorating vascular risk as assessed by the responsible clinician. In the COMPASS trial and in XATOA, the MACE rates were similar. However, in XATOA the MALE rate was substantially higher, and the major bleeding rate was substantially lower. Key differences between XATOA and COMPASS include the higher proportion of PAD patients and geographic differences (e.g. a lower proportion of patients from South America and Asia were enrolled in XATOA; Figure 2).
Most patients in XATOA were initiated on DPI because of risk characteristics, such as multivessel CAD or lower-extremity PAD, and about 70% of patients had a high cardiovascular risk profile. Factors included in the definition of a high cardiovascular risk profile in XATOA were hypertension, hyperlipidaemia, diabetes, chronic renal dysfunction, smoking, a family history of vascular disease, age >65 years, and a high body mass index. In a subsidiary analysis of the COMPASS trial, polyvascular disease, heart failure, renal insufficiency, and diabetes were identified as the strongest predictors of vascular risk.21 A higher number of risk factors that are poorly controlled have been shown in the COMPASS trial to be associated with higher incidence of ischaemic events.22 Fontaine class 3 or 4 PAD, prior peripheral revascularization, or prior amputation were additional co-morbidities associated with increased vascular risk in patients with lower-extremity PAD in COMPASS.23 Patients with these characteristics were shown to have the largest absolute benefit in terms of vascular risk reduction with DPI versus aspirin.23–25 Thus, the risk characteristics of patients included in XATOA, and the high proportion of patients with PAD, suggest that patients with the potential for greater absolute benefit with DPI are being selected for this treatment in clinical practice. 21,23,24 Prior MI, ACS, or PCI was given as a reason for initiating DPI in some cases. However, in XATOA, the time between MI, ACS, or PCI, and the initial study visit was 100, 48, and 70 months, respectively. In some cases, the end of DAPT was also listed as the reason for initiating DPI. Therefore, these patients may have been initiated on DPI at the end of their planned period of DAPT for MI, ACS, or PCI.
In XATOA, 72.7% of patients had CAD, 58.9% had PAD, and 31.6% had both CAD and PAD, while in COMPASS, 90.6% of patients had CAD, 27.3% had PAD, and 18.0% had both CAD and PAD. Consistent with prior studies, secondary prevention measures were more widely used in CAD patients than in patients with PAD only. Because of the greater proportion of PAD patients recruited in XATOA than in COMPASS, a higher frequency of limb events would be expected, and this was observed (Figure 4). The findings suggest that patients with PAD or polyvascular disease are being prioritized for DPI therapy in clinical practice. In contrast to patients with CAD, where several intensified antithrombotic therapies have been demonstrated to improve outcomes and have been included in guidelines, there is a relative paucity of such evidence-based medical therapies in patients with PAD.1,4 Overall, a high proportion of patients in XATOA and in COMPASS were receiving secondary prevention therapies at baseline, although not as high a proportion in XATOA as in COMPASS (69.9% and 78.9% of patients in XATOA and COMPASS received angiotensin-converting enzyme inhibitors or ARBs, respectively). Future studies will determine whether these findings are accounted for by the higher proportion of CAD patients in COMPASS.
To account for the different follow-up periods in XATOA (15 months) and COMPASS (23 months),10 incidence rates of clinical events per 100 patient-years were calculated. Although the studies cannot be compared directly, the annualized incidence rates of MACE in XATOA and the DPI arm of COMPASS were highly consistent. In XATOA, the rate of clinically recognized major bleeding (0.95 per 100 patient-years) was relatively lower than the rate of ischaemic events, such as MACE (2.26 per 100 patient-years). In COMPASS, the rate of major bleeding (1.7 per 100 patient-years) was also lower than the rate of MACE (2.18 per 100 patient-years). In contrast, the rate of non-major bleeding was slightly lower in XATOA (4.43 per 100 patient-years) than in COMPASS (5.11 per 100 patient-years). The lower rates of bleeding in XATOA than in COMPASS could be related to various factors. For example, physicians may have chosen, in clinical practice, to initiate DPI in patients with a lower perceived bleeding risk rather than higher perceived bleeding risk. While the rates of MACE were similar between the studies, relatively higher annualized rates of acute limb ischaemia (1.54 per 100 patient-years) and MALE (3.57 per 100 patient-years) were observed in XATOA than in COMPASS (0.12 and 0.19 per 100 patient-years, respectively). This is likely due to the enrolment of a higher proportion of patients with PAD in XATOA than in COMPASS. The adverse events associated with DPI in XATOA, including the rates of bleeding, are consistent with previous evidence on the safety profile of rivaroxaban.
The XATOA study highlights the frequency of peripheral vascular events in this vascular risk population, including those with atherothrombotic disease manifesting in both the CAD and PAD territories. Underdiagnosis of PAD in clinical practice and the presence of occult PAD in patients with CAD may all contribute to the future risk of PAD events.4 Systematic evaluation of PAD and occult PAD is not routine in cardiology clinics. However, PAD assessments in cardiology clinics could be justified to identify high vascular risk patients and the potential for benefit with DPI.
The ongoing XATOC registry (Xarelto + Acetylsalicylic Acid: Treatment Patterns and Outcomes Across the Disease Continuum in Patients With CAD and/or PAD [XATOC] NCT04401761) is expected to include patients from additional countries beyond those included in XATOA and a more ethnically diverse patient population.
Limitations
As in other observational studies, there is a possibility of selection bias, but patients were screened consecutively to reduce selection bias. Measures were taken to ensure that the enrolled patients were representative of the population at each study site. Because outcomes were collected in different ways in XATOA and COMPASS, differences between outcomes in the studies are inherent. In an observational study like XATOA, there may be lower ascertainment of bleeding events than in a phase III trial setting. Most patients were male and of White European origin, and although this is consistent with prior studies, it limits the generalizability of the findings to other populations. A large proportion of patients were enrolled in Germany, and this should be taken into account when interpreting the results.
Conclusion
In summary, the XATOA registry shows that high-risk vascular patients are prioritized for DPI therapy in clinical practice. The clinical outcome rates for MACE were similar in XATOA and COMPASS, but MALE rates were higher in XATOA than in COMPASS. This is consistent with the higher proportion of patients in XATOA with PAD. Major bleeding rates were low in XATOA, and this provides support for a favourable net clinical benefit of DPI in vascular risk patients in clinical practice.
Acknowledgements
The authors would like to acknowledge Lizahn Zwart, PhD, who provided editorial support funded by Bayer AG, as well as Sophie Maille, MSc, for her work as Study Manager, and Danja Monje, Dipl. Biol., for her work as Study Manager.
Funding
The XATOA study and editorial support for this manuscript were funded by Bayer AG.
Conflicts of interest: K.A.A.F. has received grants and personal fees from Bayer/Janssen during the conduct of the study; outside the submitted work, he has received grants from AstraZeneca, and personal fees from Sanofi/Regeneron and Verseon. V.A. has received personal fees from Bayer during the conduct of the study; outside the submitted work, he has received personal fees from BMS/Pfizer Alliance, Novartis, Novo Nordisk, and Sanofi. E.S.D. is a member of the XATOA Executive Committee and advisor for Bayer; he has received institutional grants from Bayer, Cook, and Terumo Aortic. U.Z. has received grants and personal fees from Bayer during the conduct of the study; outside the submitted work, he has received grants and personal fees from AstraZeneca and BMS/Pfizer, and personal fees from Boehringer Ingelheim, MSD, Novartis, Sanofi, and Trommsdorff. K.V. and A.G. are employees of Bayer AG. M.R.C. has received research grants from Bayer, Boston Scientific, ResMed, and St Jude Medical; provided consultancy advice to and received speaker's fees from Bayer, Boston Scientific, FIRE1 Foundry, Medtronic, NeuroTronik, Novartis, Pfizer, ResMed, Roche Diagnostics, Servier, St Jude Medical/Abbott, and Vifor; and serves as non-executive director of the National Institute for Health and Care Excellence (NICE). M.P. has received research grants from Bayer, Janssen, HeartFlow, Medtronic; and provided consultancy advice to Bayer, Janssen, HeartFlow, and Novartis. R.C.W. has received research grants or personal fees from Bayer, Boehringer Ingelheim, Edwards Lifesciences, Novartis, Pfizer, and PenoPharm. J.B. receives funds from Bayer for participation in Steering Committee and Adjudication activities. S.S.A. has received consulting and speaker fees from Bayer and Janssen.
Data availability
Data cannot be shared for ethical/privacy reasons.
