The vast majority of the blood supply to the left ventricle is provided by the left main coronary artery (LMCA), and therefore, coronary artery disease (CAD) with stenosis at this anatomical location has a relevant prognostic impact.1 Therefore, an optimal treatment is particularly important and remains challenging. Treatment approaches include coronary artery bypass graft surgery (CABG) and percutaneous coronary intervention (PCI) with stent implantation. Both options are feasible and reasonable in patients with low to intermediate CAD complexity.2,3 Current recommendations from European guideline-writing authorities support the less invasive approach of PCI with DES, provided complete revascularization comparable to that provided by CABG is achieved.2

Very long-term follow-up data (eg, 10 years) from patients treated with PCI and DES implantation for LMCA disease are mostly collected from studies that included patients treated with early-generation DES, while very long-term follow-up data of patients receiving new-generation DES for LMCA disease are lacking. Furthermore, the comparative performance of different generations of DES in patients with LMCA disease included in randomized controlled clinical trials has not been studied.4

In this context, the present study aimed to evaluate the 10-year clinical performance of early- and new-generation DES in patients with LMCA disease by pooling patient-level data from 2 randomized trials in which patients underwent PCI with DES implantation for LMCA disease.

A total of 1,257 patients were included in the ISAR-LEFT MAIN and ISAR-LEFT MAIN 2 trials, of which 650 were treated with new-generation DES and 607 with early-generation DES. Overall, the baseline clinical characteristics were well balanced, and no significant differences were observed regarding age, gender, diabetes, or clinical presentation between the groups. An overview of the clinical characteristics is shown in table 1. In terms of angiographic and procedural parameters, distal left main stenoses were observed more frequently in patients treated with early-generation DES. Provisional stenting was the predominant stenting technique in the new-generation DES group, whereas culotte stenting was performed more often in the early-generation DES group. Further angiographic and procedural details are presented in table 1.

In the new-generation DES group, 96.5% received clopidogrel and 3.5% received prasugrel in addition to aspirin at discharge, while all patients in the early-generation DES group were discharged on aspirin and clopidogrel (P<.001). Compared with patients receiving early-generation DES, patients receiving new-generation DES were less often prescribed statins (90.0% vs 95.4%, P<.001), angiotensin-converting-enzyme inhibitors (76.8% vs 86.3%, P<.001) and beta-blockers (92.5% vs 97.9%, P<.001). Angiotensin-1 blockers were prescribed more often in the new-generation DES group compared with early-generation DES group (16.2% vs 11.9%, P=.04).

The median follow-up of the entire patient cohort was 11.3 [interquartile range 10.0-13.4] years. The 10-year follow-up was not available in 152 patients, and the follow-up duration in these patients was 3.7 [2.9-4.3] years in these patients, with no statistically significant differences between groups.

After 10 years of follow-up, all-cause mortality was 42.7% in patients treated with new-generation DES and 40.5% in those treated with early-generation DES, with a significantly lower risk of all-cause death in patients undergoing implantation of new-generation DES (adjusted HR, 0.78; 95%CI, 0.62-0.97, P=.03). Compared with patients included in the early-generation DES group, those treated with new-generation DES showed a significantly lower risk of TLR (19.6% vs 25.8%, adjusted HR, 0.66; 95%CI, 0.49-0.89, P=.01), definite stent thrombosis (0.8% vs 2.2%, adjusted HR, 0.13; 95%CI, 0.04-0.49, P<.01) and myocardial infarction (4.8% vs 7.0%, adjusted HR, 0.43; 95%CI, 0.23-0.80, P<.01). Of note, compared with early-generation DES, the risk of myocardial infarction was significantly lower within 30 days after PCI with new-generation DES (P=.003) and comparable thereafter (P=.41). Further details of the clinical outcomes are displayed in figure 1 and table 2 and a study summary is presented in figure 2. A subgroup analysis showed no significant interactions regarding mortality, whereas a significant interaction with treatment effect regarding TLR was seen for diabetes, with new-generation DES being more effective in nondiabetics (figure 3).

Figure 1.

Ten-year Kaplan-Meier time to event curves. Clinical outcomes at 10 years in patients with left main coronary artery disease treated with either new-generation drug-eluting stent (NG-DES) or early-generation drug-eluting stent (EG-DES) in terms of (A) all-cause mortality, (B) myocardial infarction, (C) target lesion revascularization, and (D) definite stent thrombosis. Data are shown as Kaplan-Meier event curves, with hazard ratios and 95% confidence intervals.

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Figure 2.

Central illustration. In this analysis, data from the randomized controlled ISAR-LEFT MAIN and ISAR-LEFT MAIN 2 trials were pooled and 10-year clinical follow-up was obtained. A total of 650 patients were treated with new-generation drug-eluting stent (NG-DES) and 607 with early-generation drug-eluting stent (EG-DES). After 10 years, mortality was comparable between patients treated with the new-generation and early-generation DES, while target lesion revascularization and definite stent thrombosis were significantly reduced by new-generation DES. Data are shown as hazard ratios with 95% confidence intervals (95%CI). HR, hazard ratio; PCI, percutaneous coronary intervention. Parts of the central illustration are used and modified from Servier Medical Arts (License: https://creativecommons.org/licenses/by/4.0/).

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Figure 3.

Subgroup analysis. Subgroup analysis of patients who underwent left main stenting with new-generation (NG) or early-generation (EG) drug-eluting stents (DES) regarding (A) all-cause mortality and (B) target lesion revascularization. Data are shown as hazard ratios with 95% confidence intervals (95%CI).

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Recurrent TLR-PCI were less frequent in the new-generation DES group. The majority of patients with recurrent TLR had 1 or 2 events; however, the proportion of patients requiring 3 or more interventions was higher in the early-generation DES group. In the new-generation DES group, stenting was less often used for the treatment of recurrent TLR compared with the early-generation DES group (41.0% vs 54.4%, P=.02). No statistically relevant differences were observed regarding the region of recurrent TLR-PCI. Further details of patients with recurrent TLR-PCI are presented in table 3.

This analysis evaluates the 10-year clinical outcomes of patients treated with either new-generation DES or early-generation DES for LMCA disease. The main findings are: a) at 10-year follow-up, mortality after PCI with DES for LMCA disease was high regardless of DES-generation; however, the risk of death in patients treated with new-generation DES was lower than that in patients receiving early-generation DES; b) compared with early-generation DES, PCI with new-generation DES for LMCA disease was associated with a lower risk of myocardial infarction, TLR, and definite stent thrombosis; and c) recurrent TLR events were more frequent after PCI with implantation of early-generation DES for LMCA disease.

Overall, randomized trials with very long follow-up data after PCI for LMCA disease are limited, and only data on the use of early-generation DES are available. To our knowledge, the present analysis is the first report of very long-term data after PCI for LMCA disease that includes new-generation DES. The results of this analysis require careful discussion.

In the MAIN-COMPARE registry, a total of 778 patients underwent PCI with 2 early-generation DES platforms for LMCA disease. After 10-year follow-up, there was no significant difference in clinical performance between DES platforms.4 In the present study, we demonstrated a lower risk of death with new-generation DES compared with early-generation DES for LMCA disease, an observation that has already been reported in other CAD locations.7 It is noteworthy that the overall mortality of PCI patients reported in the current analysis is approximately 40% and is likely attributable to the enrollment of an older population with a higher EuroSCORE compared with previous studies dealing with patients presenting with LMCA disease.4,8,9

The lower incidence of TLR and definite stent thrombosis at 10 years in the new-generation DES group compared with the early-generation DES group has repeatedly been documented in other studies in a wide range of coronary anatomies treated with PCI. In the randomized Intracoronary Stenting and Angiographic Results: Test Efficacy of 3 Limus-Eluting Stents (ISAR-TEST-4) trial, 2603 patients with various CAD locations were randomized to receive either a new-generation DES or an early-generation DES.7 After 10 years, the incidences of major adverse cardiac events and definite stent thrombosis were significantly higher in the early-generation DES group as compared with the new-generation DES group. In addition, higher rates of TLR were observed when comparing new-generation DES with early-generation DES.7 Consistently, the 10-year outcomes from the Randomized Evaluation of Sirolimus-Eluting vs Everolimus-Eluting Stent Trial (RESET) also show lower rates of target lesion and vessel failure for new-generation DES compared with early-generation DES and the rate of stent thrombosis was also numerically lower in the new-generation DES group.10 Another analysis from a cohort of 12 339 patients who underwent unrestricted DES implantation showed lower rates of very late stent thrombosis with new-generation DES compared with early-generation DES.11 Finally, findings from the Swedish Coronary Angiography and Angioplasty Registry (SCAAR) also confirmed lower rates of failure with new-generation DES compared with early-generation DES in 94 384 patients.12

The lower risk of myocardial infarction through to 10 years, observed with new-generation DES compared with early-generation DES in the current analysis, is consistent with a previous observation from the same cohort,13 and was predominantly due to a lower risk of myocardial infarction in the first 30 days after PCI with new-generation DES. This result may be related, at least in part, to the predominance of the single-stenting strategy in the new-generation DES group, which has been associated with better outcomes, including lower rates of periprocedural myocardial infarction.14 However, the lower risk of definite stent thrombosis over 10 years in patients receiving new-generation DES compared with early-generation DES should also be recognized.

Of interest, the current analysis reported significantly more recurrent TLR events in the early-generation DES group than in the new-generation DES group. This finding is of clinical relevance and is a unique feature of this report. In fact, only limited data are available on recurrent TLR events in patients undergoing PCI with DES, and dedicated data on LMCA disease are missing.15–17 An explanation for this observation could be that the Kaplan-Meier method, most commonly used in clinical trials to calculate the rates of clinical events, censors recurrent events. Additionally, the follow-up phase is often limited to a relatively short period. Notably, compared with the early-generation DES group, recurrent TLR events in the new-generation DES group were more often treated with drug-coated balloon, which might reflect the growing use of drug-coated balloons for DES failure over time. However, the optimal treatment of these patients remains unclear, although data support the use of both DES and drug-coated balloon angioplasty in this setting.16

In the present analysis of the ISAR-LEFT-MAIN and ISAR-LEFT MAIN 2 trials, the overall mortality after stenting of the LMCA was high, irrespective of the implanted stent type. After 10 years of follow-up, patients treated with new-generation DES showed lower rates of TLR and stent thrombosis compared with patients treated with early-generation DES.

None.

All patients received and signed a written informed consent form to participate in the study. Both trials were conducted in accordance with the provisions of the Declaration of Helsinki and the International Conference on Harmonisation Good Clinical Practices. The protocol was approved by the medical ethics committee for all participating centers. A further vote by the ethics committee was obtained for the evaluation of the 10-year clinical follow-up, as this post hoc analysis was not part of the initial protocols of the included trials. According to SAGER guidelines, gender was included as a variable for adjustment, but this study does not contain a gender-specific analysis. This information was added to the limitations section.

No artificial intelligence was used in the preparation of this study.

J. Wiebe reports speaker fees from Abbott Vascular, AstraZeneca, and Translumina, as well as an institutional research grant from Abbott Vascular. C. Kuna has received speaker fees from AstraZeneca. S. Kufner reports speaker and consulting fees from AstraZeneca, Bristol Myers Squibb, and Bentley, as well as speaker fees from Abbott, Boehringer Ingelheim, and Translumina, and a research grant from Bentley, not related to the current work. H. Schunkert received consulting fees from AMGEN, AstraZeneca, Boehringer Ingelheim, Daiichi-Sankyo, and Servier; speaker fees from AstraZeneca, Bayer Vital, Novartis, Servier, Sanofi-Aventis, Synlab, Bristol Myers Squibb, and AMARIN; and a research grant from AstraZeneca, St. Jude, and Boston Scientific. All other authors have no conflicts of interest to declare.

All authors substantially contributed to the conception or design of the work or the acquisition, analysis, or interpretation of the data for the work. J. Wiebe, A. Kastrati, and S. Cassese drafted the work and all authors revised it critically for important intellectual content. All authors approved the submitted version to be published. All authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.