thrombus predicts ischemic complications during percutaneous coronary intervention in saphenous vein...

CORONARY ARTERY DISEASE

Original Studies

Thrombus Predicts Ischemic Complications DuringPercutaneous Coronary Intervention in Saphenous

Vein Grafts: Results From TARGET (Do Tirofibanand ReoPro Give Similar Efficacy Trial?)

Arun Kalyanasundaram,1* MD, MPH, James C. Blankenship,1 MD, Peter Berger,1 MD,Howard Herrmann,2 MD, Rick McClure,3 MD, and David Moliterno,3 MD

Background: Saphenous vein graft (SVG) percutaneous coronary intervention (PCI)carries a high risk of ischemic complications. However, there are scant recent data toidentify which SVG lesions carry particularly high risk in recent years. We studieddemographic and angiographic factors associated with ischemic complications afterSVG PCI without distal protection in the TARGET (do tirofiban and reopro give similarefficacy trial?) study. Methods: TARGET was a multicenter double-dummy, double-blinded study randomizing 4,809 PCI patients to tirofiban or abciximab. Of these, 254patients underwent PCI involving an SVG lesion. The primary endpoint of this analysiswas major adverse cardiac events (MACEs) at 30 days, including death, nonfatal myo-cardial infarction (MI), and urgent target vessel revascularization. Results: No demo-graphic characteristic was associated with 30-day MACE. Lesion length > 20 mm (oddsratio [OR] = 2.7, P = 0.03), thrombus (OR = 3.9, P = 0.003), eccentricity (P = 0.001),thrombolysis in myocardial infarction flow < 3 postprocedure (OR = 5.6, P = 0.037), and>1 target lesion (OR = 2.5, P = 0.035) were univariate variables associated with30-day MACE. Multivariate analysis associated only thrombus (OR = 3.8, P = 0.015) with30-day MACE. No difference in outcomes was noted between patients receiving abcixi-mab and tirofiban. SVG patients had lesser angiographic success (95.6% vs. 98%, P =0.04) and increased 30-day Q-wave MI (2.5% vs. 0.9%, P = 0.039) compared with non-SVG patients, but a similar incidence of death (0% vs. 0.4%), non-Q-MI (5.9% vs. 4.5%),and target vessel revascularization (0.5% vs. 1%). Conclusion: In the era of routinestenting and GpIIb/IIIa inhibitors, thrombus is the angiographic characteristic mostclosely associated with adverse outcomes of SVG PCI ' 2006 Wiley-Liss, Inc.

Key words: glycoprotein IIb/IIIa inhibitors; saphenous vein graft; stents; percutaneouscoronary intervention

INTRODUCTION

Percutaneous coronary intervention (PCI) of saphenousvein bypass graft (SVG) lesions carries an increased riskof distal embolization and myocardial infarction (MI)compared with PCI of native vessels [1,2]. These is-chemic complications are associated with an increasedrisk of in-laboratory adverse angiographic events [3]and adverse clinical events [4,5]. Distal and proximalprotection devices reduce the incidence of distal embo-lization and enzyme elevation [6,7]. However, thesedevices are utilized in fewer than 50% of patientsundergoing PCI of SVG lesions [8].

1Department of Cardiology, Geisinger Medical Center, Danville,Pennsylvania2Cardiovascular Medicine Division, University of PennsylvaniaMedical Center, Philadelphia, Pennsylvania3Division of Cardiovascular Medicine, University of Kentucky,Lexington, Kentucky

*Correspondence to: Arun Kalyanasundaram, Geisinger Medical

Center 21-60, 100 North Academy Drive, Danville PA 17822.

E-mail: [email protected]

Received 5 June 2006; Revision accepted 6 September 2006

DOI 10.1002/ccd.20963

Published online 27 December 2006 in Wiley InterScience (www.

interscience.wiley.com).

' 2006 Wiley-Liss, Inc.

Catheterization and Cardiovascular Interventions 69:623–629 (2007)

Angiographic lesion characteristics might identifypatients at high risk of distal embolization, for whomdistal protection would hold the greatest benefit. How-ever, there are scant data on angiographic predictors ofcomplications from the current era. We studied 254patients enrolled in the TARGET (do tirofiban and reo-pro give similar efficacy trial?) trial undergoingplanned stenting of SVG without distal protection andwith either intravenous tirofiban or abciximab to iden-tify clinical and pre-intervention angiographic factorsassociated with an increased risk of ischemic compli-cations during PCI to SVG [9].

METHODS

Study Population

TARGET was a multicenter, multinational study ran-domizing 4,809 patients undergoing PCI between tirofi-ban and abciximab on a double-dummy, double-blindbasis [9]. Exclusion criteria included acute myocardialinfarction, cardiogenic shock, unprotected left maincoronary artery lesions, decompensated heart failure,renal insufficiency, thrombocytopenia, or bleeding dis-orders. Tirofiban dosing was the same as used in therandomized efficacy study of tirofiban for outcome andrestenosis (10 mcg/kg bolus and 0.15 mcg/kg/min infu-sion for 18–24 hr), a lower dose than that utilized inseveral recent trials [10–12]. (Abciximab dosing was0.25 mg/kg bolus and a 0.125 mcg/kg/min infusion for12 hr. All patients received 250–500 mg of aspirinwithin 24 hr before the procedure and 75–325 mgorally once daily for the duration of the study. Clopi-dogrel was recommended for all patients (300 mg oralloading dose within 2–6 hr of the procedure, followedby 75 mg daily for 30 days). Heparin was weight-adjusted (70 U/kg bolus) and subsequent boluses wereadministered according to a nomogram to achieve anactivated clotting time of 250–300 sec. Procedural suc-cess, in-lab adverse events, and pre- and postprocedurethrombolysis in myocardial infarction (TIMI) flow wererecorded. Creatine kinase (CK) and CK-MB isoenzymeswere measured after the procedure and every 6 hr for24 hr.For this study we analyzed the 254 patients in the

TARGET trial who underwent SVG PCI.

Endpoints

The primary end point of the TARGET trial and ofthis substudy was the occurrence of a major adversecardiac event (MACE), including death, MI, and urgen-t target vessel revascularization (TVR) within 30 days.MI was defined as an elevation of the CK-MB to threetimes the upper limit of normal in two separate blood

samples or by the presence of new Q waves in two ormore contiguous electrocardiographic leads. Secondaryclinical end points included each component of theprimary end point.

Statistical Analyses

The clinical ischemic endpoints in this study werethe primary endpoints used in the TARGET trial. Con-tinuous variables were analyzed as median (25th, 75thpercentiles) and categorical variables as frequencies(percentages). Chi-square analysis was used to studythe incidence of endpoints in the treatment groups.Fisher’s exact test was used when cell sizes were verysmall. Logistic regression was used to determine jointeffect of variables with outcomes. Statistical signifi-cance was inferred when P < 0.05.Analyses of demographic, angiographic, and proce-

dural variables included all 254 SVG PCI patients inTARGET. Of these 254 patients, 50 underwent PCI ofa native coronary lesion at the same session as SVGPCI. To avoid confounding the effects of native coro-nary and SVG PCI, these 50 patients with PCI of bothan SVG and a native coronary lesion were excludedfrom multivariate analyses associating lesion character-istics with MACE, and from analyses of MACE inSVG vs. native coronary lesions.

RESULTS

Among patients undergoing PCI of an SVG, nodemographic characteristic was associated with 30-dayMACE (Table I). Among angiographic variables(Table II), the presence of thrombus correlated withmore frequent MACE at 30 days (odds ratio [OR] ¼3.9, P ¼ 0.003, compared with no thrombus). Otherangiographic factors that correlated with 30-day MACEwere eccentricity (13% vs. 0% for noneccentric lesions,P ¼ 0.001) and length of lesion > 20 mm (OR ¼ 2.7,P ¼ 0.03) (Table II). PCI involving more than one tar-get lesion was associated with increased 30-day MACE(OR ¼ 2.5, P ¼ 0.035) (Table III). Angiographicsuccess (OR ¼ 0.14, P ¼ 0.018) and TIMI-3 flowpostprocedure (OR ¼ 0.18, P ¼ 0.037) were associatedwith fewer 30-day adverse outcomes (Table III).Multivariate analysis, including all demographic, an-

giographic, and procedural variables, associated onlythrombus (OR ¼ 3.8. CI [1.3, 11.1], P ¼ 0.015) to beassociated with 30-day MACE in patients that hadsingle-vessel PCI involving grafts. Length of lesion(OR ¼ 2.6 [0.986, 6.9], P ¼ 0.051), greater than onetarget lesion (OR ¼ 2.5 [0.8, 7.7], P ¼ 0.1), andangiographic success (OR ¼ 0.3 [0.05, 1.8], P ¼ 0.18)showed nonsignificant trends. No difference in 30-day

624 Kalyanasundaram et al.

Catheterization and Cardiovascular Interventions DOI 10.1002/ccd.Published on behalf of The Society for Cardiovascular Angiography and Interventions (SCAI).

MACE was noted between those SVG patients whowere treated with abciximab vs. tirofiban.Among patients whose SVG lesions were eccentric,

thrombotic, or long (>20 mm), the presence of anycombination of these characteristics carried a particu-larly high risk of 30-day MACE. Long thromboticlesions (present in 5% of patients) carried a 25% riskof 30-day MACE (versus 7.0% in all other patients,P ¼ 0.016), long eccentric lesions (present in 12.5%of patients) carried a 25% risk of MACE (versus 6.3%in all other patients, P ¼ 0.014), and thromboticeccentric lesions (present in 21% of patients) carried a22% risk of MACE (versus 3.5% in all other patients,P ¼ 0.001).When PCI of SVG was compared with PCI of non-

SVG lesions (Table IV), SVG patients had lesserangiographic success (95.6% vs. 98%, P ¼ 0.04). Theincidence of 30-day Q-wave MI was higher in theSVG patients when compared with the non-SVGpatients (2.5% vs. 0.9%, P ¼ 0.039), but incidence ofdeath (0% vs. 0.4%), non-Q-MI (5.9% vs. 4.5%), andTVR (0.5% vs. 1%) were not statistically different.

DISCUSSION

This study identified angiographic characteristics thatcorrelated with MACE at 30 days in patients under-going PCI of SVG lesions. Thrombus, lesion length

> 20 mm, and lesion eccentricity were associated withadverse clinical outcomes by univariate analysis;thrombus remained associated in multivariate analyses.Combinations of these characteristics carried particu-larly high risks.While there is extensive data on angiographic char-

acteristics of native coronary lesions that predict ad-verse outcomes, data on SVG lesions are fairly limited[13–17]. Lefkovits et al. found that presence of throm-bus was independently associated with distal emboliza-tion during PCI to graft lesions [18]. Since then, thepresence of thrombus has been used as a surrogate toidentify high-risk SVG lesions [6]. However, data toconfirm that this remains true in the stent era for graftinterventions are scant.Distal and proximal protection devices decrease the

risk of distal embolization and MI during PCI of SVG

TABLE II. Odds Ratios (and 95% CI) for Baseline Angiographic Characteristics of SVG (n = 254) andNon-SVG (n = 4,519) Patients

SVG Non-SVG

N

Any major

adverse cardiac

event

Odds ratio

[95% CI] P N

Any major

adverse cardiac

event

Odds ratio

[95% CI] P

Minimum pre-TIMI flow 0–2 72 9 (13) 1.6 [0.7, 3.8] 0.31 814 64 (8) 1.3 [1.0, 1.7] 0.1

Maximum length > 20 mm 51 9 (18) 2.7 [1.1, 6.6] 0.030 705 77 (11) 2.0 [1.5, 2.6] 0.001

Thrombus 62 12 (19) 3.9 [1.6, 9.3] 0.003 396 36 (9) 1.5 [1.0, 2.1] 0.038

Restenosed lesion 38 2 (5) 0.5 [0.1, 2.1] 0.54 270 18 (7) 1.0 [0.6, 1.7] 0.96

Eccentric 176 23 (13) NA 0.001 2931 224 (8) 1.7 [1.3, 2.2] 0.001

Values in parentheses indicate percentages. SVG, saphenous vein graft; CI, confidence interval; TIMI, thrombolysis in myocardial infarction.

TABLE I. Odds Ratios (and 95% CI) for Demographic Characteristics of SVG (n = 254) and Non-SVG (n = 4,519) Patients

SVG Non-SVG

N

Any major

adverse cardiac

event

Odds ratio

[95% CI] P N

Any major

adverse cardiac

event

Odds ratio

[95% CI] P

Male 201 22 (11) 3.1 [0.7, 28.3] 0.17 3,305 218 (7) 1.0 [0.8, 1.3] 0.99

Diabetes mellitus 84 10 (12) 1.5 [0.6, 3.5] 0.35 1,028 55 (5) 0.8 [0.6, 1.0] 0.068

Dyslipidemia 222 20 (9) 0.7 [0.2, 3.0] 0.71 3,352 209 (6) 0.8 [0.6, 1.0] 0.094

Hypertension 194 18 (9) 0.9 [0.3, 2.4] 0.87 2,895 192 (7) 1.0 [0.8, 1.3] 0.90

Current smoker 32 4 (13) 1.4 [0.3, 4.8] 0.71 1,017 69 (7) 1.0 [0.8, 1.4] 0.78

Previous MI 137 12 (9) 0.8 [0.4, 1.9] 0.68 1,757 129 (7) 1.2 [1.0, 1.5] 0.11

Clopidogrel before procedure 14 2 (14) 1.7 [0.2, 8.2] 0.78 296 16 (5) 0.8 [0.5, 1.3] 0.39

Country—USA 229 24 (10) NA 0.15 3,433 257 (7) 2.1 [1.5, 2.9] 0.001

History of angina 227 21 (9) 0.8 [0.2, 4.6] 0.97 3,821 262 (7) 1.4 [0.9, 1.9] 0.10

Acute coronary syndrome 185 21 (11) 2.8 [0.8, 15.2] 0.13 2,831 215 (8) 1.6 [1.2, 2.1] 0.001

Values in parentheses indicate percentages. SVG, saphenous vein graft; CI, confidence interval.

Ischemic Complications in Graft Interventions 625


[6,16,19–21]. Recent guidelines for PCI advocate theuse of distal embolic protection (as a class I indica-tion) ‘‘when technically feasible in patients undergoingPCI to saphenous vein grafts’’ [22]. However, as oflate in 2005, these devices are used for only a minority(35–40%) of SVG PCI procedures (personal communica-tion, Kate Buckley, Embolic Protection Marketing, Bos-ton Scientific, Natick, MA). Anatomic characteristicspreclude the use of distal protection devices in 20–60%of SVG PCIs [23]. Additional cost and effort for theinterventionist (without reimbursement) may prohibit thediffusion of this technology [8]. Identification of high-risk SVG lesions characteristics may help intervention-ists select SVG patients for whom the extra cost andeffort of embolization protection would be most useful.

SVG vs. Non-SVG Lesions

Balloon angioplasty of SVG lesions is associatedwith worse outcomes compared with procedures involv-

ing the native circulation. A pooled analysis of fiverandomized controlled trials identified lesion locationin an SVG (compared with lesions in the native circu-lation) as a highly significant predictor of death, MI,or urgent revascularization at 30 days and at 6 months[15]. However, in these studies only a limited numberof patients received stents and glycoprotein IIb/IIIa.The lack of difference in our study in 30-day MACEbetween SVG and non-SVG lesions at 30 days mightbe secondary to more frequent use of stenting andglycoprotein IIb/IIIa in the TARGET trial comparedwith earlier trials.Ross et al. analyzed the association of lesion charac-

teristics with clinical events in the main TARGET trial,including all SVG and native coronary lesions. Theirresults were similar to those of this study. In multivari-ate analysis, length > 20 mm, thrombus, and eccentri-city were all independently associated with 40–90%increases in 30-day MACE [24].

TABLE IV. Outcomes and Ischemic Endpoints of SVG Intervention Patients Comparedwith Non-SVG Intervention Patients at 30 Days in Single Vessel Patients

Non-SVG (N ¼ 3,757) SVG (N ¼ 204) P

Angiographic success—all lesions 3,670 (98.0) 194 (95.6) 0.040 EX

30-day death/MI/TVR 237 (6.3) 17 (8.3) 0.250

30-day death 16 (0.4) 0 (0.0) 1.000 EX

30-day MI 205 (5.5) 17 (8.3) 0.082

30-day Q-wave MI 32 (0.9) 5 (2.5) 0.039 EX

30-day Non-Q-wave MI 170 (4.5) 12 (5.9) 0.368

30-day TVR 38 (1.0) 1 (0.5) 0.721 EX

30-day urgent TVR—CABG 6 (0.2) 0 (0.0) 1.000 EX

Values in parentheses indicate percentages. SVG, saphenous vein graft; EX, exact test; MI, myocar-

dial infarction; TVR, target vessel revascularization; CABG, coronary artery bypass graft.

TABLE III. Odds Ratios (and 95% CI) for Procedural Characteristics of SVG (n = 254) Intervention and Non-SVG (n = 4,519)Intervention Patients

SVG intervention Non-SVG intervention

N

Any major

adverse cardiac

event

Odds ratio

[95% CI] P-value N

Any major

adverse cardiac

event

Odds ratio

[95% CI] P-value

Intervention

Rotational atherectomy 8 0/8 (0) NA 0.89 253 18/253 (7) 1.1 [0.7, 1.8] 0.73

Stent 242 24/242 (10) NA 0.59 4,368 289/4,368 (7) 1.0 [0.5, 1.9] 0.95

Directional atherectomy 1 1/1 (100) NA 0.19 19 6/19 (32) 6.6 [2.1, 18.9] 0.002

Extraction atherectomy 7 2/7 (29) 4.1 [0.4, 26.6] 0.27 7 1/7 (14) 2.4 [0.1, 20.0] 0.76

Laser 0 0/0 (NA) NA NA 0 0/0 (NA) NA NA

Target vessela

Graft to LAD 65 3/65 (5) 0.4 [0.1, 1.3] 0.15 27 1/27 (4) 0.5 [0.01, 3.3] 0.92

Graft to LCX 102 11/102 (11) 1.3 [0.6, 3.0] 0.55 28 2/28 (7) 1.1 [0.1, 4.4] 0.99

Graft to RCA 90 10/90 (11) 1.3 [0.6, 3.2] 0.50 24 4/24 (17) 2.9 [0.7, 8.6] 0.14

>1 target lesion 106 15/106 (14) 2.5 [1.1, 6.1] 0.035 1,595 142/1,595 (9) 1.7 [1.4, 2.2] 0.001

Angiographic success—all lesions 242 20 (8) 0.16 [0.03, 0.7] 0.018 4,413 278 (6) 0.25 [0.15, 0.4] 0.001

Final TIMI flow grade < 3 12 4 (25) 5.5 [1.5, 20.0] 0.037 60 13 (22) 4.0 [2.2, 7.6] 0.001

Values in parentheses indicate percentages. SVG, saphenous vein graft; CI, confidence interval; TIMI, thrombolysis in myocardial infarction.aThree patients underwent PCI of lesions in two SVGs.



Glycoprotein IIb/IIIa Inhibitors and SVG PCI

In EPIC [25], abciximab bolus and infusion therapyin saphenous graft interventions resulted in a significantreduction of distal embolization and a trend towardsreduction in early large non-Q-wave AMI [26]. How-ever, other studies of glycoprotein IIb/IIIa inhibitorsduring PCI have found no benefit during vein graftinterventions [15,17], perhaps because the burden ofdebris is so large despite platelet inhibition. The TAR-GET trial primary results demonstrated a reduction inMI in 30 days in acute coronary syndrome patientstreated with abciximab vs. tirofiban [27] and a trendtoward abciximab superiority across high risk angio-graphic subgroups. Our study of SVG lesions was notpowered to identify a difference in MACE betweenabciximab and tirofiban.

Comparison to Other SVG Trials

Table V summarizes 14 other studies of SVG PCI.Shortterm MACE (at hospital discharge or 30-dayfollow-up) ranges from 9% to 17% in these studies.The 30-day MACE in the TARGET trial was 9.4%,perhaps reflecting a relatively lower risk profile ofTARGET SVG patients.Stone et al. in a study of 278 SVG PCI patients

with distal filter protection found that thrombus (15.8%vs. 4.9% without thrombus, OR ¼ 3.2, P ¼ 0.05) andabove average lesion length (18.2% vs. 5.7% in belowaverage length lesions, OR ¼ 3.2, P ¼ 0.02) but noteccentricity were associated with 30-day MACE inunivariate analysis. In multivariate analysis, only aboveaverage lesion length (OR ¼ 3.69, P ¼ 0.015) corre-lated with 30-day MACE [21].In a study of 651 patients undergoing SVG PCI who

were randomized between a distal occlusion device vs.

a distal filter, Stone et al. found that the presence ofthrombus conferred a 2-fold higher risk of 30-dayMACE, above average length conferred a 2.4-fold riskof 30-day MACE, and degenerated SVG conferred a2.8-fold risk of 30-day MACE. In contrast, eccentric-ity, slow baseline flow, and severe stenosis conferredless than a 1.3-fold risk of 30-day MACE. (Statisticsdescribing significance were not provided.) [20]In SAFER, multivariate predictors of adverse out-

comes included extent of vein graft degeneration andbulkiness of the target lesion [31]. By univariate analy-sis, lesion length (OR ¼ 1.06, P ¼ 0.0001) and throm-bus (OR ¼ 1.89, P ¼ 0.06) correlated with adverseoutcomes.

Limitations

This study has all of the limitations of a retrospec-tive subgroup analysis. Case report forms did not allowfor collection of data on all American College ofCardiology/American Heart Association Type B and Clesion characteristics. The small number of patientsin this study may have prevented clinically significantfindings from reaching statistical significance. Otherrelevant variables, such as graft age, were not availablein this retrospective study. Troponin levels were notmeasured. Finally, angiography has a low sensitivityfor detection of intracoronary thrombus, and it is likelythat the true incidence of thrombus was underestimatedby TARGET angiographers [32,33].In conclusion, simple angiographic characteristics

continue to identify patients at markedly increased riskof procedural MI and other complications. Althoughdistal protection has been recommended in all graft in-terventions when feasible, patients with these high-risk

TABLE V. Outcomes of SVG Percutaneous Coronary Intervention in Studies Reported From 1994–2006 Compared to Target

Study Number

Procedure

(% stented)

Myocardial

infarction (%)

Death

(%)

Death, myocardial infarction,

repeat revascularization (%)

Piana et al. [2] 150 0 7.3 0.6 49

Mak et al. [26] 101 0 9a 1a 12a

Savage [28] 215 50 6 2 9

Mathew et al. [17] 343 80 16 5 –

Keeley [29] 1,062 42 11 0 13

Hong et al. [5] 2,019 60 17 2 –

Roffi et al. [15] 605 20 12a 2.0a 14.5a

Baim et al. [16] (SAFER) (control arm) 433 97 14.7a 1.0a 16.5a

Baim et al. [16] (SAFER) (distal protection arm)b 442 97 8.6a 2.3a 9.6a

Stone et al. [21,27] (phase 2)b 248 97 10.0a 1.7a 11.3a

Stone et al. [20]b 651 98 9.5a 0.9a 10.8a

Leborgne et al. [14] 527 100 23 1 –

Carrozza et al. [19]b 631 99 9.4a 1.0a 10.6

TARGET (2001) 254 95 8a 0a 9.4a

aOutcomes are reported in-hospital or at 30 days.bStudies with distal protection during intervention.



angiographic features deserve particular considerationfor distal embolic or other protective strategies.

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thrombus predicts ischemic complications during percutaneous coronary intervention in saphenous vein...

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