One-Year Outcomes of Biodegradable Polymer-Coated Sirolimus-Eluting Coronary Stent in Acute Coronary Syndrome: A Patient-Level Pooled Analysis from Two Indian Registries Free

Acute coronary syndromes (ACSs), which comprise ST-segment elevation myocardial infarction (MI) (STEMI), non-STEMI (NSTEMI), and unstable angina, are characterized by abrupt reduction in myocardial blood supply. It is estimated that more than 7 million individuals worldwide are diagnosed with ACS annually [1]. Percutaneous coronary intervention (PCI) with drug-eluting stents (DESs) is the standard recommended approach for treating patients with ACS [2, 3]. However, unlike patients with stable angina, patients with ACS tend to have a greater burden of atherosclerotic plaque and inflammatory responses, which results in a significant delay in vascular healing and incomplete endothelialization post-DES implantation. The prolonged delay in healing and endothelization is associated with an increased risk of recurrent stent-related adverse events over the long term [4‒6]. To address the issue, it is imperative to have a stent design that promotes early and adequate strut coverage and vascular healing for patients with ACS.

Newer-generation DES with improved stent characteristics has been developed with a goal to reduce chronic inflammation and arterial injury while promoting rapid endothelialization and improving clinical outcomes after PCI in comparison to second-generation durable polymer DES. The newer advancements include the use of different antiproliferative drugs with varying release kinetics, thinner and improved stent struts with better designs, and the use of biodegradable polymer coatings or a polymer-free technology. The Supra family of DES (Sahajanand Medical Technologies Ltd., Surat, India) is the newer-generation sirolimus-eluting stents (SES) with biodegradable polymer coating on an ultrathin cobalt-chromium (Co-Cr) platform with unique long-dual Z-link design. According to a meta-analysis published in 2021, the use of ultrathin strut DES has been associated with a 15% lower risk of TLF in patients with ACS and 26% lower risk of TLF in patients with STEMI who underwent primary PCI, in comparison to second-generation DES with thicker struts [7]. While multiple registries and randomized controlled trials have demonstrated safety of the Supra family of SES in all-comers populations, including those with ACS, there remains a lack of clinical data regarding the use of ultrathin Supra family SES specifically in ACS-only patients [8‒15]. Therefore, we have performed this patient-level pooled analysis from two, stent-specific, real-world Indian registries and investigated 1-year clinical outcomes of the Supra family of SES in patients with ACS and STEMI.

The present analysis was based on patient-level pooled data from two retrospective real-world registries (T-Flex registry and Tetriflex real-world registry) involving patients with coronary artery disease who were treated with Supra family of SES. “T-Flex” [11] (n = 1,203) and “Tetriflex real world” [13] (n = 1,269) were both observational, multi-center retrospective registries conducted at different tertiary-care centers in India. Patients who underwent PCI for ACS were selected, and their baseline clinical characteristics, lesion and procedural data, as well as 1-year clinical outcomes data were combined for the purpose of conducting this pooled analysis.

The detailed description of the device has previous been published [11, 13]. In brief, the study device is a latest-generation biodegradable polymer-coated SES with Tetrinium L-605 cobalt-chromium ultrathin (60 μm) platform (Sahajanand Medical Technologies Ltd., Surat, India). It comprises multi-layer conformal coating of biodegradable polymers blended with sirolimus drug (average coating thickness: 4–6 μm). The outermost layer comprises a drug-free hydrophilic polymer (polyvinylpyrrolidone) followed by the middle and innermost layers, which comprise a combination of hydrophobic (poly-l-lactic acid and poly[l-lactide-co-ε-caprolactone]) polymers and sirolimus drug. Around 80% sirolimus drug is programmed for release in 1 month and the remaining 20% is programmed for controlled release up to 3 months. After releasing the drug, biodegradable polymers undergo hydrolysis and then gradually get excreted from the body as biologically acceptable molecules. It has a unique long-dual Z-link with “valley-to-valley” connection between the strut rings that increases the flexibility and trackability [16].

PCI was performed according to routine practices of all the study centers. In both the registries, all patients were pretreated with a loading dose of aspirin (150–300 mg) and either clopidogrel (600 mg), prasugrel (60 mg), or ticagrelor (two tablets of 90 mg each) during PCI. During the procedure, all patients received intravenous heparin or bivalirudin in the standard dosage as recommended by the guidelines, and use of glycoprotein IIb/IIIa inhibitors was left to the operator. In both the registries, the patients were prescribed dual antiplatelet therapy for at least up to 12 months (aspirin: 75–100 mg and clopidogrel: 75 mg daily or prasugrel: 10 mg daily or ticagrelor: 90 mg twice daily) followed by aspirin daily for life.

In this pooled analysis, the clinical endpoints were reported as originally defined in each registry [11, 13]. The primary endpoint was the occurrence of target lesion failure (TLF) at 1-year follow-up, which was a composite of cardiac death, target-vessel myocardial infarction (TV-MI), or target lesion revascularization (TLR). Secondary endpoints included device success, procedural success, and incidence of all separate components of the primary endpoint. At each follow-up, events of stent thrombosis, defined as per the Academic Research Consortium (ARC) definition [17], were evaluated as an additional safety endpoint.

Datasets from both the registries were first combined into one single dataset and then analyzed using IBM SPSS (version 20.0). Continuous variables were reported as the mean and standard deviation and dichotomous variables as counts and proportions. The incidence of events over time was studied with the use of the Kaplan-Meier method.

The current patient-level pooled analysis from two real-world Indian registries (n = 2,472 patients) includes 1,824 patients who were diagnosed with ACS and underwent PCI with the Supra family of SES. Among 1,824 patients with ACS, 689 patients who underwent PCI for STEMI were pooled further for the analysis.

The mean age of the whole pooled ACS cohort was 56.0 ± 10.8 years with male predominance (72.9%). Diabetes mellitus and hypertension were the risk factors of ACS in 32.0% (n = 583) and 30.4% (n = 555) patients, respectively. Among all, unstable angina (n = 796, 43.6%) was the clinical presentation in most of the ACS patients followed by STEMI (n = 689, 37.8%) and NSTEMI (n = 339, 18.6%). A total of 2,395 Supra family of SES were implanted for the treatment of 2,128 coronary lesions in 1,824 patients with ACS during the study duration. Of 2,128 lesions, 76.7% were type B2/C lesions and 16.2% were totally occluded. During PCI, 38.6% lesions were predilated and 44.6% lesions were post-dilated in the ACS cohort. The detailed baseline, lesion, and procedural characteristics of ACS cohort are outlined in Table 1, 2.

A total of 689 patients who underwent primary PCI for STEMI were further pooled from the ACS cohort and investigated. The mean age of patients with STEMI was 55.3 ± 11.5 years. Among all STEMI patients, hypertension was found in 40.1%, diabetes mellitus in 28.2%, and hypercholesterolemia in 28% patients. Around 21% of patients presented with STEMI were smokers. A total of 40.8% (n = 288) patients had multivessel disease and the left anterior descending artery was the culprit vessel in 50.5% of patients. A total of 784 lesions were treated with implantation of 893 Supra family SES of which 76.7% lesions were type B2/C and 21.9% lesions were totally occluded. The detailed characteristics of STEMI cohort are outlined in Table 1 and Table 2.

One-year clinical outcomes of the pooled ACS cohort (n = 1,824) and pooled STEMI cohort (n = 689) are summarized in Table 3. One-year follow-up data were available for 96.1% patients in the ACS cohort and 95.8% patients in STEMI cohort.

In the ACS cohort, cardiac deaths occurred in 15 (0.9%) patients, TV-MI in 43 (2.5%), and TLR in 34 (1.9%) patients resulting in a total of 92 (5.3%) TLF at 1-year follow-up. The overall stent thrombosis rate was 0.6% (n = 11) in the ACS cohort at 1-year follow-up. Among these, 2 cases were identified as definite stent thrombosis, both were acute (within 30 days). Four cases were classified as probable stent thrombosis, with three occurring acutely (within 30 days) and one presenting late (>1 month to 12 months).

In the STEMI cohort, 1-year TLF rates were 6.2% (n = 41), which included 1.4% (n = 9) cardiac death, 2.1% (n = 14) TV-MI, and 2.7% (n = 18) TLR. The rate of overall stent thrombosis was 1.2% (n = 8) at 1-year follow-up. Among this, there were 5 cases of definite/probable stent thrombosis, all of which were acute (within 30 days). The time to even curves for 1-year cumulative rate of TLF in patients with ACS and STEMI are presented in Figures 1 and 2, respectively.

The present pooled analysis, from two all-comers registries, focused on evaluating the newer-generation ultrathin Supra family of SES in the setting of ACS, involving a cohort of 1,824 patients, which includes 689 patients with STEMI. At 1-year follow-up, the Supra family of SES demonstrated favorable rates of TLF in patients with ACS (5.3%) as well as in patients with STEMI (6.2%). In addition, the Supra family of SES also demonstrated a high level of safety with minimal incidence of definite/probable stent thrombosis – 0.3% in patients with ACS and 0.7% in patients with STEMI, at 1-year follow-up.

Despite the technological advancements of DES, patients with ACS continue to exhibit increased risks of recurrent revascularization and worse prognosis after PCI. In the context of ACS, the plaque is more vulnerable and extremely prone to inflammatory reactions contributing toward delayed arterial healing and adverse vessel remodeling leading to stent thrombosis and restenosis [18‒22]. Theoretically, the newer-generation ultrathin strut DESs decrease flow disturbance, reduce vessel wall injury, and decrease thrombogenicity, which potentially limit inflammatory reactions and facilitate early vascular healing. As per several meta-analyses, these properties may translate into differential clinical outcomes with lower risk of TLF not only in all-comer patients [23] (16% lower risk of TLF) but also in patients with ACS [7] (15% lower risk of TLF) treated with newer-generation ultrathin strut DES when compared to contemporary thicker strut second-generation DES up to 1-year follow-up. Here, in the present analysis, a 5.3% incidence of TLF has been reported after implantation of the newer-generation ultrathin strut biodegradable polymer-coated Supra family of SES in patients with ACS, at 1-year follow-up. In line with our findings, the BIOFLOW V trial reported 5.6% TLF with ultrathin biodegradable polymer SES compared to 11% TLF with second-generation thin strut durable polymer everolimus-eluting stents in the ACS subgroup at 1-year follow-up, but the study excluded high-risk STEMI patients [24]. Similarly, the results of the SORT OUT X trial also reported 4.1% TLF rate with ultrathin biodegradable SES among ACS subgroup [25]. The results of a recently published FIRE trial reported that physiology-guided complete revascularization using Supraflex Cruz SES was associated with a lower occurrence of the composite of death, MI, stroke, or ischemia-driven revascularization than culprit-only revascularization in elderly patients (≥75 years) with acute MI (including STEMI and NSTEMI) [26].

In South Asia, STEMI constitutes the majority of ACS cases (∼60%). Primary PCI is the recommended reperfusion strategy for these patients, although its efficacy decreases if not performed within 120 min of initial medical contact [27‒29]. The literature provides substantial evidence linking STEMI with the unfavorable lesion morphology, high thrombus burden and platelet activity, and persistent inflammatory reactions, all of which contribute to the delay of arterial healing and vascular remodeling. These have highlighted STEMI as one of the major risk factors for early as well as late restenosis and late stent thrombosis following primary PCI [20, 30‒32]. However, latest-generation DES has gradually improved safety and efficacy outcomes compared with earlier generation DES and bare metal stents in patients with STEMI [33, 34]. A meta-analysis of 16 randomized controlled trials (22,766 patients) found a 26% reduction in TLF risk among patients with STEMI who underwent primary PCI with ultrathin strut DES compared with thicker strut second-generation DES [7]. The present pooled analysis of two real-world all-comers registries reported a TLF rate of 6.2% in patients with STEMI at 1-year follow-up. In line with our findings, the BIOFLOW-III all-comers registry [35] reported a TLF rate of 7.2% and the BIOFLOW-III Italian Satellite registry [36] reported a TLF rate of 5% with the Orsiro SES in patients with acute MI at 1-year follow-up. Similarly, the TALENT trial reported 2.5% device-oriented composite events with ultrathin Supraflex SES in patients with STEMI. In addition, the BIOSCIENCE trial [37] and BIOSTEMI trial [37] reported TLF rates of 3% and 4%, respectively, with Orsiro SES in patients with STEMI, at 1-year follow-up.

The newer-generation ultrathin strut DES with biodegradable polymers is designed to minimize acute arterial injury and to provide early vessel healing and uniform intimal coverage, which has been clinically demonstrated in intravascular imaging studies [38‒41]. Previous intravascular imaging studies have shown that the presence of uncovered and malapposed struts are the major causes of stent thrombosis [42]. In the TAXCO study (95% patients with ACS), ultrathin Supra family of SES showed almost complete stent coverage (97.6%) after 6 months of implantation by optical coherence tomography analysis [40]. This enhanced and favorable healing response may lead to improved clinical outcomes in the setting of ACS. Moreover, the results of an ongoing optical coherence tomography study evaluating the use of ultrathin strut biodegradable polymer-coated Supra family of SES in patients with STEMI (CTRI/2019/05/019298) will provide valuable insights into the vascular response of ultrathin DES in the context of STEMI. The present analysis reported low rate of definite/probable stent thrombosis in the ACS (0.1%) and STEMI (0.3%) subgroups. In contrast, the results of the BIOFLOW III all-comer registry (0.5%) and BIOFLOW V trial (0.5%) reported numerically higher rates of definite stent thrombosis with Orsiro SES in patients with acute MI and ACS without STEMI, respectively, at 1-year follow-up.

We have noted significant variability in the event rates reported across different randomized control trials and registries involving patients with ACS and STEMI. Several factors, in addition to the type of DES, such as patient and lesion complexity, medical therapy, functional assessment for myocardial ischemia, endpoint definitions, event reporting, data monitoring, and event adjudication can impact the reported event rates across different studies. Therefore, it is imperative to interpret the discrepancies in TLF rates while considering all of these factors and their potential influence on the reported outcomes.

The results of the present patient-level pooled analysis provide evidence for the safe and effective use of the Supra family of SES in complex patient populations such as ACS and STEMI, with favorable rates of TLF and stent thrombosis at 1-year follow-up.

Author Dr. Manohar K Inamdar and author Dr. Abhijit Pathak were not available to confirm co-authorship, but the corresponding author Dr. Ramesh Babu Pothineni affirms that author Dr. Manohar K Inamdar and author Dr. Abhijit Pathak contributed to the paper, had the opportunity to review the final version to be published, and guaranteed author Dr. Manohar K Inamdar and author Dr. Abhijit Pathak co-authorship status and the accuracy of the author contribution and conflict-of-interest statements.

The protocols of both the registries were approved by the institutional Ethics Committee of coordinating center (Dr. Ramesh Cardiac and Multispecialty Hospital [ECR/81/INST/AP/2013/RR/2016]). The registries were conducted in accordance with ethical principles and good clinical practice guidelines. The informed written consent was obtained from all the patients.

The authors have no conflicts of interest to declare.

The authors have not received any financial support.

Ramesh Babu Pothineni and Prakash Ajmera: conceptualization, data curation, formal analysis, investigation, methodology, validation, writing – original draft, and writing – review and editing; Kamal Kumar Chawla, Sai Sudhakar Mantravadi, and Abhijit Pathak: conceptualization, validation, and writing – review and editing; Manohar K. Inamdar and Pankaj Vinod Jariwala: data curation, formal analysis, investigation, methodology, validation, and writing – review and editing; Vikrant Vijan, Vinod Vijan, and Anil Potdar: conceptualization, data curation, methodology, validation, and writing – review and editing.

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.