# Effect of Peripheral Interventions in Patients with Peripheral Artery Disease Receiving Rivaroxaban and Aspirin: Analyses from the XATOA Registry

E. Sebastian Debus, Victor Aboyans, Jackie Bosch, Keith a A Fox, Manesh R Patel, Robert C Welsh, Uwe Zeymer, Ala Gay, Kai Vogtländer, Sonia S Anand

► To cite this version:

E. Sebastian Debus, Victor Aboyans, Jackie Bosch, Keith a A Fox, Manesh R Patel, et al.. Effect of Peripheral Interventions in Patients with Peripheral Artery Disease Receiving Rivaroxaban and Aspirin: Analyses from the XATOA Registry. European Journal of Vascular and Endovascular Surgery, 2024, 68 (6), pp.784 - 795. 10.1016/j.ejvs.2024.07.017. hal-05020443

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# Effect of Peripheral Interventions in Patients with Peripheral Artery Disease Receiving Rivaroxaban and Aspirin: Analyses from the XATOA Registry

E. Sebastian Debus<sup>a, *, </sup> Victor Aboyans<sup>b</sup>, Jackie Bosch<sup>c,d</sup>, Keith A.A. Fox<sup>e</sup>, Manesh R. Patel<sup>f</sup>, Robert C. Welsh<sup>g</sup>, Uwe Zeymer<sup>h</sup>, Ala Gay<sup>i</sup>,
Kai Vogtländer<sup>j</sup>, Sonia S. Anand<sup>d,k</sup>

## WHAT THIS PAPER ADDS

Little is known about the use of dual pathway inhibition in patients with peripheral artery disease in real world clinical practice. This subanalysis of XATOA in patients with lower extremity peripheral artery disease with or without lower extremity revascularisation (LER) demonstrates that prior LER is associated with increased rates of clinical incidents, particularly limb events, compared with no prior LER, consistent with published findings. Incidence rates of clinical events were generally higher with more recent LER, regardless of LER type, supporting temporal trends of post-revascularisation clinical event rates in previous studies.

**Objective:** To assess the characteristics and clinical outcomes of patients with lower extremity peripheral artery disease (PAD) in XATOA receiving dual pathway inhibition (DPI) with rivaroxaban 2.5 mg twice daily plus aspirin according to lower extremity revascularisation (LER) history.

**Methods:** XATOA is an international, multicentre, prospective, single arm registry study. This subanalysis investigated patients with lower extremity PAD according to LER history.

Patients with coronary artery disease, PAD, or both, receiving DPI were followed for 12 or more months. Baseline characteristics and clinical outcomes were assessed according to LER history. A time dependency analysis assessed outcomes by time between the most recent LER procedure and the start of DPI. A multivariable analysis assessed the influence of patient characteristics on clinical outcomes.

**Results:** In XATOA (n = 5 532), 2 820 (51.0%) patients had lower extremity PAD, of whom 1 736 (61.6%) had prior LER and 1 084 (38.4%) had no prior LER. Baseline characteristics were generally similar between patients with or without prior LER. A higher proportion of patients with prior LER experienced any treatment emergency clinical events compared with those without prior LER (15.0% vs. 9.4%, respectively), with greater differences observed between incidence rates of limb events, including major adverse limb events (9.06 vs. 4.09 events per 100 patient years, respectively). Similar rates of myocardial infarction, stroke, and major bleeding were observed in both subgroups. Clinical event rates were generally higher in patients who had previous LER for six months or less compared with patients who had previous LET for more than six months before starting DPI, regardless of LER type. Multivariable analyses showed that prior LER was predictive of limb events.

**Conclusion:** This subanalysis of XATOA found that prior LER was associated with increased rates of limb events, consistent with results of COMPASS and VOYAGER PAD. Rates of bleeding were also low regardless of LER history and consistent with the findings from these trials.

**Keywords:** Lower extremity, Operative, Peripheral artery disease, Rivaroxaban, Surgical procedures

Article history: Received 24 October 2023, Accepted 11 July 2024, Available online 14 July 2024

© 2024 The Authors. Published by Elsevier B.V. on behalf of European Society for Vascular Surgery. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

<footnote><sup>a</sup>Department of Vascular Medicine, Vascular Surgery, Angiology, Endovascular Therapy, University of Hamburg-Eppendorf, Hamburg, Germany</footnote>

<footnote><sup>b</sup>Department of Cardiology, Dupuytren University Hospital, and EpiMaCT, Inserm U1094/IRD290, Limoges, France</footnote>

<footnote><sup>c</sup>School of Rehabilitation Science and Chanchlani Research Centre, McMaster University, Hamilton, Ontario, Canada</footnote>

<footnote><sup>d</sup>Population Health Research Institute, McMaster University, Hamilton Health Sciences, Hamilton, Ontario, Canada</footnote>

<footnote><sup>e</sup>Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK</footnote>

<footnote><sup>f</sup>Division of Cardiology, Duke Clinical Research Institute, Duke University, Durham, NC, USA</footnote>

<footnote><sup>g</sup>Mazankowski Alberta Heart Institute and University of Alberta, Edmonton, Alberta, Canada</footnote>

<footnote><sup>h</sup>Klinikum der Stadt Ludwigshafen, Medizinische Klinik B, and Institut für Herzinfarktforschung, Ludwigshafen am Rhein, Germany</footnote>

<footnote><sup>i</sup>Bayer AG, Berlin, Germany</footnote>

<footnote><sup>j</sup>Bayer AG, Wuppertal, Germany</footnote>

<footnote><sup>k</sup>Department of Medicine, McMaster University, Hamilton, Ontario, Canada</footnote>

<footnote>* Corresponding author. Department of Vascular Medicine, Vascular Surgery, Angiology, Endovascular Therapy, University of Hamburg-Eppendorf, 20246 Hamburg, Germany.</footnote>

<footnote>E-mail address: s.debus@uke.de (E. Sebastian Debus).</footnote>

<footnote>1078-5884/© 2024 The Authors. Published by Elsevier B.V. on behalf of European Society for Vascular Surgery. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).</footnote>

<footnote>https://doi.org/10.1016/j.ejvs.2024.07.017</footnote>
## INTRODUCTION

Patients with peripheral artery disease (PAD) are at high risk of cardiovascular events, including major adverse limb events (MALE), encompassing limb loss and other limb complications, and death.¹⁻⁴ Even after revascularisation, patients with PAD remain at high risk of thrombotic events or death, and need protection from repeat events and hospitalisation.⁵,⁶

In the PAD cohort of the phase 3 COMPASS trial,⁷ dual pathway inhibition (DPI) with rivaroxaban 2.5 mg twice daily plus aspirin significantly reduced the incidence of major adverse cardiovascular events (MACE) and MALE, total vascular amputations, peripheral vascular interventions, and all peripheral vascular outcomes compared with aspirin alone in patients with symptomatic lower extremity PAD. The risk of major bleeding was increased but rates of fatal or intracranial bleeding events were low, with a favourable overall efficacy and safety profile for DPI.⁷⁻¹⁰ Similarly, the phase 3 VOYAGER PAD trial¹¹ demonstrated that DPI reduced the risk of major adverse vascular events compared with aspirin in patients with PAD undergoing infrainguinal lower extremity revascularisation (LER), with no significant difference in thrombolysis in myocardial infarction major bleeding, including intracranial bleeding or fatal bleeding. Therefore, a favourable net clinical benefit was associated with DPI in VOYAGER PAD.¹¹

In several countries, DPI is now available for use in patients with coronary artery disease (CAD), PAD, or both.¹²,¹³ Several European and international guidelines recommend DPI in a broader population of patients with PAD than those enrolled in the COMPASS study.¹⁰,¹⁴⁻¹⁸ Little is known, however, about the use of DPI in patients with PAD in routine clinical practice.

The international, multicentre, prospective, single arm XATOA registry study was established to complement and build upon existing evidence from the COMPASS study by assessing treatment patterns and outcomes in patients with CAD, PAD, or both, who receive DPI in routine clinical practice.¹⁹,²⁰ The XATOA study previously showed that DPI is being used in high risk patients in clinical practice, and that rates of MACE were similar, rates of MALE were higher, and rates of major bleeding were lower compared with the COMPASS trial.²⁰ This was consistent with the inclusion of more patients with PAD in XATOA than in COMPASS;²⁰ previous studies have shown that the risk of cardiovascular events increases with the number of affected vascular beds, and that cardiovascular events tend to occur in the affected vascular beds.²¹⁻²³

In the present study, results are presented from a subgroup analysis of XATOA to assess the characteristics and clinical outcomes of patients with lower extremity PAD according to their history of LER. The findings of this subanalysis are compared with those reported for patients with symptomatic lower extremity PAD in COMPASS and those in VOYAGER PAD.

## MATERIALS AND METHODS

XATOA is an international, multicentre, prospective, observational, single arm registry study. The design and methods of the trial have been published previously.¹⁹

### Patient population and follow up

XATOA enrolled adults (aged ≥ 18 years) with CAD, PAD, or both, receiving rivaroxaban 2.5 mg twice daily plus aspirin within four weeks before enrolment according to locally approved indications. Patients meeting the enrolment criteria who provided informed consent received treatment according to the judgement of the prescribing clinician. Details of the eligibility criteria used for XATOA are included in the Supplementary Material S1. The study aimed to enrol 8 000 – 10 000 patients from 22 countries between November 2018 and May 2020. Patient follow up was conducted for 12 or more months after enrolment at routine clinical visits. Data were collected using an electronic data capturing system at baseline and at each follow up visit. In the present analysis, the XATOA population was divided into patients with lower extremity PAD with or without prior LER.

### Study outcomes

Baseline characteristics and clinical outcomes were assessed according to history of LER. The incidence of clinical outcomes, including MACE (composite of cardiovascular death, myocardial infarction, or stroke) and MALE (composite of severe or acute limb ischaemia [ALI], chronic limb ischaemia [CLI], and major amputation above the forefoot, as defined in the COMPASS trial) were investigated. Haemorrhagic events and complications included International Society on Thrombosis and Haemostasis (ISTH) major bleeding (composite of fatal, symptomatic bleeding into a critical organ, or both, associated with a 2 g/dL or larger reduction in haemoglobin, or requiring a transfusion of two or more units of packed red blood cells or whole blood) and ISTH non-major bleeding (all bleeding events not meeting the definition of ISTH major bleeding).

### Statistical analyses

The full analysis set included patients who received one or more doses of DPI. The safety analysis set consisted of patients who received one or more doses of rivaroxaban. Incidence proportions, cumulative incidences, and incidence rates with 95% confidence intervals were used to assess clinical outcomes. Statistical analyses were descriptive and exploratory. A time dependency analysis was conducted to assess clinical outcomes by time between the most recent LER procedure and the initiation of DPI (≤ 1, 1–6, or > 6 months). A multivariable Cox regression analysis assessed the influence of patient characteristics on clinical outcomes, including comorbidities, medication, and type of intervention. The models included covariables with $p < .20$ in prior univariable Cox regressions. The results were contextualised against those in patients receiving DPI enrolled in COMPASS (representing the chronic phase) and VOYAGER PAD (representing the post-revascularisation phase).²⁴,²⁵ Results of XATOA, COMPASS, and VOYAGER PAD should be interpreted in the light of their different designs and patient populations, which have reported previously. In addition, clinical event rates reported for
COMPASS and VOYAGER PAD are not comparable with those from XATOA. As such, direct comparisons between the trials were not conducted.

## RESULTS

The XATOA population (n = 5532) included 3258 (58.9%) patients with PAD (patients with PAD alone or with any comorbidity), and 2820 patients (51.0% of the total population; 86.6% of the PAD population) with lower extremity PAD (Fig. 1). A total of 1736 (61.6%) patients with lower extremity PAD in XATOA had prior LER and 1084 (38.4%) had no prior LER. One patient in the prior LER group was diagnosed with CAD only. The mean observation period was 15 ± 6 months.

## Baseline characteristics

Baseline characteristics were generally similar between the XATOA lower extremity PAD subgroups with and without prior LER (Table 1). Most patients with lower extremity PAD

in XATOA had an ankle brachial index of less than 0.9, a Fontaine classification IIb or higher, and had received single antiplatelet therapy (mainly aspirin) and statins at baseline. Of patients with prior LER, more patients had an endovascular (57.4%) rather than a surgical revascularisation (35.0%), or both (7.6%). Most patients in XATOA had their most recent LER more than six months before DPI initiation (60.3%) and had only one prior LER procedure (70.0%) (Supplementary Table S1).

## Clinical events

Overall, proportions of clinical events in XATOA in patients with lower extremity PAD were low irrespective of prior LER; 261 (15.0%) patients with prior LER had clinical events vs. 102 (9.4%) patients without LER. The clinical outcome with the highest incidence in patients with prior LER was MALE (incidence rate 9.06, 95% CI 7.77 – 10.50) (Fig. 2). Non-major bleeding was the outcome with the highest incidence in patients without prior LER (incidence rate 5.26,

<figure><img src="image_2.png" /></figure>
<table><caption>Table 1. Baseline characteristics of 2820 patients with lower extremity peripheral artery disease in XATOA.</caption><thead><tr><th rowspan="2">Characteristics</th><th colspan="2">XATOA (n = 5532)</th></tr><tr><th>Lower extremity peripheral artery disease and prior lower extremity revascularisation* (n = 1736)</th><th>Lower extremity peripheral artery disease without prior lower extremity revascularisation (n = 1084)</th></tr></thead><tbody><tr><td><strong>Demographics</strong></td><td></td><td></td></tr><tr><td>Age - y</td><td>68.2 ± 9.0</td><td>69.1 ± 9.2</td></tr><tr><td>Female sex</td><td>446 (25.7)</td><td>305 (28.1)</td></tr><tr><td><strong>Ethnic groups, reported</strong></td><td></td><td></td></tr><tr><td>White</td><td>1 652 (95.2)</td><td>997 (92.0)</td></tr><tr><td>Black or African American</td><td>2 (0.1)</td><td>2 (0.2)</td></tr><tr><td>Asian</td><td>15 (0.9)</td><td>11 (1.0)</td></tr><tr><td>Other or not reported</td><td>67 (3.9)</td><td>74 (6.8)</td></tr><tr><td><strong>Geographic regions</strong></td><td></td><td></td></tr><tr><td>Western Europe and North America</td><td>1 336 (77.0)</td><td>730 (67.3)</td></tr><tr><td>Latin America/South America</td><td>48 (2.8)</td><td>62 (5.7)</td></tr><tr><td>Middle East</td><td>81 (4.7)</td><td>91 (8.4)</td></tr><tr><td>Eastern Europe</td><td>261 (15.0)</td><td>198 (18.3)</td></tr><tr><td>Asia Pacific</td><td>10 (0.6)</td><td>3 (0.3)</td></tr><tr><td><strong>Clinical characteristics</strong></td><td></td><td></td></tr><tr><td>Body mass index - kg/m²</td><td>27.16 ± 4.6</td><td>28.2 ± 4.7</td></tr><tr><td>Tobacco use</td><td>601 (34.7)</td><td>742 (19.6)</td></tr><tr><td><strong>Fontaine classification</strong></td><td></td><td></td></tr><tr><td>I</td><td>197 (11.7)</td><td>112 (10.6)</td></tr><tr><td>IIa</td><td>404 (24.1)</td><td>359 (33.9)</td></tr><tr><td>IIb</td><td>764 (45.6)</td><td>473 (44.7)</td></tr><tr><td>III</td><td>140 (8.3)</td><td>65 (6.1)</td></tr><tr><td>IV</td><td>172 (10.3)</td><td>50 (4.7)</td></tr><tr><td><strong>Ankle brachial index</strong></td><td></td><td></td></tr><tr><td>&lt;0.9</td><td>745 (73.9)</td><td>398 (82.6)</td></tr><tr><td>≥0.9</td><td>263 (26.1)</td><td>84 (17.4)</td></tr><tr><td><strong>Co-morbidities</strong></td><td></td><td></td></tr><tr><td>Myocardial infarction</td><td>415 (23.9)</td><td>298 (27.5)</td></tr><tr><td>Heart failure</td><td>198 (11.4)</td><td>192 (17.7)</td></tr><tr><td>Stroke</td><td>127 (7.3)</td><td>303 (8.0)</td></tr><tr><td>Intermittent claudication</td><td>1 218 (70.2)</td><td>680 (62.7)</td></tr><tr><td>Diabetes</td><td>686 (39.5)</td><td>441 (40.7)</td></tr><tr><td>Hypertension</td><td>1 390 (80.1)</td><td>845 (78.0)</td></tr><tr><td>Estimated glomerular filtration rate - mL/min/1.73 m²</td><td>74.89 ± 20.41</td><td>71.12 ± 20.62</td></tr><tr><td>&lt;60</td><td>142 (26.4)</td><td>81 (31.4)</td></tr><tr><td>≥60</td><td>396 (73.6)</td><td>177 (68.6)</td></tr><tr><td><strong>Prior interventions and revascularisations</strong></td><td></td><td></td></tr><tr><td>Surgical</td><td>588 (35.0)</td><td>Not available</td></tr><tr><td>Endovascular</td><td>964 (57.4)</td><td>Not available</td></tr><tr><td>Surgical and endovascular</td><td>127 (7.6)</td><td>Not available</td></tr><tr><td>Days from lower extremity revascularisation to randomisation</td><td>336.0 (54.0, 1 312.0)</td><td>Not available</td></tr><tr><td><strong>Prior medications of interest</strong></td><td></td><td></td></tr><tr><td>Statins</td><td>1 338 (77.1)</td><td>715 (66.0)</td></tr><tr><td>Beta blockers</td><td>813 (46.8)</td><td>570 (52.6)</td></tr><tr><td>Angiotensin converting enzyme inhibitors or angiotensin receptor blockers</td><td>1 166 (67.2)</td><td>693 (63.9)</td></tr><tr><td><strong>Single antiplatelet therapy before rivaroxaban initiation</strong></td><td></td><td></td></tr><tr><td>Aspirin only</td><td>1 186 (93.2)</td><td>759 (92.7)</td></tr><tr><td>Other antiplatelet therapy only</td><td>87 (6.8)</td><td>60 (7.3)</td></tr><tr><td>Dual antiplatelet therapy</td><td>319 (18.4)</td><td>129 (11.9)</td></tr></tbody></table>

Data are presented as n (%), mean ± standard deviation, or median (interquartile range).

* Included one patient reported as having coronary artery disease only despite prior lower extremity revascularisation.

95% CI 4.06 - 6.71), with rates higher than those of both MALE and MACE in this cohort.

Incidence rates of clinical outcomes were generally higher among patients with lower extremity PAD and a

more recent LER compared with patients with a less recent LER or without prior LER (Fig. 3). This trend was most pronounced for rates of limb events. Incidence rates of major bleeding were low in patients with lower extremity PAD,
<figure><img src="image_3.png" /></figure>

<figure><img src="image_4.png" /></figure>

**Figure 2.** Incidence rates of clinical events in patients with lower extremity peripheral artery disease in XATOA according to lower extremity revascularisation (LER) status. Incidence rates (95% confidence intervals) are shown for patients with (A) and without (B) prior LER. Bleeding rates are shown for the safety analysis set (LER, *n* = 1 757; no LER, *n* = 1 113). ALI = acute limb ischaemia; CLI = critical limb ischaemia; CV = cardiovascular; LET = lower extremity revascularisation; MACE = major adverse cardiovascular events; MALE = major adverse limb events; MI = myocardial infarction; TIA = transient ischaemic attack; \* Amputation above the forefoot from vascular cause.

regardless of LER history. Incidence rates of MACE did not appear to differ substantially based upon the existence or recency of a prior LER. Incidence rates of clinical events were largely similar in patients with a prior LER more than six months before DPI initiation compared with patients without prior LER.

Incidence rates of MALE were similar between patients with endovascular and surgical LER (Fig. 4). Comparatively high incidence rates of MALE, ALI, and CLI were observed in patients with lower extremity PAD who had undergone surgical and endovascular LER 1 – 6 months before starting DPI vs. patients who had undergone both LER types one month or earlier or more than six months before starting

DPI. MALE also occurred more frequently in patients with higher Fontaine scores than those with lower scores (Fig. 5).

## Multivariable analysis

A multivariable Cox regression analysis was conducted to determine the effect of patient characteristics, co-medications, and risk factors on clinical outcomes (Fig. 6). Strong predictors of MALE included LER, diabetes, CAD, intermittent claudication, Fontaine classification stage IV, and beta blocker use at baseline. Prior stroke was the only strong predictor of MACE, with Fontaine classification stage IV, intermittent claudication, and heart failure displaying a
A

<table><thead><tr><th>Clinical outcome</th><th>Time since LER - mo</th><th>Incidence rate per 100 patient years (95% CI)</th><th>Incidence rate per 100 patient years (95% CI)</th></tr></thead><tbody><tr><td rowspan="4">Major adverse cardiovascular events</td><td>No LER</td><td></td><td>2.89 (2.03-4.01)</td></tr><tr><td>≤1</td><td></td><td>2.12 (0.91-4.17)</td></tr><tr><td>1-6</td><td></td><td>3.11 (1.61-5.44)</td></tr><tr><td>>6 mo</td><td></td><td>2.52 (1.72-3.55)</td></tr><tr><td rowspan="4">Myocardial infarction</td><td>No LER</td><td></td><td>0.80 (0.38-1.48)</td></tr><tr><td>≤1</td><td></td><td>0.53 (0.06-1.90)</td></tr><tr><td>1-6</td><td></td><td>1.81 (0.73-3.73)</td></tr><tr><td>>6 mo</td><td></td><td>0.94 (0.49-1.64)</td></tr><tr><td rowspan="4">Stroke</td><td>No LER</td><td></td><td>0.72 (0.33-1.37)</td></tr><tr><td>≤1</td><td></td><td>0.79 (0.16-2.32)</td></tr><tr><td>1-6</td><td></td><td>0.52 (0.06-1.87)</td></tr><tr><td>>6 mo</td><td></td><td>0.55 (0.22-1.13)</td></tr><tr><td rowspan="4">Cardiovascular death</td><td>No LER</td><td></td><td>1.60 (0.98-2.47)</td></tr><tr><td>≤1</td><td></td><td>0.79 (0.16-2.31)</td></tr><tr><td>1-6</td><td></td><td>1.03 (0.28-2.65)</td></tr><tr><td>>6 mo</td><td></td><td>1.25 (0.72-2.03)</td></tr></tbody></table>

B

<table><thead><tr><th>Clinical outcome</th><th>Time since LER - mo</th><th>Incidence rate per 100 patient years (95% CI)</th><th>Incidence rate per 100 patient years (95% CI)</th></tr></thead><tbody><tr><td rowspan="4">Major adverse limb event</td><td>No LER</td><td></td><td>4.09 (3.04-5.39)</td></tr><tr><td>≤1</td><td></td><td>13.32 (9.79-17.71)</td></tr><tr><td>1-6</td><td></td><td>13.58 (10.05-17.95)</td></tr><tr><td>>6 mo</td><td></td><td>6.53 (5.18-8.13)</td></tr><tr><td rowspan="4">Amputation*</td><td>No LER</td><td></td><td>0.16 (0.02-0.58)</td></tr><tr><td>≤1</td><td></td><td>0.26 (0.01-1.47)</td></tr><tr><td>1-6</td><td></td><td>0.52 (0.06-1.88)</td></tr><tr><td>>6 mo</td><td></td><td>0.24 (0.05-0.69)</td></tr><tr><td rowspan="4">Acute limb ischaemia</td><td>No LER</td><td></td><td>1.54 (0.92-2.40)</td></tr><tr><td>≤1</td><td></td><td>6.51 (4.17-9.69)</td></tr><tr><td>1-6</td><td></td><td>4.18 (2.39-6.79)</td></tr><tr><td>>6 mo</td><td></td><td>3.11 (2.21-4.24)</td></tr><tr><td rowspan="4">Critical limb ischaemia</td><td>No LER</td><td></td><td>2.76 (1.91-3.85)</td></tr><tr><td>≤1</td><td></td><td>7.16 (4.68-10.49)</td></tr><tr><td>1-6</td><td></td><td>9.01 (6.20-12.65)</td></tr><tr><td>>6 mo</td><td></td><td>3.94 (2.91-5.21)</td></tr></tbody></table>

C

<table><thead><tr><th>Clinical outcome</th><th>Time since LER - mo</th><th>Incidence rate per 100 patient years (95% CI)</th><th>Incidence rate per 100 patient years (95% CI)</th></tr></thead><tbody><tr><td rowspan="4">Major bleeding</td><td>No LER</td><td></td><td>1.49 (0.90-2.33)</td></tr><tr><td>≤1</td><td></td><td>1.84 (0.74-3.79)</td></tr><tr><td>1-6</td><td></td><td>2.07 (0.89-4.07)</td></tr><tr><td>>6 mo</td><td></td><td>0.70 (0.32-1.33)</td></tr><tr><td rowspan="4">Non-major bleeding</td><td>No LER</td><td></td><td>5.26 (4.06-6.71)</td></tr><tr><td>≤1</td><td></td><td>7.56 (5.03-10.93)</td></tr><tr><td>1-6</td><td></td><td>5.80 (3.63-8.78)</td></tr><tr><td>>6 mo</td><td></td><td>3.82 (2.81-5.06)</td></tr></tbody></table>

**Figure 3.** Clinical event rates according to the time between prior lower extremity revascularisation (LER) and dual pathway inhibition (initiation in patients with lower extremity peripheral artery disease in XATOA). Incidence stratified by time point of prior LER for (A) cardiovascular events, (B) limb events, and (C) bleeding. Bleeding is shown for the safety analysis set (n = 5615). CI = confidence interval; LET = lower extremity revascularisation; * Amputation above the forefoot from vascular cause.

trend towards being predictive. Heart failure was the sole predictor of myocardial infarction, whereas stroke was predicted by prior stroke and body mass index of 20 – 25

kg/m². A history of LER was predictive of ALI, in addition to diabetes, age 65 years or older, and body mass index below 20 and of 20 – 25 kg/m², whereas CLI was predicted by
<figure><img src="image_5.png" /><figcaption>Figure 4. Clinical event rates according to the time between prior lower extremity revascularisation and start of dual pathway inhibition and lower extremity revascularisation type in patients with lower extremity peripheral artery disease in XATOA. CI = confidence interval; PAD = periphery artery disease. * = Amputation above the forefoot from vascular cause.</figcaption></figure>

prior LER, Fontaine classification stage IV, and chronic kidney disease. Prior LER also showed a trend towards being predictive of stroke.

## DISCUSSION

To the best of the authors' knowledge, XATOA is the only prospective registry with long term data on patients with PAD receiving DPI in a real world setting. The present analysis showed that patients with lower extremity PAD and prior LER had higher rates of MALE and limb events than those without prior LER. Clinical event rates were generally higher among patients with a more recent LER, regardless of LER type.

Following the COMPASS and VOYAGER PAD trials and the approval of DPI for the prevention of thrombotic events in eligible patients with CAD, PAD, or both, a need was identified to investigate the characteristics and clinical outcomes according to prior LER among patients with lower extremity PAD receiving DPI in clinical practice.

Clinical characteristics were broadly similar between lower extremity PAD patients with and without prior LER. Beta blocker use was less frequent in those with prior LER, which could be related to the beta blocker contraindication

in patients with severe PAD.²⁶⁻²⁸ Although an ankle brachial index less than 0.9 was less frequent among patients with lower extremity PAD and prior LER, their Fontaine classifications showed that more severe PAD symptoms were also more frequent in this group, suggesting that the relationship between prior revascularisation and PAD symptoms may warrant further investigation.

It is important to consider the findings of the present study in the context of previous data on DPI and broader research on the treatment of PAD. Differences in study designs and patient populations, however, inherently led to differences between the patient populations of XATOA, COMPASS, and VOYAGER PAD.⁸,¹¹ For example, a history of heart failure was more common in patients with lower extremity PAD receiving DPI in COMPASS than in XATOA or VOYAGER PAD, whereas intermittent claudication was more frequent in VOYAGER PAD than in COMPASS or XATOA (Supplementary Table S2).⁷,¹¹

Endovascular revascularisation was more frequent than surgical revascularisation in all studies, and the use of prior medications, such as statins, beta blockers, and angiotensin converting enzyme inhibitors and angiotensin receptor blockers, was consistent across the studies.⁷,¹¹ VOYAGER
<figure><img src="image_6.png" /><figcaption>**Figure 5.** (A) Cumulative Kaplan-Meier estimate of incidence of major adverse limb events in patients with lower extremity peripheral artery disease (PAD) with and without lower extremity revascularisation (LER); (B) cumulative incidence of major adverse limb events in patients with lower extremity PAD and prior LER stratified by Fontaine score, prior amputation, and prior limb revascularisation; (C) cumulative incidence of patients who have had a major adverse limb event with lower extremity PAD without prior LER stratified by Fontaine score. LET = lower extremity revascularisation; PAD = peripheral artery disease.</figcaption></figure>

PAD exclusively enrolled patients within 10 days after successful LER, whereas COMPASS enrolled patients with chronic CAD or PAD with no requirement to have

undergone a recent LER.¹⁰,¹¹ In XATOA, the time from LER to randomisation among most patients was more than six months before DPI initiation, suggesting that physicians were mainly following the treatment approach used in the COMPASS trial. This was expected because XATOA was designed to be complementary mainly to COMPASS, but it may also have been a consequence of the completion of VOYAGER PAD near the end of the enrolment period in XATOA.¹¹,¹⁹

Patients with lower extremity PAD and prior LER in XATOA had higher incidence rates of limb events than those with lower extremity PAD and no prior LER. Similar incidence rates of MACE, myocardial infarction, transient ischaemic attack, and stroke were observed in both subgroups, and, although incidence rates of major bleeding were slightly lower among patients with lower extremity PAD with vs. without prior LER in XATOA, the difference was small and not expected to be clinically relevant. Clinical event rates directly comparable with those in XATOA have not been published for COMPASS and VOYAGER PAD. These results of XATOA, however, are consistent with previous analyses from COMPASS, VOYAGER PAD, the EUCLID trial²⁹ of patients with symptomatic lower extremity PAD receiving ticagrelor 90 mg twice daily (AstraZeneca, Södertälje, Sweden) or clopidogrel 75 mg once daily (Sanofi Winthrop Industrie, Gentilly, France), and a healthcare database analysis which showed that the risk of limb and other cardiovascular events is high after peripheral revascularisation, and is often considerably higher in patients with vs. without prior peripheral revascularisation.⁵,⁷,¹¹,²⁹ Additionally, results from a retrospective analysis of the prospective COPART registry³⁰ showed that the rates of ischaemic events were higher among patients hospitalised for symptomatic lower extremity PAD in France than in COMPASS or VOYAGER PAD, suggesting that DPI therapy could lead to greater absolute risk reductions among these patients in clinical practice than observed in the phase three trials.

Temporal trends in the risk of ischaemic and bleeding events were observed in XATOA, with generally higher rates in patients with prior LER six months or less before starting DPI compared with patients who underwent LER more than six months before starting DPI, regardless of the type of LER. Patients who had undergone surgical and endovascular LER 1–6 months before starting DPI had the highest rates of limb events. VOYAGER PAD and other studies have shown similar temporal trends in the risk of thrombotic and bleeding events after revascularisation, with the highest event rates observed during approximately the first year after revascularisation and declining thereafter.⁵,¹¹,²⁹,³¹ The temporal patterns in clinical event rates from six months after LER in XATOA could contribute to the definition of a time point to distinguish between the subacute and chronic phases after LER.

The present study also advanced knowledge of features contributing to the risk of clinical events among patients with lower extremity PAD. The multivariable Cox regression analysis demonstrated that a history of LER was not predictive of MACE, myocardial, or cardiovascular death, but
A

<table><thead><tr><th>Covariable</th><th>HR (95% CI)</th><th>p value</th></tr></thead><tbody><tr><td>Lower extremity revascularisation</td><td>0.647 (0.225-1.858)</td><td>.42</td></tr><tr><td>Age ≥ 65 years</td><td>1.130 (0.701-1.821)</td><td>.62</td></tr><tr><td>Fontaine classification IIa</td><td>0.629 (0.266-1.492)</td><td>.30</td></tr><tr><td>Fontaine classification IIb</td><td>1.126 (0.522-2.426)</td><td>.77</td></tr><tr><td>Fontaine classification III</td><td>1.910 (0.760-4.803)</td><td>.17</td></tr><tr><td>Fontaine classification IV</td><td>2.303 (0.929-5.711)</td><td>.072</td></tr><tr><td>Coronary artery disease (all)</td><td>1.756 (0.893-3.454)</td><td>.10</td></tr><tr><td>Chronic kidney disease</td><td>1.120 (0.698-1.797)</td><td>.64</td></tr><tr><td>Diabetes</td><td>1.433 (0.912-2.253)</td><td>.12</td></tr><tr><td>Stroke</td><td>2.345 (1.362-4.037)</td><td>.002</td></tr><tr><td>Hyperlipidemia</td><td>1.322 (0.780-2.241)</td><td>.30</td></tr><tr><td>Intermittent claudication</td><td>1.629 (0.957-2.775)</td><td>.072</td></tr><tr><td>Time since periphery artery disease diagnosis ≥ 6 mo</td><td>1.239 (0.658-2.333)</td><td>.51</td></tr><tr><td>Myocardial infarction</td><td>1.219 (0.723-2.055)</td><td>.46</td></tr><tr><td>Hypertension</td><td>1.116 (0.575-2.165)</td><td>.75</td></tr><tr><td>Heart failure</td><td>1.610 (0.962-2.694)</td><td>.070</td></tr><tr><td>Prior coronary procedures</td><td>0.913 (0.511-1.631)</td><td>.76</td></tr><tr><td>Prior peripheral procedures</td><td>1.414 (0.482-4.149)</td><td>.53</td></tr></tbody></table>

B

<table><caption>**Figure 6.** Multivariable Cox regression model assessing the effect of patient characteristics on the incidence of clinical outcomes in patients with lower extremity peripheral artery disease in XATOA. Effect of factors on the incidence of (A) major adverse cardiovascular events, (B) major adverse limb events, (C) myocardial infarction, (D), stroke, (E) cardiovascular death, (F) acute limb ischaemia, and (G) critical limb ischaemia. HR = hazard ratio.</caption><thead><tr><th>Covariable</th><th>HR (95% CI)</th><th>p value</th></tr></thead><tbody><tr><td>Lower extremity revascularisation</td><td>2.086 (1.500-2.901)</td><td>&lt;.001</td></tr><tr><td>Sex, male</td><td>0.825 (0.614-1.110)</td><td>.21</td></tr><tr><td>Age ≥ 65 years</td><td>1.135 (0.844-1.525)</td><td>.40</td></tr><tr><td>Fontaine classification IIa</td><td>1.517 (0.817-2.820)</td><td>.19</td></tr><tr><td>Fontaine classification IIb</td><td>1.615 (0.894-2.917)</td><td>.11</td></tr><tr><td>Fontaine classification III</td><td>1.775 (0.863-3.652)</td><td>.12</td></tr><tr><td>Fontaine classification IV</td><td>2.667 (1.374-5.177)</td><td>.004</td></tr><tr><td>Race, white</td><td>6.288 (0.877-45.079)</td><td>.067</td></tr><tr><td>Coronary artery disease (all)</td><td>0.686 (0.505-0.932)</td><td>.016</td></tr><tr><td>Chronic kidney disease</td><td>1.328 (0.989-1.784)</td><td>.059</td></tr><tr><td>Diabetes</td><td>1.394 (1.056-1.841)</td><td>.019</td></tr><tr><td>Intermittent claudication</td><td>1.394 (1.007-1.929)</td><td>.045</td></tr><tr><td>Time since periphery artery disease diagnosis ≥ 6 mo</td><td>0.837 (0.591-1.186)</td><td>.32</td></tr><tr><td>Beta blocker at initial visit</td><td>1.435 (1.066-1.933)</td><td>.017</td></tr></tbody></table>

was predictive of limb events and demonstrated a trend towards being predictive of stroke. This complements a subgroup analysis of patients with symptomatic lower extremity PAD in the COMPASS trial, which showed that prior amputation, Fontaine classification stage III or IV, prior peripheral revascularisation, kidney impairment, heart failure, diabetes, and polyvascular disease were features associated with increased risks of MACE or MALE.⁷ The observation that prior LER may increase the risk of stroke suggests that outcomes such as major adverse vascular events could be used instead of separate MACE and MALE outcomes in this patient population.

The strengths and limitations of the XATOA study have been described.¹⁹,²⁰ Strengths include the prospective design of XATOA, pre-defined study outcomes, robust

quality review process, and enrolment of a broad patient population that allowed the aims of the study to be achieved.

Limitations include the potential for selection bias, although patients were screened consecutively to reduce selection bias, limited availability of medical history, and the limited opportunity to enrol patients similar to those in VOYAGER PAD because of the timing of the studies. Some authors had direct involvement in the registry as trial investigators and as members of the XATOA Executive Committee, which may create the potential for bias. Furthermore, a considerable proportion of patients were enrolled in Germany, and this should be taken into account when interpreting the results. Overall, however, a wide range of treating physicians, e.g. cardiologists, vascular
<figure><img src="image_7.png" /><figcaption>Figure 6. (continued).</figcaption></figure>

specialists, internists, elderly care specialists, and general practitioners, participated in the study. In addition, treatment or event reporting may differ depending on local guidelines. A limitation of the multivariable analysis is the possibility of unmeasured variables associated with a higher risk of events in patients with LER. No adjustments were made for multiple statistical testing.

## Conclusions

XATOA is the only prospective registry with long term data on patients with PAD receiving DPI in a real world setting. Overall, the findings of this XATOA subanalysis were consistent with the results of COMPASS and VOYAGER PAD. The present analysis showed that patients with lower extremity

PAD and prior LER had higher rates of MALE than those without prior LER. Clinical event rates were generally higher among patients with a more recent LER, regardless of LER type. A history of LER was also predictive of limb events. Other factors predictive of MALE included diabetes and CAD. The six month period following LER was also particularly associated with the occurrence of clinical outcomes.

## FUNDING

The XATOA study (NCT03746275) and editorial support for this manuscript were funded by Bayer AG. There are no conflicts of interest, other grants or financial support for this research and or article preparation to declare.
<figure><img src="image_8.png" /><figcaption>Figure 6. (continued).</figcaption></figure>

## DECLARATION

The XATOA study compiled with the relevant local laws and regulations pertaining to observational studies and data protection. ESD is a member of the XATOA Executive Committee and advisor for Bayer; he has received institutional grants from Bayer, Cook, and Terumo Aortic; VA has received personal fees from Bayer during the conduct of the study; he has received personal fees from BMS/Pfizer Alliance, Novartis, Novo Nordisk, and Sanofi; JB receives funds from Bayer for participation in Steering Committee and Adjudication activities; KAAF has received grants and personal fees from Bayer/Janssen during the conduct of the study; he has received grants from AstraZeneca, and personal fees from Sanofi/Regeneron and Verseon; MRP has received research grants from Bayer, HeartFlow, Janssen, Medtronic, and provided consultancy advice to Bayer, HeartFlow, Janssen, and Novartis; RCW has received research grants or personal fees from Bayer, Boehringer Ingelheim, Edwards Lifesciences, Novartis, PenoPharm, and Pfizer; UZ has received grants and personal fees from Bayer during the conduct of the study; he has received grants and personal fees from AstraZeneca and BMS/Pfizer, and personal fees from Boehringer Ingelheim, MSD, Novartis, Sanofi, and Trommisdorff; KV and AG are employees of Bayer AG; SSA has received consulting and speaker fees from Bayer and Janssen.

## APPENDIX A. SUPPLEMENTARY DATA

Supplementary data to this article can be found online at https://doi.org/10.1016/j.ejvs.2024.07.017.

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