APPENDIX
Expanded Methods
The SYNTAX Trial is a randomized, prospective, multicenter, ‘all-comers’ trial investigating
subjects with unprotected left main coronary artery (ULMCA) disease (isolated or associated
with 1-, 2-, or 3-vessel disease [3VD]) or de novo 3VD, and has previously been described.
(1,2) In total, 1800 subjects were recruited and randomized from 85 centers in 18 countries
from Europe and the United States. Exclusion criteria were minimal, consisting of subjects
with prior coronary revascularization, planned need for concomitant cardiac surgery (e.g.
valve surgery or resection of aortic or left ventricular aneurysm), or on-going acute MI.
During the local Heart Team meeting, the interventional cardiologist and cardiac surgeon
specified the number of coronary lesions requiring treatment, and their angiographic location
and characteristics utilizing the anatomical SYNTAX Score as a tool to aid in this process.
(1-3) All subjects considered by the Heart Team as potentially achieving “equivalent
anatomic” revascularization with percutaneous or surgical revascularization were
randomized on a 1:1 basis (n=1800) to either PCI with TAXUS Express paclitaxel-eluting
stents (Boston Scientific Corporation, Natick, Mass), or CABG. Patients unsuitable for
randomization were nested into registries.
The calculation of the anatomical SYNTAX Score, and recording of its individual
components, were carried out by the Heart Team prior to randomization, and corroborated by
an independent core laboratory (Cardialysis BV, Rotterdam, The Netherlands), blinded to the
treatment assignment. An independent Clinical Events Committee (CEC), including
cardiologists, cardiac surgeons, and a neurologist, reviewed all the primary clinical end points
and ST/GO events. All deaths were subdivided into cardiovascular or non-cardiovascular
deaths by the CEC. Cardiac deaths were classified as related or unrelated to a cardiac
procedure by the CEC. In the event of any uncertainty arising in the classification of a
clinical event, the CEC assisted the investigator in reaching his/her final classification. The
CEC decision was able to overrule the investigator’s classification.
Stent Thrombosis and Graft Occlusion
As the SYNTAX Trial was commenced prior to the publication of the Academic Research
Consortium (ARC) Definition, (4) the SYNTAX Trial instigated a protocol definition for ST.
To allow direct comparison between ST and GO, a similarly defined protocol definition of
GO was devised (Table 2a). The protocol definitions of ST/GO required clinical presentation
with acute coronary syndrome, and confirmation by coronary angiography, multislice
computerized tomography or autopsy.
Subsequently, the ARC criteria (4) for ST was implemented and reported by a separate CEC
(see Acknowledgements), and is reported in the study. To allow comparisons of ARC ST
events to GO, ‘ARC like’ definitions were formulated for GO (i.e. definite, probable or
possible GO), using adapted ARC definitions (Table 2b). The definition of definite GO was
identical to the protocol definition. Since subjects had left main or de novo 3VD, the
assumption was made that a MI in any of the 3 vessel territories for 3VD, or the left coronary
system for ULMCA disease, without subsequent angiographic confirmation of graft patency,
was classified as a probable GO. Possible GO was identical to the ARC definition of possible
ST (unexplained death beyond 30 days). ‘ARC like’ definitions for GO were retrospectively
assessed in conjunction with the safety reporting data performed by the CEC.
Statistical Analysis
Continuous variables are expressed as means (±SD), binary variables as counts and/or
percentages. Time-to-event variables are presented as Kaplan-Meier (KM) estimates, and
compared using the log-rank test. Corrected KM curves were constructed by removing the ST
adjudicated clinical event from the KM curves, in line with that previously reported. (5)
Multivariable analyses were conducted with Cox regression using the forced enter method
(variable entry criteria 0.05, and no exit criteria). The variables examined are detailed in the
baseline characteristics (Table 1). There was no departure from the proportionality of hazards
assumption using the global proportional hazards test based on Schoenfeld residuals. (6)
Variables were screened for correlation before entering into the multivariable model, none
were sufficiently correlated to warrant removal. A 2-sided p-value <0.05 was considered
significant for all tests. All analyses were conducted using SPSS 20.0 (SPSS Inc., Chicago
IL, USA) and SAS System Software Version 9.2 (SAS Institute, Cary, North Carolina, USA).
Expanded Results
Online Table 1
Baseline characteristics of patients with and without definite stent thrombosis or definite graft
occlusion.
Stent Thrombosis (ARC)
Definite ST
No Definite
p-value
(n=48)
ST (n=855)
Clinical Characteristics
Age (years)
Male
BMI
Diabetes
Medically treated diabetes*†
Hypertension
Hyperlipidemia
Peripheral vascular disease
Current smoker
Unstable angina
Previous myocardial infarction
GI Bleeding/Peptic ulcer disease
COPD
LVEF (%)
Creatinine clearance (ml/min)‡
Total Parsonnet Score
Additive EuroSCORE
Logistic EuroSCORE
Anatomical Characteristics
SYNTAX Score
Left Main Disease§†
Number of lesions
Any total occlusions
Any bifurcation lesion
Any trifurcation lesion
Diffuse or small vessel disease
Any aorto-ostial lesion
Any angiographically visible thrombus
Any heavy calcification
Any severe tortuosity
Left arterial dominance
Proximal LAD (Segment 6) lesion
Any circumflex lesion
Any right coronary artery lesion
Any lesion length >20 mm
Peri-/Post- Procedural
Characteristics
Procedure Time (hours)
Intra-aortic balloon pump
Complete Revascularization||
Lack of pre-procedural antiplatelet therapy#
Lack of post-procedural antiplatelet therapy#
One post-procedural antiplatelet therapy**
Graft Occlusion (‘ARC like’)
Definite GO
No Definite
p(n=32)
GO (n=865)
value
64.4±11.2
75.5%
27.6±5.2
28.6%
26.5%
58.3%
73.5%
12.2%
24.5%
38.8%
46.9%
6.1%
8.2%
54.1±14.2
88.3±35.5
8.1±6.6
4.3±2.6
4.1±3.1
65.3±9.5
76.4%
28.2±4.8
28.0%
25.2%
74.7%
78.9%
8.5%
17.4%
28.1%
30.6%
4.0%
7.8%
54.9±11.8
86.5±35.6
8.6±7.0
3.7±2.6
3.7±4.6
0.51
0.89
0.42
0.93
0.84
0.012
0.37
0.37
0.21
0.11
0.017
0.48
0.93
0.65
0.74
0.65
0.15
0.55
64.1±9.3
78.1%
26.3±3.6
31.2%
25.0%
76.7%
78.1%
18.8%
31.2%
34.4%
15.6%
3.1%
9.4%
60.7±12.1
83.2±24.5
7.3±6.3
3.4±2.2
2.9±2.0
65.0±9.8
79.0%
28.0±4.6
28.4%
24.6%
77.0%
77.1%
10.3%
21.7%
27.7%
34.5%
4.3%
9.2%
58.1±13.2
86.7±28.7
8.5±6.9
3.8±2.7
3.9±4.5
0.61
0.91
0.042
0.73
0.96
0.97
0.90
0.13
0.20
0.41
0.027
0.74
0.98
0.35
0.52
0.35
0.42
0.011
29.3±11.2
34.7%
4.0±1.4
20.4%
69.4%
10.2%
22.4%
12.2%
6.1%
61.2%
65.3%
12.2%
61.2%
93.9%
87.8%
69.4%
28.4±11.4
40.1%
4.0±1.7
24.2%
62.5%
7.3%
22.0%
15.8%
2.2%
49.0%
66.9%
18.4%
58.3%
85.3%
81.5%
55.0%
0.59
0.46
0.70
0.55
0.33
0.45
0.95
0.50
0.084
0.095
0.82
0.28
0.69
0.094
0.27
0.048
27.5±12.5
43.8%
3.9±1.8
28.1%
62.5%
6.2%
21.9%
21.9%
6.2%
43.8%
56.2%
6.2%
65.6%
90.6%
81.2%
65.6%
29.2±11.3
38.7%
4.0±1.7
22.0%
64.6%
7.1%
20.9%
14.8%
3.4%
48.8%
68.2%
16.6%
57.4%
83.4%
81.1%
56.4%
0.41
0.56
0.69
0.42
0.81
0.86
0.97
0.27
0.39
0.57
0.16
0.29
0.36
0.28
0.99
0.30
1.9±1.0
0.0%
42.9%
2.0%
6.1%
4.1%
1.7±0.9
2.3%
57.2%
0.7%
0.9%
4.3%
0.22
0.28
0.050
0.32
0.001
0.95
3.5±1.0
3.1%
78.1%
21.9%
3.1%
-
3.4±1.1
0.9%
62.6%
35.4%
8.6%
-
0.92
0.22
0.075
0.11
0.27
-
Total number of stents
Stent length (mm)
Stent length >100 mm
Off pump
Blood cardioplegia
Grafts per patient
LIMA LAD
LIMA/RIMA
Complete arterial revascularization
Complete venous revascularization
At least one jump graft
At least one Y graft
Small/unsatisfactory vessel at anastomosis site
Calcification at anastomosis site
Endarterectomy performed
4.8±2.1
90.3±50.3
29.2%
-
4.6±2.3
86.3±47.9
34.0%
-
0.62
0.58
0.50
-
25.0%
43.8%
2.7±0.7
74.2%
19.4%
16.1%
3.2%
29.0%
9.7%
29.0%
29.0%
3.2%
13.9%
47.7%
3.0±0.7
88.8%
21.4%
18.7%
2.7%
31.2%
11.9%
27.4%
24.7%
2.9%
*Medically treated diabetes is defined as diabetic patients requiring oral medications or insulin for glycemic
control.
†Prespecified patient subsets
‡Cockcroft and Gault formula
§Isolated or associated with 1, 2 or 3VD
||SYNTAX protocol definition
# Aspirin nor thienopyridine. Pre-procedurally, the study protocol mandated aspirin (>70 mg per day) at least 12
hours pre-CABG, aspirin (>70 mg per day) at least 12 hours pre-PCI, and clopidogrel (300+ mg 24 hours prePCI) or ticlopidine (2x250 mg daily 48 hours pre-PCI).(7)
**Aspirin or thienopyridine. Post-procedurally, aspirin (>70 mg per day) was mandated in the CABG and PCI
arms, and clopidogrel or ticlopidine (2 x 250 mg) for at least 6 months in the PCI arm.(7)
Abbreviations: Abbreviations: ARC, Academic Research Consortium;(4) BMI body mass index; Def definite;
LAD left anterior descending artery; LIMA left internal mammary artery; LVEF left ventricular ejection
fraction; MI myocardial infarction; ml millimeter; mm millimeter; min minute; PCI percutaneous coronary
intervention; Poss possible; Prob probable; RIMA right internal mammary artery; ST stent thrombosis; TO total
occlusion
0.20
0.76
0.024
0.013
0.79
0.72
0.85
0.80
0.71
0.84
0.58
0.92
Online Table 2
Association of adjudicated first ST event (Protocol definition) (a), or GO event (Protocol
definition) (b) to 5-year cardiac death. Time frame (median, IQR, range) from ST /GO to
cardiac death are also detailed. Binary values are given.
a) Stent Thrombosis (Protocol Definition)
SYNTAX Trial
PCI Arm (n=903)
SYNTAX Protocol Definition
Time Frame
Acute/subacute (≤30 days)
Late (31 days to 1 year)
Very Late (>1 year)
Incidence of Stent
Thrombosis at
5 Years
47 (5.2%)
No. of Cardiac
Deaths Post ST
Until 5 years
15/47 (31.9%)
19 (2.1%)
8 (0.9%)
20 (2.2%)
8/19 (42.1%)
2/8 (25.0%)
5/20 (25.0%)
Time Elapsing From Index ST to
Cardiac Death (Days)
Median
IQR
Min-Max
0
0-17
0-321
1
0
0-19
0-12
0-321
0-17
b) Graft Occlusion (Protocol Definition)
SYNTAX Trial
CABG Arm (n=897)
SYNTAX Protocol Definition
Time Frame
Acute/subacute (≤30 days)
Late (31 days to 1 year)
Very Late (>1 year)
Incidence of Graft
Occlusion
at 5 Years
32 (3.6%)
No. of Cardiac
Deaths Post ST
Until 5 years
0/31 (0%)
6 (0.7%)
12 (1.3%)
14 (1.6%)
0/6 (0%)
0/12 (0%)
0/13 (0%)
Time Elapsing from Index GO to
Cardiac Death (Days)
Median
IQR
Min-Max
-
Abbreviations: ARC, Academic Research Consortium; MI, myocardial infarction; IQR, interquartile
range; and ST, stent thrombosis.
-
-
Online Figure 1. Comparison of incidence of protocol defined stent thrombosis and
graft occlusion at 5 years
Patient level data shown.
Abbreviations: ARC Academic Research Consortium(4), CABG coronary artery bypass graft surgery, PCI
percutaneous coronary intervention, d days
Online Figure 2. Kaplan-Meier estimates of protocol defined stent thrombosis and protocol
defined graft occlusion at 5 years
5 year outcomes are illustrated (upper) with landmark analyses at 30 days and 31 days - 5 years
(lower).
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