European Journal of Cardiovascular Medicine

The most frequent cause of morbidity and mortality in the world is atherosclerosis, which manifests as cardiovascular disease, carotid artery disease, peripheral vascular disease, and renal artery stenosis.1,2 The two major therapies for blocked or constricted arteries are coronary artery bypass grafts (CABG) and percutaneous coronary interventions (PCI). While the current main treatment approach for severe CAD patients, especially for those with acute coronary syndromes (ACS), is PCI with stent. Annually, more than 1.5 million PCI procedures—mostly intracoronary stenting—are carried out worldwide. Despite significant device advancements, in-stent restenosis (ISR) remains a serious challenge.3 This is due to the injury to the endothelium of the arterial wall during PCI, weakening the arterial wall, and causing restenosis, or a narrowing of the artery. Major adverse outcomes including myocardial infarction and stroke became more likely as a result.4

Stenosis that occupies more than 50% of the vessel lumen diameter is referred to as ISR.5 The development of neointima and smooth muscle cell proliferation are the major causes of ISR. Modern PCI procedures have made drug-eluting stents (DESs) more effective in reducing restenosis rates. However, the rates of ISR, which were reported to be between 6% and 10% following DES implantation, have not significantly decreased.6

The main cause of ISR is neointimal hyperplasia due to endothelial damage to the balloon and/or struts of the stent. The damaged areas promote the activation of inflammatory cells, platelets, and mural thrombus. Circulating neutrophils and tissue macrophages are activated by vascular damage, mural thrombus, and a metallic foreign body. These components cause the production of cytokines and growth factors, which activate smooth muscle and stimulate the expression of genes that promote cell division, such as c-myc, resulting in increased cell proliferation. When metalloproteases are created, the extracellular matrix support matrix is remodelled, and smooth muscle cell migration is started.7

There are other reasons beyond stent characteristics that might cause it, including patient characteristics and concurrent comorbidities, procedural issues including under-expansion, additional drugs, etc.8 ISR can be either focal, diffusive, proliferative, or occlusive. Additionally, different types of stents have different ISR formation rates. Neointimal hyperplasia (NIH) and increasing numbers of smooth muscle cells in the vascular wall describe the diffuse, typical ISR of bare metal stents (BMS).9 ISR can be diagnosed with intravascular ultrasound or optical coherence tomography which further aid in management strategies.10

Indian studies evaluating the clinical presentation, patient characteristics, and management for ISR cases are scarce, and hence this study was conducted to address this research gap with an aim to study the clinical profile and angiographic patterns of patients admitted with ISR and they were followed for 6 months for outcomes associated with different treatment modalities.

After obtaining Institutional Ethical Committee approval and written informed consent from all the patients, this prospective, observational study was conducted in the Department of Cardiology, at tertiary care teaching hospital during a period between January 2022 to March 2023. The study population were adult males and females’ patients of age more than 18 years admitted with ISR and voluntarily agreed to participate in the study were included in the study. Saphenous vein grafts or other non-native coronary vessels ISR, patients having cardiogenic shock at the time of the index ISR procedure and had an estimated life expectancy <6 months due to non-cardiac illness were excluded from the study. Study protocol was approved from institutional ethics committee. The demographic details of the patients were noted down at the start of the study (Age, gender, BMI). A detailed medical and personal history was taken (hypertension, dyslipidaemia, diabetes mellitus, smoking, and chronic kidney disease not treated with dialysis). All patients underwent a general and cardiac evaluation. We evaluated the types of clinical presentation, average time of occurrence of ISR, laboratory parameters (Lipid profile, Total cholesterol, LDL, HDL, TG), the type of treatment performed, angiographic characteristics of ISR, treatment modalities used for stenting ISR lesions and the outcomes that occurred within a minimum period of 6 months from the date of the clinical presentation. The occurrence of a major adverse cardiac event (MACE), defined as cardiovascular death, nonfatal MI was assessed on follow-up at 3 months and 6 months. Unless otherwise noted, cardiac death was assumed in every case as myocardial infarction (MI). According to current guidelines, MI is classified as either ST-segment elevation MI (STEMI) or non-ST-segment elevation MI (NSTEMI). The existence of symptoms together with elevated cardiac markers served as a warning sign for the STEMI, while NSTEMI by ST-segment elevation or new or presumably new left-bundle branch block. Statistical Analysis Data analysis was done with the help of statistical software Graphpad InStat v3.0 Quantitative data was presented with the help of Mean and Standard deviation. Categorical variables were presented as frequency and percentages(%). Clinical and angiographic characteristics of patients were compared with the Chi-square test/ Fisher’s exact test/ Student’s t-test/ or Mann–Whitney test, according to the type and distribution of the variable. P value of less than 0.05 was statistically significant

A total of 200 patients were enrolled in the study. The commonest age group was 51-60 years (37.5%) with mean age of 57.90±10.16 years, ranged from 31-81 years. Majority of enrolled patients were males (79.5%). Diabetes mellitus was the most common comorbidities (80; 40%) among them 72 patients (90%) had uncontrolled DM. 34 of the enrolled patients had smoking habit (17%). Unstable angina (39.5%) and NSTEMI (36%) were the common clinical presentations noted for ISR cases. The range of blood pressure noted in study was 70-176 mm Hg for SBP and 48-110 mm Hg for DBP, (Table 1). Also, the mean laboratory findings have been mentioned in table 1.

The ejection fraction status was fair in 18.5% cases, mildly compromised in 23% cases, moderately compromised in 27% cases and severely compromised in 31.5% cases. RWMA was noted in 81.5% of the enrolled cases while it was absent in 18.5% of the cases. 88% of the enrolled patients suffered from right-dominant disease while 12% from left-dominant disease. 46% of the cases suffered from single vessel disease, while 27% patients each suffered from either double-vessel or triple-vessel disease. The commonest vessel impacted by ISR was LAD (60%) followed by RCA (27%) and LCx (14.5%), (Table 2).

Out of the 106 enrolled cases (53%) were those with 2nd generation stent, 51 cases (25.5%) with ISR were having 1st generation stent and 43 patients (21.5%) were noted to have BMS stent. The commonest clinical presentation for ISR patients with BMS was unstable angina (46.51%) followed by NSTEMI (27.91%). The most common clinical presentation for ISR patients with 1st generation stent was NSTEMI (37.25%) followed by (31.37%). For patients with 2nd generation stent, unstable angina was most common presentation (40.57%) followed by NSTEMI (38.68%). Overall, the presentation status was comparable between the BMS, 1st generation stent and 2nd generation stent subgroups (p>0.05). Non-focal ISR constituted 130 cases (65%). Overall, 25% were diffuse, 6.5% were proliferative and 33.5% patients had total occlusion as depicted in figure 1.

IVUS was utilized in 68 (34%) of the cases. For these 68 patients, under expansion was noted in 30 cases, neo-atherosclerosis in 32 cases and 6 cases showed neointimal hyperplasia. IVUS findings based on type of previous stents were also noted. Most patients with previous BMS stent had neo-atherosclerosis (56.25%) followed by neointimal hyperplasia (31.25%). For DES, the commonest IVUS finding was under expansion (53.84%) followed by neo atherosclerosis (44.23%).

Prior to ISR presentation, 78% cases were on ecosprin, 3 patients were on clopidogrel, 12.5% cases were on ecosprin plus ticagrelor, and 8% cases were on both ecosprin and clopidogrel. 148 patients received loading dose for E, while 7 patients for C in study. Commonest treatment modality adopted for ISR cases was PTCA (64%) followed by 32 patients (16%) underwent management with Agg. MMX, 23 patients (11.5%) by CABG and 17 patients (8.5%) by POBA. Cutting ball was used in 14 of the patients. For the patients who underwent PTCA, 55 patients (42.97%) underwent XPLL stent placement, 47 patients (36.72%) underwent XV stent placement, 22 patients (17.19%) underwent PE stent placement while 17 patients (13.28%) underwent RI stent placement.

The mean stent length (35.19±6.80) and the stent diameter (3.37±0.39) were both noted to be significantly increased after ISR management with PTCA, versus the baseline length (28.58±6.21) and diameter (3.02±0.34) respectively at admission (p<0.05).

Before ISR management at admission, the stent length of ≤25 mm and 26-30 mm was significantly greater than that after ISR management (p <0.05). After ISR management, the stent length of >35 mm was significantly greater versus the before ISR management (p<0.05). Before ISR management at admission, the stent diameter of ≤2.5 mm was significantly greater than that after ISR management (p<0.05). After ISR management, the stent diameter of 3.1-3.5 mm and >3.5 mm was significantly greater versus the before ISR management (p<0.05).

After ISR management, 136 of the enrolled patients (68%) were prescribed E+T antiplatelet combination while 64 patients (32%) were prescribed E+C combination.  Out of 200, 195 patients (97.5%) were discharged from hospital after ISR management, while 5 of the admitted patients expired at hospital (2.5%), (Figure 2). Most patients had hospitalization of 4-5 days (51%) followed by ≤3 days (69; 34.5%) and ≥6 days (29; 14.5%).

For the 5 patients who died, 2 patients suffered from NSTEMI while 3 patients suffered from STEMI after ISR management. One patient was readmitted later after discharge with unstable angina but was discharged later after management of same, (Figure 3). 160 of the patients were prescribed atorvastatin at discharge while 35 discharged patients were prescribed rosuvastatin. 194 of the 195 discharged patients were symptom-free at 3-month follow up, while all patients were symptom-free at 6-month follow-up.

Table 1: Demographics and clinical profile of patients with in-stent restenosis

Table 2: Cardiac function and disease status in study participants

Figure 1: Type of ISR in study participants

In the present study, majority of patients with ISR were between 51-60 years age group (37.5%) followed by 61-70 years (28%) which is comparable with the previous studies.11-13 Most of the ISR cases were males (79.5%), which may be because most of patients undergoing stent placement are males. To foretell and prevent ISR in advance, it is essential to identify its risk factors. According to several studies, diabetes mellitus is one of the key determinants of ISR.14 This was aligned with current study findings, wherein 40% of ISR cases had diabetes mellitus as a comorbidity, while 36.5% had hypertension and 18% had dyslipidaemia. Additionally in present study, 90% of DM patients were uncontrolled with high HbA1c. Diabetes itself increases the risk of BMS-ISR by 30%–50%.14 17% of patients who presented with ISR were smokers. The commonest clinical presentation amongst enrolled ISR cases was unstable angina (39.5%), followed by NSTEMI (36%), and chronic stable angina (11.5%). Most of the enrolled patients had severe compromise of EF (31.5%) followed by moderate compromise of EF (27%). From the clinical point of view, published literature mentions that restenosis is often associated with the recurrence of angina symptoms or an acute coronary syndrome, and may drive to a reintervention either with coronary artery bypass or re-PCI.10

Non-focal ISR constituted 130 cases (65%) and focal ISR was found in 70 cases (35%). Overall, 25% were diffuse, 6.5% were proliferative and 33.5% patients had total occlusion. Similar findings are reported in study conducted by Mohan S et al.15

In the present study, based on IVUS, 68 patients were evaluated, and the key causes noted were under expansion (15%), neo-atherosclerosis (16%) and neointimal hyperplasia (3%). IVUS findings based on type of previous stents were also noted. Most patients with previous BMS stent had neoatherosclerosis (56.25%) followed by neointimal hyperplasia (31.25%). For DES, the commonest IVUS finding was under expansion (53.84%) followed by neo-atherosclerosis (44.23%). ISR of the stent was mentioned in figure 3.

Cutting balloon of various sizes were used in calcified ISR lesions which provided better lumen diameter for stent placement and also reduces the chances for future ISR. Patients who had lesions in many arteries were recently discovered to be more susceptible to ISR. In current study, 54% of cases had multivessel disease while 46% patients had single vessel disease. ISR rate appears to be higher when the patient has a multivessel disease rather than a single-vessel disease, as demonstrated in the study of Mohan et al15 and Zhao LP et al.16

According to multiple studies, length (stent length), and small vessel size also play vital role in ISR development.14 In current study, mean stent length and the stent diameter were both noted to be significantly increased after ISR management with PTCA, versus the baseline length and diameter respectively at admission. After ISR management, the stent length of >35 mm was significantly greater versus the before ISR management (p<0.05). Similarly, the stent diameter of 3.1-3.5 mm and >3.5 mm was significantly greater versus the before ISR management (p<0.05). This indicates that ISR management by PTCA led to a significant increase in both stent length and diameter, which was a strong determinant of positive outcomes. In the period of bare-metal stents (BMS), the clinical incidence of ISR ranged from 20 to 35 percent. These findings were aligned with the published literature.17

In the present study, 64% of presenting ISR patients underwent PTCA, 8.5% cases underwent POBA, 11.5% cases underwent CABG while 16% cases underwent aggresive MMX. The best approach for ISR cannot yet be determined without data from extensive randomized studies. Management of ISR is still difficult, and the best percutaneous therapeutic approach is still up for dispute. As a result, ISR continues to be a significant clinical problem after PCI and acts as a standalone predictor of death post-PCI.18,19

Overall, the ISR patients responded well to management. 97.5% of patients were discharged after undergoing treatment for ISR. Overall, all patients were symptom free at 6 months after discharge. Most patients had hospitalization of 4-5 days (51%) while 14.5% cases had a hospitalization stay of more than or equal to 6 days.

There are some limitations of the study which includes- study was conducted at only one centre with limited sample size with shorten duration of follow up. Hence, the overgeneralization of the study findings should be done with caution and future studies with multicentre study design can help in validating our study findings.

The study demonstrated that unstable angina and NSTEMI were the prevalent clinical presentations among Indian patients with in-stent restenosis (ISR). The majority of these patients had single vessel disease predominantly involving the LAD, with uncontrolled diabetes mellitus as a significant contributing factor. Non-focal ISR patterns were more common, with a considerable number of patients showing neo-atherosclerosis in previous BMS and under-expanded stents in previous DES cases. Percutaneous transluminal coronary angioplasty (PTCA) emerged as the most frequently employed treatment modality, leading to significant improvements in stent length and diameter. The short-term outcomes were highly encouraging, with a 97.5% discharge rate and satisfactory health status maintained at the 6-month follow-up. This study highlights the effectiveness of current ISR management strategies and underscores the need for ongoing monitoring and tailored treatment approaches in the Indian population.

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