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Revascularization for unprotected left main coronary artery disease- an update from recent trials
05 December 2016
BCS Editorial
By: Muhammad Mahmood
In June 2010 and March
2014 BCS editorials provided updates on revascularization of left main coronary
artery (LMCA) disease. A number of relevant trials have since been reported.
Importantly 2 key trials, EXCEL and NOBLE, were published last month. Following
is the current state of play on LMCA revascularization in view of recent
evidence. Left main coronary
artery (LMCA) disease About 4-7 % patients undergoing coronary angiogram have significant
left main coronary artery (LMCA) disease1,2; a finding that has
prognostic implications because of the amount of myocardium at risk. In the
Coronary Artery Surgery Study (CASS) registry survival without surgical
revascularization in the presence of LMCA, even in asymptomatic patients, was
57% at 5 years, which was improved to 88% with coronary artery bypass surgery
(CABG)2. CABG has traditionally been the preferred mode of revascularization
of LMCA; an early consensus that was further reinforced because of limited
experience and sub-optimal outcomes with percutaneous coronary intervention (PCI)
on LMCA in the balloon angioplasty and bare metal stent era. Early evidence With the advances in the PCI techniques and adjunct
pharmacotherapy, there has been a renewed interest in using PCI for LMCA
revascularization over the last decade with reporting of several trials. This
included reporting of early outcomes of LE MANS, PreCOMBAT, SYNTAX and other
RCTs as well as meta-analyses and registry data, as described in the earlier
BCS editorials. This early evidence supported a role of PCI in LMCA
revascularization, mainly with low or intermediate coronary artery disease
(CAD) complexity, which was reflected in the major society guidelines on
myocardial revascularization. Guidelines In the European Society of Cardiology (ESC) guidelines on
myocardial revascularization (2014) CABG has a class 1 recommendation for LMCA
disease regardless of the SYNTAX score3. For PCI; patients with LMCA
and SYNTAX score <22 have a class I and those with SYNTAX score 23-32, a
class IIa indication. PCI is not indicated for patients with LMCA disease and
SYNTAX score >33 (a class III indication). Recent evidence Long-term follow up
data from earlier trials The 10-year outcomes of the Study of Unprotected Left Main Stenting
versus Bypass Surgery (LE-MANS) were
reported earlier this year4. In this prospective, multicentre trial
105 patients with unprotected LMCA disease and low to medium complexity CAD were
randomised to PCI or CABG. At 10 years PCI was associated with favourable
primary (change in left ventricular ejection fraction) and secondary (major
adverse cardiac and cerebrovascular events(MACCE)) outcomes. The Premier of
Randomized Comparison of Bypass Surgery versus Angioplasty using
Sirolimus-Eluting Stent in Patients with Left Main Coronary Artery Disease (PreCOMBAT) reported 5 years outcomes
last year5. The trial had randomized 600 patients to PCI or CABG. At
5 years there was no significant difference in the primary endpoint (MACCE)
between the 2 cohorts. These earlier trials were limited by small sample sizes
and/or use of first generation DES. The landmark Synergy between PCI with Taxus
and Cardiac Surgery (SYNTAX) trial
randomised a subset of 705 patients with unprotected LMCA to PCI (with first
generation drug eluting stent (DES) Taxus Express) or CABG6. At 5
years, overall there was no significant difference in MACCE between the two
cohorts. However the outcomes from PCI were dependant on the complexity of the
CAD. At low to medium complexity (objectively quantified by the SYNTAX tertiles
of 0-22 and 22-32) the outcomes were similar between PCI and CABG. With the
more complex CAD (SYNTAX tertile of score >32) CABG had better outcomes than
PCI. Also post procedural stroke was more frequent with CABG (4.3% vs 1.5%) and
repeat revascularization with PCI (26.7% 15.5%). The SYNTAX trial supported the
idea of “heart team” and objective quantification of CAD complexity by SYNTAX
score. Although these early trials supported the use of PCI in
select patients with LMCA, the exact role of PCI, using the contemporary DES,
modern pharmacological agents and surgical techniques, remains somewhat
undefined. Recently 2 key trials (EXCEL and NOBLE) comparing CABG with PCI for
the treatment of unprotected left main disease have been published. Recent trials The Everolimus-Eluting
Stents or Bypass Surgery for Left Main Coronary Artery Disease (EXCEL) trial randomized 1905 patients with unprotected LMCA disease and
low (SYNTAX score <22) or intermediate (SYNTAX score 23-32) complexity CAD to
PCI with a DES (mean stents 2.4, mean stent length 49 per patient) vs. CABG
(Internal mammary graft 99%, total arterial grafts 25%). Two or three vessel CAD was present in 51% of
the patients and distal left main bifurcation (or trifurcation) disease in 80%.
The trial showed that PCI in this context is non-inferior (but not superior) to
CABG. At median follow up of 3 years, primary end point (composite of all-cause
death, myocardial infarction or stroke) occurred with similar frequency in both
groups (15.4 % for PCI vs. 14.7% for CABG, P=0.02 for non-inferiority, P=0.98
for superiority). Cardiac mortality was
similar between the two groups. It was also evident that in the first 30 days,
more primary end point events (primarily myocardial infarction and stroke)
occurred following CABG than after PCI but between 30 days to 3 years there was
an increase in primary end point events in PCI group with similar outcomes at 3
years. At 3 years ischemia-driven revascularization occurred more frequently
after PCI (12.6%) than after CABG (7.5%, P<0.001). The incidence of definite
stent thrombosis and stroke following PCI was 0.7% and 2% respectively at 3
years. This further demonstrated the lower peri-procedural morbidity of PCI (peri-procedural
major adverse events 8% vs 23%) but a higher repeat revascularization rate
compared to CABG. The Percutaneous
coronary angioplasty versus coronary artery bypass grafting in treatment of
unprotected left main stenosis (NOBLE),
a non-inferiority, trial randomised 1201 patients to PCI with a DES (11% first
generation, 89% Biolimus-eluting second generation) or CABG (86% with arterial
graft to left anterior descending artery). In both groups 81% patients had
distal left main bifurcation disease. In patients undergoing PCI, 33% had 1
additional and 9% patients had 2 additional lesions treated. The 5 year Kaplan-Meier estimates of composite
primary end point (MACCE; all cause mortality, non procedural myocardial
infarction, repeat revascularization or stroke) were supportive of superiority
of CABG over PCI (19% vs. 29% respectively,
P=0.0066). For the individual components of the composite primary end point,
the all cause mortality was not significantly different between CABG and PCI (9
% vs. 12% respectively, P=0.77) and the difference was primarily driven by higher
non procedural myocardial infarction (2% vs. 7%, P=0.0040) and repeat
revascularization (10% vs. 16%, P=0.032) estimates following PCI. Somewhat
surprisingly, the PCI was also associated with increased 5 year estimates of
stroke (5% vs. 2%, P=0.073). Considering that there were no incidents of stroke
at 30 days in the PCI cohort, the 5-year estimate may be a chance finding. Both EXCEL and NOBLE trials seem to have reached a
conflicting conclusion, however some points are worth noting. The inclusion of
repeat revascularization in composite primary end points in NOBLE trial may
partly explain the increased MACCE following PCI. Also the incidence of stent
thrombosis (3%) and stroke (5%) following PCI in the NOBLE trial was
unexpectedly higher. The late increase (between 30 days and 3 years) in event
rates in the PCI cohort in EXCEL trial also makes the availability of long-term
data quite important. Conclusions The EXCEL and NOBLE trial are a valuable addition to the
decision making in treatment of patients with unprotected left main coronary
artery disease. The role of heart team enabling an informed patient decision
remains paramount. Based on the available evidence, PCI is a suitable
alternative to CABG in patients with unprotected LMCA and low to intermediate
anatomic complexity. Long term follow up
data from the recent trials would be important. References; 1. Main left coronary artery disease. Clinical experience
from 1964-1974. Cohen MV, Gorlin R. Circulation. 1975
;52(2):275-85. 2. Asymptomatic
left main coronary artery disease in the Coronary Artery Surgery Study (CASS)
registry. Taylor HA et al. Circulation. 1989;
79: 1171-1179. DOI: 10.1161/01.CIR.79.6.1171. 3. 2014 ESC/EACTS Guidelines on
myocardial revascularization. Windecker
S et al. Eur Heart J. 2014 Oct
1;35(37):2541-619. DOI: 10.1093/eurheartj/ehu278. 4. Left Main Stenting in Comparison With Surgical
Revascularization: 10-Year Outcomes of the (Left Main Coronary Artery Stenting)
LE MANS Trial. Buszman PE et
al. J Am Coll Cardiol Intv. 2016;9(4):318-327. 5. Randomized Trial of Stents Versus Bypass Surgery for
Left Main Coronary Artery Disease: 5-Year Outcomes of the PRECOMBAT
Study. Ahn J et al. J Am Coll Cardiol.2015;65(20):2198-2206. 6. 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. Morice MC et al. Circulation. 2014 Jun 10; 129 (23): 2388-94. 7. Everolimus-Eluting Stents or
Bypass Surgery for Left Main Artery Coronary Disease. Stone GW et al.
N Engl J Med. 2016 Oct 31. [Epub ahead of print]. PMID:27797291.DOI:
10.1056/NEJMoa1610227. 8. Percutaneous
coronary angioplasty versus coronary artery bypass grafting in treatment of
unprotected left main stenosis (NOBLE):
a prospective, randomised, open-label, non-inferiority trial. Mäkikallio T et
al. Lancet. 2016 Oct 31. pii:
S0140-6736(16)32052-9. doi: 10.1016/S0140-6736(16)32052-9. [Epub ahead of
print].
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