safety and effectiveness of drug-eluting versus bare-metal ...background stenosis of saphenous vein...

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Safety and Effectiveness ofDrug-Eluting Versus Bare-MetalStents in Saphenous Vein Bypass GraftPercutaneous Coronary Interventions
Insights From the Veterans Affairs CART Program
Vikas Aggarwal, MD, MPH,*yz Maggie A. Stanislawski, MS,*yz Thomas M. Maddox, MD, MSC,*yzBrahmajee K. Nallamothu, MD, MPH,x Gary Grunwald, PHD,*yz Jill C. Adams, RN,* P. Michael Ho, MD, PHD,*yzSunil V. Rao, MD,k Ivan P. Casserly, MB, BCH,{ John S. Rumsfeld, MD, PHD,*yz Emmanouil S. Brilakis, MD, PHD,#**Thomas T. Tsai, MD, MSC*yzyy

ABSTRACT

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BACKGROUND Stenosis of saphenous vein grafts (SVGs) after coronary artery bypass grafting (CABG) is common and

often requires percutaneous coronary interventions (PCI) for treatment. However, data for the effectiveness of drug-

eluting stents (DES) versus bare-metal stents (BMS) in SVG-PCI are unclear.

OBJECTIVES This study sought to examine the association between DES versus BMS used during SVG PCI and clinical

outcomes in the national Veterans Affairs integrated healthcare system.

METHODS We studied a national cohort of 2,471 post-CABG veterans undergoing SVG-PCI between 2008 and 2011 at

all Veterans Affairs hospitals and compared clinical outcomes of between those receiving DES and BMS. Clinical outcomes

included procedural complications, myocardial infarction (MI), and all-cause mortality. Comparisons were made in a

propensity-matched cohort using Cox proportional hazards regression models.

RESULTS DES were used in 1,549 SVG-PCI patients (63%) and the use of DES increased progressively with each cal-

endar year (50% in 2008 to 69% in 2011). Incidence of procedural complications was low and comparable in both groups

(2.8% among BMS vs. 2.3% among DES patients; p ¼ 0.54). During long-term (>2 years) follow-up, use of DES was

associated with lower mortality than BMS (hazard ratio [HR]: 0.72; 95% confidence interval [CI]: 0.57 to 0.89) and

similar rates of MI (HR: 0.94; 95% CI: 0.71 to 1.24) in the propensity-matched cohort.

CONCLUSIONS In a national cohort of veterans, we observed widespread and increasing use of DES during SVG-PCI.

In long-term follow-up, compared with BMS, DES use was safe and effective in SVG-PCI patients. (J Am Coll Cardiol

2014;64:1825–36) © 2014 by the American College of Cardiology Foundation.

m the *VA Eastern Colorado Health Care System, Denver, Colorado; yUniversity of Colorado, Denver Anschutz Medical

mpus, Aurora, Colorado; zColorado Cardiovascular Outcomes Research Consortium, Denver, Colorado; xUniversity of Michigan,

n Arbor, Michigan; kDurham VA Medical Center, Durham, North Carolina; {Mater Private Hospital, Dublin, Ireland; #VA North

xas Health Care System, Dallas, Texas; **University of Texas Southwestern Medical School, Dallas, Texas; and the yyInstitute for

alth Research, Kaiser Permanente, Denver, Colorado. The views expressed in this paper are those of the authors and do not

cessarily reflect the position or policy of the Department of Veterans Affairs or the United States government. Dr. Aggarwal is

pported by American Heart Association post-doctoral fellowship award 13POST16340011. Dr. Maddox is supported by VA Health

rvices Research and Development career development award HSR&D-CDA 08-021. Dr. Brilakis is a consultant for and has

eived speaker honoraria from St. Jude Medical, Terumo, Janssen, Sanofi-Aventis, Asahi, Abbott Vascular, and Boston Scientific;

s received research support from Guerbet; and Dr. Brilakis’ spouse is an employee of Medtronic. All other authors have reported

t they have no relationships relevant to the contents of this paper to disclose.

ten to this manuscript’s audio summary by JACC Editor-in-Chief Dr. Valentin Fuster.

u can also listen to this issue’s audio summary by JACC Editor-in-Chief Dr. Valentin Fuster.

nuscript received January 19, 2014; revised manuscript received May 21, 2014, accepted June 30, 2014.

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http://dx.doi.org/10.1016/j.jacc.2014.06.1207

Total number of SVG intacross all VA healthcare faciOctober 1, 2007 and Septe

(N=3,762).

All veterans undergoing any VA healthcare facility du

duration included in th(N=2,471).

Cohort of veterans undergpropensity-matched for

(N=1,728).

Number of veterans whotheir first SVG-PCI across all

facilities during the stud(N=2,825).

FIGURE 1 Flow Diagram Illus

BMS ¼ bare-metal stent(s); DES

intervention; SVG ¼ saphenous

ABBR EV I A T I ON S

AND ACRONYMS

BMS = bare-metal stent(s)

DES = drug-eluting stent(s)

HR = hazard ratio

ICD-9 = International

Classification of Diseases-9th

Revision

MI = myocardial infarction

PCI = percutaneous

coronary intervention

SVG = saphenous venous graft

TLR = target lesion

revascularization

TVR = target vessel

revascularization

VA = Veterans Affairs

Aggarwal et al. J A C C V O L . 6 4 , N O . 1 7 , 2 0 1 4

DES Safety in SVG PCI O C T O B E R 2 8 , 2 0 1 4 : 1 8 2 5 – 3 6

1826

S aphenous vein graft (SVG) stenosis af-ter coronary artery bypass grafting(CABG) is common, occurring in as

many as 50% of patients at 5 years (1). Percuta-neous intervention (PCI) and stent placementin SVG (SVG-PCI) is routinely performed, withSVG-PCI accounting for approximately 6%of total PCI volume (2). However, there arefundamental differences between the patho-physiology of SVG stenosis and that of nativecoronary artery stenosis, such as fibro-muscular hyperplasia from abnormal flowdynamics, excessive wall shear stress, andsuture site inflammatory response (3). There-fore, the advantages and disadvantages ofdrug-eluting stent (DES) versus bare-metalstent (BMS) PCI in native coronary artery dis-ease may not translate into SVG-PCI.

SEE PAGE 1837

There are limited data comparing DES and BMS inSVG-PCI. Three prospective randomized controlled

erventionslities betweenmber 30, 2011

Patients receiving no stent(n=176). Patients receiving

both DES and BMS(n=178).

SVG-PCI atring the studyis dataset

Patients who werenot propensity-matched

(n=742).

oing SVG-PCI stent type

underwent VA healthcarey duration

trating the Study Cohort Creation

¼ drug-eluting stent(s); PCI ¼ percutaneous coronary

vein graft; VA ¼ Veterans Affairs.

trials with conflicting results have been published todate (4–7). These studies all included routine follow-up angiography that can magnify the potentialbenefit of DES. In addition, the use of DES maynecessitate prolonged dual antiplatelet therapy,placing patients at risk for bleeding. Given the risksassociated with DES use and the uncertain benefitcompared with BMS in SVG-PCI, the role of DES inSVG-PCI remains unclear.

The Veterans Affairs Clinical Assessment Reportingand Tracking (VA-CART) program included all patientand procedural data linked to longitudinal outcomesfor all PCIs performed in the national VA healthcaresystem as part of a national quality assessmentand improvement program (8). Hence, VA-CARTprovided a unique opportunity to assess thecomparative effectiveness and safety of DESs versusthat of BMSs in a large national contemporary cohortof patients receiving SVG-PCI. Specifically, we com-pared procedure-related in-laboratory complications,myocardial infarction (MI), and mortality in thosewho received DES with those who received BMSduring SVG-PCI. This study will help provide insightinto the impact of stent type on long-term outcomesand address knowledge gaps in the contemporaryclinical practice of SVG-PCI.

METHODS

STUDY DESIGN, SETTING, AND POPULATION. Thiswas a retrospective study of a national cohort of post-CABG veterans undergoing SVG- PCI at all 63 VA PCIcenters from October 1, 2007 through September 30,2011 (Figure 1). Procedures with missing proceduraldetails, such as indication for procedure or stenttype were excluded, as were patients who receivedboth BMS and DES. The first SVG-PCI procedureduring the study period was defined as the indexprocedure, and outcomes were assessed throughSeptember 30, 2012.

DATA SOURCE. The VA-CART program is a nationalclinical quality improvement program for VA cathe-terization laboratories (CL). It uses a software appli-cation (CART-CL) for medical record documentationof key patient and procedural data for all proceduresconducted in the VA catheterization laboratoriesnationwide. CART-CL is embedded in the VA electronichealth record, allowing for linkage to longitudinaloutcome data. In addition, it is also linked to fee-baseddata to account for veterans who receive non-VA care.Data elements in CART-CL are standardized andbased on American College of Cardiology’s nationalcardiovascular data catheterization-PCI registry (9).A dedicated staff provides continuous monitoring,

TABLE 1 Temporal Trends in Stent Use During SVG PCI Performed During 2008–2011 in the VA Health System Nationwide

Use All 2008 2009 2010 2011

All PCIs Non-SVG 37,903 (91.0) 7,855 (90.2) 8,660 (90.3) 10,458 (91.4) 10,930 (91.7)

SVG 3,762 (9.0) 856 (9.8) 935 (9.7) 988 (8.6) 983 (8.3)

Study cohort BMS 922 (37.3) 280 (50.1) 228 (35.7) 218 (34.3) 196 (30.7)

DES 1549 (62.7) 279 (49.9) 410 (64.3) 417 (65.7) 443 (69.3)

Values are n (%). The p value for the overall temporal trend from 2008 to 2011 was <0.001.

BMS ¼ bare-metal stent(s); DES ¼ drug-eluting stent(s); FY ¼ fiscal year; PCI ¼ percutaneous coronary intervention; SVG ¼ saphenous vein graft.

J A C C V O L . 6 4 , N O . 1 7 , 2 0 1 4 Aggarwal et al.O C T O B E R 2 8 , 2 0 1 4 : 1 8 2 5 – 3 6 DES Safety in SVG PCI

1827

maintenance, and updating of the application. Qualitychecks of CART data are periodically conducted forcompleteness and accuracy. Additional details ofCART and the validity, completeness, and timelinessof the CART data were previously described (8).

EXPOSURE VARIABLE. The primary exposure vari-able of interest was type of stent received during theindex SVG-PCI. Stents used during the procedurewere characterized as BMS or DES, and patientsreceiving both stent types were excluded from the

TABLE 2 Baseline Demographic and Clinical Characteristics of the Ov

Unmatched Cohort

All(n ¼ 2,471)

BMS(n ¼ 922)

DES(n ¼ 1,549)

Age, yrs 67 (62–75) 68 (62–77) 66 (62–75)

Male 2,456 (99.4) 921 (99.9) 1,535 (99.1)

White 2,250 (91.1) 846 (91.8) 1,404 (90.6)

Hypertension 2,404 (97.3) 894 (97.0) 1,510 (97.5)

Hyperlipidemia 2,385 (96.5) 881 (95.6) 1,504 (97.1)

Diabetes mellitus 1,474 (59.7) 526 (57.0) 948 (61.2)

Tobacco use 1,413 (57.2) 516 (56.0) 897 (57.9)

Obese 1,156 (46.8) 390 (42.3) 766 (49.5)

CHF 914 (37.0) 359 (38.9) 555 (35.8)

COPD 624 (25.3) 247 (26.8) 377 (24.3)

Stroke/TIA 741 (30.0) 285 (30.9) 456 (29.4)

PVD 903 (36.5) 341 (37.0) 562 (36.3)

Kidney disease 412 (16.7) 170 (18.4) 242 (15.6)

Previous PCI 1,752 (70.9) 659 (71.5) 1,093 (70.6)

Previous MI 1,265 (51.2) 455 (49.3) 810 (52.3)

PCI indication

STEMI 101 (4.1) 51 (5.5) 50 (3.2)

NSTEMI 667 (27.0) 272 (28.5) 395 (25.5)

Unstable angina 732 (29.6) 258 (28.0) 474 (30.6)

ACS-unknown details 55 (2.2) 27 (2.9) 28 (1.8)

Stable angina 651 (26.3) 190 (20.6) 461 (29.8)

Chest pain 92 (3.7) 38 (4.1) 54 (3.5)

No angina 36 (1.5) 21 (2.3) 15 (1.0)

Other 137 (5.5) 68 (7.4) 69 (4.5)

Cardiogenic shock 26 (1.1) 11 (1.2) 15 (1.0)

Values are median (interquartile range) or n (%).

ACS ¼ acute coronary syndrome; CHF ¼ congestive heart failure; COPD ¼ chronic obelevation myocardial infarction; PVD ¼ peripheral vascular disease; STEMI ¼ ST-segmentin Table 1.

study cohort. Stent type is a discrete data elementselected by the physicians from a pull-down list in theCART-CL software application. First-generation DESwas defined as paclitaxel-eluting or sirolimus-elutingstent, and second-generation DES was defined aseverolimus-eluting or zotarolimus-eluting stent.Quality and validity of data entered into CART werepreviously described (8).

OUTCOME ASSESSMENT. Outcomes assessed includedboth short-term (procedure-related in-laboratory

erall and Propensity-Matched Cohorts

Propensity-Matched Cohort

p ValueAll

(n ¼ 1,796)BMS

(n ¼ 895)DES

(n ¼ 901) p Value

<0.001 68 (62–76) 68 (62–76) 68 (62–76) 0.76

0.44 1,721 (95.8) 862 (96.3) 859 (95.3) 0.45

0.59 1,579 (87.9) 788 (88.0) 791 (87.8) 0.80

0.13 1,676 (93.3) 838 (93.6) 838 (93.0) 1.00

0.01 1,660 (92.4) 829 (92.6) 831 (92.2) 0.81

0.03 987 (55.0) 500 (55.9) 487 (54.1) 0.53

0.28 991 (55.2) 484 (54.1) 507 (56.3) 0.26

<0.001 769 (42.8) 372 (41.6) 397 (44.1) 0.23

0.15 644 (35.9) 337 (37.7) 307 (34.1) 0.14

0.20 447 (24.9) 227 (25.4) 220 (24.4) 0.70

0.49 543 (30.2) 269 (30.1) 274 (30.4) 0.80

0.80 650 (36.2) 325 (36.3) 325 (36.1) 1.00

0.08 294 (16.4) 159 (17.8) 135 (15.0) 0.12

0.77 1,248 (69.5) 622 (69.5) 626 (69.5) 0.83

0.12 874 (48.7) 426 (47.6) 448 (49.7) 0.29

<0.001 82 (4.6) 41 (4.6) 41 (4.6) 0.70

515 (28.7) 252 (28.1) 263 (29.2)

491 (27.3) 253 (28.3) 238 (26.4)

39 (2.2) 24 (2.7) 15 (1.7)

393 (21.9) 187 (20.9) 206 (22.9)

64 (3.6) 35 (3.9) 29 (3.2)

29 (1.6) 16 (1.8) 13 (1.4)

115 (6.4) 56 (6.3) 59 (6.5)

0.61 21 (1.2) 9 (1.0) 12 (1.3) 0.51

structive pulmonary disease; MI ¼ myocardial infarction; NSTEMI ¼ non-ST segmentelevation myocardial infarction; TIA ¼ transient ischemic attack; other abbreviations as

TABLE 3 Procedural

Target native vessel

Diagonal

LAD

OM/ramus/LPL

RCA/PDA/RPL/RPAV

Other

Unknown

Graft lesion location

Anastomotic

Aortic-Ostial

Body

Unknown

Procedure details

Fluoroscopy time, m

Contrast, mL

Embolic protection d

Number of stents

1

2

3

>3

Pre-TIMI flow grade

0

1

2

3

Unknown

Post-TIMI flow grade

0

1

2

3

Unknown

Values are n (%) or median

LAD ¼ left anterior desceRPL ¼ right posterolateral



1828

complications) and long-term (mortality and MI)outcomes.

1. Procedure-related in-laboratory complications. Weassessed the incidence of death, periprocedural MI,no-reflow, dissection, perforation, and acute targetvessel closure. The treating physician directlyentered this information into CART-CL as adiscrete data element (8).

2. Myocardial infarction. We used the VA national pa-tient care database to assess the occurrence andtiming of MI hospitalizations that were based onvalidated inpatient primary International Classifi-cation of Diseases, ninth revision (ICD-9) dischargediagnosis codes (10). A random sample of MI

Characteristics of the Entire and Propensity-Matched Cohorts

Unmatched CohortN ¼ 2,471

AllBMS

(n ¼ 922)DES

(n ¼ 1,549) p Value

<0.01

413 (14.4) 116 (10.9) 297 (16.4)

162 (5.7) 63 (5.9) 99 (5.5)

1,203 (42.0) 451 (42.5) 752 (41.6)

1,048 (36.6) 414 (39.1) 634 (35.1)

24 (0.8) 8 (0.8) 16 (0.9)

17 (0.6) 8 (0.8) 9 (0.5)

<0.01

314 (11.0) 76 (7.2) 238 (13.2)

598 (20.9) 217 (20.5) 381 (21.1)

1,875 (65.4) 751 (70.8) 1,124 (62.2)

80 (2.8) 16 (1.5) 64 (3.5)

in 25 (17–39) 26 (17–40) 25 (16–37) 0.01

230 (150–335) 235 (160–350) 230 (150–327) 0.20

evice 936 (37.9) 360 (38.9) 576 (37.3) 0.41

0.22

2,421 (84.4) 889 (83.9) 1,532 (84.8)

326 (11.4) 116 (10.9) 210 (11.6)

78 (2.7) 36 (3.4) 42 (2.3)

42 (1.5) 19 (1.8) 23 (1.3)

0.04

121 (4.2) 54 (5.1) 67 (3.7)

144 (5.0) 54 (5.1) 67 (3.7)

516 (18.0) 197 (18.6) 319 (17.7)

1,859 (64.8) 690 (65.1) 1,169 (64.7)

227 (7.9) 65 (6.1) 162 (9.0)

<0.01

19 (0.7) 10 (0.9) 9 (0.5)

16 (0.6) 10 (0.9) 6 (0.3)

59 (2.1) 30 (2.8) 29 (1.6)

2,544 (88.7) 943 (89.0) 1,601 (88.6)

229 (8.0) 67 (6.3) 162 (9.0)

(IQR).

nding artery; LPL¼ left posterolateral artery; OM ¼ obtuse marginal; PDA ¼ posterior descenartery; TIMI ¼ Thrombolysis In Myocardial Infarction; other abbreviations as in Tables 1 an

patients also underwent individual chart reviewto validate this outcome in accordance with thethird universal definition of MI (11). Codes for MIhospitalizations during the first 14 days afterPCI discharge date were subsequently disregardedbecause a review of cases showed that most of thesecodes were related to the index hospitalization.

3. All-cause mortality. The VA vital status file wasused to assess mortality outcome. This file has98.3% sensitivity and 97.6% exact agreement withdates compared with the National Death Index (12).

STATISTICAL ANALYSIS. Comparison of baselinecharacteristics and in-laboratory complications be-tween the DES and BMS groups were performed using

Propensity-Matched CohortN ¼ 1,796

AllBMS

(n ¼ 895)DES

(n ¼ 901) p Value

0.04

266 (13.3) 109 (11.0) 157 (15.5)

118 (5.9) 56 (5.7) 62 (6.1)

845 (42.3) 419 (42.4) 426 (42.1)

738 (36.9) 390 (39.4) 348 (34.4)

19 (1.0) 8 (0.8) 11 (1.1)

14 (0.7) 7 (0.7) 7 (0.7)

<0.001

202 (1.1) 72 (3.7) 130 (12.9)

414 (20.7) 208 (21.0) 206 (20.4)

1,330 (66.5) 694 (70.2) 636 (62.9)

54 (2.7) 15 (1.5) 39 (3.9)

25 (17–39) 26 (17–40) 25 (16–37) 0.08

230 (160–341) 232 (160–350) 230 (159–334) 0.57

647 (37.4) 332 (38.4) 315 (36.5) 0.40

0.18

1,676 (83.8) 827 (83.6) 849 (84.0)

233 (11.7) 108 (10.9) 125 (12.4)

58 (2.9) 36 (3.6) 22 (2.2)

33 (1.7) 18 (1.8) 15 (1.5)

0.09

96 (4.8) 52 (5.3) 44 (4.4)

94 (4.7) 51 (5.2) 43 (4.3)

376 (18.8) 184 (18.6) 192 (19.0)

1,284 (64.2) 643 (65.0) 641 (63.4)

150 (7.5) 59 (6.0) 91 (9.0)

<0.01

14 (0.7) 10 (1.0) 4 (0.4)

15 (0.8) 10 (1.0) 5 (0.5)

40 (2.0) 26 (2.6) 14 (1.4)

1,778 (88.9) 882 (89.2) 896 (88.6)

153 (7.7) 61 (6.2) 92 (9.1)

ding artery; RCA ¼ right coronary artery; RPAV ¼ right posterior arteriovenous artery;d 2.


1829

Pearson chi-square or Fischer’s exact test for categor-ical variables and Mann-Whitney-Wilcoxon nonpara-metric tests for continuous variables. Binary logisticregression was used to estimate propensity forreceiving a DES. The following variables were consid-ered for inclusion in the propensity score model:age, sex, white race, ethnicity, cardiogenic shockon arrival, PCI indication, diabetes, hypertension,hyperlipidemia, history of tobacco use, cerebrovascu-lar disease, peripheral vascular disease (PVD), previ-ous PCI, previous MI, and fall risk. These variableswere included on the basis of clinical rationale and/orprevious studies. Fall risk was a categorical variableon the basis of the Morse Fall Scale results from6 months before the procedure, with a score of <25being low-risk; 25 to 45, moderate-risk; and >45, high-risk (13). When the Morse Fall Scale was missing, weassumed low risk. There was adequate overlap in pro-pensity scores for DES and BMS cases. A greedy 5-to-1matching algorithm was used to create a 1-to-1matched cohort (i.e., 1 BMS case matched to 1 DEScase). Balance in the matched cohort was evaluatedusing standardized differences for all covariates.An absolute difference of <10% in all variables iscommonly considered adequate balance (14). Themaximum standardized difference in the chosencohort was 7.8%. The C statistic for the propensityscore model was 0.6319. We compared outcomes ofpatients receiving DES versus those receiving BMS inthe propensity-matched cohort. We used the Kaplan-Meier method to determine event-free survival andcompared the 2 groups using the log-rank test, survivalcurves, and the estimated event rates at 1 and 2 years.

TABLE 4 Procedure-Related In-Laboratory Complications Seen in the

Complication

Unmatched Cohort

All(n ¼ 2,471)

BMS(n ¼ 922)

DES(n ¼ 1,549)

No complication 2,409 (97.5) 900 (97.6) 1,509 (97.4)

Dysrhythmia 19 (0.8) 10 (1.1) 9 (0.6)

Periprocedural MI 12 (0.5) 9 (1.0) 3 (0.2)

Pulmonary edema 2 (0.1) 1 (0.1) 1 (0.1)

Cardiogenic shock 3 (0.1) 3 (0.3) 0 (0)

Stroke 1 (0.04) 0 (0) 1 (0.1)

Death during procedure 1 (0.04) 0 (0) 1 (0.1)

No reflow 82 (3.3) 45 (4.9) 37 (2.4)

Dissection 15 (0.6) 3 (0.3) 12 (0.8)

Perforation 13 (0.5) 10 (1.1) 3 (0.2)

Acute closure 5 (0.2) 4 (0.4) 1 (0.1)

Successful reopening 2 (0.1) 1 (0.1) 1 (0.1)

Other complications 27 (1.1) 5 (0.5) 22 (1.4)

Values are n (%).

Abbreviations as in Tables 1 and 2.

We also fit Cox proportional hazard models in thepropensity-matched cohort, with stent type as thepredictor and robust sandwich covariance matrixestimates to account for intrahospital dependence(15). In order to evaluate the proportional hazardsassumption in the Cox model, we used a Kolmogorov-type supremum test of proportionality (16). Thesediagnostic results indicated that the relationshipbetween stent type and outcomes of interest met theproportional hazards assumption. Because a 1-to-1match does not include the entire study cohort,we also performed similar comparisons using theentire study cohort with stabilized inverse probabilityweighting analysis as a sensitivity analysis (17).Our results remained similar and hence are notpresented. We performed 2 additional sensitivityanalyses involving the Cox proportional hazardsmodels described above. First, we included targetnative vessel and lesion location as predictors in theoutcome models in addition to stent type. These werenot included in the propensity model because theyare procedural factors, but they did differ by stenttype after propensity matching. Second, we includedonly stent type as a predictor, as in the main analysis,but we stratified the DES group by DES generation.First-generation DES included paclitaxel-elutingand sirolimus-eluting stents, and second-generationDES included everolimus-eluting and zotarolimus-eluting stents.

For all analyses reported, p values are 2-sided andp values <0.05 were considered significant. All ana-lyses were performed using SAS software version 9.3(SAS Institute, Cary, NC). Institutional Review Boards

Study Cohort Stratified by Stent Type


p ValueAll

(n ¼ 1,796)BMS

(n ¼ 895)DES

(n ¼ 901) p Value

0.63 1,684 (93.8) 840 (93.9) 844 (93.7) 0.54

0.17 16 (0.9) 10 (1.1) 6 (0.7) 0.32

0.01 10 (0.6) 8 (0.9) 2 (0.2) 0.06

1.00 2 (0.1) 1 (0.1) 1 (0.1) 1.00

0.05 3 (0.2) 3 (0.3) 0 (0) 0.25

1.00 1 (0.1) 0 (0) 1 (0.1) 1.00

1.00 1 (0.1) 0 (0) 1 (0.1) 1.00

<0.001 63 (3.5) 42 (4.7) 21 (2.3) 0.01

0.19 11 (0.6) 3 (0.3) 8 (0.9) 0.23

0.01 11 (0.6) 10 (1.1) 1 (0.1) 0.01

0.07 5 (0.3) 4 (0.4) 1 (0.1) 0.37

1.00 2 (0.1) 1 (0.1) 1 (0.1) 1.00

0.04 14 (0.8) 5 (0.6) 9 (1.0) 0.28

0 250 500 750

1.00

0.95

0.90

0.85

0.80

0.75

0.70

Log rank p value = 0.65

365

TIME (DAYS) STENT TYPE MI RATE (95% CL)

730

Time (days)

Myo

card

ial I

nfar

ctio

n

0 250 500 750

1.00

0.95

0.90

0.85

0.80

0.75

0.70

Log rank p value = 0.0004

365

TIME (DAYS) STENT TYPE DEATH RATE (95% CL)

730

Time (days)

Mor

talit

y

7.75 (6.20, 9.70)BMS

6.02 (4.60, 7.80)DES

11.38 (9.40, 13.70)BMS

10.49 (8.60, 12.80)DES

11.65 (9.70, 14.00)BMS

8.80 (7.10, 10.90)DES

21.07 (18.40, 24.00)BMS

15.46 (13.20, 18.10)DES

CENTRAL ILLUSTRATION Probability of Experiencing Myocardial Infarction or Mortality

Kaplan-Meier curves are shown for probability of experiencing myocardial infarction or mortality in the propensity-matched cohort.

BMS ¼ bare-metal stent(s); DES ¼ drug-eluting stent(s); MI ¼ myocardial infarction.



1830

at the VA Eastern Colorado Health Care Systemsapproved this study.

RESULTS

PATIENT POPULATION. Between October 1, 2007 andSeptember 30, 2011, a total of 3,762 SVG interventionswere performed nationwide in the VA healthcaresystem. Those patients with previous SVG in-terventions were excluded, and 2,825 new patientswho underwent index SVG-PCI (first SVG-PCI proce-dure during the study period) were identified. Afterexcluding 176 patients who did not receive a stentand 178 patients who received both BMS and DES,the final cohort included 2,471 patients (65.7%),

and the propensity-matched cohort had 1,796patients (47.7%) (Figure 1), matching 1 BMS patientto 1 DES patient. Overall, DES were used morefrequently, increasing from 50% of SVG-PCIs in 2008to 69% by 2011 (Table 1). Of those receiving a DES,34% (n ¼ 519) received first-generation DES, andthe remainder (n ¼ 1030 [66%]) received second-generation DES.

BASELINE CHARACTERISTICS. Table 2 describes thebaseline pre-procedural characteristics for the entirecohort and for the propensity-matched cohort. Themean age of veterans undergoing SVG-PCI was 67years, 99.4% were males, and 91% were Caucasian.Compared with patients receiving BMS, patientsreceiving DES were younger (68 vs. 66 years,

1.00

0.80

0.75

0.700 250

Log rank p value= 0.7311

500

Time (Days)

Myo

card

ial I

nfar

ctio

n

750

0.85

0.95

0.90

Time (days)

365

730

BMS 7.75 (6.20, 9.70)4.64 (2.90, 7.40)

7.03 (5.10, 9.70)

11.38 (9.40, 13.70)

11.16 (8.60, 14.40)

9.48 (6.90, 13.00)

BMS

DES 1st gen

DES 2nd gen

DES 1st gen

DES 2nd gen

Stent type Event rate

FIGURE 2 Kaplan-Meier Curves for Probability of

Experiencing Myocardial Infarction in the


MI ¼ myocardial infarction; other abbreviations as in Figure 1.

TABLE 5 Adjusted Mortality and Myocardial Infarction Rates Seen

in the Study Cohort Stratified by Stent Type

MortalityHR (95% CI)

Myocardial InfarctionHR (95% CI)

DES 2nd generation vs. BMS 0.65 (0.50–0.84) 1.00 (0.72–1.36)

DES 1st generation vs. BMS 0.78 (0.61–1.00) 0.88 (0.62–1.23)

DES 2nd generation vs.1st generation

0.83 (0.66–1.06) 1.13 (0.81–1.58)

1st-generation DES include paclitaxel-eluting and sirolimus-eluting stents; 2nd-generation stentsrefer to everolimus-eluting and zotarolimus-eluting stents.

CI ¼ confidence interval; HR ¼ hazard ratio; other abbreviations as in Table 1.


1831

respectively; p <0.001) but were more likely tohave hyperlipidemia (95.6% vs. 97.1%, respectively;p ¼ 0.01) and diabetes mellitus (57.0% vs. 61.2%,respectively; p ¼ 0.03). There were no significantdifferences between baseline characteristics of the 2comparison groups after propensity matching, andthe maximum standardized difference was 7.8% (datanot shown).

PROCEDURAL CHARACTERISTICS. Table 3 showsbaseline comparisons of procedural characteristics forthe overall and propensity-matched cohorts. The mostcommon native vessel territories receiving SVG-PCIwere the circumflex/ramus, followed by the right cor-onary artery. Patients receiving SVG-PCI in the rightcoronary artery territory were more likely to receive aBMS both in the overall and propensity-matchedcohorts. Conversely, those receiving SVG-PCI in thediagonal territory were more likely to receive a DES.Furthermore, the graft lesion location in patientsreceiving a BMS was more likely to be in the SVG bodyand less likely to be anastomotic, compared with thosereceiving a DES. Overall, an embolic protection devicewas used in a third of all SVG-PCIs, and there were nodifferences in the use of embolic protection by stenttype in either the overall or propensity-matchedcohorts. Use of contrast medium was also similar inboth (DES and BMS) stent subgroups. Additionally,there were no significant differences in number ofstents placed during index SVG-PCI.

CLINICAL OUTCOMES. Procedure-related in-laboratorycomplications. Table 4 shows all reported procedure-related in-laboratory complications for the overalland propensity-matched cohorts. The incidence ofany procedure-related in-laboratory complication inthe overall cohorts was 2.5%, with no differences bystent type. No-reflow was the most common peri-procedural complication and was noted in 82 (3.3%)patients overall, with a higher incidence in patientsreceiving a BMS compared with those receiving DES(4.9% vs. 2.4%, respectively; p < 0.001), even afterpropensity matching (4.7% vs. 2.3%, respectively; p ¼0.01). Periprocedural MI and dissection were notedin 19 patients (0.8%) and 15 patients (0.6%), respec-tively. Compared with patients receiving BMS, theincidence rates of periprocedural MI and dissectionwere similar after propensity matching among thosereceiving a DES. Vessel perforation during SVG-PCIwas seen in 13 patients (0.5%) with a significantlyhigher incidence in the BMS group before (10 vs. 3patients, respectively; p ¼ 0.01) and after (10 vs. 1patient, respectively; p ¼ 0.01) propensity matching.Furthermore, there was only 1 periprocedural deathin the overall cohort. There were no significant

differences in the incidence rates of proceduraldysrhythmia, pulmonary edema, cardiogenic shock,or stroke in the 2 comparison groups.Myocard ia l infarct ion . In the year following PCI,there were 119 MI events (6.6%) in the propensity-matched cohort; 67 (7.5%) among BMS patients, and52 (5.8%) among DES patients. Kaplan-Meier esti-mated 1-year MI event rates in the propensity-matched cohort were similar to the overall cruderates. In the propensity-matched cohort, there wereno differences in the hazard of experiencing MI inpatients receiving a DES compared with thosereceiving a BMS (hazard ratio [HR]: 0.94; 95%



1832

confidence interval [CI]: 0.71 to 1.24) (CentralIllustration) over a mean follow-up of 30 months.These results remained similar after adjusting forindividual lesion location and target native vessel(HR: 0.98; 95% CI: 0.74 to 1.29). Similarly, no signif-icant differences in MI rates were noted betweenpatients receiving second-generation DES and thosereceiving first-generation DES (Figure 2, Table 5).Morta l i ty . In the year following PCI, there were 177deaths (9.9%) in the propensity-matched cohort: 101(11.3%) among BMS patients and 76 (8.4%) amongDES patients (p ¼ 0.04). In the propensity-matchedcohort, patients receiving DES were less likely toexperience mortality (HR: 0.72; 95% CI: 0.57 to 0.89)(Central Illustration) compared with patients withBMS SVG-PCI over a mean follow-up of 33 months.These results remained unchanged, even afterincluding individual lesion location and targetnative vessel (HR: 0.71; 95% CI: 0.56 to 0.89).Repeat analysis after stratifying the DES cohort intofirst-generation and second-generation DES showedthat patients receiving second-generation DES hadlower mortality rates, but this difference in mortal-ity between second-generation and first-generationDES was not statistically significant (Figure 3,Table 5).

1.00

0.80

0.75

0.700 250

Log rank p value= 0.0010

500

Time (Days)

Mor

talit

y

750

0.85

0.95

0.90

Time (days)

365

730

BMS 11.69 (9.70, 14.00)7.92 (5.60, 11.20)

9.44 (7.20, 12.40)

21.07 (18.40, 24.00)

15.43 (12.40, 19.00)

15.32 (12.00, 19.50)

BMS

DES 1st gen

DES 2nd gen

DES 1st gen

DES 2nd gen

Stent type Event rate

FIGURE 3 Kaplan-Meier Curves for Probability of Mortality

in the Propensity-Matched Cohort

Abbreviations as in Figure 1.

DISCUSSION

The objective of this study was to describe contem-porary patterns of stent use and outcomes amongveterans undergoing SVG-PCI nationwide. We ob-served that DES were used twice as often as BMSduring SVG-PCI and that DES use increased over timecompared with BMS. Overall complication rates werelow and did not differ by stent type. We observedlower all-cause mortality and similar MI rates withDES than with BMS on longitudinal follow-up afterpropensity matching. Therefore, the safety of DESversus BMS is observed in patients undergoing SVG-PCI and is associated with similar rates of MI andreduced rates of death.

PREVIOUS STUDIES. Although both randomizedcontrolled trials and observational studies haveattempted to address the question of optimal stenttype for SVG-PCI, conflicting results have been seenwith the 2 study designs. In the RRISC (Reduction ofRestenosis In Saphenous vein grafts with Cypherstent) trial, despite a reduction in 6-month restenosisand repeat revascularization rate, higher mortality at32 months in patients receiving DES raised concernsabout their safety in SVG-PCI (6,7). However, therewere no deaths among patients receiving BMS duringthe follow-up period, and patients receiving DES weremandated to receive dual anti-platelet therapy foronly 2 months, which could potentially explainhigher rates of mortality in the DES group. The SOS(Stenting of Saphenous Vein Grafts) trial was poweredto examine differences in angiographic outcomesonly; hence, there were no significant differencesdetected in clinical outcomes between patientsreceiving DES versus BMS (4). More recently, in theISAR-CABG (drug-eluting versus bare-metal stents insaphenous vein graft lesions) trial, the use of DES wasassociated with lower risk of a composite of death,MI, and target lesion revascularization (TLR) (5).However, the follow-up duration was shorter (12months) than in the RRISC trial. Subsequently,smaller observational studies and their meta-analyseshave compared DES with BMS in SVG-PCI and showedlower TLR and target vessel revascularization (TVR),but those studies were either underpowered ortoo heterogeneous to draw any conclusions aboutlong-term safety (mortality) of DES in such patients(5,18–22). Table 6 (4–7,15,18,20,23–39) summarizes theexisting evidence comparing DES versus BMS and howthey differ from our study. Overall, given the lack oflarger original studies, this reduction in TVR or TLRwith DES use has never been consistently extended tomortality and major cardiovascular outcomes.

TABLE 6 Summary of Existing Evidence Comparing DES With BMS in SVG-PCI

First Author (Ref. #)

Number ofPatients

Study EndpointsFollow-UpDuration Results LimitationsBMS DES

Retrospective cohort

Assali et al. (23) 43 68 TLR, TVR, MI, death 24 months DES with lower TLR, TVR. Statisticallynon-significant difference fordeath and MI.

Small sample size, underpoweredfor death and MI as outcomes.

Bansal et al. (24) 72 37 Death, MI, restenosis, stentthrombosis, TLR, TVR

36 months No difference between DES and BMSfor any outcome assessed.

Small sample size, underpoweredto assess differences in endpoints.

Gioia et al. (25) 72 99 Death, STEMI, TLR, TVR 24 months No difference between DES and BMSfor any outcome assessed.

Small sample size, underpoweredto assess differences in endpoints,matched for only 2 variables.

Goswami et al. (26) 95 284 Mortality, MI, TLR,stent thrombosis


Small sample size, underpoweredto assess differences in endpoints.

Kaplan et al. (27) 33 37 TLR, TVR, mortality, MI,composite of all as MACE

12 months DES use associated with lower TLR,TVR and MACE. No differencefor MI and death.

Only ostial SVG lesions assessed.Short follow-up, small size,underpowered to assessdifferences for death and MI.

Lee et al. (15) 84 139 Death, MI, TVR 9 months Lower unadjusted death, TVR, MI withDES use. Multivariable adjustmentnot possible.

Small size, very few events(4 deaths, 23 MI, and 55 TVR),short duration of follow-up.

Lozano et al. (28) 113 98 Death, TVR 30 months No difference between DES and BMSfor any outcome assessed.

Small size, few events, historicalBMS group used as control.

Minutello et al. (29) 50 59 Death, MI, TVR, TLR,Stent thrombosis

20 months Lower TVR with DES use. No differencebetween BMS and DES for otheroutcomes.

Historical BMS cohort, smallersample size and shorter durationof follow-up, underpowered todetect differences in outcomes.

Okabe et al. (20) 344 138 TLR, TVR, death, MI,stent thrombosis


Small size, underpowered toassess difference.

Ramana et al. (30) 170 131 TLR, TVR, death, MI, compositeof all as MACE

34 months Unadjusted event rates lower in DESfor all outcomes. No differencebetween BMS and DES for anyoutcome assessed aftermultivariable adjustment.


van Twisk et al. (31) 128 122 Mortality, composite ofmortality, MI, TVR



Prospective cohort

Brodie et al. (18) 343 785 TVR, TLR, death, MI, death/MI,death/MI/TVR

24 months DES with lower death, TVR and death/MI/TVR. No difference for MI only,TLR and death/MI.

Smaller sample size comparedwith our study.

Chu et al. (32) 57 48 Death, MI, TLR, TVR, TLR/MACE,TVR/MACE


Smaller sample size and shorterduration of follow-up, lackof propensity matching ormultivariable adjustmentin examining association.

Ellis et al. (33) 175 175 TVR, death 12 months No difference in TVR/death. Smaller sample size and shorterduration of follow-up.

Ge et al. (34) 89 61 Death, MI, TLR, TVR 6 months DES use associated with fewer TLRand TVR. No difference for MI, death.

Smaller sample size and shorterduration of follow-up, lackof propensity matching inexamining association.

Hoffmann et al. (35) 60 60 MACE (composite of MI, TLR,death, MI, TVR), TLR

6 months DES use associated with lesserMACE and TLR.

Smaller sample size, shortduration of follow-up.

Shishehbor et al. (36) 349 217 Composite of mortality, MI, TLR 35 months No difference in outcome betweenDES and BMS.

Small cohort size. HistoricalBMS cohort used.

Vignali et al. (37) 288 72 MACE (composite of mortality,re-infarction, TVR)

12 months No difference in outcome betweenDES and BMS.

Smaller sample size, short durationof follow-up, underpoweredto assess difference.

Wöhrle et al. (38) 26 13 MACE (composite of mortality,TVR, and MI)

12 months DES use associated with lower MACE. Small sample size, short follow-upduration.

Continued on the next page


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STUDY IMPLICATIONS. Our study addresses this gapin knowledge by demonstrating improved long-termsafety in clinical outcomes among patients receivingDES during SVG-PCI. To the best of our knowledge,

our cohort is one of the largest, with one of thelongest durations of outpatient follow-up, of anypublished study on this subject. Additionally, in ourcohort, most patients receiving DES received a

TABLE 6 Continued

First Author (Ref. #)

Number ofPatients

Study EndpointsFollow-UpDuration Results LimitationsBMS DES

Randomized controlled trials

Brilakis et al. (4) 39 41 In-stent restenosis, death,MI, TVR, TLR

18 months DES use associated with lower in-stentrestenosis and TLR. Other outcomesstatistically non-significant.

Due to small sample size, lack ofpower in examining clinicallyrelevant outcomes includingMI and death.

Jeger et al. (39) 13 34 MACE (death, MI, TVR) 18 months DES use associated with lower incidenceof MACE driven by TVR.

Secondary analysis of BASKETrandomized clinical trial.

Vermeersch et al. (6) 37 38 In-stent lumen loss, angiographicrestenosis, MACE (death, MI,TLR, TVR)

6 months DES use associated with lowerangiographic in-stent lumen loss.No difference in MACE.

Small sample size resulted in theclinical trial being underpoweredfor clinical outcomes.

Vermeersch et al. (7) 37 38 Mortality, MI, TVR 32 months DES associated with greater mortalitycompared with BMS. No differencein MI and TVR.

Secondary post-hoc analysis of RRISCtrial, patients on DES mandatedto receive only 3 months of dualanti-platelet therapy.

Mehilli et al. (5) 307 303 Composite of death, MI, TLR 12 months DES associated with lower compositeof MI, death, and TLR. Incidence ofTLR lower with DES withoutdifference in death or MI.

Shorter follow-up duration comparedwith our study.

For the search strategy, see the Online Appendix.

MACE ¼ major adverse cardiovascular events; SVG-PCI ¼ saphenous vein graft percutaneous coronary intervention; TLR ¼ target lesion revascularization; TVR ¼ target vessel revascularization;other abbreviations as in Tables 1 and 2.



1834

second-generation DES, which suggests that second-generation DES and BMS have comparable safety.

The fact that previous observations showed amortality benefit with DES and that second-generation DES have safety profiles comparable toBMS and first-generation DES (40,41) may explainwhy our results differ from those of previous studies.Furthermore, our results show trends with respectto stent type used, with close to 7 of 10 patientsreceiving DES during SVG-PCI by 2011, despite a lackof definitive evidence for their clinical safety andeffectiveness. We observed relatively lower incidenceof no-reflow with DES, but given the observationalnature of this dataset, this could also have resultedfrom underlying, unmeasured confounders. One po-tential confounder not accounted for in this analysiswas vein graft size, and previous reports suggestedhigher incidence of no-reflow with larger vein grafts(42). It is, therefore, plausible that larger vein graftspreferentially received BMS, as they were too largefor a DES. We believe this observation is potentiallyhypothesis-generating and should be explored insubsequent analyses. These results highlight theneed for future research directed toward testingthe efficacy of new generation DES compared withBMS in patients undergoing SVG-PCI by assessingclinically relevant outcomes rather than angiographicdifferences.

STUDY LIMITATIONS. First, our cohort wascomposed exclusively of U.S. veterans; this cohort ispredominantly male and has a high burden of

comorbidities, including coronary artery disease. Ourresults do not necessarily generalize to cohortsunder-represented in this study (e.g., women or non-U.S. populations). However, most clinical trialsinclude VA patients, and previous coronary diseasereports showed outcomes for VA patients that werecomparable to those for non-VA patients (43). The VAhealthcare system is the largest integrated healthcaresystem in the United States and provides a uniqueopportunity to assess procedural characteristics andoutcomes due to the high reliability and validity of itsdata sources. Second, MI event rates were potentiallyunderestimated, secondary to non-VA healthcare use.We attempted to minimize this by acquiring data forhospitalizations outside of the VA system via linkageto fee-based files (care paid for by the VA but whichoccurred outside the VA system). Third, MI outcomeswere determined using ICD-9 codes, and only arandom sample of MI patients underwent individualchart reviews for validation in accordance with thethird universal definition of MI (11). The VA vital in-dex file, which has a very high sensitivity for mor-tality, was used for all-cause mortality, and ICD-9code algorithms used in this study for MI rates werepreviously validated in VA cohorts (10,12). Addition-ally, we did not have data for cardiac mortality, spe-cifically, and angiographic data to capture TLR or TVRas an endpoint. We would also like to caution againstextrapolating these results toward arterial conduitinterventions, as this report focused on SVG in-terventions. Fourth, as with all observational studies,

PERSPECTIVES

COMPETENCY IN MEDICAL KNOWLEDGE: The long-term

outcomes of PCI for patients with stenotic lesions in SVG are

generally worse than those associated with PCI for native coro-

nary arteries.

TRANSLATIONAL OUTLOOK: Although this propensity-

matched comparison of the use of BMS versus DES in a cohort of

veterans undergoing PCI for SVG disease suggests favorable

clinical outcomes with DES, future research should examine the

impact of later-generation DES devices on clinical outcomes

related to ischemic heart disease.


1835

residual confounding cannot be entirely eliminated.Nonetheless, we used robust statistical methods suchas propensity scores and accounted for a large num-ber of covariates in an attempt to minimize this.

CONCLUSIONS

These results suggest that DES use in SVG-PCI is safeand effective in a large national cohort of veterans.While we await results of larger randomized trials(such as the DIVA trial) to better establish the efficacyof drug-eluting stents in SVG-PCI, these findings arereassuring and helpful to clinicians in stent selectionduring SVG-PCI.

REPRINT REQUESTS AND CORRESPONDENCE: Dr.Thomas T. Tsai, VA Eastern Colorado HealthcareSystem, Department of Veterans Affairs, 1055

Clermont Street (111B), Denver, Colorado 80220-3808.E-mail: [email protected].

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KEY WORDS bare-metal stent, drug-eluting stent, percutaneous coronaryintervention, repeat revascularization,saphenous venous graft

APPENDIX For supplemental information,please see the online version of this article.






































































































safety and effectiveness of drug-eluting versus bare-metal ...background stenosis of saphenous vein...

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