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One-year clinical outcomes in patients with chronic renal failure treated by percutaneous coronary intervention with drug-eluting stent
Archives of Cardiovascular Disease (2011) 104, 604—610
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CLINICAL RESEARCH
One-year clinical outcomes in patients with chronic renal failure treated by percutaneous coronary intervention with drug-eluting stent Résultats cliniques à un an de l’angioplastie coronaire avec stent actif chez les patients avec insuffisance rénale chronique Olivier Barthelemy , Gérard Helft , Johanne Silvain , Anne Bellemain-Appaix , Farzin Beygui , Rémi Choussat , Emmanuel Berman , Jean-Philippe Collet , Gilles Montalescot , Jean-Philippe Metzger , Claude Le Feuvre ∗ Centre hospitalier universitaire Pitié-Salpêtrière, AP—HP, institut de cardiologie, 47, boulevard de l’hôpital, 75013 Paris, France Received 3 December 2010; received in revised form 9 May 2011; accepted 9 May 2011
KEYWORDS Renal failure; Percutaneous coronary intervention; Drug-eluting stent; Thrombosis
∗
Summary Background. — It is unknown whether the efficacy and safety of drug-eluting stents (DES) apply in patients with chronic renal failure (CRF). Aims. — To compare DES with bare metal stents (BMS) for percutaneous coronary intervention (PCI) in CRF patients. Patients and methods. — Consecutive patients treated by PCI were allocated to four groups according to type of stent used (DES versus BMS) and creatinine clearance (CrCl). CRF was defined as CrCl less than 60 mL/minute. Cardiovascular death, major adverse cardiac events (MACE, defined as cardiovascular death, myocardial infarction, stroke and target lesion revascularization [TLR]), TLR and definite stent thrombosis (ST) were recorded at 1 year. Results. — We note that 1376 consecutive patients underwent PCI with stent within 18 months: 534 (39%) and 492 (36%) patients without CRF and 224 (16%) and 126 (9%) patients with CRF were treated with BMS and DES, respectively. In the entire cohort, patients treated with DES had a higher restenosis risk profile. BMS were predominantly (87%) used for ST-segment elevation myocardial infarction. At 1 year, 6.2% had cardiovascular death, 15.8% MACE, 7.3% TLR and 1.5% ST. Cardiovascular death and MACE occurred less frequently in DES groups. The TLR rate was not significantly different in the CRF groups (BMS 9.8% vs DES 7.1%; P = 0.44). No excess of ST
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1875-2136/$ — see front matter © 2011 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.acvd.2011.05.010
DES in renal failure patients
605 was observed in the DES groups and use of DES was independently associated with absence of MACE and TLR. Conclusions. — In patients with CRF, DES appear to be at least as effective as BMS —– despite a higher restenosis risk profile —– with no excess of ST at 1 year. © 2011 Elsevier Masson SAS. All rights reserved.
MOTS CLÉS Insuffisance rénale ; Angioplastie coronaire ; Stent actif ; Thrombose
Résumé Context. — Peu de données sont disponibles sur l’efficacité et la sécurité des stents actifs (DES) chez les patients avec insuffisance rénale (CRF). Objectif Comparer DES et stents nus (BMS) lors de l’angioplastie coronaire (PCI) chez les patients avec CRF. Patients et méthodes. — Une série consécutive de patients traités par PCI ont été répartis en quatre groupes selon le stent utilisé (DES ou BMS), et la clairance de la créatinine (CrCl). CRF était défini par une CrCl inférieure à 60 mL/min. Les décès cardiovasculaire (CV), revascularisation de la lésion cible (TLR), thrombose certaine de stent (ST), événement cardiaque majeur (MACE) incluant décès CV, infarctus, accident vasculaire cérébral et TLR ont été analysés à un an. Résultats. — On note que 1376 patients consécutifs ont été traités par PCI en 18 mois : 534 (39 %), 492 (36 %), 224 (16 %) et 126 (9 %) patients ont été répartis dans les groupes BMS, DES, BMS CRF et DES CRF. Les patients traités par DES avaient un plus haut risque de resténose. Le BMS était préférentiellement utilisé en phase aiguë d’infarctus. À un an, le taux de décès CV était de 6,2 %, avec 15,8 % de MACE, 7,3 % de TLR et 1,1 % de ST. Les décès CV et MACE étaient moins fréquents dans les groupes avec DES. Dans le groupe avec CRF, le taux de TLR était comparable avec BMS et DES (9,8 % vs 7,1 % ; p = 0,44). Il n’a pas été observé d’excès de ST avec le DES, et l’utilisation de DES était associée de manière indépendante à un moindre risque de MACE et TLR. Conclusion. — Chez les patients avec CRF, le DES apparaît au moins aussi efficace que le BMS, malgré un profil plus à risque de resténose, sans excès de ST à un an. © 2011 Elsevier Masson SAS. Tous droits réservés.
Background Patients with chronic renal failure (CRF) carry the risk of severe coronary artery disease, with cardiovascular death accounting for almost 50% of the total mortality in this population [1,2]. Outcomes after percutaneous coronary intervention (PCI) —– with balloon or bare metal stents (BMS) —– remain poor compared with in patients with normal renal function [1,3], with no prognostic benefit demonstrated with this revascularization strategy [4]. Some authors report an increased rate of silent in-stent restenosis in CRF patients, which could partly explain these adverse outcomes [1]. Drug-eluting stents (DES) dramatically decrease the rates of in-stent restenosis and subsequent target lesion revascularization (TLR) compared with BMS in the general population [5,6]. However, little is known about the subset of patients with CRF. The purpose of the present study was to assess the efficacy and safety of DES (vs BMS) in the contemporary practice of PCI (elective or urgent) in a consecutive, non-selected population of patients with CRF.
Patients and methods Patient population All patients treated by PCI with at least one stent in our institution were included between August 2007 and January 2009. This was an ‘‘all-comers’’, prospective, single-centre registry. Patients treated by balloon angioplasty without
subsequent stent implantation (n = 68) were excluded. During the 1-year follow-up period, new PCIs were counted as outcomes (n = 124). Clinical and angiographical data were prospectively entered into the web-based ‘‘Middle Care’’ database. Aspirin and clopidogrel pretreatment or loading dose (300 to 900 mg) was given before PCI. Periprocedural 0.9% saline intravenous perfusion (100 mL/hour) was achieved 12 hours before and after PCI, except in patients with congestive heart failure. All patients —– except those previously treated by vitamin K antagonists —– received intravenous low molecular weight heparin during PCI. The use of glycoprotein IIb/IIIa inhibitors was left to the operators’ discretion; they were mostly used in cases of primary PCI for ongoing stent thrombosis (ST)-segment elevation myocardial infarction, in high-risk acute coronary syndrome patients or in bail-out situations. PCI was performed according to standard guidelines, mostly by the radial approach, using five or six French sheaths with systematic stent implantation (unless inappropriate). The usual aspirin maintenance dose was 75 mg/day while the daily clopidogrel dose was 75 to 150 mg. Dual antiplatelet therapy was maintained for 12 months in cases of acute coronary syndrome or DES implantation and could be switched to single antithrombotic therapy after 1 month in cases of BMS implantation in a non-urgent setting.
Patient assessments Patients were allocated to four patient groups according to the stent used (BMS versus DES) and renal function (CRF
606 vs NO CRF). Chronic renal failure was defined as creatinine clearance (CrCl) less than 60 mL/minute calculated with the Cockroft formula. Patients treated with both DES and BMS were allocated to the DES groups. Death was defined as death from any cause. Cardiovascular death was defined as death from cardiovascular cause or sudden death without extracardiovascular cause. Myocardial infarction was defined as recurrent chest pain and/or electrocardiogram changes with at least one of the following criteria: creatine kinase and troponin I ≥ 2 times the upper limit of normal with an increase of more than 50% of the prior value; and the appearance of a new left bundle-branch block or new Q waves. Stroke was defined as an acute neurological deficit lasting for more than 24 hours, classified by neurological evaluation. Clinical TLR was defined as new revascularization of the treated lesion mandated by clinical symptoms or documented ischaemia. Major adverse cardiac events (MACE) were defined as the composite of cardiovascular death, myocardial infarction, stroke and TLR. Stent thrombosis (ST) was defined as definite ST according to the American Research Consortium criteria [7].
Cardiovascular events The primary endpoint was the rate of MACE and the secondary endpoint was the rate of TLR at 1 year. The safety endpoint was the rate of ST at 1 year. One-year clinical outcomes were obtained by medical consultation, from the rehospitalization medical report or by telephone call.
Statistical analyses Categorical variables are expressed as numbers and percentages (%); continuous variables are expressed as means ± standard deviations. Univariate analyses were performed using the chi-square test for categorical variables and Student’s t test for continuous variables. Kaplan-Meier curves were drawn using GraphPad Prism (version 5.01 for Windows; GraphPad Software, San Diego, CA, USA). Multivariable analyses were performed using a multiple logistic regression model. The statistical analyses were performed with Statview software (version 5.0; SAS Institute Inc., Cary, NC, USA).
O. Barthelemy et al. older, were women and had a lower body mass index, more hypertension and more prior stroke but were less likely to be current smokers or to have a family history of coronary artery disease. Patients underwent PCI mostly for acute coronary syndrome (n = 728) but patients with CRF were more likely to be in cardiogenic shock or out-of-hospital cardiac arrest at entrance. The radial artery was the main access for PCI (n = 1087), although radial PCI was used slightly less frequently in patients with CRF. Patients with CRF had multivessel disease more frequently, with stenosis more often located on the left main or left anterior descending artery. The number, length and diameter of stents (per patient) were not significantly different, whatever the renal function.
Chronic renal failure subgroups CRF patients treated with DES had twice more history of PCI and were rarely treated for acute myocardial infarction or cardiogenic shock compared with those treated with BMS. In this CRF subset, the average stent diameter was significantly lower in DES patients versus BMS patients and the stent length was greater, although not significantly.
One-year outcomes One-year outcomes are shown in Fig. 1. Follow-up was completed for 1338 patients (97.2%) at 1 year. During that period, 118 (8.6%) patients died, 85 (6.2%) from a cardiovascular cause, 218 (15.8%) had MACE and 101 (7.3%) had TLR. Definite ST occurred in 20 (1.5%), probable ST in four (0.5%) and possible ST in 12 (0.9%) patients.
Chronic renal failure patients versus NO chronic renal failure patients Patients with CRF had an increased risk of cardiovascular death and MACE at 1 year, with a stepwise increase according to CrCl (3.4% and 12.3% in patients with CrCl ≥ 60 mL/minute;12.8% and 25.5% in patients with 30 mL/minute ≤ CrCl < 60 mL/minute; 20.3% and 28.8% in patients with CrCl < 30 mL/minute, respectively). Definite ST occurred in 2.8% (n = 15) of the NO CRF-BMS group, 0.4% (n = 1) of the NO
Results Baseline characteristics Among the 1376 consecutive patients who underwent PCI with stent implantation in our institution, 534 (39%), 492 (36%), 224 (16%) and 126 (9%) patients were allocated to the NO CRF-BMS, NO CRF-DES, CRF-BMS and CRF-DES groups, respectively. Baseline clinical and procedural characteristics according to renal function and stent type are shown in Table 1.
Chronic renal failure patients versus NO chronic renal failure patients Among the 350 patients with renal dysfunction, 63 (18%) had severe renal failure (CrCl < 30 mL/minute) and 38 (11%) were on dialysis. More frequently, patients with CRF were
Figure 1. Event rates according to renal function and stent type (unadjusted). BMS: bare metal stent; CV: cardiovascular; DES: drug-eluting stent; MACE: major adverse cardiac events; ST: stent thrombosis; TLR: target lesion revascularization.
DES in renal failure patients Table 1
607
Baseline clinical and procedural characteristics according to renal function and the type of stent (n = 1376).
Age (years) Women BMI Diabetes Dyslipidaemia Current smoker Hypertension Hx of CAD Prior MI Prior PCI Prior CABG Prior stroke Creatinine CrCl Dialysis ACS AMI Cardiogenic shock Out-of-hospital cardiac arrest Radial access Multivessel disease LM LAD Circ RCA Graft Number of stents/patient Total stent length/patient Average stent diameter/patient Cypher© Taxus© Endeavor© Other DES
CRF-BMS (n = 224; 16%)
CRF-DES (n = 126; 9%)
NO CRF-BMS (n = 534; 39%)
NO CRF-DES (n = 492; 36%)
P
75 ± 11 76 (34) 25 ± 4 57 (25) 121 (54) 28 (13) 146 (65) 16 (7) 42 (19) 44 (20) 22 (10) 25 (11) 157 ± 137 42 ± 13 22 (10) 67 (30) 59 (27) 25 (11) 9 (4) 169 (82) 143 (64) 19 (8) 163 (73) 102 (46) 127 (57) 61 (27) 1.6 ± 0.9 25 ± 18 2.9 ± 0.4 — — — —
72 ± 11 39 (31) 24 ± 4 40 (32) 81 (64) 15 (12) 98 (78) 17 (13) 27 (21) 57 (45) 11 (9) 7 (6) 162 ± 141 42 ± 14 16 (15) 50 (41) 1 (1) 1 (8) 1 (1) 90 (81) 72 (57) 7 (6) 82 (65) 54 (43) 67 (53) 27 (21) 1.7 ± 0.9 27 ± 17 2.7 ± 0.4 38 (30) 47 (37) 46 (37) 12 (10)
62 ± 12 93 (17) 27 ± 5 123 (23) 271 (51) 210 (39) 280 (53) 91 (17) 86 (16) 78 (15) 33 (6) 32 (6) 78 ± 18 98 ± 32 — 151 (29) 189 (36) 18 (3) 9 (2) 425 (88) 253 (48) 14 (3) 318 (59) 214 (40) 289 (54) 95 (18) 1.5 ± 0.8 23 ± 14 3.0 ± 1.0 — — — —
61 ± 11 77 (16) 27 ± 4 145 (30) 331 (67) 149 (30) 272 (55) 110 (22) 124 (25) 182 (37) 40 (8) 16 (3) 78 ± 17 100 ± 31 — 174 (36) 37 (8) 1 (0) 1 (0) 403 (90) 297 (61) 21 (4) 337 (68) 219 (45) 248 (50) 121 (25) 1.7 ± 1.0 28 ± 19 2.8 ± 0.8 174 (35) 174 (35) 201 (41) 30 (6)
< 0.0001 < 0.0001 < 0.0001 0.056 < 0.0001 < 0.0001 < 0.0001 < 0.0001 0.004 < 0.0001 0.325 0.0005 < 0.0001 < 0.0001 — 0.010 < 0.0001 < 0.0001 0.001 0.009 < 0.0001 0.004 0.001 0.410 0.417 0.011 0.002 < 0.0001 0.006 0.273 0.686 0.375 0.173
Data are mean ± standard deviation or number (%). ACS: acute coronary syndrome; AMI: acute myocardial infarction; BMI: body mass index; BMS: bare metal stent; CABG: coronary artery bypass surgery; Circ: circumflex artery; CrCl: creatinine clearance; CRF: chronic renal failure; DES: drug-eluting stent; Hx of CAD: family history of coronary artery disease; LAD: left anterior descending artery; LM: left main; MI: myocardial infarction; PCI: percutaneous coronary intervention; RCA, right coronary artery.
CRF-DES group, 1.3% (n = 3) of the CRF-BMS group and 0.8% (n = 1) of the CRF-DES group. In cases of BMS implantation, definite ST occurred within the first month after PCI in 72% (n = 13). The two DES thromboses occurred after the fifth month.
Chronic renal failure subgroups Among CRF patients, the use of DES was significantly associated with a lower rate of outcomes, with a trend for less TLR without any increase in ST at 1 year. Kaplan-Meier MACE-free survival curves according to renal function and stent type are shown in Fig. 2.
Independent predictors After multivariable analyses (Table 2) of the entire cohort, the use of DES appeared to be significantly associated with
the absence of MACE (Odds Ratio [OR] 0.376, 95% confidence interval [CI] 0.252—0.561) and TLR (OR 0.386, 95% CI 0.242—0.615) at 1 year. The other independent predictors of MACE were cardiogenic shock, out-of-hospital cardiac arrest and radial PCI, with an additional trend towards an excess of MACE in CRF patients (OR 1.483, 95% CI 0.990—2.221). Prior PCI was independently correlated with TLR.
Discussion The main finding of our study is that in the contemporary practice of elective and urgent PCI, the use of DES in nonselected patients with CRF appears to be as least as effective and safe as BMS at 1 year, although these patients carry a higher risk of restenosis. DES is independently associated with the absence of MACE and TLR. Patients with CRF do not
608
O. Barthelemy et al.
Figure 2. One-year event-free survival according to renal function and the type of stent (Kaplan-Meier). BMS: bare metal stent; CRF: chronic renal failure; DES: drug-eluting stent; MACE: major adverse cardiac events.
have any excess of definite ST within 1 year compared with patients with normal renal function. It is well established that patients with CRF have a worse prognosis compared with patients with normal renal function [1,2,8,9], a finding that we clearly report in our study, with a two-fold increase in MACE and a four-fold increase in the cardiovascular death rate in cases of CRF. Our patients with CRF carry a higher risk of adverse events, with more comorbidities (older age, more hypertension) but also more severe cardiovascular disease (more cardiogenic shock and out-of-hospital cardiac arrest at entrance, with more multivessel disease). However, other factors specific
to CRF —– hyperparathyroidism, hyperhomocysteinaemia, coagulation problems, etc. —– are known to be involved in this unfavourable outcome [1,2,10]. This excess of events is mostly driven by an excess of cardiovascular death (14.0% in CRF vs 3.4%), a finding that has already been widely reported, with non-ischaemia-related cardiac death occurring with high frequency [11]. In our study, CRF was associated with adverse outcomes, although not significantly (P = 0.056) due to a lack of power and a predominant causal effect of other covariables (such as cardiogenic shock or DES) on the prognosis. Data on outcomes in patients with CRF undergoing PCI are sparse. Indeed, CRF is usually an exclusion criterion in randomized trials and no dedicated randomized study has been done in this setting. PCI remains more difficult in cases of CRF, with poor long-term results [1,12,13] and more periprocedural complications, especially at the arterial puncture site [8,14,15]. There is growing evidence that radial access for PCI leads to fewer bleeding complications and a better outcome [16—18]. In our study, more than 80% of CRF patients had PCI by the radial approach and radial PCI was found to be an independent predictor of survival without MACE (OR 0.59). Although our study cannot conclude on this issue, results suggest a benefit for the systematic use of radial access for PCI, except in patients with an arteriovenous fistula for ongoing dialysis. PCI (with balloon, BMS or DES) has never demonstrated any survival benefit in patients with CRF [1,3,4]. In stable patients, PCI with DES appears to have no beneficial effect on hard events compared with optimal medical therapy alone [4]. In fact, as previously suggested, noncardiovascular deaths account widely for mortality in these patients and PCI has no impact on it. The lower cardiovascular death and MACE rates we observed in our study are
Table 2 Independent predictors of major adverse cardiac events and target lesion revascularization at 1 year (logistic regression). Variables
Odds Ratio
95% CI
P
Predictors of MACE Age Family history of CAD Acute MI Cardiogenic shock Out-of-hospital cardiac arrest CrCl < 60 mL/minute Radial access Multivessel disease DES Number of stents Total stent length
1.007 0.683 0.866 8.407 5.283 1.483 0.590 1.364 0.376 1.119 1.010
0.991—1.022 0.406—1.148 0.568—1.321 3.581—19.734 1.625—17.182 0.990—2.221 0.369—0.945 0.943—1.973 0.252—0.561 0.760—1.647 0.988—1.031
0.395 0.151 0.505 < 0.0001 0.006 0.056 0.028 0.099 < 0.0001 0.570 0.376
Predictors of TLR Prior angioplasty DES Number of stents Total stent length
2.074 0.386 1.277 1.010
1.309—3.286 0.242—0.615 0.845—1.938 0.987—1.033
0.002 < 0.0001 0.401 0.376
a
CAD: coronary artery disease; CrCl: creatinine clearance; DES, drug-eluting stent; MACE: major adverse cardiac events; MI: myocardial infarction; TLR: target lesion revascularization. a CV death, non-fatal MI, non-fatal stroke and TLR.
DES in renal failure patients due to the discrepancy in baseline characteristics. Patients treated with DES were less likely to have acute myocardial infarction and other comorbidities (bleeding diasthesis, planned surgery, poor compliance, etc.). Restenosis remains a matter of concern in patients with CRF, occurring in up to 60% of cases, although it does not seem to lead to more subsequent revascularization than in the general population [19,20]. However, it has been hypothesized that severe silent ischaemia due to angiographic restenosis may account for this increased cardiac mortality [1]. Large randomized trials and pooled analyses have shown a dramatic decrease in restenosis and subsequent TLR rates in the general population with DES versus BMS. Whether or not this finding applies to CRF patients remains unclear. Only small, often retrospective studies have been conducted, with controversial results, some reporting reduced TLR and/or in-stent restenosis rates [21—24], while others not [25—27]. In our study —– one of the largest to our knowledge —– we did not observe any significant reduction in the TLR rate after DES implantation in CRF patients (7% vs 10% with BMS; P = 0.44). This may be due to a lack of power and the discrepancy in baseline clinical and angiographical characteristics between groups in this ‘‘all-comers’’ registry, with a higher restenosis risk profile in the DES group (more prior PCI, more small stent diameters; Table 1). Indeed, DES appears to be independently associated with a 60% decrease in TLR in the entire cohort. DES was also found to be independently associated with the absence of ischaemic events (OR 0.376) at 1 year, suggesting its additional value in patients with CRF. As previously reported, we did not observe any excess of definite ST (American Research Consortium definition) [7] with DES at 1 year in the CRF group compared with BMS [21,23,24]. However, our study was not designed to assess whether or not DES increased late ST rates in CRF patients, which remains a major concern in this setting, with longer follow-up needed [28,29]. Although CRF is an independent predictor of ST, we did not observe any excess of ST at 1 year between CRF and NO CRF patients [30].
Limitations The strengths of the present study are the relative high sample size in this setting, the consecutive and prospective inclusion and the nearly complete 1-year follow-up. However, several limitations inherent to registry data exist. This was an observational, non-controlled, non-randomized study. Some patients allocated to the DES groups had concomitant BMS implantation during the same procedure; however, this accounts for only a few patients (n = 59, 4.2%). This was an all-comers, single-centre registry, with stent type (especially DES) left to the operators’ discretion; our results therefore reflect ‘‘real life’’ practice but cannot be generalized to other practice and do not compare a type of DES with BMS. Medication data, especially the duration of dual antiplatelet therapy, were not systematically collected.
Conclusion In patients with CRF, the use of DES for PCI appears to be at least as effective as BMS, with no increase in ST at 1 year.
609 However, a larger, randomized trial with long-term follow-up is needed in this setting.
Disclosure of interest Dr. Silvain has received research grants from Sanofi-aventis, Daiichi-Sankyo, Eli Lilly, INSERM, the FFC and the Société franc ¸aise de cardiologie; consultant fees from DaiichiSankyo and Eli Lilly; and lecture fees from AstraZeneca, Daiichi-Sankyo and Eli Lilly. Dr. Beygui has received lecture fees from Roche, Sanofi-aventis, Pfizer and Astellas. Dr. Collet has received research grants (to the institution) from Bristol-Myers Squibb, sanofi-aventis, Eli Lilly, Guerbet Medical, Medtronic, Boston Scientific, Cordis, Stago, Fondation de France, INSERM, the FFC and the Société franc ¸aise de cardiologie; has served as a consultant (honoraria for past 2 years) for Sanofi-aventis, Eli Lilly and Bristol-Myers Squibb; and has received lecture fees from Bristol-Myers Squibb, sanofi-aventis and Eli Lilly. Dr. Montalescot has received research grants (to the institution) from Bristol-Myers Squibb, Sanofi-aventis, Eli Lilly, Guerbet Medical, Medtronic, Boston Scientific, Cordis, Stago, Centocor, fondation de France, Inserm, the FFC, the Société franc ¸aise de cardiologie, ITC Edison and Pfizer; and consulting or lecture fees from Accumetrics, AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Eisai, Eli Lilly, Menarini, MSD, Novartis, Portola, Sanofiaventis, Schering-Plough and The Medicines Company.
Acknowledgements The authors received a grant from the Fédération franc ¸aise de cardiologie (FFC). The FFC had no role in the study design, in the collection, analysis and interpretation of data or in the writing of this report.
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CLINICAL RESEARCH
One-year clinical outcomes in patients with chronic renal failure treated by percutaneous coronary intervention with drug-eluting stent Résultats cliniques à un an de l’angioplastie coronaire avec stent actif chez les patients avec insuffisance rénale chronique Olivier Barthelemy , Gérard Helft , Johanne Silvain , Anne Bellemain-Appaix , Farzin Beygui , Rémi Choussat , Emmanuel Berman , Jean-Philippe Collet , Gilles Montalescot , Jean-Philippe Metzger , Claude Le Feuvre ∗ Centre hospitalier universitaire Pitié-Salpêtrière, AP—HP, institut de cardiologie, 47, boulevard de l’hôpital, 75013 Paris, France Received 3 December 2010; received in revised form 9 May 2011; accepted 9 May 2011
KEYWORDS Renal failure; Percutaneous coronary intervention; Drug-eluting stent; Thrombosis
∗
Summary Background. — It is unknown whether the efficacy and safety of drug-eluting stents (DES) apply in patients with chronic renal failure (CRF). Aims. — To compare DES with bare metal stents (BMS) for percutaneous coronary intervention (PCI) in CRF patients. Patients and methods. — Consecutive patients treated by PCI were allocated to four groups according to type of stent used (DES versus BMS) and creatinine clearance (CrCl). CRF was defined as CrCl less than 60 mL/minute. Cardiovascular death, major adverse cardiac events (MACE, defined as cardiovascular death, myocardial infarction, stroke and target lesion revascularization [TLR]), TLR and definite stent thrombosis (ST) were recorded at 1 year. Results. — We note that 1376 consecutive patients underwent PCI with stent within 18 months: 534 (39%) and 492 (36%) patients without CRF and 224 (16%) and 126 (9%) patients with CRF were treated with BMS and DES, respectively. In the entire cohort, patients treated with DES had a higher restenosis risk profile. BMS were predominantly (87%) used for ST-segment elevation myocardial infarction. At 1 year, 6.2% had cardiovascular death, 15.8% MACE, 7.3% TLR and 1.5% ST. Cardiovascular death and MACE occurred less frequently in DES groups. The TLR rate was not significantly different in the CRF groups (BMS 9.8% vs DES 7.1%; P = 0.44). No excess of ST
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1875-2136/$ — see front matter © 2011 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.acvd.2011.05.010
DES in renal failure patients
605 was observed in the DES groups and use of DES was independently associated with absence of MACE and TLR. Conclusions. — In patients with CRF, DES appear to be at least as effective as BMS —– despite a higher restenosis risk profile —– with no excess of ST at 1 year. © 2011 Elsevier Masson SAS. All rights reserved.
MOTS CLÉS Insuffisance rénale ; Angioplastie coronaire ; Stent actif ; Thrombose
Résumé Context. — Peu de données sont disponibles sur l’efficacité et la sécurité des stents actifs (DES) chez les patients avec insuffisance rénale (CRF). Objectif Comparer DES et stents nus (BMS) lors de l’angioplastie coronaire (PCI) chez les patients avec CRF. Patients et méthodes. — Une série consécutive de patients traités par PCI ont été répartis en quatre groupes selon le stent utilisé (DES ou BMS), et la clairance de la créatinine (CrCl). CRF était défini par une CrCl inférieure à 60 mL/min. Les décès cardiovasculaire (CV), revascularisation de la lésion cible (TLR), thrombose certaine de stent (ST), événement cardiaque majeur (MACE) incluant décès CV, infarctus, accident vasculaire cérébral et TLR ont été analysés à un an. Résultats. — On note que 1376 patients consécutifs ont été traités par PCI en 18 mois : 534 (39 %), 492 (36 %), 224 (16 %) et 126 (9 %) patients ont été répartis dans les groupes BMS, DES, BMS CRF et DES CRF. Les patients traités par DES avaient un plus haut risque de resténose. Le BMS était préférentiellement utilisé en phase aiguë d’infarctus. À un an, le taux de décès CV était de 6,2 %, avec 15,8 % de MACE, 7,3 % de TLR et 1,1 % de ST. Les décès CV et MACE étaient moins fréquents dans les groupes avec DES. Dans le groupe avec CRF, le taux de TLR était comparable avec BMS et DES (9,8 % vs 7,1 % ; p = 0,44). Il n’a pas été observé d’excès de ST avec le DES, et l’utilisation de DES était associée de manière indépendante à un moindre risque de MACE et TLR. Conclusion. — Chez les patients avec CRF, le DES apparaît au moins aussi efficace que le BMS, malgré un profil plus à risque de resténose, sans excès de ST à un an. © 2011 Elsevier Masson SAS. Tous droits réservés.
Background Patients with chronic renal failure (CRF) carry the risk of severe coronary artery disease, with cardiovascular death accounting for almost 50% of the total mortality in this population [1,2]. Outcomes after percutaneous coronary intervention (PCI) —– with balloon or bare metal stents (BMS) —– remain poor compared with in patients with normal renal function [1,3], with no prognostic benefit demonstrated with this revascularization strategy [4]. Some authors report an increased rate of silent in-stent restenosis in CRF patients, which could partly explain these adverse outcomes [1]. Drug-eluting stents (DES) dramatically decrease the rates of in-stent restenosis and subsequent target lesion revascularization (TLR) compared with BMS in the general population [5,6]. However, little is known about the subset of patients with CRF. The purpose of the present study was to assess the efficacy and safety of DES (vs BMS) in the contemporary practice of PCI (elective or urgent) in a consecutive, non-selected population of patients with CRF.
Patients and methods Patient population All patients treated by PCI with at least one stent in our institution were included between August 2007 and January 2009. This was an ‘‘all-comers’’, prospective, single-centre registry. Patients treated by balloon angioplasty without
subsequent stent implantation (n = 68) were excluded. During the 1-year follow-up period, new PCIs were counted as outcomes (n = 124). Clinical and angiographical data were prospectively entered into the web-based ‘‘Middle Care’’ database. Aspirin and clopidogrel pretreatment or loading dose (300 to 900 mg) was given before PCI. Periprocedural 0.9% saline intravenous perfusion (100 mL/hour) was achieved 12 hours before and after PCI, except in patients with congestive heart failure. All patients —– except those previously treated by vitamin K antagonists —– received intravenous low molecular weight heparin during PCI. The use of glycoprotein IIb/IIIa inhibitors was left to the operators’ discretion; they were mostly used in cases of primary PCI for ongoing stent thrombosis (ST)-segment elevation myocardial infarction, in high-risk acute coronary syndrome patients or in bail-out situations. PCI was performed according to standard guidelines, mostly by the radial approach, using five or six French sheaths with systematic stent implantation (unless inappropriate). The usual aspirin maintenance dose was 75 mg/day while the daily clopidogrel dose was 75 to 150 mg. Dual antiplatelet therapy was maintained for 12 months in cases of acute coronary syndrome or DES implantation and could be switched to single antithrombotic therapy after 1 month in cases of BMS implantation in a non-urgent setting.
Patient assessments Patients were allocated to four patient groups according to the stent used (BMS versus DES) and renal function (CRF
606 vs NO CRF). Chronic renal failure was defined as creatinine clearance (CrCl) less than 60 mL/minute calculated with the Cockroft formula. Patients treated with both DES and BMS were allocated to the DES groups. Death was defined as death from any cause. Cardiovascular death was defined as death from cardiovascular cause or sudden death without extracardiovascular cause. Myocardial infarction was defined as recurrent chest pain and/or electrocardiogram changes with at least one of the following criteria: creatine kinase and troponin I ≥ 2 times the upper limit of normal with an increase of more than 50% of the prior value; and the appearance of a new left bundle-branch block or new Q waves. Stroke was defined as an acute neurological deficit lasting for more than 24 hours, classified by neurological evaluation. Clinical TLR was defined as new revascularization of the treated lesion mandated by clinical symptoms or documented ischaemia. Major adverse cardiac events (MACE) were defined as the composite of cardiovascular death, myocardial infarction, stroke and TLR. Stent thrombosis (ST) was defined as definite ST according to the American Research Consortium criteria [7].
Cardiovascular events The primary endpoint was the rate of MACE and the secondary endpoint was the rate of TLR at 1 year. The safety endpoint was the rate of ST at 1 year. One-year clinical outcomes were obtained by medical consultation, from the rehospitalization medical report or by telephone call.
Statistical analyses Categorical variables are expressed as numbers and percentages (%); continuous variables are expressed as means ± standard deviations. Univariate analyses were performed using the chi-square test for categorical variables and Student’s t test for continuous variables. Kaplan-Meier curves were drawn using GraphPad Prism (version 5.01 for Windows; GraphPad Software, San Diego, CA, USA). Multivariable analyses were performed using a multiple logistic regression model. The statistical analyses were performed with Statview software (version 5.0; SAS Institute Inc., Cary, NC, USA).
O. Barthelemy et al. older, were women and had a lower body mass index, more hypertension and more prior stroke but were less likely to be current smokers or to have a family history of coronary artery disease. Patients underwent PCI mostly for acute coronary syndrome (n = 728) but patients with CRF were more likely to be in cardiogenic shock or out-of-hospital cardiac arrest at entrance. The radial artery was the main access for PCI (n = 1087), although radial PCI was used slightly less frequently in patients with CRF. Patients with CRF had multivessel disease more frequently, with stenosis more often located on the left main or left anterior descending artery. The number, length and diameter of stents (per patient) were not significantly different, whatever the renal function.
Chronic renal failure subgroups CRF patients treated with DES had twice more history of PCI and were rarely treated for acute myocardial infarction or cardiogenic shock compared with those treated with BMS. In this CRF subset, the average stent diameter was significantly lower in DES patients versus BMS patients and the stent length was greater, although not significantly.
One-year outcomes One-year outcomes are shown in Fig. 1. Follow-up was completed for 1338 patients (97.2%) at 1 year. During that period, 118 (8.6%) patients died, 85 (6.2%) from a cardiovascular cause, 218 (15.8%) had MACE and 101 (7.3%) had TLR. Definite ST occurred in 20 (1.5%), probable ST in four (0.5%) and possible ST in 12 (0.9%) patients.
Chronic renal failure patients versus NO chronic renal failure patients Patients with CRF had an increased risk of cardiovascular death and MACE at 1 year, with a stepwise increase according to CrCl (3.4% and 12.3% in patients with CrCl ≥ 60 mL/minute;12.8% and 25.5% in patients with 30 mL/minute ≤ CrCl < 60 mL/minute; 20.3% and 28.8% in patients with CrCl < 30 mL/minute, respectively). Definite ST occurred in 2.8% (n = 15) of the NO CRF-BMS group, 0.4% (n = 1) of the NO
Results Baseline characteristics Among the 1376 consecutive patients who underwent PCI with stent implantation in our institution, 534 (39%), 492 (36%), 224 (16%) and 126 (9%) patients were allocated to the NO CRF-BMS, NO CRF-DES, CRF-BMS and CRF-DES groups, respectively. Baseline clinical and procedural characteristics according to renal function and stent type are shown in Table 1.
Chronic renal failure patients versus NO chronic renal failure patients Among the 350 patients with renal dysfunction, 63 (18%) had severe renal failure (CrCl < 30 mL/minute) and 38 (11%) were on dialysis. More frequently, patients with CRF were
Figure 1. Event rates according to renal function and stent type (unadjusted). BMS: bare metal stent; CV: cardiovascular; DES: drug-eluting stent; MACE: major adverse cardiac events; ST: stent thrombosis; TLR: target lesion revascularization.
DES in renal failure patients Table 1
607
Baseline clinical and procedural characteristics according to renal function and the type of stent (n = 1376).
Age (years) Women BMI Diabetes Dyslipidaemia Current smoker Hypertension Hx of CAD Prior MI Prior PCI Prior CABG Prior stroke Creatinine CrCl Dialysis ACS AMI Cardiogenic shock Out-of-hospital cardiac arrest Radial access Multivessel disease LM LAD Circ RCA Graft Number of stents/patient Total stent length/patient Average stent diameter/patient Cypher© Taxus© Endeavor© Other DES
CRF-BMS (n = 224; 16%)
CRF-DES (n = 126; 9%)
NO CRF-BMS (n = 534; 39%)
NO CRF-DES (n = 492; 36%)
P
75 ± 11 76 (34) 25 ± 4 57 (25) 121 (54) 28 (13) 146 (65) 16 (7) 42 (19) 44 (20) 22 (10) 25 (11) 157 ± 137 42 ± 13 22 (10) 67 (30) 59 (27) 25 (11) 9 (4) 169 (82) 143 (64) 19 (8) 163 (73) 102 (46) 127 (57) 61 (27) 1.6 ± 0.9 25 ± 18 2.9 ± 0.4 — — — —
72 ± 11 39 (31) 24 ± 4 40 (32) 81 (64) 15 (12) 98 (78) 17 (13) 27 (21) 57 (45) 11 (9) 7 (6) 162 ± 141 42 ± 14 16 (15) 50 (41) 1 (1) 1 (8) 1 (1) 90 (81) 72 (57) 7 (6) 82 (65) 54 (43) 67 (53) 27 (21) 1.7 ± 0.9 27 ± 17 2.7 ± 0.4 38 (30) 47 (37) 46 (37) 12 (10)
62 ± 12 93 (17) 27 ± 5 123 (23) 271 (51) 210 (39) 280 (53) 91 (17) 86 (16) 78 (15) 33 (6) 32 (6) 78 ± 18 98 ± 32 — 151 (29) 189 (36) 18 (3) 9 (2) 425 (88) 253 (48) 14 (3) 318 (59) 214 (40) 289 (54) 95 (18) 1.5 ± 0.8 23 ± 14 3.0 ± 1.0 — — — —
61 ± 11 77 (16) 27 ± 4 145 (30) 331 (67) 149 (30) 272 (55) 110 (22) 124 (25) 182 (37) 40 (8) 16 (3) 78 ± 17 100 ± 31 — 174 (36) 37 (8) 1 (0) 1 (0) 403 (90) 297 (61) 21 (4) 337 (68) 219 (45) 248 (50) 121 (25) 1.7 ± 1.0 28 ± 19 2.8 ± 0.8 174 (35) 174 (35) 201 (41) 30 (6)
< 0.0001 < 0.0001 < 0.0001 0.056 < 0.0001 < 0.0001 < 0.0001 < 0.0001 0.004 < 0.0001 0.325 0.0005 < 0.0001 < 0.0001 — 0.010 < 0.0001 < 0.0001 0.001 0.009 < 0.0001 0.004 0.001 0.410 0.417 0.011 0.002 < 0.0001 0.006 0.273 0.686 0.375 0.173
Data are mean ± standard deviation or number (%). ACS: acute coronary syndrome; AMI: acute myocardial infarction; BMI: body mass index; BMS: bare metal stent; CABG: coronary artery bypass surgery; Circ: circumflex artery; CrCl: creatinine clearance; CRF: chronic renal failure; DES: drug-eluting stent; Hx of CAD: family history of coronary artery disease; LAD: left anterior descending artery; LM: left main; MI: myocardial infarction; PCI: percutaneous coronary intervention; RCA, right coronary artery.
CRF-DES group, 1.3% (n = 3) of the CRF-BMS group and 0.8% (n = 1) of the CRF-DES group. In cases of BMS implantation, definite ST occurred within the first month after PCI in 72% (n = 13). The two DES thromboses occurred after the fifth month.
Chronic renal failure subgroups Among CRF patients, the use of DES was significantly associated with a lower rate of outcomes, with a trend for less TLR without any increase in ST at 1 year. Kaplan-Meier MACE-free survival curves according to renal function and stent type are shown in Fig. 2.
Independent predictors After multivariable analyses (Table 2) of the entire cohort, the use of DES appeared to be significantly associated with
the absence of MACE (Odds Ratio [OR] 0.376, 95% confidence interval [CI] 0.252—0.561) and TLR (OR 0.386, 95% CI 0.242—0.615) at 1 year. The other independent predictors of MACE were cardiogenic shock, out-of-hospital cardiac arrest and radial PCI, with an additional trend towards an excess of MACE in CRF patients (OR 1.483, 95% CI 0.990—2.221). Prior PCI was independently correlated with TLR.
Discussion The main finding of our study is that in the contemporary practice of elective and urgent PCI, the use of DES in nonselected patients with CRF appears to be as least as effective and safe as BMS at 1 year, although these patients carry a higher risk of restenosis. DES is independently associated with the absence of MACE and TLR. Patients with CRF do not
608
O. Barthelemy et al.
Figure 2. One-year event-free survival according to renal function and the type of stent (Kaplan-Meier). BMS: bare metal stent; CRF: chronic renal failure; DES: drug-eluting stent; MACE: major adverse cardiac events.
have any excess of definite ST within 1 year compared with patients with normal renal function. It is well established that patients with CRF have a worse prognosis compared with patients with normal renal function [1,2,8,9], a finding that we clearly report in our study, with a two-fold increase in MACE and a four-fold increase in the cardiovascular death rate in cases of CRF. Our patients with CRF carry a higher risk of adverse events, with more comorbidities (older age, more hypertension) but also more severe cardiovascular disease (more cardiogenic shock and out-of-hospital cardiac arrest at entrance, with more multivessel disease). However, other factors specific
to CRF —– hyperparathyroidism, hyperhomocysteinaemia, coagulation problems, etc. —– are known to be involved in this unfavourable outcome [1,2,10]. This excess of events is mostly driven by an excess of cardiovascular death (14.0% in CRF vs 3.4%), a finding that has already been widely reported, with non-ischaemia-related cardiac death occurring with high frequency [11]. In our study, CRF was associated with adverse outcomes, although not significantly (P = 0.056) due to a lack of power and a predominant causal effect of other covariables (such as cardiogenic shock or DES) on the prognosis. Data on outcomes in patients with CRF undergoing PCI are sparse. Indeed, CRF is usually an exclusion criterion in randomized trials and no dedicated randomized study has been done in this setting. PCI remains more difficult in cases of CRF, with poor long-term results [1,12,13] and more periprocedural complications, especially at the arterial puncture site [8,14,15]. There is growing evidence that radial access for PCI leads to fewer bleeding complications and a better outcome [16—18]. In our study, more than 80% of CRF patients had PCI by the radial approach and radial PCI was found to be an independent predictor of survival without MACE (OR 0.59). Although our study cannot conclude on this issue, results suggest a benefit for the systematic use of radial access for PCI, except in patients with an arteriovenous fistula for ongoing dialysis. PCI (with balloon, BMS or DES) has never demonstrated any survival benefit in patients with CRF [1,3,4]. In stable patients, PCI with DES appears to have no beneficial effect on hard events compared with optimal medical therapy alone [4]. In fact, as previously suggested, noncardiovascular deaths account widely for mortality in these patients and PCI has no impact on it. The lower cardiovascular death and MACE rates we observed in our study are
Table 2 Independent predictors of major adverse cardiac events and target lesion revascularization at 1 year (logistic regression). Variables
Odds Ratio
95% CI
P
Predictors of MACE Age Family history of CAD Acute MI Cardiogenic shock Out-of-hospital cardiac arrest CrCl < 60 mL/minute Radial access Multivessel disease DES Number of stents Total stent length
1.007 0.683 0.866 8.407 5.283 1.483 0.590 1.364 0.376 1.119 1.010
0.991—1.022 0.406—1.148 0.568—1.321 3.581—19.734 1.625—17.182 0.990—2.221 0.369—0.945 0.943—1.973 0.252—0.561 0.760—1.647 0.988—1.031
0.395 0.151 0.505 < 0.0001 0.006 0.056 0.028 0.099 < 0.0001 0.570 0.376
Predictors of TLR Prior angioplasty DES Number of stents Total stent length
2.074 0.386 1.277 1.010
1.309—3.286 0.242—0.615 0.845—1.938 0.987—1.033
0.002 < 0.0001 0.401 0.376
a
CAD: coronary artery disease; CrCl: creatinine clearance; DES, drug-eluting stent; MACE: major adverse cardiac events; MI: myocardial infarction; TLR: target lesion revascularization. a CV death, non-fatal MI, non-fatal stroke and TLR.
DES in renal failure patients due to the discrepancy in baseline characteristics. Patients treated with DES were less likely to have acute myocardial infarction and other comorbidities (bleeding diasthesis, planned surgery, poor compliance, etc.). Restenosis remains a matter of concern in patients with CRF, occurring in up to 60% of cases, although it does not seem to lead to more subsequent revascularization than in the general population [19,20]. However, it has been hypothesized that severe silent ischaemia due to angiographic restenosis may account for this increased cardiac mortality [1]. Large randomized trials and pooled analyses have shown a dramatic decrease in restenosis and subsequent TLR rates in the general population with DES versus BMS. Whether or not this finding applies to CRF patients remains unclear. Only small, often retrospective studies have been conducted, with controversial results, some reporting reduced TLR and/or in-stent restenosis rates [21—24], while others not [25—27]. In our study —– one of the largest to our knowledge —– we did not observe any significant reduction in the TLR rate after DES implantation in CRF patients (7% vs 10% with BMS; P = 0.44). This may be due to a lack of power and the discrepancy in baseline clinical and angiographical characteristics between groups in this ‘‘all-comers’’ registry, with a higher restenosis risk profile in the DES group (more prior PCI, more small stent diameters; Table 1). Indeed, DES appears to be independently associated with a 60% decrease in TLR in the entire cohort. DES was also found to be independently associated with the absence of ischaemic events (OR 0.376) at 1 year, suggesting its additional value in patients with CRF. As previously reported, we did not observe any excess of definite ST (American Research Consortium definition) [7] with DES at 1 year in the CRF group compared with BMS [21,23,24]. However, our study was not designed to assess whether or not DES increased late ST rates in CRF patients, which remains a major concern in this setting, with longer follow-up needed [28,29]. Although CRF is an independent predictor of ST, we did not observe any excess of ST at 1 year between CRF and NO CRF patients [30].
Limitations The strengths of the present study are the relative high sample size in this setting, the consecutive and prospective inclusion and the nearly complete 1-year follow-up. However, several limitations inherent to registry data exist. This was an observational, non-controlled, non-randomized study. Some patients allocated to the DES groups had concomitant BMS implantation during the same procedure; however, this accounts for only a few patients (n = 59, 4.2%). This was an all-comers, single-centre registry, with stent type (especially DES) left to the operators’ discretion; our results therefore reflect ‘‘real life’’ practice but cannot be generalized to other practice and do not compare a type of DES with BMS. Medication data, especially the duration of dual antiplatelet therapy, were not systematically collected.
Conclusion In patients with CRF, the use of DES for PCI appears to be at least as effective as BMS, with no increase in ST at 1 year.
609 However, a larger, randomized trial with long-term follow-up is needed in this setting.
Disclosure of interest Dr. Silvain has received research grants from Sanofi-aventis, Daiichi-Sankyo, Eli Lilly, INSERM, the FFC and the Société franc ¸aise de cardiologie; consultant fees from DaiichiSankyo and Eli Lilly; and lecture fees from AstraZeneca, Daiichi-Sankyo and Eli Lilly. Dr. Beygui has received lecture fees from Roche, Sanofi-aventis, Pfizer and Astellas. Dr. Collet has received research grants (to the institution) from Bristol-Myers Squibb, sanofi-aventis, Eli Lilly, Guerbet Medical, Medtronic, Boston Scientific, Cordis, Stago, Fondation de France, INSERM, the FFC and the Société franc ¸aise de cardiologie; has served as a consultant (honoraria for past 2 years) for Sanofi-aventis, Eli Lilly and Bristol-Myers Squibb; and has received lecture fees from Bristol-Myers Squibb, sanofi-aventis and Eli Lilly. Dr. Montalescot has received research grants (to the institution) from Bristol-Myers Squibb, Sanofi-aventis, Eli Lilly, Guerbet Medical, Medtronic, Boston Scientific, Cordis, Stago, Centocor, fondation de France, Inserm, the FFC, the Société franc ¸aise de cardiologie, ITC Edison and Pfizer; and consulting or lecture fees from Accumetrics, AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Eisai, Eli Lilly, Menarini, MSD, Novartis, Portola, Sanofiaventis, Schering-Plough and The Medicines Company.
Acknowledgements The authors received a grant from the Fédération franc ¸aise de cardiologie (FFC). The FFC had no role in the study design, in the collection, analysis and interpretation of data or in the writing of this report.
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