One Ring to Revascularize Them All: Assessing The End Results of Coronary Bioresorbable Vascular Scaffolds as Revascularization Approach for Chronic Total Occlusions

Following the era of percutaneous coronary intervention (PCI), the occurrence of revascularization in chronic total occlusions (CTO) is correlated with positive and longstanding echocardiographic and clinical outcomes. The benecial outcomes of bioresorbable vascular scaffolds (BVS) treatment to manage CTO are currently inconclusive, since patients presenting with CTO were frequently ruled out from a vast number of randomized clinical trials (RCTs) which assess BVS. This systematic review is aimed to review and recapitulate available reports on the clinical outcomes of CTO with BVS treatment. Available data in the Cochrane Library, EMBASE, MEDLINE, and, clinicaltrials.gov are being examined to gather investigations on BVS-treated CTO. Outcomes of concern involved vessel restenosis, scaffold thrombosis, target lesion revascularization, myocardial infarction, major adverse cardiac events (MACE), and all-cause mortality. Thirteen papers have met the criteria for inclusion. All papers were written based on observational studies cumulative population samples of 1,077. Two papers were found to involve retrospective comparison of drug-eluting stents (DES) group with BVS group. The investigations had varying group size and duration of follow-up. This review presented benecial results for BVS-treated CTO. In double-arm studies, the recorded MACE incidence diverged from 0% to 6.7% with no notable differences between DES and BVS populations. While reports on the implantation of the rst-generation BVS in CTO populations are infrequent and recruited only insucient observational studies samples, the available data is promising. The data shows satisfactory results which are analogous to second-generation DES. However, additional investigation by means of RCTs and the application of more novel scaffolds is necessitated.


Introduction
In coronary artery diseases, the condition of chronic total occlusion (CTO) is described as a fully occluded vessel with thrombolysis in myocardial infarction (TIMI) patients, with a grade of ow 0 and persisting for longer than three months [1]. CTOs exist in roughly 20% of individuals who are receiving elective angiography due to coronary artery disease [2]. CTO revascularization approach by percutaneous coronary intervention (PCI) is correlated with a relief of chest pain (angina), moderation in infarct expansion of the myocardium, better function of the left ventricular, smaller probability for the need of future coronary artery bypass grafting, and greater patients survival despite existing manifestation of collateral circulation [3][4][5]. However, since the use of multiple, consecutive, and extended stents (known as the vessel caging) are usually needed to administer a vessel with CTO, the vessel is predisposed to hazards of delayed restenosis and stent thrombosis [6][7][8]. A substitute choice for treatment is offered by the bioresorbable vascular scaffolds (BVS). The novel characteristics of BVS enable them to advance the healing process of vessel, facilitating for the remodelling of the vascular system, preventing delayed lumen enlargement, and reviving the normal vasomotion. All these effects result in escaping the issues of vessel caging and the hazard of delayed thrombosis [9,10]. The bene cial outcomes derived from incorporating bioresorbable vascular scaffolds (BVS) to manage CTO are currently inconclusive since patients presenting with CTO were frequently ruled out from a vast number of randomized clinical trials (RCTs) assessing BVS. This systematic review is aimed to compile available reports on the clinical outcomes of CTO with BVS treatment.

Materials And Methods
This review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [11]. Systematic electronic searches were implemented in the Cochrane library, EMBASE, MEDLINE, and clinicaltrials.gov for systematic reviews, observational studies, case series, and clinical trials on Abbott Vascular's Absorb bioresorbable vascular scaffolds in patients presenting with chronic total occlusions. Extensive search keywords were incorporated: "chronic total occlusion" and "bioresorbable vascular scaffold". These keywords were consolidated employing the Boolean operator.
Furthermore, to gather supplementary references, additional publications were sought from the chosen papers and papers that cited the chosen investigations.
Studies were chosen to review once they satis ed the following criteria of inclusion: patients with age of equal to or more than 18 years; chronic total occlusion (CTO) manifestations of one or more coronary arteries; incorporating bioresorbable vascular scaffolds implantation; disclosed a minimum of one e cacy and safety outcomes: vessel restenosis, stent or scaffold thrombosis (ST), target lesion revascularization (TLR), myocardial infarction (MI), major adverse cardiac events (MACE), cardiac death, and all-cause mortality; having a minimum of three months of patients follow-up.
Exclusion criteria for studies elimination were: investigations using a language other than English; case series and case reports having fewer than ten samples; investigations recruiting subjects other than human. The collection of papers for tness of criteria and data harvesting was performed by PHW. Selected evidence included study design, study type, publication year, clinical and demographic features, primary and secondary outcomes, and follow-up duration. Selected outcomes were successful procedure approach, ST, TLR, target vessel revascularization (TVR), MI, MACE, and deaths by non-cardiac and cardiac causes. Outcomes were recorded quantitatively and published as the total study population percentages. On account of the heterogeneity of study design among the included investigations, metaanalysis of evidence was not conducted. Selected papers were assessed for possible biases utilizing the Cochrane risk of bias assessment tool (ROBINS-I).

Results
Applying the strategy for evidence search as outlined, we distinguished potential data, and 95 identical papers were spotted and eliminated. The remaining papers were ltered. Papers using a language other than English, editorials, review articles, conference abstracts, case series and case reports having fewer than ten samples were further eliminated. A sum of thirteen papers ful lled the criteria of inclusion for investigation.

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All investigations selected were observational study. A total of 1,077 patients were included, having a median size of the population of 41, with interquartile range (IQR) of 29.5 to 67.5 individuals. The median follow-up period was 3.3 months to 23.5 months. Male patients were dominant in the population (77.5% to 98%), comprising a mean age of 56.9 years to 65.7 years. Of 13 papers selected, 11 were retrospective cohort investigations, and therefore did not constitute a control population. The remaining two were double-arm investigations which constituted comparator populations which retrospectively contrasted drug-eluting stents (DES) with BVS. All investigations described the term CTO identically as a complete vessel occlusion with TIMI ow of zero for longer than three months period. The primary and secondary outcomes differ moderately from one investigation to another, as seen in Table 1. However, they were primarily concentrated on the effect of combination or individual impact of major adverse cardiovascular events such as ischemia-driven target lesion revascularization, myocardial infarction, and cardiac death.

Single-Arm Studies
Eleven single-arm investigations were selected, most of which were small retrospective and prospective studies [6, 12-14, 16-19, 21-23]. Clinical and demographic features were alike in all investigations as do with their published end results.
The median duration of follow-up in this population ranged from 108 days to 556 days. A combination of target lesion revascularization, target vessel MI, and cardiac death was published in ve investigations, resulting in 2.64% (95% CI: 1.04% to 4.24%). Yamaç et al. conducted an investigation which recorded one cardiac death (3 percent of their samples) throughout the period of follow-up [16]. However, only Maeremans et al. recorded one non-cardiac mortality (2.4% of their samples) [14]. The non-fatal myocardial infarction incidence was reported to be 1.07% (95% CI: 0.09% to 2.06%). Target lesion revascularization incidence was reported to be 2.51% (95% CI: 0.86% to 4.16%). The greatest rate of target lesion revascularization was 8.6% as recorded by Yamaç et al. [16]. The scaffold or stent thrombosis incidence was reported to be 1.3% (95% CI: -0.09% to 2.39%). The combined restenosis rate, as reported in six investigations, was 4.45% (95% CI: 2.04% to 6.86%). Using the primary tool of ROBINS-I to evaluate the non-randomized investigations, each paper went through a detailed assessment of possible biases. Considering that a minimum of one evaluated areas of every investigation was concluded to possess a risk for critical bias, the tool revealed that twelve investigations had an overall risk for critical bias. The report by Azzalini et al. was assessed to possess a severe bias risk.

Double-Arm Studies
Two double-arm investigations were selected, comparing DES with BVS in detailed evidence of follow-up as seen in Table 2. The bigger investigation was conducted by Azzalini et al. in a multi-center retrospective registry, involving 537 subjects [20]. The study juxtaposed the end results of patients (n=153) who were implanted with the rst-generation Absorb BVS and compared them to another group (n=384) who were treated with second-generation DES.
The primary outcome was a target vessel failure (TVF), being described as the combination of ischemiadriven TLR, target vessel myocardial infarction, and cardiac death. The median duration of follow-up was 703 days with IQR of 426 days to 989 days. There were no notable differences in events rates among the two groups.  Discussion DES still leads as the preferred device for percutaneous coronary interventions, however, BVS was invented as a substitute to DES. The theoretical bene t of BVS lies on full resorption of scaffolds or stents after two years of implantation with the resultant vasomotion rehabilitation. This condition avoids the potential "caged vessel" complication which eventually leads to delayed thrombosis of the stent [9,10]. Theoretically, those features should be favorable for the revascularization procedures of CTO where an extended length of scaffold segment is frequently necessitated. Nonetheless, these favorable features would require con rmation in clinical trials before being approved for comprehensive technology use.
This review collected 13 investigations of generally moderate evidence. The analysis of selected papers exhibited promising outcomes for the implantation of BVS in CTO population. The majority of the investigations exhibited a relatively small incidence of combination and individual outcomes after a reasonable period of follow-up.
Azzalini et al. executed a comprehensive double-arm investigation which carried out the unadjusted analysis and the primary adjusted analysis. They did not exhibit any statistically signi cant difference in the long-term results within the BVS and DES population. However, the investigation revealed an inclination to a greater adjusted risk in the BVS group for ischemia-driven target lesion failure than the DES group [20]. Despite showing moderate-quality evidence in CTO, three new trials have pointed out a heightened stent thrombosis risk in comparison with DES in PCI [24][25][26]. The differences of conclusions from selected RCTs could be attributed to variable hemodynamics in CTO stenting, selection of patients, inadequate follow-up, and variations in reporting in this review.
This inclination could be described by distinguishing the rst-generation BVS with second-generation DES, since the latter is equipped with ner struts and therefore generating lower blood ow turbulence in addition to less thrombosis restenosis risk [27]. As a consequence of ow disturbances, concerns about rising cases of scaffold thrombosis (ST) were brought up and were also con rmed by multiple trials and meta-analysis. Those investigations revealed a heightened scaffold thrombosis incidence in comparison to DES [24][25][26]. However, this review did not show any distinction in the rate of thrombosis between BVS and DES groups in CTO patients. Additionally, in single-arm observational investigations, the incidence of thrombosis was found to be faint. This nding could be associated with inadequate sample size. It can also be explained by careful selection of lesion for intervention to avoid small vessels with a lower velocity of blood ow and more skillful operators who are exposed to the lesions' complexity using supplementary imaging modalities, such as optical coherence tomography or intravascular ultrasound. Finally, recent concerns should also be examined, especially related to the possible subclinical complication of restenosis in CTO lesion and also stent or scaffold thrombosis [20].
Angiographic follow-up is essential for the aforementioned reason to reveal the accurate incidence rates of scaffold thrombosis and restenosis. In this review, eight investigations conducted a concrete noninvasive or invasive angiographic follow-up after the implantation of BVS. However, in most investigations, this imaging method was performed not in all patients, making the accurate rates of scaffold thrombosis or restenosis to be underestimated. For example, Mitomo et al. in 2017 reported that only as much as 33.8% of patients went through the angiographic follow-up [13] while in 2018, Maeremans et al. recorded approximately 83% of patients went through the multi-slice computed tomography angiographic follow-up [14]. Despite encouraging ndings, the rst-generation BVS was withdrawn from the guideline for clinical practice in an account of the safety alert issued by Food and Drug Administration to Absorb BVS (Abbott) device owing to its con rmed heightened rates for ST [28]. The next-generation BVS, with enhanced ow parameters and ner struts, is recently undergoing research with promising preliminary outcomes [29]. Simultaneously, published evidence on the effectiveness of second-generation stents or scaffolds for CTO are currently absent.

LIMITATIONS
This review has multiple constraints. First, involved investigations were observational in design, and published RCTs are absent to date. This condition makes the available evidence prone to possible biases, such as confounding and selection biases. The existence of such biases was considered to be of inferior quality in this review. Second, given a notable heterogeneity in studies involved, a meta-analysis could not be executed. Therefore, a systematic review is preferred. Third, the median duration of follow-up for most of the studies was shorter than two years, putting hindrances on the capacity to evaluate the theoretical bene ts of BVS after the scaffold or stent resorption. Fourth, involved investigations studied only the rstgeneration BVS Absorb, which possess un attering ow characteristics.

Conclusions
The evidence studying the application of the rst-generation BVS in CTO patients is not many in number and restricted by inadequate sample in observational studies. Currently, the available evidence is optimistic and implies satisfactory outcomes as compared to the second-generation DES. Additional research and investigation by means of randomized clinical trials and the employment of newer, more superiorly-designed generation of stents and scaffolds is necessitated to control confounders and to determine the existence of a signi cant distinction among these devices.

Declarations
Funding None.

Con ict of Interest
The author declares there is no con ict of interest regarding all aspect of the study.

Author Contribution
PHW is responsible for the study from the search of papers and articles, data gathering, data analysis, until reporting the results of the review.