Effect of Chronic Kidney Disease in
Women Undergoing Percutaneous
Coronary Intervention With
Drug-Eluting Stents
A Patient-Level Pooled Analysis of
Randomized Controlled Trials
Usman Baber, MD, MSC,*Gennaro Giustino, MD,*Samantha Sartori, PHD,*Melissa Aquino, MSC,* Giulio G. Stefanini, MD,yP. Gabriel Steg, MD,zStephan Windecker, MD, PHD,xMartin B. Leon, MD,k
William Wijns, MD, PHD,{Patrick W. Serruys, MD, PHD,#Marco Valgimigli, MD, PHD,**Gregg W. Stone, MD,k George D. Dangas, MD, PHD,*Marie-Claude Morice, MD,yyEdoardo Camenzind, MD,zzGiora Weisz, MD,# Pieter C. Smits, MD, PHD,xxDavid Kandzari, MD,kkClemens Von Birgelen, MD,{{Ioannis Mastoris, MD,* Soren Galatius, MD,##Raban V. Jeger, MD,***Takeshi Kimura, MD,yyyGhada W. Mikhail, MD,zzz Dipti Itchhaporia, MD,xxxLaxmi Mehta, MD,kkkRebecca Ortega, MD,{{{Hyo-Soo Kim, MD,### Adnan Kastrati, MD,****Alaide Chieffo, MD,yyyyRoxana Mehran, MD*
ABSTRACT
OBJECTIVESThis study sought to evaluate: 1) the effect of impaired renal function on long-term clinical outcomes in women undergoing percutaneous coronary intervention (PCI) with drug-eluting stent (DES); and 2) the safety and efficacy of new-generation compared with early-generation DES in women with chronic kidney disease (CKD).
BACKGROUNDThe prevalence and effect of CKD in women undergoing PCI with DES is unclear.
METHODSWe pooled patient-level data for women enrolled in 26 randomized trials. The study population was categorized by creatinine clearance (CrCl)<45 ml/min, 45 to 59 ml/min, and $60 ml/min. The primary endpoint was the 3-year rate of major adverse cardiovascular events (MACE). Participants for whom baseline creatinine was missing were excluded from the analysis.
RESULTSOf 4,217 women included in the pooled cohort treated with DES and for whom serum creatinine was available, 603 (14%) had a CrCl<45 ml/min, 811 (19%) had a CrCl 45 to 59 ml/min, and 2,803 (66%) had a CrCl $60 ml/min. A significant stepwise gradient in risk for MACE was observed with worsening renal function (26.6% vs. 15.8% vs. 12.9%; p< 0.01). Following multivariable adjustment, CrCl <45 ml/min was independently associated with a higher risk of MACE (adjusted hazard ratio: 1.56; 95% confidence interval: 1.23 to 1.98) and all-cause mortality (adjusted hazard ratio: 2.67; 95% confidence interval: 1.85 to 3.85). Compared with older-generation DES, the use of newer-generation DES was associated with a reduction in the risk of cardiac death, myocardial infarction, or stent thrombosis in women with CKD. The effect of new-generation DES on outcomes was uniform, between women with or without CKD, without evidence of interaction.
CONCLUSIONSAmong women undergoing PCI with DES, CKD is a common comorbidity associated with a strong and independent risk for MACE that is durable over 3 years. The benefits of newer-generation DES are uniform in women with or without CKD. (J Am Coll Cardiol Intv 2016;9:28–38) © 2016 by the American College of Cardiology Foundation.
From *The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York City, New York;yDivision of Clinical and Interventional Cardiology, Humanitas Research Hospital, Rozzano, Milan, Italy; zDépartement Hospitalo Universitaire Fibrose, Inflammation et REmodelage, Assistance Publique-Hôpitaux de Paris, Université Paris Diderot, INSERM U698, Paris, France;xDepartment of Cardiology, Bern University Hospital, Bern, Switzerland; kDivision of Cardiology, Columbia University Medical Center, New York City, New York;{Cardiovascular Center Aalst, Onze-Lieve-Vrouwziekenhuis Ziekenhuis, Aalst, Belgium; #Thoraxcenter, Erasmus MC, Rotterdam, the Netherlands; **Department of Cardiology, University of Ferrara, Ferrara, Italy;yyDepartment of Cardiology and Cardiovascular Surgery, Institut Cardiovasculaire Paris Sud, France;
A
mong patients with coronary artery disease (CAD) undergoing percutaneous coronary intervention (PCI), the presence of even mild chronic kidney disease (CKD) is associated with a strong and independent risk for adverse cardiovas-cular events(1–4). Moreover, several studies suggest that the safety and efficacy of drug-eluting stent (DES) implantation may be attenuated in the setting of renal dysfunction(5,6). Possible mechanistic link-ages between CKD and cardiovascular risk after PCI include accelerated atherosclerosis within and outside of the stented vascular segment and a pro-inflammatory milieu (7). Moreover, enhanced bloodthrombogenicity related to renal dysfunction in-creases risk for myocardial infarction (MI) and stent
thrombosis (ST) in patients with CKD (7–9).
Impaired renal function is also a common comorbid-ity among women undergoing PCI and may be a contributor to post-PCI risk in female patients
(4,10,11). However, data on clinical
out-comes associated with DES implantation in women with CKD are scarce as a result of their restricted inclusion in randomized controlled trials (RCTs).
In 2011, the Food and Drug Administra-tion issued guidance for assessing sex dis-parities in RCTs evaluating medical devices (12). In response, the Society for Cardio-vascular Angiography and Interventions’ Women in Innovation Initiative convened the Gender Data Forum to discuss the out-comes of DES in women, leading to the performance of an individual patient-level data pooled analysis from available ran-domized trials of DES. The safety and efficacy of DES in women have been previously reported (13). Accordingly, we sought to evaluate, by pooling patient-level data from RCTs, the prognostic effect of various degrees of impaired renal function in women undergoing PCI with DES and the safety and SEE PAGE 39
A B B R E V I A T I O N S A N D A C R O N Y M S CAD= coronary artery disease CKD= chronic kidney disease CrCl= creatinine clearance DES= drug-eluting stent(s) MI= myocardial infarction PCI= percutaneous coronary intervention RCT= randomized controlled trial ST= stent thrombosis TLR= target lesion revascularization
zzInstitut Lorrain du Coeur et des Vaisseaux (ILCV) University Hospital Nancy—Brabois Vandoeuvre-lès-Nancy France; xxDepartment of Cardiology, Maasstad Hospital, Rotterdam, the Netherlands; kkPiedmont Heart Institute, Atlanta, Georgia; {{Thoraxcentrum Twente, Enschede, the Netherlands; ##Department of Cardiology, Bispebjerg University Hospital, Copenhagen, Denmark; ***Department of Cardiology, University Hospital Basel, Basel, Switzerland;yyyDepartment of Cardiology, Kyoto University Graduate School of Medicine, Kyoto, Japan;zzzDepartment of Cardiology, Imperial College Healthcare NHS Trust, London, United Kingdom;xxxDepartment of Cardiology, Hoag Memorial Hospital Presbyterian, Newport Beach, California; kkkDepartment of Cardiology, Ohio State University Medical Center, Columbus, Ohio; {{{Society of Cardiovascular Angiography and Interventions, Washington, DC; ###Department of Cardiology, Seoul National University Main Hospital, Seoul, South Korea; ****Herzzentrum, Munich, Germany; and theyyyyInterventional Cardiology Unit, San Raffaele Scientific Institute, Milan, Italy. The Gender Data Forum was sponsored by the Women in Innovation Initiative of the Society of Cardiovascular Angiography and Interventions. Dr. Stefanini has received speaker fees from Abbott Vascular, AstraZeneca, Biosensors, Biotronik, and The Medi-cines Company. Dr. Steg has received honorarium from Medtronic as a steering committee member in the PROTECT trial; has received research grants from Sanofi and Servier; has received funding from Amarin, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo-Lilly, GlaxoSmithKline, Medtronic, Merck, Novartis, Pfizer, Regeneron, Sanofi, Servier, and The Medicines Company; and is a stockholder in Aterovax. Dr. Windecker has received research contracts to the institution from Abbott, Biotronik, Boston Scientific, Biosensors, Cordis, Medtronic, and St. Jude; and has received speakers honoraria from AstraZeneca, Eli Lilly, Abbott, Biotronik, Biosensor, Boston Scientific, Medtronic, Edwards Lifesciences, and Bayer. Dr. Wijns has received institutional research grants from Boston, Medtronic, Abbott, Terumo, and Biosensors; is an investigator for sponsored trials by Boston, Medtronic, Abbott, Terumo, and Biosensors; is a nonexecutive board member and shareholder of Argonauts Partners, Cardio3BioSciences, and Genae; and fees or honoraria on his behalf from Boston, Medtronic, Abbott, Terumo, and Biosensors go to the Cardiovascular Center Aalst. Dr. Valgimigli has received honoraria for lectures or advisory board and research grants from Merck, Iroko, Eli Lilly, and Medtronic; honoraria for advisory board and lectures from The Medicines Company, Eli Lilly, Daiichi Sankyo, St. Jude, and Abbott Vascular; and honoraria for lectures from Cordis, Carbostent and Implantable Devices, and Terumo. Dr. Smits has received institutional research grants and speakers fees from Abbott Vascular, St. Jude, and Terumo. Dr. Kandzari has received research or grant support from Medtronic, Abbott, and Boston Scientific; and has received consulting honoraria from Medtronic, Biotronik, and Boston Scientific. Dr. Von Birgelen is a consultant to and has received lecture fees or travel expenses from Abbott Vascular, AstraZeneca, Biotronik, Boston Scientific, Medtronic, and Merck Sharp and Dohme; and his research department Thoraxcentrum Twente has received educational or research grants from Abbott Vascular, Astra-Zeneca, Biotronik, Boston Scientific, and Medtronic. Dr. Galatius has received grant support from St. Jude, Abbott, Terumo, and Biotronik; and has received advisory board honorarium from Eli Lilly and Servier. Dr. Mikhail has received an interventional fellowship from Abbott Vascular; and has received speakers honoraria from AstraZeneca. Dr. Mehran has received institutional research grant support from The Medicines Company, AstraZeneca, Bristol-Myers Squibb, Sanofi, Lilly, and Daiichi Sankyo; has received consulting fees from Abbott Vascular, AstraZeneca, Bayer, Boston Scientific, CSL Behring, Covidien, Janssen Pharma-ceuticals, Maya Medical, Merck, Osprey Medical Inc., Regado Biosciences, Watermark Research Partners, and Sanofi; and serves on the scientific advisory board of Abbott Laboratories, Boston Scientific Corporation, Covidien, Janssen Pharmaceuticals, The Medicines Company, and Sanofi. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Thefirst 2 authors contributed equally to this work.
efficacy profile of new-generation compared with early-generation DES in women with CKD.
METHODS
STUDY POPULATION. The rationale of the present patient-level pooled database, list of trials, analytic strategies, and pre-specified endpoints have been previously reported(13). Briefly, female participants from 26 RCTs were pooled: RAVEL (The Initial Double-Blind Drug-Eluting Stent vs Bare-Metal Stent Study) (14), SIRIUS (Study of Sirolimus-Coated BX VELOCITY Balloon-Expandable Stent in Treatment of de Novo Native Coronary Artery Lesions) (15), E-SIRIUS (The Study of the BX VELOCITY Stent In Patients With De Novo Coronary Artery Lesions)(16), C-SIRIUS (The Study of the BX Velocity Stent in the Treatment of De Novo Artery Lesions)(17), TAXUS-I (Randomized, Double-Blind Trial on a Slow-Release
Paclitaxel-Eluting Stent for De Novo Coronary
Lesions)(18), TAXUS-II SR (A Randomized Study to Assess the Effectiveness of Slow- and Moderate-Release Polymer-Based Paclitaxel-Eluting Stents for De Novo Coronary Artery Lesions) (19), TAXUS-IV (Treatment of De Novo Coronary Disease Using a Single Paclitaxel-Eluting Stent) (20), TAXUS-V (A Randomized, Double-blind Trial to Assess TAXUS Paclitaxel-Eluting Coronary Stents, SR Formulation,
in the Treatment of De Novo Coronary Lesions) (21), SIRTAX (Sirolimus-Eluting Versus Paclitaxel-Eluting Stents for Coronary Revascularization) (22), ENDEAVOR II (Randomized Controlled Trial to Eval-uate the Safety and Efficacy of the Medtronic AVE ABT-578 Eluting Driver Coronary Stent in De Novo Native Coronary Artery Lesions)(23), ENDEAVOR III (A Randomized Controlled Trial of the Medtronic Endeavor Drug [ABT-578] Eluting Coronary Stent System Versus the Cypher Sirolimus-Eluting Coro-nary Stent System in De Novo Native CoroCoro-nary Artery Lesions)(24), ENDEAVOR-IV (Randomized Compari-son of Zotarolimus-Eluting and Paclitaxel-Eluting Stents in Patients with Coronary Artery Disease)(25), SPIRIT II (A Clinical Evaluation of the XIENCE V Everolimus Eluting Coronary Stent System in the Treatment of Patients With de Novo Native Coronary Artery Lesions)(26), SPIRIT III (A Clinical Evaluation of the Investigational Device XIENCE V Everolimus Eluting Coronary Stent System in the Treatment of Subjects With de Novo Native Coronary Artery Le-sions) (27), SPIRIT IV (Clinical Evaluation of the XIENCE V Everolimus Eluting Coronary Stent System in the Treatment of Subjects With de Novo Native
Coronary Artery Lesions) (28), BASKET-PROVE
(Evaluation of Late Clinical Events After Drug-eluting Versus Bare-metal Stents in Patients at Risk: BAsel Stent Kosten Effektivitäts Trial - PROspective
FIGURE 1 Study Population Flow Diagram
Validation Examination Part II) (29), COMPARE I (A Randomized Controlled Trial of Everolimus-eluting Stents and Paclitaxel-Everolimus-eluting Stents for Coro-nary Revascularization in Daily Practice) (30), COMPARE II (Comparison of the Everolimus Eluting With the Biolimus A9 Eluting Stent)(31), EXCELLENT (The Efficacy of Xience/Promus Versus Cypher to Reduce Late Loss After Stenting) (11), RESET (REal Safety and Efficacy of 3-month dual antiplatelet Therapy following Endeavor zotarolimus-eluting stent implantation) (32), RESOLUTE AC (Random-ized, Two-Arm, Non-inferiority Study Comparing Endeavor-Resolute Stent With Abbot Xience-V Stent) (33), TWENTE (The Real-World Endeavor Resolute Versus XIENCE V Drug-Eluting Stent Study in Twente)(34), LEADERS (A Randomized Comparison of a Biolimus-Eluting Stent With a Sirolimus-Eluting Stent for Percutaneous Coronary Intervention) (35), ISAR TEST 4 (Prospective, Randomized Trial of 3-limus Agent-eluting Stents With Different Polymer Coatings) (36), PRODIGY (PROlonging Dual Anti-platelet Treatment In Patients With Coronary Artery Disease After Graded Stent-induced Intimal Hyper-plasia studY) (37), and PROTECT (Patient Related OuTcomes With Endeavor Versus Cypher Stenting Trial)(38). Characteristics of the RCTs included in the present study are summarized inOnline Table 1. All of the included randomized controlled trials were per-formed between 2000 and 2013.
According to baseline creatinine clearance (CrCl), the study population was stratified by: 1) CrCl <45 ml/min, 2) CrCl between 45 and 59 ml/min, and 3) CrCl $60 ml/min (Figure 1). Women receiving
bare-metal stents were excluded from the present
analysis. Participants whose baseline creatinine was not available were also excluded from the analysis. All trials included in our analysis complied with the provisions of the Declaration of Helsinki, and the study protocols were approved by the institutional review board at each study center. All patients pro-vided written informed consent for participation in each study.
DRUG-ELUTING STENTS. The following DES have been included in the present analysis: sirolimus-eluting stents (Cypher and Cordis, Johnson & John-son, Miami Lakes, Florida), paclitaxel-eluting stents (Taxus, Boston Scientific, Natick, Massachu-setts), everolimus-eluting stents (Xience, Abbott Vascular, Santa Clara, California; Promus, Boston Scientific), zotarolimus-eluting stents (Endeavor, Medtronic, Santa Rosa, California; Resolute, Med-tronic), biolimus-eluting stents with biodegradable polymer coating (Biomatrix, Biosensors, Newport
Beach, California; Nobori, Terumo, Tokyo, Japan), and sirolimus-eluting stents with biodegradable polymer coating (Yukon, Translumina, Hechingen, Germany).
Coronary stents used among trials were classified as early-generation DES (including sirolimus- and paclitaxel-eluting stents) and new-generation DES (including everolimus-eluting stents, zotarolimus-eluting stents with durable polymer, and biolimus-and sirolimus-eluting stents with biodegradable polymer).
ENDPOINTS. We evaluated the effect of impaired renal function on 3-year risk of major adverse cardiac events (MACE) defined as the composite of all-cause death, MI, target lesion revascularization (TLR), or ST. Subsequently, we evaluated the effect of new-generation DES (versus early-new-generation DES) on the risk of device-oriented safety endpoints comprising cardiac death, MI, or ST. The clinical endpoint defi-nitions used across trials are shown inOnline Table 2.
FUNDING SOURCE. No funding source was available for the gathering of these data, statistical analyses, or
TABLE 1 Baseline Clinical and Angiographic Characteristics CrCl<45 ml/min (n¼ 603) CrCl 45–59 ml/min (n¼ 811) CrCl$60 ml/min (n¼ 2,803) p Value Age, yrs 76.7 8.2 73.8 7.6 64.0 9.7 0.01 BMI, kg/m2 24.1 4.5 25.8 4.4 29.2 5.7 <0.01 Risk factors Diabetes mellitus 222 (36.8) 246 (30.3) 981 (35) 0.01 IDDM 84 (37.8) 74 (30.1) 307 (31.3) 0.12 Arterial hypertension 517 (85.7) 658 (81.1) 2,058 (73.4) <0.01 Hypercholesterolemia 390 (64.7) 566 (69.8) 1,948 (69.5) 0.06 Smoking 114 (19.0) 214 (26.4) 1,106 (39.5) <0.01 Family history of CAD 123 (21.8) 230 (29.6) 1,018 (37.6) <0.01 Clinical history Previous MI 145 (24.0) 178 (21.9) 541 (19.3) <0.01 Previous PCI 171 (28.4) 184 (22.7) 517 (18.5) <0.01 Previous CABG 45 (7.5) 54 (6.7) 122 (4.4) <0.01 LVEF, % 53.9 16.7 54.6 18.7 53.2 21.9 0.31 Multivessel disease 243 (40.0) 241 (30.0) 664 (23.7) <0.01 Angiographic characteristics
Number of lesions treated 1.3 0.6 1.3 0.6 1.3 0.6 0.12 Number of stents implanted 1.6 0.9 1.6 0.9 1.3 0.6 0.07 Mean stent diameter, mm 2.9 0.4 2.9 0.4 3.0 0.4 <0.01 Total stent length, mm 31.1 21.4 30.8 20.0 29.3 19.5 <0.01 Type B2/C lesion 429 (73.1) 515 (65.3) 1,644 (59.7) <0.01 Moderate/severe calcifications 170 (33.5) 237 (32.9) 656 (25.1) <0.01 Bifurcation lesion 60 (22.2) 53 (18.6) 201 (22.6) 0.35 Type of stent implanted <0.01
Early-generation DES 322 (53.4) 402 (49.6) 1,361 (48.6) New-generation DES 281 (46.6) 409 (50.4) 1,442 (51.4)
Values are mean SD or n (%).
BMI¼ body mass index; CABG ¼ coronary artery bypass graft; CAD ¼ coronary artery disease; DES ¼ drug-eluting stent(s); IDDM¼ insulin-dependent diabetes mellitus; MI ¼ myocardial infarction; NSTEMI ¼ non–ST-segment elevation myocardial infarction; PCI¼ percutaneous coronary intervention; SA ¼ stable angina; STEMI ¼ ST-segment elevation myocardial infarction; UA¼ unstable angina.
FIGURE 2 3-Year Adverse Events According to Baseline Renal Function in Women Undergoing PCI With DES
Kaplan-Meier survival curves for major adverse cardiac events (A) and death (B) at 3 years in women according to baseline renal function. The p values are from log-rank test. CrCl¼ creatinine clearance; MACE ¼ major adverse cardiac event(s).
drafting of this report. The collaborative nature of the present investigation initiative has been reported previously (14). All of the contacted principal in-vestigators and device manufacturers shared indi-vidual patient data for female patients enrolled in randomized controlled trials evaluating the safety and efficacy of different types of DES.
STATISTICAL ANALYSIS. All patient-level data were aggregated and combined as 1 dataset using pre-specified extraction sheet. Baseline clinical, de-mographic, and procedural characteristics of CKD groups were compared using linear regression for continuous variables and chi-square tests for cate-gorical variables. Cumulative event rates were
calculated with the Kaplan-Meier method and
compared between groups using the log-rank test. For these analyses, the total follow-up was defined as the time from index procedure until death, last follow-up date, or 3 years, whichever came first. The median follow-up time was 3 years in patients with CrCl$60 ml/min and between 45 and 59 ml/min, and was 2 years in those with CrCl<45 ml/min. The indepen-dent associations between CKD severity and stent generation and outcomes were assessed with the Cox proportional hazards models that included a frailty term (
g
) to assess random effects in the trials(39,40). Frailties are the unmeasured factors that affect trial-specific baseline risk and are distributed asg
random variables with a mean of 1 and varianceq
. The variance parameter is interpreted as a metric of het-erogeneity in baseline risk between trials. In the analysis evaluating the effect of renal function on outcomes, CrCl >60 ml/min served as the referent category. For the DES-level analysis, older-generation DES served as the referent category. As median follow-up time differed significantly across stent generations (2 and 3 years among those receivingnew- and older-generation DES, respectively),
comparative analyses between DES groups were censored at 2 years. Stent group, age, and baseline variables showing significant differences between groups were included as covariates in the multivari-able model (body mass index, diabetes, previous myocardial infarction, family history of CAD, previ-ous percutaneprevi-ous intervention for multivessel dis-ease, smoking, presentation with an acute coronary syndrome, number of stents per patient, and type B2 or C lesions). For the DES-level analysis, the consis-tency of the effect of new-generation DES in patients with or without CKD was evaluated with a formal interaction test. We judged p values<0.05 to be sig-nificant, and all analyses were done with SAS version 9.2 software (SAS Institute, Cary, North Carolina).
RESULTS
BASELINE CHARACTERISTICS. Of 10,620 women included in the pooled dataset and who received a DES, baseline creatinine level was available for 4,217 (39.7%). Of them, 1,414 had CKD (33.5%). Among those with CKD, 603 (14.3%) had severe renal impairment (CrCl <45 ml/min) and 811 (19.2%) had moderate renal impairment (CrCl 45 to 59 ml/min).
Clinical characteristics according to baseline renal
function are reported in Table 1. Women with
CrCl <45 ml/min were older, had lower body mass index, and had greater prevalence of diabetes melli-tus, arterial hypertension, previous MI, and previous percutaneous or surgical coronary revascularization. Conversely, they had lower prevalence of family his-tory of CAD, active smoking, and hypercholesterole-mia. Angiographic and procedural data are reported
inTable 1. Women with CrCl<45 ml/min had a higher
prevalence of multivessel CAD, moderate or severe calcifications, and type B2/C lesions and had longer total stent length.
EFFECT OF RENAL FUNCTION ON 3-YEAR CLINICAL OUTCOMES. A significant stepwise increase in 3-year rates of MACE (Figure 2A,Online Figure 1) (12.9% vs. 15.8% vs. 26.6%; p < 0.01), all-cause mortality (Figure 2B) (3.1% vs. 6.4% vs. 16.1%; p< 0.01), cardiac mortality (3.1% vs. 6.4% vs. 16.1%; p< 0.01), MI (5.2% vs. 6.3% vs. 10.2%; p< 0.01), and the composite of death, MI, or stent thrombosis (8.0% vs. 11.1% vs. 22.4%; p< 0.01) was observed in the transition from normal (CrCl$60 ml/min) to severely impaired renal function (CrCl <45 ml/min). Conversely, there were no differences in the rate of TLR at 3 years among groups (6.4% vs. 6.1% vs. 6.8%; p¼ 0.77).
Following adjustment for baseline confounders, severe impairment of renal function (CrCl<45 ml/min) was independently associated with an increased risk
TABLE 2 Adjusted 3-Year Clinical Outcomes According to Renal Function CrCl$60 ml/min (Reference Group) CrCl 45–59 ml/min CrCl<45 ml/min p Value for Trend Death 1.00 1.12 (0.77–1.64) 2.67 (1.85–3.85) <0.01 Cardiac death 1.00 1.40 (0.84–2.35) 2.75 (1.65–4.61) <0.01 Myocardial infarction 1.00 0.95 (0.66–1.38) 1.33 (0.90–1.97) <0.01 TLR 1.00 0.79 (0.54–1.15) 0.95 (0.62–1.45) 0.56 Definite or probable ST 1.00 0.91 (0.42–1.99) 1.54 (0.70–3.39) 0.05 Death or MI 1.00 1.01 (0.76–1.33) 1.91 (1.44–2.52) <0.01 Death, MI, or ST 1.00 0.98 (0.74–1.29) 1.85 (1.40–2.44) <0.01 MACE 1.00 0.94 (0.75–1.19) 1.56 (1.23–1.98) <0.01
Values are hazard ratio (95% confidence interval) unless otherwise indicated.
MACE¼ major adverse cardiac event(s); ST ¼ stent thrombosis; TLR ¼ target lesion revascularization; other abbreviations as inTable 1.
FIGURE 3 2-Year Adverse Events According to Chronic Kidney Disease Status and DES Generation
Kaplan-Meier survival curves for the composite of cardiac death, myocardial infarction (MI), or stent thrombosis (A) and cardiac death (B) at 3 years in women treated with early- or new-generation (Gen) drug-eluting stents according to chronic kidney disease (CKD) status. The p values are from log-rank test.
of MACE (Table 2) (adjusted hazard ratio [adjHR]: 1.56; 95% confidence interval [CI]: 1.23 to 1.98; trend p < 0.01), all-cause mortality (adjHR: 2.67; 95% CI: 1.85 to 3.85; trend p< 0.01), cardiac mortality (adjHR: 2.75; 95% CI: 1.65 to 4.61; trend p < 0.01), MI (HR: 1.33; 95% CI: 0.90 to 1.97; trend p < 0.01), and the composite of death, MI, or stent thrombosis (adjHR: 1.85; 95% CI: 1.40 to 2.44; trend p< 0.01) compared with normal renal function (CrCl $60 ml/min) or moderate renal impairment (CrCl 45 to 59 ml/min). Moreover, a trend toward a higher risk of ST was observed in patients with severely impaired renal function (adjHR: 1.54; 95% CI: 0.70 to 3.39; trend p¼ 0.05). Conversely, severe renal impairment was not associated with an increased risk of TLR. Finally, moderate renal dysfunction (CrCl 45 to 59 ml/min) was not independently associated with a higher risk of adverse events compared with normal renal function.
EARLY- VERSUS NEW-GENERATION DES IN WOMEN WITH CKD. In women with CKD, at unadjusted analysis, new-generation DES were associated with lower 2-year rates of the composite of cardiac death, MI, or stent thrombosis (Figure 3A) (9.2% vs. 11.1%; p ¼ 0.002) and cardiac death (Figure 3B) (5.6% vs. 4.2%; p < 0.0001). Following multivariable adjustment for baseline confounders (Table 3), use of new-generation DES in women with CKD was asso-ciated with a reductions in cardiac death, MI, or ST (adjHR: 0.70; 95% CI: 0.49 to 1.00), death or MI (adjHR: 0.72; 95% CI: 0.53 to 1.00), and cardiac death (adjHR: 0.58; 95% CI: 0.35 to 0.97). The magnitude and direction of the effect of new-generation DES use was uniform between patients with or without CKD, with no evidence of interaction. The effect of new-generation DES on outcomes was consistent using a CrCl threshold of <45 ml/min (Online Table 3).
DISCUSSION
To the best of our knowledge, the present report is the largest to date to examine the effect of CKD and different DES platforms on long-term risk after PCI in female randomized trial participants. Our results demonstrate that: 1) CKD is a common comorbidity among women undergoing PCI with DES and is associated with a strong and durable risk for MACE and mortality; 2) the effect of renal dysfunction on adverse events is graded, particularly among those with CrCl<45 ml/min; and 3) compared with early-generation DES, use of newer-early-generation DES is associated with improved safety and efficacy in women with CKD.
EFFECT OF RENAL FUNCTION ON ADVERSE EVENTS IN WOMEN. Consistent with previous reports eval-uating the effect of CKD in cardiovascular disease, impaired renal function was associated with a higher risk for MACE and death compared with preserved renal function (7,8). We observed an in-flection point for excess risk at levels of CrCl <45 ml/min, similar to a threshold previously reported in a large population-based sample of U.S. adults (7). Despite these well-documented associations, analogous data examining long-term outcomes in women with CKD across the spectrum of clinical
CAD presentations remain limited. Among
ST-segment elevation MI patients, for example, a post-hoc analysis of the HORIZONS-AMI (Harmo-nizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction) trial showed sub-stantial and excess thrombotic risk associated with CKD in both male and female patients. Renal impairment was not linked with higher rates of TLR in that report, as is consistent with our results. Consequently, our findings, in concert with earlier observations, highlight the prognostic relevance of TABLE 3 Adjusted 2-Year Clinical Outcomes Between Early- and New-Generation DES in Women With or Without CKD
No CKD (CrCl$60 ml/min) CKD (CrCl<60 ml/min) p Value for Interaction Early-Generation DES New-Generation DES Adjusted HR (95% CI) Early-Generation DES New-Generation DES Adjusted HR (95% CI) Death 27 (2.0) 30 (2.1) 1.08 (0.61–1.91) 62 (8.3) 51 (7.1) 0.70 (0.47–1.04) 0.29 Cardiac death 15 (1.1) 18 (1.3) 0.99 (0.48–2.04) 42 (5.6) 30 (4.2) 0.58 (0.35–0.97) 0.28 Myocardial infarction 67 (4.9) 64 (4.4) 0.80 (0.54–1.18) 53 (7.1) 44 (6.2) 0.76 (0.49–1.17) 0.76 TLR 74 (5.4) 73 (5.1) 1.23 (0.84–1.80) 35 (4.7) 37 (5.2) 1.36 (0.82–2.25) 0.84 Definite or probable ST 16 (1.2) 10 (1.4) 0.59 (0.27–1.32) 11 (1.5) 10 (1.4) 0.75 (0.31–1.78) 0.57 Death or MI 88 (6.5) 89 (6.2) 0.92 (0.66–1.29) 102 (13.6) 82 (11.5) 0.72 (0.53–1.00) 0.34 Cardiac death, MI, or ST 79 (5.8) 83 (5.8) 0.88 (0.62–1.25) 83 (11.1) 66 (9.2) 0.70 (0.49–1.00) 0.44
Values are n (%) unless otherwise indicated.
renal dysfunction as a strong and robust marker of excess long-term risk in women undergoing PCI.
Renal-attributable risk is at least partially due to the higher prevalence of comorbidities that increase in the transition from normal to severely impaired renal function (CrCl <45 ml/min). Concordant with this clinical phenotype, we also showed a greater burden and complexity of CAD among women with CrCl <45 ml/min. Nevertheless, the association be-tween moderate to severe renal dysfunction and increased MACE risk persisted after adjusting for baseline imbalances between CKD groups, suggesting that alternative and independent mechanisms may be contributory in such patients. Indeed, common risk factors for both CKD and atherosclerosis, including advanced age, arterial hypertension, dyslipidemia and diabetes mellitus, suggest a shared pathophysi-ological substrate for both conditions, yet do not fully account for the observed morbidity in female patients with moderate to severe CKD. Excess risk may also be attributable to a systemic inflammatory state, oxida-tive stress, and significant endothelial dysfunction, factors that may act in a synergistic manner to enhance thrombosis(7,10).
Of note, baseline creatinine levels were available in less than one-half of our entire pooled patient popu-lation. Given the importance of CKD as a risk factor for subsequent MACE and mortality, this finding emphasizes the importance to measure baseline creatinine levels in patients undergoing PCI for optimal risk stratification and implementation of strategies to avoid contrast-induced nephropathy.
NEW-GENERATION DES IN WOMEN WITH CKD.
Compared with early-generation DES, the improved safety and efficacy of new-generation DES has been demonstrated in a multitude of RCTs and meta-analyses(41). In the present study, we shed light on the relative safety and efficacy of new-generation DES in women with CKD. Although previous studies sug-gested an attenuation of benefit of newer-generation DES in the setting of CKD(6,42), we observed non-differential reduction in risks for cardiac death, MI, or ST irrespective of CKD status. Potential mecha-nisms by which CKD might increase the risk of DES failure include enhanced propensity for thrombosis, increased systemic inflammation, disturbances in glucose homeostasis that might affect the patterns of endothelialization and the burden of neointimal hyperplastic response, and a milieu of accelerated atherosclerosis with subsequent development of neoatherosclerosis within the implanted DES plat-form. However, newer-generation DES, by optimiza-tion of biocompatibility, drug-release kinetics,
vascular healing, and endothelial coverage, overcome limitations of early-generation DES and provide consistent benefits irrespective of renal function(41).
STUDY LIMITATIONS.Although our findings rely on individual patient-level, high-quality data from pro-spective, randomized trials with data monitoring and event adjudication by clinical event committees, several limitations have to be disclosed. First, some trials included in the analysis were performed more than 1 decade ago, since which time clinical practice and device technology have changed. To reduce the trial effect on outcomes, we included trial as a random effect in our adjusted analyses. Second, pa-tient populations across trials were heterogeneous; early trials focused only on stable CAD with simple lesions, whereas more recent trials included more complex patient and lesion subsets. Third, the exclusion of male participants from this study pre-cludes sex-specific analysis, limiting the external validity of ourfindings. Fourth, as a post-hoc analysis of randomized trials, our results are subject to resid-ual or unmeasured confounding. Fifth, the relatively low numbers for each early- and new-generation DES type limits our ability to perform between-stent comparisons within each renal function category. Sixth, angiographic follow-up was not available in the pooled dataset, mitigating our ability to compare angiographic performances of new-generation DES in such a high-risk population. Seventh, serum creati-nine was not available in all study participants (>10,000 women), rendering our point estimates and subgroup comparisons less precise. Finally, data on dual antiplatelet therapy adherence, potency, and duration were not available, limiting thefindings of the DES generation-level analysis.
CONCLUSIONS
CKD is a common comorbidity among women with
CAD undergoing percutaneous revascularization
with DES. Impaired renal function is associated with a strong, dose-dependent effect on the long-term risk of MACE and mortality. Compared with early-generation DES, use of newer-generation DES is associated with consistent and uniform benefits in women with or without CKD.
REPRINT REQUESTS AND CORRESPONDENCE: Dr. Roxana Mehran, The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1030, New York, New York 10029. E-mail:Roxana.Mehran@
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PERSPECTIVES
WHAT IS KNOWN?Previous studies suggested that CKD attenuates the safety and efficacy of new-generation DES. The magnitude of this effect in women undergoing PCI is unknown.
WHAT IS NEW?Among women undergoing PCI with DES, CKD is a common comorbidity associated with a strong and independent risk of major adverse events and
mortality. Compared with early-generation DES, new-generation devices are associated with consistent and uniform benefits in women with or without CKD.
WHAT IS NEXT?Evaluation of renal function in women undergoing PCI should be a standard of care for optimal risk stratification and implementation of contrast-induced nephropathy avoidance strategies.
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KEY WORDS chronic kidney disease, drug-eluting stents, outcomes, women
APPENDIX For a supplementalfigure and tables, please see the online version of this article.
