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Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease logoLink to Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease
. 2023 Jun 29;12(13):e029300. doi: 10.1161/JAHA.122.029300

Outcomes of Percutaneous Coronary Intervention for In‐Stent Restenosis Versus De Novo Lesions: A Meta‐Analysis

Ayman Elbadawi 1, Alexander T Dang 2, Ingy Mahana 3, Mohammed Elzeneini 4, Fernando Alonso 5, Subhash Banerjee 1, Dharam J Kumbhani 1, Islam Y Elgendy 6,✉, Gary S Mintz 7
PMCID: PMC10356080  PMID: 37382147

Abstract

Background

In‐stent restenosis (ISR) is commonly encountered even in the era of contemporary percutaneous coronary intervention (PCI). There is a paucity of data on the comparative outcomes of PCI for ISR lesions versus de novo lesions.

Methods and Results

An electronic search was conducted for MEDLINE, Cochrane, and Embase through August 2022 for studies comparing the clinical outcomes after PCI for ISR versus de novo lesions. The primary outcome was major adverse cardiac events. Data were pooled using a random‐effects model. The final analysis included 12 studies, with a total of 708 391 patients, of whom 71 353 (10.3%) underwent PCI for ISR. The weighted follow‐up duration was 29.1 months. Compared with de novo lesions, PCI for ISR was associated with a higher incidence of major adverse cardiac events (odds ratio [OR], 1.31 [95% CI, 1.18–1.46]). There was no difference on a subgroup analysis of chronic total occlusion lesions versus none (P interaction=0.69). PCI for ISR was associated with a higher incidence of all‐cause mortality (OR, 1.03 [95% CI, 1.02–1.04]), myocardial infarction (OR, 1.20 [95% CI, 1.11–1.29]), target vessel revascularization (OR, 1.42 [95% CI, 1.29–1.55]), and stent thrombosis (OR, 1.44 [95% CI, 1.11–1.87]), but no difference in cardiovascular mortality (OR, 1.04 [95% CI, 0.90–1.20]).

Conclusions

PCI for ISR is associated with higher incidence of adverse cardiac events compared with PCI for de novo lesions. Future efforts should be directed toward prevention of ISR and exploring novel treatment strategies for ISR lesions.

Keywords: de novo lesions, in‐stent restenosis, percutaneous coronary intervention

Subject Categories: Catheter-Based Coronary and Valvular Interventions

Nonstandard Abbreviations and Acronyms

CTO

chronic total occlusion

DES

drug‐eluting stent

ISR

in‐stent restenosis

MACE

major adverse cardiac events

TVR

target vessel revascularization

Clinical Perspective.

What Is New?

  • Percutaneous coronary intervention (PCI) for in‐stent restenosis was associated with a higher incidence of risk‐adjusted major adverse cardiac events compared with PCI for de novo lesions at a median of ≈30 months.

  • PCI for in‐stent restenosis was associated with higher incidences of all‐cause mortality, myocardial infarction, target vessel revascularization, and stent thrombosis.

  • There was no evidence of interaction for the outcomes for chronic total occlusion versus non‐chronic total occlusion.

What Are the Clinical Implications?

  • In‐stent restenosis is not a benign entity, and major efforts should be directed toward optimizing index PCI procedures.

  • Further research is warranted to evaluate the outcomes of PCI of in‐stent restenosis compared with de novo lesions using state‐of‐the‐art PCI techniques, including routine intravascular imaging, transradial access, and advanced modalities such as laser atherectomy, brachytherapy, and drug‐coated balloons.

Percutaneous coronary intervention (PCI) remains the cornerstone in the management of patients with acute coronary syndrome and those with chronic coronary syndrome refractory to medical management. 1 The use of metallic coronary stents (ie, drug eluting and bare metal) has revolutionized this space during the past 2 decades. 2 However, metallic coronary stents have introduced another disease (ie, in‐stent restenosis [ISR]). 3 ISR could present clinically with either chronic coronary syndrome or acute coronary syndrome. 2 Although the rates of ISR have decreased considerably with the more widespread use of drug‐eluting stents (DES), especially second–generation, ISR remains a challenge even with DES, and the incidence is up to 5% to 15% after 5 years. 4 , 5 Despite the large number of PCIs performed annually in the United States and worldwide, data evaluating the long‐term outcomes with PCI for ISR are limited. Moreover, comparative data on the outcomes associated with PCI with DES for ISR versus de novo lesions are limited. In that context, we aimed to perform a comprehensive meta‐analysis investigating the comparative long‐term outcomes with PCI for ISR versus de novo lesions.

Methods

The authors declare that all supporting data are available within the article and its online supplementary files.

Data Sources and Search Strategy

We conducted a digital search of the following databases: MEDLINE, Cochrane, and Embase, through July 2022, using the terms “in‐stent restenosis,” “de novo stenosis,” “revascularization,” and “percutaneous coronary intervention” separately and in combination to identify studies that evaluated the outcomes with PCI for ISR versus de novo coronary artery lesions. We also conducted a simultaneous search of the abstracts presented at major societal meetings (American College of Cardiology, European Society of Cardiology, American Heart Association, and Society for Cardiovascular Angiography and Interventions meetings) using similar keywords through August 2022. We searched the bibliographies of the retrieved studies, as well as ClinicalTrials.gov, to capture eligible studies that were not obtained through the initial search. This systematic review and meta‐analysis was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses guidelines (Table S1). 6 A protocol for this meta‐analysis was prospectively registered at PROSPERO (CRD42022364832). This study was deemed exempt from institutional review board evaluation, because it is a study‐level meta‐analysis.

Selection Criteria

We included studies that compared the clinical outcomes with PCI for ISR versus de novo coronary lesions. We included randomized or observational studies. In studies with multiple reports, we used data from the longest follow‐up. We excluded studies that only reported outcomes after PCI for ISR without a comparator group of de novo PCI. Two investigators (I.M. and M.E.) conducted an independent screening, and discrepancies among investigators were resolved by consensus.

Data Extraction

Two independent investigators (I.M. and M.E.) extracted the following data: the study design, baseline characteristics, intervention strategies, and clinical outcomes. In case of discrepancies among investigators, this was resolved by consensus.

Outcomes

The primary outcome of the study was the composite of major adverse cardiovascular events (MACE). The secondary outcomes included all‐cause mortality, cardiovascular mortality, myocardial infarction (MI), repeat ischemia‐driven target vessel revascularization (TVR), and stent thrombosis. Definitions of outcomes were adopted as per each study.

Assessment of the Quality of the Included Studies

Because all of the included studies were observational, we assessed the quality of the included studies using the Newcastle‐Ottawa quality assessment scale. Accordingly, the quality of the studies was classified as very good, good, satisfactory, or unsatisfactory corresponding to a score of 9 to 10, 7 to 8, 5 to 6, or 0 to 4 points, respectively. 7

Statistical Analysis

Interrater agreement between the 2 researchers conducting study selection and data extraction was evaluated using κ coefficient. A random‐effects model was used, and data were pooled using the DerSimonian‐Laird inverse variance method. A random‐effects model provides more conservative results than a fixed‐effects model and assumes that each sample comes from a different population, and that the effects in these populations may also differ. Meta‐analysis was conducted using pooled effect sizes from the included studies using risk‐adjusted data when available. Statistical heterogeneity among the included studies was evaluated using I2 statistics and Cochran Q test. I2 statistic values <25%, 25% to 50%, and >50% corresponded to low, moderate, and high degree of heterogeneity, respectively. 8 , 9 Publication bias was assessed using the Egger test. 10 A prespecified subgroup analysis was conducted for the primary outcome according to chronic total occlusion (CTO) versus non‐CTO coronary lesions. Sensitivity analysis for the primary outcome was conducted after excluding studies without risk‐adjusted outcomes and studies with less than good quality based on the Newcastle‐Ottawa scale. In the prespecified study protocol, we planned to report summary estimates using risk ratios. After conclusion of the study search, the studies meeting the selection criteria were mainly observational studies, and there were no available randomized clinical trials. As such, we decided to report summary estimates using odds ratios (ORs). 11 P values were considered statistically significant if ≤0.05. Statistical analyses were conducted using RevMan 5.0 software (Cochrane Collaboration, Oxford, UK).

Results

Included Studies

The study selection process is outlined in Figure 1. The final analysis included 12 studies published between 2011 to 2021, with a total of 708 391 patients: 71 353 patients underwent PCI for ISR, and 637 038 patients underwent PCI for de novo lesions. 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 There was good interrater agreement between the 2 researchers performing study selection (κ=0.79; standard error=0.09) and data extraction (κ=0.81; standard error=0.06). The weighted follow‐up duration was 29.8 months. The study characteristics are outlined in Table 1. Six studies were retrospective studies, and the remaining 6 studies were prospective studies. Four of the included studies exclusively evaluated patients with PCI for CTO. 12 , 13 , 16 , 21 PCI with stenting was used in the ISR group in 46% to 49% of patients in 3 studies, 12 , 17 , 20 75% to 89% in 3 studies, 13 , 14 , 16 and 97% to 100% in the remaining studies. Stents used during PCI procedures were exclusively DES in 7 studies, 12 , 16 , 18 , 19 , 20 , 22 , 23 predominantly DES in 3 other studies, 14 , 17 , 21 and in 2 studies the types of stents were not reported. 13 , 15 Baseline characteristics of included patients and procedural characteristics appear in Table 2 and Table 3. The weighted mean age was 64.3 years and included predominantly men.

Figure 1. Study flowchart.

Figure 1

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Table 1.

Characteristics of Included Studies

Study Year Study design No. PCI with stents % DES % Use of IVUS Use of OCT Focal ISR % Diffuse ISR % Occlusive ISR % Follow‐up
Abdelwahab et al 18 2011 Prospective multicenter 872/4272 97.7/97.9 100/100 NA NA NA NA 4.9 12.4 mo
Richardt et al 23 2013 Prospective multicenter 281/3194 100/100 100/100 NA NA NA NA NA 2 y
Gao et al 22 2013 Retrospective single center 1300/27 211 100/100 100/100 4.1/3.5 NA NA NA NA 17 mo
Shimonaga et al 15 2015 Prospective single center 34/87 NA NA NA NA 53 47 0 In‐hospital
Redfors et al 19 2017 Prospective multicenter 840/7742 100/100 100/100 42.3/38.8 NA NA NA 6 2 y
Buchanan et al 17 2018 Retrospective single center 472/1888 46.6/95.7 81.7/93.2 54/61 NA NA NA NA 12 mo
Lee et al 16 2020 Retrospective multicenter 164/1208 89.1/93.3 100/100 NA NA NA NA 100 5 y
Takeuchi et al 20 2021 Retrospective single center 280/1258 49.3/87.9 100/100 79.6/91.6 27.9/11.1 NA NA NA 2 y
Tamez et al 14 2021 Retrospective multicenter 66 718/586 586 80.6/93 91.1/77.2 NA NA NA NA NA 4 y
Tang et al 12 2021 Prospective single center 69/357 48.4/79.4 100/100 17.9/15 NA NA NA 100 2 y
Wang et al 13 2021 Retrospective single center 212/2447 75.5/73.9 NA 6.8/6.8 NA NA NA 100 5 y
Azzalini et al 21 2017 Prospective multicenter 111/788 100/100 97.9/87.9 9.9/13.3 NA NA NA 100 15.7 mo
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DES indicates drug‐eluting stent; ISR, in‐stent restenosis; IVUS, intravascular ultrasound; NA, not applicable; OCT, optical coherence tomography and PCI, percutaneous coronary intervention.

Table 2.

Baseline Characteristics of Included Patients

Study Age, y, mean±SD Men % Tobacco use % HTN % Diabetes % Prior MI % GFR FH of CAD % HLD % ACS %
Abdelwahab et al 18 66.2±10.4/65±10.5 75.9/74.4 16.2/23.5 86.9/83.3 28.8/32.2 49.8/26.2 NA 39.5/35.5 84.5/79.6 22/27.3
Richardt et al 23 65.3±10.5/63.6±11.1 77.6/77.4 14.6/25.8 79.0/68.0 31.0/27.9 53.9/25.3 NA 36.2/32.0 81.1/62.4 47.3/56.0
Gao et al 22 57.31±10.94/57.75±10.73 83.2/78.6 42.1/31.7 47.2/40.3 21.3/15.0 33.2/24.4 NA 4.2/3.4 34.5/26.3 63.4/60.2
Shimonaga et al 15 71.1±9.8/70.8±8.4 64.7/80.5 55.9/69 82.4/90.8 67.6/58.6 47.1/18.4 NA NA 73.5/73.6 0/0
Redfors et al 19 63.6±10.9/63.6±10.9 76.5/73.8 19.9/22.9 90.2/78.5 37.0/31.9 48.2/22.7 92.8±38.4/94.2±37.7 NA 89.4/72.7 47.9/52.1
Buchanan et al 17 65±11/66±11 68/64 16/16 96/97 47/45 53/52 NA NA 95/96 67/59
Lee et al 16 59.1±10.3/62.2±10.9 69.5/77.6 22/31.5 53.7/62.8 30.5/41.4 42.7/16.2 68.3±33.2/68.4±37.2 NA 49.4/49.3 40.9/31.7
Takeuchi et al 20 69.4±10.0/67.9±11.2 83.9/80.0 16.4/21.7 83.9/70.0 54.7/39.2 NA 64.6±27.5/70.9±25.8 28.6/27.3 86.1/72.4 11.8/28.2
Tamez et al 14 74.2±6.8/74.6±7.0 65.7/62.7 12.6/13.7 92.5/85.8 43.1 /36.1 50.4 /24.7 NA 21.2 /19.1 92.7/79.8 63.9/64.7
Tang et al 12 64.8±9.8/63.1±11.6 82.6/83.8 39.1/44.8 69.6/70.3 50.7/46.5 58.0/17.9 93.3±27.2 /94.9±27.4 NA 71.0/61.3 56.5/56.3
Wang et al 13 56.80±10.26/57.23±10.52 81.1/83.6 36.8/41.7 59.4/65.3 33.0/31.4 59.0/40.2 NA NA 87.3/84.0 NA
Azzalini et al 21 65.1±10.3/65.1±10.8 82.9/87.1 21.6/23.3 79.4/74.3 41.3/37.3 70.4/45.1 82.7±26.5/83.6±28.5 NA 85.0/79.8 18.2/18.3
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ACS indicates acute coronary syndrome; CAD, coronary artery disease; FH, family history; GFR, glomerular filtration rate; HLD, hyperlipidemia HTN, hypertension; MI, myocardial infarction and NA, not applicable.

Table 3.

Procedure Characteristics

Study Lesion length, mm, mean±SD or median (IQR) LM disease >50% Px LAD disease % Any LAD disease % RCA disease % LCX disease % SVG disease % Radial access % Rotational atherectomy % Laser atherectomy % Scoring/cutting balloon % Contrast volume , mL Procedural duration , min No. of stents , mean±SD or % Average stent length mm Average stent diameter
Abdelwahab et al 18 18 (12–23)/15 (10–20) 1.3/1.3 NA 45.1/50.4 31.2/25.7 22.5/20.7 5.6/4.8 NA NA NA NA NA NA NA 20 (16–28)/18 (13–24) 3 (2.8–3)/3 (2.8–3)
Richardt et al 23 18.0±12.9/16.6±10.1 1.6/1.9 NA 36.7/43.9 34.6/28.7 22.9/24.0 3.6/1.4 NA NA NA NA NA NA NA 22.1±6.4/20.9±6.6 3.2±0.5/3.1±0.5
Gao et al 22 23.79±15.57/25.32±16.28 3.7/3.6 NA 40.5/43.1 34.0/30.8 20.5/22.3 1.3/0.3 70.1/80.6 NA NA 3.8/1.2 NA NA 2.04±1.09/1.90±1.04 (stents per patient) 29.95±17.71/30.73±17.77 3.02±0.43/3.06±0.47
Shimonaga et al 15 14.6±7.0/22.0±11.7 NA NA 44.1/55.2 32.4/24.1 23.5/20.7 NA NA NA NA NA NA NA 0/1.3±0.5 0/27.5±14.6 0/3.09±0.49
Redfors et al 19 27.3±20.7/27.1±20.0 3.3/3.8 NA 41.8/46.5 44.3/36.3 29.8/31.1 9.4/4.5 5.2/4.3 NA NA NA NA NA 1.71±1.03/1.70±1.00 33.1±23.5/32.4±22.2 NA
Buchanan et al 17 NA 1.8/3 NA 21/36 33/32 20/28 23/0 NA 1.0/4.9 1.6/0.3 19.0/5.4 NA NA 1.17±0.87/1.29±0.95 19±6.4/19±6.7 NA
Lee et al 16 16.4±11.1/19.6±14.1 NA NA 43.3/38.3 38.4/40.8 18.3/20.9 NA NA NA NA NA 190.3±89.2/216.2±123.6 Fluoroscopic time 40.1±64.4/25.5±26.1 1.8±0.5/1.84±0.6 30.2±14.9/30.2±17.1 2.94±0.4/3.08±0.9
Takeuchi et al 20 21.8±12.2/21.5±11.9 NA NA 40.4/52.0 36.8/27.8 18.2/16.4 0.4/0.5 NA 3.6/6.4 NA 69.6/40.9 NA NA 49.3/87.9 NA NA
Tamez et al 14 18.46±11.22/18.40±10.57 NA NA NA NA NA NA NA 0.9/1.6 0.5/0.1 17.3/3.8 NA NA DES G1/G2 76 939 (90.7%), 640 432 (77.7%); and BMS G1/G2 7876 (9.3%), 184 142 (22.3%) 19.20±7.5518.53±7.06 2.99±0.50 .96±0.52
Tang et al 12 NA 1.4/5.9 NA 39.1/44.8 50.7/46.8 26.1/26.6 NA 77.5/81.5 NA NA NA 239 (180, 280)/250 (200, 300) NA NA NA NA
Wang et al 13 24.2±17.3/16.9±11.5 83.5/84.9 NA NA NA NA 51.09±30.72/56.90±37.91 75.4/73.9 26.19±5.28/26.10±5.25 3.00±0.41/2.91±0.40
Azzalini et al 21 Lesion length >20 mm: 68.5%/42.5% NA NA 27.0/28.6 55.0/51.8 18.0/19.6 NA 34.2/42.7 NA NA NA 302±134/332±137 115±75/128±69 (min) 2.34±1.31/2.20±1.27 (stents per patient) 77.3±49.7/69.1±40.7 NA
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BMS indicates bare‐metal stent; DES, drug‐eluting stent; IQR, interquartile range; LAD, left anterior descending artery; LM, left main coronary artery; NA, not applicable; Px, proximal; RCA, right coronary artery and SVG, saphenous vein graft.

The quality of included studies is outlined in Table S2. Based on the Newcastle‐Ottawa scale, all studies were considered to be of very good quality, except for 1 study, which was considered as good quality. 13

Outcomes

MACE was reported in 11 studies (Table S3). Adjusted data were pooled from 9 studies as outlined in Table S4. Compared with de novo PCI, PCI with ISR was associated with a higher incidence of MACE (OR, 1.31 [95% CI, 1.18–1.46]; I2=92%; Q=127.61, P<0.001) (Figure 2). Funnel plot inspection showed no publication bias (P=0.16) (Figure S1). Subgroup analysis showed no significant interaction according to CTO versus non‐CTO lesions (P interaction=0.69). Sensitivity analyses excluding studies not reporting risk‐adjusted estimates (ie, Richardt et al 23 and Wang et al 13 ) (OR, 1.34 [95% CI, 1.20–1.50]) showed similar results (Figure S2).

Figure 2. Forrest plot for long‐term major adverse cardiovascular events after PCI of ISR vs de novo lesions.

Figure 2

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CTO indicates chronic total occlusion; exp(ES), Exponentiated log effect‐size; ISR, in‐stent restenosis; and PCI, percutaneous coronary intervention.

All‐cause mortality was reported in 7 studies. There was a higher incidence of all‐cause mortality among the ISR versus the de novo group (OR, 1.03 [95% CI, 1.02–1.04]; I2=0%; Q=4.86, P=0.56). Subgroup analysis showed no significant interaction according to CTO versus non‐CTO lesions (P interaction=0.91) (Figure 3).

Figure 3. Forrest plot for secondary outcomes after PCI of ISR vs de novo lesions.

Figure 3

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CTO indicates chronic total occlusion; exp(ES), Exponentiated log effect‐size; ISR, in‐stent restenosis; and PCI, percutaneous coronary intervention.

Cardiovascular mortality was reported in 5 studies.2,3,5,8 There was no difference in cardiovascular mortality between the ISR and de novo groups (OR, 1.04 [95% CI, 0.90–1.20]; I2=0%; Q=1.88, P=0.76). MI was reported in 11 studies (definition of MI according to each study is reported in Table S5). There was a higher incidence of MI among the ISR versus de novo groups (OR, 1.20 [95% CI, 1.11–1.29]; I2=38%; Q=16.10, P=0.10). Subgroup analysis showed no significant interaction according to CTO versus non‐CTO lesions (P interaction=0.73). TVR was reported in 9 studies.1–5,9 Compared with de novo lesions, the ISR group had a higher incidence of TVR (OR, 1.42 [95% CI, 1.29–1.55]; I2=86%; Q=57.00, P<0.001). Subgroup analysis showed no significant interaction according to CTO versus non‐CTO lesions (P interaction=0.86). Stent thrombosis was reported in 5 studies.3–5,9 Analysis showed a higher incidence of stent thrombosis with PCI for ISR versus de novo lesions (OR, 1.44 [95% CI, 1.11–1.87]; I2=84%; Q=26.43, P<0.001) (Figure 3).

Discussion

In this meta‐analysis of 12 studies including 708 391 patients, we evaluated the outcomes of PCI of ISR versus de novo lesions. The salient findings were: (1) PCI for ISR was associated with a higher incidence of risk‐adjusted MACE compared with PCI for de novo lesions at a median of ≈30 months. (2) This was driven by a higher incidence of all‐cause mortality, MI, TVR, and stent thrombosis in the ISR group. (3) There was no evidence of interaction for the outcomes in the CTO versus non‐CTO subgroups (Figure 4).

Figure 4. Summary of the outcomes with PCI for ISR vs de novo lesions.

Figure 4

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ISR indicates in‐stent restenosis; OR, odds ratio; and PCI, percutaneous coronary intervention.

ISR PCI represents about 10% of all PCI in the contemporary DES era. 24 Patients with ISR present in the form of acute coronary syndrome in more than two‐thirds of patients and tend to present more often with unstable angina and less often with MI than de novo coronary lesions. 17 , 25 Clinicians have attempted to stratify different classes of ISR, either angiographically or by mechanism. 26 , 27 Focal patterns, which were predominantly treated with angioplasty and stenting, were associated with better clinical outcomes compared with more diffuse lesion patterns or CTOs. 26

In this study, we pooled the totality of available data for the outcomes of PCI for ISR, compared with PCI for de novo lesions. This analysis is the largest to date, and showed a higher incidence of adverse clinical events, including all‐cause mortality, after PCI for ISR versus de novo lesions. These findings are line with results of individual studies. The higher risk of adverse events with PCI for ISR is probably related to the unique pathophysiology of ISR lesions as well as the challenging nature of interventions for ISR lesions. ISR lesions have a distinctive pathophysiology, which is characterized by neointimal hyperplasia and neoatherosclerosis, 28 as opposed to the atherosclerotic plaque formation with fibro‐fatty calcified core in de novo coronary artery disease. Optical coherence tomography studies have demonstrated the neointimal changes that occur with time inside DES. These include increased neointimal thickness and transformation from a homogenous to heterogenous or lipid‐laden intima, with formation of cholesterol‐rich plaques and thin‐cap atheromas. 29 , 30 These neoatherosclerotic changes occur more frequently and earlier in DES than bare‐metal stents and play a role in DES ISR. 31 , 32 Lipid‐laden neointima also plays a role in the increased risk of late stent thrombosis with DES, in addition to delayed neointimal coverage of stent struts. 33 , 34 Although new‐generation everolimus‐eluting stents demonstrate better vessel healing and neointimal stent coverage than first‐generation sirolimus‐ and paclitaxel‐eluting stents, they have a similar prevalence of neoatherosclerosis. 35 In addition to vessel remodeling following DES, mechanical factors, such as stent under expansion due to underlying calcification and malposition, also play a role in ISR. 36 Patient‐related factors such as diabetes and renal failure have also been reported to be independent risk factors for ISR. 37 , 38

Given its unique pathophysiology and complex clinical presentation, intervening on ISR portends a challenging subset of PCI procedures. Different intervention techniques are used in clinical practice, which are mainly based on clinical presentation, type of ISR lesions (ie, focal versus diffuse), and mechanism of ISR lesions. A mechanism‐driven approach should be always considered when selecting a strategy for treatment of ISR, including restenting, balloon angioplasty, cutting and scoring balloons, rotational atherectomy, brachytherapy, or using drug‐coated balloons. 5 Even with the wide variety of interventions, 2 modalities are preferred, repeat PCI with DES or angioplasty with drug‐coated balloons. 39 , 40 In the current meta‐analysis, the proportion of PCI with stenting among the ISR group varied across different studies from 48.4% to 100%, mainly with DES. Comparatively, a national cohort study of >5 million patients observed that 23.5% of patients with ISR did not receive DES and were more likely to receive other treatments. 24 Restenting ISR with DES, specifically everolimus stents, was found to be superior in both angiographic and clinical outcomes compared with other PCI methods. 41 , 42 However, operators should be mindful of multilayered stenting, and recurrent DES implantations could exacerbate a cycle of restenosis. Drug‐coated balloons, although providing less lumen gain than restenting, are also a viable option, because they do not add a stent layer and still provide favorable outcomes. 43 , 44 Coronary artery bypass graft should ultimately be considered in patients with diffuse, recurrent ISR with associated multivessel disease, but this approach may be limited due to poor target vessels. 45 The use of intracoronary imaging to guide PCI can optimize lesion preparation, stent deployment, and may assist with identifying the mechanism of stent failure, reducing the risk of MACE compared with angiography‐guided PCI. 46 Limited data were reported in the current analysis on the use of intracoronary imaging during PCI for ISR. Further research is warranted to evaluate the outcomes of PCI of ISR compared with de novo lesions using the state‐of‐the‐art PCI techniques, including routine intravascular imaging, transradial access, and using advanced modalities such as laser atherectomy, brachytherapy, and drug‐coated balloons.

In this analysis, the higher risk of adverse events with PCI for ISR, was observed irrespective of ISR morphology (ie, CTO or non‐CTO). CTO ISR lesions represent the extreme end of the spectrum of ISR lesions, and share similar morphological patterns, including neointimal hyperplasia, neoatherosclerosis, and stent under expansion in CTO ISR. PCI for CTO ISR lesions entails different technical considerations. At 1 side, the previously deployed stent acts as a roadmap of the target vessel and also doubles as a guard against coronary dissection during PCI of the CTO. 16 However, the previous stent may obstruct the path of the wire and lead to suboptimal reentry for PCI. Lee et al additionally observed that stenting of ISR in CTO was a risk factor for MI and TVR, possibly explained by an abnormal vessel reaction and thrombus formation attributed to multilayered stenting. 16

The collective data in this study demonstrated that PCI for ISR is associated with worse outcomes compared with de novo lesions. This highlights the need for optimization of index PCI procedures to reduce the chances of future ISR by adopting best practices such as adequate lesion preparation and intracoronary image‐guided interventions. Future directions should be directed toward increasing awareness for adoption of these best practices, and toward exploring novel/alternative approaches for PCI of ISR.

Limitations

The current analysis has certain limitations. First, due to the observational nature of included studies, there is an inherent risk for selection bias. In our analysis, we have pooled risk‐adjusted effect sizes to minimize this risk. Nevertheless, residual confounding cannot be ruled out. Second, there was a considerable degree of statistical heterogeneity for some of the study outcomes. Also, there were some variabilities among the included studies in the definition of the primary outcome. Nevertheless, we have adopted a random‐effects model to mitigate the effects of such heterogeneity. Third, some of the included studies only reported data for patients who underwent stent implantation, and data for unsuccessful PCIs were not reported. This might have introduced selection bias by not reporting data for patients with unsuccessful PCIs or ISR with anatomies not amenable to stenting. Fourth, patients with recurrent ISR may be treated with different approaches and management strategies, contributing to heterogeneity of outcomes. Insufficient patient‐level data precluded further subgroup analyses. Finally, the use of intracoronary imaging and laser atherectomy were either not reported or extremely low in the included studies in our analysis. This could impact the external generalizability of the findings to contemporary practice, given the viable role of these modalities in contemporary management of ISR lesions.

Conclusions

Compared with de novo lesions, PCI of ISR was associated with a higher incidence of risk‐adjusted MACE at a weighted follow‐up of 29.8 months. This was mainly driven by a higher incidence of all‐cause mortality, MI, repeat revascularization, and stent thrombosis. This association was demonstrated regardless of the nature of ISR (ie, CTO versus non‐CTO). These findings crystallize the notion that both ISR itself and PCI for ISR are not benign entities, and major efforts should be directed toward optimizing index PCI procedures.

Sources of Funding

None.

Disclosures

None.

Supporting information

Tables S1–S5

Figures S1–S2

Click here for additional data file. (734.3KB, pdf)

This article was sent to Katherine C. Wu, MD, Senior Associate Editor, for review by expert referees, editorial decision, and final disposition.

For Sources of Funding and Disclosures, see page 11.

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Supplementary Materials

Tables S1–S5

Figures S1–S2

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