Background: Coronary artery disease (CAD) is becoming increasingly prevalent in aging populations. Long-diffuse CAD (ldCAD), characterized by lesions ≥30 mm, poses significant treatment challenges. This study aimed to evaluate the long-term prognostic differences between single long stents (SLS) and overlapping stents (OLS) in patients with ldCAD using second-generation and later drug-eluting stents (DES).

Methods and Results: A systematic review and meta-analysis of studies published between 2000 and October 2024 in PubMed, Embase, Web of Science, and the Cochrane Library was conducted. The primary outcome was major adverse cardiovascular events (MACE) over 1 year. The secondary outcomes were cardiac death, target lesion revascularization, target vessel revascularization (TVR), and fatal or non-fatal myocardial infarction (MI). The analysis included 5 studies with 2,756 patients, indicating no significant differences between SLS and OLS regarding MACE and TVR. However, MI incidence was significantly lower with SLS, whereas OLS showed a higher MI incidence, likely due to differences in lesion length rather than the strategy itself. Subanalyses indicated that SLS significantly reduced contrast volume compared with OLS, with a trend toward shorter lesions and stent lengths.

Conclusions: Stent overlap has minimal impact on prognosis with newer DES. Despite limitations from non-randomized data, further research is needed to optimize ldCAD treatment strategies and guide clinical practice.

Coronary artery disease (CAD) becomes increasingly common with aging populations. The total number of patients with CAD in Japan is 720,000,¹ while that in the United States is 20.5 million.² Diffuse CAD was defined as a lesion measuring >20 mm³ or covering ≥75% of the coronary artery section.⁴ However, as the population ages, lesions exceeding 60 mm have become increasingly common,⁵ and treating long-diffused CAD (ldCAD) that is longer than the conventional threshold of ≥25 mm⁶ or ≥30 mm is becoming more frequent.⁷

ldCAD is initially treated with optimal medical therapy; however, if symptoms do not improve or if they worsen, revascularization becomes an option.⁸ Revascularization of ldCAD includes coronary artery bypass grafting (CABG) and percutaneous coronary artery intervention (PCI). However, treating ldCAD using either method is challenging due to lesion calcification and tortuosity.⁹ Guidelines recommend CABG for the treatment of ldCAD,^4,10 as it is associated with a low rate of major adverse cardiac events (MACE), incomplete revascularization, and superior long-term prognosis.¹¹ However, due to the high invasiveness of CABG, it may not be feasible in older patients or in those with comorbidities. Therefore, the demand for less invasive PCI is increasing in aging societies of the developing world. Even in ldCAD, PCI can potentially be performed safely and effectively when appropriate strategies are used.¹²

Drug-eluting stent (DES) implantation during PCI is fundamental for the treatment of ldCAD. The most common stent placement method is overlapping stenting (OLS), in which a short DES overlaps and covers the entire length of the ldCAD lesion. However, due to its high metal loading, stent fracture, and incomplete stent apposition, OLS may compromise angiography and long-term clinical outcomes, including death, myocardial infarction (MI), and stent thrombosis.^13,14

Treatment with a single long stent (SLS) ≥48 mm has been introduced to eliminate the overlapping area.^15,16 A meta-analysis comparing the outcomes of OLS and SLS indicated that SLS reduced the incidence of cardiac death and target lesion revascularization (TLR) compared with that in response to OLS; however, this analysis included bare-metal stents (BMS) and first-generation DES that are no longer in use.¹⁷ Recent comparative studies have reported no significant differences in the outcomes between SLS and OLS.¹⁸ Therefore, this study clarifies the long-term prognostic differences between SLS and OLS, focusing exclusively on second-generation and later DES while excluding BMS and first-generation DES in patients with long diffuse CAD ≥30 mm through systematic review and meta-analysis.

This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.¹⁹ The PRISMA checklist for Systematic Reviews and Meta-Analyses was used. We systematically searched the PubMed, Embase, Web of Science, and Cochrane Library databases for articles published between January 1, 2000 and October 1, 2024. The key search terms included ‘long coronary lesion OR long coronary stenosis OR diffuse coronary artery disease OR small coronary artery AND PCI OR percutaneous coronary intervention OR PTCA OR percutaneous transluminal coronary angioplasty OR DES OR drug-eluting stent OR SLS OR single long stent OR OLS OR overlapping stents’.

Target studies were limited to adult patients aged ≥18 years with ldCAD (lesion length ≥30 mm) and included at least 1 year of clinical follow up. The 2 treatment strategies included: (1) OLS treatment of the entire lesion by overlapping 2 or more stents; and (2) SLS treatment. Studies comparing ldCAD treatment strategies using these 2 methods were eligible for inclusion. Exclusions were made for studies focusing solely on populations with conditions that could significantly impact outcomes (e.g., trials that included only patients with diabetes or those undergoing hemodialysis), those that included BMS or first-generation DES, and those that were not written in English. In cases of multiple publications with the same population, we included a study that provided detailed data for 1 year.

Two reviewers (M.I., K.H.) independently evaluated the eligibility and quality of the trials and extracted the relevant data. The senior author (K.I.) was contacted if the data required completion or clarification. Data from the final list of studies retained after the full-text review were extracted and crosschecked by both authors for consistency.

Quality was evaluated using the Cochrane Collaboration tool to assess the risk of bias in the randomized studies.²⁰ Cohort studies were evaluated for quality using the Newcastle-Ottawa scale.²¹ To assess the strength of evidence for each outcome, we used the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) approach (Supplementary Table). Publication bias was evaluated by visually inspecting the funnel plots (Supplementary Figure). The extracted data included baseline clinical characteristics, diffuse coronary artery lesion length, clinical follow-up length, and stent generation or name.

The primary outcome was major adverse cardiovascular events (MACEs) over 1 year, defined as cardiac death, non-fatal MI, and revascularization. MI was defined based on elevated cardiac enzyme levels. The secondary outcomes were cardiac death, TLR, target vessel revascularization (TVR), and fatal or non-fatal MI within 1 year.

RevMan 5.4 was selected as the meta-analysis software for this research. The standardized or weighted mean differences were used for continuous variables, whereas 95% confidence intervals (CIs) aligned with odds ratios (OR) were applied for dichotomous variables. Heterogeneity was evaluated using forest plots and I² statistics, where values <25%, between 25% and 50%, and >50% represented low, moderate, and high degrees of heterogeneity, respectively.

The search yielded 6,123 results, of which 80 were considered potentially eligible for inclusion. Five studies^{7,15,18,22,23} were included in the analysis, none of which were randomized controlled trials (RCTs). Figure 1 presents a flowchart of the study design and the reasons for exclusion. Funnel plots showed no publication bias (Supplementary Figure).

Figure 1.

Flow diagram of the search for published studies. BMS, bare-metal stent; DES, drug-eluting stent.

The analysis included 2,756 patients with ldCAD treated using the 2 PCI strategies, where 1,753 and 1,003 patients were treated with SLS and OLS, respectively. The median follow-up period was 12 months (interquartile range 12–24 months). The mean length of the coronary artery lesions was 43.67±0.04 mm, and the mean age of the included patients was 73.19±0.05 years. Additionally, 68.07%, 36.8%, and 39.2% of the patients were male, had diabetes, and exhibited a history of smoking, respectively. The baseline patient characteristics are presented in Table 1. The follow-up durations and incidence rates of MACE, cardiac death, TLR, and MI in each study are presented in Table 2.

No significant differences were observed between SLS and OLS for MACE (OR=0.89; 95% CI [0.58, 1.37]; P=0.6) and low heterogeneity (I²=25%; P=0.25). Significant differences were also not observed in cardiac death (OR=0.71; 95% CI [0.33, 1.53]; P=0.38; I²=11%; P=0.34), TLR (OR=0.88; 95% CI [0.48, 1.59]; P=0.67; I²=0%; P=0.93), and TVR (OR=0.80; 95% CI [0.49, 1.59]; P=0.36; I²=0%; P=0.86). However, a significant difference was observed for MI (OR=0.72; 95% CI [0.72, 0.99]; P=0.04; I²=0%; P=0.89; Figure 2). A subanalysis evaluated the lesion length, total stent length, and contrast volume. The contrast volume was significantly higher in the OLS group than it was in the SLS group. However, heterogeneity was significantly higher in the total stent length and contrast volume analyses (total stent length I²=95%, P<0.00001; contrast volume I²=100%, P<0.00001). No significant differences were observed in lesion length (MD=−10.53; 95% CI [−22.26, 1.2]; P=0.08) or total stent length (MD=−15.26; 95% CI [−34.02, 3.51]; P=0.11). Nevertheless, the heterogeneity was significantly higher for both lesion lengths (I²=100%; P<0.00001). Due to the high heterogeneity, a potential for bias was likely in the subanalysis. However, SLS was significantly associated with reduced contrast agent usage compared with that for OLS, and there was a tendency for shorter lesions and total stent lengths in SLS (Figure 3).

Figure 2.

Forest plot of the meta-analysis of SLS vs. OLS. (A) Major adverse cardiac events (MACE). (B) Cardiac death. (C) Myocardial infarction (MI). (D) Target lesion revascularization (TLR). (E) Target vessel revascularization (TVR). CI, confidence interval; OLS, overlapping stent; OR, odds ratio; SLS, single long stent.

Figure 3.

Forest plot of meta-analysis of SLS vs. OLS. (A) Lesion length. (B) Total stent length. (C) Contrast volume. CI, confidence interval; OLS, overlapping stent; OR, odds ratio; SLS, single long stent.

We performed a meta-analysis to investigate the efficacy of DES for managing ldCAD measuring ≥30 mm. The main findings were as follows: (1) no significant difference in MACE was noted between SLS and OLS; (2) no significant difference in TLR or cardiac death was observed, contrasting with the findings of a previous meta-analysis that included BMS;¹⁷ (3) the incidence of MI was significantly higher in OLS than in SLS; and (4) the subanalysis revealed that SLS significantly reduced contrast volume compared with OLS and was associated with a trend towards shorter lesions and stent lengths.

Diffuse CAD significantly affects the prognosis of patients undergoing PCI. Long lesions that exceed the available stent lengths often require OLS and are associated with complications such as restenosis and stent thrombosis. First-generation DES, such as sirolimus-eluting and paclitaxel-eluting stents, are known to delay endothelialization and provoke inflammatory responses, contributing to late and very late stent thrombosis.²⁴ Moreover, the increased metal burden in OLS may promote neointimal hyperplasia, further elevating the likelihood of restenosis, especially when using BMS or first-generation DES.¹⁴ These issues lead to side-branch occlusion, difficulty in accessing these branches, persistent inflammation, fibrin deposition, and delayed endothelial formation in overlapping areas, potentially culminating in occlusion and restenosis.²⁵ In contrast, second-generation DES with biocompatible or biodegradable polymers have demonstrated low rates of adverse events due to improved endothelialization and reduced inflammatory reactions.²⁴ These finding suggest that OLS with firstgeneration DES or BMS in long lesions poses a higher risk of adverse clinical outcomes compared with second-generation DES. Recent advances in third-generation or the latest long stents (≥48 mm)^{7,15,16,18,22,23} have enabled the placement of DES in long lesions without the need to overlap, thereby reducing the volume of the contrast medium required, procedural duration, and treatment costs.¹⁷

The absence of significant differences in cardiac death and TVR observed in this meta-analysis, compared with previous meta-analyses that included first-generation DES and BMS, suggests that the impact of stent overlap on prognosis may be minimal in the era of second-generation or later DES. Because SLS may pose a risk of incomplete stent apposition or overexpansion due to significant diameter differences between the proximal and distal stent ends, selecting OLS to address such diameter mismatches may be a rational choice. The appropriate selection of SLS or OLS based on lesion-specific characteristics by operators may explain the comparable prognostic outcomes between the 2 strategies, alongside advancements in DES technology.

While SLS was associated with a significantly lower incidence of MI compared with OLS, this finding may have been influenced by differences in lesion length. In two of the studies analyzed,^18,22 lesion length was significantly longer in the OLS group than in the SLS group, which likely impacted the overall results (Figure 3A). Lesion length is closely associated with procedural complexity, as longer lesions increase technical challenges and elevate the risk of adverse events, such as stent thrombosis and restenosis.^5,14,25 Therefore, the higher MI incidence observed in the OLS group is not directly attributable to the choice of OLS but rather reflects the greater prevalence of ldCAD, which inherently carry a higher risk of MI. Longer lesions often require broader stent coverage with OLS, which can increase the risk of side-branch or perforator injury, potentially contributing to the observed increase in MI incidence. Even in the current era of advanced DES, careful long-term follow up is essential, as ldCAD requiring OLS due to insufficient SLS length may still pose a risk of MI within 1 year or later.

No RCTs to date have directly compared SLS and OLS while standardizing lesion length. Thus, the potential MI-reducing effect of avoiding stent overlap remains unclear. Previous studies have reported complications associated with stent overlap in OLS, raising concerns about using OLS for lesions that can be treated with SLS. Given these challenges, conducting future RCTs in this field may be difficult. Nevertheless, the findings of this study suggest that, with second-generation or later DES, stent overlap may not significantly impact MACE outcomes. As newer generations of DES have been shown to promote vascular healing more effectively,²⁶ the use of second-generation or later DES may have sufficiently reduce the incidence of late stent thrombosis in OLS, leading to comparable MACE outcomes between OLS and SLS. This insight may help mitigate concerns in designing RCTs in this area and provide a foundation for further research into optimal stenting strategies for ldCAD.

Recently, drug-eluting balloons (DEBs) have drawn considerable attention as a key component of the ‘leave nothing behind’ strategy.²⁷ Notably, their non-inferiority to DES has been demonstrated in the treatment of small vessel coronary artery disease,²⁸ supporting their broader applicability beyond focal lesions. Furthermore, ldCAD is often associated with severe calcified lesions,⁹ for which the use of DEBs may serve as an alternative treatment option from the perspective of lifetime lesion management.²⁹ By avoiding the implantation of permanent metallic devices, DEBs offer potential advantages such as reducing the risk of very late stent thrombosis, facilitating future CABG, and minimizing the duration of dual antiplatelet therapy.²⁹ Moreover, recent studies such as the HYPER Study have shown that combining DEBs with DES can be an effective strategy for de novo diffuse CAD, demonstrating favorable procedural and 1-year outcomes.³⁰ For ldCAD that exceeds the maximum length of SLS, this combination approach may provide a viable treatment option, warranting further studies to evaluate the clinical outcomes of such strategies.

The primary limitation of this study is that the meta-analysis was conducted using non-RCT studies. Typically, a meta-analysis requires that the patient populations being integrated are sufficiently similar, indicating that for each trial, the design, target populations, and outcomes must be adequately comparable. Hence, RCTs are typically used. As trial designs and patient populations may vary significantly across prospective and retrospective studies, there may be instances in which a combined analysis is not feasible, requiring careful judgment regarding its feasibility. In this meta-analysis, using non-RCTs, we carefully evaluated the quality of each study, the similarities between patient populations, and the outcomes to ensure the feasibility of the analysis. We believe that the results of this study are consistent with and provide credible insights into clinical practice outcomes. Future meta-analysis based on RCTs may provide more definitive information on this topic.

This meta-analysis revealed that in patients with ldCAD treated with second-generation or later DES, no significant differences in MACE, cardiac death, TLR, or TVR were observed between SLS and OLS. However, the incidence of MI was higher in OLS than in SLS, which may be attributed to the differences in lesion length rather than the stenting strategy itself. These findings suggest that stent overlap may have a minimal impact on prognosis with second-generation or later DES. While the reliance on nonrandomized data presents certain limitations, the results support the need for further research to optimize treatment strategies for ldCAD, potentially guiding future clinical practice.

We thank Editage (www.editage.jp) for English language editing.

This study was partially supported by a research project conducted at the Institute for Medical Regulatory Science, the Comprehensive Research Organization of Waseda University.

K.I. is a member of Circulation Reports’ Editorial Team. The other authors declare that there are no conflicts of interest.

M.I.: Writing the original draft, analysis, and investigation. K.H.: Investigation, writing – review and editing. H.N.: Writing – review and editing. K.I.: Conceptualization, resources, investigation, writing – review and editing, and project administration.

This study is a systematic review and meta-analysis of previously published studies and does not involve any new studies with human participants or animals performed by the authors. Therefore, ethical approval was not required.

Not applicable.

Please find supplementary file(s);

https://doi.org/10.1253/circrep.CR-25-0075

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