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Editor's Choice – External Applicability of the COMPASS and VOYAGER-PAD Trials on Patients with Symptomatic Lower Extremity Artery Disease in France: The COPART Registry

  • François-Xavier Lapébie
    Correspondence
    Corresponding author. Department of Vascular Medicine, Toulouse University Hospital, Hôpital Rangueil, 1 avenue du Pr Jean Poulhès, TSA50032, Toulouse Cedex 9, 31059, Toulouse, France.
    Affiliations
    Department of Vascular Medicine, Toulouse University Hospital, Toulouse, France

    UMR 1295 INSERM, CERPOP, Toulouse III – Paul Sabatier University, Toulouse, France
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  • Victor Aboyans
    Affiliations
    Department of Cardiology, Limoges University Hospital, Limoges, France

    UMR 1094 INSERM & IRD, Limoges University, Limoges, France
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  • Philippe Lacroix
    Affiliations
    UMR 1094 INSERM & IRD, Limoges University, Limoges, France

    Department of Cardiovascular and Thoracic Surgery – Vascular Medicine, Limoges University Hospital, Limoges, France
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  • Joël Constans
    Affiliations
    Department of Vascular Medicine, Bordeaux University Hospital, Bordeaux, France

    Bordeaux University, Bordeaux, France
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  • Carine Boulon
    Affiliations
    Department of Vascular Medicine, Bordeaux University Hospital, Bordeaux, France
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  • Emmanuel Messas
    Affiliations
    Department of Vascular Medicine, Assistance Publique – Hôpitaux de Paris, Paris, France

    UMR 970 INSERM, Paris Descartes University, Paris, France
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  • Jean Ferrières
    Affiliations
    UMR 1295 INSERM, CERPOP, Toulouse III – Paul Sabatier University, Toulouse, France

    Department of Epidemiology, Toulouse University Hospital, Toulouse, France

    Federation of Cardiology, Toulouse University Hospital, Toulouse, France
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  • Vanina Bongard
    Affiliations
    UMR 1295 INSERM, CERPOP, Toulouse III – Paul Sabatier University, Toulouse, France

    Department of Epidemiology, Toulouse University Hospital, Toulouse, France

    Federation of Cardiology, Toulouse University Hospital, Toulouse, France
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  • Alessandra Bura-Rivière
    Affiliations
    Department of Vascular Medicine, Toulouse University Hospital, Toulouse, France

    UMR 1031 INSERM, StromaLab, Toulouse III – Paul Sabatier University, Toulouse, France
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Open ArchivePublished:July 28, 2021DOI:https://doi.org/10.1016/j.ejvs.2021.05.028

      Objective

      The aim of this study was to examine the external applicability of the COMPASS and the VOYAGER-PAD trials in patients with lower extremity artery disease (LEAD) in the real world.

      Methods

      This was a multicentre retrospective analysis of prospectively collected COPART data, a French multicentre registry of patients hospitalised for symptomatic LEAD. The proportion of patients eligible for the combination of rivaroxaban 2.5 mg twice daily plus aspirin based on either COMPASS or VOYAGER-PAD criteria is reported. The one year cumulative incidence of outcomes between eligible and non-eligible patients, as well as eligible patients vs. control arms of the COMPASS (LEAD patient subgroup) and the VOYAGER-PAD trials were compared. Analyses were performed using Cox models.

      Results

      Of 2 259 evaluable patients, only 679 (30.1%) were eligible for a low dose rivaroxaban plus aspirin regimen. Others were not eligible because of the need for anticoagulant (48.5% and 38.9% of patients meeting COMPASS and VOYAGER-PAD exclusion criteria, respectively) or dual antiplatelet therapy use (15.7% and 16.5%, respectively), high bleeding risk (14.4% and 11.6%, respectively), malignancy (26.1% and 21.0%, respectively), history of ischaemic/haemorrhagic stroke (21.1% and 19.8%, respectively), and severe renal failure (13.2% and 10.5%, respectively). COMPASS and VOYAGER-PAD eligible and ineligible patients were at higher risk of ischaemic events than participants in these trials. The one year cumulative incidences were 6.0% (95% CI 4.3 – 8.1) in the COMPASS eligible subset vs. 3.5% (95% CI 2.9 – 4.3) in the COMPASS control arm for major adverse cardiovascular events, and 27.9% (95% CI 19.9 – 38.3) in the VOYAGER-PAD eligible subset vs. 6.0% (95% CI 5.3 – 6.9) in the VOYAGER-PAD control arm for major adverse limb events.

      Conclusion

      Many patients hospitalised for symptomatic LEAD in France are not eligible for the low dose rivaroxaban plus aspirin combination. In turn, those eligible may potentially have greater absolute benefit because of higher risk than those enrolled in the trials.

      Keywords

      Only 30.1% of patients hospitalised for symptomatic lower extremity artery disease are eligible for rivaroxaban 2.5 mg twice daily plus aspirin, based on the COMPASS or VOYAGER-PAD criteria. These patients have higher rates of ischaemic events than those in these trials. The one year cumulative incidences were 6.0% (95% confidence interval [CI] 4.3 – 8.1) in the COMPASS eligible subset vs. 3.5% (95% CI 2.9 – 4.3) in the COMPASS control arm for major adverse cardiovascular events, and 27.9% (95% CI 19.9 – 38.3) in the VOYAGER-PAD eligible subset vs. 6.0% (95% CI 5.3 – 6.9) in the VOYAGER-PAD control arm for major adverse limb events. This regimen may have greater benefits in the real world population.

      Introduction

      Patients with lower extremity artery disease (LEAD) are at heightened risk of major adverse cardiovascular events (MACE), including cardiovascular (CV) death, myocardial infarction (MI), and stroke, and are also at increased risk of all cause mortality. Despite antithrombotic therapy, the one year cumulative incidence of MACE is at least 12%, and is as high as 16.8% after revascularisation for chronic limb threatening ischaemia (CLTI).
      • Sigvant B.
      • Hasvold P.
      • Kragsterman B.
      • Falkenberg M.
      • Johansson S.
      • Thuresson M.
      • et al.
      Cardiovascular outcomes in patients with peripheral arterial disease as an initial or subsequent manifestation of atherosclerotic disease: results from a Swedish nationwide study.
      ,
      • Sigvant B.
      • Kragsterman B.
      • Falkenberg M.
      • Hasvold P.
      • Johansson S.
      • Thuresson M.
      • et al.
      Contemporary cardiovascular risk and secondary preventive drug treatment patterns in peripheral artery disease patients undergoing revascularization.
      Limb related event rates are also high. In a meta-analysis, over a five year follow up, 21% of patients with intermittent claudication (IC) were diagnosed as having CLTI, with 4% – 27% undergoing amputation.
      • Sigvant B.
      • Lundin F.
      • Wahlberg E.
      The risk of disease progression in peripheral arterial disease is higher than expected: a meta-analysis of mortality and disease progression in peripheral arterial disease.
      To improve both the general CV and limb outcome, guidelines recommend medical therapy, including antiplatelet medication, as a pillar of CV death prevention.
      • Aboyans V.
      • Ricco J.-B.
      • Bartelink M.-L.E.L.
      • Björck M.
      • Brodmann M.
      • Cohnert T.
      • et al.
      2017 ESC Guidelines on the Diagnosis and Treatment of Peripheral Arterial Diseases, in collaboration with the European Society for Vascular Surgery (ESVS): Document covering atherosclerotic disease of extracranial carotid and vertebral, mesenteric, renal, upper and lower extremity arteries. Endorsed by: the European Stroke Organization (ESO) The Task Force for the Diagnosis and Treatment of Peripheral Arterial Diseases of the European Society of Cardiology (ESC) and of the European Society for Vascular Surgery (ESVS).
      ,
      • Gerhard-Herman M.D.
      • Gornik H.L.
      • Barrett C.
      • Barshes N.R.
      • Corriere M.A.
      • Drachman D.E.
      • et al.
      2016 AHA/ACC Guideline on the Management of Patients With Lower Extremity Peripheral Artery Disease: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
      However, even when this therapy is well implemented, the residual risk in patients with LEAD is notable. Hence, new antithrombotic strategies have been assessed recently, with promising results.
      • Eikelboom J.W.
      • Connolly S.J.
      • Bosch J.
      • Dagenais G.R.
      • Hart R.G.
      • Shestakovska O.
      • et al.
      Rivaroxaban with or without aspirin in stable cardiovascular disease.
      ,
      • Bonaca M.P.
      • Bauersachs R.M.
      • Anand S.S.
      • Debus E.S.
      • Nehler M.R.
      • Patel M.R.
      • et al.
      Rivaroxaban in peripheral artery disease after revascularization.
      The COMPASS trial (Cardiovascular Outcomes for People Using Anticoagulation Strategies) tested the combination of rivaroxaban 2.5 mg twice daily plus aspirin for the long term management of patients with stable atherosclerotic disease, and showed a significant reduction of 24% of MACE with this combination vs. the aspirin alone arm, with consistent and significant results in the subgroup of patients with symptomatic LEAD.
      • Eikelboom J.W.
      • Connolly S.J.
      • Bosch J.
      • Dagenais G.R.
      • Hart R.G.
      • Shestakovska O.
      • et al.
      Rivaroxaban with or without aspirin in stable cardiovascular disease.
      ,
      • Kaplovitch E.
      • Eikelboom J.W.
      • Dyal L.
      • Aboyans V.
      • Abola M.T.
      • Verhamme P.
      • et al.
      Rivaroxaban and aspirin in patients with symptomatic lower extremity peripheral artery disease: a subanalysis of the COMPASS randomized clinical trial.
      The VOYAGER-PAD trial (Vascular Outcomes Study of Acetylsalicylic acid Along with Rivaroxaban in Endovascular or Surgical Limb Revascularisation for Peripheral Artery Disease) tested the same combination and doses of rivaroxaban and aspirin in selected patients with symptomatic LEAD immediately after a successful revascularisation procedure, a setting with a high risk of ischaemic and bleeding complications. This trial showed a significant reduction of 15% of the composite outcome of acute limb ischaemia (ALI), major amputation for vascular causes, and MACE in the low dose rivaroxaban plus aspirin arm vs. the aspirin plus placebo arm.
      • Bonaca M.P.
      • Bauersachs R.M.
      • Anand S.S.
      • Debus E.S.
      • Nehler M.R.
      • Patel M.R.
      • et al.
      Rivaroxaban in peripheral artery disease after revascularization.
      In both trials, while an excess of bleeding was reported, the benefit/risk ratio was overall in favour of the use of this combined antithrombotic strategy.
      However, it is widely accepted that the results obtained in trials need further validation in real world clinical practice, as patients enrolled in CV trials are, on average, at lower risk because of younger age and fewer comorbidities.
      • Sigvant B.
      • Hasvold P.
      • Kragsterman B.
      • Falkenberg M.
      • Johansson S.
      • Thuresson M.
      • et al.
      Cardiovascular outcomes in patients with peripheral arterial disease as an initial or subsequent manifestation of atherosclerotic disease: results from a Swedish nationwide study.
      ,
      • Kennedy-Martin T.
      • Curtis S.
      • Faries D.
      • Robinson S.
      • Johnston J.
      A literature review on the representativeness of randomized controlled trial samples and implications for the external validity of trial results.
      ,
      • Paraskevas K.I.
      • de Borst G.J.
      • Veith F.J.
      Why randomized controlled trials do not always reflect reality.
      Regarding patients with LEAD, the number eligible for the low dose rivaroxaban plus aspirin combination is uncertain. It is also unclear whether patients selected for treatment with the combination of low dose rivaroxaban plus aspirin will have a similar risk in clinical practice to those enrolled in the COMPASS and the VOYAGER-PAD trials.
      Therefore, the external applicability of the COMPASS and the VOYAGER-PAD trials results was examined by describing the proportion of COMPASS and VOYAGER-PAD eligible patients in a cohort of consecutive patients hospitalised for symptomatic LEAD in the vascular medicine departments in France. Outcome rates between eligible and noneligible patients for the COMPASS and VOYAGER-PAD trials, and between these eligible patients and those randomised in the reference arm (i.e., aspirin arm) in those two trials were compared.

      Materials and methods

      The COMPASS trial

      The COMPASS trial was a phase III, double blind randomised controlled trial (RCT) that randomly assigned 27 395 patients with stable atherosclerotic vascular disease (coronary artery disease [CAD], LEAD, or carotid artery disease) to receive rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg once daily), rivaroxaban (5 mg twice daily) plus placebo, or aspirin (100 mg once daily) plus placebo.
      • Eikelboom J.W.
      • Connolly S.J.
      • Bosch J.
      • Dagenais G.R.
      • Hart R.G.
      • Shestakovska O.
      • et al.
      Rivaroxaban with or without aspirin in stable cardiovascular disease.
      The detailed COMPASS inclusion and exclusion criteria are described in Supplementary Table S1.

      The VOYAGER-PAD trial

      The VOYAGER-PAD trial was a phase III, double blind RCT that randomly assigned 6 564 patients with LEAD who had undergone revascularisation to receive rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg once daily), or aspirin (100 mg once daily) plus placebo.
      • Bonaca M.P.
      • Bauersachs R.M.
      • Anand S.S.
      • Debus E.S.
      • Nehler M.R.
      • Patel M.R.
      • et al.
      Rivaroxaban in peripheral artery disease after revascularization.
      Clopidogrel also could be prescribed at the discretion of the investigator, but not for more than six months. The detailed VOYAGER-PAD inclusion and exclusion criteria are described in Supplementary Table S3.

      The COPART registry

      The COPART (COhorte de Patients ARTériopathes) registry is an ongoing (since 2006) multicentre, observational, cohort study that is prospectively collecting data on consecutive patients hospitalised for symptomatic LEAD in the vascular medicine departments of four French academic centres (Bordeaux, Limoges, Paris, and Toulouse). Patients may have been hospitalised for scheduled surgery following a consultation, or for emergency care, or have been transferred from other hospitals or from other departments in the same hospital. Patients requiring only outpatient care for LEAD are not included in the COPART registry. Details on the study protocol have been published elsewhere.
      • Cambou J.P.
      • Aboyans V.
      • Constans J.
      • Lacroix P.
      • Dentans C.
      • Bura A.
      Characteristics and outcome of patients hospitalised for lower extremity peripheral artery disease in France: the COPART Registry.
      Patient care was provided according to usual practice. After the initial hospitalisation, patients were followed for at least 12 months. Data were collected prospectively by trained medical COPART investigators, following a computerised standardised case report form, and using all records available during hospitalisation and follow up. Patients, their families, and/or their physicians were systematically contacted one year after hospital discharge. The patients gave their informed consent to participate. The study complies with the declaration of Helsinki and was approved by the ethics committee of Toulouse University Hospital. The current report is based on a database locked in October 2017 and including patients recruited from 2006 to 2015.
      Inclusion criteria for the COPART registry are age ≥ 18 years, consent to participate, and that the patient is specifically hospitalised for the treatment and/or management of symptomatic LEAD of atherosclerotic origin. Clinical presentation includes either an IC, associated with abnormal ankle brachial index (ABI) < 0.90 or > 1.30, or, in the case of normal ABI at rest, a positive treadmill test (Strandness protocol, 3.2 km/hour on a 10% slope); arterial stenosis > 50% on duplex ultrasound or computerised tomography angiography, or angiography; or ischaemic rest pain, ulceration, or gangrene or ALI related to documented LEAD with significant arterial stenosis.
      Patients for whom follow up was improbable (i.e., patients who could not be contacted after hospitalisation and follow up carried out in a foreign country), those with arterial occlusive disease not related to atherosclerosis, those with ALI without LEAD, and those refusing to participate were not included.

      “COMPASS eligible” and “VOYAGER-PAD eligible” study populations

      Patients with missing data regarding eligibility criteria for COMPASS or VOYAGER-PAD were excluded. Then, the analysis started with COMPASS inclusion and exclusion criteria (Supplementary Table S1). A detailed list of adjustments made in these criteria for the analysis of the COPART registry is provided in Supplementary Table S2. First, patients meeting any adapted COMPASS exclusion criteria were excluded; the main reasons for exclusion were reported. Second, the remaining patients were included in the “COMPASS eligible” subset if they fulfilled adapted COMPASS inclusion criteria. The analysis continued with VOYAGER-PAD inclusion and exclusion criteria (Supplementary Table S3). A detailed list of adjustments made in these criteria for the analysis of the COPART registry is provided in Supplementary Table S4. First, patients not undergoing limb revascularisation were excluded. Second, patients meeting any adapted VOYAGER-PAD exclusion criteria were excluded; the main reasons for these exclusions were reported. Third, remaining patients were included in the “VOYAGER-PAD eligible” subset if they fulfilled adapted VOYAGER-PAD inclusion criteria. Patients excluded from VOYAGER-PAD and those of the “VOYAGER-PAD eligible” subset were included in the “COMPASS eligible” subset if they fulfilled adapted COMPASS inclusion criteria without meeting any adapted COMPASS exclusion criteria.

      Primary and secondary outcomes

      For this study, the primary outcome was MACE, a composite of CV death, MI, and stroke, similar to the primary outcome of the COMPASS trial. The primary outcome of VOYAGER-PAD trial was the composite of MACE, ALI, and major amputation for vascular causes. ALI during follow up is not specifically recorded in the COPART registry; however, major amputation and limb revascularisation are recorded, so ALI was included in the composite of limb revascularisation or major amputation. Secondary outcomes also available in the COPART, COMPASS, and VOYAGER-PAD databases were also analysed: all cause death; CV death; non-CV death; MI; stroke; major amputation; and major adverse limb events (MALE; a composite of major amputation and limb revascularisation). Revascularisation could be achieved by percutaneous angioplasty (with or without stenting), subintimal recanalisation, endarterectomy, embolectomy, surgical vein, or prosthetic bypass. Amputation above the ankle was considered major, and minor when below.

      Statistical analysis

      Baseline characteristics of the following subgroups were described using mean ± standard deviation, median (interquartile range) for continuous variables, and frequencies and percentages for categorical variables:
      • COMPASS eligible subset: COPART patients with all the COMPASS inclusion criteria and none of the COMPASS exclusion criteria;
      • COMPASS non-eligible subset: COPART patients without all the COMPASS inclusion criteria and/or with at least one COMPASS exclusion criterion;
      • COMPASS participants with symptomatic LEAD of the aspirin alone arm: patients with symptomatic LEAD randomised in the aspirin alone group of the COMPASS trial;
        • Kaplovitch E.
        • Eikelboom J.W.
        • Dyal L.
        • Aboyans V.
        • Abola M.T.
        • Verhamme P.
        • et al.
        Rivaroxaban and aspirin in patients with symptomatic lower extremity peripheral artery disease: a subanalysis of the COMPASS randomized clinical trial.
      • VOYAGER-PAD eligible subset: COPART patients with limb revascularisation, with all the VOYAGER-PAD inclusion criteria and none of the VOYAGER-PAD exclusion criteria;
      • VOYAGER-PAD non-eligible subset: COPART patients with limb revascularisation, without all the VOYAGER-PAD inclusion criteria and/or with at least one VOYAGER-PAD exclusion criterion;
      • VOYAGER-PAD participants of the placebo arm: patients randomised in the aspirin group of the VOYAGER-PAD trial, with clopidogrel, which can be additionally prescribed up to six months after limb revascularisation.
        • Bonaca M.P.
        • Bauersachs R.M.
        • Anand S.S.
        • Debus E.S.
        • Nehler M.R.
        • Patel M.R.
        • et al.
        Rivaroxaban in peripheral artery disease after revascularization.
      Proportions of COMPASS exclusion criteria and VOYAGER-PAD exclusion criteria were reported.
      As rivaroxaban was given to patients with stable LEAD in the COMPASS trial, the index date for COMPASS eligible and non-eligible subsets was the date of discharge from the index hospitalisation. For VOYAGER-PAD eligible and non-eligible subsets, the index date was the date of the qualifying revascularisation procedure.
      Comparisons between subgroups were done using the chi square test for categorical variables or Fisher’s exact test, when appropriate, while the Student’s t test and the Mann–Whitney U test were used for continuous variables. A z test was used to compare continuous variables between the COMPASS eligible subset and COMPASS participants with symptomatic LEAD in the aspirin arm. The Kaplan–Meier method was used to estimate the cumulative incidence of outcomes at one year, with the 95% confidence interval. Patients were censored at the date of the first considered outcome. If they did not develop the outcome during the year of follow up, they were censored at the date of the one year final record completion or at the date of loss of follow up. In order to allow statistical comparisons of outcomes between COMPASS participants with symptomatic LEAD and COMPASS eligible subset, and between VOYAGER-PAD participants and the VOYAGER-PAD eligible subset, estimations of p value based on 95% CI were given according to Krzywinski and Altman graphs.
      • Krzywinski M.
      • Altman N.
      Points of significance: error bars.
      No imputation was made on missing data. A p value < .05 was considered to be statistically significant. Analyses were performed with STATA (release 14.2; StataCorp, College Station, TX, USA).

      Results

      Rivaroxaban plus aspirin eligible patients in COPART registry

      Of 2 520 patients in COPART registry, 261 were excluded because of missing data in COMPASS, or VOYAGER-PAD exclusion or inclusion criteria (Fig. 1).
      Figure 1
      Figure 1Flowchart for the identification of COMPASS and VOYAGER-PAD eligible patients with lower extremity artery disease in the COPART registry. Of the VOYAGER-PAD non-eligible patients, 277 were eligible for COMPASS and 695 were not. All the VOYAGER-PAD eligible patients were also eligible for COMPASS.
      Of the remaining 2 259 evaluable patients, 679 (30.1%) were eligible for COMPASS. Of the 1 580 evaluable patients not eligible for COMPASS, 1 374 had at least one COMPASS exclusion criterion; the main reasons for exclusion were an indication for full dose oral anticoagulant treatment, known malignancy, and history of haemorrhagic or ischaemic stroke (Fig. 2).
      Figure 2
      Figure 2Main reasons for exclusion of patients with lower extremity artery disease in the COPART registry, according to the exclusion criteria in COMPASS trial.
      Of the 1 073 evaluable patients undergoing limb revascularisation, 101 (9.4%) were eligible for VOYAGER-PAD. Of the 972 evaluable patients undergoing limb revascularisation not eligible for VOYAGER-PAD, 868 had at least one VOYAGER-PAD exclusion criterion; the main reasons for exclusion were an indication for full dose oral anticoagulant treatment, major tissue loss, and known malignancy (Fig. 3).
      Figure 3
      Figure 3Main reasons for exclusion of patients revascularised for lower extremity artery disease in COPART registry, according to the exclusion criteria in VOYAGER-PAD trial. TIA = transient ischaemic attack.
      All VOYAGER-PAD eligible patients were also eligible for COMPASS; therefore, only 30.1% of the entire COPART evaluable cohort was eligible for the rivaroxaban 2.5 mg twice daily plus aspirin 100 mg once daily regimen, based on either COMPASS or VOYAGER-PAD criteria. The proportion of patients eligible for this regimen varied according to the year of inclusion in the COPART registry: between 21.2% and 38.1% based on COMPASS criteria, and between 3.6% and 16.0% based on VOYAGER-PAD criteria, with a trend toward a decrease over the most recent years.

      Comparison of baseline characteristics and outcomes of COMPASS eligible and COMPASS non-eligible subsets

      Compared with other COPART patients, COMPASS eligible patients were younger, with a lower prevalence of diabetes, history of CAD, stroke, heart failure, and renal failure (Table 1). The clinical presentation of LEAD was less severe and use of statin more frequent. Regarding outcome, the cumulative incidences of MACE and all cause mortality were lower than those non-eligible for COMPASS (Fig. 4 and Supplementary Table S5).
      Table 1Baseline characteristics of total 2 259 COMPASS eligible and COMPASS non-eligible patients from the COPART registry at the time of hospital discharge
      CharacteristicsCOMPASS eligible (n = 679)COMPASS non-eligible (n = 1 580)p value
      p value of difference between COMPASS eligible and COMPASS non-eligible subsets.
      Demographic data
       Age – y66.7 ± 12.972.6 ±12.3<.001
       Men523 (77.1)1168 (74.3).15
      Cardiovascular risk factors
       Diabetes282 (41.5)842 (53.3)<.001
       Dyslipidaemia540 (79.5)1 171 (74.2).007
       Hypertension564 (83.1)1385 (87.7).003
       Current smoker250 (37.0)303 (19.5)<.001
       Obesity119 (18.7)305 (21.2).19
      Medical history
       Coronary artery disease211 (31.2)632 (40.2)<.001
       Ischaemic stroke23 (3.4)337 (21.5)<.001
       Heart failure35 (5.2)252 (16.3)<.001
       Atrial fibrillation0 (0)502 (32.3)<.001
       COPD or asthma124 (18.7)300 (19.6).61
       Cancer0 (0)359 (22.7)<.001
       Renal failure186 (27.4)774 (49.0)<.001
       Hepatic failure0 (0)21 (1.3).003
      Laboratory exams
       eGFR – mL/min/1.73 m277.6 ± 32.459.2 ± 25.2<.001
      LEAD at hospital admittance
       Prior revascularisation287 (42.5)464 (29.7)<.001
       Prior amputation90 (13.4)220 (14.1).66
      LEAD classification<.001
      Rutherford 04 (0.6)13 (0.8)
      Rutherford 1, 2, or 3261 (38.6)319 (20.3)
      Rutherford 480 (11.8)150 (9.5)
      Rutherford 5 or 6285 (42.1)965 (61.3)
       Acute limb ischaemia47 (6.9)128 (8.1)
       Gangrene59 (8.9)216 (14.1).001
      Medical treatment at hospital discharge
       Aspirin or clopidogrel637 (93.8)1033 (74.3)<.001
       Oral anticoagulant0 (0)432 (27.4)<.001
       Statin542 (79.8)994 (71.4)<.001
       ACEI or ARB417 (62.0)812 (59.8).34
       Beta blockers170 (25.1)487 (35.7)<.001
      Data are presented as n (%) or mean ± standard deviation. COPD = chronic obstructive pulmonary disease; eGFR = estimated glomerular filtration rate; LEAD = lower extremity artery disease; ACEI = angiotensin converting enzyme inhibitors; ARB = angiotensin receptor blockers.
      p value of difference between COMPASS eligible and COMPASS non-eligible subsets.
      Figure 4
      Figure 4Comparison of one year cumulative incidences (95% confidence intervals) of outcomes for the COMPASS eligible and non-eligible subsets from COPART, and COMPASS participants with symptomatic lower extremity artery disease of the aspirin alone arm. CV = cardiovascular; MI = myocardial infarction. ∗ p < .05; § p < .010; ∗∗ p < .001; and p > .05.

      Comparison of baseline characteristics and outcomes of COMPASS eligible subset and COMPASS participants with symptomatic lower extremity artery disease in the aspirin alone arm

      Compared with participants with symptomatic LEAD randomised in the aspirin alone arm of COMPASS, the proportions of diabetes, history of CAD, and heart failure were higher in the COMPASS eligible subset, but LEAD was less severe (Table 2). The cumulative incidence of MACE was higher in the COMPASS eligible subset (Fig. 4 and Supplementary Table S6). The one year cumulative incidence of MALE in COMPASS participants with symptomatic LEAD of the aspirin alone arm was not available, but the risk of MALE in the COMPASS eligible subset was higher, given the 30 month Kaplan–Meier incidence risk in the former group.
      • Kaplovitch E.
      • Eikelboom J.W.
      • Dyal L.
      • Aboyans V.
      • Abola M.T.
      • Verhamme P.
      • et al.
      Rivaroxaban and aspirin in patients with symptomatic lower extremity peripheral artery disease: a subanalysis of the COMPASS randomized clinical trial.
      Table 2Baseline characteristics of total 2 038 COMPASS eligible patients in COPART and the actual subgroup of COMPASS participants with symptomatic lower extremity artery disease (LEAD) from the aspirin alone reference arm
      CharacteristicsCOMPASS eligible in COPART (n = 679)Actual COMPASS participants with symptomatic LEAD of aspirin alone arm (n = 1 359)p value
      p value of difference between COMPASS eligible subset and COMPASS participants with symptomatic LEAD in the aspirin alone arm.
      Demographic data
       Age – y66.7 ± 12.966.7 ± 8.81.0
       Men523 (77.1)960 (70.6).002
      Risk factors and coexisting conditions
       Diabetes282 (41.5)644 (47.4).012
       Current smoker250 (37.0)442 (32.5).046
       Coronary artery disease211 (31.2)725 (53.3)<.001
       Ischaemic stroke23 (3.4)65 (4.8).14
       Heart failure35 (5.2)226 (16.6)<.001
       Renal failure186 (27.4)371 (27.3).96
      LEAD history
       Previous revascularisation287 (42.5)563 (41.4).64
       Previous amputation90 (13.4)103 (7.6)<.001
      LEAD classification
      Rutherford 1, 2, or 3261 (38.6)943 (69.4)<.001
      Rutherford 480 (11.8)44 (3.2)<.001
      Rutherford 5 or 6285 (42.1)12 (0.9)<.001
      Medication
       Aspirin or clopidogrel637 (93.8)1359 (100)<.001
       Aspirin497 (73.2)1359 (100)<.001
       Clopidogrel140 (20.6)0 (0)<.001
       Statin542 (79.8)1051 (77.3).20
       ACEI and/or ARB417 (62.0)920 (67.7).010
      Data are presented as n (%) or mean ± standard deviation. ACEI = angiotensin converting enzyme inhibitors; ARB = angiotensin receptor blockers.
      p value of difference between COMPASS eligible subset and COMPASS participants with symptomatic LEAD in the aspirin alone arm.

      Comparison of baseline characteristics and outcomes of VOYAGER-PAD eligible and VOYAGER-PAD non-eligible subsets

      Compared with other COPART revascularised patients, proportions of hypertension, history of CAD, heart failure, and renal failure were lower in the VOYAGER-PAD eligible subset (Table 3). There was no statistically significant difference between the two groups regarding cumulative incidences of outcomes (Fig. 5 and Supplementary Table S7).
      Table 3Baseline characteristics of total 1 073 VOYAGER-PAD eligible and VOYAGER-PAD non-eligible patients revascularised from COPART at the time of index revascularisation
      CharacteristicsVOYAGER-PAD eligible (n = 101)VOYAGER-PAD non-eligible (n = 972)p value
      p value of difference between VOYAGER-PAD eligible and VOYAGER-PAD non-eligible subsets.
      Demographic data
       Age – y69.2 ± 11.770.2 ± 12.7.41
       Men78 (77.2)725 (75.1).64
      Cardiovascular risk factors
       Diabetes41 (40.6)491 (50.5).058
       Dyslipidaemia80 (79.2)750 (77.2).65
       Hypertension78 (77.2)850 (87.5).004
       Current smoker34 (33.7)232 (24.0).032
       Obesity14 (14.7)189 (20.2).20
      Medical history
       Coronary artery disease30 (29.7)389 (40.2).039
       Ischaemic stroke0 (0.0)163 (16.8)<.001
       Heart failure4 (4.0)128 (13.3).007
       Atrial fibrillation0 (0.0)238 (24.7)<.001
       COPD or asthma22 (22.0)185 (19.4).54
       Cancer0 (0.0)182 (18.7)<.001
       Renal failure30 (29.7)412 (42.4).014
       Hepatic failure0 (0.0)9 (0.9)1.0
      Laboratory investigations
       eGFR – mL/min/1.73 m275.3 ± 23.363.8 ± 31.9.001
      LEAD at hospital admittance
       Prior revascularisation41 (40.6)317 (32.8).11
       Prior amputation7 (6.9)99 (10.3).29
      LEAD classification<.001
      Rutherford 00 (0.0)3 (0.3)
      Rutherford 1, 2, or 330 (29.7)276 (28.5)
      Rutherford 427 (26.7)79 (8.1)
      Rutherford 5 or 644 (43.6)496 (51.1)
       Acute limb ischaemia0 (0.0)116 (12.0)
       Gangrene7 (7.1)93 (9.7).39
      Medical treatment at hospital discharge
       Aspirin or clopidogrel98 (97.0)723 (80.9)<.001
       Oral anticoagulant0 (0.0)237 (24.4)<.001
       Statin83 (82.2)713 (79.6).54
       ACEI or ARB64 (64.0)533 (60.9).55
       Beta blockers20 (19.8)316 (35.8).001
      Data are presented as n (%) or mean ± standard deviation. COPD = chronic obstructive pulmonary disease; eGFR = estimated glomerular filtration rate; LEAD = lower extremity artery disease; ACEI = angiotensin converting enzyme inhibitors; ARB = angiotensin receptor blockers.
      p value of difference between VOYAGER-PAD eligible and VOYAGER-PAD non-eligible subsets.
      Figure 5
      Figure 5Comparison of one year cumulative incidences (95% confidence intervals) of outcomes for the VOYAGER-PAD eligible and non-eligible subsets from COPART, and VOYAGER-PAD participants of the placebo arm with lower extremity artery disease. CV = cardiovascular; MI = myocardial infarction. ∗ p < .05; ∗∗ p < .001; and p > .05.

      Comparison of baseline characteristics and outcomes differences between the VOYAGER-PAD eligible subset and VOYAGER-PAD participants of the placebo arm

      Compared with VOYAGER-PAD participants randomised in the placebo arm, LEAD presentation was more severe in the VOYAGER-PAD eligible subset and qualifying revascularisation more often required surgery (Table 4). Compared with the VOYAGER-PAD placebo arm, VOYAGER-PAD eligible patients from COPART had a higher risk of major amputation (Fig. 5 and Supplementary Table S8). The cumulative incidence of overall mortality was higher in the VOYAGER-PAD eligible subset than in the VOYAGER-PAD placebo arm, but the difference was driven by non-CV death (Fig. 5 and Supplementary Table S8).
      Table 4Baseline characteristics of total 3 379 VOYAGER-PAD eligible patients in COPART and actual VOYAGER-PAD participants from the aspirin reference arm
      CharacteristicsVOYAGER-PAD eligible in COPART (n = 101)Actual VOYAGER-PAD participants (aspirin reference arm) (n = 3 278)p value
      p value of difference between the VOYAGER-PAD eligible subset and VOYAGER-PAD participants in the aspirin reference arm.
      Age – y69.2 ± 11.767.0 ± 12.0NA
      Men78 (77.2)2 421 (73.9).45
      Body mass index – kg/m224.6 ± 4.326.0 ± 5.9NA
      Risk factors and co-existing conditions
       Diabetes41 (40.6)1 316 (40.1).93
       Dyslipidaemia80 (79.2)1 968 (60.0)<.001
       Hypertension78 (77.2)2 658 (81.1).33
       Current smokers34 (33.7)1 132 (34.5).86
       Coronary artery disease30 (29.7)1 015 (31.0).787
       Renal failure30 (29.7)666 (20.3).022
      LEAD history
       Prior revascularisation41 (40.6)1 155 (35.2).27
       Prior amputation7 (6.9)196 (6.0).69
      Qualifying revascularisation
       Performed for claudication30 (29.7)2 504 (76.4)<.001
       Performed for critical limb ischaemia71 (70.3)771 (23.5)<.001
       Endovascular35 (34.7)2 140 (65.3)<.001
       Surgical66 (65.3)1 138 (34.7)<.001
      Medication
       Aspirin at randomisation76 (75.3)3 248 (99.1)<.001
       Clopidogrel at randomisation22 (21.8)1 655 (50.5)<.001
       Statin83 (82.2)2 641 (80.6).69
       ACEI or ARB64 (64.0)2 063 (62.9).83
      Data are presented as n (%) or median ± interquartile range. NA = not available; LEAD = lower extremity artery disease; ACEI = angiotensin converting enzyme inhibitors; ARB = angiotensin receptor blockers.
      p value of difference between the VOYAGER-PAD eligible subset and VOYAGER-PAD participants in the aspirin reference arm.

      Discussion

      RCTs constitute the highest level of evidence for new drug applications, line extensions, and recommendations for treatment. In 2018, the Committee for Medicinal Products for Human Use of the European Medicines Agency (EMA) issued a favourable opinion about the use of low dose rivaroxaban in addition to aspirin in patients with CAD or symptomatic LEAD at high risk of ischaemic events. Multiple international agencies also granted low dose rivaroxaban approval. Since then, this combination is being incorporated into international guidance statements: this association is suggested in patients with CAD or LEAD, including CLTI.
      • Conte M.S.
      • Bradbury A.W.
      • Kolh P.
      • White J.V.
      • Dick F.
      • Fitridge R.
      • et al.
      Global vascular guidelines on the management of chronic limb-threatening ischemia.
      • Frank U.
      • Nikol S.
      • Belch J.
      • Boc V.
      • Brodmann M.
      • Carpentier P.H.
      • et al.
      ESVM Guideline on peripheral arterial disease.
      • Knuuti J.
      • Wijns W.
      • Saraste A.
      • Capodanno D.
      • Barbato E.
      • Funck-Brentano C.
      • et al.
      2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes.
      However, patient samples in RCTs, including those focused on LEAD, are highly selected with a lower risk profile than real world populations, and are not broadly representative of patients encountered in daily practice.
      • Sigvant B.
      • Hasvold P.
      • Kragsterman B.
      • Falkenberg M.
      • Johansson S.
      • Thuresson M.
      • et al.
      Cardiovascular outcomes in patients with peripheral arterial disease as an initial or subsequent manifestation of atherosclerotic disease: results from a Swedish nationwide study.
      ,
      • Kennedy-Martin T.
      • Curtis S.
      • Faries D.
      • Robinson S.
      • Johnston J.
      A literature review on the representativeness of randomized controlled trial samples and implications for the external validity of trial results.
      ,
      • Paraskevas K.I.
      • de Borst G.J.
      • Veith F.J.
      Why randomized controlled trials do not always reflect reality.
      Moreover, new therapies may be used in a broader patient population in clinical practice than that enrolled in the RCTs, and the regulatory approval may also extend beyond the inclusion and exclusion criteria of the trials.
      • Fox K.A.A.
      • Anand S.S.
      • Aboyans V.
      • Cowie M.R.
      • Debus E.S.
      • Zeymer U.
      • et al.
      Xarelto plus Acetylsalicylic acid: Treatment patterns and Outcomes in patients with Atherosclerosis (XATOA): rationale and design of a prospective registry study to assess rivaroxaban 2.5 mg twice daily plus aspirin for prevention of atherothrombotic events in coronary artery disease, peripheral artery disease, or both.
      The application of real world data (RWD), mostly drawn from registries, to support drug approvals is now accepted by regulatory authorities such as the EMA and the U.S. Food and Drug Administration.
      • Bolislis W.R.
      • Fay M.
      • Kühler T.C.
      Use of real-world data for new drug applications and line extensions.
      RWD can complement the results of phase III RCTs by providing insight into their applicability to clinical practice and informing health technology assessment bodies and payers.
      • Fox K.A.A.
      • Anand S.S.
      • Aboyans V.
      • Cowie M.R.
      • Debus E.S.
      • Zeymer U.
      • et al.
      Xarelto plus Acetylsalicylic acid: Treatment patterns and Outcomes in patients with Atherosclerosis (XATOA): rationale and design of a prospective registry study to assess rivaroxaban 2.5 mg twice daily plus aspirin for prevention of atherothrombotic events in coronary artery disease, peripheral artery disease, or both.
      In the present study, only 30.1% of the COPART evaluable cohort was eligible for the rivaroxaban 2.5 mg twice daily plus aspirin regimen. VOYAGER-PAD criteria did not allow more patients to be eligible for this regimen than COMPASS criteria alone.
      To date, no other registry has assessed the external applicability of the VOYAGER-PAD trial. Concerning the external applicability of the COMPASS trial, in the REACH registry (Reduction of Atherothrombosis for Continued Health), 59.3% of patients with CAD or peripheral artery disease (PAD) were eligible for secondary prevention with low dose rivaroxaban plus aspirin: 68.4% of patients with PAD alone, 60.4% of patients with PAD plus CAD, and 48.7% of patients with only CAD.
      • Darmon A.
      • Bhatt D.L.
      • Elbez Y.
      • Aboyans V.
      • Anand S.
      • Bosch J.
      • et al.
      External applicability of the COMPASS trial: an analysis of the reduction of atherothrombosis for continued health (REACH) registry.
      Only patients with CAD have been included in other cohorts, with 14.9% – 44.2% of them eligible for combined low dose rivaroxaban and aspirin treatment.
      • Würtz M.
      • Olesen K.K.W.
      • Thim T.
      • Kristensen S.D.
      • Eikelboom J.W.
      • Maeng M.
      External applicability of the COMPASS trial: the Western Denmark Heart Registry.
      • Desperak P.
      • Hudzik B.
      • Gąsior M.
      Assessment of patients with coronary artery disease who may benefit from the use of rivaroxaban in the real world: implementation of the COMPASS trial criteria in the TERCET registry population.
      • Faria D.
      • Santos M.
      • Baptista S.B.
      • Ferreira J.
      • Leal P.
      • Abreu P.F.E.
      • et al.
      Eligibility for extended antithrombotic therapy for secondary prevention of acute coronary syndrome.
      • Schiele F.
      • Puymirat E.
      • Ferrières J.
      • Simon T.
      • Fox K.A.A.
      • Eikelboom J.
      • et al.
      The FAST-MI 2005-2010-2015 registries in the light of the COMPASS trial: the COMPASS criteria applied to a post-MI population.
      As found in the REACH registry, an indication for full dose anticoagulant or dual antiplatelet therapy, and high bleeding risk, are among the main reasons for being ineligible for the low dose rivaroxaban plus aspirin regimen.
      • Darmon A.
      • Bhatt D.L.
      • Elbez Y.
      • Aboyans V.
      • Anand S.
      • Bosch J.
      • et al.
      External applicability of the COMPASS trial: an analysis of the reduction of atherothrombosis for continued health (REACH) registry.
      Severe renal failure and major tissue loss are exclusion criteria in about 10% of ineligible patients in COMPASS and VOYAGER subsets and in a third in the VOYAGER-PAD subset, respectively. These patients are at high risk of ischaemic events. Indeed, in the COMPASS trial, patients with symptomatic LEAD with high risk limb presentations (prior amputation, Fontaine III or IV symptoms, and previous peripheral artery revascularisation) or high risk comorbidities (kidney dysfunction, heart failure, diabetes, and polyvascular disease) had a higher incidence of MACE and MALE than those with neither high risk limb presentation nor high risk comorbidities.
      • Kaplovitch E.
      • Eikelboom J.W.
      • Dyal L.
      • Aboyans V.
      • Abola M.T.
      • Verhamme P.
      • et al.
      Rivaroxaban and aspirin in patients with symptomatic lower extremity peripheral artery disease: a subanalysis of the COMPASS randomized clinical trial.
      Moreover, after MALE, one year cumulative incidences of MACE, all cause mortality, and amputation were high.
      • Anand S.S.
      • Caron F.
      • Eikelboom J.W.
      • Bosch J.
      • Dyal L.
      • Aboyans V.
      • et al.
      Major adverse limb events and mortality in patients with peripheral artery disease: the COMPASS trial.
      As people in this non-eligible population are likely to be among those who will benefit the most from combination therapy, further studies are needed to explore the applicability of this strategy. ALI was found in 13% of ineligible patients in the VOYAGER-PAD subset; even if low dose rivaroxaban plus aspirin has not primarily been investigated after ALI, a small subgroup of patients within the COMPASS trial who had ALI also had a marked reduction in amputation and mortality rate, as highlighted in the European Society for Vascular Surgery guidelines.
      • Björck M.
      • Earnshaw J.J.
      • Acosta S.
      • Bastos Gonçalves F.
      • Cochennec F.
      • Debus E.S.
      • et al.
      Editor’s Choice – European Society for Vascular Surgery (ESVS) 2020 Clinical Practice Guidelines on the Management of Acute Limb Ischaemia.
      Finally, malignancy (found in about 20% of ineligible patients) is another major reason for ineligibility.
      In the COPART registry, VOYAGER-PAD eligible patients had the same risk of MACE as VOYAGER-PAD participants in the reference arm and even higher risks of non-CV death, MALE, and major amputation. COMPASS eligible patients had higher risks of MACE and MALE than COMPASS LEAD participants in the reference arm. These results support the fact that the COMPASS and VOYAGER-PAD inclusion criteria define high risk patients, which may derive particular benefit from a low dose rivaroxaban plus aspirin regimen.
      However, COMPASS ineligible patients had an even higher risk of MACE than COMPASS eligible patients, which advocates for further studies enrolling these high risk patients, in order to clarify the benefit of this intervention in more representative populations. This is an aim of the prospective post-approval XATOA registry study (Xarelto plus Acetylsalicylic acid: Treatment patterns and Outcomes in patients with Atherosclerosis).
      • Fox K.A.A.
      • Anand S.S.
      • Aboyans V.
      • Cowie M.R.
      • Debus E.S.
      • Zeymer U.
      • et al.
      Xarelto plus Acetylsalicylic acid: Treatment patterns and Outcomes in patients with Atherosclerosis (XATOA): rationale and design of a prospective registry study to assess rivaroxaban 2.5 mg twice daily plus aspirin for prevention of atherothrombotic events in coronary artery disease, peripheral artery disease, or both.
      There are limitations to this analysis. Because the COPART registry recruited patients from 2006 to 2015 (recent data being entered), the management and prognosis of some patients could be different from what is currently observed. The differences found in event rates between the registry and the RCT may, at least partially, reflect the developments of revascularisation procedures and secondary prevention during this period. The population from the COPART registry represents a nationwide sample of patients hospitalised for LEAD in university hospitals in France but cannot necessarily be extrapolated to patients hospitalised in non-university hospitals, outpatients, or patients from other countries. Of note, the results from the main COMPASS trial differed by geographical location, with a high efficacy seen in the Asia-Pacific and Eastern European regions.
      • Eikelboom J.W.
      • Connolly S.J.
      • Bosch J.
      • Dagenais G.R.
      • Hart R.G.
      • Shestakovska O.
      • et al.
      Rivaroxaban with or without aspirin in stable cardiovascular disease.
      A few COMPASS and VOYAGER-PAD eligibility criteria were not collected as part of the COPART registry, and others required adjustment. For example, the exclusion criteria of a high bleeding risk was not captured in the COPART registry, so it was approached by the composite of any medical history of major bleeding and/or platelet count < 100 x 109/L. Moreover, the date of major bleeding during follow up was not captured in the registry so the Cox analysis was not available for this outcome. Finally, the cost of rivaroxaban is not considered when it could be a factor limiting the use of the treatment.

      Conclusion

      Based on the COMPASS or VOYAGER-PAD criteria, patients eligible for low dose rivaroxaban plus aspirin represent only a third of patients with LEAD hospitalised in vascular departments of four tertiary care hospitals in France. The higher rates of MALE and major amputation in these patients vs. those in the VOYAGER-PAD trial, and the higher rates of MACE vs. those in the COMPASS trial, may result in greater benefits from this regimen in the real world population. However, ineligible patients represent a higher risk population, who could have benefited more from this regimen, and requires further research. There is a need for further clinical trials assessing the LEAD population that may benefit from this treatment in routine clinical practice.

      Conflicts of Interest

      Dr Lapébie reports the receipt of personal fees from Bayer healthcare SAS, outside the submitted work. Dr Aboyans reports the receipt of personal fees from Bayer Healthcare, BMS/Pfizer, Novartis, and Sanofi, outside the submitted work. Dr Lacroix, Dr Constans, Dr Boulon, Dr Messas and Dr Ferrières have nothing to disclose. Dr Bongard reports the receipt of personal fees from Sanofi outside the submitted work. Dr Bura-Rivière reports the receipt of grants, personal fees, non-financial support, and other support from Bayer Healthcare and BMS/Pfizer, and grants and non-financial support from AstraZeneca , outside the submitted work.

      Funding

      The COPART registry is supported by the French Vascular Medicine Society (SFMV) and received grants from Toulouse University Hospital, AstraZeneca France, Bayer France, Bristol-Myers Squibb (BMS) France, and Sanofi-Aventis France.

      Acknowledgements

      The authors thank the team of research assistants for their technical help and data collection: Delphine Baudoin, Clémence Labetoulle, Emmanuelle Lorian, Marion Mangin, Béatrice Montalègre, Monique Pailhol, Brigitte Pelvet, and Irina Smoliy.

      Appendix A. Supplementary data

      The following is the Supplementary data to this article:

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