|Year : 2020 | Volume
| Issue : 3 | Page : 55-60
Clinical profile and angiographic patterns of patients undergoing treatment for in-stent restenosis and outcomes associated with the treatment
Shivanand Patil, Mainak Chatterjee, Natraj Setty, Santosh Jadhav
Department of Cardiology, Sri Jayadeva Institute of Cardiovascular Sciences and Research, Bengaluru, Karnataka, India
|Date of Submission||30-Jun-2020|
|Date of Decision||22-Jul-2020|
|Date of Acceptance||01-Aug-2020|
|Date of Web Publication||26-Oct-2020|
Dr. Shivanand Patil
Department of Cardiology, Sri Jayadeva Institute of Cardiovascular Sciences and Research, Jayanagar 9th Block, Bannerghatta Road, Bengaluru - 560 069, Karnataka
Source of Support: None, Conflict of Interest: None
Context: The optimal treatment strategy for in-stent restenosis (ISR) still remains under debate. Moreover, there have been scarce data on Indian patients relating to ISR treatment. Aim: The aim of this study was to determine the clinical profile and angiographic pattern of patients with ISR and to evaluate the outcome of these patients being treated for ISR. Settings and Design: This was a cross-sectional study which consisted of patients who had coronary angiographic characteristic of ISR. Materials and Methods: Patients were divided into subgroups as per presentation, acute coronary syndrome (ACS), and non-ACS. After the ISR event and treatment, the patients were followed up for a minimum period of 6 months for any adverse events. The primary outcome of the study was occurrence of a major adverse cardiac event. Statistical Analysis: Chi-square test, Fisher's exact test, Student's t-test, or Mann–Whitney test was applied according to type and distribution of variable (SPSS software). Results: One hundred patients with 109 culprit lesions of ISR were included in the study. The ACS was dominant clinical presentation mode, occurring in 62 patients. Fifty-four percent of the patients were treated with percutaneous coronary intervention, 26% were managed with coronary artery bypass grafting, and 19% were treated with optimized medical therapy. Majority of the adverse events (12 out of 15 patients) occurred in the ACS group, with a statistically significant difference at 6-month follow-up (P = 0.021). Conclusion: Patients with ISR have ACS as the most common mode of presentation. Patients with ISR presenting with ACS are at high risk and must be closely monitored. The treatment of ISR with drug-eluting stent or drug-coated balloon is most effective.
Keywords: Acute coronary syndrome, drug-eluting stent, in-stent restenosis, percutaneous coronary intervention
|How to cite this article:|
Patil S, Chatterjee M, Setty N, Jadhav S. Clinical profile and angiographic patterns of patients undergoing treatment for in-stent restenosis and outcomes associated with the treatment. Res Cardiovasc Med 2020;9:55-60
|How to cite this URL:|
Patil S, Chatterjee M, Setty N, Jadhav S. Clinical profile and angiographic patterns of patients undergoing treatment for in-stent restenosis and outcomes associated with the treatment. Res Cardiovasc Med [serial online] 2020 [cited 2020 Dec 3];9:55-60. Available from: https://www.rcvmonline.com/text.asp?2020/9/3/55/298987
| Introduction|| |
In the era of contemporary percutaneous coronary interventional techniques, the latest generation drug-eluting stents (DESs) have achieved better efficacy in lowering the incidences of restenosis. However, the rates of in-stent restenosis (ISR) have not been dwindled majorly, reporting around 6%–10% after DES implantation., There are a myriad of factors affecting its occurrence other than stent features, such as patient characteristics and concomitant comorbidities, procedural factors such as /underexpansion, other medications, etc. The ISR, defined as >50% diameter stenosis in a previously stented segment, majorly results from increased neointimal hyperplasia.
The patterns of ISR formation have been varying, being focal, diffusive, proliferative, or occlusive. Moreover, the development of ISR also differs among type of stents. The ISR of bare metal stent (BMS) is usually diffuse and characterised mainly by neointimal hyperplasia (NIH) along with escalating amounts of vascular smooth muscle cells. The ISR of DES is mostly focal and is characterized by proteoglycan-rich NIH and neoatherosclerosis with relatively lower amounts of smooth muscle cells., The assessment of ISR segment can be appropriately done using intravascular ultrasound or optical coherence tomography. These can assist to determine the presence of underexpansion, NIH, neoatherosclerosis, and calcification, thus guiding the choice of particular treatment modality. However, the optimal treatment strategy for ISR still remains under debate. Moreover, there have been scarce data on Indian patients relating to the ISR treatment. Thus, this study aimed to determine the clinical profile and angiographic pattern of patients with ISR and to evaluate the outcome of these patients being treated for ISR.
| Materials and Methods|| |
This was a cross-sectional study, and the cohort consisted of patients admitted to a tertiary care hospital in India from January 1, 2018, to June 30, 2019, and had coronary angiographic characteristic of ISR. Patients were divided into subgroups as per presentation, acute coronary syndrome (ACS), and non-ACS. After the ISR event and treatment, the patients were followed up for a minimum period of 6 months for the outcome. This study included all the patients aged ≥18 years and had coronary angiographic characteristics of ISR. Patients with restenosis in arterial or venous grafts or patients with significant coronary stenosis in a vessel other than where the stent was implanted were excluded from the study.
The ISR was defined as angiographic evidence of either a new stenosis ≥50% in the previously treated vessel, inside the stent, or 5 mm proximally or distally to the lesion requiring a new revascularization of the target lesion.
The study applied the Mehran's classification for ISR, dividing it into four classes, namely Class I (”focal;” <10 mm in length), Class II (”diffuse;” >10 mm in length, but confined to the stent), Class III (”proliferative;” >10 mm and extending beyond the margins of the stent), and Class IV (”occlusive;” presenting as a total occlusion).
Information about the clinical characteristics of the patients at baseline was retrieved from medical records. We considered the occurrence of prior acute myocardial infarction (MI), prior coronary bypass surgery, left ventricular ejection fraction (LVEF) determined by echocardiogram, and risk factors for cardiovascular disease (age, gender, hypertension, dyslipidemia, diabetes mellitus, smoking, and chronic kidney disease not treated with dialysis) for baseline information.
We evaluated the types of clinical presentation, whether ISR had occurred after implantation of BMS or DES, the type of treatment performed, angiographic characteristics of ISR, and the outcomes that occurred within a minimum period of 6 months from the date of the clinical presentation. The treatment of ISR was divided into three types: percutaneous coronary intervention (PCI), coronary artery bypass grafting (CABG), and medical treatment.
Follow-up and outcomes
The primary outcome was the occurrence of a major adverse cardiac event (MACE), defined as cardiovascular death, nonfatal MI, including periprocedural events, and re-target lesion revascularization (re-TLR).
Outcomes were initially assessed through telephone contact at least 6 months after the treatment for ISR. In the occurrence of an event before 6 months, a clinical visit was already performed and was noted in medical records. All the events and data were confirmed with information in medical records. If more than one event had occurred during follow-up, the outcome that occurred first was considered.
All deaths were considered cardiac unless otherwise documented. MI was defined according to current standards as either non-ST-segment elevation MI (NSTEMI) or ST-segment elevation MI (STEMI). The former was indicated by the presence of symptoms in association with increased cardiac markers or, which required prompt intervention, the latter by ST-segment elevation or new or presumably new left-bundle branch block. Re-TLR was the reintervention due to recurrence of the lesion within the stent implanted in the index procedure or in the vascular segment extending 5 mm proximally or distally to the stent.
Continuous variables were presented as mean ± standard deviation, whereas categorical variables were presented as frequency and percentages (%). Clinical and angiographic characteristics of patients with and without outcomes 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 < 0.05 was considered statistically significant. All analyses were performed with SPSS version 20.0 (IBM, Chicago, IL, USA).
| Results|| |
The study included 100 patients who were admitted to our hospital with angiographic characteristics of ISR. Total 109 culprit lesions with ISR were identified in the study cohort. The ACS was the dominant clinical presentation mode, occurring in 62% of the patients. Among patients presenting with ACS, 53 (85%) had NSTEMI and 9 (15%) had STEMI. The mean age at presentation was 61 ± 10 years, and 81% were males [Table 1]. It was found that patients with chronic kidney disease and gender had shown a statistically significant difference in the mode of presentation with P = 0.02 and 0.034, respectively, such that females and patients with chronic kidney disease majorly presented with ACS. History of prior MI was present in 52% of the study population. In the present admission, ACS patients had more incidence of Congestive cardiac failure (CCF) and poor functional class as compared to the non-ACS group, which was statistically significant. The average LVEF was above 50% in both study cohorts.
|Table 1: Demographics and clinical profile of patients with in-stent restenosis|
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All the patients who presented with ISR were treated with DES, among which both second- and third-generation DESs were used. Among lesions which were prior treated with PCI, maximum were of type C (53%) in severity, and calcified lesions were about 55%. Majority of the ISR occurred in stents with length of 15–25 mm (50%) and diameter between 2.5 and 3.4 mm (69%). Diameter ranges of stents that were stenosed were as follows: 1.5–2.4 mm in 13%, 2.5–2.9 mm – 33%, 3.0–3.4 mm – 36%, and >3.5 mm – 18%. Length ranges were as follows: 15–28 mm in 51%, >28 mm – 28%, and <15 mm – 21%. Left anterior descending artery was the most common vessel to have ISR with 58% occurrence rate.
There were total 109 lesions in 100 patients. Majority of the ISR were focal in nature (63%), and the second most common type was occlusive ISR (21%) [Table 2]. The patterns of ISR presented in patients included in the study are shown in [Figure 1]. Coronary angiogram revealed single-vessel disease in 38% of the patients, double-vessel disease in 35%, and triple-vessel disease in 27%.
|Table 2: Angiographic and procedural characteristics of prior percutaneous coronary intervention|
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|Figure 1: Patterns of in-stent restenosis presented in patients included in the study|
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The patients were managed by three modalities of treatment. Following coronary angiogram and considering disease burden and clinical profile, 59 (54%) patients were treated with PCI. The PCI was done in 34 (50%) ACS patients and 25 (60%) non-ACS patients [Figure 2]. Total 29 (26%) patients were managed with CABG. The rest of the patients, i.e., 21 (19%), were treated with optimized medical therapy. During PCI procedure of ISR lesions, new DESs were used in 39 (68%) lesions. Plain old balloon angioplasty (POBA) was done in 14 (23.7%) lesions and drug-coated balloon (DCB) was used in 6 (10%) lesions. Adjunctive devices such as Rotablator (ROTA) and cutting or noncompliant balloons were used in 1 and 13 lesions, respectively, during lesion preparation before PCI. Among the DESs used, everolimus-eluting stents (EESs) were the maximum used stents (21 lesions; 38%). The sirolimus-eluting stent (SES) and zotarolimus-eluting stent (ZES) were used in 6 (9%) and 12 (21%) of the PCI procedures, respectively.
|Figure 2: Management of in-stent restenosis distributed as per clinical presentation|
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Majority of the adverse events (12 out of 15 patients) occurred in the ACS group, and a statistically significant difference was noted on the outcomes at 6-month follow-up (P = 0.021). Patients with ISR who had ACS during index hospitalization were 2.2 times more prone to develop adverse outcomes than non-ACS patients in the form of death, repeat revascularization, or MI (hazard ratio [HR], 2.23; 95% confidence interval [CI], 1.09–6.50; P = 0.021). One patient had stent thrombosis during index hospitalization who had MI on presentation. On follow-up during the 6-month period, death occurred in six patients, three patients had MI, and six patients required repeat revascularization. Among the different modes of treatment, there were more adverse events in the PCI group (21%). None among patients treated with CABG had adverse events. The effect of clinical presentation on outcomes at 6-month follow-up is represented in [Figure 3].
|Figure 3: Effect of clinical presentation on outcomes at 6-month follow-up|
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| Discussion|| |
The occurrence of ISR has been an open challenge even in this DES era. Literature states that smaller vessel size and longer stent lengths have been chief predictors of ISR. Moreover, other relevant clinical factors, such as age, presence of diabetes mellitus, current smoker, previous CABG, and low LVEF, have also been associated with ISR. Rarely, procedural factors such as stent underexpansion, geographical miss, and stent fractures have also been responsible for ISR. Pathologically, the mechanisms linked closely to ISR are early elastic recoil, vascular remodeling, and NIH.
In the present study, we have included 100 patients with ISR, of which 62 patients presented with ACS and 38 with non-ACS. The probable hypothesis behind dividing the patients as per ACS presentation was the possible correlation between ISR being presented as ACS and outcomes related to it. Studies state that superimposed thrombus and aggressive patterns of formation of NIH in the vessel with ISR might instigate the incidence of ACS. Besides increased incidence of ISR presentation as ACS, the adverse events have also been parallelly allied to ACS. A previous study reported that ACS patients accounted for higher rates of MACE (death, MI, and re-TLR) at 6 months compared with non-ACS. Our study also reported a similar effect of ACS presentation on outcomes. Patients with ISR who had ACS during index hospitalization were 2.2 times more prone to develop adverse outcomes than non-ACS patients in the form of death, repeat revascularization, or MI (HR, 2.23; 95% CI, 1.09–6.50; P = 0.021). Other characteristics of majority of the patients that presented with ISR were elderly patients, males, hypertensive, and diabetic. In a previous study by Marino et al., univariate analysis demonstrated association between primary outcome in patients with clinical ISR and diabetic patients under insulin treatment and male gender.
Several treatment approaches have been available for managing ISR lesions, however, any single modality has not been proven to be an established one. Mostly either DESs,,, drug-coating balloons, POBA, scoring/cutting balloons, rotational atherectomy, or CABG have been applied. The balloon angioplasty is the most primordial technique. It is mostly applied for focal lesions, stent underexpansion, and in patients under risk of long-term dual antiplatelet therapy. In case of stent underexpansion, a high-pressure noncompliant balloon must be preferred. Balloon slippage has been a major limitation of balloon angioplasty, which can be overcome by the use of shorter balloon or using a scoring/cutting balloon. However, the higher profile of scoring/cutting balloon may limit its deliverability. Another approach, rotational atherectomy, has been mainly indicated for lesions refractory to high-pressure balloon inflation and for undilatable underexpanded stents. On the other hand, some studies have demonstrated mixed results on comparing rotational atherectomy to balloon angioplasty for the treatment of ISR.,
Majorly, DESs have been shown to possess superior results as compared to balloon angioplasty or BMS.,, Moreover, a network meta-analysis of 27 trials reported that EESs were the most effective in treating ISR and DCB ranked the second most effective treatment, but DCB did not show significant differences from SES or PES. However, recently transpired technique, DCB, indirectly poses to be as effective in treating ISR as DES because it prevents an additional metal layover in the diseased vessel and thereby reducing the chronic inflammatory reaction. Moreover, in another network meta-analysis, both DCB and DES were superior to other treatment modalities in managing ISR, as DESs have benefit of better angiographic and clinical outcomes and DCBs owe the boon to dodge a new stent layer. In this current study, 54% of the patients were treated with PCI, 26% were managed with CABG, and the rest 19% were treated with optimized medical therapy. The PCI technique included the use of either EES, SES, ZES, DCB, POBA, cutting balloon, or ROTA. The choice of management strategy in the patients was dependent on individual's characteristics and comorbidity.
The study describes differences in outcomes of ACS and non-ACS patients with ISR, which would be helpful in the routine clinical practice. The major imitation of this study is that it lacks intravascular imaging of the stenosed stents.
| Conclusion|| |
In light of the results of this study, patients with ISR have ACS as the most common mode of presentation. Patients with ISR presenting with ACS are at high risk and must be closely monitored. The treatment of ISR with DES or DCB is most effective. Moreover, ACS is found to be the main predictor of adverse events at short-term follow-up after reintervention. However, novel technologies to eradicate ISR must be focused in the future studies.
Due to observational design of the study, ethical approval was not taken.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Her AY, Shin ES. Current management of in-stent restenosis. Korean Circ J 2018;48:337-49.
Marino BC, Nascimento GA, Rabelo W, Marino MA, Marino RL, Ribeiro AL. Clinical coronary in-stent restenosis follow-up after treatment and analyses of clinical outcomes. Arq Bras Cardiol 2015;104:375-86.
Cassese S, Byrne RA, Tada T, Pinieck S, Joner M, Ibrahim T, et al.
Incidence and predictors of restenosis after coronary stenting in 10 004 patients with surveillance angiography. Heart 2014;100:153-9.
Otsuka F, Byrne RA, Yahagi K, Mori H, Ladich E, Fowler DR, et al
. Neoatherosclerosis: Overview of histopathologic findings and implications for intravascular imaging assessment. Eur Heart J 2015;36:2147-59.
Byrne RA, Joner M, Kastrati A. Stent thrombosis and restenosis: What have we learned and where are we going? The Andreas Grüntzig Lecture ESC 2014. Eur Heart J 2015;36:3320-31.
Mehran R, Dangas G, Abizaid AS, Mintz GS, Lansky AJ, Satler LF, et al
. Angiographic patterns of in-stent restenosis: Classification and implications for long-term outcome. Circulation 1999;100:1872-8.
Buccheri D, Piraino D, Andolina G, Cortese B. Understanding and managing in-stent restenosis: A review of clinical data, from pathogenesis to treatment. J Thorac Dis 2016;8:e1150-62.
Magalhaes MA, Minha S, Chen F, Torguson R, Omar AF, Loh JP, et al
. Clinical presentation and outcomes of coronary in-stent restenosis across 3-stent generations. Circ Cardiovasc Interv 2014;7:768-76.
Kastrati A, Mehilli J, von Beckerath N, Dibra A, Hausleiter J, Pache J, et al
. Sirolimus-eluting stent or paclitaxel-eluting stent vs balloon angioplasty for prevention of recurrences in patients with coronary in-stent restenosis: A randomized controlled trial. JAMA 2005;293:165-71.
Alfonso F, Pérez-Vizcayno MJ, Cárdenas A, García del Blanco B, García-Touchard A, López-Minguéz JR, et al
. A prospective randomized trial of drug-eluting balloons versus everolimus-eluting stents in patients with in-stent restenosis of drug-eluting stents: The RIBS IV randomized clinical trial. J Am Coll Cardiol 2015;66:23-33.
Alfonso F, Pérez-Vizcayno MJ, Cárdenas A, García Del Blanco B, Seidelberger B, Iñiguez A, et al
. A randomized comparison of drug-eluting balloon versus everolimus-eluting stent in patients with bare-metal stent-in-stent restenosis: The RIBS V Clinical Trial (Restenosis Intra-stent of Bare Metal Stents: Paclitaxel-eluting balloon vs. everolimus-eluting stent). J Am Coll Cardiol 2014;63:1378-86.
Byrne RA, Neumann FJ, Mehilli J, Pinieck S, Wolff B, Tiroch K, et al
. Paclitaxel-eluting balloons, paclitaxel-eluting stents, and balloon angioplasty in patients with restenosis after implantation of a drug-eluting stent (ISAR-DESIRE 3): A randomised, open-label trial. Lancet 2013;381:461-7.
Elezi S, Kastrati A, Hadamitzky M, Dirschinger J, Neumann FJ, Schömig A. Clinical and angiographic follow-up after balloon angioplasty with provisional stenting for coronary in-stent restenosis. Catheter Cardiovasc Interv 1999;48:151-6.
Waksman R, Iantorno M. Refractory in-stent restenosis: Improving outcomes by standardizing our approach. Curr Cardiol Rep 2018;20:140.
Ferri LA, Jabbour RJ, Giannini F, Benincasa S, Ancona M, Regazzoli D, et al
. Safety and efficacy of rotational atherectomy for the treatment of undilatable underexpanded stents implanted in calcific lesions. Catheter Cardiovasc Interv 2017;90:e19-24.
Sharma SK, Kini A, Mehran R, Lansky A, Kobayashi Y, Marmur JD. Randomized trial of Rotational Atherectomy Versus Balloon Angioplasty for Diffuse In-stent Restenosis (ROSTER). Am Heart J 2004;147:16-22.
vom Dahl J, Dietz U, Haager PK, Silber S, Niccoli L, Buettner HJ, et al
. Rotational atherectomy does not reduce recurrent in-stent restenosis: Results of the angioplasty versus rotational atherectomy for treatment of diffuse in-stent restenosis trial (ARTIST). Circulation 2002;105:583-8.
Alfonso F, Pérez-Vizcayno M-J, Hernandez R, Bethencourt A, Martí V, López-Mínguez JR, et al
. A randomized comparison of sirolimus-eluting stent with balloon angioplasty in patients with in-stent restenosis: Results of the restenosis intrastent: Balloon Angioplasty Versus Elective Sirolimus-Eluting Stenting (RIBS-II) trial. J Am Coll Cardiol 2006;47:2152-60.
Mehilli J, Byrne RA, Tiroch K, Pinieck S, Schulz S, Kufner S, et al
. Randomized trial of paclitaxel- versus sirolimus-eluting stents for treatment of coronary restenosis in sirolimus-eluting stents: The ISAR-DESIRE 2 (Intracoronary Stenting and Angiographic Results: Drug Eluting Stents for In-Stent Restenosis 2) study. J Am Coll Cardiol 2010;55:2710-6.
Siontis GC, Stefanini GG, Mavridis D, Siontis KC, Alfonso F, Pérez-Vizcayno MJ, et al
. Percutaneous coronary interventional strategies for treatment of in-stent restenosis: A network meta-analysis. Lancet 2015;386:655-64.
Giacoppo D, Gargiulo G, Aruta P, Capranzano P, Tamburino C, Capodanno D. Treatment strategies for coronary in-stent restenosis: Systematic review and hierarchical Bayesian network meta-analysis of 24 randomised trials and 4880 patients. BMJ 2015;351:h5392.
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[Table 1], [Table 2]