JACC: CARDIOVASCULAR INTERVENTIONS
3, 2020
ª 2020 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
PUBLISHED BY ELSEVIER
EDITORIAL COMMENT
Left Main PCI Decision
Is it Time to Move on From the Original SYNTAX Score?*
Bernard Chevalier, MD
C ontinuous development of coronary stents
along with bifurcation technique refine-
ments have resulted in left main (LM) percu-
taneous coronary intervention’s (PCI) being proposed
as a valuable alternative to coronary artery bypass
grafting (CABG) in many cases, with a high level of
recommendation in the most recent guidelines (1,2).
However, in both the U.S. (Class IIa, Level of
Evidence: B) and European (Class I, Level of
Evidence: B) documents, it is strongly suggested
that selection of a revascularization modality be
based on risk stratification using angiographic evalu-
ation by means of the SYNTAX (Synergy Between
PCI With Taxus and Cardiac Surgery) score (SS),
which is conventionally classified according to the 3
terciles of the original study: low (<23), intermediate
(23 to 32), and high (>32).
SEE PAGE 361
In this issue of JACC: Cardiovascular Interventions,
Yoon et al. (3) present the longest term follow-up in a
prospective observational study of LM revasculari-
zation, MAIN-COMPARE (Ten-Year Outcomes
Stents Versus Coronary-Artery Bypass Grafting for
Left Main Coronary Artery Disease), combining both
the bare-metal stent and drug-eluting stent (DES)
eras. The investigators should be congratulated for
their effort considering the paucity of follow-up data
beyond 5 years in patients with LM disease treated
with DES. They evaluated the impact of SS on 10-year
outcomes, showing reassuringly similar outcomes in
terms of mortality (hazard ratio [HR]: 1.1; 95%
*Editorials published in JACC: Cardiovascular Interventions reflect the
views of the authors and do not necessarily represent the views of JACC:
Cardiovascular Interventions or the American College of Cardiology.
From Ramsay Générale de Santé, Institut Cardiovasculaire Paris Sud,
Massy, France. Dr. Chevalier is a consultant for Biotronik, Medtronic, and
Terumo; and is a shareholder in CERC.
ISSN 1936-8798/$36.00
VOL. 13, NO.
confidence interval [CI]: 0.78 to 1.54; p ¼ 0.589) or a
composite endpoint of death, Q-wave myocardial
infarction, and stroke (HR: 1.17; 95% CI: 0.84 to 1.62;
p ¼ 0.352) in both the PCI and CABG populations
when SS was in the low or intermediate range.
Conversely, when treated with PCI, high-SS patients
were exposed to a marginally but significantly higher
mortality risk (HR: 1.39; 95% CI: 1.00 to 1.92;
p ¼ 0.048), with a trend toward greater risk for the
composite endpoint (HR: 1.27; 95% CI: 0.94 to 1.74;
p ¼ 0.123). The 2 SS subgroups had a higher risk for
target revascularization (HRs: 4.78 and 8.29, respec-
tively) in the PCI arm.
These data partly replicate those of the original
SYNTAX study, in which the LM subgroup was pre-
specified for 5-year endpoint analysis (4), showing a
mortality benefit of PCI with equipoise in terms of
major adverse cardiac and cerebrovascular events in
the combined low and intermediate terciles.
Recently, a 10-year collaborative non-pre-specified
follow-up of the SYNTAX study evaluated the
impact of revascularization modality on survival.
With a follow-up duration identical to that of MAIN-
of
COMPARE, no interaction was found between death
and SS in the LM subgroup (5). A larger proportion of
high SS (43.2%) and the nonrandom PCI decision may
explain this difference compared with the SYNTAX
trial, the most vulnerable patients being frequently
refused CABG as shown in the SYNTAX PCI registry,
with worse outcomes compared with the PCI arm of
the randomized cohort (6).
In the SYNTAX trial, SS established that PCI was
sensitive to coronary atheroma burden, providing a
value to quantify its diffusion and its complexity.
Conversely, this finding did not apply to CABG, which
is in line with the CABG immunity reported in MAIN-
COMPARE, in which PCI selection was based on the
investigators’ clinical judgment. SS internal valida-
tion was updated by external validation, with uneven
results in subsequent trials (7,8). Despite good
https://doi.org/10.1016/j.jcin.2019.11.007
JACC: CARDIOVASCULAR INTERVENTIONS VOL. 13, NO. 3, 2020
FEBRUARY 10, 2020:372–4
discrimination in the PCI group, SS had fair calibra-
tion in the original study.
Two more recent randomized trials assessing the
so-called second-generation DES versus surgery
enrolled patients with LM lesions and showed
discrepant findings. The EXCEL trial demonstrated
similar outcomes in terms of death, myocardial
infarction, and stroke whatever the SS, but with a
progressive increase in major adverse cardiac and
cerebrovascular event rates from low- to high-SS
groups (9,10) driven by revascularizations. The NO-
BLE trial failed to show PCI noninferiority, with
paradoxically worse performance in the low-SS
group, which was the main contributor to the global
study failure (11). This unexpected result was not
clearly explained even if, on the basis of primary
endpoint analysis, the NOBLE PCI arm showed
greater noncardiac mortality, stent thrombosis, and
stroke than the EXCEL PCI arm. Because these 2
studies used mainly (NOBLE) or exclusively (EXCEL)
second-generation DES, high-SS patients may have
derived greater benefit from device improvements as
they received more stents, the total stent length be-
ing predictive of long-term outcomes in the SYNTAX
trial. Moreover, dual-antiplatelet therapy and intra-
vascular guidance have evolved since enrollment for
SYNTAX, a trial in which the 5-year stent thrombosis
rate was particularly high. Thus, enhanced stenting
strategies seem to partly play a role of equalizer in
terms of hard safety endpoints in patients with heavy
coronary burden.
Of note, 25.4% of EXCEL patients and 9.5% of
NOBLE patients had SS >32, when assessed by a core
laboratory, despite the related exclusion criteria (SS
>32 in EXCEL, non-LM complex lesions in NOBLE).
This underestimation by the sites was present in
74.4% of EXCEL patients, in full concordance with a
61.8% rate in the SYNTAX trial. These findings raise
the question of SS calculation variability. Previous
evaluations (12,13) have shown fair to moderate levels
of reproducibility, a substantial level (kappa >0.60)
being found only in the identification of total occlu-
sions and aorto-ostial lesions, with the worst perfor-
mance in long or thrombus-containing lesions, small
and diffusely diseased vessels, and bifurcations. This
apparent weakness is not fully inherent to SS, as an
advanced training process significantly improved
consistency (13). A more educational calculator might
help improve SS reliability. Of course, this limitation
affects the clinical utility of SS.
Chevalier 373
Left Main PCI and SYNTAX Score
To improve both score discrimination and cali-
bration, several combinations of clinical risk scores
with SS have been proposed (14), while SS II has been
developed to add clinical parameters and to correct
some overweight of LM lesion in the PCI group, with
a significant predictability benefit even when SS II
used the site-reported SS (15,16). However, a math-
ematical bias could have been possible, as LM lesion
is counted twice in SS II, but external validation was
conducted with appropriate prediction of 4-year
outcomes (15–17). Another attempt to increase SS
utility was to combine angiographic description with
a functional approach using fractional flow reserve to
evaluate the clinical relevance of the counted lesions
(18). This approach is attractive but time consuming
and raises the issue of measurement interaction be-
tween high-grade LM stenosis and more distal le-
sions. Calculation of a score is also time dependent:
the interaction of SS with 5-year mortality in the
SYNTAX trial was no longer present at 10 years. In
the specific setting of PCI versus CABG, the chro-
nology question is crucial, as PCI patients are more
exposed to atheroma progression than CABG pa-
tients, for whom the proximal and mid segments are
bypassed and frequently occluded soon after
revascularization.
Yoon et al. (3) confirmed that PCI revasculariza-
tion has very long-term validity to address LM le-
sions with modest SS discrimination in terms of
hard safety endpoints. SS was not designed to
stratify patients but to establish a common language
for this specific trial. Predictive accuracy with
respect to LM PCI performance seems currently to
be far beyond its ability, particularly if we consider
the “magic 33” cutoff, because of inherent limita-
tions, the partial obsolescence of PCI practice in the
SYNTAX trial, and the absence of clinical and func-
tional data. This central role in the decision-making
process is outdated: angiographic burden quantifi-
cation is only one of the criteria to be taken into
account when the heart team evaluates the options,
informs the patient, and records the patient’s
preference.
ADDRESS FOR CORRESPONDENCE: Dr. Bernard
Chevalier, Ramsay Générale de Santé, Institut Car-
diovasculaire Paris Sud, Hôpital Privé Jacques Cartier,
6 Avenue du Noyer Lambert, 91300 Massy, France.
E-mail: b.chevalier@angio-icps.com.fr.
374 Chevalier
Left Main PCI and SYNTAX Score
REFERENCES
1. Fihn SD, Gardin JM, Abrams J, et al. ACCF/AHA/
ACP/AATS/PCNA/SCAI/STS guideline for the diag-
nosis and management of patients with stable
ischemic heart disease. J Am Coll Cardiol 2012;60:
e44–164.
2. Neumann FJ, Sousa-Uva M, Ahlsson A, et al., for
the ESC Scientific Document Group. 2018 ESC/
EACTS guidelines on myocardial revascularization.
Eur Heart J 2019;40:87–165.
3. Yoon Y-H, Ahn J-M, Kang D-Y, et al. Impact of
SYNTAX score on 10-year outcomes after revas-
cularization for left main coronary artery disease.
J Am Coll Cardiol Intv 2020;13:361–72.
4. Morice MC, Serruys PW, Kappetein AP, et al.
Five-year outcomes in patients with left main
disease treated with either percutaneous coronary
intervention or coronary artery bypass grafting in
the Synergy Between Percutaneous Coronary
Intervention With Taxus and Cardiac Surgery trial.
Circulation 2014;129:2388–94.
5. Thuijs DJFM, Kappetein AP, Serruys PW, et al.,
for the SYNTAX Extended Survival Investigators.
Percutaneous coronary intervention versus coro-
nary artery bypass grafting in patients with
three-vessel or left main coronary artery disease:
10-year follow-up of the multicenter randomised
controlled SYNTAX trial. Lancet 2019;394:
1325–34.
6. Mohr FW, Morice MC, Kappetein AP, et al.
Coronary artery bypass graft surgery versus
percutaneous coronary intervention in patients
with three-vessel disease and left main coronary
disease: 5-year follow-up of the randomised,
clinical SYNTAX trial. Lancet 2013;381:629–38.
JACC: CARDIOVASCULAR INTERVENTIONS VOL. 13, NO. 3, 2020
7. Garg S, Serruys PW, Silber S, et al. The prog-
nostic utility of the SYNTAX score on 1-year
outcomes after revascularization with zotar-
olimus- and everolimus-eluting stents: a substudy
of the RESOLUTE All Comers Trial. J Am Coll
Cardiol Intv 2011;4:432–41.
8. Farkouh ME, Domanski M, Sleeper LA, et al., for
the FREEDOM Trial Investigators. Strategies for
multivessel revascularization in patients with dia-
betes. N Engl J Med 2012;367:2375–84.
9. Shlofmitz E, Généreux P, Chen S, et al. Left
main coronary artery disease revascularization
according to the SYNTAX score. Circ Cardiovasc
Interv 2019;12:e008007.
10. Stone GW, Kappetein AP, Sabik JF, et al. Five-
year outcomes after PCI or CABG for left main
coronary disease. N Engl J Med 2019;381:
1820–30.
11. Christiansen EH, Five-year outcome after
percutaneous coronary angioplasty or coronary
artery bypass grafting in treatment of unprotected
left main stenosis. Updated results from the pro-
spective, randomized, open-label, non inferiority
NOBLE trial. Presented at: Transcatheter Cardio-
vascular Therapeutics 2019; San Francisco, CA;
September 24–28, 2019.
12. Garot P, Tafflet M, Kumar S, et al. Reproduc-
ibility and factors influencing the assessment of
the SYNTAX score in the Left Main XIENCE study.
Catheter Cardiovasc Interv 2012;80:231–7.
13. Généreux P, Palmerini T, Caixeta A, et al.
SYNTAX score reproducibility and variability be-
tween interventional cardiologists, core laboratory
FEBRUARY 10, 2020:372–4
technicians, and quantitative coronary measure-
ments. Circ Cardiovasc Interv 2011;4:553–61.
14. Capodanno D, Caggegi A, Miano M, et al.
Global risk classification and clinical SYNTAX
(Synergy Between Percutaneous Coronary Inter-
vention With Taxus and Cardiac Surgery) score in
patients undergoing percutaneous or surgical left
main revascularization. J Am Coll Cardiol Intv
2011;4:287–97.
15. Farooq V, van Klaveren D, Steyerberg EW, et al.
Anatomical and clinical characteristics to guide
decision making between coronary artery bypass
surgery and percutaneous coronary intervention
for individual patients: development and validation
of SYNTAX score II. Lancet 2013;381:639–50.
16. Zhang YJ, Iqbal J, Campos CM, et al. Prog-
nostic value of site SYNTAX score and rationale for
combining anatomic and clinical factors in decision
making: insights from the SYNTAX trial. J Am Coll
Cardiol 2014;64:423–32.
17. Modolo R, Chichareon P, van Klaveren D, et al.
Impact of non-respect of SYNTAX score II recom-
mendation for surgery in patients with left main
coronary artery disease treated by percutaneous
coronary intervention: an EXCEL substudy. Eur J
Cardiothorac Surg 2019 Oct 16 [E-pub ahead of
print].
18. Nam CW, Mangiacapra F, Entjes R, et al., for
the FAME Study Investigators. Functional SYNTAX
score for risk assessment in multivessel coronary
artery disease. J Am Coll Cardiol 2011;58:1211–8.
KEY WORDS CABG, drug-eluting stent,
left main PCI, SYNTAX score