Introduction

Since the advent of drug-eluting stents (DES), significant advancements have been achieved in the management of coronary artery disease. The replacement of bare-metal stents with DES in standard clinical practice has led to noticeable decreases in in-stent restenosis and target lesion revascularization.1 However, it has been observed that DES carry a heightened risk of late stent thrombosis due to delayed reendothelialization.2,3 The durable polymer has been shown to cause vessel wall inflammation and hinder arterial healing, potentially increasing the risk of late thrombosis.4,5 Polymer-free technologies have since emerged, with polymer-free DES designed to prevent adverse events resulting from hypersensitivity reactions and chronic inflammation associated with polymers.6,7

It is important to note that inflammation is considered a contributing factor in the development of type 2 diabetes mellitus (DM). A growing body of evidence indicates that inflammation plays a critical intermediary role in its pathogenesis. Substantial experimental data and extensive cross-sectional studies suggest that interleukin 6 (IL-6) and C-reactive protein (CRP), sensitive markers of sub-clinical systemic inflammation, are linked to hyperglycemia, insulin resistance, and overt type 2 DM.8,9

Therefore, we hypothesize that in diabetic patients experiencing heightened inflammation, the use of polymer-coated stents may worsen the inflammatory response. This, in turn, could impede vascular reendothelialization after stent implantation, ultimately affecting clinical outcomes. This study aimed to evaluate the long-term clinical outcomes of polymer-free sirolimus-eluting stents (PF-SES) in comparison to polymer-coated sirolimus-eluting stents (SES) in patients with type 2 DM.

MethodsPatient Population

This retrospective analysis included 2646 consecutive diabetes patients with coronary artery disease (CAD) who underwent coronary stents at The First Bethune Hospital of Jilin University. Patients were divided into two groups according to the type of coronary stents they received: PF-SES and SES (Figure 1). Patients diagnosed with type 2 DM were eligible for inclusion if they exhibited clinical symptoms of ischemia, indicating the presence of coronary artery stenosis necessitating the use of coronary stents.10 The eligibility criteria for patient inclusion: (i) confirmed diagnosis of type 2 DM; (ii) presence of clinical symptoms of ischemia; (iii) evidence of coronary artery stenosis; and (iv) indication for coronary stent placement due to ischemic symptoms and stenosis. The exclusion criteria included: (i) pregnant women; (ii) left main trunk lesions; and (iii) any chronic illnesses such as cancer, liver cirrhosis, heart failure, or end-stage renal failure. Type 2 diabetes can be diagnosed if any of the following criteria is met:11 (i) fasting plasma glucose (FPG) ≥126 mg/dL (7.0 mmol/L); or (ii) 2-h PG ≥200 mg/dL (11.1 mmol/L) during oral glucose tolerance test (OGTT); or (iii) A1C ≥6.5% (48 mmol/mol); or (iv) in a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma glucose ≥200 mg/dL (11.1 mmol/L).

Figure 1 Flow chart of patients we analyzed in the present study.

Study Device

The PF-SES used in our study is the Nano Plus stent, a new type of polymer-free sirolimus-eluting stent developed by Lepu Medical in Beijing, China. This stent employs nanoporous surface technology to carry and control drug release. The stent’s abluminal surface features uniformly distributed nano-sized pores with an average diameter of 400 nm, which is 1/800th of the stent thickness (Figure 2A–C). The control stent used was the commercially available PARTNER stent, a self-expanding nitinol stent with a polymer-coated sirolimus delivery system (Figure 2a–c).

Figure 2 Scanning electron microscopy of stent surface between polymer-free sirolimus-eluting stent and polymer-coated sirolimus-eluting stent. (A–C) The magnification of polymer-free sirolimus-eluting stent is 30×, 1000× and 4000×, respectively; (a–c) The magnification of polymer-coated sirolimus-eluting stent is 30×, 1000× and 4000×, respectively.

The Nano Plus stents is manufactured by Lepu Medical Technology, a leading company in the medical device industry. These stents are designed to provide optimal performance for coronary interventions. The stents are available in various lengths ranging from 12 mm to 36 mm with diameter options of 2.5 mm to 4.0 mm, ensuring a wide range of applicability for different patient needs.

Key manufacturing features of the Nano Plus stents include:

(i) Material Composition: The stents are made from cobalt-chromium alloy, which offers a balance of strength and flexibility while minimizing the risk of restenosis.

(ii) Coating Technology: These stents utilize advanced drug-eluting technology with a biodegradable polymer coating to ensure controlled drug release, enhancing the healing process and reducing the likelihood of thrombosis.

(iii) Precision Engineering: The stents are engineered using laser-cutting techniques to ensure precision and consistency in stent design, promoting optimal deployment and integration within the coronary arteries.

(iv) Quality Control: Each stent undergoes rigorous quality control processes, including in-vitro and in-vivo testing, to ensure they meet stringent safety and efficacy standards.

For more detailed information on the product specifications and benefits, you can refer to the following link: https://pdf.medicalexpo.com.cn/pdf-en/lepu-medical/coronary-stent-nano/95737-263490.html#open657723.

The Partner stents are manufactured by Lepu Medical Technology, a renowned company in the medical device industry. These stents are designed to offer superior performance in coronary interventions. The stents come in a variety of lengths from 12 mm to 36 mm and are available in diameters ranging from 2.5 mm to 4.0 mm, ensuring they can meet a wide range of patient needs.

Key manufacturing features of the Partner stents include:

(i) Flexible Stent Design: The Partner stents incorporate a sine wave pattern with a 3-3-3 link and a double helix structure, providing flexibility and strength.

(ii) Balanced Strut Thickness: The stents have an optimized strut thickness that balances radial force and flexibility, ensuring effective support and minimal vessel injury.

(iii) High Radial Force: They provide high radial force for excellent vessel scaffolding, reducing the risk of stent collapse.

(iv) Large Open Cell Design: This design allows for optimal blood flow and facilitates access to side branches during procedures.

(v) Precise Positioning Markers: The stents are equipped with markers that enable accurate positioning during deployment.

(vi) Ultra Smooth Surface: The stents feature an ultra-smooth surface that minimizes friction and facilitates easy placement.

(vii) Double Layer Polymer Coating: The stents are coated with a double layer of polymer that enhances biocompatibility and drug delivery.

(viii) Sirolimus Drug Coating: Coated with Sirolimus, the stents provide controlled drug release over a 90-day period, promoting healing and reducing restenosis.

For more detailed information on the product specifications and benefits, you can refer to the following link: https://pdf.medicalexpo.com.cn/pdf-en/lepu-medical/coronary-stent-partner/95737-263492.html#open657726.

Coronary Angiography and Stenting

All primary coronary angiography and stenting were conducted at The First Bethune Hospital of Jilin University, by experienced interventional cardiologists with an annual experience for over 500 cases of percutaneous coronary intervention (PCI). These cardiologists were not associated with the current study. Baseline demographics, angiographic characteristics, as well as laboratory and physical examination data during hospitalization, were systematically documented by reviewing the patients’ medical records.12

Coronary stenting was performed in accordance with the current standard of practice.13 Revascularization strategies and stent implantation techniques were performed at the operator’s discretion.14 All patients were pretreated with aspirin and a P2Y12 inhibitor (clopidogrel or ticagrelor) according to the standard of care and provided DAPT for at least 12 months according to the guidelines.15 The continuation of DAPT beyond the duration of the recommended guidelines was performed at the physician’s discretion. Additional medications for secondary prevention, including statins, beta-blockers, and angiotensin-converting enzyme inhibitors, were prescribed according to the guidelines.13

OCT Imaging and Analysis

The intracoronary imaging technique of optical coherence tomography (OCT) was previously outlined.16 In the present study, either a frequency-domain OCT system (C7-XR OCT Intravascular Imaging System; St. Jude Medical, St. Paul, MN, USA) was utilized. All OCT images were digitally stored and forwarded to the core laboratories of intracoronary imaging at THE FIRST BETHUNE HOSPITAL OF JILIN UNIVERSITY (Changchun, China) for offline analyses. In summary, within the frequency domain OCT system, a 2.7 F OCT imaging catheter (Dragonfly, Light Lab Imaging, Inc) was advanced at least 10 mm distal to the imaging target lesion. OCT image acquisition was then performed with automatic pullback (20 mm per second) and continuous intracoronary contrast injection. Each OCT catheter pullback imaged a total of 54 mm of the vessel.

Assessment of atherosclerosis involved identifying the presence of lipids and plaque microstructure (Figure 3). Lipid plaques were characterized as signal-poor areas with diffuse borders.17 A plaque was deemed lipid-rich if lipid was present in ≥90 degree in any cross-sectional image within the plaque.18 The fibrous cap thickness of the lipid plaque was measured three times at its thinnest part, and the values were averaged.19 Thin cap fibroatheroma (TCFA) was defined as a plaque with a maximum lipid arc of >90 degrees and a cap thickness <65 μm. Micro-vessel were identified as sharply delineated signal-poor voids with a diameter of 50–300 μm, not connected to the vessel lumen, and present on >3 consecutive frames.20

Figure 3 Representative cases with each tissue morphologies in stents assessed with OCT. OCT, optical coherence tomography. (A) Complete endothelial coverage on the surface of the stent; (B) Incomplete endothelial coverage on the surface of the stent; (C) In-stent neo-atherosclerosis; (D) Lipid-laden intima is observed as a signal-poor band region with poorly delineated border; (E) In-stent calcified plaque; (F) In-stent thrombosis.

Follow-Up

Patients were contacted by telephone or during a scheduled outpatient clinic visit arranged by their physicians. Follow-up data were collected up to 5 years post-procedure.

Statistical Analysis

Quantitative data are expressed as the mean value ± standard deviation, while qualitative data are expressed as frequency (percentage). The independent two-sample t-test was used for comparisons between cohorts. The chi-square test or Fisher’s exact test was used to compare categorical variables, as applicable. To estimate survival status, the Kaplan Meier (KM) technique was utilized, and the Log rank test was used to compare survival distributions. Two-sided P-values of <0.05 were deemed statistically significant. SPSS version 25.0 (SPSS Inc., Chicago, IL, USA) was used to conduct all statistical analyses.

ResultsBaseline Characteristics

In terms of basic characteristics, the proportion of current smoker (37.0% vs 32.0%, P = 0.008) in the PF-SES group was significantly higher than that in the SES group (Table 1). Among different types of CAD patients, the proportion of patients with stable angina in the PF-SES cohort is significantly higher than in the SES cohort (71.3% vs 64.4%, P < 0.001), while the proportion of patients with unstable angina (15.3% vs 20.2%, P = 0.001) and ST-elevation myocardial infarction (STEMI) in the PF-SES cohort (5.2% vs 8.3%, P = 0.002) is significantly lower (Table 1).

Table 1 Basic Characteristics in Patients

Angiographic Findings

The comparison of coronary angiography and stenting between two groups is shown in Table 2. The PF-SES group exhibited significantly higher rate of left anterior descending (LAD) lesion and more stents per patient compared to the SES group (46.4% vs 42.1%, P = 0.026).

Table 2 Coronary Angiography and Stenting Therapy

OCT Findings

The OCT findings are listed in Table 3. The value of minimum lumen area (MLA), neointimal area (NA) and neointimal thickness (NT) was significantly larger in the PF-SES group (P < 0.001). When compared with the SES group, the PF-SES group had a lower prevalence of heterogeneous, lipid layer, intimal tears, thrombi and micro-vessels (P < 0.001).

Table 3 Optical Coherence Tomography Findings in Follow-Up

Long Term Follow-Up

In 5-year follow-up, the all-cause mortality, in-stent restenosis (ISR) and target vessel revascularization (TVR) were considerably lower in the PF-SES cohort than in the SES cohort (6.4% vs 8.6%, P = 0.033 and 7.6% vs 9.9%, P = 0.046 and 12.4% vs 21.1%, P < 0.001; Table 4 and Figure 4).

Table 4 Clinical Outcomes in 5-Year Follow-Up

Figure 4 All-cause mortality between two groups in 5-year follow-up.

Discussion

The Nano Plus stent is an innovative polymer-free stent featuring nano-sized pores that serve as drug carriers for the antiproliferative drug sirolimus. It is one of the most widely used DES in China. The Nano Plus stent, with its improved uniform distribution on the abluminal stent surface compared to microporous or textured rough surface stents, significantly differs from traditional SES in terms of the drug-eluting mechanism (Figure 5). To our knowledge, this is the first study to demonstrate the safety and efficacy of PF-SES compared to SES assessed by OCT in CAD patients with type 2 DM for a long-term follow-up in real-world practice. The main findings were as follows. (i) PF-SES could effectively improve in-stent reendothelialization in patients with type 2 diabetes, (ii) positively impacting the survival rate. (iii) PF-SES may be considered an alternative treatment option for improving long-term clinical outcomes.

Figure 5 Demonstration of the different drug-eluting mechanisms between PF-SES and SES.

The traditional DES consists of three components: the stent, anti-proliferative drug, and the drug carrier.21 The drug carrier is composed of one or more organic compounds forming a polymer.22 It is coated onto the surface of the traditional metal stent along with anti-proliferative drug. The polymer material involved here refers to high molecular weight compounds formed by repetitive covalent bonding of many identical, simple structural units.23 Typically, polymer coatings exhibit two main characteristics: serving as a reservoir for anti-proliferative drugs and determining the rate of drug release.24 Stent design, anti-proliferative drug, and the presence and type of polymer are the key factors of a DES platform relate to its clinical efficacy.

Inflammation plays a critical role in the pathological mechanism of neointimal proliferation following stent placement. The polymer used in DES, which helps load and control the release of antiproliferative drugs, has been suspected of contributing to inflammatory responses and delayed arterial healing.4 The presence of a permanent polymer coating has been identified as a potential trigger for inflammatory reactions, which may contribute to the development of neo-atherosclerosis, resulting in ISR and subsequent TVR.10,25 Polymer-free DESs were initially developed with the hope that eliminating the polymer would reduce the risk of polymer-related inflammation and late thrombotic events.26

Prospective studies have demonstrated that CRP, a general marker of systemic inflammation, is associated with an increased risk of diabetes.27 Studies that have identified an independent association between CRP and diabetes suggest various pathways. Many researchers argue that this association reflects the effects of cytokines, such as IL-6 and tumor necrosis factor (TNF)-α, on insulin resistance.28,29 The inflammatory process plays a significant role in the development of diabetes. Cross-sectional epidemiological data have shown that elevated serum CRP levels are associated with obesity, insulin resistance, and glucose intolerance.30 These findings suggest that inflammation impacts blood glucose levels and raises the risk of diabetes through pathways involving obesity or insulin resistance. An accumulating body of evidence indicates that inflammation may play a critical intermediary role in the pathogenesis of diabetes, linking it to numerous commonly coexisting conditions believed to originate through inflammatory mechanisms.8 The clinical outcomes in our study, which were worse for polymer-coated stents, appear to support the hypothesis that the additional inflammation induced by the polymer, combined with the heightened inflammation associated with diabetes, results in an additive pro-inflammatory effect at the site of vascular reendothelialization following stent implantation.

Stent implantation-induced vascular injury triggers the release of growth factors from endothelial cells, platelets, and macrophages. These growth factors play a crucial role in reendothelialization.31 The inflammatory response to durable polymer coatings or drugs delays cell coverage during the initial stages of strut coverage, which is the primary mechanism behind stent thrombosis—a major factor leading to adverse cardiac events after coronary stent implantation.31,32 In our study, no significant difference in serum CRP levels was observed between the PF-SES and SES groups. However, the CRP levels in both groups exceeded the normal range, indicating a state of chronic inflammation in CAD patients with type 2 DM. Serum CRP reflects the overall inflammatory state of the body rather than the local inflammatory level of coronary atherosclerotic lesions. Therefore, we utilized OCT to evaluate both local tissue structural changes and the local inflammatory level of the intima after stent implantation in coronary atherosclerotic lesions. Indicators such as heterogeneous, lipid layer, intimal tears, thrombi, and micro-vessels were used to reflect these local inflammatory levels.

OCT has emerged as a highly valuable tool for assessing reendothelialization following stent implantation.33 This intravascular imaging technique provides high-resolution, cross-sectional images of the coronary arteries, allowing for detailed visualization of the stent and the surrounding vascular tissue.34 Particularly in patients with type 2 diabetes, who are at a higher risk of adverse cardiovascular events, OCT can offer critical insights into the healing process post-stent implantation. By identifying areas of incomplete reendothelialization, neointimal hyperplasia, and potential in-stent restenosis, OCT helps clinicians make informed decisions regarding patient management and follow-up care.35 Moreover, OCT can differentiate between various tissue components within the vessel wall, such as lipid-laden intima and plaque microstructures, which is essential for a comprehensive assessment of atherosclerosis.36 This detailed visualization supports the optimization of stent design and the development of new therapeutic strategies aimed at improving long-term outcomes for CAD patients with type 2 DM.

The traditional SES are associated with an inflammatory response due to the durable polymer coatings. This inflammation can delay cell coverage during the initial stages of strut coverage, which is a primary mechanism behind stent thrombosis. Stent thrombosis is a significant factor leading to adverse cardiac events after coronary stent implantation. For patients with type 2 DM, who already have higher baseline levels of inflammation, this additional inflammatory response could potentially worsen clinical outcomes.37,38 In contrast, the PF-SES, such as the Nano Plus stent, have an improved uniform drug distribution on the abluminal stent surface. This design significantly differs from traditional SES in terms of the drug-eluting mechanism, potentially leading to lower levels of inflammation. For type 2 DM patients, this could mean a reduced risk of inflammation-induced vascular complications. Therefore, for diabetic patients, who are at a heightened risk of inflammation, PF-SES might be a more suitable option. The reduced inflammatory response could help in better vascular reendothelialization and potentially improve long-term clinical outcomes.

Some limitations warrant discussion. Our study is subject to several limitations. First, its retrospective nature may introduce inherent biases and constraints commonly associated with such study designs. However, the current analysis highlights the safety and efficacy of PF-SES in an unselected population in a real-world setting. Second, data were collected solely from one medical center, potentially limiting the generalizability of our findings to broader population characteristics. In terms of patient disease composition, the proportion of STEMI patients in the polymer-free group was notably lower than that in the polymer-coated group. Given the poorer prognosis associated with STEMI patients, this could potentially lead to inferior clinical outcomes in the polymer-coated group. Due to the presence of such selection bias, we plan to conduct a prospective, multicenter, randomized controlled trial in the future.

Conclusions

PF-SES could effectively improve in-stent reendothelialization in patients with type 2 DM, with positive effects on survival rate and may, therefore, be considered as an alternative treatment option for improving clinical long-term outcomes.

Data Sharing Statement

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Ethics Approval and Consent to Participate

This study protocol, approved by the ethics committees of the First Hospital of Jilin University, adhered to the principles outlined in the Declaration of Helsinki and its subsequent amendments. Prior to participation, all patients were provided with detailed information regarding the study objectives, following which their consent was obtained.

Acknowledgments

The authors thank the study subjects for their participation and support of this study.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Funding

This work was supported by China postdoctoral science foundation (grant no. 2018M641870 to RZ).

Disclosure

All authors report no conflicts of interest in this work.

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