Elsevier Editorial System(tm) for American Journal of Cardiology Manuscript Draft Manuscript Number: AJC-D-13-01775R1 Title: Prognostic Utility of the SYNTAX Score in Patients with Single vs. Multivessel Disease Undergoing Percutaneous Coronary Intervention (From the ACUITY Trial) Article Type: Full Length Article Keywords: SYNTAX score; acute coronary syndromes; risk stratification; single vessel disease; mutlivessel disease. Corresponding Author: Dr. Gregg W. Stone, MD Corresponding Author's Institution: Columbia University Medical Center First Author: Adriano Caixeta, MD Order of Authors: Adriano Caixeta, MD; Philippe Généreux, MD, PhD; Tullio Palmerini, MD; Alexandra J Lansky, MD; Roxana Mehran, MD; George D Dangas, MD, PhD; Ke Xu, PhD; Sorin J Brener, MD; Gregg W Stone, MD Abstract: SYNTAX score (SS) is an effective angiographic predictor of clinical outcomes in patients with multivessel coronary artery disease (MVD) undergoing percutaneous coronary intervention (PCI). It is not known whether this relationship is independent of number of diseased vessels. The aim of this study is to assess the relationship between the SS and major adverse cardiac events (MACE) in patients with single (SVD) and (MVD) undergoing PCI. In ACUITY, SS was determined in 2,627 patients undergoing PCI. The relationship between SS and 1-year clinical outcomes was assessed according to SS tertiles: <5 (n = 441), ≥5 and <10 (n = 525) and ≥10 (n = 495) for SVD; and <10 (n = 361), ≥10 and <18 (n = 401) and ≥18 (n = 404) for MVD. At 1-year follow-up, among MVD patients in the 1st, 2nd and 3rd tertiles, the rates of MACE were 16.8%, 24.7%, and 23.7%, p = 0.02; among SVD patients the respective rates were 13.3%, 15.3%, and 19.1%, p = 0.01. In patients with MVD, SS independently predicted 1-year MACE (HR 1.02, 95% CI 1.01-1.03; p = 0.002), MI (HR 1.02, 95% CI 1.00-1.04; p = 0.02), and cardiac death (HR 1.05, 95% CI 1.02-1.09; p = 0.005). In patients with SVD, SS independently predicted 1-year MACE (HR 1.03, 95% CI 1.01-1.05; p = 0.0009), and MI (HR 1.05, 95% CI 1.02-1.07; p = 0.002). In the overall study cohort, SS was an independent predictor of MACE and death, while MVD (vs. SVD) was not. In conclusion, SS is a useful angiographic predictive tool for patients with SVD and MVD.

August 18, 2013 William C. Roberts, MD Editor-in-Chief The American Journal of Cardiology Baylor Heart & Vascular Hospital, Baylor University Medical Center, Wadley Tower No. 457, 3600 Gaston Avenue, Dallas, TX 75246 Dear Dr. Roberts, We are pleased to resubmit the manuscript, “Prognostic Utility of the SYNTAX Score in Patients with Single vs. Multivessel Disease Undergoing Percutaneous Coronary Intervention (From the ACUITY Trial)” for publication in The American Journal of Cardiology. We have addressed the editor’s requests in this new version of the manuscript, which is uploaded in the “Revised Submission” section. Thank you very much for you time in revising our paper. We are looking forward to hearing from you at your earliest convenience. Sincerely, Gregg W. Stone, MD Corresponding author Professor of Medicine, Director of Research and Education Center for Interventional Vascular Therapy New York-Presbyterian Hospital Columbia University Medical Center The Cardiovascular Research Foundation 111 E. 59th St., 11th Floor New York, NY 10022 tel: 212-851-9304 fax: 212-851-9396 e-mail: gstone@crf.org & Adriano Caixeta, MD First author From Hospital Israelita Albert Einstein, São Paulo, Brazil; Columbia University Medical Center and the Cardiovascular Research Foundation, New York, NY

Cover Letter_Revised paper

August 18, 2013 William C. Roberts, MD Editor-in-Chief The American Journal of Cardiology Baylor Heart & Vascular Hospital, Baylor University Medical Center, Wadley Tower No. 457, 3600 Gaston Avenue, Dallas, TX 75246 Dear Dr. Roberts, We hereby resubmit our manuscript, “Prognostic Utility of the SYNTAX Score in Patients with Single vs. Multivessel Disease Undergoing Percutaneous Coronary Intervention (From the ACUITY Trial)” after incorporating all the comments as follow:

1. The title of the manuscript has been updated; 2. The title page is limit to the first page and that the abstract begins on the page #2; 3. The disclosure is now after the text; 4. All the references have been revised including #23; 5. All the subheading have been excluded; 6. All the Tables were updated and abbreviations spelled out; 7. The conclusions at the end of the paper has been deleted; and 8. We checked all technical requirements and they were implemented accordingly.

We are looking forward to hearing from you at your earliest convenience. Sincerely, Gregg W. Stone, MD Corresponding author Professor of Medicine, Director of Research and Education Center for Interventional Vascular Therapy New York-Presbyterian Hospital Columbia University Medical Center The Cardiovascular Research Foundation 111 E. 59th St., 11th Floor New York, NY 10022 tel: 212-851-9304 fax: 212-851-9396 e-mail: gstone@crf.org & Adriano Caixeta, MD First author From Hospital Israelita Albert Einstein, São Paulo, Brazil; Columbia University Medical Center and the Cardiovascular Research Foundation, New York, NY

*Responses to Reviewers

1

Prognostic Utility of the SYNTAX Score in Patients with Single vs.

Multivessel Disease Undergoing Percutaneous Coronary Intervention

(From the ACUITY Trial)

Adriano Caixeta, MD, PhDa,b, Philippe Généreux, MDb,c, Tullio Palmerini, MDd, Alexandra J.

Lansky, MDe, Roxana Mehran, MDf, George D. Dangas, MD, PhDf, Ke Xub, PhD, Sorin J.

Brener, MDg, and Gregg W. Stone, MDb,*

aHospital Israelita Albert Einstein, São Paulo, Brazil; bColumbia University Medical Center and

the Cardiovascular Research Foundation, New York, NY, cHôpital du Sacré-Coeur de Montréal,

Montréal, Canada, dIstituto Cardiologia, Policlinico S. Orsola, Bologna, Italy; eYale University

School of Medicine, New Haven, CT; fMount Sinai Medical Center, New York, NY, gWeill Cornel

Medical College, New York, NY (SJB)

(Acute Catheterization and Urgent Intervention Triage StrateY [ACUITY]); ClinicalTrials.gov

Identifier NCT00093158

Running title: SYNTAX score in single vessel disease

Financial support: The ACUITY trial was funded by The Medicines Company, Parsippany, NJ,

USA, and Nycomed, Roskilde, Denmark

* Corresponding author:

Gregg W. Stone, MD

Columbia University Medical Center

New York-Presbyterian Hospital

The Cardiovascular Research Foundation

111 E. 59th St., 11th Floor

New York, NY 10022

Tel: 646-434-4131

Fax: 646-434-4715

e-mail: gs2184@columbia.edu

*Manuscript_RevisedClick here to view linked References

2

Abstract

SYNTAX score (SS) is an effective angiographic predictor of clinical outcomes in patients with

multivessel coronary artery disease (MVD) undergoing percutaneous coronary intervention

(PCI). It is not known whether this relationship is independent of number of diseased vessels.

The aim of this study is to assess the relationship between the SS and major adverse cardiac

events (MACE) in patients with single (SVD) and (MVD) undergoing PCI. In ACUITY, SS was

determined in 2,627 patients undergoing PCI. The relationship between SS and 1-year clinical

outcomes was assessed according to SS tertiles: <5 (n = 441), ≥5 and <10 (n = 525) and ≥10 (n

= 495) for SVD; and <10 (n = 361), ≥10 and <18 (n = 401) and ≥18 (n = 404) for MVD. At 1-year

follow-up, among MVD patients in the 1st, 2nd and 3rd tertiles, the rates of MACE were 16.8%,

24.7%, and 23.7%, p = 0.02; among SVD patients the respective rates were 13.3%, 15.3%, and

19.1%, p = 0.01. In patients with MVD, SS independently predicted 1-year MACE (HR 1.02,

95% CI 1.01-1.03; p = 0.002), MI (HR 1.02, 95% CI 1.00-1.04; p = 0.02), and cardiac death (HR

1.05, 95% CI 1.02-1.09; p = 0.005). In patients with SVD, SS independently predicted 1-year

MACE (HR 1.03, 95% CI 1.01-1.05; p = 0.0009), and MI (HR 1.05, 95% CI 1.02-1.07; p =

0.002). In the overall study cohort, SS was an independent predictor of MACE and death, while

MVD (vs. SVD) was not. In conclusion, SS is a useful angiographic predictive tool for patients

with SVD and MVD.

Key-words: SYNTAX score, acute coronary syndromes, single vessel disease, mutlivessel

disease.

3

The SYNTAX (The SYNergy between percutaneous intervention with TAXus drug eluting

stents and cardiac surgery) score (SS) is an angiographic scoring system developed during the

SYNTAX trial for risk stratification of patients according to the complexity of coronary anatomy.1

It has been shown to be an effective angiographic tool for predicting the risk of major adverse

cardiac events (MACE), mostly in stable patients with multivessel disease (MVD) and those with

unprotected left main disease (UPLMD) undergoing percutaneous coronary intervention (PCI).2-

7 Accordingly, SS has been incorporated in a daily practice when facing complex coronary artery

disease dilemma. More recently, its application has been extended to a variety of other clinical

setting including an all-comers population 8 and in patients with ST-elevation myocardial

infarction (STEMI) 9, 10 undergoing primary PCI. Although we have recently demonstrated the

prognostic value of the SS in a broad range of patients with non ST-segment elevation acute

coronary syndromes (NSTEACS) enrolled in the Acute Catheterization and Urgent Intervention

Triage StrategY (ACUITY) trial treated with PCI,11 the usefulness of the SS to predict clinical

events in patients with single vessel disease (SVD) has never been investigated. The aim of the

present study is to assess the impact of the SS on ischemic outcomes in patients with SVD

undergoing PCI compared with those with MVD from the large-scale, multicenter, prospective

randomized ACUITY trial.

Methods

The design and primary results of the ACUITY trial have been previously reported.12

Briefly, 13,819 patients with moderate- and high-risk NSTEACS undergoing an early invasive

management strategy were randomly assigned to heparin plus glycoprotein IIb-IIIa inhibitors,

bivalirudin plus glycoprotein IIb-IIIa inhibitors or bivalirudin monotherapy before coronary

angiography. Clinical follow-up was performed at 30 days and 1 year. All MACE events were

adjudicated by an independent clinical events committee. Retrospectively, all stent thrombosis

events were re-adjudicated using the Academic Research Consortium (ARC) definitions.13

4

As part of the present study, only PCI patients who had quantitative coronary

angiography (QCA) (Cardiovascular Research Foundation, New York, NY) performed within the

formal angiographic substudy of the ACUITY trial were included. In the ACUITY trial, QCA was

performed in 6,921 patients, including 3,664 PCI patients. After excluding patients with a history

of prior CABG (862 patients) and patients for whom the SS score could not be calculated for

technical reasons (338 patients), 2,627 patients remained available for analysis. Patients with

infarct-related occluded arteries were scored as total occlusion of undetermined duration.

Lesions with in-stent restenosis were scored as de novo lesions. The SS score was

retrospectively calculated by 3 experienced interventional cardiologists who were blinded to

treatment assignment and clinical outcomes. In order to assess inter-observer reproducibility

among the 3 readers, a Fleiss Kappa statistic value for multiple readers (tertile partitioning) was

determined. 14 Each lesion with ≥ 50% diameter stenosis in vessels ≥1.5 mm was scored using

the SS algorithm, which has been fully described elsewhere 1 and is available on the SS website

(www.syntaxscore.com). The Fleiss Kappa statistic 15 (tertile partitioning), determined for the 3

readers from 50 films read independently, was 0.57, meaning inter-observer reproducibility was

comparable to that previously reported from the SYNTAX trial.16

Continuous variables are expressed as mean ± standard deviation and were compared

using the Student t test or the Mann-Whitney Rank Sum Test, as appropriate. Categorical

variables are presented as percentage and n/N and were compared by chi-square or Fisher’s

exact test. Patients with SVD and MVD were grouped into tertiles of SS separately. One-year

outcomes are summarized as Kaplan-Meier estimates and compared using the log-rank test

and hazards ratios. Stepwise Cox multivariable regression analyses were performed to assess

the association between the SS and 1-year MACE, all-cause mortality, cardiac mortality,

myocardial infarction (MI) and target vessel revascularization (TVR) in patients with SVD and

MVD. Potential predictors were entered into the model with entry and stay criteria of a 0.1/0.1.

The following baseline and procedure variables were included in the models: SS (as a

continuous variable), age, male gender, diabetes, renal insufficiency, left ventricular ejection

5

fraction (LVEF), baseline troponin elevation, ST-segment deviation, prior MI, and prior PCI. The

numbers of independent variables included in the models were carefully chosen to avoid

overfitting, i.e., as having too many covariates relative to the number of observations. In order to

evaluate the predictive value of the SS as compared to the number of vessels disease, MVD vs.

SVD as a covariate was forced in the model of 1-year clinical outcome of the entire population.

All statistical tests were performed using SAS software (version 9.1, SAS Institute, Cary, North

Carolina) and p values <0.05 denote statistical significance.

Results

In the present analysis SS was determined in 2,627 PCI patients, comprising 1,461

(55.6%) patients with SVD and 1,166 (44.4%) with MVD. In patients with MVD, the median SS

was 14, whereas in patients with SVD the median SS was 7. Figure 1 shows the distribution of

the SS in SVD and in MVD patients according the tertile of the entire population, i.e., lowest (<

7), middle (7 to 13), and highest (> 13) SS. Table 1 shows the baseline characteristics of

patients with SVD and MVD. Patients with MVD had more comorbidities and less favorable

coronary anatomy. There were no significant differences in in-hospital antithrombotic medication

use between the 2 groups.

Clinical outcomes stratified according to SS tertiles in patients with SVD and MVD are

shown in Table 2 and in Figures 2 and 3.

Compared to patients in the first and second tertile, those in the third tertile had higher

MACE (13.4%, 15.3%, 19.1%; ptrend = 0.01), death or MI (5.5%, 8.5%, 11.6%; ptrend = 0.003), MI

(4.4%, 7.7%, 10.5%; ptrend = 0.002), and probable or definite stent thrombosis (0.2%, 0.6%,

2.1%; ptrend = 0.01).

Compared to patients in the lowest tertile, those in the intermediate and upper tertiles

had higher MACE (16.8%, 24.7%, 23.7%; Ptrend = 0.02), death or MI (7.0%, 17.8%, 14.9%; ptrend

6

= 0.003), all-cause death (1.4%, 4.2%, 4.6%; P=0.046), cardiac death (0.6%, 2.6%, 3.2%; ptrend

= 0.04), MI (6.2%, 15.2%, 12.1%; ptrend = 0.002), and probable or definite stent thrombosis

(0.2%, 0.6%, 2.1%; ptrend = 0.01). Figure 4 compares MACE in SVD and MVD patients in each

tertile of the overall population. Notably, the rates of MACE in the highest SS tertile are similar

among SVD and MVD patients.

As shown in Table 3, the SS was an independent predictor of MACE, all-cause death,

cardiac death, MI, and TVR in the overall population. Even after including the number of vessels

disease (MVD vs. SVD) in the model, the SS still remained a powerful predictor of ischemic

events, while MVD was not. After adjusting for possible confounders, SS was also an

independent predictor of ischemic events in SVD as well as in MVD patients, separately (Table

4)

Discussion

The principal findings of the present study evaluating the SS in moderate- and high-risk

NSTEACS undergoing PCI are as follows: (1) patients with MVD had, expectedly, a SS twice as

high as those with SVD; (2) in patients with MVD, SS independently predicted 1-year MACE, all-

cause death, cardiac death, MI and TVR. In patients with SVD, SS independently predicted 1-

year MACE, MI and TVR; (3) SS was a more powerful predictor of clinical events than the

number of diseased vessels.

The SS is an anatomical scoring system based on the coronary angiogram, which

quantifies the complexity of coronary artery disease. Recent studies have shown that the SS

can stratify risk and predict outcomes of patients with complex coronary artery disease

undergoing PCI.3, 7 In the SYNTAX trial, PCI patients in the upper SS tertile (>32) had 1.5- and

twofold higher rate of major adverse cardiac and cerebrovascular events, and mortality,

respectively, compared to PCI patients in the lowest tertile (<22). Additionally, SS was an

independent correlate of mortality in PCI-treated patients.17 The Future Revascularization

7

Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease

(FREEDOM) trial also showed that in PCI patients with diabetes and MVD, the higher the SS -

the worse the clinical outcome at 5-year follow-up was.18 Likewise, the value of the SS in

predicting clinical outcomes in patients who underwent PCI for UPLMD has been validated. In

one study, 7 patients in the highest SS tertile (>36) had more unfavorable clinical outcomes

when compared with those in the lower SS tertiles. Accordingly, SS has been incorporated as

an important variable in clinical decision making for the individual patient with MVD in need of

coronary revascularization.19, 20 The present large-scale study corroborates and extends these

findings by showing the prognostic utility of the SS in SVD and lower-risk MVD patients. Indeed,

the SS upper tertile in the present analysis (≥18) is lower than even the lowest SS tertile in both

the SYNTAX and FREDOM trials (< 22). In addition, only 2.3% of the patients enrolled in the

present ACUITY angiographic substudy had a SS of ≥ 33, compared with one-third of the

patients in the SYNTAX and FREEDOM trials.3, 18 It is important to highlight that the value of SS

in risk prediction had been previously demonstrated mostly in stable patients with multivessel

disease; in contrast, the present analysis depicts only NSTEACS patients who were categorized

into 2 separate groups, MVD and SVD. Although we have recently demonstrated the prognostic

value of the baseline and the residual SS after PCI in a broad range of patients with NSTEACS

11, 21 the utility of the SS for clinical events prediction in patients with SVD has never been

investigated. The present study is the first to assess the pre-PCI SS for risk prediction of

ischemic outcomes in SVD patients undergoing PCI. It shows that even with a very low cutoff

margin (ranging from 5 to 10), higher SS still identifies patients at increased risk and is a

valuable tool for predicting clinical outcomes at 1 year. Intriguingly, the same patterns of

discrimination demonstrated in this study and others 3, 18 among tertiles of multivessel disease is

found in the SVD cohort: the upper SS tertile (≥10) patients had 1.5- and twofold higher MACE

and death rates, respectively, compared to those in the lowest tertile (<5). The increased 1-year

rates of MACEdriven by death and MI, and not by TVR (Figure 2)with higher SS may be

explained by the higher procedure risk associated with complex coronary anatomy (i.e.,

multiples lesions in the same vessel, bifurcations, calcification, total occlusions, ostial lesions,

8

etc.), as demonstrated by the very early separation of the event curves. Of note, SVD patients in

the highest SS tertile had a higher rate of events than patients with MVD in the lower tertile,

highlighting the importance of categorizing patients based on the complexity of coronary lesions

as a whole, and not only by the number of vessels compromised (Figure 4). By multivariable

analysis, SS also emerged as an independent predictor of MACE, MI and TVR, regardless of

number of diseased vessels.

The present analysis has certain limitations. It is a retrospective analysis from a large-

scale randomized trial, and results should be considered exploratory, requiring confirmation in

additional studies. The patient cohort in the present study was drawn from the U.S-based

angiographic substudy representing only one fifth of the original ACUITY population. The

multivariable analysis performed in this study, although detailed, cannot exclude residual

confounding for unmeasured and unknown variables. The stent types used in the ACUITY trial

were either first generation DES or BMS; thus, the value of the SS as a prognostic tool in the

era of newer-generation DES still needs to be determined. However, preliminary data from

recent randomized trials have confirmed the ability of the SS to identify patients who are at

highest risk of adverse events using new-genenation DES.8, 22 Patients with previous CABG

were excluded from this analysis since the SS algorithm was developed for patients with native

coronary artery disease. Angiography alone has limited accuracy in determining the severity of

the stenosis in terms of inducing ischemia. In addition to its independence as a marker of risk

from other significant risk factors, the addition of the SS to conventional risk factors can improve

its ability to risk stratify patients over the longer term. Recalculating the SS by incorporating

clinical variables23 or ischemia-producing lesions as determined by fractional flow reservethe

so-called functional SSmight better determine risk of adverse events in patients undergoing

PCI.24 This approach needs to be examined in NSTEACS patients in future investigations. Total

occlusions were scored as having unknown duration according to the SS algorithm; many of

these occlusions in the ACUITY trial may have been of recent duration, most likely causing the

overestimation of the SS. The number of deaths in patients with SVD was quite low and this

9

may explain the lack of statistical association between mortality as an individual endpoint and

the SS. Finally, the results of this study have limited generalizability since they apply only to

native coronary artery disease in NSTEACS patients of being treated with an early invasive

strategy.

Disclosure

Dr. Mehran is a consultant for Abbott Vascular, AstraZeneca, Cardiva, Cordis, Ortho-McNeil,

The Medicines Company and Regado Biosciences, and has received research grants from

Sanofi/Bristol Myers Squibb. Dr. Dangas has received honoraria from The Medicines Company,

Cordis, Sanofi/Bristol Myers Squibb and is a consultant to AstraZeneca. Martin Fahy and Ke Xu

are employed by the Cardiovascular Research Foundation. Dr. Stone serves on the scientific

advisory boards for and has received honoraria from Abbott Vascular and Boston Scientific, and

is a consultant to The Medicines Company. All other authors have reported that they have no

relationships to disclosure.

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Mehran R, Serruys PW, Stone GW. Quantification and impact of untreated coronary

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15

Figure legends

Figure 1: Distribution of the SS in patients with single and multivessel disease of the entire

population. Each point may represent more than 1 patient if SS is identical.

Figure 2: Time-to-event curves in patients with multivessel disease. One-year cumulative event

curves for rates of (A) cardiac mortality, (B) myocardial infarction, (C) target vessel

revascularization, and (D) MACE - stratified by tertiles of SYNTAX score.

Figure 3: Time-to-event curves in patients with single vessel disease. One-year cumulative event

curves for rates of (A) cardiac mortality, (B) myocardial infarction, (C) target vessel

revascularization, and (D) MACE - stratified by tertiles of SYNTAX score.

Figure 4: Clinical outcomes at 1-year in the overall population comparing MACE in SVD and MVD

in each tertile.

Table 1. Baseline Characteristics and Antithrombotic Medication Use in Patients with Single and Multivessel Disease

Variables Single Vessel Disease

(n = 1461) Multivessel Disease

(n = 1166) p Value

Age (years) 59.00 [51.00, 68.00] (1461) 61.00 [53.00, 71.00] (1166) <0.0001

Men 65.9% (962/1461) 69.6% (811/1166) 0.05

Weight (kg) 86.26 [75.82, 99.88] 86.13 [75.00, 100.33] 0.70

Diabetes mellitus 25.3% (368/1456) 32.5% (376/1158) <0.0001

Insulin-requiring 7.2% (104/1456) 8.6% (100/1158) 0.16

Hypertension 64.3% (934/1454) 67.2% (783/1165) 0.12

Hyperlipidemia 57.1% (818/1435) 55.1% (635/1153) 0.32

Current smoking 36.8% (535/1455) 33.4% (389/1163) 0.08

Previous myocardial infarction 27.4% (392/1430) 31.2% (357/1146) 0.04

Previous percutaneuos coronary intervention 45.6% (664/1457) 42.1% (491/1166) 0.07

Renal insufficiency 13.5% (184/1360) 17.9% (197/1098) 0.003

Baseline cardiac biomarker elevation 56.7% (763/1346) 64.5% (707/1096) <0.0001

Baseline troponin elevation 58.2% (717/1231) 63.7% (662/1039) 0.008

ST-segment deviation ≥1mm 24.5% (358/1461) 26.5% (309/1166) 0.26

TIMI Risk Score

Low (0-2) 16.8% (204/1211) 15.3% (141/920) 0.37

Intermediate (3-4) 60.5% (733/1211) 57.4% (528/920) 0.15

High (5-7) 22.6% (274/1211) 27.3% (251/920) 0.01

Left ventricular ejection fraction 55.00 [50.00, 60.00] (1147) 55.00 [45.00, 60.00] (936) <0.0001

Target coronary artery

Left anterior descending 40.8% (579/1418) 47.9% (532/1110) 0.0004

Right 34.9% (495/1418) 45.9% (509/1110) <0.0001

Left circunflex 26.2% (372/1418) 46.0% (511/1110) <0.0001

Others 0.0% (0/1418) 0.2% (2/1110) 0.19

Number of coronary angioplasty vessels per patient 1.02 ± 0.14 (1418) 1.40 ± 0.53 (1110) <0.0001

Number of narrowings per patient 3.03 ± 1.84 (1459) 4.61 ± 2.08 (1164) <0.0001

Extent of disease (mm) 27.07 [16.50, 43.00] (1426) 43.00 [29.00, 63.25] (1153) <0.0001

All final TIMI Flow 3 97.2% (1407/1447) 95.9% (1497/1561) 0.05

All final TIMI 3 and all Blush 3 77.9% (1127/1447) 73.9% (1154/1561) 0.01

Drug-eluting stent use 84.8% (1238/1461) 85.0% (991/1166) 0.91

Bare-metal stent use 11.2% (164/1461) 17.6% (205/1166 <0.0001

Both drug-eluting and bare-metal stent use 32.7% (477/1461) 9.2% (107/1166) <0.0001

Total number of stents 1.03 ± 0.44 (1461) 1.55 ± 0.86 (1166) <0.0001

Target lesion

Baseline reference vessel diameter (mm) 2.77 ± 0.55 (1661) 2.72 ± 0.54 (1776) 0.008

Baseline minimal luminal diameter (mm) 0.72 ± 0.48 (1661) 0.71 ± 0.45 (1776) 0.0008

Final minimal luminal diameter (mm) 2.35 ± 0.56 (1659) 2.29 ± 0.56 (1760) 0.001

Final diameter stenosis (%) 16.67 ± 11.29 (1659) 17.19 ± 12.36 (1760) 0.20

Antithrombotic medication*

Bivalirudin 64.7% (945/1461) 66.9% (780/1166) 0.25

Unfractionated heparin 20.4% (298/1461) 18.8% (219/1166) 0.30

Enoxaparin 13.2% (192/1461) 13.4% (156/1166) 0.86

Glycoprotein IIb/IIIa inhibitor 32.7% (477/1461) 32.6% (380/1166) 0.97

Aspirin 98.5% (1435/1458) 98.4% (1142/1161) 0.87

Thienopyridine 32.7% (477/1456) 58.3% (675/1157) 0.45

Values are presented as mean ± standard deviation (n) or median (interquartile range). Renal insufficiency is defined as a

Table_1

calculated creatinine clearance rate of <60 ml/minute determined by the Cokcroft-Gault equation. TIMI = Thrombolysis In Myocardial Infarction. * Administered post randomization and pre angiography.

Table 2. Clinical Outcomes at 1 year in Patients with Single Vessel and Multivessel Disease according to Syntax Score Tertiles

Variables

< 5 Syntax Score ≥5 and < 10

≥ 10

Overall p Value

Single vessel disease

Major adverse cardiac events 13.4% (54) 15.3% (77) 19.1% (93) 0.01

Death/myocardial infarction 5.5% (24) 8.5% (43) 11.6% (57) 0.003

Death 1.2% (5) 1.4% (7) 2.2% (11) 0.35

Cardiac death 0.2% (1) 0.4% (2) 1.2% (6) 0.11

Myocardial infarction 4.4% (19) 7.7% (39) 10.5% (51) 0.002

Q-Wave 0.5% (2) 1.4% (7) 1.6% (8) 0.23

Non Q-Wave 3.9% (17) 6.4% (32) 8.8% (43) 0.008

Target vessel revascularization 6.9% (26) 7.2% (36) 7.8% (37) 0.57

Definite/probable stent thrombosis 0.2% (1) 0.6% (3) 2.1% (10) 0.01

Multivessel disease < 10 Syntax Score ≥10 and < 18

≥ 18

Major adverse cardiac events 16.8% (59) 24.7% (97) 23.7% (94) 0.02

Death/myocardial infarction 7.0% (25) 17.8% (70) 14.9% (59) 0.0001

Death 1.4% (5) 4.2% (16) 4.6% (18) 0.05

Cardiac Death 0.6% (2) 2.6% (10) 3.2% (13) 0.04

Myocardial infarction 6.2% (22) 15.2% (60) 12.1% (48) 0.0006

Q-Wave MI 0.9% (3) 2.6% (10) 3.3% (13) 0.07

Non Q-Wave MI 5.3% (19) 12.9% (51) 8.9% (35) 0.002

Target vessel revascularization 6.4% (22) 10.0% (39) 10.4% (40) 0.10

Definite/probable stent thrombosis 1.1% (4) 2.0% (8) 3.8% (15) 0.05

One-year outcomes are summarized as Kaplan Meier % and compared between groups with log-rank tests.

Table_2

Table 3. Multivariate Predictors of 1-Year Clinical Outcomes in the Overall Population

Hazard Ratio

[95% C.I.] p Value

MACE

MVD vs. SVD 1.19 [0.97, 1.46] 0.09

Syntax Score (1 point increment) 1.03 [1.01, 1.04] <0.0001

Diabetes 1.25 [1.03, 1.53] 0.02

Renal insufficiency 1.59 [1.27, 1.99] <0.0001

Previous percutaneous coronary intervention

1.44 [1.19, 1.74] 0.0002

All-cause death

MVD vs. SVD 1.37 [0.71, 2.65] 0.34

Syntax score (1 point increment) 1.03 [1.00, 1.06] 0.03

Age (10 years increment) 1.80 [1.38, 2.33] <0.0001

Diabetes 2.23 [1.25, 3.98] 0.007

Left ventricular ejection fraction 0.97 [0.95, 1.00] 0.019

Cardiac death

MVD vs. SVD 2.16 [0.82, 5.71] 0.12

Syntax score (1 point increment) 1.05 [1.01, 1.08] 0.006

Age (10 years increment) 1.45 [1.05, 2.01] 0.02

Diabetes 2.21 [1.03, 4.71] 0.04

Left ventricular ejection fraction 0.96 [0.93, 0.99] 0.005

Myocardial infarction

MVD vs. SVD 1.33 [1.00, 1.78] 0.05

Syntax score (1 point increment) 1.03 [1.01, 1.04] 0.0006

Age (10 years increment) 0.85 [0.74, 0.97] 0.01

Renal insufficiency 2.63 [1.83, 3.77] <0.0001

Previous percutaneous coronary intervention

1.40 [1.04, 1.89] 0.03

Baseline troponin elevation or ST-segment deviation

1.48 [1.04, 2.09] 0.03

Target vessel revascularization

MVD vs. SVD 1.25 [0.97, 1.61] 0.09

Syntax Score (1 point increment) 1.03 [1.01, 1.04] <0.0001

Age (10 years increment) 0.81 [0.72, 0.91] 0.0005

Table_3

Renal insufficiency 1.67 [1.17, 2.38] 0.005

Previous percutaneous coronary intervention

1.89 [1.49, 2.41] <0.0001

MVD = multivessel disease. SVD = single vessel disease. MVD vs. SVD is a covariate forced in this model in order to compare its relative predictive value with the Syntax score. Note that Syntax score was a powerful predictor of clinical events, whereas the number of diseased vessels did not predict events.

Table 4. Multivariate Predictors of 1-Year Clinical Outcomes in Patients with Single and Multivessel Disease Undergoing PCI

Single Vessel Disease Multivessel Disease

Hazard Ratio

[95% C.I.] p Value

Hazard Ratio [95% C.I.]

p Value

Major adverse cardiac events

Major adverse cardiac events

Syntax Score (1 point increment)

1.03 [1.01, 1.05] 0.0009 Syntax Score (1 point increment)

1.02 [1.01, 1.03] 0.002

Diabetes 1.56 [1.17, 2.08] 0.002 Renal insufficiency 1.46 [1.08, 1.97] 0.01

Previous percutaneous coronary intervention

1.73 [1.31, 2.28] 0.0001

Renal insufficiency 2.32 [1.55, 3.46] <0.0001

Age (10 year increment) 0.85 [0.74, 0.98] 0.02

All-cause death All-cause death

Syntax score 1.02 [0.97, 1.08] 0.48 Syntax Score (1 point increment)

1.04 [1.01, 1.07] 0.02

Diabetes 2.15 [0.94, 4.92] 0.07 Age (10 years increment) 1.35 [1.00, 1.83] 0.05

Age (10 years increment) 2.51 [1.67, 3.77] <0.0001 Left ventricular ejection fraction

0.97 [0.94, 0.99] 0.02

Cardiac death Cardiac death

Syntax score (1 point increment)

1.06 [0.96, 1.17] 0.24 Syntax Score (1 point increment)

1.05 [1.02, 1.09] 0.005

Renal insufficiency 7.26 [1.46, 36.17] 0.01 Diabetes 2.19 [0.93, 5.18] 0.07

Left ventricular ejection fraction

0.93 [0.87, 0.99] 0.02 Left ventricular ejection fraction

0.97 [0.94, 1.00] 0.04

Myocardial infarction Myocardial infarction

Syntax score (1 point increment)

1.05 [1.02, 1.07] 0.002 Syntax Score (1 point increment)

1.02 [1.00, 1.04] 0.02

Diabetes 1.71 [1.09, 2.69] 0.02 Renal insufficiency 2.54 [1.59, 4.06] <0.0001

Previous percutaneous coronary intervention

2.04 [1.27, 3.29] 0.003 Age (10 years increment) 0.80 [0.67, 0.95] 0.01

Renal insufficiency 2.55 [1.59, 4.08] <0.0001

Baseline troponin elevation 2.05 [1.22, 3.42] 0.006

Target vessel revascularization

Target vessel revascularization

Syntax Score (1 point increment)

1.03 [1.00, 1.06] 0.02 Syntax Score (1 point increment)

1.02 [1.00, 1.03] 0.03

Diabetes 1.69 [1.17, 2.43] 0.005

Renal insufficiency 2.02 [1.17, 3.46] 0.01

Age (10 years increment) 0.75 [0.63, 0.90] 0.001

Table_4

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