Ultrathin Strut Biodegradable Polymer-Coated Sirolimus-Eluting Coronary Stents: Patient-Level Pooled Analysis From Two Indian Registries

Background Despite significant evolution in stent technology, female gender, and patients with diabetes mellitus, multivessel disease, total occlusions, long lesions, and small vessels represent the “Achilles' heel” of contemporary percutaneous coronary intervention (PCI). We performed a pooled analysis of high-risk subgroup on patient-level data from the T-Flex registry (1,203 patients) and a real-world Indian registry (1,269 patients), with the aim of assessing one-year safety and clinical performance of ultrathin strut biodegradable polymer-coated Supra family of sirolimus-eluting stents (SES) (Sahajanand Medical Technologies Limited, Surat, India) in the real-world, all-comer population. Method We pooled the following high-risk subgroups data from two all-comer registries: female gender (n=678), diabetes mellitus (n=852), multivessel disease (n=406), total occlusions (n=420), long lesions (≥28 mm) (n=1241), and small vessels (≤2.5 mm) (n=726). Both the registries included patients with coronary artery disease who underwent implantation of at least one SES belonging to the Supra family of stents from May 2016 until March 2018, irrespective of lesion complexity and comorbidities. The primary endpoint was the incidence of target lesion failure (TLF), a composite of cardiac death, target vessel myocardial infarction, and clinically indicated target lesion revascularization by percutaneous or surgical methods up to one year. The safety endpoint was stent thrombosis. Results According to prespecified high-risk subgroups, one-year rates of TLF and overall stent thrombosis, respectively, were as follows: female gender (4.9% and 0.6%), diabetes mellitus (6.9% and 1.0%), multivessel disease (6.4% and 0.8%), total occlusions (5.2% and 0.5%), long lesions (≥28 mm) (6.6% and 0.8%), and small vessels (≤2.5 mm) (6.1% and 1.3%). Conclusion This present pooled analysis demonstrated the one-year safety and clinical performance of ultrathin strut biodegradable polymer-coated Supra family of SES in a real-world, all-comer population, with considerably low rates of TLF and stent thrombosis.


Introduction
Percutaneous coronary intervention (PCI) is the frontline treatment for interventional cardiologists in managing coronary artery disease (CAD). Although no universal definition of complex PCI exists [1], there is an emerging consensus that complex PCI and higher-risk indicated populations involve clinical risk factors and characteristics of coronary lesions and PCI procedures. Approximately 30% of all PCI procedures are considered complex depending on the lesion or anatomic factors [2]. The complex PCI population remains at higher risk of mid-to long-term adverse ischemic events [2,3].
Coronary anatomic complexity serves as an important determinant in the decision-making between PCI and coronary artery bypass graft (CABG). U.S. Food and Drug Administration (USFDA) gave an on-label indication for the use of drug-eluting stents (DES) in simple, single, de novo coronary lesions in low-risk patients with CAD. Nevertheless, a number of PCIs are currently performed in patients with high-risk clinical and anatomic characteristics [4][5][6][7][8]. It has been reported that the complex PCI with DES is associated with a markedly higher ischemic risk, in a graded fashion, with expected lower procedural success rates with an increased risk of procedural complications [9,10]. Several clinical trials have shown that DES has limited capability to prevent target lesion revascularization (TLR) in patients with complex lesions, whereas many studies confirmed similar clinical outcomes between patients with complex PCI and those with noncomplex PCI [11][12][13]. These conflicting findings have driven clinical studies to investigate the safety and effectiveness of the latest-generation DES in complex PCI subsets.
The Supra family of stents (Sahajanand Medical Technologies Limited, Surat, India) are the latestgeneration ultrathin strut biodegradable polymer-coated sirolimus-eluting stents (SES). One-year safety and efficacy of the Supra family of SES in real-world, all-comer CAD population has already been addressed in the literature [14][15][16][17]. However, there is a lack of data about its safety and efficacy in the most frequently encountered challenging PCI subsets -female gender and patients with diabetes mellitus, multivessel disease, total occlusions, long lesions, and small vessels. Against this background, we aimed to assess the one-year safety and clinical performance of the Supra family of SES in a real-world all-comer population, using a pooled analysis of high-risk subgroups on patient-level data from two all-comer registries [15,17].

Study design and population
We pooled high-risk subgroup data from 2471 CAD patients enrolled in two all-comer registries: T-Flex registry (n=1,203) [15] and a real-world Indian registry (n=1,269) [17]. High-risk subgroups derived from two all-comer registries included female gender (n=678), diabetes mellitus (n=852), multivessel disease (n=406), total occlusions (n=420), long lesions (≥28 mm) (n=1241), and small vessels (≤2.5 mm) (n=726). Both the registries comprised patients with CAD who underwent implantation of at least one SES belonging to the Supra family of SES between May 2016 and March 2018, irrespective of lesion complexity and comorbidities. Institutional Ethics Committee (IEC) granted approval for the study protocol and both registries adhered to the tenets of the Declaration of Helsinki. Signed informed consent was obtained from each patient for data collection and analysis for research purposes and the use of anonymized clinical data.

Description of study stent
The study stents were ultrathin strut (60 µm) biodegradable polymer-coated SES designed with a unique long dual-Z link (LDZ-link) between 'valley-to-valley' on Tetrinium L-605 cobalt-chromium alloy as its stent platform (Sahajanand Medical Technologies Limited, Surat, India). These latest-generation stents feature a multilayer conformal coating on the surface, which contains 1.4 μg/mm2 of sirolimus in the centre and the innermost layer, amalgamate with a biodegradable polymeric matrix composed of a combination of hydrophobic [PLLA: poly(L-lactide)], PLCL: poly(L-lactide-co-caprolactone)], and outer drug-free hydrophilic polymers (PVP: polyvinylpyrrolidone). Approximately 80% of the drug is released within four weeks in biological media. The remaining drug is programmed to be released at a slow rate in about three months. Once the drug is released, biodegradable polymers progressively degrade into biologically acceptable molecules and excreted from the body. The average coating thickness of SES is between 4 and 6 μm.

Coronary interventional procedure and adjuvant medications
Coronary interventional procedures and adjuvant medications were carried out in accordance with standard practice guidelines. All the patients were recommended for dual antiplatelet therapy (DAPT) for at least up to 12 months (aspirin 75-300 mg daily indefinitely and clopidogrel 75 mg daily or prasugrel 10 mg daily or ticagrelor 90 mg twice daily) after the procedure. Follow-up was obtained either via clinical followup or telephonic contact one year after stent implantation.
The baseline demographic and clinical details of the pooled high-risk subgroups are outlined in Table 1 Lesion details, n (%)  The one-year follow-up data obtained for high-risk subgroups were as follows (  One-year cumulative TLF rates for stated high-risk subgroups determined by the Kaplan-Meier method are depicted in Figures 1-3.

Discussion
As expected, findings emerged from the present pooled analysis demonstrated that one-year safety and clinical performance of ultrathin strut (60 µm) biodegradable polymer-coated SES was favourable in treating complex PCI subsets, including female gender, diabetes mellitus, multivessel disease, total occlusions, long lesions, and small vessels, with low events of TLF and stent thrombosis.
Many previous studies asserted that gender disparities significantly affect the clinical outcomes of PCI. Compared to males, females are more prone to major cardiovascular adverse events (including death) and target vessel failure after PCI [18][19][20][21][22]. These higher event rates in females are mainly attributed to postmenopausal states, smaller coronary arteries [23], and smaller radial arteries [24]. Hormonal changes after menopause, as such, low plasma estrogen levels and elevated luteinizing hormone (LH) and folliclestimulating hormone (FSH) levels, have a significant impact on the metabolism of plasma lipids and lipoproteins, ultimately leading to cardiac-related diseases [25,26]. Smaller coronary artery diameter has proved to be associated with low PCI success rate and higher incidence of subsequent in-hospital major adverse events [23]. Smaller radial arteries are more susceptible to vascular spasms, which is a primary cause of radial procedure failure [24]. Briefly, females designate one of the challenging subsets of the complex PCI population. Our study demonstrated a lower death rate (1.4%) in females than that of earlier reported rates in the Melbourne Interventional Group (MIG) PCI registry (6.4%) [27] [29].
Diabetes is often viewed as a "dreadful threat" in patients with CAD. It has been allied with adverse events such as increased incidence of restenosis, repeat revascularization, stent thrombosis (ST), and all-cause mortality after PCI. Of concern, diabetes patients exhibit diverse anatomical patterns of CAD, including multivessel stenosis, smaller vessel size, left main involvement, and rapidly progressing, more diffuse, and longer atherosclerotic lesions [30], which make revascularization more challenging. A subgroup analysis of the SIRIUS trial [31] and the DIABETES trial [32] paved the way for beginning a new SES era in CAD patients with diabetes. However, safety-related concerns are raised with SES implantation as diabetic patients have increased thrombocyte aggregation and thrombotic events [33]. We found a 6.9% one-year TLF rate with ultrathin strut biodegradable polymer-coated SES in the diabetic population.  With a growing number of aging population with various comorbidities, including diabetes and obesity, the prevalence of multivessel disease has been projected to rise, representing 30% to 40% of CAD patients [38]. Patients with multivessel disease are more likely to have worse clinical outcomes than those with singlevessel disease [39]. PCI and CABG are the established revascularization strategies in patients with multivessel CAD. Nonetheless, the selection of optimal revascularization strategies remains a subject of intense discussion and debate. The discovery of DES has greatly enriched the conventional PCI era with promising outcomes in complex lesions, including multivessel disease. Consistent with one-year TLF rate for multivessel disease with the Ultimaster SES (Terumo Corporation, Tokyo, Japan) in e-Ultimaster registry (4.2%) [40] and Supraflex SES (10%) and Xience EES (5.7%) in TALENT trial [14], the present study demonstrated 6.4% one-year TLF rate with ultrathin strut biodegradable polymer-coated SES in multivessel disease subgroup ( Table 4).
Labeled as the most challenging and growing subset of the complex PCI population, total occlusions have been plagued by a number of procedural complications including coronary perforation, periprocedural myocardial infarction, arrhythmias, cardiogenic shock, stroke, major bleeding, donor vessel thrombosis, contrast-induced nephropathy, radiation damage, and death and adverse clinical events [41]. It has been stated that chronic total occlusions (CTO-PCI) are high-risk procedures with low success rates than standard PCI. A significant breakthrough in recanalization techniques, the introduction of dedicated equipment and the development of systematic algorithmic approaches have significantly improved procedural success and reduced the occurrence of major complications [42,43]. Numerous risk factors including sex, hypertension, smoking, and diabetes can affect the prognosis in patients with CTO lesions, which could lead to an increase in the frequency of adverse cardiovascular events. Control of these influential risk factors should be encouraged with routine follow-up. Despite the presence of multiple comorbidities/history, such as hypertension (45.0%), hypercholesteremia (35.0%), diabetes mellitus (31.2%), and previous revascularization (1.2% CABG and 7.1% PCI), we observed a 5.2% one-year TLF rate with ultrathin strut biodegradable polymer-coated SES in total occlusions subgroup. These values were in accordance with the values reported for Ultimaster SES in the e-Ultimaster registry (3.3%) [40], and Orsiro SES in BIOFLOW III Italian Satellite Registry (5.3%) [35] ( Table 4).
Long lesions are associated with more adverse events after DES implantation, including higher rates of restenosis, periprocedural myocardial infarction, and stent thrombosis, which portrays the Achilles' heel of PCI. Despite refinement in devices and techniques, the intervention of long lesions poses technical difficulties such as stent deliverability, stent overlap, geographical miss, and prolonged intracoronary manipulation because of the multiple and overlapping stent placement which may impair the vessel wall integrity [44]. Mounting evidence supports the concept that multiple stent implantations in long lesions appear to have similar clinical outcomes to that of single long stent implantation [45][46][47][48]. The implantation of a single long stent yield reduction in catheterization time, dye volume for the patient, radiation exposure for both patient and operator, and procedural costs, compared to multiple stent implantations [48]. Long lesions have been frequently under-represented in clinical trials because of apparent heterogeneity in published definitions and limited stent length [49]. Latest-generations DES have emerged to treat long lesions in concert with unique stent characteristics, such as low loss rate to reduce restenosis risks, thin struts to enhance deliverability and reduce the risk of periprocedural infarction, and availability of long lengths to minimize overlap and avoid geographical miss [44].
Although the history of PCI has been transitioned from plain old balloon angioplasty and bare metal stents to a variety of DES generations, clinical outcomes in small vessels remain far from satisfactory than those with large vessels. Higher incidences of in-stent restenosis and overall recurrent ischemic events have been reported after PCI of small vessels, which mainly occurs due to neointimal hyperplasia and inflammation [56]. There is a lack of standardized definitions for small vessel CAD. At one year, the TLF occurred in 6.1% of patients with ultrathin strut biodegradable polymer-coated SES in our subgroup of small vessels (≤2.5 mm reference vessel diameter). This TLF rate compared favourably with previous data wherein small lesions treated with Supraflex SES (8%) and Xience EES (5.8%) in the TALENT trial [14], Xience V EES from Xience V USA Condition of Approval Post-Market study (5.7%) [57], Orsiro SES (8%) and Xience EES (11%) from BIOFLOW V trial [51], Ultimaster SES in CENTURY JSV study (4.3%,) [58] Xience V EES in SPIRIT Small Vessel Trial (8.1%) [59], and Resolute Integrity ZES in the RESTORE SVD China Randomized Trial (5.0%) [60] ( Table 4).
The rates of stent thrombosis in all six subgroups were also comparable with other similar studies [36,41,52] -0.6% in female patients, 1% in patients with diabetes mellitus, 0.8% in patients with multi-vessel disease, 0.5% in patients with total occlusion, 0.8% in patients with long coronary lesions (≥28 mm), and 1.3% in patients with small diameter vessels (≤2.5 mm).
The key strength of this pooled subgroup analysis is that we focused exclusively on complex-PCI populations from two large-scale, multicentre, real-world Indian registries with adequate patient sizes in each subgroup; hence, the results can be generalized to the overall population.
Thankful to the latest-generation DES, which has appreciably improved procedural success rates in complex PCI. Overall, the results with the ultrathin strut SES in this pooled analysis were favourable in terms of low rates of TLF rate and stent thrombosis at one year. The Supra family of SES demonstrated favourable clinical outcomes in challenging lesion subsets and patient population, which is mainly attributable to stent design innovation, including ultrathin strut (60 µm) along with biodegradable polymer matrix and unique LDZ-link design.

Conclusions
This pooled subgroup analysis confirmed the one-year safety and clinical performance of ultrathin strut biodegradable polymer-coated Supra family of SES in a real-world, all-comer Indian population, with markedly low rates of TLF and stent thrombosis.
The Supra family of SES has already been established as highly deliverable drug-eluting stents with low clinical event rates. This analysis covered an extensive range of complex and heterogenous PCI population in real-world settings providing additional data on efficacy and safety in complex patient and lesion subsets.

Additional Information Disclosures
Human subjects: Consent was obtained or waived by all participants in this study. Institutional Ethics Committee, Ramesh Hospitals, Vijayawada, India issued approval ECR/81/INST/AP/2013/RR/2016. The Institutional Ethics Committee (IEC) granted approval for the study protocol. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. 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.