Clinical Outcomes of Polymer-Free Versus Polymer-Coated Drug-Eluting Stents in Patients With Coronary Artery Disease: A Systematic Review and Meta-Analysis

Drug-eluting stents have transformed the treatment of coronary artery disease (CAD), and there are two types: polymer-free and polymer-coated stents. Polymer-free stents have a coating that is quickly absorbed by the body, whereas polymer-coated stents have a coating that remains on the stent surface. This meta-analysis and systematic review aimed to compare the clinical outcomes of these two stent types in patients with coronary artery disease. The literature and abstracts from significant databases were reviewed to compare polymer-free drug-eluting stents (PF-DES) and polymer-coated drug-eluting stents (PC-DES) for the treatment of coronary artery disease (CAD). The primary efficacy endpoints of the study were all-cause mortality and deaths from cardiovascular and non-cardiovascular causes. Among the secondary outcomes were incidences of myocardial infarction (MI), target lesion revascularization (TLR), target vessel revascularization (TVR), stent thrombosis, stroke, and major adverse cardiovascular events (MACEs). In terms of the primary outcomes, the combined analysis revealed a marginally lower risk of all-cause mortality (relative risk, RR (95% CI) = 0.92 (0.85, 1.00), p = 0.05, I2 = 0%) with the use of PF-DES versus PC-DES. Nonetheless, there was no significant difference in cardiovascular mortality (RR (95% CI) = 0.97 (0.87, 1.08)) or non-cardiovascular mortality (RR (95% CI) = 0.87 (0.69, 1.10), p = 0.25, I2 = 9%) between the groups. Furthermore, univariate meta-regression revealed that male gender and prior myocardial infarction were independently associated with an increased risk of all-cause mortality and cardiovascular disease. According to the current meta-analysis, no statistically significant differences existed in PF-DES and PC-DES outcomes. More extensive research is needed to investigate these findings further and establish their validity.

polymers is an approach for mitigating this negative effect. The second is the creation of a biodegradable polymer that dissipates over time, leaving only BMS behind. Theoretically, BP-DES has the benefit of leaving only the BMS after complete drug elution and polymer degradation, which may reduce vascular inflammation and the risk of late stent-related complications [4]. In comparison to first-generation DP-DES, early-generation BP-DES demonstrated superior safety and a decrease in patient-centered outcomes. However, it has been demonstrated that more recent generations of durable polymers are thromboresistant and even safer than BMS [5]. PF-DES was developed to provide similar benefits to BMS (lower chances of stent thrombosis) and DP-DES (less risk of lesion revascularization). The key obstacle for PF-DES has achieved a high enough level of the antiproliferative agent in the inorganic coating to confirm neointimal hyperplasia and in-stent restenosis inhibition [6].
There are currently conflicting prognostic data reported for PF-DES, and few randomized controlled trials (RCTs) have been conducted to compare the clinical outcomes of the polymer-free drug-eluting stent (PF-DES) approach to that of polymer-coated DES (PC-DES). In this meta-analysis, we report findings from a review of the relevant literature. Therefore, the purpose of the present study was to conduct a comprehensive meta-analysis of available randomized controlled trials (RCTs) and cohort studies, equating the effect of PF-DES versus PC-DES on patient outcomes.

Methodology
This study followed the preferred reporting items for systematic review and meta-analysis (PRISMA) [7] guidelines to ensure the highest quality results from this meta-analysis.

Search Strategy and Selection
A systematic literature search was performed on PubMed, Embase, and MEDLINE databases up until January 23, 2023, using the following subject keywords and their MeSH terms: (Polymer-free drug-eluting stents OR PF-DES) AND (Polymer-coated drug-eluting stents OR PC-DES) AND (Coronary artery disease OR Ischemic heart disease OR CAD). Appendix 1 summarizes the detailed search approach. MK and SK independently evaluated the search results. In the event of disagreement, a third reviewer (KM) was consulted. The eligibility of studies was initially determined based on the study's title and abstract; then, the full text was evaluated. In addition, the references of the chosen studies were meticulously examined.

Study Inclusion and Exclusion Criteria
Inclusion criteria: The inclusion criteria for studies in this research involved comparative analyses between PF-DES and PC-DES that use either permanent or bioresorbable polymer coatings. Additionally, studies must have complete clinical and outcome data available to ensure accurate assessments of the effectiveness of each type of drug-eluting stent. Only studies that meet these inclusion criteria were considered for this research.
Several exclusion criteria had been established to ensure the integrity and reliability of the study results: First, follow-up data must be available for at least 90% of patients. Second, ongoing studies or studies with irretrievable data will be excluded. Third, bare metal stents in the control group will not be accepted. Finally, studies without clinical outcome endpoints will also be excluded. By applying these exclusion criteria, the study will only consider high-quality research with complete and reliable data that can provide valid conclusions regarding comparative studies between PF-DES and polymer-coated DES (PC-DES) with either permanent or bioresorbable polymer. This approach will help ensure that the results obtained from this study are accurate and trustworthy and can be used to guide future clinical decision-making. Reviews, editorials, protocols, case reports, and studies lacking a comparison and outcome were excluded. No language restrictions were enforced.

Data Extraction
Two researchers independently extracted the data (SK and MK). If data needed to be completed or clarified, the authors were contacted. Disputes were resolved through consensus. The data were managed following the principle of intention-to-treat.
Data extraction from the relevant studies included: the first author, year of publication, study type (cohort or randomized controlled trial), study follow-up duration, the total number of patients with coronary artery disease (CAD), and the number of patients in each group (PF-DES and PC-DES). Also extracted were baseline characteristics such as age, gender, body mass index (BMI), history of myocardial infarction (MI), history of stroke, and the number of vessels involved. The primary outcomes of all-cause, cardiovascular, and non-cardiovascular mortality were extracted from the tables and text of the individual studies after a thorough examination. MI, stent thrombosis, target lesion revascularization (TLR), target vessel revascularization (TVR), target lesion failure, target vessel failure, stroke, and major adverse cardiovascular events were secondary outcomes (MACE).

Assessment of Risk of Bias
All observational studies were evaluated using the Newcastle-Ottawa scale [8], while randomized controlled trials were assessed using the Cochrane risk of bias tool [9].

Data Analysis
Only comparative studies were analyzed statistically using Review Manager 5.4.1 (The Nordic Cochrane Center, The Cochrane Collaboration, 2014, Denmark) and comprehensive meta-analysis. This meta-analysis provides a pooled effect of relative risks (RRs) for dichotomous outcomes and weighted mean differences (WMDs) for continuous outcomes calculated utilizing the generic-inverse variance with a random-effects model. Forest plots were used to display the results of pooled analyses. To assess publication bias, funnel plots were constructed for each primary outcome. Low (25%), moderate (25-75%), and high (>75%) levels of heterogeneity were determined using the Higgins I 2 test [10]. The association between baseline variables such as age, male gender, and previous myocardial infarction and outcomes such as death from all causes and cardiovascular death was investigated using univariate meta-regression. All analyses were considered significant if the p-value was less than 0.05. Since the data were compiled and synthesized from earlier clinical trials for which the researchers had already received informed consent, no ethics committee approval was required for this study.

Eligible Studies
As depicted in the PRISMA flowchart in Figure 1, a total of 488 studies were screened for inclusion in the meta-analysis. Four studies that compared PF-DES to bare metal stents were omitted (BMS) [11][12][13][14]. One study was excluded as it was a single-arm study with no control group [15]. After excluding studies with duplicate data [16][17][18] and conducting a meta-analysis, we finally included 23 studies , which comprised of 20 RCTs and three observational studies with a total of 28,555 patients. There were 14,951 (52.3%) patients assigned to a PF-DES strategy and 13,566 (47.5%) patients assigned to a PC-DES approach. In most studies, PF-DES was compared to permanent-polymer (PP) DES. Three studies compared PF-DES to bioresorbable polymer DES (BP-DES), whereas two studies randomized participants to either BP or PP-DES. Seven trials permitted the inclusion of ST-elevation myocardial infarction (STEMI) patients, with one study comprising the entire population, whereas 16 studies excluded patients with acute MI. Two clinical trials were conducted on people at increased risk, including all diabetic patients. Only preliminary data were available for one study, whereas full-text manuscripts were available for the remaining 15 studies. In all studies, patients received a dual antiplatelet therapy (DAPT) regimen lasting at least six months. Appendix 2 displays the study characteristics of the included trials. The duration of follow-up varied widely, from 12 months to 60 months (median 24 months).

Baseline Characteristics of Patients
The characteristics of the included patients at the outset are listed in Table 1. Most of the patients included in the study were middle-aged or older men who smoked and who suffered from conditions like diabetes, hypertension, and a previous myocardial infarction.

Quality Assessment and Publication Bias
The Newcastle-Ottawa scale, a tool used to assess study quality, discovered a low likelihood of bias in observational studies, as shown in Table 2. Using the Cochrane method of assessing RCTs, we found trials of medium-to-high quality, as shown in Figure 2.  The Newcastle-Ottawa scale quality instrument is scored by awarding a point for each answer that is marked with an asterisk below. Possible total points are four points for selection, two points for comparability, and three points for outcomes. Good quality: three or four stars in the selection domain and one or two stars in the comparability domain and two or three stars in the outcome/exposure domain fair quality: two stars in the selection domain and one or two stars in the comparability domain and two or three stars in outcome/exposure domain poor quality: zero or one star in selection domain or zero stars in comparability domain or zero or one stars in outcome/exposure domain.

Secondary Outcomes
Myocardial infarction: All 23 studies reported the number of patients who experienced myocardial infarction following treatment in the follow-up period, and pooled analysis revealed that there was no significant difference between the two groups (RR (95% CI) = 1.04 (0.93, 1.16), p = 0.52, I 2 = 0%) as shown in Figure 8.

Effect of age, male gender, and previous myocardial infraction on death from all causes and cardiovascular death
According to a univariate meta-regression shown in Table 3, male gender and a history of myocardial infarction (MI) are independently associated with an increased risk of death from all causes and cardiovascular death, while age has no effect.

Discussion
Almost 28,555 participants were included in 20 randomized controlled trials and three observational studies for this recent meta-analysis evaluating PF-DES versus PC-DES. We found that PF-DES lowered mortality relative to conventional DES and that this improvement was independent of preventing large recurrent ischemia episodes, but on the other hand, it also increased the risk of stent thrombosis.
The emergence of drug-eluting stents (DES) transformed the care of coronary heart disease, with substantial declines in adverse outcomes following percutaneous coronary intervention (PCI), particularly in comparison to balloon angioplasty and bare metal stents (BMS). There is concern that polymer coatings, which are necessary for efficient drug release, may cause localized inflammation within the coronary segment to be treated, increasing the likelihood of prolonged healing time and thrombotic complications. Drug-eluting stents (DES) have an evident advantage over conventional bare metal stents in reducing the rate of recurring revascularization, but this advantage has been offset by a higher rate of late thrombotic events and restenosis [42]. Nonpolymeric drug-coated stents have been developed as a replacement for biodegradable and long-lasting polymeric DES. However, the absence of a drug carrier has been associated with decreased effectiveness in inhibiting neointimal hyperplasia, most likely due to inadequate or uncontrolled drug delivery at the target coronary site [18].
Polymer-free biofilms A9-coated BioFreedom stent and the ultrathin strut biodegradable polymer sirolimuseluting Orsiro stent were compared for the first time in the SORT OUT IX trial [18]. There was no statistically significant difference between the two stents on the composite target lesion failure (TLF) endpoint at the two-year follow-up. TLR risk persisted for an additional two years in the BioFreedom stent group. The risk of TLR was similar between groups in the second year after implant placement, while the risk of medically driven TLR was larger during the first year [36]. Different DES technologies used by the BioFreedom stent and the other stents tested resulted in a higher TLR rate for the former. Drug release from the study stent occurs at a different rate than from other stents. BioFreedom stents, which are polymer-free, release 90% of their drug within 48 hours. The Orsiro stent is coated in a polymer made of silicon carbide, which breaks down over the course of 12 to 24 months to release the drug gradually over the course of three months. Second, the BioFreedom stent's struts are thicker (120 m) than the Orsiro's (60-80 m), and this is known to affect restenosis risk [35,36].
Numerous studies have examined the causes of these post-DES implant delayed events and found that stent features and fundamental health factors, such as older age, diabetes, and acute manifestations, may operate as independent risk factors of late stent consequences. Ullah et al. [43] suggested that patients who received either PF-DES or PC-DES appeared to have a similar risk of major adverse cardiovascular events (MACEs), strokes, MI, stent thrombosis, and the need for target lesion and vessel revascularization (TLR and TVR) [43]. Their overall results were consistent across multiple subgroup analyses based on the length of follow-up (one month to 10 years), the presence of diabetes mellitus (DM), the clinical presentation (angina vs. STEMI), and the kind of drug-eluting PF stents used. In comparison to PC-DES, the odds of overall noncardiovascular and all-cause mortality in PF-DES were 22% and 13% lower, respectively. Regardless of the clinical presentation (angina or acute coronary syndrome (ACS)) or history of diabetes mellitus (DM), these observations were most emphasized at long follow-up intervals and in patients receiving rapamycin plus probucol eluting PF stents. In all of the foregoing predetermined subgroup analyses, there was no longer a difference between the two groups in mortality or any other clinical outcomes.
In an investigation, 3002 people with coronary heart disease were given either polymer-free sirolimus-and probucol-eluting stents (PF-SES: n = 2002) or durable zotarolimus-eluting stents (DP-ZES: n = 1000) as their treatment. In the randomized Intracoronary Stenting and Angiographic Restenosis-Test Equivalence Between Two Drug-Eluting Stents (ISAR-TEST) 5 trial, the rates of all-cause mortality, any myocardial infarction, and any revascularization were significant but similar in patients with diabetes mellitus handled with PF-SES as compared to DP-ZES (74.8% vs. 79.6%; P = 0.08; hazard ratio 0.86; 95% CI 0.73-1.02) and patients without diabetes mellitus (PF-SES 62.5% vs. DP-ZES 62.2%; P = 0.88; hazard ratio 0.99; 95% CI 0.88-1.11) [44]. Death rates were lower in the 3151 patients who participated in the SORT OUT IX trial [18], which equated PF-DES with the coming generation of BP-sirolimus eluting stents, but the rate of TLR was more than doubled (3.5% vs. 1.3%), leading to a null prognostic effect. Even though PF-DES has been shown to speed up re-endothelization and decrease late-lumen loss upon angiographic re-evaluation of the stent, its effects on the outcome are still up for debate.
This recent paper of more extensive randomized clinical trials allows us to conduct the current metaanalysis, which compares PF-DES to PC-DES, including PP and BP-DES. We discovered that patients who received the new stents had a reduced all-cause mortality rate, similar to what Nogic et al. [45] discovered. However, this increase in survival was not due to a reduction in recurring ischemic episodes or cardiovascular deaths. Admittedly, our study's findings were unaffected by patients' risk profiles, as validated by meta-regression analysis or the expulsion of trials undertaken in specific patient subgroups, such as STEMI or diabetic patients. Indeed, it could be argued that the low frequency of events influenced the results of previous and current meta-analyses. In particular, 1% of patients developed stent thrombosis, which could be attributed to the inclusion of a low-risk community of stable patients with confined outgrowths of cardiovascular problems. The vast majority of trials were underwhelming in assessing actual result metrics, and the greatest benefits of PF-DES were confirmed in trials encompassing subgroups of patients at greater risk [44,45].
In a cohort of patients receiving percutaneous coronary intervention for coronary bifurcation disease, Gallone et al. [39] reported no significant difference in the risk of major adverse cardiac events (MACE) between the polymer-free-biolimus eluting stent (PF-BES) and the ZES stents at 400 days. Patients who were presented with stable coronary artery disease or non-left main (LM) bifurcation lesions had a trend towards higher rates of adverse events with the PF-BES, but these rates were not statistically significant [39]. In aspects of major adverse cardiovascular events, all-cause mortality, stent thrombosis, and target lesion revascularizations, the current analysis suggests that both PF-BES and ZES have an improved therapeutic profile when used for the cure of bifurcation lesions. Relevantly, despite being largely non-statistically significant, numerical differences were discovered in the hazard ratios of the majority of the investigated outcomes. These differences were consistent in both the primary and sub-group analyses, suggesting that they may have clinical significance [36].
We used univariate meta-regression to evaluate heterogeneity and investigate possible differences between the datasets. This study found that the male gender and a history of myocardial infarction (MI) independently contributed to a higher risk of death from all causes and cardiovascular death. At the same time, age played no role in the association. Using meta-regression analysis, Verdoia et al. [46] defined multiple correlations; nevertheless, the advantages of the more recent PFDES method were not dependent on the patient's identified risks (p = 0.91), the prevalence of diabetes mellitus (r = 0.008, p = 0.08), or the incidence of acute coronary syndromes (p = 0.14).

Study Limitations
Our study has some limitations. The first one relates to the combination of multiple trials. Although the outcomes showed no notable heterogeneity, there were differences in the baseline risk profiles of the participants included in the study, such as patients with stable and acute coronary syndromes, as well as various stent comparators in the comparison group, including older and newer generation PP-DES and BP-DES. Additionally, the analysis included fewer, more extensive trials, which may have resulted in insignificant secondary outcomes due to their low occurrence rate. Thirdly, the follow-up duration varied widely among studies, with some indicating much longer durations than others. It is preferable to conduct long-term studies when evaluating the efficacy and safety of surgical implants, particularly in heart surgery, to identify the most significant benefits and harms.

Conclusions
Our recent meta-analysis shows that compared to conventional DES, PF-DES is associated with lower risks of all-cause mortality but no difference in the incidence of cardiovascular mortality, cerebrovascular accidents, myocardial infarction, or major adverse cardiovascular events. Future research will undoubtedly be required to explore and corroborate our study findings, particularly in specific clinical subsets such as those at higher risk of bleeding or experiencing an acute myocardial infarction.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.