Abstract: Objective. To assess the efficacy and safety of coronary left main (LM) disease interventions in patients with acute coronary syndromes (ACS) as compared to those without LM coronary artery disease. Methods. A total of 2899 patients with ACS, enrolled in the prospective Swiss Program University Medicine ACS (SPUM-ACS) cohort, were included. The primary endpoints of independently adjudicated major adverse cardiovascular and cerebrovascular event (MACCE) and net adverse clinical event (NACE) were determined at 30-day follow-up. Results. Seventy-one (2.0%) of the 2899 ACS patients had significant LM disease. At 30-day follow-up, the primary outcomes of MACCE and NACE occurred in 140 patients (4.8%) and 272 patients (9.4%), respectively. Compared to those without LM disease, patients in the LM group were significantly older (P<.001), had a higher incidence of hypertension (P<.001) and diabetes (P=.013), and more often had a history of coronary artery bypass graft (CABG) surgery (P<.001). Analyses on non-matched populations showed a nearly significant trend toward a higher incidence of MACCE (P=.06) and NACE (P=.10) in patients with LM disease compared to those without LM disease. This trend, however, disappeared after matching the populations for all significant confounding variables on a 3:1 basis. This subanalysis showed MACCE rates of 10.0% in the LM group and 7.3% in the non-LM group (P=.61). Notably, the matched patients with LM disease treated with percutaneous coronary intervention had a lower NACE incidence when compared to those undergoing urgent CABG surgery (P<.01). Conclusions. In ACS patients with LM disease, revascularization with PCI is feasible and safe, with short-term outcomes comparable to ACS patients without significant LM disease.
J INVASIVE CARDIOL 2018;30(3):98-104.
Key words: left main, acute coronary syndrome, percutaneous coronary intervention, myocardial infarction, coronary artery bypass graft, drug-eluting stent
Around 5%-7% of patients undergoing coronary angiography suffer from unprotected left main (LM) coronary artery disease.1 This condition is of particular clinical importance due to the much larger area of myocardium with compromised blood supply when compared to other coronary lesions. Indeed, depending on the anatomical dominance, around 75%-100% of the left ventricular myocardium is supplied by the LM coronary artery. Hence, a severe stenosis of the LM can lead to life-threatening ischemia, with subsequent left ventricular dysfunction and/or fibrillation.1
As an isolated lesion, LM stenosis occurs in only 6%-9% of patients, while in the majority of cases, it is associated with multivessel coronary artery disease.2 Lesions most frequently occur in the distal segment of the LM and commonly extend distally into the proximal parts of the left anterior descending (LAD) coronary artery and/or circumflex (CX) coronary artery.2
Even after multiple randomized studies comparing coronary artery bypass graft (CABG) surgery with percutaneous coronary intervention (PCI) in this population, the debate regarding optimal revascularization therapy is still ongoing.3-13 Until recently, CABG was considered the gold standard for LM stenosis; however, due to major advances in PCI techniques and stent technologies, PCI has evolved from an experimental approach to a recommended treatment strategy for selected patients. Patients suitable for PCI include those with ostial LM disease, a lower anatomical Syntax score, a high risk for surgery, or those who refuse CABG.1,6,14-16
Overall, outcomes after LM stenting seem to be comparable to CABG as reported by several, but not all trials.6,7,10,11,13,16-19 There seems to be no significant differences in overall major adverse cardiac and cerebrovascular event (MACCE) rates between drug-eluting stent (DES) implantation and CABG, while PCI is associated with higher revascularization rates at follow-up, but lower stroke rates.7,8,17 Furthermore, transradial PCI appears to be non-inferior to CABG in ACS patient presenting with LM disease as regards composite safety outcomes.3 Of note, any outcome after PCI is influenced by multiple anatomical factors, such as the presence of ostial and mid-shaft lesions, which are associated with more favorable clinical and angiographic outcomes, while distal lesions and in particular bifurcation lesions tend to be predictors of repeat revascularization and an overall higher incidence of MACCE after PCI.1,8,20,21
PCI with stenting of the LM is currently endorsed by the latest European Society of Cardiology guidelines as an acceptable revascularization strategy, specifically when the lesion is ostial, mid shaft, and/or the anatomical Syntax score is <22.14 This recommendation is based on the more favorable results achieved with DES implantation, advances in adjunctive tools like intravascular ultrasound and fractional flow reserve (FFR), and the use of more effective antiplatelet agents.16,22
The most recent data come from two large, multicenter, randomized trials, ie, EXCEL19 and NOBLE.23 While NOBLE sought to investigate whether PCI with DES would be non-inferior in regard to clinical outcomes compared to CABG in patients with unprotected LM stenosis, EXCEL focused on the subset of patients with LM disease of low or intermediate anatomical complexity using an everolimus-eluting stent or CABG, respectively. EXCEL confirmed PCI with everolimus-eluting stents to be non-inferior to CABG in patients with LM disease of low or intermediate complexity at 3-year follow-up.19 NOBLE, on the other hand, found that the 5-year estimates of MACCE were significantly higher with PCI as compared to CABG, and concluded that CABG provided a better clinical outcome in LM disease than PCI.
An important aspect that affects outcomes particularly in distal LM lesions is the stenting technique. Both the need for multiple stents and the T-stenting technique were associated with a higher incidence of in-stent restenosis and target-lesion revascularization.24
Randomized controlled trials, such as the ones mentioned above, commonly enroll highly selected patients who only partly reflect real-world practice. In particular, patients presenting with ACS and LM disease have been under-investigated so far. Registries, such as the current study, do provide additional insights into outcomes beyond randomized trials. Hence, we sought to compare short-term outcomes as well as MACCE and NACE at 30 days in an all-comer ACS cohort with protected or unprotected LM disease that were treated percutaneously or surgically and compared these patients to those with non-LM disease in the large, prospective, SPUM-ACS (Swiss Program University Medicine – Acute Coronary Syndromes and Inflammation) cohort.
Study population. The prospective, multicenter SPUM-ACS cohort (ClinicalTrials.gov identifier, NCT01000701) enrolled consecutive patients who were referred for coronary angiography with a diagnosis of ACS to one of the participating Swiss university hospitals (Zürich, Bern, Lausanne, and Geneva) between December 2009 and October 2014.
Inclusion criteria comprised patients of both genders, aged ≥18 years, presenting within 5 days (preferably within 72 hours) after pain onset with a main diagnosis of ST-elevation myocardial infarction (STEMI), non-ST elevation myocardial infarction (NSTEMI), or unstable angina (UA). Enrolled patients had symptoms compatible with angina pectoris (chest pain, dyspnea) and fulfilled at least one of the following criteria: (1) electrocardiographic (ECG) changes, such as persistent ST-segment elevation or depression, T-inversion or dynamic ECG changes or new left bundle-branch block (LBBB); (2) evidence of positive (predominantly conventional) troponin by local laboratory reference values (with a rise and/or fall in serial troponin levels); and/or (3) known coronary artery disease specified by its status after MI, CABG, or PCI, or newly documented ≥50% stenosis of an epicardial coronary artery during the initial catheterization.
Clinical outcome definitions. All-cause mortality included cardiac, vascular, and non-cardiovascular causes of death. Cerebrovascular events comprised stroke (any, ischemic, hemorrhagic, unclear etiology) or transient ischemic attack (TIA). Repeat revascularization included any repeat coronary revascularization (target and non-target vessel). Clinically indicated repeat revascularization included any clinically driven repeat coronary revascularization (target and non-target vessel). Myocardial infarction was defined based on the universal definition including periprocedural MI in patients with UA.
The primary endpoint of our study was adjudicated MACCE (defined as the composite of cardiac death, clinically indicated revascularization, stroke, or MI at 30 days) and adjudicated NACE (defined as the composite of all-cause mortality, cerebrovascular events, any repeat revascularization or MI, or any bleeding at 30 days).
Statistical analysis. Continuous variables are expressed as mean ± standard deviation or median with interquartile range (IQR), and were compared using 1-way ANOVA, Student’s t-test, Kruskal-Wallis, or Mann-Whitney, as appropriate. Categorical data are presented as frequency with percentage, and were compared using the Fisher’s exact test or the Chi-square test.
A propensity score with matching was performed at a 3:1 ratio basis. First, logistic regression analysis for all baseline features that were different according to the presence of LM disease was performed, and then matching was computed after division in quintiles using methods of the nearest available value on the estimated propensity score. All statistical analyses were performed with SPSS 22 and differences were considered significant at α=0.05.
Study population baseline characteristics. Baseline characteristics and risk factors of the entire population are shown in Table 1 and Figure 1. Seventy-one patients (2.0%)out of the 2899 patients presenting with ACS had LM disease (Figure 2). Those with LM disease were significantly older, had a higher incidence of hypertension, and more often had a history of CABG (P<.001), diabetes mellitus (P=.01), chronic obstructive pulmonary disease (P=.01), and malignancy (P<.01). On the other hand, a history of dialysis was more prevalent in the non-LM group (P<.01) (Figure 1).
The groups also differed in their ACS presentation. While more patients with LM disease presented with NSTEMI, the non-LM group more commonly presented with STEMI (P<.01). Lesion and procedural characteristics are described in Supplementary Table S1.
Thirty-day incidence of NACE and MACCE in the entire study population. The 30-day incidence of NACE and MACCE did not differ significantly between the groups (Table 2 and Figure 3), although there was a strong trend toward a higher incidence of MACCE in the LM disease group (P=.05).
Matched population baseline characteristics. Characteristics of the propensity-matched populations based on previously significantly different variables between the two groups are shown in Table 3 and Figure 4. In this analysis, the differences between the LM and non-LM group related to age, diabetes, hypertension, chronic obstructive pulmonary disease, and left ventricular ejection fraction were no longer present. However, a trend toward a higher use of intraaortic balloon pump in the LM group remained, with a borderline P-value of .05.
Thirty-day incidence of NACE and MACCE in the matched population. The analysis of the 30-day incidence of NACE and MACCE in the matched population showed no significant difference between the two groups (Table 4). Interestingly, the initial trend toward a higher incidence of MACCE in the LM group ceased to exist (P=.61).
Revascularization treatment of patients in the LM group. In a subanalysis, patients within the LM group were split in two groups according to the revascularization technique used, ie, PCI (n = 45) or CABG (n = 25), while 1 patient was managed conservatively (Table 5 and Figure 5). The 30-day NACE and MACCE rates, as well as the 30-day incidence of GUSTO moderate bleeding, were compared between the two groups (Table 5 and Figure 6). The NACE rate (6.7% vs 32.0%; P<.01) and GUSTO moderate bleeding rate (2.2% vs 16.0%; P=.05) were significantly higher in patients undergoing CABG vs those treated with PCI.
Tables 1-5; Supplementary Table 1
In the current prospective SPUM-ACS registry, we show that LM revascularization with PCI in a real-world setting of ACS patients is safe and feasible, with comparable short-term outcomes as compared to those without significant LM disease.
While there is extensive evidence on the efficacy and safety of percutaneous coronary revascularization in stable patients with significant LM disease, little is known when it comes to the setting of ACS. Our current prospective cohort included only patients presenting with ACS who were followed up for 30 days with their events adjudicated by an independent committee of experienced cardiologists. In the unmatched population, the preliminary results showed a clear trend toward a higher incidence of adverse cardiovascular events in the LM group. However, it is worth noting that these patients had a significantly higher incidence of prognostically relevant comorbidities, such as diabetes, hypertension, malignancies, and impaired ventricular function, and they were also significantly older at the time of enrollment. Some of these differences in baseline characteristics could be attributed to the fact that LM disease is frequently associated with multiple coronary artery involvement2 and therefore more advanced disease, which could explain the significantly higher prevalence of comorbidities in our patients. As such, not surprisingly, a higher proportion of patients within the LM group had a history of CABG. In line with that, another study comparing sirolimus-eluting stents in unprotected and protected LM disease25 found that those with protected LM disease had more advanced coronary disease than those with unprotected LM disease.25 Surprisingly, this difference did not translate into worse outcomes in those with LM disease, both at short-term and long-term follow-up.
Another interesting finding is the different manifestation of ACS between the two groups. Indeed, while patients with LM disease presented mostly as NSTEMI, those in the non-LM group had a significantly higher proportion of patients presenting as STEMI. This finding could at least in part be related to the fact that patients with an acute LM occlusion are less likely to reach the hospital in a stable condition and are more likely to die suddenly.
As the overall cumulative MACCE and NACE rates in the LM group were 9.9% and 15.5%, respectively, we also sought to identify any differences in outcomes in those treated with primary PCI or by emergency CABG. This subgroup analysis showed no difference in the MACCE rates; however, the overall NACE rate was significantly higher in the CABG group, which was mostly driven by excess bleeding events.
Comparison with other studies. Many studies have focused on the outcome of PCI or CABG in patients with stable (rather than ACS) LM disease.3-8,10,11,13,16-18 While several studies did use anatomical complexity scores (eg, Syntax score or EuroScore), they did not compare patients with and without treatment of the LM. Rather, they focused on the association of outcome of PCI in different clinical settings (eg, ACS, long-term vs short-term outcomes)21,26 or stenting techniques and stent types.24,27 Various anatomical variables, such as lesion complexity, coronary artery dominance, trifurcation morphology, etc,24 were also addressed. However, the study populations commonly consisted only of patients with unprotected LM disease,24 while patients with and without treatment of LM disease were not compared, as was done in the present study. One study of particular relevance to the current study is the j-Cypher registry, which enrolled 12,812 patients (approximately 25%-30% with ACS) and presented 5-year outcomes in patients with and without unprotected LM involvement treated with sirolimus-eluting stents.28 After a follow-up of 5 years, the unadjusted mortality rate after 5 years was significantly higher in patients with unprotected LM stenting than in patients without it;28 however, after adjusting for confounders, no significant difference remained. These results are comparable to what we have found at short-term follow-up after matching the two populations for a vast array of confounding variables and comorbidities. Indeed, the highly significant trend toward higher 30-day MACCE rate in the LM group disappeared after propensity-score matching. Thus, the primary driving factor of MACCE in LM disease must be attributed to the overall sicker population. It is also worth noting that the safety and efficacy of the transradial approach for LM and multivessel stenting in the ACS population seems to be comparable to CABG, as recently reported by Chinese investigators.3
Study limitations. This study is limited by the moderate number of patients in the LM disease group, as well as the absence of data addressing the presence of concomitant multivessel disease (hence, this variable was not included in the matching criteria). In addition, due to the smaller number of patients in the LM group, it was not feasible to divide this entity into protected and unprotected LM disease, although a history of CABG was matched for the entire population.
LM disease in the setting of ACS represents one of the most challenging situations for both interventionists and cardiac surgeons, as such patients commonly present with a large number of comorbidities and therefore fall into a higher-risk category. However, as demonstrated in this real-world cohort, coronary revascularization with PCI of LM disease in the acute setting provides a similar outcome in the short term when compared to a matched population without LM involvement. Furthermore, it appears that PCI is at least comparable to CABG in this setting, with fewer bleeding events.
Acknowledgments. We appreciate the work of the clinical events committee for SPUM-ACS: Matthias Pfisterer, MD, University of Basel (chair), Switzerland; Tiziano Moccetti, MD, CardioCentro Lugano, Switzerland; and Lukas Kappenberger, MD, University of Lausanne, Switzerland. We thank the local study nurses (Anika Adam, Maja Müller, Christa Schönenberger, Therese Fahrni, and Saskia Bühlmann), the central data monitors (Katja Heinimann, Daria Bochenek, and Timon Spörri), the electronic data capturing system (2mt GmbH Ulm, Jürgen Nagler-Ihlein, Torsten Illmann), research coordinator Lambertus J. van Tits, PhD, Sven Trelle, MD, CTU Bern, and the members of the local catheter teams for their invaluable work.
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From the Department of Cardiology, University Heart Center, University Hospital Zurich, Switzerland and Royal Brompton & Harefield Hospital, Imperial College, London, United Kingdom.
ClinicalTrials.gov identifier: NCT01000701
Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Räber reports personal fees from Abbott Vascular, Sanofi, Regeneron, and Biotronik. Dr Roffi reports institutional grants from Boston Scientific, Terumo, Medtronic, Biotronik, and Abbott Vascular. Dr Matter reports grants from the Swiss National Science Foundation, Roche, Eli Lilly, Astra Zeneca, Amgen, MSD, and Sanofi; lecture fees from MSD, Roche, Sanofi, and Amgen. Prof Windecker reports grants to his institution from Biotronik, Boston Scientific, Bracco Pharmaceuticals, Edward Lifesciences, Medtronic, Terumo, and St. Jude Medical. Dr Lüscher reports grants from AstraZeneca, Eli Lilly, Medtronic, Amgen, Abbott Vascular, and Biotronik. The remaining authors report no conflicts of interest regarding the content herein.
Manuscript submitted November 7, 2017, provisional acceptance given November 14, 2017, final version accepted December 4, 2017.
Address for correspondence: Thomas F. Lüscher, MD, FESC, FACC, FRCP, Professor of Cardiology, Royal Brompton & Harefield Hospital, Imperial College, London, SW3 6NP, United Kingdom. Email: email@example.com