Canadian Journal of Cardiology 30 (2014) 1407e1414
Clinical Research
Long-term Outcome of Unprotected Left Main Stenting: A Canadian Tertiary Care Experience Matthew Sibbald, MD, PhD, William Chan, MD, PhD, Paul Daly, MD, Eric Horlick, MD, Douglas Ing, MD, Joan Ivanov, PhD, Karen Mackie, RN, Mark D. Osten, MD, Christopher B. Overgaard, MD, MSc, and Vladimír Dzavík, MD Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada
See editorial by Lavi and Yadegari, pages 1256-1258 of this issue. ABSTRACT
RESUM E
Background: Coronary stenting is increasingly used to treat unprotected left main disease in selected patients. However, there is a paucity of data on the long-term outcome of these patients in a Canadian context outside of clinical trials. Methods: We retrospectively reviewed all provincially-insured patients undergoing left main coronary stenting at a large tertiary referral centre from 2000-2011. Pre-procedural angiograms were reviewed to identify the location of left main disease, and extent of concomitant coronary disease quantified by calculating Synergy Between Percutaneous Coronary Intervention With TAXUS Drug-Eluting Stent and Cardiac Surgery (SYNTAX) scores for each patient. In-hospital death and major adverse cardiac event (MACE) rates were evaluated as were long-term death and MACE rates obtained via linkage of our institutional registry with the Ontario health claims database. Results: Two hundred twenty-one patients underwent unprotected left main stenting with 29 (13.1%) in-hospital death and 34 (15.4%) a
Introduction : L’implantation d’endoprothèses coronariennes est de quente pour traiter la maladie du tronc commun plus en plus fre ge de patients se lectionne s. Cependant, les coronaire gauche non prote es sur les re sultats à long terme de ces patients dans un condonne texte canadien autre que les essais cliniques sont insuffisantes. thodes : Nous avons re trospectivement passe en revue les patients Me gime d’assurance provincial ayant subi l’implantacouverts par un re tion d’une endoprothèse au tronc commun coronaire gauche dans un cialise tertiaire de 2000 à 2011. Les angiogrammes grand centre spe interventionnels ont e te passe s en revue pour situer le siège de la pre tendue de la mamaladie du tronc commun coronaire gauche et l’e e par le calcul des scores ladie coronarienne concomitante quantifie SYNTAX (SYNergy between percutaneous coronary intervention with TAXus drug-eluting stent and cardiac surgery) de chacun des patients. cès intrahospitaliers et d’e ve nements cardiovasculaires Les taux de de sirables majeurs (ECIM) ont e te e value s, de même que les taux de inde
Untreated significant left main coronary stenosis carries a poor prognosis.1 Although coronary artery bypass graft surgery is the traditional gold standard treatment, several randomized trials2-4 and registries5-9 provide support for coronary stenting as an alternate approach. Outcomes with coronary stenting vary compared with bypass surgery according to patient subsets.4 Predictors of adverse outcomes after left main stenting include bifurcation disease,10 bifurcation stenting technique,11-14 lack of intravascular ultrasound (IVUS) guidance,15,16 stent type,17-20 and burden of disease measured using the scoring system developed and validated in the Synergy Between
Percutaneous Coronary Intervention With TAXUS DrugEluting Stent and Cardiac Surgery (SYNTAX) trial.4,21,22 The American College of Cardiology 2009 and European Society of Cardiology 2010 revascularization guidelines have evolved to reflect this accumulating evidence, suggesting that coronary stenting can be considered an alternative to bypass surgery in subsets of patients with unprotected left main disease.23,24 However, both guidelines recommend careful selection of patients. The American College of Cardiology 2009 guidelines suggest selecting patients with anatomic conditions associated with low risk of complications related to coronary stenting. The European Society of Cardiology 2010 guidelines give varied levels of recommendation depending on the location of left main stenosis (ie, whether the bifurcation of the left main is involved) and the burden of coronary disease, measured according to number of vessels involved or by SYNTAX score. There are 3 challenges with the application of these guidelines. First, none of the previous randomized trials were
Received for publication February 27, 2014. Accepted May 15, 2014. Corresponding author: Dr Vladimír Dzavík, Division of Cardiology, Peter Munk Cardiac Centre, University Health Network, 6-246 EN, Toronto General Hospital, 200 Elizabeth St, Toronto, Ontario M5G 2C4, Canada. Tel.: þ1-416-340-4800 6265; fax: þ1-416-340-3390. E-mail: [email protected] See page 1413 for disclosure information.
http://dx.doi.org/10.1016/j.cjca.2014.05.023 0828-282X/Ó 2014 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.
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MACE. At an average follow-up of 3.1 2.8 years, 109 patients (49.3%) died and 151 (68.3%) experienced a MACE. Higher SYNTAX tertile and use of bare metal rather than drug-eluting stents was associated with increased rates of in-hospital and long-term death. Conclusions: This study reports, to our knowledge, the largest Canadian cohort of unprotected left main stenting over more than a decade. Coronary stenting was associated with acceptable in-hospital event rates, but poor long-term outcomes, reflecting the higher-risk population traditionally selected for this procedure.
cès et d’ÉCIM à long terme obtenus par le couplage du registre de de tablissement à la base de donne es des demandes de notre e de l’Ontario. remboursement du système de soins de sante sultats : Deux cent vingt-et-un (221) patients ont subi l’implantation Re ge d’une endoprothèse au tronc commun coronaire gauche non prote 29 (13,1 %) de cès intrahospitaliers et 34 (15,4 %) ECIM. qui a entraîne taient morts Au suivi moyen de 3,1 2,8 ans, 109 patients (49,3 %) e leve du SYNTAX et 151 (68,3 %) avaient subi un ECIM. Le tertile plus e tal nu plutôt que d’endoproet l’utilisation d’endoprothèses en me dicamente es ont e te associe s à l’augmentation des taux de thèses me cès intrahospitaliers et à long terme. de tude pre sente la plus Conclusions : À notre connaissance, cette e grande cohorte canadienne ayant subi l’implantation d’une endo ge depuis plus prothèse au tronc commun coronaire gauche non prote cennie. L’implantation d’une endoprothèse coronarienne a e te d’une de e à des taux acceptables d’e ve nements intrahospitaliers, mais associe sultats me diocres à long terme refle tant la population expose e à des re leve , soit celle qui est traditionnellement à un risque plus e lectionne e pour subir cette intervention. se
designed to evaluate outcomes of coronary stenting compared with bypass surgery in the specific patient subsets endorsed by the guidelines. The ongoing Evaluation of XIENCE Everolimus Eluting Stent Versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization (EXCEL) trial is currently enrolling patients to answer this question.25 Second, there are discrepancies in the existing evidence. Better outcomes are reported with a single stent or simple stenting strategy for bifurcation disease in some cohorts,11-13 but not all.14 Similarly, better outcomes are reported with drug eluting stents in some cohorts,17-19 but not all.20 Third, few data are available in a Canadian context. Only 3 small case series have been published: 8 patients who presented in cardiogenic shock from left main occlusion successfully treated with coronary stenting,26 40 consecutive patients with unprotected left main lesions treated with zotarolimus-eluting stents with 15% major cardiac event (MACE) rate at mean follow up of 12 months,27 and 104 octogenarians treated with coronary stenting for unprotected left main disease with a MACE rate of 43% at a mean follow-up of 23 months.28 Therefore, the aim of this study was to describe the longterm outcome of a Canadian cohort of patients undergoing unprotected left main coronary artery stenting. The significance of bifurcation disease, bifurcation stenting technique, stent type, use of IVUS guidance, and SYNTAX score was systematically investigated.
hospital with acute coronary syndrome), emergent (ongoing chest pain or ST-elevation suggestive of acute coronary occlusion) and cardiogenic shock (persistent hypotension not responsive to fluids requiring vasopressors or mechanical support). Patients were categorized into 2 groups depending on the date of procedure: before 2008 (early time period) and 2008 or later.
Methods Study patients All provincially insured patients who underwent unprotected left main percutaneous coronary intervention (PCI) at the Peter Munk Cardiac Centre, University Health Network, between 2000 and 2011 were identified using a prospectively collected registry (n ¼ 227). Unprotected left main disease was defined as disease requiring a stent in the left main where there were no functioning bypass grafts to either the left anterior descending or circumflex vessels. Indications for revascularization were defined as elective, urgent (admitted to
Coronary angiographic analysis All available angiograms were individually reviewed (M.S.). Angiograms for 6 patients (3%) could not be retrieved, and these patients were excluded from the analysis. Ostial disease was defined as visually assessed angiographic stenosis > 50% involving the aortic insertion of the left main, regardless of whether there was angiographically significant disease in the left main body or bifurcation. Bifurcation disease was defined as angiographically significant disease involving the distal left main (ie, > 50% visual stenosis), or ostial disease of left anterior descending or circumflex vessels (ie, > 70% visual stenosis), which required left main stenting. Among patients with bifurcation disease, stenting technique was categorized as either simple if stenting only involved the left main and 1 of the branching vessels, or complex if stenting involved 2 or more branches of the left main. Stent type was categorized as bare metal or drug-eluting (sirolimus-, paclitaxel-, everolimus, or zotarolimus-eluting stents). SYNTAX scores were calculated using the online calculator (version 2.11, http://www. syntaxscore.com/). The component of the SYNTAX score attributed to the left main lesion was recorded separately. SYNTAX scores were divided into tertiles. IVUS guidance was defined as IVUS use at any time during the stenting procedure. In-hospital outcomes In-hospital outcomes were prospectively collected by dedicated, specially trained nurses. Outcomes included death, new myocardial infarction (MI), coronary artery bypass surgery, repeat PCI, and stroke. MI was defined as an increase in creatine kinase 2 times the upper limit of normal after the
Sibbald et al. Unprotected Left Main Stenting in Canada
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Table 1. Baseline characteristics Syntax tertile Characteristic Patients, n Age Male sex, n (%) Body mass index CCS class, n (%) 0 I II III IV Hypertension, n (%) Diabetes mellitus, n (%) Smoker, n (%) Hyperlipidemia, n (%) Family history of IHD, n (%) Peripheral arterial disease, n (%) COPD, n (%) LV ejection fraction, n (%) 20-39% < 20% PCI indication, n (%) Elective Urgent (nonelective) Rescue Primary Cardiogenic shock Previous PCI MI within past 30 days
All
1
2
3
221 70.8 13.5 132 (59.7) 26.7 5.7
65 67.6 14.7 28 (43.1) 26.8 6.3
82 71.8 12.3 49 (59.8) 27.2 6.3
74 72.4 13.4 55 (74.3) 26.1 4.3
13 5 16 28 159 167 82 132 159 36 52 15
(5.9) (2.3) (7.2) (12.7) (72.0) (75.6) (37.1) (59.7) (72.0) (16.4) (23.5) (6.8)
50 (22.6) 13 (5.9)
7 2 3 6 47 48 27 39 45 14 10 3
(10.8) (3.1) (4.6) (9.2) (72.3) (73.9) (41.5) (60.0) (69.2) (21.5) (15.4) (4.6)
4 3 9 12 54 64 30 50 62 14 25 5
(4.9) (3.7) (11.0) (14.7) (65.9) (78.1) (36.6) (61.0) (75.6) (17.1) (30.5) (6.1)
2 (2.7) 0 4 (5.4) 10 (13.5) 58 (78.4) 55 (74.3) 25 (33.8) 43 (58.1) 52 (70.3) 8 (11.1) 17 (23.0) 7 (9.5)
10 (15.4) 2 (3.1)
19 (23.2) 2 (2.44)
21 (28.4) 9 (12.2)
17 35 1 2 5 18 31
23 (28.1) 33 (40.2) 0 1 (1.2) 10 (12.2) 20 (24.4) 41 (50.0)
16 29 3 7 11 10 46
P 0.07 0.0008 0.46 0.11
0.80 0.64 0.93 0.64 0.30 0.09 0.51 0.02 0.05
56 97 4 10 26 48 118
(25.3) (43.9) (1.8) (4.5) (11.8) (21.7) (53.4)
(26.2) (55.9) (1.5) (3.1) (7.7) (27.7) (47.7)
(21.6) (39.2) (4.1) (9.5) (14.9) (13.5) (62.2)
0.09 0.17
CCS, Canadian Cardiovascular Society; COPD, chronic obstructive lung disease; IHD, ischemic heart disease; LV, left ventricular; MI, myocardial infarction; PCI, percutaneous coronary intervention.
procedure, regardless of levels before the procedure. MACE was defined as a composite of death from any cause, MI, and repeat revascularization (coronary artery bypass surgery or repeat PCI). Long-term outcomes Patient records were crossed-referenced with the Ontario health insurance database at Institute for Clinical Evaluative Sciences (ICES) to identify death, admissions for reinfarction, and revascularization (repeat stenting or bypass surgery). The composite end points of death, admission for reinfarction, and revascularization were treated as the primary end point, with each of its components treated as secondary end points. Statistical analysis Categorical variables were compared using the c2 or Fisher exact tests. Continuous variables are presented as mean ( standard deviation), and compared using analysis of variance or Student t test. Survival curves for time-to-event variables were constructed on the basis of all available follow-up data with the use of Kaplan-Meier estimates and compared using the log-rank test. A forced Cox regression to calculate the fully-adjusted hazard ratios of the primary and secondary end points was performed using the following covariates: SYNTAX tertile, bifurcation disease, stent type, stenting technique, and IVUS use. Statistical analysis was performed using SAS 9.1 (SAS Institute, Cary, NC). Two-sided P values of < 0.05 were regarded as statistically significant.
Results During the study period, 221 patients underwent unprotected left main stenting (Table 1). Patients were predominantly male, with multiple cardiac risk factors. Sixty-three patients (29%) had significant left ventricular dysfunction (ejection fraction < 40%). More than half of the patients had a recent MI, and 26 (12%) presented in cardiogenic shock. Patients in a higher SYNTAX tertile tended to be male, with greater incidence of left ventricular dysfunction, and were more likely to present in cardiogenic shock. The average SYNTAX score of the entire cohort was 28 11, and the average SYNTAX score of the left main lesion was 19 8 (Table 2). Patients had an average of 2.3 1.2 lesions treated with an average of 2.4 1.4 stents. Most left main lesions were type C (68%) and involved the left main bifurcation (74%). Complex stenting techniques were used in 19%, with drug-eluting stents in 57% and IVUS guidance in 26%. Drug eluting stents and IVUS were used less often in patients in higher SYNTAX tertiles. In-hospital outcomes In-hospital death occurred in 29 cases (13%), periprocedural MI in 18, and 1 patient underwent bypass surgery. The overall MACE rate was 15%. Death and MACEs were more frequent among patients in the highest SYNTAX tertile. There were no differences in composite or secondary inhospital outcomes between patients with ostial and those with bifurcation disease. Use of drug-eluting stents was associated with fewer in-hospital deaths and MACEs (Table 3).
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Table 2. Procedural characteristics Syntax tertile All
1
2
3
P
221 2.3 1.2
65 1.4 0.6
82 2.6 1.1
74 2.8 1.2
< 0.0001
116 (52.5) 69 (31.2) 38 (17.2) 28.4 11.4 19.3 7.7 151 (68.3) 35.6 74.4 25 (11.3) 2 (0.9) 11 (5.0) 8 (3.6) 56.6 25 (11.3) 2 (0.9) 11 (5.0) 8 (3.6) 56.6 19.0 58 (26.2) 136 (61.5) 2.4 1.4 21.0 8.3 3.5 0.5
13 (20.0) 7 (10.8) 5 (7.7) 15.1 4.3 13.2 4.2 33 (50.8) 38 (58.5) 26 (40.0) 5 (7.7) 0 0 3 (4.6) 45 (69.2) 5 (7.7) 0 0 3 (4.6) 45 (69.2) 2 (3.1) 27 (41.5) 35 (53.9) 1.5 0.9 15.0 5.9 3.6 0.5
50 (61.0) 30 (36.6) 19 (23.2) 28.4 3.1 19.5 6.3 61 (74.4) 25 (30.5) 71 (86.6) 9 (11.0) 2 (2.4) 6 (7.3) 4 (4.9) 47 (57.3) 9 (11.0) 2 (2.4) 6 (7.3) 4 (4.9) 47 (57.3) 21 (25.6) 21 (25.6) 50 (61.0) 2.7 1.3 23.0 8.1 3.4 0.4
53 (71.6) 32 (43.2) 14 (18.9) 41.8 6.1 25.5 7.1 57 (77.0) 12 (18.8) 60 (93.8) 11 (14.9) 0 5 (6.8) 1 (1.4) 33 (44.6) 11 (14.9) 0 5 (6.8) 1 (1.4) 33 (44.6) 17 (26.6) 10 (13.5) 51 (68.9) 3.0 1.4 24.2 7.4 3.4 0.4
Characteristic Patients, n Number of lesions treated Other vessels treated, n (%) Left anterior descending Circumflex Right coronary Syntax score Left main Syntax score Lesion type C, n (%) Ostium (%) Bifurcation, n (%) Pre PCI TIMI < 3, n (%) Post PCI TIMI < 3, n (%) Intra-aortic balloon pump, n (%) Lesion restenosis, n (%) Drug eluting stent, n (%) TIMI < 3 before PCI, n (%) TIMI < 3 after PCI, n (%) Intra-aortic balloon pump, n (%) Lesion restenosis, n (%) Drug eluting stent, n (%) Complex stenting technique Intravascular ultrasound use, n (%) Glycoprotein IIb/IIIa inhibitor use, n (%) Number of stents Stent length Stent diameter
< 0.0001 < 0.0001 0.03 < 0.0001 0.002 < 0.0001 < 0.0001 0.40 0.14 0.02 0.38 0.01 0.40 0.14 0.02 0.38 0.01 < 0.0001 0.0008 0.19 < 0.0001 < 0.0001 0.002
PCI, percutaneous coronary intervention; TIMI, Thrombolysis In Myocardial Infarction.
Long-term outcomes
Discussion
During an average follow-up period of 3.1 2.8 years (Table 4), 151 patients (68%) experienced the composite end point, 109 patients (49%) died, 39 (18%) required repeat revascularization, and 62 (28%) were admitted for subsequent MI. During the long-term follow up, patients with higher SYNTAX tertiles had higher rates of MACEs, death, and MI (likelihood ratio, 1.4 [95% confidence interval (CI), 1.1-1.8], P ¼ 0.004; likelihood ratio, 1.5 [95% CI, 1.1-2.0], P ¼ 0.01, and likelihood ratio, 1.5 [95% CI, 1.1-2.2], P ¼ 0.05, respectively; Figs. 1 and 2). In contrast, use of drug-eluting stents was associated with reduced death (likelihood ratio [LR] 0.56 [95% CI, 0.340.85], P ¼ 0.01). Ostial disease was associated with a trend toward repeat revascularization (LR, 2.3 [95% CI, 1.0-5.4], P ¼ 0.06). Bifurcation disease and complexity of stent technique were not significantly associated with any primary or secondary end points.
Coronary stenting for unprotected left main disease is increasingly viewed as an acceptable treatment option in certain patient subsets. However, long-term outcomes vary. We report the largest single centre series of coronary stenting for unprotected left main disease in a Canadian context. Strengths of our study include our 100% follow-up using a provincial database, inclusion of nearly all patients who received coronary stenting for unprotected left main disease (97%), and angiographic review of all procedures. In this series, hospital mortality and MACE rates were 13% and 15%, respectively. These rates are higher than those reported in a systematic review of unprotected left main stenting in 1278 patients who received first-generation drugeluting stents, where in-hospital mortality was 2.3% and periprocedural MI was 2.5%.29 Our more inclusive definition of reinfarction (CK of 2 times the upper limit of normal) might have contributed to our report of a greater number of
Table 3. In-hospital outcomes Syntax tertile n Primary outcome MACE Secondary outcomes Death CABG MI Stroke
Stent type
All
1
2
3
221
65
82
74
34 (15.4)
5 (7.7)
12 (14.6)
17 (23.0)
29 1 18 5
5 1 3 2
8 (9.8) 0 10 (12.2) 1 (1.2)
16 (21.6) 0 5 (6.8) 2 (2.7)
(13.1) (0.45) (8.1) (2.3)
(7.7) (1.5) (4.6) (3.1)
P
P
BMS
DES
96
125
0.04
22 (22.9)
12 (9.6)
0.01
0.03 0.29 0.22 0.70
18 1 11 1
11 (8.8) 0 7 (5.6) 4 (3.2)
0.03 0.25 0.12 0.26
(18.8) (1.04) (11.5) (1.04)
BMS, bare-metal stent; CABG, coronary artery bypass grafting; DES, drug-eluting stent; MACE, major adverse cardiac events; MI, myocardial infarction.
Sibbald et al. Unprotected Left Main Stenting in Canada
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Table 4. Long-term outcomes Syntax tertile n Years of follow-up Primary outcome MACE Secondary outcomes Death Repeat revascularization PCI CABG MI Stroke
Stent type
All
1
2
3
221 3.1 2.8
65 3.5 2.6
82 3.1 2.6
74 2.7 3.0
151 (68.3)
37 (56.9)
57 (69.5)
57 (77.0)
109 39 33 10 62 4
24 12 10 2 14 1
41 17 13 6 24 1
44 10 10 2 24 2
(49.3) (17.7) (14.9) (4.5) (28.1) (1.8)
(36.9) (18.5) (15.4) (3.1) (21.5) (1.5)
(50.0) (20.7) (15.9) (7.3) (29.3) (1.2)
(59.5) (13.5) (13.5) (2.7) (32.4) (2.7)
P
P
BMS
DES
96 3.0 3.2
125 3.2 2.4
0.51
0.04
72 (75.0)
79 (63.2)
0.06
0.03 0.48 0.91 0.32 0.34 0.78
60 13 10 3 30 1
49 26 23 7 32 3
0.0006 0.16 0.10 0.37 0.36 0.44
(62.5) (13.5) (4.5) (3.1) (31.3) (1.04)
(39.2) (20.8) (18.4) (5.6) (25.6) (2.4)
BMS, bare metal stent; CABG, coronary artery bypass grafting; DES, drug-eluting stent; MACE, major adverse cardiac events; MI, myocardial infarction; PCI, percutaneous coronary intervention.
MACEs, although reinfarction was relatively infrequent compared with in-hospital mortality in our cohort. Our experience is similar to the population of 5672 patients studied in the National Cardiovascular Data Registry (NCDR) who underwent unprotected left main stenting with 13% in-hospital mortality.20 In a Canadian context, RodesCabau et al. reported 6% in-hospital deaths and 18% in-hospital MACEs in their older population of octogenarians.28 Over longer-term follow-up, we observed 49% death and 68% MACE rates after an average of 37 months. These rates are comparable to the 43% death and 58% MACE rates reported in the NCDR registry at an average of 30 months of follow-up,20 and somewhat higher than the 36% death and 54% MACE reported by a tertiary centre in the Netherlands during 4 years of follow-up where all patients received drugeluting stents.30 Patients undergoing unprotected left main PCI in our cohort are clearly different from those randomized in recent trials that did not enroll higher-risk patients such as those
Figure 1. Kaplan-Meier curves for long-term outcomes by Synergy Between Percutaneous Coronary Intervention With TAXUS Drug-Eluting Stent and Cardiac Surgery (SYNTAX) tertiles. MACE, major adverse cardiac event; MI, myocardial infarction.
presenting in cardiogenic shock, or undergoing primary PCI.4,31 These differences are reflected in the much higher event rate reported in this series, suggesting caution when extrapolating the results of randomized data to an all-comers population of unprotected left main disease. Patients in our cohort were also heavily selected, unlike previous cohorts.7 Most of the patients at our institution with unprotected left main disease underwent bypass surgery. Those selected for unprotected left main disease were in the minority, varying from 1.0% to 4.5% in 2000-2005, from 6.5% to 6.9% in 2006-2007, and from 11.7% to 12.9% after 2008, suggesting that clinicians are choosing left main stenting very selectively, potentially restricting its use to a group of patients with severe acute illness or comorbidity where the risks of surgery would be prohibitive. In contrast, in the cohort reported by Park et al. 49% of all patients diagnosed with left main disease underwent PCI.7 These patients were younger (mean age, 61 years) and received left main stenting for non-MI indications (3% of asymptomatic ischemia, 32% for chronic stable angina, and 55% for unstable angina). Their 5-year death and MACE rates were correspondingly lower at 11.8% and 12.2% at 5 years. The discrepancy in outcomes highlights the importance of patient selection. Restrictive use of left main stenting with selection of those who are poorer candidates for surgery, might miss those who are likely to have the best outcomes with PCI. Consistent with previous studies,4,21,22,30,32 we found a robust association between SYNTAX tertiles with in-hospital and long-term outcomes despite controlling for differences in patient presentation and characteristics. In contrast, the location of left main disease and use of complex stenting techniques were somewhat surprisingly not predictive of in-hospital or long-term outcomes. However, the small numbers of patients with ostial (n ¼ 75) and nonbifurcation disease (n ¼ 54) limit the power of our sample to identify significant differences. Importantly, the complexity of left main disease is incorporated in the SYNTAX score. Higher SYNTAX scores are associated with more complex left main disease and more severe concomitant non-left main coronary disease. As a result, we might understate the prognostic significance of distal left main disease by taking into account the SYNTAX score. The use of drug-eluting stents was associated with lower in-hospital and long-term mortality, consistent with previous reports.20,33 However, unmeasured confounders might have
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Figure 2. Cox plots of death (A) and MACE (B) in long-term follow-up. CI, confidence interval; IVUS, intravascular ultrasound; MACE, major adverse cardiac event.
influenced the choice of stent type, which was left to the discretion of the operators. For instance, drug eluting stents would not have been used in patients with known active malignancy who were anticipating urgent noncardiac surgery, and who would have had poor prognosis because of noncardiac causes. Several limitations of this study are worth mentioning. First, as a retrospective cohort, it is difficult to control for competing causes of mortality that would have led operators to select stenting as a revascularization option for unprotected left main disease. Throughout most of the study period, bypass surgery would have been the treatment of choice for patients who were suitable candidates. Second, because of the substantial advances in equipment, stent platforms, and techniques, reported event rates might not reflect contemporary practice. Third, in despite performing adjusted statistical analyses to examine predictors of in-hospital and long-term outcomes, there are likely unmeasured factors and confounders that could influence outcomes.
In conclusion, we report in-hospital death and MACE rates among a diverse and unselected group of patients undergoing coronary stenting for unprotected left main disease similar to those reported in American registry data.20 Long-term outcomes of these patients are poor, suggesting that the use of left main stenting has been reserved selectively for a heavily comorbid population in this Canadian context. These results suggest a need for further investigation into the use of stenting in unprotected left main disease. We await the results of the EXCEL trial, which is enrolling patients with unprotected left main disease and SYNTAX scores < 33, who will be randomized to receive either bypass surgery or second-generation drug eluting stents. In addition, there is a need for ongoing registry data to monitor event rates among patients treated with stenting outside of clinical trials to determine the effects of guideline changes that recommend coronary stenting as a reasonable treatment option for certain left main coronary artery patient subsets.
Sibbald et al. Unprotected Left Main Stenting in Canada
Acknowledgements The authors thank Sanh Bui for his help in obtaining archived angiograms. Funding Sources This study was supported by the ICES through an annual grant from the Ontario Ministry of Health and Long Term Care. The opinions, results, and conclusions in this article are solely of the authors and independent from funding sources. No endorsement by ICES or Ontario Ministry of Health and Long Term Care is intended or should be inferred. This study was also supported by unrestricted research grants from the Brompton Funds Group.
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10. Palmerini T, Sangiorgi D, Marzocchi A, et al. Ostial and midshaft lesions vs. bifurcation lesions in 1111 patients with unprotected left main coronary artery stenosis treated with drug-eluting stents: results of the survey from the Italian Society of Invasive Cardiology. Eur Heart J 2009;30: 2087-94. 11. Park SJ. Which is the most appropriate stenting technique with drugeluting stent for unprotected left main bifurcation stenosis? Catheter Cardiovasc Interv 2008;71:173-4. 12. Kim YH, Park SW, Hong MK, et al. Comparison of simple and complex stenting techniques in the treatment of unprotected left main coronary artery bifurcation stenosis. Am J Cardiol 2006;97:1597-601. 13. Kim WJ, Kim YH, Park DW, et al. Comparison of single- versus twostent techniques in treatment of unprotected left main coronary bifurcation disease. Catheter Cardiovasc Interv 2011;77:775-82.
Disclosures Dr Dzavík received speaker honoraria and unrestricted educational grants from Abbott Vascular Canada, and unrestricted educational grants from Medtronic Canada. The remaining authors have no conflicts of interest to disclose.
14. Lehmann R, Ehrlich JR, De Rosa S, et al. Impact of interventional strategy for unprotected left main coronary artery percutaneous coronary intervention on long-term survival. Can J Cardiol 2012;28:553-60.
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16. Park SJ, Kim YH, Park DW, et al. Impact of intravascular ultrasound guidance on long-term mortality in stenting for unprotected left main coronary artery stenosis. Circ Cardiovasc Interv 2009;2:167-77.
1. Coronary artery surgery study (CASS): a randomized trial of coronary artery bypass surgery. Survival data. Circulation 1983;68:939-50. 2. Buszman PE, Kiesz SR, Bochenek A, et al. Acute and late outcomes of unprotected left main stenting in comparison with surgical revascularization. J Am Coll Cardiol 2008;51:538-45. 3. Boudriot E, Thiele H, Walther T, et al. Randomized comparison of percutaneous coronary intervention with sirolimus-eluting stents versus coronary artery bypass grafting in unprotected left main stem stenosis. J Am Coll Cardiol 2011;57:538-45. 4. Morice MC, Serruys PW, Kappetein AP, et al. Outcomes in patients with de novo left main disease treated with either percutaneous coronary intervention using paclitaxel-eluting stents or coronary artery bypass graft treatment in the Synergy Between Percutaneous Coronary Intervention with TAXUS and Cardiac Surgery (SYNTAX) trial. Circulation 2010;121:2645-53. 5. Chieffo A, Magni V, Latib A, et al. 5-year outcomes following percutaneous coronary intervention with drug-eluting stent implantation versus coronary artery bypass graft for unprotected left main coronary artery lesions the Milan experience. JACC Cardiovasc Interv 2010;3:595-601. 6. Sanmartin M, Baz JA, Claro R, et al. Comparison of drug-eluting stents versus surgery for unprotected left main coronary artery disease. Am J Cardiol 2007;100:970-3. 7. Park DW, Seung KB, Kim YH, et al. Long-term safety and efficacy of stenting versus coronary artery bypass grafting for unprotected left main coronary artery disease: 5-year results from the MAIN-COMPARE (Revascularization for Unprotected Left Main Coronary Artery Stenosis: Comparison of Percutaneous Coronary Angioplasty Versus Surgical Revascularization) registry. J Am Coll Cardiol 2010;56:117-24. 8. Palmerini T, Marzocchi A, Marrozzini C, et al. Comparison between coronary angioplasty and coronary artery bypass surgery for the treatment of unprotected left main coronary artery stenosis (the Bologna Registry). Am J Cardiol 2006;98:54-9. 9. Lee MS, Sillano D, Latib A, et al. Multicenter international registry of unprotected left main coronary artery percutaneous coronary intervention with drug-eluting stents in patients with myocardial infarction. Catheter Cardiovasc Interv 2009;73:15-21.
15. Park SJ, Hong MK, Lee CW, et al. Elective stenting of unprotected left main coronary artery stenosis: effect of debulking before stenting and intravascular ultrasound guidance. J Am Coll Cardiol 2001;38:1054-60.
17. Tamburino C, Di Salvo ME, Capodanno D, et al. Comparison of drugeluting stents and bare-metal stents for the treatment of unprotected left main coronary artery disease in acute coronary syndromes. Am J Cardiol 2009;103:187-93. 18. Palmerini T, Marzocchi A, Tamburino C, et al. Two-year clinical outcome with drug-eluting stents versus bare-metal stents in a real-world registry of unprotected left main coronary artery stenosis from the Italian Society of Invasive Cardiology. Am J Cardiol 2008;102:1463-8. 19. Kim YH, Park DW, Lee SW, et al. Long-term safety and effectiveness of unprotected left main coronary stenting with drug-eluting stents compared with bare-metal stents. Circulation 2009;120:400-7. 20. Brennan JM, Dai D, Patel MR, et al. Characteristics and long-term outcomes of percutaneous revascularization of unprotected left main coronary artery stenosis in the United States: a report from the National Cardiovascular Data Registry, 2004 to 2008. J Am Coll Cardiol 2012;59: 648-54. 21. Kim YH, Park DW, Kim WJ, et al. Validation of SYNTAX (Synergy between PCI with Taxus and Cardiac Surgery) score for prediction of outcomes after unprotected left main coronary revascularization. JACC Cardiovasc Interv 2010;3:612-23. 22. Chen SL, Ye F, Zhang JJ, et al. Prediction of clinical outcomes in patients with unprotected left main trifurcation lesions treated by drug-eluting stents: importance of 2-stent technique and SYNTAX score. J Interv Cardiol 2010;23:352-7. 23. Wijns W, Kolh P, Danchin N, et al. Guidelines on myocardial revascularization. Eur Heart J 2010;31:2501-55. 24. Kushner FG, Hand M, Smith SC Jr, et al. 2009 Focused updates: ACC/ AHA guidelines for the management of patients with ST-Elevation myocardial infarction (updating the 2004 Guideline and 2007 Focused Update) and ACC/AHA/SCAI Guidelines on percutaneous coronary intervention (updating the 2005 Guideline and 2007 Focused Update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2009;120:2271-306.
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25. Ielasi A, Latib A, Chieffo A, et al. Very long-term outcomes following drug-eluting stent implantation for unprotected left main coronary artery stenosis: a single center experience. Rev Esp Cardiol 2013;66:24-33. 26. Hussain F, Nguyen T, Elmayergi N, et al. The acutely occluded left main coronary artery culprit in cardiogenic shock and initial percutaneous coronary intervention: a substudy of the Manitoba “no option” left main PCI registry. Can J Physiol Pharmacol 2012;90:1325-31. 27. Simard T, Hibbert B, Chong AY, et al. Unprotected left main coronary artery stenting with zotarolimus (Endeavor) drug-eluting stents: a single center retrospective experience. Catheter Cardiovasc Interv 2012;80: E15-22. 28. Rodes-Cabau J, Deblois J, Bertrand OF, et al. Nonrandomized comparison of coronary artery bypass surgery and percutaneous coronary intervention for the treatment of unprotected left main coronary artery disease in octogenarians. Circulation 2008;118:2374-81. 29. Biondi-Zoccai GG, Lotrionte M, Moretti C, et al. A collaborative systematic review and meta-analysis on 1278 patients undergoing percutaneous drug-eluting stenting for unprotected left main coronary artery disease. Am Heart J 2008;155:274-83.
Canadian Journal of Cardiology Volume 30 2014 30. Onuma Y, Girasis C, Piazza N, et al. Long-term clinical results following stenting of the left main stem: insights from RESEARCH (RapamycinEluting Stent Evaluated at Rotterdam Cardiology Hospital) and T-SEARCH (Taxus-Stent Evaluated at Rotterdam Cardiology Hospital) Registries. JACC Cardiovasc Interv 2010;3:584-94. 31. Park SJ, Kim YH, Park DW, et al. Randomized trial of stents versus bypass surgery for left main coronary artery disease. N Engl J Med 2011;364:1718-27. 32. Chen SL, Chen JP, Mintz G, et al. Comparison between the NERS (New Risk Stratification) score and the SYNTAX (Synergy between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery) score in outcome prediction for unprotected left main stenting. JACC Cardiovasc Interv 2010;3:632-41. 33. Erglis A, Narbute I, Kumsars I, et al. A randomized comparison of paclitaxel-eluting stents versus bare-metal stents for treatment of unprotected left main coronary artery stenosis. J Am Coll Cardiol 2007;50: 491-7.
Clinical Research
Long-term Outcome of Unprotected Left Main Stenting: A Canadian Tertiary Care Experience Matthew Sibbald, MD, PhD, William Chan, MD, PhD, Paul Daly, MD, Eric Horlick, MD, Douglas Ing, MD, Joan Ivanov, PhD, Karen Mackie, RN, Mark D. Osten, MD, Christopher B. Overgaard, MD, MSc, and Vladimír Dzavík, MD Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada
See editorial by Lavi and Yadegari, pages 1256-1258 of this issue. ABSTRACT
RESUM E
Background: Coronary stenting is increasingly used to treat unprotected left main disease in selected patients. However, there is a paucity of data on the long-term outcome of these patients in a Canadian context outside of clinical trials. Methods: We retrospectively reviewed all provincially-insured patients undergoing left main coronary stenting at a large tertiary referral centre from 2000-2011. Pre-procedural angiograms were reviewed to identify the location of left main disease, and extent of concomitant coronary disease quantified by calculating Synergy Between Percutaneous Coronary Intervention With TAXUS Drug-Eluting Stent and Cardiac Surgery (SYNTAX) scores for each patient. In-hospital death and major adverse cardiac event (MACE) rates were evaluated as were long-term death and MACE rates obtained via linkage of our institutional registry with the Ontario health claims database. Results: Two hundred twenty-one patients underwent unprotected left main stenting with 29 (13.1%) in-hospital death and 34 (15.4%) a
Introduction : L’implantation d’endoprothèses coronariennes est de quente pour traiter la maladie du tronc commun plus en plus fre ge de patients se lectionne s. Cependant, les coronaire gauche non prote es sur les re sultats à long terme de ces patients dans un condonne texte canadien autre que les essais cliniques sont insuffisantes. thodes : Nous avons re trospectivement passe en revue les patients Me gime d’assurance provincial ayant subi l’implantacouverts par un re tion d’une endoprothèse au tronc commun coronaire gauche dans un cialise tertiaire de 2000 à 2011. Les angiogrammes grand centre spe interventionnels ont e te passe s en revue pour situer le siège de la pre tendue de la mamaladie du tronc commun coronaire gauche et l’e e par le calcul des scores ladie coronarienne concomitante quantifie SYNTAX (SYNergy between percutaneous coronary intervention with TAXus drug-eluting stent and cardiac surgery) de chacun des patients. cès intrahospitaliers et d’e ve nements cardiovasculaires Les taux de de sirables majeurs (ECIM) ont e te e value s, de même que les taux de inde
Untreated significant left main coronary stenosis carries a poor prognosis.1 Although coronary artery bypass graft surgery is the traditional gold standard treatment, several randomized trials2-4 and registries5-9 provide support for coronary stenting as an alternate approach. Outcomes with coronary stenting vary compared with bypass surgery according to patient subsets.4 Predictors of adverse outcomes after left main stenting include bifurcation disease,10 bifurcation stenting technique,11-14 lack of intravascular ultrasound (IVUS) guidance,15,16 stent type,17-20 and burden of disease measured using the scoring system developed and validated in the Synergy Between
Percutaneous Coronary Intervention With TAXUS DrugEluting Stent and Cardiac Surgery (SYNTAX) trial.4,21,22 The American College of Cardiology 2009 and European Society of Cardiology 2010 revascularization guidelines have evolved to reflect this accumulating evidence, suggesting that coronary stenting can be considered an alternative to bypass surgery in subsets of patients with unprotected left main disease.23,24 However, both guidelines recommend careful selection of patients. The American College of Cardiology 2009 guidelines suggest selecting patients with anatomic conditions associated with low risk of complications related to coronary stenting. The European Society of Cardiology 2010 guidelines give varied levels of recommendation depending on the location of left main stenosis (ie, whether the bifurcation of the left main is involved) and the burden of coronary disease, measured according to number of vessels involved or by SYNTAX score. There are 3 challenges with the application of these guidelines. First, none of the previous randomized trials were
Received for publication February 27, 2014. Accepted May 15, 2014. Corresponding author: Dr Vladimír Dzavík, Division of Cardiology, Peter Munk Cardiac Centre, University Health Network, 6-246 EN, Toronto General Hospital, 200 Elizabeth St, Toronto, Ontario M5G 2C4, Canada. Tel.: þ1-416-340-4800 6265; fax: þ1-416-340-3390. E-mail: [email protected] See page 1413 for disclosure information.
http://dx.doi.org/10.1016/j.cjca.2014.05.023 0828-282X/Ó 2014 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.
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MACE. At an average follow-up of 3.1 2.8 years, 109 patients (49.3%) died and 151 (68.3%) experienced a MACE. Higher SYNTAX tertile and use of bare metal rather than drug-eluting stents was associated with increased rates of in-hospital and long-term death. Conclusions: This study reports, to our knowledge, the largest Canadian cohort of unprotected left main stenting over more than a decade. Coronary stenting was associated with acceptable in-hospital event rates, but poor long-term outcomes, reflecting the higher-risk population traditionally selected for this procedure.
cès et d’ÉCIM à long terme obtenus par le couplage du registre de de tablissement à la base de donne es des demandes de notre e de l’Ontario. remboursement du système de soins de sante sultats : Deux cent vingt-et-un (221) patients ont subi l’implantation Re ge d’une endoprothèse au tronc commun coronaire gauche non prote 29 (13,1 %) de cès intrahospitaliers et 34 (15,4 %) ECIM. qui a entraîne taient morts Au suivi moyen de 3,1 2,8 ans, 109 patients (49,3 %) e leve du SYNTAX et 151 (68,3 %) avaient subi un ECIM. Le tertile plus e tal nu plutôt que d’endoproet l’utilisation d’endoprothèses en me dicamente es ont e te associe s à l’augmentation des taux de thèses me cès intrahospitaliers et à long terme. de tude pre sente la plus Conclusions : À notre connaissance, cette e grande cohorte canadienne ayant subi l’implantation d’une endo ge depuis plus prothèse au tronc commun coronaire gauche non prote cennie. L’implantation d’une endoprothèse coronarienne a e te d’une de e à des taux acceptables d’e ve nements intrahospitaliers, mais associe sultats me diocres à long terme refle tant la population expose e à des re leve , soit celle qui est traditionnellement à un risque plus e lectionne e pour subir cette intervention. se
designed to evaluate outcomes of coronary stenting compared with bypass surgery in the specific patient subsets endorsed by the guidelines. The ongoing Evaluation of XIENCE Everolimus Eluting Stent Versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization (EXCEL) trial is currently enrolling patients to answer this question.25 Second, there are discrepancies in the existing evidence. Better outcomes are reported with a single stent or simple stenting strategy for bifurcation disease in some cohorts,11-13 but not all.14 Similarly, better outcomes are reported with drug eluting stents in some cohorts,17-19 but not all.20 Third, few data are available in a Canadian context. Only 3 small case series have been published: 8 patients who presented in cardiogenic shock from left main occlusion successfully treated with coronary stenting,26 40 consecutive patients with unprotected left main lesions treated with zotarolimus-eluting stents with 15% major cardiac event (MACE) rate at mean follow up of 12 months,27 and 104 octogenarians treated with coronary stenting for unprotected left main disease with a MACE rate of 43% at a mean follow-up of 23 months.28 Therefore, the aim of this study was to describe the longterm outcome of a Canadian cohort of patients undergoing unprotected left main coronary artery stenting. The significance of bifurcation disease, bifurcation stenting technique, stent type, use of IVUS guidance, and SYNTAX score was systematically investigated.
hospital with acute coronary syndrome), emergent (ongoing chest pain or ST-elevation suggestive of acute coronary occlusion) and cardiogenic shock (persistent hypotension not responsive to fluids requiring vasopressors or mechanical support). Patients were categorized into 2 groups depending on the date of procedure: before 2008 (early time period) and 2008 or later.
Methods Study patients All provincially insured patients who underwent unprotected left main percutaneous coronary intervention (PCI) at the Peter Munk Cardiac Centre, University Health Network, between 2000 and 2011 were identified using a prospectively collected registry (n ¼ 227). Unprotected left main disease was defined as disease requiring a stent in the left main where there were no functioning bypass grafts to either the left anterior descending or circumflex vessels. Indications for revascularization were defined as elective, urgent (admitted to
Coronary angiographic analysis All available angiograms were individually reviewed (M.S.). Angiograms for 6 patients (3%) could not be retrieved, and these patients were excluded from the analysis. Ostial disease was defined as visually assessed angiographic stenosis > 50% involving the aortic insertion of the left main, regardless of whether there was angiographically significant disease in the left main body or bifurcation. Bifurcation disease was defined as angiographically significant disease involving the distal left main (ie, > 50% visual stenosis), or ostial disease of left anterior descending or circumflex vessels (ie, > 70% visual stenosis), which required left main stenting. Among patients with bifurcation disease, stenting technique was categorized as either simple if stenting only involved the left main and 1 of the branching vessels, or complex if stenting involved 2 or more branches of the left main. Stent type was categorized as bare metal or drug-eluting (sirolimus-, paclitaxel-, everolimus, or zotarolimus-eluting stents). SYNTAX scores were calculated using the online calculator (version 2.11, http://www. syntaxscore.com/). The component of the SYNTAX score attributed to the left main lesion was recorded separately. SYNTAX scores were divided into tertiles. IVUS guidance was defined as IVUS use at any time during the stenting procedure. In-hospital outcomes In-hospital outcomes were prospectively collected by dedicated, specially trained nurses. Outcomes included death, new myocardial infarction (MI), coronary artery bypass surgery, repeat PCI, and stroke. MI was defined as an increase in creatine kinase 2 times the upper limit of normal after the
Sibbald et al. Unprotected Left Main Stenting in Canada
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Table 1. Baseline characteristics Syntax tertile Characteristic Patients, n Age Male sex, n (%) Body mass index CCS class, n (%) 0 I II III IV Hypertension, n (%) Diabetes mellitus, n (%) Smoker, n (%) Hyperlipidemia, n (%) Family history of IHD, n (%) Peripheral arterial disease, n (%) COPD, n (%) LV ejection fraction, n (%) 20-39% < 20% PCI indication, n (%) Elective Urgent (nonelective) Rescue Primary Cardiogenic shock Previous PCI MI within past 30 days
All
1
2
3
221 70.8 13.5 132 (59.7) 26.7 5.7
65 67.6 14.7 28 (43.1) 26.8 6.3
82 71.8 12.3 49 (59.8) 27.2 6.3
74 72.4 13.4 55 (74.3) 26.1 4.3
13 5 16 28 159 167 82 132 159 36 52 15
(5.9) (2.3) (7.2) (12.7) (72.0) (75.6) (37.1) (59.7) (72.0) (16.4) (23.5) (6.8)
50 (22.6) 13 (5.9)
7 2 3 6 47 48 27 39 45 14 10 3
(10.8) (3.1) (4.6) (9.2) (72.3) (73.9) (41.5) (60.0) (69.2) (21.5) (15.4) (4.6)
4 3 9 12 54 64 30 50 62 14 25 5
(4.9) (3.7) (11.0) (14.7) (65.9) (78.1) (36.6) (61.0) (75.6) (17.1) (30.5) (6.1)
2 (2.7) 0 4 (5.4) 10 (13.5) 58 (78.4) 55 (74.3) 25 (33.8) 43 (58.1) 52 (70.3) 8 (11.1) 17 (23.0) 7 (9.5)
10 (15.4) 2 (3.1)
19 (23.2) 2 (2.44)
21 (28.4) 9 (12.2)
17 35 1 2 5 18 31
23 (28.1) 33 (40.2) 0 1 (1.2) 10 (12.2) 20 (24.4) 41 (50.0)
16 29 3 7 11 10 46
P 0.07 0.0008 0.46 0.11
0.80 0.64 0.93 0.64 0.30 0.09 0.51 0.02 0.05
56 97 4 10 26 48 118
(25.3) (43.9) (1.8) (4.5) (11.8) (21.7) (53.4)
(26.2) (55.9) (1.5) (3.1) (7.7) (27.7) (47.7)
(21.6) (39.2) (4.1) (9.5) (14.9) (13.5) (62.2)
0.09 0.17
CCS, Canadian Cardiovascular Society; COPD, chronic obstructive lung disease; IHD, ischemic heart disease; LV, left ventricular; MI, myocardial infarction; PCI, percutaneous coronary intervention.
procedure, regardless of levels before the procedure. MACE was defined as a composite of death from any cause, MI, and repeat revascularization (coronary artery bypass surgery or repeat PCI). Long-term outcomes Patient records were crossed-referenced with the Ontario health insurance database at Institute for Clinical Evaluative Sciences (ICES) to identify death, admissions for reinfarction, and revascularization (repeat stenting or bypass surgery). The composite end points of death, admission for reinfarction, and revascularization were treated as the primary end point, with each of its components treated as secondary end points. Statistical analysis Categorical variables were compared using the c2 or Fisher exact tests. Continuous variables are presented as mean ( standard deviation), and compared using analysis of variance or Student t test. Survival curves for time-to-event variables were constructed on the basis of all available follow-up data with the use of Kaplan-Meier estimates and compared using the log-rank test. A forced Cox regression to calculate the fully-adjusted hazard ratios of the primary and secondary end points was performed using the following covariates: SYNTAX tertile, bifurcation disease, stent type, stenting technique, and IVUS use. Statistical analysis was performed using SAS 9.1 (SAS Institute, Cary, NC). Two-sided P values of < 0.05 were regarded as statistically significant.
Results During the study period, 221 patients underwent unprotected left main stenting (Table 1). Patients were predominantly male, with multiple cardiac risk factors. Sixty-three patients (29%) had significant left ventricular dysfunction (ejection fraction < 40%). More than half of the patients had a recent MI, and 26 (12%) presented in cardiogenic shock. Patients in a higher SYNTAX tertile tended to be male, with greater incidence of left ventricular dysfunction, and were more likely to present in cardiogenic shock. The average SYNTAX score of the entire cohort was 28 11, and the average SYNTAX score of the left main lesion was 19 8 (Table 2). Patients had an average of 2.3 1.2 lesions treated with an average of 2.4 1.4 stents. Most left main lesions were type C (68%) and involved the left main bifurcation (74%). Complex stenting techniques were used in 19%, with drug-eluting stents in 57% and IVUS guidance in 26%. Drug eluting stents and IVUS were used less often in patients in higher SYNTAX tertiles. In-hospital outcomes In-hospital death occurred in 29 cases (13%), periprocedural MI in 18, and 1 patient underwent bypass surgery. The overall MACE rate was 15%. Death and MACEs were more frequent among patients in the highest SYNTAX tertile. There were no differences in composite or secondary inhospital outcomes between patients with ostial and those with bifurcation disease. Use of drug-eluting stents was associated with fewer in-hospital deaths and MACEs (Table 3).
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Table 2. Procedural characteristics Syntax tertile All
1
2
3
P
221 2.3 1.2
65 1.4 0.6
82 2.6 1.1
74 2.8 1.2
< 0.0001
116 (52.5) 69 (31.2) 38 (17.2) 28.4 11.4 19.3 7.7 151 (68.3) 35.6 74.4 25 (11.3) 2 (0.9) 11 (5.0) 8 (3.6) 56.6 25 (11.3) 2 (0.9) 11 (5.0) 8 (3.6) 56.6 19.0 58 (26.2) 136 (61.5) 2.4 1.4 21.0 8.3 3.5 0.5
13 (20.0) 7 (10.8) 5 (7.7) 15.1 4.3 13.2 4.2 33 (50.8) 38 (58.5) 26 (40.0) 5 (7.7) 0 0 3 (4.6) 45 (69.2) 5 (7.7) 0 0 3 (4.6) 45 (69.2) 2 (3.1) 27 (41.5) 35 (53.9) 1.5 0.9 15.0 5.9 3.6 0.5
50 (61.0) 30 (36.6) 19 (23.2) 28.4 3.1 19.5 6.3 61 (74.4) 25 (30.5) 71 (86.6) 9 (11.0) 2 (2.4) 6 (7.3) 4 (4.9) 47 (57.3) 9 (11.0) 2 (2.4) 6 (7.3) 4 (4.9) 47 (57.3) 21 (25.6) 21 (25.6) 50 (61.0) 2.7 1.3 23.0 8.1 3.4 0.4
53 (71.6) 32 (43.2) 14 (18.9) 41.8 6.1 25.5 7.1 57 (77.0) 12 (18.8) 60 (93.8) 11 (14.9) 0 5 (6.8) 1 (1.4) 33 (44.6) 11 (14.9) 0 5 (6.8) 1 (1.4) 33 (44.6) 17 (26.6) 10 (13.5) 51 (68.9) 3.0 1.4 24.2 7.4 3.4 0.4
Characteristic Patients, n Number of lesions treated Other vessels treated, n (%) Left anterior descending Circumflex Right coronary Syntax score Left main Syntax score Lesion type C, n (%) Ostium (%) Bifurcation, n (%) Pre PCI TIMI < 3, n (%) Post PCI TIMI < 3, n (%) Intra-aortic balloon pump, n (%) Lesion restenosis, n (%) Drug eluting stent, n (%) TIMI < 3 before PCI, n (%) TIMI < 3 after PCI, n (%) Intra-aortic balloon pump, n (%) Lesion restenosis, n (%) Drug eluting stent, n (%) Complex stenting technique Intravascular ultrasound use, n (%) Glycoprotein IIb/IIIa inhibitor use, n (%) Number of stents Stent length Stent diameter
< 0.0001 < 0.0001 0.03 < 0.0001 0.002 < 0.0001 < 0.0001 0.40 0.14 0.02 0.38 0.01 0.40 0.14 0.02 0.38 0.01 < 0.0001 0.0008 0.19 < 0.0001 < 0.0001 0.002
PCI, percutaneous coronary intervention; TIMI, Thrombolysis In Myocardial Infarction.
Long-term outcomes
Discussion
During an average follow-up period of 3.1 2.8 years (Table 4), 151 patients (68%) experienced the composite end point, 109 patients (49%) died, 39 (18%) required repeat revascularization, and 62 (28%) were admitted for subsequent MI. During the long-term follow up, patients with higher SYNTAX tertiles had higher rates of MACEs, death, and MI (likelihood ratio, 1.4 [95% confidence interval (CI), 1.1-1.8], P ¼ 0.004; likelihood ratio, 1.5 [95% CI, 1.1-2.0], P ¼ 0.01, and likelihood ratio, 1.5 [95% CI, 1.1-2.2], P ¼ 0.05, respectively; Figs. 1 and 2). In contrast, use of drug-eluting stents was associated with reduced death (likelihood ratio [LR] 0.56 [95% CI, 0.340.85], P ¼ 0.01). Ostial disease was associated with a trend toward repeat revascularization (LR, 2.3 [95% CI, 1.0-5.4], P ¼ 0.06). Bifurcation disease and complexity of stent technique were not significantly associated with any primary or secondary end points.
Coronary stenting for unprotected left main disease is increasingly viewed as an acceptable treatment option in certain patient subsets. However, long-term outcomes vary. We report the largest single centre series of coronary stenting for unprotected left main disease in a Canadian context. Strengths of our study include our 100% follow-up using a provincial database, inclusion of nearly all patients who received coronary stenting for unprotected left main disease (97%), and angiographic review of all procedures. In this series, hospital mortality and MACE rates were 13% and 15%, respectively. These rates are higher than those reported in a systematic review of unprotected left main stenting in 1278 patients who received first-generation drugeluting stents, where in-hospital mortality was 2.3% and periprocedural MI was 2.5%.29 Our more inclusive definition of reinfarction (CK of 2 times the upper limit of normal) might have contributed to our report of a greater number of
Table 3. In-hospital outcomes Syntax tertile n Primary outcome MACE Secondary outcomes Death CABG MI Stroke
Stent type
All
1
2
3
221
65
82
74
34 (15.4)
5 (7.7)
12 (14.6)
17 (23.0)
29 1 18 5
5 1 3 2
8 (9.8) 0 10 (12.2) 1 (1.2)
16 (21.6) 0 5 (6.8) 2 (2.7)
(13.1) (0.45) (8.1) (2.3)
(7.7) (1.5) (4.6) (3.1)
P
P
BMS
DES
96
125
0.04
22 (22.9)
12 (9.6)
0.01
0.03 0.29 0.22 0.70
18 1 11 1
11 (8.8) 0 7 (5.6) 4 (3.2)
0.03 0.25 0.12 0.26
(18.8) (1.04) (11.5) (1.04)
BMS, bare-metal stent; CABG, coronary artery bypass grafting; DES, drug-eluting stent; MACE, major adverse cardiac events; MI, myocardial infarction.
Sibbald et al. Unprotected Left Main Stenting in Canada
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Table 4. Long-term outcomes Syntax tertile n Years of follow-up Primary outcome MACE Secondary outcomes Death Repeat revascularization PCI CABG MI Stroke
Stent type
All
1
2
3
221 3.1 2.8
65 3.5 2.6
82 3.1 2.6
74 2.7 3.0
151 (68.3)
37 (56.9)
57 (69.5)
57 (77.0)
109 39 33 10 62 4
24 12 10 2 14 1
41 17 13 6 24 1
44 10 10 2 24 2
(49.3) (17.7) (14.9) (4.5) (28.1) (1.8)
(36.9) (18.5) (15.4) (3.1) (21.5) (1.5)
(50.0) (20.7) (15.9) (7.3) (29.3) (1.2)
(59.5) (13.5) (13.5) (2.7) (32.4) (2.7)
P
P
BMS
DES
96 3.0 3.2
125 3.2 2.4
0.51
0.04
72 (75.0)
79 (63.2)
0.06
0.03 0.48 0.91 0.32 0.34 0.78
60 13 10 3 30 1
49 26 23 7 32 3
0.0006 0.16 0.10 0.37 0.36 0.44
(62.5) (13.5) (4.5) (3.1) (31.3) (1.04)
(39.2) (20.8) (18.4) (5.6) (25.6) (2.4)
BMS, bare metal stent; CABG, coronary artery bypass grafting; DES, drug-eluting stent; MACE, major adverse cardiac events; MI, myocardial infarction; PCI, percutaneous coronary intervention.
MACEs, although reinfarction was relatively infrequent compared with in-hospital mortality in our cohort. Our experience is similar to the population of 5672 patients studied in the National Cardiovascular Data Registry (NCDR) who underwent unprotected left main stenting with 13% in-hospital mortality.20 In a Canadian context, RodesCabau et al. reported 6% in-hospital deaths and 18% in-hospital MACEs in their older population of octogenarians.28 Over longer-term follow-up, we observed 49% death and 68% MACE rates after an average of 37 months. These rates are comparable to the 43% death and 58% MACE rates reported in the NCDR registry at an average of 30 months of follow-up,20 and somewhat higher than the 36% death and 54% MACE reported by a tertiary centre in the Netherlands during 4 years of follow-up where all patients received drugeluting stents.30 Patients undergoing unprotected left main PCI in our cohort are clearly different from those randomized in recent trials that did not enroll higher-risk patients such as those
Figure 1. Kaplan-Meier curves for long-term outcomes by Synergy Between Percutaneous Coronary Intervention With TAXUS Drug-Eluting Stent and Cardiac Surgery (SYNTAX) tertiles. MACE, major adverse cardiac event; MI, myocardial infarction.
presenting in cardiogenic shock, or undergoing primary PCI.4,31 These differences are reflected in the much higher event rate reported in this series, suggesting caution when extrapolating the results of randomized data to an all-comers population of unprotected left main disease. Patients in our cohort were also heavily selected, unlike previous cohorts.7 Most of the patients at our institution with unprotected left main disease underwent bypass surgery. Those selected for unprotected left main disease were in the minority, varying from 1.0% to 4.5% in 2000-2005, from 6.5% to 6.9% in 2006-2007, and from 11.7% to 12.9% after 2008, suggesting that clinicians are choosing left main stenting very selectively, potentially restricting its use to a group of patients with severe acute illness or comorbidity where the risks of surgery would be prohibitive. In contrast, in the cohort reported by Park et al. 49% of all patients diagnosed with left main disease underwent PCI.7 These patients were younger (mean age, 61 years) and received left main stenting for non-MI indications (3% of asymptomatic ischemia, 32% for chronic stable angina, and 55% for unstable angina). Their 5-year death and MACE rates were correspondingly lower at 11.8% and 12.2% at 5 years. The discrepancy in outcomes highlights the importance of patient selection. Restrictive use of left main stenting with selection of those who are poorer candidates for surgery, might miss those who are likely to have the best outcomes with PCI. Consistent with previous studies,4,21,22,30,32 we found a robust association between SYNTAX tertiles with in-hospital and long-term outcomes despite controlling for differences in patient presentation and characteristics. In contrast, the location of left main disease and use of complex stenting techniques were somewhat surprisingly not predictive of in-hospital or long-term outcomes. However, the small numbers of patients with ostial (n ¼ 75) and nonbifurcation disease (n ¼ 54) limit the power of our sample to identify significant differences. Importantly, the complexity of left main disease is incorporated in the SYNTAX score. Higher SYNTAX scores are associated with more complex left main disease and more severe concomitant non-left main coronary disease. As a result, we might understate the prognostic significance of distal left main disease by taking into account the SYNTAX score. The use of drug-eluting stents was associated with lower in-hospital and long-term mortality, consistent with previous reports.20,33 However, unmeasured confounders might have
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Canadian Journal of Cardiology Volume 30 2014
Figure 2. Cox plots of death (A) and MACE (B) in long-term follow-up. CI, confidence interval; IVUS, intravascular ultrasound; MACE, major adverse cardiac event.
influenced the choice of stent type, which was left to the discretion of the operators. For instance, drug eluting stents would not have been used in patients with known active malignancy who were anticipating urgent noncardiac surgery, and who would have had poor prognosis because of noncardiac causes. Several limitations of this study are worth mentioning. First, as a retrospective cohort, it is difficult to control for competing causes of mortality that would have led operators to select stenting as a revascularization option for unprotected left main disease. Throughout most of the study period, bypass surgery would have been the treatment of choice for patients who were suitable candidates. Second, because of the substantial advances in equipment, stent platforms, and techniques, reported event rates might not reflect contemporary practice. Third, in despite performing adjusted statistical analyses to examine predictors of in-hospital and long-term outcomes, there are likely unmeasured factors and confounders that could influence outcomes.
In conclusion, we report in-hospital death and MACE rates among a diverse and unselected group of patients undergoing coronary stenting for unprotected left main disease similar to those reported in American registry data.20 Long-term outcomes of these patients are poor, suggesting that the use of left main stenting has been reserved selectively for a heavily comorbid population in this Canadian context. These results suggest a need for further investigation into the use of stenting in unprotected left main disease. We await the results of the EXCEL trial, which is enrolling patients with unprotected left main disease and SYNTAX scores < 33, who will be randomized to receive either bypass surgery or second-generation drug eluting stents. In addition, there is a need for ongoing registry data to monitor event rates among patients treated with stenting outside of clinical trials to determine the effects of guideline changes that recommend coronary stenting as a reasonable treatment option for certain left main coronary artery patient subsets.
Sibbald et al. Unprotected Left Main Stenting in Canada
Acknowledgements The authors thank Sanh Bui for his help in obtaining archived angiograms. Funding Sources This study was supported by the ICES through an annual grant from the Ontario Ministry of Health and Long Term Care. The opinions, results, and conclusions in this article are solely of the authors and independent from funding sources. No endorsement by ICES or Ontario Ministry of Health and Long Term Care is intended or should be inferred. This study was also supported by unrestricted research grants from the Brompton Funds Group.
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10. Palmerini T, Sangiorgi D, Marzocchi A, et al. Ostial and midshaft lesions vs. bifurcation lesions in 1111 patients with unprotected left main coronary artery stenosis treated with drug-eluting stents: results of the survey from the Italian Society of Invasive Cardiology. Eur Heart J 2009;30: 2087-94. 11. Park SJ. Which is the most appropriate stenting technique with drugeluting stent for unprotected left main bifurcation stenosis? Catheter Cardiovasc Interv 2008;71:173-4. 12. Kim YH, Park SW, Hong MK, et al. Comparison of simple and complex stenting techniques in the treatment of unprotected left main coronary artery bifurcation stenosis. Am J Cardiol 2006;97:1597-601. 13. Kim WJ, Kim YH, Park DW, et al. Comparison of single- versus twostent techniques in treatment of unprotected left main coronary bifurcation disease. Catheter Cardiovasc Interv 2011;77:775-82.
Disclosures Dr Dzavík received speaker honoraria and unrestricted educational grants from Abbott Vascular Canada, and unrestricted educational grants from Medtronic Canada. The remaining authors have no conflicts of interest to disclose.
14. Lehmann R, Ehrlich JR, De Rosa S, et al. Impact of interventional strategy for unprotected left main coronary artery percutaneous coronary intervention on long-term survival. Can J Cardiol 2012;28:553-60.
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