Author + information
- Received September 16, 2015
- Revision received October 14, 2015
- Accepted October 24, 2015
- Published online February 22, 2016.
- Pawel E. Buszman, MD, PhDa,b,
- Piotr P. Buszman, MD, PhDa,c,∗ (, )
- Iwona Banasiewicz-Szkróbka, MD, PhDa,
- Krzysztof P. Milewski, MD, PhDa,
- Aleksander Żurakowski, MD, PhDa,
- Bartłomiej Orlik, MD, PhDa,
- Magda Konkolewska, MDa,
- Błażej Trela, MDa,
- Adam Janas, MDa,
- Jack L. Martin, MDd,
- R. Stefan Kiesz, MDe and
- Andrzej Bochenek, MD, PhDa,b
- aAmerican Heart of Poland, Center for Cardiovascular Research and Development, Katowice, Poland
- bMedical University of Silesia, Katowice, Poland
- cIIIrd Clinical Department of Cardiology of Medical University of Silesia, Silesian Center for Heart Diseases, Zabrze, Poland
- dUniversity of Texas Health Sciences, San Antonio, Texas
- eSharpe Strumia Research Foundation, Bryn Mawr, Pennsylvania
- ↵∗Reprint requests and correspondence:
Dr. Piotr P. Buszman, Center for Cardiovascular Research and Development, American Heart of Poland Inc., 41 Czajek Strasse, Katowice 40-761, Poland.
Objectives This study has reported 10-year clinical follow-up of patients enrolled in the prospective, randomized LE MANS (Left Main Stenting) trial.
Background The very long-term outcome after left main stenting in comparison with surgical revascularization remains unknown.
Methods In this prospective, multicenter trial, we randomly assigned 105 patients with unprotected left main coronary artery stenosis with low and medium complexity of coexisting coronary artery disease according to SYNTAX (Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery) score to percutaneous coronary intervention (PCI) with stenting (n = 52) or coronary artery bypass grafting (CABG) (n = 53). Drug-eluting stents were implanted in 35%, whereas arterial grafts to the left anterior descending artery were utilized in 81%. Currently, the mean long-term follow-up was collected at 9.8 ± 1.0 years. Follow up for all-cause mortality is complete, whereas the incidence of major adverse cardiovascular and cerebral events (MACCE) was reported from 90% of patients. Ambulatory follow-up was completed in 46 (43.9%) patients.
Results At 10 years, there was a trend toward higher ejection fraction in stenting when compared with surgery (54.9 ± 8.3% vs. 49.8 ± 10.3%; p = 0.07). The mortality (21.6% vs. 30.2%; p = 0.41) and MACCE (51.1% vs. 64.4%; p = 0.28) were statistically not different between groups; however, numerically the difference was in favor of stenting. Similarly, there was no difference in the occurrence of myocardial infarction (8.7 vs. 10.4%; p = 0.62), stroke (4.3 vs. 6.3%; p = 0.68), and repeated revascularization rates (26.1% vs. 31.3%; p = 0.64). The probability of very long-term survival up to 14 years was comparable between PCI and CABG (74.2% vs. 67.5%; p = 0.34; hazard ratio: 1.45, 95% confidence interval: 0.67 to 3.13); however, there was a trend toward higher MACCE-free survival in the PCI group (34.7% vs. 22.1%; p = 0.06; hazard ratio: 1.71, 95% confidence interval: 0.97 to 2.99).
Conclusions In patients with unprotected left main coronary artery stenosis with low and medium complexity of coexisting coronary artery disease, stenting offers numerically, but statistically nonsignificant, favorable long-term outcome up to 10 years in terms of safety and efficacy outcome measures, therefore, constitutes an alternative therapy for CABG.
For more than a decade, left main stenting has completed a rough clinical and investigational route from an experimental and controversial treatment up to a recommended revascularization strategy in a certain subset of patients (1,2). More importantly, left main stenting has been adopted before in clinical routine practice as a response to previously published landmark randomized trials, which reported at least a comparable outcome when compared with coronary artery bypass revascularization (CABG) with regard to safety outcomes such as survival, incidence of myocardial infarction, or stroke (3–6). Furthermore, it has been commonly used in patients who are not eligible or who refuse CABG. This immense progress was possible due to technological refinements such as introduction of bare-metal stents (BMS) and first- and second-generation drug-eluting stents (DES), intravascular imaging techniques, growing experience of operators, as well as heart team referrals. Although many aspects of left main stenting have been extensively investigated, a few questions remain to be answered. The outcome of left main stenting with second-generation DES in comparison with CABG will be definitively addressed in the EXCEL (Evaluation of XIENCE PRIME Everolimus Eluting Stent System [EECSS] or XIENCE V EECSS or XIENCE Xpedition EECSS or XIENCE PRO EECSS Versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization) trial (NCT01205776). In the current study, for the first time, we report very long clinical and ambulatory 10-year outcome of patients included in the LE MANS (Left Main Coronary Artery Stenting) trial, in which left main percutaneous and surgical revascularization were first compared nearly a decade ago (4).
Study design, protocol, and 1-year results were reported previously (4). Briefly, we enrolled 105 patients with at least 50% diameter stenosis of the unprotected left main coronary artery (ULMCA), with or without multivessel coronary artery disease, eligible for equal revascularization both with percutaneous coronary intervention (PCI) and CABG. All patients had to be symptomatic with documented myocardial ischemia. Exclusion criteria included acute myocardial infarction, total occlusion of the left main, comorbid conditions or coronary anatomic considerations that increased the surgical risk to a EuroSCORE of 8 or more, stroke or transient ischemic attack within 3 months, renal dysfunction, or contraindication to antiplatelet therapy.
On the basis of a joint decision by the lead interventional and surgical investigators, 122 patients were suitable for both procedures; 105 gave consent and were randomized to either PCI (n = 52) or CABG (n = 53). Both groups were comparable with regard to basic clinical and angiographic characteristics. All randomized patients underwent their assigned therapy (no crossovers).
Left main stenting was performed according to the previously reported LE MANS protocol (7). Direct stenting of the left main was a preferred strategy except for cases with critical luminal narrowing, for which pre-dilation was performed with small balloons (2.0 to 2.5 mm). For distal left main stenosis, stenting across the bifurcation toward the left anterior descending was performed first, and then provisional stenting of the circumflex artery with T-stenting or “culottes” technique was preferred. The crush stent technique was avoided. Post-dilation with kissing balloon angioplasty was always used to finish the distal left main stenting procedure. DES were used for the left main with a reference diameter <3.8 mm, and BMS were implanted if the left main reference diameter was ≥3.8 mm. On the basis of these criteria, the left main was treated with DES in 35% of PCI patients. Stent length and diameter were selected on the basis of online quantitative coronary angiography (balloon to artery ratio 1:1.1) and post-dilated at high pressure (at least 16 atm). A control intravascular ultrasound was recommended to assess the final results.
Operations were performed using standard anesthetic techniques. All but 1 operation were performed through a median sternotomy, with standard cardiopulmonary bypass and moderate systemic hypothermia. One patient underwent off-pump CABG. Left internal mammary artery grafts were used in 72% of CABG patients, and radial artery grafts were used in 9%.
Follow-up and data collection
A detailed follow-up schematic is presented in Figure 1. Follow up data on all-cause mortality were obtained from the National Health System registry, which guarantees complete data collection. Follow-up on major adverse cardiovascular events, including myocardial infarction, stroke, and repeated revascularization either with PCI or CABG, was obtained either by telephone conversation or ambulatory visit and confirmed with data available from the National Health Fund as well as hospitalization discharge files in cases of an adverse event.
Study endpoints and definitions
The primary endpoint of the LE MANS trial was left ventricular ejection fraction (LVEF) assessed by 2-dimensional echocardiography at 1 year.
At 10-year follow-up, the secondary endpoints included major adverse cardiovascular and cerebral events (MACCE). Angina severity according to the Canadian Cardiovascular Society classification and heart failure according to New York Heart Association functional class were also assessed. MACCE included total mortality, myocardial infarction, target vessel revascularization, and stroke. Target vessel revascularization was defined as any repeat intervention (PCI or CABG) caused by a narrowing of the stented ULMCA.
All clinical outcomes were analyzed by the clinical events committee. Echocardiographic and stress test recordings were read centrally by a group of independent investigators unaware of treatment assignment. LVEF was assessed according to the recommendations of the American Society of Echocardiography, on the basis of the Simpson method of left ventricular volume measurement and second harmonic imaging (8). Reproducibility for 2-dimensional echocardiography recordings and measurements of LVEF calculated as a coefficient of variance ranged between 3.6% and 4.0%.
All analyses were performed according to the intention-to-treat principle. The data with parametric distribution were expressed as mean ± SD, whereas nonparametric data were expressed as absolute numbers and percentage. Moreover, 95% confidence intervals (CIs) and hazard ratios (HRs) for results of the primary endpoint and selected secondary endpoints were calculated.
The parametric variables between the groups were compared using the unpaired Student t test. The repeated measures analysis of variance (ANOVA) and Newman-Keuls tests were used for comparison of the parametric data between and within the 2 groups at different time points if the Shapiro-Wilk test showed normal distribution of variables and the Levene test showed homogeneity of variances. For parametric data not fulfilling this criteria, the Wilcoxon rank sum test was used to compare the variables within the group at different time points and the Mann-Whitney U test to compare variables between the groups at the same time points. The analysis of variance Friedman test was used to compare rank variables of different time points and the Mann-Whitney U test to compare variables between the groups at the same time points. The chi-square test or Fisher exact test was used for comparison of nonparametric variables. Survival curves were drawn using Kaplan-Meier analysis. The F-Cox test was used for comparison of the survival curves between the treatment arms.
Follow-up and data collection
The detailed study flowchart is presented in Figure 1 and the clinical baseline characteristics in Table 1. The data on all-cause mortality were available from all patients and confirmed by the National Health Fund. The follow-up on the incidence of MACCE was collected from 45 patients in PCI group (87%) and 48 patients in the CABG group (90.5%). Therefore, 7 patients in the PCI and 5 in the CABG group were lost to a detailed follow-up on MACCE due to lack of contact. It must be stressed that on the basis of the National Health Fund data, patients who were lost to MACCE follow-up were definitely alive. A total of 23 patients in each group, constituting 57% of the survivors in the PCI group and 62% of survivors in the CABG group, underwent ambulatory follow-up. The remaining patients (22 in the PCI and 25 in the CABG group) were contacted, but either refused or did not present at ambulatory follow-up.
Left ventricle ejection fraction
The control echocardiography was acquired in 23 patients in each group. The mean LVEF values at baseline, 12 months, and 10 years are presented in Figure 2, and the comparison of LVEF in categories is presented in Table 2. At 10 years, the ejection fraction tended to be higher after stenting when compared with surgery (54.9 ± 8.3% vs. 49.8 ± 10.3%; p = 0.07), and was similar to baseline values (mean difference: +0.53%, 95% CI: −7.72% to 6.67%, F = 0.23; p = 0.86). On the other hand, in the CABG group, a numerical, nonsignificant decrease in EF was reported (mean difference: −3.36%, 95% CI: −11.3% to 4.6%, F = 0.72; p = 0.48). The LVEF decreased similarly beyond 1 year in both groups; therefore, the final difference was driven by the previously reported 1-year benefit in PCI group.
Major adverse cardiovascular and cerebral events
The MACCE incidence at 10-year follow-up and between-group comparison is shown in Figure 3, whereas the very long-term MACCE-free survival Kaplan-Meier estimates are presented in Figure 4. The incidence of MACCE was numerically lower in the PCI group, although not significantly. However, there was a trend toward higher very long-term MACCE-free survival in the percutaneous revascularization group (HR: 1.57; 95% CI: 0.90 to 2.73; p = 0.10). There was also a nonsignificant reduction in mortality in the PCI group when compared with surgical revascularization. The comparison of survival curves (Figure 5A⇓) showed a tendency toward improved survival in the stenting group when compared with CABG, but it was not statistically significant (HR: 1.55; 95% CI: 0.71 to 3.39; p = 0.26).
The incidence of myocardial infarction and long-term myocardial infarction–free survival (Figure 5B), although numerically in favor of stenting, was not statistically different between the study groups (HR: 1.14; 95% CI: 0.30 to 4.25; p = 0.83). The results were similar with regard to the incidence of cerebrovascular accidents such as stroke and transient ischemic attack (HR: 2.85; 95% CI: 0.40 to 20.4; p = 0.29) (Figure 5C). Interestingly, the rate of repeated revascularizations was comparable between groups (HR: 1.34; 95% CI: 0.61 to 2.95; p = 0.46) driven mostly by increase in those events in CABG group beyond 2-year follow-up (Figure 5D).
There were no cases of definite, 2 cases of probable, and 1 of possible very late stent thrombosis according to the Academic Research Consortium definition (9).
Angina functional class
At 10 years, the angina class was low to moderate and comparable between the revascularization strategies (1.7 ± 0.9 vs. 1.59 ± 0.8; p = 0.64). Both procedures offered similar and durable angina relief up to 10 years (PCI mean difference: −1.57; 95% CI: −2.22 to −0.91; F = 18.7; p < 0.01; CABG mean difference: 0.96; 95% CI: −1.65 to −0.27; F = 26.9; p < 0.01). There was no difference in angina between 1 and 10-year follow-up in the stenting group (mean difference: +0.17; 95% CI: −0.39 to 0.72; p = 1.0). In contrast, there was a trend toward increase in angina scale in the CABG group between 1 and 10-year follow-up (mean difference +0.73; 95% CI: −0.06 to 1.53; p = 0.08) (Figure 6).
The details on concomitant pharmacotherapy are presented in Table 3. At 10-year follow-up, there was no difference with regard to therapeutic regimen between the groups. The adherence to low-dose aspirin, beta-blockers, angiotensin inhibition, and statin therapy was high in both groups.
In the current study, we report 10-year outcomes of the LE MANS study, the first prospective trial that randomly evaluated left main stenting and coronary bypass surgery for unprotected left main stenosis with low and medium complexity of coexisting coronary artery disease according to SYNTAX (Synergy Between Percutaneous Coronary Intervention With Taxus And Cardiac Surgery) score (4). Furthermore, this is the longest outcome reported after random assignment of left main revascularization strategies.
At very long-term follow-up, there was a trend toward improved LVEF in the stenting group, which initially was the primary endpoint of this study. This result is consistent with the 1-year follow-up; however, due to a lower number of patients eligible for the follow-up (mortality, no response, or no show) the statistical significance was not reached. Importantly, the LVEF in the stenting group was preserved at 10 years, thus highlighting the durability of the PCI procedure. Most probably, this outcome translated into a tendency toward improved MACCE-free survival and numerically, although not statistically, significantly higher survival in the stenting group. Both strategies offered very good long-term outcome, reaching nearly 70% and 80% survival in the surgical and percutaneous group, respectively. Interestingly, there was no difference in the incidence of myocardial infarction as well as repeated revascularization rates.
The follow-up methodology involved a combination of patient ambulatory visits, phone call check-ups, and most importantly, validation with National Health Fund data; this data guarantees completeness of follow-up regarding mortality and confirmation of incidence of major adverse events, which resulted in 7 patients lost to contact in the PCI and 5 in the CABG group. It must be highlighted that at the time of follow-up, these patients were alive according to the National Health Fund data. More than one-half of surviving patients underwent an ambulatory visit; the missing ones were either not contacted (7 in PCI and 5 in CABG) or refused ambulatory visit (10 in PCI and 9 in CABG) due to good general condition or distance required for travel. Therefore, we believe that the completeness of follow-up obtained in this study is satisfactory and similar to other randomized studies that reported 10-year follow-up rates (10,11).
The only available data showing probability of 10-year survival and MACCE-free survival were reported in the LE MANS registry, in which 10-year survival after left main stenting was nearly 70%. It must be highlighted that the overall cohort included a wide spectrum of coronary disease as well as acute coronary syndromes (7). Patients in the MAIN-COMPARE (Revascularization for Unprotected Left Main Coronary Artery Stenosis: Comparison of Percutaneous Coronary Angioplasty Versus Surgical Revascularization) registry (12), who received BMS for left main with less complex coronary artery disease, showed a 10-year survival probability at 83.1%, which is nearly identical to the current report.
The positive results for left main stenting, although unanticipated especially with high penetration of BMS, can be explained by 2 facts. Although the SYNTAX score was unknown more than a decade ago, our study from the beginning included only patients with low and moderate complexity of disease suitable for revascularization both with PCI and CABG as established by the heart team. In the post hoc analysis of coronary angiographies, all patients’ SYNTAX scores have fallen into the range of 0 to 32 (mean 25.2). Therefore, a closer look into the published data, and especially recently published 5-year outcomes of the left main cohort of the SYNTAX trial (13), may help to understand and rationalize this outcome. In the subset of patients with left main stenosis and low to moderate complexity of concomitant coronary artery disease as evidenced by SYNTAX score <32, the risk of mortality was nearly halved in the PCI group when compared with CABG and was very similar to mortality reported in our trial at 5 years. The HRs of the cumulative incidence of MACCE, cerebrovascular incidence, and most interestingly, rates of repeated revascularization were nearly identical to the those reported in the current study. Contrary to our study, higher repeated revascularization rates after stenting with DES were reported both in randomized trials and meta-analyses, including the complete cohort of the SYNTAX trial (13–16). These studies, however, involved the wide spectrum of coronary artery disease complexity. Interestingly, in the current study, repeated revascularization was more frequent in CABG than in PCI beyond 5 years; therefore, we look forward to observing a similar trend in large randomized studies. We believe that comparison of revascularization rates beyond 5 years after PCI and CABG should attract the attention of large randomized trial investigators. Additionally, in our study, at 10 years, the stroke incidence was similar between PCI and CABG. This result is divergent with the SYNTAX trial, in which a higher rate of cerebrovascular events was observed after CABG. On the other hand, our result is consistent with the 5-year follow-up of the PRECOMBAT (Bypass Surgery Versus Angioplasty Using Sirolimus-Eluting Stent in Patients With Left Main Coronary Artery Disease) trial (17).
There are several advantages of this report. First, as previously mentioned, this is the longest observation of patients who underwent randomization to left main stenting and surgical revascularization. Second, the follow-up data were recorded prospectively under quality assurance, and the completeness of follow-up on mortality and MACCE is guaranteed by the National Health Fund.
The main limitation of our study is the relatively small number of randomized patients. This limitation has been widely discussed in the original paper. This is related to the fact that surgical revascularization a decade ago was considered the treatment of choice for patients with severe narrowing of ULMCA, and the local bioethical committee disapproved the larger sample size. Therefore, a pre-specified number of patients had to be randomized to show the advantage of left main stenting for improvement of left ventricular function. Because of the size of this study and low statistical power, it must be considered hypothesis-generating rather than offering a definitive answer. In the PCI group, first-generation DES and BMS were used only, whereas in the surgical arm, the left internal mammary artery was used only in 73% of patients, which was a standard of care at the time of randomization. Additionally, low ambulatory follow-up was mainly caused by high mortality at 10 years in both treatment groups.
Our 15-year experience with left main stenting reflects its continuous progress. First, we demonstrated significant reduction of angina, improvement of left ventricular systolic function, and preservation of exercise capacity at 1- and 5-year follow-up (7,18). Second, we provided evidence for superiority of ULMCA stenting over CABG in terms of restoring LVEF along with a trend for better survival (4) in patients with low and moderate complexity of coronary disease. In the current study, we establish very long-term durability of left main stenting in terms of LVEF preservation and equivalency to coronary bypass grafting with regard to occurrence of major adverse cardiac events.
WHAT IS KNOWN? Left main stenting is a safe and feasible procedure. At 5 years in subgroups with low and medium complexity of coexisting coronary artery disease, the incidence of death and myocardial infarction is at least similar to bypass surgery; however, the incidence of cerebrovascular events is lower.
WHAT IS NEW? This is the longest observation (10 years) of patients who underwent randomization to left main stenting and surgical revascularization. At 10 years, there were no differences in the incidence of MACCE, including stroke and repeated revascularization rates.
WHAT IS NEXT? A definitive, statistically-powered trial showing noninferiority of PCI and CABG in patients with left main disease and low and medium complexity of coexisting coronary artery disease, with results extending to 5-year follow-up is required.
The authors have reported that they have no relationships related to the contents of this paper to disclose.
- Abbreviations and Acronyms
- bare-metal stent(s)
- coronary artery bypass grafting
- drug-eluting stent(s)
- left ventricular ejection fraction
- major adverse cardiac and cerebrovascular event(s)
- percutaneous coronary intervention
- unprotected left main coronary artery
- Received September 16, 2015.
- Revision received October 14, 2015.
- Accepted October 24, 2015.
- 2016 American College of Cardiology Foundation
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