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SYNTAX Score in Patients With Diabetes Undergoing Coronary Revascularization in the FREEDOM Trial
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
VOL. 72, NO. 23, 2018
ª 2018 PUBLISHED BY ELSEVIER ON BEHALF OF THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
SYNTAX Score in Patients With Diabetes Undergoing Coronary Revascularization in the FREEDOM Trial Rodrigo B. Esper, MD, PHD,a,b,* Michael E. Farkouh, MD, MSC,c,* Expedito E. Ribeiro, MD, PHD,a Whady Hueb, MD, PHD,a Michael Domanski, MD,d Taye H. Hamza, PHD,e Flora S. Siami, MPH,e Lucas Colombo Godoy, MD,a,c Verghese Mathew, MD,f John French, MBCHB, PHD,g Valentin Fuster, MD, PHDh,i
ABSTRACT BACKGROUND Diabetes mellitus (DM) is associated with complex coronary artery disease (CAD), which in turn results in increased morbidity and mortality from cardiovascular disease. OBJECTIVES This study sought to evaluate the utility of SYNTAX score (SS) for predicting future cardiovascular events in patients with DM and complex CAD undergoing either coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI). METHODS The FREEDOM (Future REvascularization Evaluation in patients with Diabetes mellitus: Optimal management of Multivessel disease) trial randomized patients with DM and multivessel CAD to undergo either PCI with drug-eluting stents or CABG. The SS was calculated retrospectively by a core laboratory. The endpoint of hard cardiovascular events (HCE) was a composite of death from any cause, nonfatal myocardial infarction, and nonfatal stroke, while the endpoint of major adverse cardiac and cerebrovascular events (MACCE) was a composite of HCE and repeat revascularization. RESULTS A total of 1,900 patients were randomized to PCI (n ¼ 953) or CABG (n ¼ 947). The SS was considered an independent predictor of 5-year MACCE (hazard ratio per unit of SS: 1.02; 95% confidence interval: 1.00 to 1.03; p ¼ 0.014) and HCE (hazard ratio per unit of SS: 1.03; 95% confidence interval: 1.01 to 1.04; p ¼ 0.002) in the PCI cohort, but not in the CABG group. There was a higher incidence of MACCE in PCI patients with low, intermediate, and high SS compared with those who underwent CABG (36.6% vs. 25.9%, p ¼ 0.02; 43.9% vs. 26.8%, p < 0.001; 48.7% vs. 29.7%, p ¼ 0.003, respectively). CONCLUSIONS In DM patients with multivessel CAD, the complexity of CAD evaluated by the SS is an independent risk factor for MACCE and HCE only in patients undergoing PCI. The SS should not be utilized to guide the choice of coronary revascularization in patients with DM and multivessel CAD. (Comparison of Two Treatments for Multivessel Coronary Artery Disease in Individuals With Diabetes [FREEDOM]; NCT00086450) (J Am Coll Cardiol 2018;72:2826–37) © 2018 Published by Elsevier on behalf of the American College of Cardiology Foundation.
I
n
(DM),
mortality from cardiovascular disease (1,2). For pa-
compared with those without DM, coronary ar-
patients
with
diabetes
mellitus
tients with DM and multivessel CAD, coronary artery
tery disease (CAD) tends to be more diffuse, com-
bypass grafting (CABG) has been definitively shown
plex, and associated with increased morbidity and
to improve outcome compared with percutaneous
Listen to this manuscript’s
From the aHeart Institute of the University of São Paulo Medical School, São Paulo, Brazil; bPrevent Senior Institute, São Paulo,
audio summary by
Brazil; cPeter Munk Cardiac Centre and the Heart and Stroke Richard Lewar Centre, University of Toronto, Toronto, Ontario,
JACC Editor-in-Chief
Canada; dDepartment of Medicine, Mount Sinai Medical Center, New York, New York; eNew England Research Institutes,
Dr. Valentin Fuster.
Watertown, Massachusetts; fDivision of Cardiology, Loyola University Stritch School of Medicine, Maywood, Illinois; gDepartment of Cardiology, University of New South Wales, Liverpool Hospital, Sydney, New South Wales, Australia; hIcahn School of Medicine at Mount Sinai, New York, New York; and the iCentro Nacional de Investigaciones Cardiovasculares, Madrid, Spain. *Drs. Esper and Farkouh contributed equally to this work. The FREEDOM trial was funded by the National Heart, Lung, and Blood Institute. The authors have reported that they have no relationships relevant to the contents of this paper to disclose. Manuscript received July 30, 2018; revised manuscript received September 13, 2018, accepted September 14, 2018.
ISSN 0735-1097/$36.00
https://doi.org/10.1016/j.jacc.2018.09.046
JACC VOL. 72, NO. 23, 2018
Esper et al.
DECEMBER 11, 2018:2826–37
SYNTAX Score in Diabetic Patients
coronary
the
This protocol was approved by the hospi-
FREEDOM (Future REvascularization Evaluation in
intervention
(PCI).
Specifically,
tals’ ethics committees and is in accordance
patients with Diabetes mellitus: Optimal manage-
with the Declaration of Helsinki. Written
ment of Multivessel disease) trial showed a reduction
informed consent was obtained from all
in mortality and in the primary composite outcomes
patients.
of death, myocardial infarction (MI), or stroke following CABG compared with PCI (3). Whether a group of multivessel diabetic CAD patients can be identified who, based on lesser lesion complexity, have results following PCI comparable to those following CABG is not known. SEE PAGE 2838
The SYNTAX score (SS) uses coronary anatomy to objectively guide decisions regarding mode of revascularization (4–6). Studies have confirmed the clinical validity of the SS for identifying higher-risk subjects and aiding decision making between CABG and PCI in a broad range of patient types (7–12). The SS is now advocated in both the European and U.S. revascularization guidelines as an aid for deciding on revascularization strategy (13–18). The final 5-year results of the SYNTAX (Synergy between PCI with Taxus and Cardiac Surgery) trial suggest that the SS not only is a valid tool for estimating the risk associated with PCI in patients with left main or multivessel CAD but also may be an effective aid in selecting those with outcomes after PCI that would be predicted to be similar to CABG (19,20).
ABBREVIATIONS AND ACRONYMS CABG = coronary artery bypass grafting
CAD = coronary artery disease
REVASCULARIZATION AND PHARMACOLOGIC THERAPY. First-generation
sirolimus-eluting
DM = diabetes mellitus HCE = hard cardiovascular
stent (Cypher stent, Cordis/Johnson & John-
events
son, Miami Lakes, Florida) and paclitaxel-
HR = hazard ratio
eluting stent (Taxus stent, Boston Scientific,
IQR = interquartile range
Boston, Massachusetts) were the ones pre-
LVEF = left ventricular
dominantly used in the FREEDOM trial.
ejection fraction
The interventional cardiologist was encour-
MACCE = major adverse
aged to treat all arteries that were likely to
cardiac and cerebrovascular
contribute to ischemia or had lesions with >70% diameter stenosis and to achieve complete anatomic revascularization. The use of glycoprotein IIb/IIIa inhibitors was recommended for patients undergoing PCI. Dual antiplatelet therapy with aspirin and clopidogrel was recommended for at least
events
MI = myocardial infarction PCI = percutaneous coronary intervention
ROC = receiver-operating characteristic
SS = SYNTAX score
12 months after stent implantation. Use of internal mammary conduits was strongly advised for all CABG cases. Medical treatment was performed to keep the patient free of angina. The recommended target lipid, glucose, and blood pressure levels were low-density lipoprotein cholesterol <70 mg/dl, blood pressure <130/80 mm Hg, and glycated hemoglobin <7%.
However, the value of the SS has not been assessed
SS CALCULATION. The SS for each patient was
specifically in a population limited to patients with
calculated retrospectively by scoring all coronary
diabetes
population
lesions with a diameter stenosis $50%, in vessels
entered into the FREEDOM trial offers an effective
$1.5 mm, using the SS algorithm, which is described
and
multivessel
CAD.
The
platform for making this assessment. We assessed the
in full elsewhere (4,5) and is available on the SS
prognostic implications of the SS in diabetic patients
website. The SS for each patient was calculated
with multivessel CAD who underwent either PCI or
retrospectively by the core laboratory at the Cardio-
CABG in the FREEDOM trial.
vascular Research Foundation. The subjects were categorized according to the level of the SS: low (0 to
METHODS STUDY POPULATION. The FREEDOM trial was a
22), intermediate (23 to 32), or high ($33) (7). MAJOR ADVERSE CARDIAC AND CEREBROVASCULAR EVENTS. Major adverse cardiac and cerebrovascular
multicenter trial that studied diabetic patients with
events (MACCE) were defined by death from any
multivessel native CAD without left main stenosis or
cause, nonfatal MI, nonfatal stroke, and need for
chronic total occlusions that had an indication for
repeat revascularization.
myocardial revascularization and were candidates for either CABG or PCI. Patients were randomized to either CABG or PCI with drug-eluting stents. Multivessel CAD was defined as stenosis of $70% in 2 or
2827
HARD CARDIOVASCULAR EVENTS. Hard cardiovas-
cular events (HCE) were defined by death from any cause, nonfatal MI, and nonfatal stroke.
more major epicardial vessels involving at least 2
STATISTICAL ANALYSIS. Continuous variables are
separate coronary artery territories. This study is a
presented as mean SD and were compared using
post hoc analysis using the subjects enrolled in the
Student’s unpaired t-test or the Mann-Whitney test,
FREEDOM trial. The methods and results of the
as
FREEDOM trial (NCT00086450) have been published
continuous
previously (3,21).
Kolmogorov-Smirnov test. Categorical variables are
appropriate.
The
variables
normality was
assumption
evaluated
by
for the
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Esper et al.
JACC VOL. 72, NO. 23, 2018
SYNTAX Score in Diabetic Patients
DECEMBER 11, 2018:2826–37
T A B L E 1 Baseline and Procedure Variables and Discharge Medications in PCI Versus
CABG Patient Groups
PCI and CABG groups, with those variables with a probability value of <0.25 in the univariate analysis being included in the backward stepwise multivari-
PCI (n ¼ 953)
CABG (n ¼ 947)
p Value
63.2 8.9
63.1 9.2
0.77
26.8
30.5
0.08
Current smoker
14.8
16.6
0.31
Hypertension
84.6
85.1
0.75
curves were made to evaluate the SS capacity of
Previous MI
26.2
25.0
0.56
discrimination to MACCE and HCE in the PCI and
Recent ACS
31.9
29.5
0.25
CABG groups. Survival curves were constructed for
Previous stroke
3.9
3.0
0.31
time-to-event variables using Kaplan-Meier estimates
COPD
3.4
5.4
0.03
and compared by the log-rank test at 5 years of
29.6 5.4
29.8 5.3
0.39
169.0 92.4
166.7 45.2
0.36
LDL cholesterol, mg/dl
92.4 35.3
93.1 37.2
0.90
HDL cholesterol, mg/dl
39.0 10.9
39.5 11.5
0.40
Triglycerides, mg/dl
193.7 411.6
177.9 132.1
0.39
of p < 0.05 was considered statistically significant,
Creatinine clearance, ml/min
89.9 44.4
88.4 40.2
0.59
and they were conducted using the statistical package
Microalbuminuria, mg/dl*
91.9 302.8
95.4 245.1
0.50
SPSS 15 (SPSS Inc., Chicago, Illinois).
20.0
19.4
0.73
7.7 1.7
7.7 1.7
0.88
33.8
30.9
0.19
Age at randomization, yrs Female
BMI, kg/m2 Total cholesterol, mg/dl
Creatinine clearance <60 ml/min Glycated hemoglobin, % Use of insulin Use of oral antidiabetic drugs
77.2
77.0
0.87
Use of aspirin
91.0
90.4
0.64
Use of beta-blocker
75.8
74.7
0.56
Use of ACE inhibitor
64.4
64.1
0.89
able model. Only variables with statistical significance (p < 0.05) remained in the Cox multivariable model.
Receiver-operating
characteristic
(ROC)
follow-up. Patients lost to follow-up were considered at risk until the date of last contact, at which point they were censored. For all analyses, a 2-sided value
RESULTS STUDY POPULATION. From April 2005 to April 2010,
32,966 patients were screened to FREEDOM trial. Of the 3,309 trial-eligible patients, 1,900 (57.4%) pro-
Use of ARB
16.2
16.5
0.90
vided written informed consent and underwent
Use of statins
82.1
82.6
0.81
randomization. A total of 1,900 patients, 953 in the
Use of nitrates
40.0
38.8
0.57
PCI group and 947 in the CABG group, were followed
58.2 11.8
58.7 11.5
0.39
prospectively.
5.8
4.9
0.41
The overall clinical, laboratory, and angiographic
0.22
characteristics were well balanced in the 2 groups
LVEF, % LVEF <40% Coronary anatomy 2-vessel disease
17.6
15.4
3-vessel disease
81.8
83.7
and for each SS category (Tables 1 and 2). The mean SS was 26.2 8.4 in the PCI group and 26.1 8.8 in
2.7 2.4
2.8 2.5
0.52
26.2 8.4
26.1 8.8
0.67
the CABG group (p ¼ 0.67). There was no difference
0.45
between PCI and CABG according to SS category
Low (#22)
34.7
36.2
distribution (34.7% of the PCI patients were in the
Intermediate (23–32)
46.2
43.3
low-SS strata vs. 36.2% of the CABG patients;
High ($33)
19.2
20.5
46.8
47.6
0.75
3.6 1.7
—
NA
EuroSCORE SYNTAX score SYNTAX score
Proximal LAD obstruction Total number of stents
proportions are 46.2% vs. 43.3% for intermediate-SS subjects and 19.2% vs. 20.5% for high-SS subjects; p ¼ 0.45). The median overall follow-up for all
Sirolimus-eluting stent
51.3
1.1†
<0.001
Paclitaxel-eluting stent
44.2
0.5†
<0.001
76.2 36.9
—
NA
4.9) years. The median follow-up until the first
Graft vessels
—
2.9 0.8
NA
MACCE event (or last-seen date) was 3.2 (IQR: 1.9
Left internal thoracic artery graft
—
89.0
NA
to 4.5) years and the median follow-up until and
Total length of stents placed, mm
Values are mean SD or %. *Microalbuminuria in 24-h urine was calculated only for measurements with U.S. units (mg/dl), for a total of 1,429 subjects. †Crossover subjects. ACE ¼ angiotensin-converting enzyme; ACS ¼ acute coronary syndrome; ARB ¼ angiotensin receptor blocker; BMI ¼ body mass index; CABG ¼ coronary artery bypass grafting; COPD ¼ chronic obstructive pulmonary disease; EuroSCORE ¼ European System for Cardiac Operative Risk Evaluation; HDL ¼ high-density lipoprotein cholesterol; LAD ¼ left anterior descending artery; LDL ¼ low-density lipoprotein cholesterol; LVEF ¼ left ventricular ejection fraction; MI ¼ myocardial infarction; NA ¼ not applicable; PCI ¼ percutaneous coronary intervention.
patients was 3.8 (interquartile range [IQR]: 2.5 to
the first HCE event (or last-seen date) was 3.5 (IQR: 2.3 to 4.6) years. In the PCI group, there was a significant difference in MACCE (p ¼ 0.04) and a nonsignificant difference for HCE (p ¼ 0.07) between SS categories (Figures 1A and 1B). In the CABG group there was no difference for the incidence of cardiovascular events between SS
presented as counts and percentages and were
categories at 5-year follow-up (Figures 1C and 1D).
compared with the chi-square test when appropriate
LONG-TERM FOLLOW-UP PREDICTORS OF MACCE
(expected frequency >5). Otherwise, Fisher exact
AND HCE IN PCI GROUP. In multivariate analysis of
test was used. Cox regression analysis was used to
the PCI cohort, left ventricular ejection fraction
find independent predictors of MACCE and HCE in
(LVEF)
<40%,
the
use
of
insulin,
creatinine
JACC VOL. 72, NO. 23, 2018
Esper et al.
DECEMBER 11, 2018:2826–37
SYNTAX Score in Diabetic Patients
T A B L E 2 Baseline and Procedure Variables and Discharge Medications in PCI Versus CABG Patient Groups, According to the SYNTAX Score
Low
Intermediate
High
PCI (n ¼ 328)
CABG (n ¼ 339)
PCI (n ¼ 438)
CABG (n ¼ 406)
PCI (n ¼ 182)
CABG (n ¼ 192)
62.3 8.6
62.5 9.0
63.9 9.0
62.9 9.5
63.2 8.8
64.3 9.0
Female
30.1
33.8
27.4
27.1
19.2
31.3
Current smoker
13.4
19.4
15.5
17.0
15.9
11.5
Hypertension
83.3
85.0
85.8
85.7
84.1
84.4
Previous MI
24.6
24.4
25.6
25.4
30.2
24.0
Recent ACS
32.5
26.8
30.1
32.0
35.2
28.1
Previous stroke
4.3
1.8
3.7
3.4
3.8
3.6
COPD
3.0
4.4
4.1
6.2
2.2
5.7
30.2 5.5
30.2 5.9
29.4 5.2
29.6 5.1
29.3 5.4
29.5 4.5
Total cholesterol, mg/dl
166.1 48.5
164.0 44.6
173.9 125.9
165.7 43.4
161.1 43.1
172.4 49.5
LDL cholesterol, mg/dl
92.1 35.7
91.5 36.7
92.6 35.9
92.5 35.0
91.3 33.1
96.6 42.1
HDL cholesterol, mg/dl
38.5 10.5
38.8 12.3
39.3 11.2
40.0 11.0
39.2 10.8
39.6 11.0
187.2 165.7
179.4 153.9
213.3 583.9
170.9 109.0
158.1 112.9
187.6 134.7
Age at randomization, yrs
BMI, kg/m2
Triglycerides median, mg/dl Creatinine clearance, ml/min
94.4 57.5
92.3 50.3
87.2 34.9
87.6 33.1
88.6 37.0
84.0 33.0
Microalbuminuria, mg/dl*
67.1 141.5
76.9 205.1
118.0 420.2
97.9 244.4
76.5 166.4
145.1 335.7
Creatinine clearance <60 ml/min
17.0
18.8
23.1
17.5
18.1
24.5
7.8 1.8
7.8 1.7
7.7 1.7
7.6 1.7
7.7 1.8
7.8 1.6
Use of insulin
37.7
27.6
30.4
34.0
35.7
30.2
Use of oral antidiabetic drugs
79.9
77.1
75.8
74.9
75.3
81.8
Use of aspirin
92.1
90.6
89.7
89.9
92.3
90.6 73.4
Glycated hemoglobin, %
Use of beta-blocker
76.3
77.4
75.3
72.9
75.8
Use of ACE inhibitor
66.3
65.0
65.8
64.5
58.8
61.5
Use of ARB
17.9
17.4
14.2
17.0
18.1
14.6
Use of statins
83.9
83.2
81.1
83.0
81.9
82.3
Use of nitrates
41.6
40.6
39.7
35.2
38.5
42.7
59.0 11.2
60.9 11.0
58.5 11.9
57.9 11.0
56.0 12.2
56.6 12.1
4.0
3.5
5.5
4.2
9.3
7.8
LVEF, % LVEF <40% Coronary anatomy 2-vessel disease
31.9
29.7
11.6
8.9
6.6
4.7
3-vessel disease
67.8
70.3
88.4
91.1
93.4
95.3
EuroSCORE
2.5 2.1
2.4 1.8
2.8 2.5
2.8 2.6
2.7 2.5
3.1 2.6
SYNTAX score
17.6 3.7
17.3 3.6
27.5 2.9
27.5 2.8
38.8 5.2
38.8 5.5 70.8
Proximal LAD obstruction
27.1
32.4
53.2
50.2
68.1
Total number of stents
3.2 1.6
—
3.7 1.8
—
4.0 1.9
—
Sirolimus-eluting stent
53.2
0.9†
48.6
1.2†
55.5
1.0†
42.9
0.9†
47.3
0.5†
37.9
—
67.2 31.6
—
78.6 37.2
—
86.4 41.8
—
Graft vessels
—
2.8 0.8
—
3.0 0.8
—
3.1 0.8
Left internal thoracic artery graft
—
88.5
—
90.9
—
87.0
Paclitaxel-eluting stent Total length of stents placed, mm
Values are mean SD or %. *Microalbuminuria in 24-h urine was calculated only for measurements with U.S. units (mg/dl), for a total of 1,429 subjects. †Crossover subjects. Abbreviations as in Table 1.
clearance <60 ml/min, and SS (hazard ratio [HR] per
age were considered a protective factor for HCE at
unit of SS: 1.02; 95% confidence interval [CI]: 1.00 to
5 years (Table 3). Although the SS was an independent
1.03; p ¼ 0.014) were independent predictors of
risk factor for MACCE and HCE at 5 years, the
MACCE at 5 years. (Table 3). The independent risk
area under the ROC curve showed a poor discrimina-
factors related to HCE at 5 years in the PCI group in
tion capability for MACCE (0.54) and HCE (0.56)
multivariate analysis were LVEF <40%, previous
(Figure 2).
stroke, creatinine clearance <60 ml/min, previous MI, insulin use, and the SS (HR per unit of SS: 1.03; 95% CI:
LONG-TERM FOLLOW-UP PREDICTORS OF MACCE
1.01 to 1.04; p ¼ 0.002). The use of angiotensin-
AND HCE IN THE CABG GROUP. In the CABG group
receptor blocker or angiotensin-converting enzyme
after adjustment for potential confounding biases by
inhibitors, triglycerides #150 mg/dl, and #70 years of
multivariate logistic Cox regression, patients with
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Esper et al.
JACC VOL. 72, NO. 23, 2018
SYNTAX Score in Diabetic Patients
DECEMBER 11, 2018:2826–37
F I G U R E 1 Kaplan-Meier Curves of MACCE and HCE Stratified by SYNTAX Score Category in the PCI and CABG Groups
A P-value = 0.04
0.9 SYNTAX Score Category
0.8
SYNTAX Low (36.6%)
0.7
SYNTAX Intermediate (43.9%)
0.6
SYNTAX High (48.7%)
0.5 0.4 0.3 0.2 0.1 0.0 0
1
2
3
HCE - PCI Group Death, Myocardial Infarction or Stroke Rate
Death, Myocardial Infarction, Stroke or Repeat Revascularization Rate
B
MACCE - PCI Group 1.0
4
1.0
P-value = 0.07
0.9 SYNTAX Score Category
0.8
SYNTAX Low (23.2%)
0.7
SYNTAX Intermediate (27.2%)
0.6
SYNTAX High (30.6%)
0.5 0.4 0.3 0.2 0.1 0.0 0
5
1
Years Since Randomization
2
3
4
5
Years Since Randomization
SYNTAX Score Category / No. at Risk
SYNTAX Score Category / No. at Risk
282
246
182
122
62
SYNTAX Low 328
300
279
213
144
69
SYNTAX Inter. 438
343
293
216
130
65
SYNTAX Inter. 438
387
348
268
169
83
SYNTAX High 182
146
124
101
59
23
SYNTAX High 182
156
139
117
74
34
4
5
Death, Myocardial Infarction, Stroke or Repeat Revascularization Rate
C
D
MACCE - CABG Group
1.0
P-value = 0.78
0.9 0.8
SYNTAX Score Category
0.7
SYNTAX Low (25.9%)
0.6
SYNTAX Intermediate (26.8%) SYNTAX High (29.7%)
0.5 0.4 0.3 0.2 0.1 0.0 0
1
2
3
4
Death, Myocardial Infarction or Stroke Rate
SYNTAX Low 328
HCE - CABG Group
1.0
P-value = 0.59
0.9 0.8
SYNTAX Score Category
0.7
SYNTAX Low (17.2%)
0.6
SYNTAX Intermediate (17.7%) SYNTAX High (22.8%)
0.5 0.4 0.3 0.2 0.1 0.0 0
5
2
1
3
Years Since Randomization
Years Since Randomization
SYNTAX Score Category / No. at Risk
SYNTAX Score Category / No. at Risk SYNTAX Low 339
286
242
188
126
63
SYNTAX Low 339
296
258
205
138
67
SYNTAX Inter. 406
334
308
237
152
68
SYNTAX Inter. 406
348
325
257
169
78
SYNTAXHigh 192
158
149
118
84
44
SYNTAX High 192
164
156
127
89
46
Kaplan-Meier curve for (A) major adverse cardiac and cerebrovascular events (MACCE) and (B) hard cardiovascular events (HCE) stratified by SYNTAX score in the percutaneous coronary intervention (PCI) group. Kaplan-Meier curve for (C) MACCE and (D) HCE stratified by SYNTAX score in the coronary artery bypass grafting (CABG) group. MI ¼ myocardial infarction.
LVEF <40% and use of insulin were independent risk
OUTCOMES
IN
PCI
factors for MACCE at 5 years (Table 4). The indepen-
ACCORDING
TO
SS
dent risk factors for HCE were use of insulin, creati-
higher incidence of MACCE in PCI patients with low,
nine clearance <60 ml/min, and LVEF <40%. The
intermediate, and high SS compared with those who
variables #70 years of age and LDL cholesterol
underwent CABG (36.6% vs. 25.9% with low SS
#100 mg/dl were independent protective factors for
category, p ¼ 0.02; 43.9% vs. 26.8% with interme-
MACCE and HCE in CABG group at 5 years (Table 4).
diate SS category, p < 0.001; 48.7% vs. 29.7% with
The SS was not an independent risk factor for MACCE
high SS, p ¼ 0.003) (Figure 3). When evaluating the
and HCE in the CABG group.
role of glycemic control and rates of MACCE, within
VERSUS
CABG
CATEGORIES. There
GROUPS
was
a
JACC VOL. 72, NO. 23, 2018
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DECEMBER 11, 2018:2826–37
SYNTAX Score in Diabetic Patients
each SS category, the benefit of CABG over PCI was consistent in all subgroups (Online Table 1, Online Figure 1).
2831
T A B L E 3 Multivariable Cox Model for Death/Stroke/MI/Need for Repeat
Revascularization (MACCE) and Death/Stroke/MI (HCE) Based on Stepwise Selection in the PCI Group
There were no statistically significant differences between PCI and CABG groups for HCE in patients
Predictor
HR (95% CI)
p Value
MACCE
with low (23.2% in the PCI group vs. 17.2% in the
SYNTAX score
1.02 (1.00–1.03)
0.014
CABG group, p ¼ 0.55) and high SS (30.6% in the PCI
LVEF <40%
2.80 (1.95–4.02)
<0.0001
group vs. 22.8% in the CABG group, p ¼ 0.11). There
Use of insulin
1.45 (1.16–1.81)
0.001
was a higher incidence of HCE in patients with in-
Creatinine clearance <60 ml/min
1.43 (1.11–1.85)
0.006
termediate SS in PCI group (27.2% in the PCI group vs. 17.7% in the CABG group, p ¼ 0.03) (Figure 4). The rates of repeat revascularization were higher in
HCE SYNTAX score
1.03 (1.01–1.04)
0.002
LVEF <40%
3.58 (2.28–5.63)
<0.0001 0.003
Previous stroke
2.46 (1.35–4.50)
Creatinine clearance <60 ml/min
1.46 (1.03–2.07)
0.033
Triglycerides #150 mg/dl
0.74 (0.55–1.00)
0.049
vs. 11.5%, p < 0.001; intermediate: 37.4% vs. 13.8%, p <
Previous myocardial infarction
1.42 (1.04–1.96)
0.03
0.001; high: 32.4% vs. 14.0%, p < 0.001). The incidence
Use of insulin
1.52 (1.13–2.04)
0.006
all SS categories of the PCI group, when compared with the same SS categories of the CABG group (low: 25.6%
of myocardial infarction was numerically higher in all
Use of angiotensin receptor blocker
0.54 (0.33–0.87)
0.012
SS categories of the PCI group compared with the
Use of angiotensin-converting enzyme
0.64 (0.46–0.89)
0.008
#70 yrs of age
0.65 (0.47–0.91)
0.012
CABG group, reaching statistical significance in the intermediate and high SS strata (low: 11.3% vs. 5.4%, p ¼ 0.15; intermediate: 15.8% vs. 5.6%, p ¼ 0.002; high:
CI ¼ confidence interval; HR ¼ hazard ratio; HCE ¼ hard cardiovascular events; MACCE ¼ major adverse cardiac and cerebrovascular events; other abbreviations as in Table 1.
16.7% vs 7.9%, p ¼ 0.01) (Table 5).
DISCUSSION
guide clinical decision making regarding the choice of coronary revascularization strategy. Some studies
This study demonstrates that the SS has a modest
have shown that angioplasty may be an alternative to
correlation with HCE and a significant correlation
CABG in patients with less complex CAD (low SS) (10),
with MACCE in patients with DM and multivessel
particularly with current-generation drug-eluting
disease undergoing PCI. Additionally, the MACCE rate
stents as recently reported in the SYNTAX 2 study
was higher after PCI compared with CABG for every
(24). In our study, the incidence of MACCE was higher
tercile of SS, thus demonstrating that the SS does not
in the PCI group regardless of SS. Unlike findings
identify a population of DM patients with multivessel
from the SYNTAX trial, our data from the FREEDOM
disease in whom PCI is equivalent or superior to
trial demonstrate that SS should not guide decision
CABG (Central Illustration).
making in diabetic patients with multivessel disease.
The optimal coronary revascularization strategy in
In our study, the SS was not an independent risk
previously
factor for HCE and MACCE in the CABG group, a result
(1,3,22,23). In 1997, the BARI (Bypass Angioplasty
that is similar to other studies (25,26). The SS includes
Revascularization Investigation) trial compared CABG
anatomic variables such as calcification, tortuosity,
with balloon angioplasty and showed better survival
type of bifurcation, and extent of CAD. However, for
in patients with diabetes who received CABG rather
the patients undergoing CABG, a major determinant
than balloon angioplasty (22). The FREEDOM trial
of graft patency is a satisfactory anastomosis to a
provided definitive proof of the superiority of CABG
suitable distal portion of the bypassed artery. So,
compared with PCI in multivessel CAD patients with
despite the complexity of CAD in proximal arterial
diabetes. Thus, current U.S. guidelines recommend
segments (which determine the SS), late post-CABG
CABG as the preferred coronary revascularization
outcomes are largely influenced by distal vessel
procedure in diabetic patients with multivessel CAD
suitability for grafting, which generally makes minor
(14,15).
contributions to the SS.
diabetic
patients
has
been
studied
Although several major guidelines provide recom-
Several studies have suggested that the SS carries a
mendations based on SS, this is not so practical to do
significant prognostic role, with higher SS associated
in day-to-day practice, and therefore, many if not
with higher burden of long-term mortality and
most revascularization decisions are made without
ischemic adverse events in patients undergoing PCI
using this approach. This is despite the view that the
(19). Most of these studies include subjects with left
SS should be calculated for 2 potential major reasons:
main
1) to predict the risk of future clinical events; and 2) to
FREEDOM trial. Anatomic data alone, particularly
disease,
which
were
excluded
from
the
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SYNTAX Score in Diabetic Patients
DECEMBER 11, 2018:2826–37
F I G U R E 2 SYNTAX Score ROC Curves for Discrimination of Cardiovascular Events in the PCI and CABG Groups
ROC Curve SYNTAX Score for Death, MI, Stroke or Repeat Revascularization Event, PCI Group
ROC Curve SYNTAX Score for Death, MI or Stroke Event, PCI Group
B
1.0
1.0
0.8
0.8
0.6
0.6
Sensitivity
Sensitivity
A
0.4
0.2
0.4
0.2 Area under the curve: 0.544
Area under the curve: 0.562
0.0
0.0 0.0
0.2
0.4
0.6
0.8
1.0
0.0
0.2
1-Specificity
0.8
1.0
ROC Curve SYNTAX Score for Death, MI or Stroke Event, CABG Group
D
1.0
1.0
0.8
0.8
0.6
0.6
Sensitivity
Sensitivity
0.6
1-Specificity
ROC Curve SYNTAX Score for Death, MI, Stroke or Repeat Revascularization Event, CABG Group
C
0.4
0.4
0.2
0.4
0.2 Area under the curve: 0.508
Area under the curve: 0.502
0.0
0.0 0.0
0.2
0.4
0.6
0.8
1.0
1-Specificity
0.0
0.2
0.4
0.6
0.8
1.0
1-Specificity
SYNTAX score receiver-operating characteristic curve (ROC) curve for (A) MACCE and (B) HCE in the PCI group. SYNTAX score ROC curve for (C) MACCE and (D) HCE in the CABG group. Abbreviations as in Figure 1.
T A B L E 4 Multivariable Cox Model for Death/Stroke/MI/Need for Repeat
Revascularization (MACCE) and Death/Stroke/MI (HCE) Based on Stepwise Selection in the CABG Group Predictor
when associated with left ventricular function, is also a strong prognostic predictor, comparable to the SS.
HR (95% CI)
p Value
MACCE
Comparisons of PCI and CABG according to the SS categories showed a higher incidence of MACCE with
Use of insulin
1.76 (1.31–2.35)
0.0002
LVEF <40%
2.19 (1.34–3.57)
0.002
#70 yrs of age
0.55 (0.40–0.74)
<0.0001
LDL cholesterol #100 mg/dl
0.73 (0.55–0.98)
0.035
PCI in all SS categories (low, intermediate, and high). In patients with low and high SS, the incidence of HCE was not statistically different between PCI and CABG, but these results should be interpreted with
HCE Use of insulin
2.05 (1.45–2.88)
<0.0001
caution because the study is underpowered to make
Creatinine clearance <60 ml/min
1.69 (1.14–2.50)
0.009
comparisons between subgroups. In a pooled analysis
LDL cholesterol #100 mg/dl
0.69 (0.49–0.97)
0.031
of patient-level data from the SYNTAX, PRECOMBAT
2.21 (1.26–3.87)
0.006
(Premier of Randomized Comparison of Bypass
0.60 (0.41–0.88)
0.009
Surgery versus Angioplasty Using Sirolimus-Eluting
LVEF <40% #70 yrs of age Abbreviations as in Tables 1 and 3.
Stent in Patients with Left Main Coronary Artery Disease) and BEST (Treatment of Patients with
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SYNTAX Score in Diabetic Patients
F I G U R E 3 Kaplan-Meier Survival Curves of MACCE According to Revascularization Strategy in Patients With Low, Intermediate, and High
SYNTAX Score
A
B
Low SYNTAX Score Patients
Intermediate SYNTAX Score Patients 0.6
P-value = 0.02 Death, Myocardial Infarction, Stroke or Repeat Revascularization Rate
Death, Myocardial Infarction, Stroke or Repeat Revascularization Rate
0.6 0.5
Revascularization Strategy 0.4
PCI (36.6%) CABG (25.9%)
0.3 0.2 0.1
P-value = <0.001
0.5 Revascularization Strategy 0.4
PCI (43.9%) CABG (26.8%)
0.3 0.2 0.1
0.0
0.0 0
2
1
3
4
5
0
3
4
5
Years Since Randomization
Revascularization Strategy / No. at Risk PCI
2
1
Years Since Randomization
Revascularization Strategy / No. at Risk
328
282
246
182
122
62
PCI
438
343
293
216
130
65
CABG 339
286
242
188
126
63
CABG 406
334
308
237
152
68
C
High SYNTAX Score Patients
Death, Myocardial Infarction, Stroke or Repeat Revascularization Rate
0.6
P-value = 0.003
0.5 Revascularization Strategy 0.4
PCI (48.7%) CABG (29.7%)
0.3 0.2 0.1 0.0 0
1
2
3
4
5
Years Since Randomization Revascularization Strategy / No. at Risk PCI
182
146
124
101
59
23
CABG
192
158
149
118
84
44
Kaplan-Meier survival curves for MACCE stratified by revascularization strategy in patients with (A) low, (B) intermediate, and (C) high SYNTAX score. Abbreviations as in Figure 1.
Multivessel Coronary Artery Disease) trials, a similar
considers only angiographic variables and does not
incidence of HCE after PCI or CABG was found in low
include clinical variables. The diameter stenosis
and intermediate SS categories after 5 years (27). The
severity, unless the artery is totally occluded (100%),
cardiovascular events rates were much lower than
does not affect the SS, with coronary stenoses of
those observed in the FREEDOM trial, despite the
50%, 70%, or 95% stenosis scoring the same value.
similar risk profile of both populations.
The score does not consider myocardial ischemia or
Many reasons could explain why the SS has
functional information. Coronary lesions in small
modest discrimination capability for hard cardio-
arteries between 1.5 and 2.0 mm in diameter are
vascular events in diabetic patients. The score
included in the SS, but most of these lesions
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SYNTAX Score in Diabetic Patients
DECEMBER 11, 2018:2826–37
F I G U R E 4 Kaplan-Meier Survival Curves of HCE According to Revascularization Strategy in Patients With Low, Intermediate, and High SYNTAX Score
A
B
P-value = 0.55
0.9 0.8 Revascularization Strategy
0.7
PCI (23.2%)
0.6
CABG (17.2%)
0.5 0.4 0.3 0.2 0.1 0.0 0
1
Intermediate SYNTAX Score Patients Death, Myocardial Infarction or Stroke Rate
Death, Myocardial Infarction or Stroke Rate
Low SYNTAX Score Patients 1.0
2
3
4
1.0
P-value = 0.03
0.9 0.8 Revascularization Strategy
0.7
PCI (27.2%)
0.6
CABG (17.7%)
0.5 0.4 0.3 0.2 0.1 0.0
5
1
0
Years Since Randomization
2
3
4
5
Years Since Randomization
Revascularization Strategy / No. at Risk PCI
328
300
279
213
144
69
Revascularization Strategy / No. at Risk PCI 438 387 348
268
169
83
CABG
339
296
258
205
138
67
CABG 406
257
169
78
C
348
325
Death, Myocardial Infarction or Stroke Rate
High SYNTAX Score Patients 1.0
P-value = 0.11
0.9 0.8
Revascularization Strategy PCI (30.6%)
0.7
CABG (22.8%)
0.6 0.5 0.4 0.3 0.2 0.1 0.0 0
1
2
3
4
5
Years Since Randomization Revascularization Strategy / No. at Risk PCI
182
156
139
117
74
34
CABG
192
164
156
127
89
46
Kaplan-Meier survival curves for HCE stratified by revascularization strategy in patients with (A) low, (B) intermediate, and (C) high SYNTAX score. Abbreviations as in Figure 1.
probably will not undergo revascularization. It may
shows that among diabetic patients, clinical char-
also simply be the case that the components of the
acteristics such as LVEF <40%, insulin-dependent
SS implying PCI procedural complexity are not,
DM, and chronic renal dysfunction are important
per se, good predictors of outcome. Indeed, their
predictors of cardiovascular events and should be
independent long-term prognostic value has not
incorporated into the risk prediction for coronary
been shown isolated, once divorced from the pri-
revascularization. Scores that include clinical and
mary determinant of the SS, which is anatomic
angiographic variables, such as SS II (28–30), clin-
burden of disease.
ical SS (31,32), and Global Risk Score (EuroSCORE
Diabetes mellitus is a disease associated with
[European System for Cardiac Operative Risk Eval-
worse outcomes in patients with CAD. Our study
uation] associated with SS) (33), could be more
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SYNTAX Score in Diabetic Patients
T A B L E 5 Kaplan-Meier Estimates of Adverse Cardiovascular and Cerebrovascular Events at 5 years After the Procedure by SYNTAX Score
Categories and Treatment Arm Low
Intermediate
High
PCI
CABG
Log-Rank p Value
PCI
CABG
Log-Rank p Value
CABG
Log-Rank p Value
MACCE
36.6
25.9
0.02
43.9
26.8
<0.001
HCE
23.2
17.2
0.55
27.2
17.7
0.03
48.7
29.7
0.003
30.6
22.8
Death
17.1
12.5
0.55
15.4
11.3
0.13
0.11
23.3
14.2
0.24
MI
11.3
5.4
0.15
15.8
5.6
Stroke
4.6
4.7
0.33
2.8
4.6
0.002
16.7
7.9
0.01
0.21
2.4
7.1
Repeat revascularization
25.6
11.5
<0.001
37.4
13.8
0.13
<0.001
32.4
14.0
<0.001
PCI
Values are %. Abbreviations as in Tables 1 and 3.
C ENTR AL I LL U STRA T I O N Major Adverse Cardiac and Cerebrovascular Events in Patients With Diabetes Mellitus With Multivessel Coronary Artery Disease Submitted to CABG or PCI According to SYNTAX Score Categories
Death, Myocardial Infarction, Stroke or Repeat Revascularization Rate
0.6
0.5
0.4
0.3
0.2
0.1
0.0 0
1
2
3
4
5
Years Since Randomization SYNTAX Score Category - Revascularization Strategy High SYNTAX - PCI Intermediate SYNTAX - PCI Low SYNTAX - PCI High SYNTAX - CABG Intermediate SYNTAX - CABG Low SYNTAX - CABG
No. at Risk 182 438 328 192 406 339
Esper, R.B. et al. J Am Coll Cardiol. 2018;72(23):2826–37.
In diabetes mellitus (DM) patients with multivessel coronary artery disease (CAD) without left main stenosis and indication for myocardial revascularization, coronary artery bypass grafting (CABG) should be the preferred method of coronary revascularization regardless of the complexity of the coronary disease. In all SYNTAX score categories, CABG had fewer major adverse cardiac and cerebrovascular events (MACCE), defined by death from any cause, nonfatal myocardial infarction, nonfatal stroke, and need for repeat revascularization, versus percutaneous coronary intervention (PCI) with drug-eluting stents in the FREEDOM (Future REvascularization Evaluation in patients with Diabetes mellitus: Optimal management of Multivessel disease) trial.
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SYNTAX Score in Diabetic Patients
DECEMBER 11, 2018:2826–37
suitable to predict MACCE and HCE in diabetic
significant predictor of MACCE only in patients un-
patients.
dergoing PCI. In DM with multivessel CAD, the inci-
The FREEDOM trial was the largest randomized
dence of MACCE is higher for the PCI compared with
study of only DM patients comparing PCI versus
CABG in all SS categories. The SS should not be uti-
CABG in patients with multivessel CAD without left
lized to guide the choice of coronary revasculariza-
main disease. In the SS algorithm, left main stenosis
tion in patients with DM and multivessel CAD.
receives a very high score. In our study, because we excluded patients with left main stenosis, patients with high SS may have severe diffuse CAD, making either bypass grafting or angioplasty more challenging. This may explain the higher incidence of cardiovascular events in patients with high SS in both the PCI and CABG groups. Our findings highlight the importance of anatomic and clinical evaluation of diabetic patients with CAD.
ADDRESS FOR CORRESPONDENCE: Dr. Michael E.
Farkouh, Peter Munk Cardiac Centre and the Heart and Stroke Richard Lewar Centre, University of Toronto,
585
University
Avenue—4N474,
Toronto,
Ontario M5G 2N2, Canada. E-mail: michael.farkouh@ uhn.ca. Twitter: @drmikefarkouh, @PMunkCardiacCtr, @UofT.
The decision-making of the best strategy for revascularization should consider not only coronary
PERSPECTIVES
angiographic aspects but also clinical aspects that could influence the outcomes. The SS alone should not be utilized to guide the choice of coronary revascularization in patients with DM and multivessel CAD.
COMPETENCY IN PATIENT CARE AND PROCEDURAL SKILLS: In patients with DM, the complexity of multivessel CAD as assessed by the SYNTAX score is an independent risk factor for
STUDY LIMITATIONS. This study is not powered to
adverse cardiovascular events in those undergoing
make comparisons between SS subgroups overall or
percutaneous revascularization but not bypass
for any individual component of MACCE; therefore,
surgery. Furthermore, the score does not identify a
these results should be regarded as observational and
subset of diabetic patients with multivessel disease in
hypothesis-generating only and need to be confirmed
whom PCI is equivalent or superior to CABG.
in subsequent adequately powered clinical trials. TRANSLATIONAL OUTLOOK: Additional research
CONCLUSIONS
is needed to clarify clinical features that identify pa-
In DM patients with multivessel CAD, the complexity of CAD evaluated by the SS is a modest independent
tients with diabetes and multivessel CAD who might be preferentially managed with PCI rather than CABG.
risk factor for hard cardiovascular events and a
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KEY WORDS CABG, coronary artery disease, diabetes, PCI, SYNTAX score
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percutaneous coronary intervention in patients
2017;38:1969–77.
paper.
A PP END IX For a supplemental table and figure, please see the online version of this
2837
VOL. 72, NO. 23, 2018
ª 2018 PUBLISHED BY ELSEVIER ON BEHALF OF THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
SYNTAX Score in Patients With Diabetes Undergoing Coronary Revascularization in the FREEDOM Trial Rodrigo B. Esper, MD, PHD,a,b,* Michael E. Farkouh, MD, MSC,c,* Expedito E. Ribeiro, MD, PHD,a Whady Hueb, MD, PHD,a Michael Domanski, MD,d Taye H. Hamza, PHD,e Flora S. Siami, MPH,e Lucas Colombo Godoy, MD,a,c Verghese Mathew, MD,f John French, MBCHB, PHD,g Valentin Fuster, MD, PHDh,i
ABSTRACT BACKGROUND Diabetes mellitus (DM) is associated with complex coronary artery disease (CAD), which in turn results in increased morbidity and mortality from cardiovascular disease. OBJECTIVES This study sought to evaluate the utility of SYNTAX score (SS) for predicting future cardiovascular events in patients with DM and complex CAD undergoing either coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI). METHODS The FREEDOM (Future REvascularization Evaluation in patients with Diabetes mellitus: Optimal management of Multivessel disease) trial randomized patients with DM and multivessel CAD to undergo either PCI with drug-eluting stents or CABG. The SS was calculated retrospectively by a core laboratory. The endpoint of hard cardiovascular events (HCE) was a composite of death from any cause, nonfatal myocardial infarction, and nonfatal stroke, while the endpoint of major adverse cardiac and cerebrovascular events (MACCE) was a composite of HCE and repeat revascularization. RESULTS A total of 1,900 patients were randomized to PCI (n ¼ 953) or CABG (n ¼ 947). The SS was considered an independent predictor of 5-year MACCE (hazard ratio per unit of SS: 1.02; 95% confidence interval: 1.00 to 1.03; p ¼ 0.014) and HCE (hazard ratio per unit of SS: 1.03; 95% confidence interval: 1.01 to 1.04; p ¼ 0.002) in the PCI cohort, but not in the CABG group. There was a higher incidence of MACCE in PCI patients with low, intermediate, and high SS compared with those who underwent CABG (36.6% vs. 25.9%, p ¼ 0.02; 43.9% vs. 26.8%, p < 0.001; 48.7% vs. 29.7%, p ¼ 0.003, respectively). CONCLUSIONS In DM patients with multivessel CAD, the complexity of CAD evaluated by the SS is an independent risk factor for MACCE and HCE only in patients undergoing PCI. The SS should not be utilized to guide the choice of coronary revascularization in patients with DM and multivessel CAD. (Comparison of Two Treatments for Multivessel Coronary Artery Disease in Individuals With Diabetes [FREEDOM]; NCT00086450) (J Am Coll Cardiol 2018;72:2826–37) © 2018 Published by Elsevier on behalf of the American College of Cardiology Foundation.
I
n
(DM),
mortality from cardiovascular disease (1,2). For pa-
compared with those without DM, coronary ar-
patients
with
diabetes
mellitus
tients with DM and multivessel CAD, coronary artery
tery disease (CAD) tends to be more diffuse, com-
bypass grafting (CABG) has been definitively shown
plex, and associated with increased morbidity and
to improve outcome compared with percutaneous
Listen to this manuscript’s
From the aHeart Institute of the University of São Paulo Medical School, São Paulo, Brazil; bPrevent Senior Institute, São Paulo,
audio summary by
Brazil; cPeter Munk Cardiac Centre and the Heart and Stroke Richard Lewar Centre, University of Toronto, Toronto, Ontario,
JACC Editor-in-Chief
Canada; dDepartment of Medicine, Mount Sinai Medical Center, New York, New York; eNew England Research Institutes,
Dr. Valentin Fuster.
Watertown, Massachusetts; fDivision of Cardiology, Loyola University Stritch School of Medicine, Maywood, Illinois; gDepartment of Cardiology, University of New South Wales, Liverpool Hospital, Sydney, New South Wales, Australia; hIcahn School of Medicine at Mount Sinai, New York, New York; and the iCentro Nacional de Investigaciones Cardiovasculares, Madrid, Spain. *Drs. Esper and Farkouh contributed equally to this work. The FREEDOM trial was funded by the National Heart, Lung, and Blood Institute. The authors have reported that they have no relationships relevant to the contents of this paper to disclose. Manuscript received July 30, 2018; revised manuscript received September 13, 2018, accepted September 14, 2018.
ISSN 0735-1097/$36.00
https://doi.org/10.1016/j.jacc.2018.09.046
JACC VOL. 72, NO. 23, 2018
Esper et al.
DECEMBER 11, 2018:2826–37
SYNTAX Score in Diabetic Patients
coronary
the
This protocol was approved by the hospi-
FREEDOM (Future REvascularization Evaluation in
intervention
(PCI).
Specifically,
tals’ ethics committees and is in accordance
patients with Diabetes mellitus: Optimal manage-
with the Declaration of Helsinki. Written
ment of Multivessel disease) trial showed a reduction
informed consent was obtained from all
in mortality and in the primary composite outcomes
patients.
of death, myocardial infarction (MI), or stroke following CABG compared with PCI (3). Whether a group of multivessel diabetic CAD patients can be identified who, based on lesser lesion complexity, have results following PCI comparable to those following CABG is not known. SEE PAGE 2838
The SYNTAX score (SS) uses coronary anatomy to objectively guide decisions regarding mode of revascularization (4–6). Studies have confirmed the clinical validity of the SS for identifying higher-risk subjects and aiding decision making between CABG and PCI in a broad range of patient types (7–12). The SS is now advocated in both the European and U.S. revascularization guidelines as an aid for deciding on revascularization strategy (13–18). The final 5-year results of the SYNTAX (Synergy between PCI with Taxus and Cardiac Surgery) trial suggest that the SS not only is a valid tool for estimating the risk associated with PCI in patients with left main or multivessel CAD but also may be an effective aid in selecting those with outcomes after PCI that would be predicted to be similar to CABG (19,20).
ABBREVIATIONS AND ACRONYMS CABG = coronary artery bypass grafting
CAD = coronary artery disease
REVASCULARIZATION AND PHARMACOLOGIC THERAPY. First-generation
sirolimus-eluting
DM = diabetes mellitus HCE = hard cardiovascular
stent (Cypher stent, Cordis/Johnson & John-
events
son, Miami Lakes, Florida) and paclitaxel-
HR = hazard ratio
eluting stent (Taxus stent, Boston Scientific,
IQR = interquartile range
Boston, Massachusetts) were the ones pre-
LVEF = left ventricular
dominantly used in the FREEDOM trial.
ejection fraction
The interventional cardiologist was encour-
MACCE = major adverse
aged to treat all arteries that were likely to
cardiac and cerebrovascular
contribute to ischemia or had lesions with >70% diameter stenosis and to achieve complete anatomic revascularization. The use of glycoprotein IIb/IIIa inhibitors was recommended for patients undergoing PCI. Dual antiplatelet therapy with aspirin and clopidogrel was recommended for at least
events
MI = myocardial infarction PCI = percutaneous coronary intervention
ROC = receiver-operating characteristic
SS = SYNTAX score
12 months after stent implantation. Use of internal mammary conduits was strongly advised for all CABG cases. Medical treatment was performed to keep the patient free of angina. The recommended target lipid, glucose, and blood pressure levels were low-density lipoprotein cholesterol <70 mg/dl, blood pressure <130/80 mm Hg, and glycated hemoglobin <7%.
However, the value of the SS has not been assessed
SS CALCULATION. The SS for each patient was
specifically in a population limited to patients with
calculated retrospectively by scoring all coronary
diabetes
population
lesions with a diameter stenosis $50%, in vessels
entered into the FREEDOM trial offers an effective
$1.5 mm, using the SS algorithm, which is described
and
multivessel
CAD.
The
platform for making this assessment. We assessed the
in full elsewhere (4,5) and is available on the SS
prognostic implications of the SS in diabetic patients
website. The SS for each patient was calculated
with multivessel CAD who underwent either PCI or
retrospectively by the core laboratory at the Cardio-
CABG in the FREEDOM trial.
vascular Research Foundation. The subjects were categorized according to the level of the SS: low (0 to
METHODS STUDY POPULATION. The FREEDOM trial was a
22), intermediate (23 to 32), or high ($33) (7). MAJOR ADVERSE CARDIAC AND CEREBROVASCULAR EVENTS. Major adverse cardiac and cerebrovascular
multicenter trial that studied diabetic patients with
events (MACCE) were defined by death from any
multivessel native CAD without left main stenosis or
cause, nonfatal MI, nonfatal stroke, and need for
chronic total occlusions that had an indication for
repeat revascularization.
myocardial revascularization and were candidates for either CABG or PCI. Patients were randomized to either CABG or PCI with drug-eluting stents. Multivessel CAD was defined as stenosis of $70% in 2 or
2827
HARD CARDIOVASCULAR EVENTS. Hard cardiovas-
cular events (HCE) were defined by death from any cause, nonfatal MI, and nonfatal stroke.
more major epicardial vessels involving at least 2
STATISTICAL ANALYSIS. Continuous variables are
separate coronary artery territories. This study is a
presented as mean SD and were compared using
post hoc analysis using the subjects enrolled in the
Student’s unpaired t-test or the Mann-Whitney test,
FREEDOM trial. The methods and results of the
as
FREEDOM trial (NCT00086450) have been published
continuous
previously (3,21).
Kolmogorov-Smirnov test. Categorical variables are
appropriate.
The
variables
normality was
assumption
evaluated
by
for the
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Esper et al.
JACC VOL. 72, NO. 23, 2018
SYNTAX Score in Diabetic Patients
DECEMBER 11, 2018:2826–37
T A B L E 1 Baseline and Procedure Variables and Discharge Medications in PCI Versus
CABG Patient Groups
PCI and CABG groups, with those variables with a probability value of <0.25 in the univariate analysis being included in the backward stepwise multivari-
PCI (n ¼ 953)
CABG (n ¼ 947)
p Value
63.2 8.9
63.1 9.2
0.77
26.8
30.5
0.08
Current smoker
14.8
16.6
0.31
Hypertension
84.6
85.1
0.75
curves were made to evaluate the SS capacity of
Previous MI
26.2
25.0
0.56
discrimination to MACCE and HCE in the PCI and
Recent ACS
31.9
29.5
0.25
CABG groups. Survival curves were constructed for
Previous stroke
3.9
3.0
0.31
time-to-event variables using Kaplan-Meier estimates
COPD
3.4
5.4
0.03
and compared by the log-rank test at 5 years of
29.6 5.4
29.8 5.3
0.39
169.0 92.4
166.7 45.2
0.36
LDL cholesterol, mg/dl
92.4 35.3
93.1 37.2
0.90
HDL cholesterol, mg/dl
39.0 10.9
39.5 11.5
0.40
Triglycerides, mg/dl
193.7 411.6
177.9 132.1
0.39
of p < 0.05 was considered statistically significant,
Creatinine clearance, ml/min
89.9 44.4
88.4 40.2
0.59
and they were conducted using the statistical package
Microalbuminuria, mg/dl*
91.9 302.8
95.4 245.1
0.50
SPSS 15 (SPSS Inc., Chicago, Illinois).
20.0
19.4
0.73
7.7 1.7
7.7 1.7
0.88
33.8
30.9
0.19
Age at randomization, yrs Female
BMI, kg/m2 Total cholesterol, mg/dl
Creatinine clearance <60 ml/min Glycated hemoglobin, % Use of insulin Use of oral antidiabetic drugs
77.2
77.0
0.87
Use of aspirin
91.0
90.4
0.64
Use of beta-blocker
75.8
74.7
0.56
Use of ACE inhibitor
64.4
64.1
0.89
able model. Only variables with statistical significance (p < 0.05) remained in the Cox multivariable model.
Receiver-operating
characteristic
(ROC)
follow-up. Patients lost to follow-up were considered at risk until the date of last contact, at which point they were censored. For all analyses, a 2-sided value
RESULTS STUDY POPULATION. From April 2005 to April 2010,
32,966 patients were screened to FREEDOM trial. Of the 3,309 trial-eligible patients, 1,900 (57.4%) pro-
Use of ARB
16.2
16.5
0.90
vided written informed consent and underwent
Use of statins
82.1
82.6
0.81
randomization. A total of 1,900 patients, 953 in the
Use of nitrates
40.0
38.8
0.57
PCI group and 947 in the CABG group, were followed
58.2 11.8
58.7 11.5
0.39
prospectively.
5.8
4.9
0.41
The overall clinical, laboratory, and angiographic
0.22
characteristics were well balanced in the 2 groups
LVEF, % LVEF <40% Coronary anatomy 2-vessel disease
17.6
15.4
3-vessel disease
81.8
83.7
and for each SS category (Tables 1 and 2). The mean SS was 26.2 8.4 in the PCI group and 26.1 8.8 in
2.7 2.4
2.8 2.5
0.52
26.2 8.4
26.1 8.8
0.67
the CABG group (p ¼ 0.67). There was no difference
0.45
between PCI and CABG according to SS category
Low (#22)
34.7
36.2
distribution (34.7% of the PCI patients were in the
Intermediate (23–32)
46.2
43.3
low-SS strata vs. 36.2% of the CABG patients;
High ($33)
19.2
20.5
46.8
47.6
0.75
3.6 1.7
—
NA
EuroSCORE SYNTAX score SYNTAX score
Proximal LAD obstruction Total number of stents
proportions are 46.2% vs. 43.3% for intermediate-SS subjects and 19.2% vs. 20.5% for high-SS subjects; p ¼ 0.45). The median overall follow-up for all
Sirolimus-eluting stent
51.3
1.1†
<0.001
Paclitaxel-eluting stent
44.2
0.5†
<0.001
76.2 36.9
—
NA
4.9) years. The median follow-up until the first
Graft vessels
—
2.9 0.8
NA
MACCE event (or last-seen date) was 3.2 (IQR: 1.9
Left internal thoracic artery graft
—
89.0
NA
to 4.5) years and the median follow-up until and
Total length of stents placed, mm
Values are mean SD or %. *Microalbuminuria in 24-h urine was calculated only for measurements with U.S. units (mg/dl), for a total of 1,429 subjects. †Crossover subjects. ACE ¼ angiotensin-converting enzyme; ACS ¼ acute coronary syndrome; ARB ¼ angiotensin receptor blocker; BMI ¼ body mass index; CABG ¼ coronary artery bypass grafting; COPD ¼ chronic obstructive pulmonary disease; EuroSCORE ¼ European System for Cardiac Operative Risk Evaluation; HDL ¼ high-density lipoprotein cholesterol; LAD ¼ left anterior descending artery; LDL ¼ low-density lipoprotein cholesterol; LVEF ¼ left ventricular ejection fraction; MI ¼ myocardial infarction; NA ¼ not applicable; PCI ¼ percutaneous coronary intervention.
patients was 3.8 (interquartile range [IQR]: 2.5 to
the first HCE event (or last-seen date) was 3.5 (IQR: 2.3 to 4.6) years. In the PCI group, there was a significant difference in MACCE (p ¼ 0.04) and a nonsignificant difference for HCE (p ¼ 0.07) between SS categories (Figures 1A and 1B). In the CABG group there was no difference for the incidence of cardiovascular events between SS
presented as counts and percentages and were
categories at 5-year follow-up (Figures 1C and 1D).
compared with the chi-square test when appropriate
LONG-TERM FOLLOW-UP PREDICTORS OF MACCE
(expected frequency >5). Otherwise, Fisher exact
AND HCE IN PCI GROUP. In multivariate analysis of
test was used. Cox regression analysis was used to
the PCI cohort, left ventricular ejection fraction
find independent predictors of MACCE and HCE in
(LVEF)
<40%,
the
use
of
insulin,
creatinine
JACC VOL. 72, NO. 23, 2018
Esper et al.
DECEMBER 11, 2018:2826–37
SYNTAX Score in Diabetic Patients
T A B L E 2 Baseline and Procedure Variables and Discharge Medications in PCI Versus CABG Patient Groups, According to the SYNTAX Score
Low
Intermediate
High
PCI (n ¼ 328)
CABG (n ¼ 339)
PCI (n ¼ 438)
CABG (n ¼ 406)
PCI (n ¼ 182)
CABG (n ¼ 192)
62.3 8.6
62.5 9.0
63.9 9.0
62.9 9.5
63.2 8.8
64.3 9.0
Female
30.1
33.8
27.4
27.1
19.2
31.3
Current smoker
13.4
19.4
15.5
17.0
15.9
11.5
Hypertension
83.3
85.0
85.8
85.7
84.1
84.4
Previous MI
24.6
24.4
25.6
25.4
30.2
24.0
Recent ACS
32.5
26.8
30.1
32.0
35.2
28.1
Previous stroke
4.3
1.8
3.7
3.4
3.8
3.6
COPD
3.0
4.4
4.1
6.2
2.2
5.7
30.2 5.5
30.2 5.9
29.4 5.2
29.6 5.1
29.3 5.4
29.5 4.5
Total cholesterol, mg/dl
166.1 48.5
164.0 44.6
173.9 125.9
165.7 43.4
161.1 43.1
172.4 49.5
LDL cholesterol, mg/dl
92.1 35.7
91.5 36.7
92.6 35.9
92.5 35.0
91.3 33.1
96.6 42.1
HDL cholesterol, mg/dl
38.5 10.5
38.8 12.3
39.3 11.2
40.0 11.0
39.2 10.8
39.6 11.0
187.2 165.7
179.4 153.9
213.3 583.9
170.9 109.0
158.1 112.9
187.6 134.7
Age at randomization, yrs
BMI, kg/m2
Triglycerides median, mg/dl Creatinine clearance, ml/min
94.4 57.5
92.3 50.3
87.2 34.9
87.6 33.1
88.6 37.0
84.0 33.0
Microalbuminuria, mg/dl*
67.1 141.5
76.9 205.1
118.0 420.2
97.9 244.4
76.5 166.4
145.1 335.7
Creatinine clearance <60 ml/min
17.0
18.8
23.1
17.5
18.1
24.5
7.8 1.8
7.8 1.7
7.7 1.7
7.6 1.7
7.7 1.8
7.8 1.6
Use of insulin
37.7
27.6
30.4
34.0
35.7
30.2
Use of oral antidiabetic drugs
79.9
77.1
75.8
74.9
75.3
81.8
Use of aspirin
92.1
90.6
89.7
89.9
92.3
90.6 73.4
Glycated hemoglobin, %
Use of beta-blocker
76.3
77.4
75.3
72.9
75.8
Use of ACE inhibitor
66.3
65.0
65.8
64.5
58.8
61.5
Use of ARB
17.9
17.4
14.2
17.0
18.1
14.6
Use of statins
83.9
83.2
81.1
83.0
81.9
82.3
Use of nitrates
41.6
40.6
39.7
35.2
38.5
42.7
59.0 11.2
60.9 11.0
58.5 11.9
57.9 11.0
56.0 12.2
56.6 12.1
4.0
3.5
5.5
4.2
9.3
7.8
LVEF, % LVEF <40% Coronary anatomy 2-vessel disease
31.9
29.7
11.6
8.9
6.6
4.7
3-vessel disease
67.8
70.3
88.4
91.1
93.4
95.3
EuroSCORE
2.5 2.1
2.4 1.8
2.8 2.5
2.8 2.6
2.7 2.5
3.1 2.6
SYNTAX score
17.6 3.7
17.3 3.6
27.5 2.9
27.5 2.8
38.8 5.2
38.8 5.5 70.8
Proximal LAD obstruction
27.1
32.4
53.2
50.2
68.1
Total number of stents
3.2 1.6
—
3.7 1.8
—
4.0 1.9
—
Sirolimus-eluting stent
53.2
0.9†
48.6
1.2†
55.5
1.0†
42.9
0.9†
47.3
0.5†
37.9
—
67.2 31.6
—
78.6 37.2
—
86.4 41.8
—
Graft vessels
—
2.8 0.8
—
3.0 0.8
—
3.1 0.8
Left internal thoracic artery graft
—
88.5
—
90.9
—
87.0
Paclitaxel-eluting stent Total length of stents placed, mm
Values are mean SD or %. *Microalbuminuria in 24-h urine was calculated only for measurements with U.S. units (mg/dl), for a total of 1,429 subjects. †Crossover subjects. Abbreviations as in Table 1.
clearance <60 ml/min, and SS (hazard ratio [HR] per
age were considered a protective factor for HCE at
unit of SS: 1.02; 95% confidence interval [CI]: 1.00 to
5 years (Table 3). Although the SS was an independent
1.03; p ¼ 0.014) were independent predictors of
risk factor for MACCE and HCE at 5 years, the
MACCE at 5 years. (Table 3). The independent risk
area under the ROC curve showed a poor discrimina-
factors related to HCE at 5 years in the PCI group in
tion capability for MACCE (0.54) and HCE (0.56)
multivariate analysis were LVEF <40%, previous
(Figure 2).
stroke, creatinine clearance <60 ml/min, previous MI, insulin use, and the SS (HR per unit of SS: 1.03; 95% CI:
LONG-TERM FOLLOW-UP PREDICTORS OF MACCE
1.01 to 1.04; p ¼ 0.002). The use of angiotensin-
AND HCE IN THE CABG GROUP. In the CABG group
receptor blocker or angiotensin-converting enzyme
after adjustment for potential confounding biases by
inhibitors, triglycerides #150 mg/dl, and #70 years of
multivariate logistic Cox regression, patients with
2829
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Esper et al.
JACC VOL. 72, NO. 23, 2018
SYNTAX Score in Diabetic Patients
DECEMBER 11, 2018:2826–37
F I G U R E 1 Kaplan-Meier Curves of MACCE and HCE Stratified by SYNTAX Score Category in the PCI and CABG Groups
A P-value = 0.04
0.9 SYNTAX Score Category
0.8
SYNTAX Low (36.6%)
0.7
SYNTAX Intermediate (43.9%)
0.6
SYNTAX High (48.7%)
0.5 0.4 0.3 0.2 0.1 0.0 0
1
2
3
HCE - PCI Group Death, Myocardial Infarction or Stroke Rate
Death, Myocardial Infarction, Stroke or Repeat Revascularization Rate
B
MACCE - PCI Group 1.0
4
1.0
P-value = 0.07
0.9 SYNTAX Score Category
0.8
SYNTAX Low (23.2%)
0.7
SYNTAX Intermediate (27.2%)
0.6
SYNTAX High (30.6%)
0.5 0.4 0.3 0.2 0.1 0.0 0
5
1
Years Since Randomization
2
3
4
5
Years Since Randomization
SYNTAX Score Category / No. at Risk
SYNTAX Score Category / No. at Risk
282
246
182
122
62
SYNTAX Low 328
300
279
213
144
69
SYNTAX Inter. 438
343
293
216
130
65
SYNTAX Inter. 438
387
348
268
169
83
SYNTAX High 182
146
124
101
59
23
SYNTAX High 182
156
139
117
74
34
4
5
Death, Myocardial Infarction, Stroke or Repeat Revascularization Rate
C
D
MACCE - CABG Group
1.0
P-value = 0.78
0.9 0.8
SYNTAX Score Category
0.7
SYNTAX Low (25.9%)
0.6
SYNTAX Intermediate (26.8%) SYNTAX High (29.7%)
0.5 0.4 0.3 0.2 0.1 0.0 0
1
2
3
4
Death, Myocardial Infarction or Stroke Rate
SYNTAX Low 328
HCE - CABG Group
1.0
P-value = 0.59
0.9 0.8
SYNTAX Score Category
0.7
SYNTAX Low (17.2%)
0.6
SYNTAX Intermediate (17.7%) SYNTAX High (22.8%)
0.5 0.4 0.3 0.2 0.1 0.0 0
5
2
1
3
Years Since Randomization
Years Since Randomization
SYNTAX Score Category / No. at Risk
SYNTAX Score Category / No. at Risk SYNTAX Low 339
286
242
188
126
63
SYNTAX Low 339
296
258
205
138
67
SYNTAX Inter. 406
334
308
237
152
68
SYNTAX Inter. 406
348
325
257
169
78
SYNTAXHigh 192
158
149
118
84
44
SYNTAX High 192
164
156
127
89
46
Kaplan-Meier curve for (A) major adverse cardiac and cerebrovascular events (MACCE) and (B) hard cardiovascular events (HCE) stratified by SYNTAX score in the percutaneous coronary intervention (PCI) group. Kaplan-Meier curve for (C) MACCE and (D) HCE stratified by SYNTAX score in the coronary artery bypass grafting (CABG) group. MI ¼ myocardial infarction.
LVEF <40% and use of insulin were independent risk
OUTCOMES
IN
PCI
factors for MACCE at 5 years (Table 4). The indepen-
ACCORDING
TO
SS
dent risk factors for HCE were use of insulin, creati-
higher incidence of MACCE in PCI patients with low,
nine clearance <60 ml/min, and LVEF <40%. The
intermediate, and high SS compared with those who
variables #70 years of age and LDL cholesterol
underwent CABG (36.6% vs. 25.9% with low SS
#100 mg/dl were independent protective factors for
category, p ¼ 0.02; 43.9% vs. 26.8% with interme-
MACCE and HCE in CABG group at 5 years (Table 4).
diate SS category, p < 0.001; 48.7% vs. 29.7% with
The SS was not an independent risk factor for MACCE
high SS, p ¼ 0.003) (Figure 3). When evaluating the
and HCE in the CABG group.
role of glycemic control and rates of MACCE, within
VERSUS
CABG
CATEGORIES. There
GROUPS
was
a
JACC VOL. 72, NO. 23, 2018
Esper et al.
DECEMBER 11, 2018:2826–37
SYNTAX Score in Diabetic Patients
each SS category, the benefit of CABG over PCI was consistent in all subgroups (Online Table 1, Online Figure 1).
2831
T A B L E 3 Multivariable Cox Model for Death/Stroke/MI/Need for Repeat
Revascularization (MACCE) and Death/Stroke/MI (HCE) Based on Stepwise Selection in the PCI Group
There were no statistically significant differences between PCI and CABG groups for HCE in patients
Predictor
HR (95% CI)
p Value
MACCE
with low (23.2% in the PCI group vs. 17.2% in the
SYNTAX score
1.02 (1.00–1.03)
0.014
CABG group, p ¼ 0.55) and high SS (30.6% in the PCI
LVEF <40%
2.80 (1.95–4.02)
<0.0001
group vs. 22.8% in the CABG group, p ¼ 0.11). There
Use of insulin
1.45 (1.16–1.81)
0.001
was a higher incidence of HCE in patients with in-
Creatinine clearance <60 ml/min
1.43 (1.11–1.85)
0.006
termediate SS in PCI group (27.2% in the PCI group vs. 17.7% in the CABG group, p ¼ 0.03) (Figure 4). The rates of repeat revascularization were higher in
HCE SYNTAX score
1.03 (1.01–1.04)
0.002
LVEF <40%
3.58 (2.28–5.63)
<0.0001 0.003
Previous stroke
2.46 (1.35–4.50)
Creatinine clearance <60 ml/min
1.46 (1.03–2.07)
0.033
Triglycerides #150 mg/dl
0.74 (0.55–1.00)
0.049
vs. 11.5%, p < 0.001; intermediate: 37.4% vs. 13.8%, p <
Previous myocardial infarction
1.42 (1.04–1.96)
0.03
0.001; high: 32.4% vs. 14.0%, p < 0.001). The incidence
Use of insulin
1.52 (1.13–2.04)
0.006
all SS categories of the PCI group, when compared with the same SS categories of the CABG group (low: 25.6%
of myocardial infarction was numerically higher in all
Use of angiotensin receptor blocker
0.54 (0.33–0.87)
0.012
SS categories of the PCI group compared with the
Use of angiotensin-converting enzyme
0.64 (0.46–0.89)
0.008
#70 yrs of age
0.65 (0.47–0.91)
0.012
CABG group, reaching statistical significance in the intermediate and high SS strata (low: 11.3% vs. 5.4%, p ¼ 0.15; intermediate: 15.8% vs. 5.6%, p ¼ 0.002; high:
CI ¼ confidence interval; HR ¼ hazard ratio; HCE ¼ hard cardiovascular events; MACCE ¼ major adverse cardiac and cerebrovascular events; other abbreviations as in Table 1.
16.7% vs 7.9%, p ¼ 0.01) (Table 5).
DISCUSSION
guide clinical decision making regarding the choice of coronary revascularization strategy. Some studies
This study demonstrates that the SS has a modest
have shown that angioplasty may be an alternative to
correlation with HCE and a significant correlation
CABG in patients with less complex CAD (low SS) (10),
with MACCE in patients with DM and multivessel
particularly with current-generation drug-eluting
disease undergoing PCI. Additionally, the MACCE rate
stents as recently reported in the SYNTAX 2 study
was higher after PCI compared with CABG for every
(24). In our study, the incidence of MACCE was higher
tercile of SS, thus demonstrating that the SS does not
in the PCI group regardless of SS. Unlike findings
identify a population of DM patients with multivessel
from the SYNTAX trial, our data from the FREEDOM
disease in whom PCI is equivalent or superior to
trial demonstrate that SS should not guide decision
CABG (Central Illustration).
making in diabetic patients with multivessel disease.
The optimal coronary revascularization strategy in
In our study, the SS was not an independent risk
previously
factor for HCE and MACCE in the CABG group, a result
(1,3,22,23). In 1997, the BARI (Bypass Angioplasty
that is similar to other studies (25,26). The SS includes
Revascularization Investigation) trial compared CABG
anatomic variables such as calcification, tortuosity,
with balloon angioplasty and showed better survival
type of bifurcation, and extent of CAD. However, for
in patients with diabetes who received CABG rather
the patients undergoing CABG, a major determinant
than balloon angioplasty (22). The FREEDOM trial
of graft patency is a satisfactory anastomosis to a
provided definitive proof of the superiority of CABG
suitable distal portion of the bypassed artery. So,
compared with PCI in multivessel CAD patients with
despite the complexity of CAD in proximal arterial
diabetes. Thus, current U.S. guidelines recommend
segments (which determine the SS), late post-CABG
CABG as the preferred coronary revascularization
outcomes are largely influenced by distal vessel
procedure in diabetic patients with multivessel CAD
suitability for grafting, which generally makes minor
(14,15).
contributions to the SS.
diabetic
patients
has
been
studied
Although several major guidelines provide recom-
Several studies have suggested that the SS carries a
mendations based on SS, this is not so practical to do
significant prognostic role, with higher SS associated
in day-to-day practice, and therefore, many if not
with higher burden of long-term mortality and
most revascularization decisions are made without
ischemic adverse events in patients undergoing PCI
using this approach. This is despite the view that the
(19). Most of these studies include subjects with left
SS should be calculated for 2 potential major reasons:
main
1) to predict the risk of future clinical events; and 2) to
FREEDOM trial. Anatomic data alone, particularly
disease,
which
were
excluded
from
the
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SYNTAX Score in Diabetic Patients
DECEMBER 11, 2018:2826–37
F I G U R E 2 SYNTAX Score ROC Curves for Discrimination of Cardiovascular Events in the PCI and CABG Groups
ROC Curve SYNTAX Score for Death, MI, Stroke or Repeat Revascularization Event, PCI Group
ROC Curve SYNTAX Score for Death, MI or Stroke Event, PCI Group
B
1.0
1.0
0.8
0.8
0.6
0.6
Sensitivity
Sensitivity
A
0.4
0.2
0.4
0.2 Area under the curve: 0.544
Area under the curve: 0.562
0.0
0.0 0.0
0.2
0.4
0.6
0.8
1.0
0.0
0.2
1-Specificity
0.8
1.0
ROC Curve SYNTAX Score for Death, MI or Stroke Event, CABG Group
D
1.0
1.0
0.8
0.8
0.6
0.6
Sensitivity
Sensitivity
0.6
1-Specificity
ROC Curve SYNTAX Score for Death, MI, Stroke or Repeat Revascularization Event, CABG Group
C
0.4
0.4
0.2
0.4
0.2 Area under the curve: 0.508
Area under the curve: 0.502
0.0
0.0 0.0
0.2
0.4
0.6
0.8
1.0
1-Specificity
0.0
0.2
0.4
0.6
0.8
1.0
1-Specificity
SYNTAX score receiver-operating characteristic curve (ROC) curve for (A) MACCE and (B) HCE in the PCI group. SYNTAX score ROC curve for (C) MACCE and (D) HCE in the CABG group. Abbreviations as in Figure 1.
T A B L E 4 Multivariable Cox Model for Death/Stroke/MI/Need for Repeat
Revascularization (MACCE) and Death/Stroke/MI (HCE) Based on Stepwise Selection in the CABG Group Predictor
when associated with left ventricular function, is also a strong prognostic predictor, comparable to the SS.
HR (95% CI)
p Value
MACCE
Comparisons of PCI and CABG according to the SS categories showed a higher incidence of MACCE with
Use of insulin
1.76 (1.31–2.35)
0.0002
LVEF <40%
2.19 (1.34–3.57)
0.002
#70 yrs of age
0.55 (0.40–0.74)
<0.0001
LDL cholesterol #100 mg/dl
0.73 (0.55–0.98)
0.035
PCI in all SS categories (low, intermediate, and high). In patients with low and high SS, the incidence of HCE was not statistically different between PCI and CABG, but these results should be interpreted with
HCE Use of insulin
2.05 (1.45–2.88)
<0.0001
caution because the study is underpowered to make
Creatinine clearance <60 ml/min
1.69 (1.14–2.50)
0.009
comparisons between subgroups. In a pooled analysis
LDL cholesterol #100 mg/dl
0.69 (0.49–0.97)
0.031
of patient-level data from the SYNTAX, PRECOMBAT
2.21 (1.26–3.87)
0.006
(Premier of Randomized Comparison of Bypass
0.60 (0.41–0.88)
0.009
Surgery versus Angioplasty Using Sirolimus-Eluting
LVEF <40% #70 yrs of age Abbreviations as in Tables 1 and 3.
Stent in Patients with Left Main Coronary Artery Disease) and BEST (Treatment of Patients with
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SYNTAX Score in Diabetic Patients
F I G U R E 3 Kaplan-Meier Survival Curves of MACCE According to Revascularization Strategy in Patients With Low, Intermediate, and High
SYNTAX Score
A
B
Low SYNTAX Score Patients
Intermediate SYNTAX Score Patients 0.6
P-value = 0.02 Death, Myocardial Infarction, Stroke or Repeat Revascularization Rate
Death, Myocardial Infarction, Stroke or Repeat Revascularization Rate
0.6 0.5
Revascularization Strategy 0.4
PCI (36.6%) CABG (25.9%)
0.3 0.2 0.1
P-value = <0.001
0.5 Revascularization Strategy 0.4
PCI (43.9%) CABG (26.8%)
0.3 0.2 0.1
0.0
0.0 0
2
1
3
4
5
0
3
4
5
Years Since Randomization
Revascularization Strategy / No. at Risk PCI
2
1
Years Since Randomization
Revascularization Strategy / No. at Risk
328
282
246
182
122
62
PCI
438
343
293
216
130
65
CABG 339
286
242
188
126
63
CABG 406
334
308
237
152
68
C
High SYNTAX Score Patients
Death, Myocardial Infarction, Stroke or Repeat Revascularization Rate
0.6
P-value = 0.003
0.5 Revascularization Strategy 0.4
PCI (48.7%) CABG (29.7%)
0.3 0.2 0.1 0.0 0
1
2
3
4
5
Years Since Randomization Revascularization Strategy / No. at Risk PCI
182
146
124
101
59
23
CABG
192
158
149
118
84
44
Kaplan-Meier survival curves for MACCE stratified by revascularization strategy in patients with (A) low, (B) intermediate, and (C) high SYNTAX score. Abbreviations as in Figure 1.
Multivessel Coronary Artery Disease) trials, a similar
considers only angiographic variables and does not
incidence of HCE after PCI or CABG was found in low
include clinical variables. The diameter stenosis
and intermediate SS categories after 5 years (27). The
severity, unless the artery is totally occluded (100%),
cardiovascular events rates were much lower than
does not affect the SS, with coronary stenoses of
those observed in the FREEDOM trial, despite the
50%, 70%, or 95% stenosis scoring the same value.
similar risk profile of both populations.
The score does not consider myocardial ischemia or
Many reasons could explain why the SS has
functional information. Coronary lesions in small
modest discrimination capability for hard cardio-
arteries between 1.5 and 2.0 mm in diameter are
vascular events in diabetic patients. The score
included in the SS, but most of these lesions
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SYNTAX Score in Diabetic Patients
DECEMBER 11, 2018:2826–37
F I G U R E 4 Kaplan-Meier Survival Curves of HCE According to Revascularization Strategy in Patients With Low, Intermediate, and High SYNTAX Score
A
B
P-value = 0.55
0.9 0.8 Revascularization Strategy
0.7
PCI (23.2%)
0.6
CABG (17.2%)
0.5 0.4 0.3 0.2 0.1 0.0 0
1
Intermediate SYNTAX Score Patients Death, Myocardial Infarction or Stroke Rate
Death, Myocardial Infarction or Stroke Rate
Low SYNTAX Score Patients 1.0
2
3
4
1.0
P-value = 0.03
0.9 0.8 Revascularization Strategy
0.7
PCI (27.2%)
0.6
CABG (17.7%)
0.5 0.4 0.3 0.2 0.1 0.0
5
1
0
Years Since Randomization
2
3
4
5
Years Since Randomization
Revascularization Strategy / No. at Risk PCI
328
300
279
213
144
69
Revascularization Strategy / No. at Risk PCI 438 387 348
268
169
83
CABG
339
296
258
205
138
67
CABG 406
257
169
78
C
348
325
Death, Myocardial Infarction or Stroke Rate
High SYNTAX Score Patients 1.0
P-value = 0.11
0.9 0.8
Revascularization Strategy PCI (30.6%)
0.7
CABG (22.8%)
0.6 0.5 0.4 0.3 0.2 0.1 0.0 0
1
2
3
4
5
Years Since Randomization Revascularization Strategy / No. at Risk PCI
182
156
139
117
74
34
CABG
192
164
156
127
89
46
Kaplan-Meier survival curves for HCE stratified by revascularization strategy in patients with (A) low, (B) intermediate, and (C) high SYNTAX score. Abbreviations as in Figure 1.
probably will not undergo revascularization. It may
shows that among diabetic patients, clinical char-
also simply be the case that the components of the
acteristics such as LVEF <40%, insulin-dependent
SS implying PCI procedural complexity are not,
DM, and chronic renal dysfunction are important
per se, good predictors of outcome. Indeed, their
predictors of cardiovascular events and should be
independent long-term prognostic value has not
incorporated into the risk prediction for coronary
been shown isolated, once divorced from the pri-
revascularization. Scores that include clinical and
mary determinant of the SS, which is anatomic
angiographic variables, such as SS II (28–30), clin-
burden of disease.
ical SS (31,32), and Global Risk Score (EuroSCORE
Diabetes mellitus is a disease associated with
[European System for Cardiac Operative Risk Eval-
worse outcomes in patients with CAD. Our study
uation] associated with SS) (33), could be more
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SYNTAX Score in Diabetic Patients
T A B L E 5 Kaplan-Meier Estimates of Adverse Cardiovascular and Cerebrovascular Events at 5 years After the Procedure by SYNTAX Score
Categories and Treatment Arm Low
Intermediate
High
PCI
CABG
Log-Rank p Value
PCI
CABG
Log-Rank p Value
CABG
Log-Rank p Value
MACCE
36.6
25.9
0.02
43.9
26.8
<0.001
HCE
23.2
17.2
0.55
27.2
17.7
0.03
48.7
29.7
0.003
30.6
22.8
Death
17.1
12.5
0.55
15.4
11.3
0.13
0.11
23.3
14.2
0.24
MI
11.3
5.4
0.15
15.8
5.6
Stroke
4.6
4.7
0.33
2.8
4.6
0.002
16.7
7.9
0.01
0.21
2.4
7.1
Repeat revascularization
25.6
11.5
<0.001
37.4
13.8
0.13
<0.001
32.4
14.0
<0.001
PCI
Values are %. Abbreviations as in Tables 1 and 3.
C ENTR AL I LL U STRA T I O N Major Adverse Cardiac and Cerebrovascular Events in Patients With Diabetes Mellitus With Multivessel Coronary Artery Disease Submitted to CABG or PCI According to SYNTAX Score Categories
Death, Myocardial Infarction, Stroke or Repeat Revascularization Rate
0.6
0.5
0.4
0.3
0.2
0.1
0.0 0
1
2
3
4
5
Years Since Randomization SYNTAX Score Category - Revascularization Strategy High SYNTAX - PCI Intermediate SYNTAX - PCI Low SYNTAX - PCI High SYNTAX - CABG Intermediate SYNTAX - CABG Low SYNTAX - CABG
No. at Risk 182 438 328 192 406 339
Esper, R.B. et al. J Am Coll Cardiol. 2018;72(23):2826–37.
In diabetes mellitus (DM) patients with multivessel coronary artery disease (CAD) without left main stenosis and indication for myocardial revascularization, coronary artery bypass grafting (CABG) should be the preferred method of coronary revascularization regardless of the complexity of the coronary disease. In all SYNTAX score categories, CABG had fewer major adverse cardiac and cerebrovascular events (MACCE), defined by death from any cause, nonfatal myocardial infarction, nonfatal stroke, and need for repeat revascularization, versus percutaneous coronary intervention (PCI) with drug-eluting stents in the FREEDOM (Future REvascularization Evaluation in patients with Diabetes mellitus: Optimal management of Multivessel disease) trial.
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SYNTAX Score in Diabetic Patients
DECEMBER 11, 2018:2826–37
suitable to predict MACCE and HCE in diabetic
significant predictor of MACCE only in patients un-
patients.
dergoing PCI. In DM with multivessel CAD, the inci-
The FREEDOM trial was the largest randomized
dence of MACCE is higher for the PCI compared with
study of only DM patients comparing PCI versus
CABG in all SS categories. The SS should not be uti-
CABG in patients with multivessel CAD without left
lized to guide the choice of coronary revasculariza-
main disease. In the SS algorithm, left main stenosis
tion in patients with DM and multivessel CAD.
receives a very high score. In our study, because we excluded patients with left main stenosis, patients with high SS may have severe diffuse CAD, making either bypass grafting or angioplasty more challenging. This may explain the higher incidence of cardiovascular events in patients with high SS in both the PCI and CABG groups. Our findings highlight the importance of anatomic and clinical evaluation of diabetic patients with CAD.
ADDRESS FOR CORRESPONDENCE: Dr. Michael E.
Farkouh, Peter Munk Cardiac Centre and the Heart and Stroke Richard Lewar Centre, University of Toronto,
585
University
Avenue—4N474,
Toronto,
Ontario M5G 2N2, Canada. E-mail: michael.farkouh@ uhn.ca. Twitter: @drmikefarkouh, @PMunkCardiacCtr, @UofT.
The decision-making of the best strategy for revascularization should consider not only coronary
PERSPECTIVES
angiographic aspects but also clinical aspects that could influence the outcomes. The SS alone should not be utilized to guide the choice of coronary revascularization in patients with DM and multivessel CAD.
COMPETENCY IN PATIENT CARE AND PROCEDURAL SKILLS: In patients with DM, the complexity of multivessel CAD as assessed by the SYNTAX score is an independent risk factor for
STUDY LIMITATIONS. This study is not powered to
adverse cardiovascular events in those undergoing
make comparisons between SS subgroups overall or
percutaneous revascularization but not bypass
for any individual component of MACCE; therefore,
surgery. Furthermore, the score does not identify a
these results should be regarded as observational and
subset of diabetic patients with multivessel disease in
hypothesis-generating only and need to be confirmed
whom PCI is equivalent or superior to CABG.
in subsequent adequately powered clinical trials. TRANSLATIONAL OUTLOOK: Additional research
CONCLUSIONS
is needed to clarify clinical features that identify pa-
In DM patients with multivessel CAD, the complexity of CAD evaluated by the SS is a modest independent
tients with diabetes and multivessel CAD who might be preferentially managed with PCI rather than CABG.
risk factor for hard cardiovascular events and a
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KEY WORDS CABG, coronary artery disease, diabetes, PCI, SYNTAX score
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percutaneous coronary intervention in patients
2017;38:1969–77.
paper.
A PP END IX For a supplemental table and figure, please see the online version of this
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