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Outcome after percutaneous coronary intervention with contemporary stents in patients with concomitant peripheral arterial disease: A patient-level pooled analysis of four randomized trials

Open AccessPublished:May 20, 2022DOI:https://doi.org/10.1016/j.atherosclerosis.2022.05.002

      Highlights

      • Patients with peripheral arterial disease have higher complication risks after percutaneous coronary intervention (PCI).
      • Peripheral arterial disease also increases the risk of repeated revascularization.
      • In addition, all-cause mortality and major adverse cardiac event risks are higher.
      • Yet, the adverse event rates are much lower as compared to historical controls.

      Abstract

      Background and aims

      A considerable number of patients who undergo percutaneous coronary intervention (PCI) also have peripheral arterial disease (PAD) – a signal of more advanced atherosclerosis. After bare metal and early-generation drug-eluting coronary stent implantation, PAD patients showed inferior outcome. As stents and medical treatment were further improved, we aimed to assess the impact of PAD on outcome of PCI with contemporary new-generation stents.

      Methods

      We analyzed 3-year pooled patient-level data from 4 large-scale randomized new-generation stent trials to compare all-comer patients with and without (core lab-verified) history of symptomatic PAD, defined as obstructive lesions in peripheral locations including lower and upper extremities, carotid, vertebral, mesenteric and renal arteries. Main endpoint was target vessel failure: cardiac death, target vessel-related myocardial infarction, or clinically indicated target vessel revascularization.

      Results

      Of all 9204 patients, 695 (7.6%) had a history of symptomatic PAD. They were older and had more often diabetes, renal failure, hypertension, hypercholesterolemia, and prior stroke. PAD was an independent risk factor for target vessel failure (adjusted-HR:1.42, 95%-CI:1.12–1.73, p = 0.001). Target vessel revascularization (adjusted-HR:1.37, 95%-CI:1.04–1.80, p = 0.026), death (adjusted-HR:1.52, 95%-CI:1.17–1.99, p = 0.002), and major adverse cardiovascular event risks (adjusted-HR:1.36, 95%-CI:1.13–1.64, p = 0.001) were also substantially higher.

      Conclusions

      A history of symptomatic PAD still allows to simply identify patients with increased risk of unfavorable clinical outcome after PCI, including a higher risk of repeated coronary revascularization, despite using contemporary stents. In clinical practice, this knowledge about higher event risks of PAD patients is helpful both during Heart Team discussions and when informing patients about the procedural risk.

      Graphical abstract

      Keywords

      1. Introduction

      Both coronary artery disease and peripheral arterial disease (PAD) are manifestations of atherosclerosis and associated with similar cardiovascular risk factors [
      • Ramzy J.
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      • Roberts L.
      • Duffy S.J.
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      Outcomes in patients with peripheral vascular disease following percutaneous coronary intervention.
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      Ankle-brachial index and extent of atherothrombosis in 8891 patients with or at risk of vascular disease: results of the international AGATHA study.
      ]. In patients with obstructive coronary artery disease, concomitant PAD indicates the presence of more advanced atherosclerosis and may be present in up to 20% of all patients who undergo coronary stent implantation [
      • Ramzy J.
      • Andrianopoulos N.
      • Roberts L.
      • Duffy S.J.
      • Clark D.
      • et al.
      Outcomes in patients with peripheral vascular disease following percutaneous coronary intervention.
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      • Jeremias A.
      • Gruberg L.
      • Patel J.
      • Connors G.
      • Brown D.L.
      Effect of peripheral arterial disease on in-hospital outcomes after primary percutaneous coronary intervention for acute myocardial infarction.
      ,
      • Guerrero M.
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      • Stone G.W.
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      • Cox D.
      • et al.
      Usefulness of the presence of peripheral vascular disease in predicting mortality in acute myocardial infarction patients treated with primary angioplasty (from the Primary Angioplasty in Myocardial Infarction Database).
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      • Dangas G.D.
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      • et al.
      Impact of symptomatic peripheral arterial disease on 1-year mortality in patients undergoing percutaneous coronary interventions.
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      • Midwall S.
      • Swaminathan R.V.
      • Charitakis K.
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      • Gordin J.
      • et al.
      Impact of peripheral vascular disease on short- and long-term outcomes in patients undergoing non-emergent percutaneous coronary intervention in the drug-eluting stent era.
      ,
      • Gupta R.
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      • Ozan M.O.
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      • Rinaldi M.J.
      • et al.
      Platelet reactivity and clinical outcomes after coronary artery implantation of drug-eluting stents in subjects with peripheral arterial disease: analysis from the ADAPT-DES study (assessment of dual antiplatelet therapy with drug-eluting stents).
      ]. In addition, PAD has been found to be associated with inferior clinical outcome up to 12 months after percutaneous coronary intervention (PCI) with bare metal and early-generation drug-eluting stents (DES) [
      • Ramzy J.
      • Andrianopoulos N.
      • Roberts L.
      • Duffy S.J.
      • Clark D.
      • et al.
      Outcomes in patients with peripheral vascular disease following percutaneous coronary intervention.
      ,
      • Nikolsky E.
      • Mehran R.
      • Mintz G.S.
      • Dangas G.D.
      • Lansky A.J.
      • et al.
      Impact of symptomatic peripheral arterial disease on 1-year mortality in patients undergoing percutaneous coronary interventions.
      ,
      • Chiu J.H.
      • Topol E.J.
      • Whitlow P.L.
      • Hsu A.P.
      • Tuzcu E.M.
      • et al.
      Peripheral vascular disease and one-year mortality following percutaneous coronary revascularization.
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      • Saw J.
      • Bhatt D.L.
      • Moliterno D.J.
      • Brener S.J.
      • Steinhubl S.R.
      • et al.
      The influence of peripheral arterial disease on outcomes: a pooled analysis of mortality in eight large randomized percutaneous coronary intervention trials.
      ,
      • Sasaki M.
      • Mitsutake Y.
      • Ueno T.
      • Fukami A.
      • Sasaki K.I.
      • et al.
      Low ankle brachial index predicts poor outcomes including target lesion revascularization during the long-term follow up after drug-eluting stent implantation for coronary artery disease.
      ,
      • Singh M.
      • Lennon R.J.
      • Darbar D.
      • Gersh B.J.
      • Holmes Jr., D.R.
      • et al.
      Effect of peripheral arterial disease in patients undergoing percutaneous coronary intervention with intracoronary stents.
      ]. In all-comer patients, mortality and myocardial infarction risk decreased after the introduction of early-generation DES [
      • Singh M.
      • Peterson E.D.
      • Roe M.T.
      • Ou F.S.
      • Spertus J.A.
      • et al.
      Trends in the association between age and in-hospital mortality after percutaneous coronary intervention: national Cardiovascular Data Registry experience.
      ,
      • Parikh S.V.
      • Saya S.
      • Divanji P.
      • Banerjee S.
      • Selzer F.
      • et al.
      Risk of death and myocardial infarction in patients with peripheral arterial disease undergoing percutaneous coronary intervention (from the National Heart, Lung and Blood Institute Dynamic Registry).
      ]. Yet, in patients with concomitant PAD, both in-hospital mortality and long-term adverse event rates remained high [
      • Jeremias A.
      • Gruberg L.
      • Patel J.
      • Connors G.
      • Brown D.L.
      Effect of peripheral arterial disease on in-hospital outcomes after primary percutaneous coronary intervention for acute myocardial infarction.
      ,
      • Midwall S.
      • Swaminathan R.V.
      • Charitakis K.
      • Kim L.K.
      • Gordin J.
      • et al.
      Impact of peripheral vascular disease on short- and long-term outcomes in patients undergoing non-emergent percutaneous coronary intervention in the drug-eluting stent era.
      ,
      • Parikh S.V.
      • Saya S.
      • Divanji P.
      • Banerjee S.
      • Selzer F.
      • et al.
      Risk of death and myocardial infarction in patients with peripheral arterial disease undergoing percutaneous coronary intervention (from the National Heart, Lung and Blood Institute Dynamic Registry).
      ].
      In the meantime, more biocompatible newer-generation DES have become available which showed better long-term outcomes in all-comers. In parallel, there has been an improvement in pharmacological therapy, including the antithrombotic regimen. In PAD patients, outcome data after PCI with new-generation DES are scarce, while in clinical practice it may be useful to simply identify high-risk patients based on their medical history. In addition, the knowledge about the event risks of PAD patients could be helpful for cardiologist during Heart Team discussions and when informing patients about their risk. Therefore, in the current study we pooled patient-level data of 4 large-scale randomized contemporary DES trials to evaluate the impact of a history of symptomatic PAD on long-term clinical outcome after PCI.

      2. Patients and methods

      2.1 Study design

      We pooled the data of demographic, clinical, and angiographic characteristics as well as clinical outcome of 9204 patients who underwent PCI with DES implantation for the treatment of chronic or acute coronary artery syndromes and were included in one of the 4 TWENTE trials (TWENTE I, (clinicaltrials.gov: NCT01066650), DUTCH PEERS (TWENTE II, NCT01331707), BIO-RESORT (TWENTE III, NCT01674803), and BIONYX (TWENTE IV, NCT02508714).
      In the TWENTE I, DUTCH PEERS, and BIONYX, patients were randomized to 2 different DES. In BIO-RESORT, patients were randomized between 3 different DES. Randomization was done in a 1:1 or 1:1:1 fashion to the different stents, respectively. Web-based randomization was performed with the use of a custom-designed computer program in random block sizes of 4 and 8. Stratification was performed for the presence of diabetes (BIO-RESORT and BIONYX) and sex (TWENTE I and BIONYX).
      In all trials, inclusion criteria were broad and patients were eligible for participation, if they were aged 18 years or older, capable of providing informed consent, and required PCI with DES implantation. In the TWENTE II-IV trials, patients with any clinical syndrome were included; in TWENTE I, patients were permitted if they had any clinical syndrome except for an ST-segment elevation myocardial infarction ≤48 h.
      Patients were included in Medisch Spectrum Twente (Enschede, the Netherlands); Haga Hospital (The Hague, the Netherlands); Scheper Hospital (Emmen, the Netherlands); Rijnstate Hospital (Arnhem, the Netherlands); Albert Schweitzer Ziekenhuis (Dordecht, the Netherlands); Jessa Hospital (Hasselt, Belgium); Centre Hospitalier Universitaire de Charleroi (Charleroi, Belgium) and Hillel Yaffe Medical Center (Haifa, Israel). Protocols of all studies have previously been published [
      • von Birgelen C.
      • Basalus M.W.
      • Tandjung K.
      • van Houwelingen K.G.
      • Stoel M.G.
      • et al.
      A randomized controlled trial in second-generation zotarolimus-eluting Resolute stents versus everolimus-eluting Xience V stents in real-world patients: the TWENTE trial.
      ,
      • von Birgelen C.
      • Sen H.
      • Lam M.K.
      • Danse P.W.
      • Jessurun G.A.
      • et al.
      Third-generation zotarolimus-eluting and everolimus-eluting stents in all-comer patients requiring a percutaneous coronary intervention (Dutch PEERS): a randomised, single-blind, multicentre, non-inferiority trial.
      ,
      • von Birgelen C.
      • Kok M.M.
      • van der Heijden L.C.
      • Danse P.W.
      • Schotborgh C.E.
      • et al.
      Very thin strut biodegradable polymer everolimus-eluting and sirolimus-eluting stents versus durable polymer zotarolimus-eluting stents in allcomers with coronary artery disease (BIO-RESORT): a three-arm, randomised, non-inferiority trial.
      ,
      • von Birgelen C.
      • Zocca P.
      • Buiten R.A.
      • Jessurun G.A.J.
      • Schotborgh C.E.
      • et al.
      Thin composite wire strut, durable polymer-coated (Resolute Onyx) versus ultrathin cobalt-chromium strut, bioresorbable polymer-coated (Orsiro) drug-eluting stents in allcomers with coronary artery disease (BIONYX): an international, single-blind, randomised non-inferiority trial.
      ].
      Of the patients with self-reported or known history of PAD, the diagnosis was verified by medical records or by contacting the general practitioner. In this study, patients with confirmed PAD were eligible for classification as patient with symptomatic PAD (i.e., a history of an obstructive lesion resulting from atherosclerosis in peripheral locations including the lower and upper extremities, carotid or vertebral arteries, and mesenteric or renal arteries) [
      • Gerhard-Herman M.D.
      • Gornik H.L.
      • Barrett C.
      • Barshes N.R.
      • Corriere M.A.
      • et al.
      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.
      ,
      • Aboyans V.
      • Ricco J.B.
      • Bartelink M.E.L.
      • Björck M.
      • Brodmann M.
      • et al.
      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 arteriesEndorsed 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).
      ].
      Technical details of all the implanted new-generation DES have been reported [
      • von Birgelen C.
      • Basalus M.W.
      • Tandjung K.
      • van Houwelingen K.G.
      • Stoel M.G.
      • et al.
      A randomized controlled trial in second-generation zotarolimus-eluting Resolute stents versus everolimus-eluting Xience V stents in real-world patients: the TWENTE trial.
      ,
      • von Birgelen C.
      • Sen H.
      • Lam M.K.
      • Danse P.W.
      • Jessurun G.A.
      • et al.
      Third-generation zotarolimus-eluting and everolimus-eluting stents in all-comer patients requiring a percutaneous coronary intervention (Dutch PEERS): a randomised, single-blind, multicentre, non-inferiority trial.
      ,
      • von Birgelen C.
      • Kok M.M.
      • van der Heijden L.C.
      • Danse P.W.
      • Schotborgh C.E.
      • et al.
      Very thin strut biodegradable polymer everolimus-eluting and sirolimus-eluting stents versus durable polymer zotarolimus-eluting stents in allcomers with coronary artery disease (BIO-RESORT): a three-arm, randomised, non-inferiority trial.
      ,
      • von Birgelen C.
      • Zocca P.
      • Buiten R.A.
      • Jessurun G.A.J.
      • Schotborgh C.E.
      • et al.
      Thin composite wire strut, durable polymer-coated (Resolute Onyx) versus ultrathin cobalt-chromium strut, bioresorbable polymer-coated (Orsiro) drug-eluting stents in allcomers with coronary artery disease (BIONYX): an international, single-blind, randomised non-inferiority trial.
      ]. The following stents were used: Resolute zotarolimus-eluting (Medtronic, Santa Rosa, California, USA); Xience V everolimus-eluting (Abbott Vascular, Santa Clara, California, USA); Promus Element everolimus-eluting (Boston Scientific, Marlborough, Massachusetts, USA); Synergy everolimus-eluting (Boston Scientific); Orsiro sirolimus-eluting (Biotronik, Bülach, Switzerland); Resolute Integrity zotarolimus-eluting (Medtronic); and Resolute Onyx zotarolimus-eluting (Medtronic) stents.
      The Medical Ethics Committee Twente and the Institutional Review Boards of all participating centers approved the original trials which complied with the Declaration of Helsinki. Written informed consent was provided by all trial participants.

      2.2 Procedures and angiographic analysis

      Coronary interventional procedures were performed according to standard techniques. Choice of concomitant medication and type and duration of antiplatelet therapy were based on routine clinical practice, current international guidelines, and the operator's judgment. After coronary stenting, electrocardiographs and cardiac biomarkers were systematically assessed with subsequent serial measurements in case of suspected ischemia. Analysts of an angiographic core laboratory performed angiographic analyses and offline quantitative coronary angiographic measurements according to current standards, using dedicated software (Qangio XA versions 7.1–7.3, Medis, Leiden, the Netherlands).

      2.3 Follow-up, monitoring, and clinical event adjudication

      Clinical follow-up was obtained via questionnaires, patient visits to outpatient clinics, or by telephone follow-up. Research staff was blinded to the assigned treatment. Trial and data management were performed by Cardiovascular Research and Education Enschede (Enschede, the Netherlands) and data monitoring by an independent clinical research organization (Diagram, Zwolle, the Netherlands).
      Adverse clinical events were adjudicated by independent, blinded clinical event committees: Cardialysis (Rotterdam, the Netherlands) for TWENTE I; Diagram (Zwolle, the Netherlands) for DUTCH PEERS and BIO-RESORT; and a committee of expert interventional cardiologists at the University of Amsterdam (Amsterdam, the Netherlands) for BIONYX.

      2.4 Definitions

      Main endpoint of this study and all the original trials was target vessel failure, a composite of cardiac death, target vessel related myocardial infarction, or clinically indicated target vessel revascularization. All clinical endpoints were defined according to the Academic Research Consortium [
      • Cutlip D.E.
      • Windecker S.
      • Mehran R.
      • Boam A.
      • Cohen D.J.
      • et al.
      Clinical end points in coronary stent trials: a case for standardized definitions.
      ,
      • Vranckx P.
      • Cutlip D.E.
      • Mehran R.
      • Kint P.P.
      • Silber S.
      • et al.
      Myocardial infarction adjudication in contemporary all-comer stent trials: balancing sensitivity and specificity. Addendum to the historical MI definitions used in stent studies.
      ]. Secondary endpoints included: the individual components of the main endpoint; all-cause death; target lesion failure (cardiac death, target vessel myocardial infarction, or clinically indicated target lesion revascularization); and major adverse cardiac events (all-cause death, any myocardial infarction, emergent coronary bypass surgery, or clinically indicated target lesion revascularization).
      Trial participants were classified as patients with symptomatic peripheral disease, if they had a history (by anamnesis or medical record) of an obstructive lesion resulting from atherosclerosis in peripheral locations, including the lower and upper extremities, carotid or vertebral arteries, and mesenteric or renal arteries [
      • Gerhard-Herman M.D.
      • Gornik H.L.
      • Barrett C.
      • Barshes N.R.
      • Corriere M.A.
      • et al.
      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.
      ,
      • Aboyans V.
      • Ricco J.B.
      • Bartelink M.E.L.
      • Björck M.
      • Brodmann M.
      • et al.
      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 arteriesEndorsed 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).
      ].

      2.5 Statistical analysis

      We compared demographics, angiographic characteristics, and clinical outcomes of patients with and without symptomatic PAD. Chi-square test was used to assess differences in categorical variables. Differences in continuous variables were assessed with the Wilcoxon Rank Sum test or Student t-test, as appropriate. Kaplan-Meier methods were used to assess time to main and secondary endpoints and the p-value of the log-rank test was applied for between-group comparisons. Cox proportional hazards analysis was used to compute hazard ratios. All potential confounders with univariate association with the main endpoint (p < 0.15) as well as the individual clinical trial were included in the first pass of a multivariate Cox regression model. Stepwise backward selection was used to exclude variables with a non-significant association with the main endpoint. The model consisted of diabetes, renal failure, prior myocardial infarction, prior coronary artery bypass grafting, at least one severely calcified lesion, and at least one ostial lesion. Statistical analyses were performed with SPSS software (version 24, IBM, Armonk, NY). p-values and confidence intervals were two-sided, and p-values <0.05 were considered significant.

      3. Results

      Of all 9204 trial participants, 695 (7.6%) had a history of (concomitant) symptomatic PAD, while 8454 (91.9%) had no symptomatic PAD. A total of 55 (0.6%) patients, in whom the PAD status was unknown, were excluded from this analysis (Fig. 1). Patient demographics and baseline clinical characteristics are reported in Table 1. Patients with a history of symptomatic PAD were older (67.9 ± 8.9 vs. 63.7 ± 10.9 years, p < 0.001) and had significantly more comorbidities, such as diabetes, renal failure, hypertension, hypercholesterolemia, and history of stroke. There was no difference in sex between patients with and without symptomatic PAD, about 27% were women. Patients with symptomatic PAD more often had a history of previous myocardial infarction, PCI, and coronary artery bypass grafting.
      Fig. 1
      Fig. 1Flowchart of patient selection for analysis.
      The number of patients treated with drug-eluting stents in the different trials distributed to peripheral arterial disease. PAD: peripheral arterial disease.
      Table 1Baseline and procedural characteristics.
      Peripheral arterial diseasep-value
      Yes (n = 695)No (n = 8454)
      General characteristics
      Age (years)67.9 ± 8.963.7 ± 10.90.001
      Age >8057 (8.2)610 (7.2)0.34
      Women193 (27.8)2221 (26.3)0.39
      Body-mass Index (kg/m2)27.7 ± 4.427.7 ± 4.30.27
      Smoker209/682 (30.6)2341/8310 (28.2)0.17
      Medical history
      Diabetes mellitus208 (29.9)1539 (18.2)0.001
      Renal failure
      Defined as previous renal failure, creatinine ≥130 μmol/L, or the need for dialysis.
      81 (11.7)293 (3.5)0.001
      Hypertension433/695 (62.3)4187/8420 (49.7)0.001
      Hypercholesterolemia387/683 (56.7)3695/8388 (44.1)0.001
      Previous stroke90/695 (12.9)435/8453 (5.1)0.001
      LVEF < 30%32 (4.7)116 (1.4)0.001
      Family history of coronary artery disease337/670 (50.3)3878/8242 (47.1)0.11
      Previous myocardial infarction190 (27.3)1686 (19.9)0.001
      Previous percutaneous coronary intervention203 (29.2)1581 (18.7)0.001
      Previous coronary bypass surgery100 (14.4)662 (7.8)0.001
      Clinical syndrome at presentation
      Stable angina pectoris294 (42.3)2896 (34.3)0.001
      STEMI82 (11.8)1978 (23.4)0.001
      NSTEMI168 (24.2)2066 (24.4)0.19
      Unstable angina pectoris151 (21.7)1514 (17.9)0.041
      Procedural characteristics
      Multivessel treatment158 (22.7)1544 (18.3)0.004
      Target vessel
      Left main stem28 (4.0)186 (2.2)0.002
      Right coronary artery310 (44.6)3124 (37.0)0.001
      Left anterior descending artery276 (39.7)4218 (49.9)0.001
      Left circumflex artery221 (31.8)2451 (29.0)0.12
      Bypass graft34 (4.9)172 (2.0)0.001
      Total stent length (mm)42.9 ± 30.438.5 ± 26.40.001
      Calcified lesion treatment194 (27.9)1682 (19.9)0.001
      Ostial lesion treatment75 (10.8)540 (6.4)0.001
      Bifurcated lesion treatment
      Target lesions were classified as bifurcated if a side branch ≥1.5 mm originated from them.
      210 (30.2)2819 (33.3)0.09
      Chronic total occlusion treatment30 (4.3)388 (4.6)0.74
      Values are mean ± SD, n (%) or n/N (%). Procedures present patient-level data.
      LVEF = left ventricle ejection fraction; NSTEMI = non–ST-segment–elevation myocardial infarction; STEMI=ST-segment–elevation myocardial infarction.
      a Defined as previous renal failure, creatinine ≥130 μmol/L, or the need for dialysis.
      b Target lesions were classified as bifurcated if a side branch ≥1.5 mm originated from them.
      The two patient groups differed in clinical syndrome at presentation (i.e., at time of the index coronary intervention). In patients with a history of symptomatic PAD, the rates of stable and unstable angina were higher (Table 1). On the other hand, in patients without symptomatic PAD, ST-segment-elevation myocardial infarction was more prevalent. In addition, ostial and calcified lesions were more prevalent in patients with a history of symptomatic PAD (Table 1).
      Table 2 presents clinical outcome data until 3 years after the index coronary intervention. At 3-year follow-up, the main endpoint target vessel failure was met by 111/695 (16.4%) patients with a history of symptomatic PAD and 783/8454 (9.4%) patients without PAD (HR 1.79, 95% CI 1.47–2.19, p < 0.001; Graphical Abstract).
      Table 2Clinical outcomes at 3-year.
      Table thumbnail fx1
      At 3-year follow-up, there were significant between-group differences in many secondary endpoints (Table 2, Fig. 2): all-cause death (HR 2.23, 95% CI 1.72–2.89, p < 0.001); cardiac death (HR 2.34, 95% CI 1.60–3.41, p < 0.001); myocardial infarction (HR 1.59, 95% CI 1.16–2.19, p = 0.004); target vessel revascularization (HR 1.56, 95% CI 1.19–2.05, p = 0.001); target lesion failure (HR 1.73, 95% CI 1.40–2.16, p < 0.001); definite-or-probable stent thrombosis (HR 1.65, 95% CI 1.07–2.55, p = 0.023), and major adverse cardiac event rates (HR 1.80, 95% CI 1.50–2.16, p < 0.001) were higher in patients with a history of symptomatic PAD.
      Fig. 2
      Fig. 2Kaplan-Meier cumulative event curves for the main endpoint target vessel failure and its individual components at 3-year follow-up.
      Kaplan-Meier cumulative incidence curves for: (A) the primary endpoint target vessel failure, a composite of cardiac death (B), target vessel related myocardial infarction (C), or clinically driven target vessel revascularization (D). Patients with (red) and without (blue) peripheral arterial disease with drug-eluting stents. HR = hazard ratio; MI = myocardial infarction.
      Multivariate adjustment for potential confounders revealed that a history of symptomatic PAD was independently associated with an increased risk of the main endpoint target vessel failure at 3-year follow-up (adjusted (adj) HR:1.42, 95% CI: 1.12–1.73, p = 0.001; Table 2). In addition, a history of symptomatic PAD was independently associated with the 3-year risks for the secondary endpoints all-cause death (adjHR:1.52, 95% CI: 1.17–1.99, p = 0.002), target vessel revascularization (adjHR:1.37, 95% CI: 1.04–1.80, p = 0.026), target lesion failure (adjHR:1.33, 95% CI: 1.07–1.67, p = 0.011) and major adverse cardiac events (adjHR:1.36, 95% CI: 1.13–1.64, p = 0.001; Table 2).
      Multivariate analysis revealed no statistically significant relation between a history of symptomatic PAD and cardiac mortality (adjHR:1.47, 95% CI: 0.99–2.16, p = 0.051), myocardial infarction (adjHR:1.34, 95% CI: 0.97–1.85, p = 0.08), or stent thrombosis (adjHR:1.14, 95% CI: 0.73–1.77, p = 0.57; Table 2).
      In multivariate analysis, potential predictors of target vessel failure, all-cause death, and major adverse cardiovascular events were assessed (Supplementary Table S1). Besides PAD, age, diabetes, renal failure, calcified lesion treatment, ostial lesion treatment, previous myocardial infarction and previous coronary bypass surgery were predictors but differed in their impact on these outcome parameters. Only calcified lesion treatment and coronary artery bypass surgery did not predict all-cause mortality.

      4. Discussion

      4.1 Main findings

      Patients with a history of symptomatic PAD have more classical risk factors of atherosclerosis and symptomatic PAD should be regarded as a signal of more advanced atherosclerotic disease. Information about a history of symptomatic PAD still allows to identify patients with an increased risk of future adverse clinical events after PCI with contemporary DES. Symptomatic PAD was an independent risk factor for reaching target vessel failure (+42% risk), death (ca. +50% risk), target vessel revascularization (+37% risk), and major adverse cardiac events (+36% risk). In addition, patients with a history of symptomatic PAD showed a higher cardiac mortality; yet, after adjustment for confounders this numeric dissimilarity did not remain statistically significant (p = 0.051).

      4.2 Definition of peripheral arterial disease

      To assess the impact of symptomatic PAD, we applied an established definition [
      • Nikolsky E.
      • Mehran R.
      • Mintz G.S.
      • Dangas G.D.
      • Lansky A.J.
      • et al.
      Impact of symptomatic peripheral arterial disease on 1-year mortality in patients undergoing percutaneous coronary interventions.
      ,
      • Gresele P.
      • Guglielmini G.
      • Del Pinto M.
      • Calabrò P.
      • Pignatelli P.
      • et al.
      Peripheral arterial disease has a strong impact on cardiovascular outcome in patients with acute coronary syndromes: from the START Antiplatelet registry.
      ], based on a history of an obstructive atherosclerotic lesion in a peripheral location, including the lower and upper extremities, carotid and vertebral arteries, or mesenteric and renal arteries. Notably, while information on self-reported or known PAD was obtained from the original trial databases, the history of symptomatic PAD was confirmed from medical record or by contacting the patient's general practitioner. Besides the definition used in our study [
      • Nikolsky E.
      • Mehran R.
      • Mintz G.S.
      • Dangas G.D.
      • Lansky A.J.
      • et al.
      Impact of symptomatic peripheral arterial disease on 1-year mortality in patients undergoing percutaneous coronary interventions.
      ,
      • Gresele P.
      • Guglielmini G.
      • Del Pinto M.
      • Calabrò P.
      • Pignatelli P.
      • et al.
      Peripheral arterial disease has a strong impact on cardiovascular outcome in patients with acute coronary syndromes: from the START Antiplatelet registry.
      ], alternative definitions of PAD have been used. The term ‘peripheral arterial disease’ generally refers to atherosclerotic disease in arteries other than the coronary arteries and aorta, while the term ‘peripheral artery disease’ is used to classify atherosclerotic disease of the lower limbs [
      • Gerhard-Herman M.D.
      • Gornik H.L.
      • Barrett C.
      • Barshes N.R.
      • Corriere M.A.
      • et al.
      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.
      ,
      • Aboyans V.
      • Ricco J.B.
      • Bartelink M.E.L.
      • Björck M.
      • Brodmann M.
      • et al.
      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 arteriesEndorsed 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).
      ]. Furthermore, in some studies the term PAD also refers to atherosclerotic disease of the lower limbs plus cerebrovascular disease [
      • Guerrero M.
      • Harjai K.
      • Stone G.W.
      • Brodie B.
      • Cox D.
      • et al.
      Usefulness of the presence of peripheral vascular disease in predicting mortality in acute myocardial infarction patients treated with primary angioplasty (from the Primary Angioplasty in Myocardial Infarction Database).
      ,
      • Midwall S.
      • Swaminathan R.V.
      • Charitakis K.
      • Kim L.K.
      • Gordin J.
      • et al.
      Impact of peripheral vascular disease on short- and long-term outcomes in patients undergoing non-emergent percutaneous coronary intervention in the drug-eluting stent era.
      ], and sometimes it includes aortic pathologies [
      • Ramzy J.
      • Andrianopoulos N.
      • Roberts L.
      • Duffy S.J.
      • Clark D.
      • et al.
      Outcomes in patients with peripheral vascular disease following percutaneous coronary intervention.
      ,
      • Jeremias A.
      • Gruberg L.
      • Patel J.
      • Connors G.
      • Brown D.L.
      Effect of peripheral arterial disease on in-hospital outcomes after primary percutaneous coronary intervention for acute myocardial infarction.
      ,
      • Singh M.
      • Lennon R.J.
      • Darbar D.
      • Gersh B.J.
      • Holmes Jr., D.R.
      • et al.
      Effect of peripheral arterial disease in patients undergoing percutaneous coronary intervention with intracoronary stents.
      ,
      • Parikh S.V.
      • Saya S.
      • Divanji P.
      • Banerjee S.
      • Selzer F.
      • et al.
      Risk of death and myocardial infarction in patients with peripheral arterial disease undergoing percutaneous coronary intervention (from the National Heart, Lung and Blood Institute Dynamic Registry).
      ].

      4.3 Different generations of coronary stents in patients with concomitant PAD

      Several studies assessed bare metal or early-generation DES and found that patients with PAD had significantly more risk factors, such as more advanced age, diabetes, hypertension, hypercholesterolemia, stroke, and chronic renal disease [
      • Ramzy J.
      • Andrianopoulos N.
      • Roberts L.
      • Duffy S.J.
      • Clark D.
      • et al.
      Outcomes in patients with peripheral vascular disease following percutaneous coronary intervention.
      ,
      • Jeremias A.
      • Gruberg L.
      • Patel J.
      • Connors G.
      • Brown D.L.
      Effect of peripheral arterial disease on in-hospital outcomes after primary percutaneous coronary intervention for acute myocardial infarction.
      ,
      • Nikolsky E.
      • Mehran R.
      • Mintz G.S.
      • Dangas G.D.
      • Lansky A.J.
      • et al.
      Impact of symptomatic peripheral arterial disease on 1-year mortality in patients undergoing percutaneous coronary interventions.
      ,
      • Midwall S.
      • Swaminathan R.V.
      • Charitakis K.
      • Kim L.K.
      • Gordin J.
      • et al.
      Impact of peripheral vascular disease on short- and long-term outcomes in patients undergoing non-emergent percutaneous coronary intervention in the drug-eluting stent era.
      ,
      • Chiu J.H.
      • Topol E.J.
      • Whitlow P.L.
      • Hsu A.P.
      • Tuzcu E.M.
      • et al.
      Peripheral vascular disease and one-year mortality following percutaneous coronary revascularization.
      ,
      • Saw J.
      • Bhatt D.L.
      • Moliterno D.J.
      • Brener S.J.
      • Steinhubl S.R.
      • et al.
      The influence of peripheral arterial disease on outcomes: a pooled analysis of mortality in eight large randomized percutaneous coronary intervention trials.
      ,
      • Singh M.
      • Lennon R.J.
      • Darbar D.
      • Gersh B.J.
      • Holmes Jr., D.R.
      • et al.
      Effect of peripheral arterial disease in patients undergoing percutaneous coronary intervention with intracoronary stents.
      ,
      • Gresele P.
      • Guglielmini G.
      • Del Pinto M.
      • Calabrò P.
      • Pignatelli P.
      • et al.
      Peripheral arterial disease has a strong impact on cardiovascular outcome in patients with acute coronary syndromes: from the START Antiplatelet registry.
      ]. The current study corroborates the finding that patients with a history of symptomatic PAD had more comorbidities and cardiovascular risk factors. In addition, previous studies reported a prevalence of PAD in 5–19% of all patients undergoing PCI [
      • Ramzy J.
      • Andrianopoulos N.
      • Roberts L.
      • Duffy S.J.
      • Clark D.
      • et al.
      Outcomes in patients with peripheral vascular disease following percutaneous coronary intervention.
      ,
      • Jeremias A.
      • Gruberg L.
      • Patel J.
      • Connors G.
      • Brown D.L.
      Effect of peripheral arterial disease on in-hospital outcomes after primary percutaneous coronary intervention for acute myocardial infarction.
      ,
      • Guerrero M.
      • Harjai K.
      • Stone G.W.
      • Brodie B.
      • Cox D.
      • et al.
      Usefulness of the presence of peripheral vascular disease in predicting mortality in acute myocardial infarction patients treated with primary angioplasty (from the Primary Angioplasty in Myocardial Infarction Database).
      ,
      • Nikolsky E.
      • Mehran R.
      • Mintz G.S.
      • Dangas G.D.
      • Lansky A.J.
      • et al.
      Impact of symptomatic peripheral arterial disease on 1-year mortality in patients undergoing percutaneous coronary interventions.
      ,
      • Midwall S.
      • Swaminathan R.V.
      • Charitakis K.
      • Kim L.K.
      • Gordin J.
      • et al.
      Impact of peripheral vascular disease on short- and long-term outcomes in patients undergoing non-emergent percutaneous coronary intervention in the drug-eluting stent era.
      ,
      • Gupta R.
      • Kirtane A.J.
      • Ozan M.O.
      • Witzenbichler B.
      • Rinaldi M.J.
      • et al.
      Platelet reactivity and clinical outcomes after coronary artery implantation of drug-eluting stents in subjects with peripheral arterial disease: analysis from the ADAPT-DES study (assessment of dual antiplatelet therapy with drug-eluting stents).
      ,
      • Gresele P.
      • Guglielmini G.
      • Del Pinto M.
      • Calabrò P.
      • Pignatelli P.
      • et al.
      Peripheral arterial disease has a strong impact on cardiovascular outcome in patients with acute coronary syndromes: from the START Antiplatelet registry.
      ]. The rate of 8% in the present study falls well into that range.
      The present study assessed the outcome of treatment with contemporary DES and corroborates most findings of previous studies with bare metal or (mainly) early-generation DES. PAD patients, treated with bare metal coronary stents, showed higher rates of short and long-term mortality [
      • Guerrero M.
      • Harjai K.
      • Stone G.W.
      • Brodie B.
      • Cox D.
      • et al.
      Usefulness of the presence of peripheral vascular disease in predicting mortality in acute myocardial infarction patients treated with primary angioplasty (from the Primary Angioplasty in Myocardial Infarction Database).
      ,
      • Nikolsky E.
      • Mehran R.
      • Mintz G.S.
      • Dangas G.D.
      • Lansky A.J.
      • et al.
      Impact of symptomatic peripheral arterial disease on 1-year mortality in patients undergoing percutaneous coronary interventions.
      ,
      • Chiu J.H.
      • Topol E.J.
      • Whitlow P.L.
      • Hsu A.P.
      • Tuzcu E.M.
      • et al.
      Peripheral vascular disease and one-year mortality following percutaneous coronary revascularization.
      ,
      • Singh M.
      • Lennon R.J.
      • Darbar D.
      • Gersh B.J.
      • Holmes Jr., D.R.
      • et al.
      Effect of peripheral arterial disease in patients undergoing percutaneous coronary intervention with intracoronary stents.
      ,
      • Dinser L.
      • Meisinger C.
      • Amann U.
      • Heier M.
      • Thilo C.
      • et al.
      Peripheral arterial disease is associated with higher mortality in patients with incident acute myocardial infarction.
      ,

      Mukherjee D, Eagle Ka Fau - Kline-Rogers E, Kline-Rogers E Fau - Feldman LJ, Feldman Lj Fau - Juliard J-M, Juliard Jm Fau - Agnelli G, et al. Impact of Prior Peripheral Arterial Disease and Stroke on Outcomes of Acute Coronary Syndromes and Effect of Evidence-Based Therapies (From the Global Registry of Acute Coronary Events). (0002-9149 (Print)).

      ], which was also found in a pooled analysis of eight randomized PCI studies with bare metal stents [
      • Saw J.
      • Bhatt D.L.
      • Moliterno D.J.
      • Brener S.J.
      • Steinhubl S.R.
      • et al.
      The influence of peripheral arterial disease on outcomes: a pooled analysis of mortality in eight large randomized percutaneous coronary intervention trials.
      ].
      Yet, short- and long-term adverse events were better after treatment with early-generation DES [
      • Ramzy J.
      • Andrianopoulos N.
      • Roberts L.
      • Duffy S.J.
      • Clark D.
      • et al.
      Outcomes in patients with peripheral vascular disease following percutaneous coronary intervention.
      ]. The 1-year all-cause mortality was 14%, and the major adverse cardiac event rate was 26.4% for all-comer PAD patients treated with bare metal stents, while that rates were 8.5% and 19.4% after treatment with early-generation DES, respectively [
      • Ramzy J.
      • Andrianopoulos N.
      • Roberts L.
      • Duffy S.J.
      • Clark D.
      • et al.
      Outcomes in patients with peripheral vascular disease following percutaneous coronary intervention.
      ,
      • Nikolsky E.
      • Mehran R.
      • Mintz G.S.
      • Dangas G.D.
      • Lansky A.J.
      • et al.
      Impact of symptomatic peripheral arterial disease on 1-year mortality in patients undergoing percutaneous coronary interventions.
      ]. In our present study, all-cause mortality and major adverse cardiac events were about 3% and 8.5% at 1-year follow-up and 9.4% and 18.8% at 3-year follow-up. At 1-year follow-up, myocardial infarction rates were 10.3% and 8.1% in patients treated with bare metal stents and early-generation DES, respectively [
      • Ramzy J.
      • Andrianopoulos N.
      • Roberts L.
      • Duffy S.J.
      • Clark D.
      • et al.
      Outcomes in patients with peripheral vascular disease following percutaneous coronary intervention.
      ,
      • Nikolsky E.
      • Mehran R.
      • Mintz G.S.
      • Dangas G.D.
      • Lansky A.J.
      • et al.
      Impact of symptomatic peripheral arterial disease on 1-year mortality in patients undergoing percutaneous coronary interventions.
      ], while in our study myocardial infarction occurred in 3.5% until 1-year follow-up and in 6.4% until 3-year follow-up.
      The comparison of these stent generation–related outcome data suggests that in patients with PAD the incidence of adverse events has decreased with refinement in stent design and technology. Yet, the improvement in coronary stents cannot be viewed separately, as it was paralleled by an improvement in medical therapy.

      4.4 Outcome after coronary stenting in patients with and without concomitant PAD

      Contradictory results regarding the impact of PAD on mortality were found in studies with mostly early- and new-generation DES. While in four studies PAD [
      • Gupta R.
      • Kirtane A.J.
      • Ozan M.O.
      • Witzenbichler B.
      • Rinaldi M.J.
      • et al.
      Platelet reactivity and clinical outcomes after coronary artery implantation of drug-eluting stents in subjects with peripheral arterial disease: analysis from the ADAPT-DES study (assessment of dual antiplatelet therapy with drug-eluting stents).
      ,
      • Saw J.
      • Bhatt D.L.
      • Moliterno D.J.
      • Brener S.J.
      • Steinhubl S.R.
      • et al.
      The influence of peripheral arterial disease on outcomes: a pooled analysis of mortality in eight large randomized percutaneous coronary intervention trials.
      ,
      • Attar R.
      • Wester A.
      • Koul S.
      • Eggert S.
      • Andell P.
      Peripheral artery disease and outcomes in patients with acute myocardial infarction.
      ,
      • Al-Zakwani I.
      • Al Siyabi E.
      • Alrawahi N.
      • Al-Mulla A.
      • Alnaeemi A.
      • et al.
      Association between peripheral artery disease and major adverse cardiovascular events in patients with acute coronary syndrome: findings from the gulf COAST registry.
      ] was an independent risk factor for mortality with an increased risk of 46%–59% [
      • Saw J.
      • Bhatt D.L.
      • Moliterno D.J.
      • Brener S.J.
      • Steinhubl S.R.
      • et al.
      The influence of peripheral arterial disease on outcomes: a pooled analysis of mortality in eight large randomized percutaneous coronary intervention trials.
      ,
      • Attar R.
      • Wester A.
      • Koul S.
      • Eggert S.
      • Andell P.
      Peripheral artery disease and outcomes in patients with acute myocardial infarction.
      ]. Another study found no increased risk of all-cause mortality after adjustment for confounders [
      • Sasaki M.
      • Mitsutake Y.
      • Ueno T.
      • Fukami A.
      • Sasaki K.I.
      • et al.
      Low ankle brachial index predicts poor outcomes including target lesion revascularization during the long-term follow up after drug-eluting stent implantation for coronary artery disease.
      ]. Our present analysis in all-comer patients, treated with contemporary stents, showed a 52% higher mortality risk in the presence of symptomatic PAD at long-term follow-up.
      Higher risks of target lesion revascularization, myocardial infarction, major cardiac and cerebrovascular events, stent thrombosis, and bleeding have been observed by others [
      • Gupta R.
      • Kirtane A.J.
      • Ozan M.O.
      • Witzenbichler B.
      • Rinaldi M.J.
      • et al.
      Platelet reactivity and clinical outcomes after coronary artery implantation of drug-eluting stents in subjects with peripheral arterial disease: analysis from the ADAPT-DES study (assessment of dual antiplatelet therapy with drug-eluting stents).
      ,
      • Sasaki M.
      • Mitsutake Y.
      • Ueno T.
      • Fukami A.
      • Sasaki K.I.
      • et al.
      Low ankle brachial index predicts poor outcomes including target lesion revascularization during the long-term follow up after drug-eluting stent implantation for coronary artery disease.
      ,
      • Gresele P.
      • Guglielmini G.
      • Del Pinto M.
      • Calabrò P.
      • Pignatelli P.
      • et al.
      Peripheral arterial disease has a strong impact on cardiovascular outcome in patients with acute coronary syndromes: from the START Antiplatelet registry.
      ,
      • Attar R.
      • Wester A.
      • Koul S.
      • Eggert S.
      • Andell P.
      Peripheral artery disease and outcomes in patients with acute myocardial infarction.
      ,
      • Al-Zakwani I.
      • Al Siyabi E.
      • Alrawahi N.
      • Al-Mulla A.
      • Alnaeemi A.
      • et al.
      Association between peripheral artery disease and major adverse cardiovascular events in patients with acute coronary syndrome: findings from the gulf COAST registry.
      ]. At a mean follow-up of 43 months, a smaller-sized retrospective single-center study observed a more than 500% higher risk of major adverse cardiac and cerebrovascular events as well as of target lesion revascularization for patients with PAD [
      • Sasaki M.
      • Mitsutake Y.
      • Ueno T.
      • Fukami A.
      • Sasaki K.I.
      • et al.
      Low ankle brachial index predicts poor outcomes including target lesion revascularization during the long-term follow up after drug-eluting stent implantation for coronary artery disease.
      ]. Our current analysis at 3-year follow-up showed a considerably lower risk difference in major adverse cardiac events of 36%, which corroborates the 35% 1-year increase found in a large-sized study that assessed patients with myocardial infarction and PAD [
      • Attar R.
      • Wester A.
      • Koul S.
      • Eggert S.
      • Andell P.
      Peripheral artery disease and outcomes in patients with acute myocardial infarction.
      ]. Potential explanations for the dissimilar findings of the two aforementioned studies [
      • Sasaki M.
      • Mitsutake Y.
      • Ueno T.
      • Fukami A.
      • Sasaki K.I.
      • et al.
      Low ankle brachial index predicts poor outcomes including target lesion revascularization during the long-term follow up after drug-eluting stent implantation for coronary artery disease.
      ,
      • Attar R.
      • Wester A.
      • Koul S.
      • Eggert S.
      • Andell P.
      Peripheral artery disease and outcomes in patients with acute myocardial infarction.
      ] are the limited sample size of some of these studies, differences among the study populations, as well as differences in the definition of PAD.
      We found no difference in target lesion revascularization risk between patients with and without PAD, while target vessel revascularization risk was 37% higher in patients with PAD. This may be explained by more advanced atherosclerosis in patients with PAD, which may lead to new coronary lesions that require revascularization during follow-up.

      4.5 Implications of the study

      Over the last three decades, the outcome of coronary stenting has gradually improved. Parallel to improvements in stent design and technology, antiplatelet therapy has been optimized regarding the type of P2Y12 inhibitor and the duration of dual antiplatelet therapy [

      Natsuaki M, Kimura T. Antiplatelet therapy after percutaneous coronary intervention - past, current and future perspectives. LID - 10.1253/circj.CJ-21-0751 [doi]. (1347-4820 (Electronic)).

      ]. Nevertheless, the presence of symptomatic PAD independently increased the risk of several clinical endpoints. The association of PAD with adverse clinical outcome still reflects the advanced level of systemic atherosclerosis, present in patients with polyvascular disease. Hence, it is important to refresh awareness of the high-risk nature of PCI patients with PAD that warrants efforts to optimize both treatment and secondary prevention. In addition, the present study shows that a history of symptomatic PAD allows to simply identify patients with an increased risk of unfavorable clinical outcome after PCI, including a higher risk of repeated revascularization. In daily clinical practice, this knowledge about a higher event risk of PAD patients is helpful during Heart Team discussions and when informing patients about their procedural risk.

      4.6 Strengths and limitations

      The study analyzed pooled patient-level data of 4 large-scale randomized coronary DES trials [
      • von Birgelen C.
      • Basalus M.W.
      • Tandjung K.
      • van Houwelingen K.G.
      • Stoel M.G.
      • et al.
      A randomized controlled trial in second-generation zotarolimus-eluting Resolute stents versus everolimus-eluting Xience V stents in real-world patients: the TWENTE trial.
      ,
      • von Birgelen C.
      • Sen H.
      • Lam M.K.
      • Danse P.W.
      • Jessurun G.A.
      • et al.
      Third-generation zotarolimus-eluting and everolimus-eluting stents in all-comer patients requiring a percutaneous coronary intervention (Dutch PEERS): a randomised, single-blind, multicentre, non-inferiority trial.
      ,
      • von Birgelen C.
      • Kok M.M.
      • van der Heijden L.C.
      • Danse P.W.
      • Schotborgh C.E.
      • et al.
      Very thin strut biodegradable polymer everolimus-eluting and sirolimus-eluting stents versus durable polymer zotarolimus-eluting stents in allcomers with coronary artery disease (BIO-RESORT): a three-arm, randomised, non-inferiority trial.
      ,
      • von Birgelen C.
      • Zocca P.
      • Buiten R.A.
      • Jessurun G.A.J.
      • Schotborgh C.E.
      • et al.
      Thin composite wire strut, durable polymer-coated (Resolute Onyx) versus ultrathin cobalt-chromium strut, bioresorbable polymer-coated (Orsiro) drug-eluting stents in allcomers with coronary artery disease (BIONYX): an international, single-blind, randomised non-inferiority trial.
      ] that assessed 9204 PCI patients. These trials applied the same established definitions of baseline characteristics and clinical endpoints, collected comprehensive clinical data, studied a relatively long follow-up of 3 years, underwent independent monitoring, and reported adverse clinical events after independent assessment. Nevertheless, this study has limitations. Although we included in the multivariate analysis all known potential confounder (i.e., demographics, cardiovascular risk factors, comorbidities, and other baseline and procedural characteristics with between-group difference in univariate analyses), we cannot exclude the presence of undetected or unmeasured confounders. The study assessed the clinical impact of symptomatic peripheral arterial disease, defined as a history (by anamnesis or medical record) of an obstructive lesion resulting from atherosclerosis in peripheral locations, including the lower and upper extremities, carotid and vertebral arteries, or mesenteric and renal arteries [
      • Gerhard-Herman M.D.
      • Gornik H.L.
      • Barrett C.
      • Barshes N.R.
      • Corriere M.A.
      • et al.
      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.
      ,
      • Aboyans V.
      • Ricco J.B.
      • Bartelink M.E.L.
      • Björck M.
      • Brodmann M.
      • et al.
      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 arteriesEndorsed 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).
      ]. Yet, we cannot exclude that some patients with asymptomatic or undiagnosed peripheral arterial disease may not have been classified as PAD patients. Nevertheless, the purpose of this study was not to examine PAD of all stages in patients undergoing PCI, but to evaluate in a large pooled database of several coronary stent trials whether readily available information on the presence or absence of a history of symptomatic PAD may allow to identify patients with an increased adverse event risk.

      4.7 Conclusions

      In patients with concomitant PAD, adverse clinical event rates after PCI with contemporary DES are relatively low. Yet, knowledge about a history of symptomatic PAD still allows to simply identify patients with an increased risk of unfavorable clinical outcome after coronary intervention, including a higher risk of repeated coronary revascularization, despite the use of contemporary stents. In clinical practice, knowledge about this higher event risk of PAD patients is useful, both during Heart Team discussions and when informing patients about their individual risk during and after the PCI procedure.

      TWENTE trials

      TWENTE I, (clinicaltrials.gov: NCT01066650), DUTCH PEERS (TWENTE II, NCT01331707), BIO-RESORT (TWENTE III, NCT01674803), and BIONYX (TWENTE IV, NCT02508714).

      Financial support

      The original randomized clinical trials were funded by Abbott Vascular , Biotronik , Boston Scientific , and Medtronic . The present study received no additional financial support.

      CRediT authorship contribution statement

      Tineke H. Pinxterhuis: Conceptualization, Methodology, Formal analysis, Investigation, Data curation, Writing – original draft, Visualization, Project administration. Eline H. Ploumen: Validation, Data curation, Investigation, Writing – original draft, Project administration. Paolo Zocca: Investigation, Resources, Writing – review & editing. Carine J.M. Doggen: Conceptualization, Formal analysis, Methodology, Writing – original draft. Carl E. Schotborgh: Investigation, Resources, Writing – review & editing. Rutger L. Anthonio: Investigation, Resources, Writing – review & editing. Ariel Roguin: Investigation, Resources, Writing – review & editing. Peter W. Danse: Investigation, Resources, Writing – review & editing. Edouard Benit: Investigation, Resources, Writing – review & editing. Adel Aminian: Investigation, Resources, Writing – review & editing. Martin G. Stoel: Conceptualization, Investigation, Resources, Writing – review & editing. Gerard C.M. Linssen: Investigation, Resources, Writing – review & editing. Robert H. Geelkerken: Conceptualization, Writing – original draft. Clemens von Birgelen: Conceptualization, Methodology, Investigation, Resources, Writing – original draft, Visualization, Supervision, Project administration, Funding acquisition.

      Declaration of competing interest

      The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: CvB reports that the research department of Thoraxcentrum Twente has received research grants provided by Abbott Vascular , Biotronik , Boston Scientific , and Medtronic . All other authors declared that they have no conflict of interest.

      Appendix A. Supplementary data

      The following is the Supplementary data to this article:

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