European Journal of Cardiovascular Medicine

In patients with coronary heart disease interventional therapy percutaneous coronary intervention (PCI) with stent placement plays a vital role and is considered a standard of care.^[1] A major significant advancement in the prevention of restenosis following percutaneous coronary procedures is the use of drug-eluting stents (DES). Although first-generation DES are quite efficient at preventing coronary restenosis, they may cause delayed healing of the stented arterial segment^[2,3]. This pathophysiological mechanism appears to be behind the modest excess of stent thrombosis events^[4,5] and marginal decrease of anti-restenotic efficacy^[6], late after device  implantation. The rationale for the development of second-generation devices therefore has been the attainment of optimal anti-restenotic efficacy at a minimum of arterial wall toxicity^[7]. Clinical results for patients undergoing percutaneous coronary intervention (PCI) were enhanced by improvements in stent design that included strut thickness, polymer matrix, and antiproliferative material.

In patients treated with early-generation stents, the polymer matrix regulates the release of the antiproliferative chemical and has been linked to a persistent inflammatory response and delayed vascular repair, which clinically shows up as extremely late stent thrombosis^[8,9]. Biodegradable polymers have been developed to reduce the risk of late events and have been combined with different stent platforms. Indeed, thinner stent strut designs have recently been shown to reduce in-stent restenosis and target lesion revascularisation (TLR) in a pooled meta-analysis.^[9] Recent research showed that ultrathin strut DES with a thickness of less than 70 µm can enhance outcomes even more than second-generation DES^[9]. According to a recent meta-analysis, ultrathin strut DES outperform- ed second-generation DES with standard thickness in terms of target lesion failure (TLF) at both 2 years and 3 years.^[10] In light of the evolving evidence base, we performed a meta-analysis of randomized controlled trials (RCTs) comparing ultrathin strut DES in comparison with current-generation DES, BP-SES versus DP-DES, and analyze how the results hold up across the designated subgroups.

Search Strategy and Selection Criteria

An electronic search of the United States National Institutes of Health clinical trials registry (www.clinic altrials.gov), United States National Library of Medicine (PubMed, at www.pubmed.gov), and the Cochrane Central Register of Controlled Trials (http://www.mrw.interscience.wiley.com/cochrane/cochrane_clcentral_articles_fs.html) was carried out to find the data.

The American College of Cardiology, the American Heart Association, Transcatheter Cardiovascular Therapeutics, the European Society of Cardiology, and Euro PCR meetings were among the other sources of data. Additionally, we located pertinent editorials and reviews from prestigious medical journals.

The information from online resources about the outcomes of cardiology research trials (www.cardio source.com/clinical trials, www.theheart.org, www.tct-md.com, www.clinicaltrial.results.com), MEDLINE, EMBASE, SCOPUS, WOS, Google Scholar, and CENTRAL were also searched. We used the following Medical Subject Headings (MeSH) terms and combined text: “Coronary Disease”, “Bioresorbable stent”, “Randomized controlled trials”, “Ultrathin strut” and “Thicker Strut” for randomized clinical trials that compared newer-generation ultrathin strut Sirolimus-Eluting Stents versus thicker strut EES. Ultrathin strut was defined as <70-μm strut thickness. Publications were excluded if they only compared two biodegradable polymer stents to each other and, for the biodegradable arm, were non-sirolimus eluting or had a strut other than an ultrathin strut.

Data Abstraction and Quality Assessment

We employed the revised Cochrane threat-of-bias tool for RCTs (RoB 2) to estimate the threat of bias in the included clinical trials. This analysis included the measurement of the outcome, deviations from the intended interventions, overall risk of bias, use of appropriate analysis to estimate the effect of assignment to intervention, selection of the reported results, and randomization process. Based on the methodological quality review, the studies were categorized as having a moderate risk of bias, a low risk, or a high risk. We utilized the Cochrane ROBINS‐I tool13, which covers the following domains: a) bias due to confounding, b) selection of participants into the study, c) measurement of outcomes, d) classification of interventions, e) deviati-ons from intended interventions, f) missing data, and g) selection of the reported result.

Statistical Analysis

All of the randomized patients' data were combined into a single data set, and we conducted the analysis according to the intention-to-treat principle. For the analysis, the random-effects model was used. An inference based on a random sample of research was drawn from the analysis. Treatment effects are presented as odds ratio with 95% confidence interval. Categorical variables were reported as counts and percentages and compared using multilevel random effect logistic regression or multilevel random effect ordered logistic regression in the case of ordered variables to account for variation between trials. Continuous variables were reported as means and standard deviations, were compared using random effect linear regression. By calculating an average inference over all trials and taking participant clustering within trials into consideration, we conducted a one-stage IPD meta-analysis. We used the Cochran Q-test to assess trial-to-trial heterogeneity. Also, we calculated the I² and τ² statistics to measure the consistency between the trials. A visual depiction of funnel plot asymmetry and Egger and Begg's regression test were used to evaluate small-study effects. A significance level of P<0.05 was established. All statistical analyses were conducted using the statistical programming environment R12 with the metaphor package.

In the current analysis, a total of ten randomized controlled trials met the inclusion criteria and supplied individual patient data. The randomized controlled trials were from different countries and regions. Together, these studies encompassed a total of 10,328 participants in experimental groups who received ultrathin-strut SES and second-generation EES. We have included studies with ultrathin strut SES, six trials of Orsiro, each trial of MiStent, BioMime, Supraflex, and M’SURE-S. The lowest strut thickness among the selected ultrathin strut SES was M’SURE-S with 59µm. The trials considered are of different follow-up periods, and the average follow-up duration was 36.6 months. We evaluated the study outcomes of TLF, TVF, MI, stent thrombosis, repeat revascularization, and mortality.

Target Lesion Failure and Target Vessel Failure

The outcomes related to target lesion failure and target vessel failure from ten studies. As illustrated in the figures 1 & 2, at the most recent follow-up, ultrathin strut SES were associated with significantly lower risk of TLF and TVF compared with conventional second-generation EES [OR 0.75 and OR 0.77; 95% CI; P=0.017 and P=0.019, respectively]. Heterogeneity was modest (I2 = 32.76% and 29.75%), with Q-values indicating consistent effect sizes across the included studies.

Figure 1. Risk of target lesion failure at the latest follow-up

Figure 2. Risk of target vessel failure at the latest follow-up

Myocardial Infarction and Stent Thrombosis

As mentioned in the figures 3 & 4, at the most recent follow-up, the risk of myocardial infarction did not significantly differ between groups (OR 1.09, 95% CI, P>0.05). However, the ultrathin strut SES showed a significantly lower risk of stent thrombosis (OR 0.69, 95% CI, P=0.005). Heterogeneity was negligible (I2=1.03% and 1.15%, respectively), and Q-statistics supported the stability of these findings.

Figure 3. Risk of myocardial infarction at the latest follow-up

Figure 4. Risk of stent thrombosis at the latest follow-up

Repeat Revascularization and Mortality

As per the Figures 5 & 6, the risk of repeat revascularization was significantly reduced with ultrathin strut SES (OR 0.75, 95% CI, P=0.018). Mortality risk showed no significant difference among the groups (OR 0.91, 95% CI, P=0.63). Heterogeneity was higher in these outcomes (I2 = 63.6% and 46.6%).

Figure 5. Risk of repeat revascularization at the latest follow-up

Figure 6. Risk of mortality at the latest follow-up

Cardiac Death and Non-Cardiac Death

As illustrated in the figures 7 & 8, at the most recent follow-up, both cardiac death (OR 0.90, 95% CI, P=0.081) and non-cardiac death (OR 1.12, 95% CI, P=0.63) were lower in the ultrathin strut SES group but were statistically non-significant. Heterogeneity was minimal (I2 = 1.18% and 44.7%).

Figure 7. Risk of cardiac death at the latest follow-up

Figure 8. Risk of non-cardiac death at the latest follow-up

Meta-analyses of randomized trials have helped to define the safety and efficacy of DES generations. This pooled analysis of 10 RCTs and 10,328 patients found consistently better outcomes with ultrathin strut SES than second-generation EES for TLF, TVF, ST, and RR. Most trials favoured ultrathin strut SES, likely due to reduced vessel trauma and better deliverability. The advantage of the biodegradable polymer may not materialize until after full resorption, in contrast to the constant effect of stent strut thickness. Unlike polymers that degrade over time, strut thickness consistently affects vascular healing. Thicker struts are known to increase vessel injury and promote neointimal proliferation. Thinner struts are associated with faster endothelialization, improved healing, and reduced thrombogenicity. These findings support the design rationale behind ultrathin strut platforms. Ten studies in our analysis used the second-generation cobalt-chromium durable polymer-based everolimus-eluting stents as the control, comparing them with the ultrathin strut 59-65µm cobalt-chromium bioabsorb-able polymer-based sirolimus-eluting stents.

Our findings are consistent with prior studies like those by Bangalore et al., but benefit from longer follow-up and a larger patient cohort. Ultrathin strut SES appear especially favorable in high-risk patients or those with small vessels prone to restenosis. Our study included 10 RCT trials to overall include 10,328 patients. The mean follow-up of the 10 trials is 36.6 months (3.5 years), allowing for a significantly higher number of events in order to increase study power. This study showed the risk in terms of events like TLF, TVF, ST, RR, MT, CD, and NCD has reduced risk with the ultrathin SES in comparison to the EES, except for the MI. This varies from the other meta-analysis trials. Mechanistically, thicker strut dimensions increase vascular injury, flow separation, and stagnation, thereby modulating thrombogenicity and neointimal hyperplasia^[11]. Increasing strut thickness is also associated with delayed or impaired endothelialisation, which may also promote increased neointimal formation^[12]. The ultrathin strut DES are observed to be more beneficial in patients with cardiac risk and diffused disease who are at high risk for restenosis. Although no significant differences were observed in MI or mortality, several confounding variables may explain these outcomes. Differences in patient selection, procedural techniques, or post-PCI medical therapy may impact long-term clinical endpoints. In comparison to conventional stents, bioresorbable stents have a substantially greater rate of stent thrombosis in blood arteries with an interior diameter of less than 2.25 mm, according to clinical studies.^[13] However, most of the studies revealed that from six months to three years post-implantation, a very thin-strut bioresorbable stent implanted exhibited almost no thrombus development. This is most likely due to the thinner strut's rapid endothelialization and tissue resorption ^[14]. Uneven stent degradation also poses a serious problem, as differential degradation rates may deform the stent and induce thrombosis^[15]. The degradation process of bioresorbable stents reduces the local arterial pH, attracting inflammatory cells^[16], increasing the likelihood of stent thrombosis.

LIMITATIONS

Our study has few notable limitations. This meta-analysis used aggregate data rather than full patient-level datasets, limiting detailed subgroup analyses. Potential confounding due to comorbidities, procedural nuances, or pharmacotherapy might not be fully accounted for. Risk of publication bias exists, as negative or null-result studies are less likely to be published. Lastly, while average follow-up was 3.5 years, longer-term outcomes remain to be determined.

This meta-analysis of 10 trials with over 10,328 patients and mean 3.5 years follow-up demonstrates that ultrathin strut sirolimus-eluting stents are associated with significantly lower risks of target lesion failure, target vessel failure, stent thrombosis, and repeat revascularization compared with second-generation everolimus-eluting stents. No significant differences were discovered in myocardial infarction or overall mortality.

ACKNOWLEDGEMENTS

We thank all the researchers and patients of the included RCTs. Special thanks to Multimedics LLP (Relisys Medical Devices Group Company), Baddi, Himachal Pradesh, India, for sponsoring this research.

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