Despite relatively high restenosis rates, bare-metal stents are still frequently used in clinical practice during PCI[14]. This is related to unaffordable prices of DES and more importantly, lower risk of bleeding due to shorter duration of dual antiplatelet therapy (DAPT) that is required after BMS compared with DES. BMS-ISR causes a significant therapeutic burden in current clinical practice. One pooled analysis reported a one-year TLR and TVR rates after BMS of 12% and 14.1% respectively[15,16]. Clinical restenosis was evident within 6-12 wk after BMS implantation[16]. Beyond 1 year, rate of BMS restenosis is negligible and most stenting events are related to disease progression in vessel segments other than the stented lesion[16].

Restenosis rate of DES increased in the recent years due to expanded use to include high-risk patients with complex coronary lesions. The DES-ISR rate has been reported in 3%-20% depending on DES type, the duration of follow-up, and the complexity of the lesions in which the stents were placed[3]. When compared with BMS, DES is associated with lower ISR. At one-year follow up, SES markedly reduced the incidence TLR from 16.6% to 4.1% when compared with BMS[17]. For first-generation DES, j-Cypher registry of 12812 patients who received SES, the TLR rate was 7.3% at 1 year, and 15.9% at 5 years[18]. Ischemia-driven TLR was also the same in patients randomly assigned to SES or PES (13.1% vs 15.1%) in the SIRTAX LATE study[19]. Second generation stents have been associated with lower death and myocardial infarction compared with first-generation DES. However, zotarolimus-eluting stent (ZES) found to be noninferior to PES for TVR at 1 and 5 years[20]. In a pooled analysis of multiple studies comparing everolimus-eluting with ZES, the rates of TVR at up to five years of follow-up were 6.3% and 5.0%, respectively[21].

Patient characteristics and comorbidities that are associated with higher rate of ISR include; metal allergy, local hypersensitivity reactions with immunologic and inflammatory response to the drug or the polymer, age, female gender, diabetes mellitus, chronic kidney disease (including hemodialysis), and multivessel coronary artery disease[3,22,23].

Lesion characteristics associated with ISR include; lesion length, smaller reference artery diameter, ostial lesion, initial plaque burden and residual plaque after implantation. In contrast with BMS, DES tends to have a more focal pattern of ISR, except in diabetics, where the ISR tends to be more confined to the stent edges[24,25]. Focal ISR (Mehran pattern I) has been associated with a lower rate of ISR recurrence than nonfocal (Mehran pattern > I) ISR[25].

Operator and technique dependent characteristics include stent undersizing, incomplete lesion coverage, stent under expansion, and malapposition. Mechanical properties of stents that may lead to recoil because of loss of radial force, stent fractures, and altering increase in shear stress are all associated with higher rates of ISR. For every 10 mm of excess stent length beyond lesion has been independently associated with increased post-procedural percent diameter stenosis by 4% and increased TLR at 9 mo (OR = 1.12, 95%CI: 1.02-1.24)[26-29]. Stent fracture, on the other hand, can trigger focal ISR or thrombosis[30-32] which can result in a reduction in drug delivery at the breakage point of the stent. Stent fracture occurs more frequently in the right coronary artery, overlapping stents, longer stents, SESs (because of the ridged closed cell structure), and excessively tortuous angulated vessels[33]. Malapposition, also known as incomplete stent apposition (ISA), is defined as the absence of contact between stent struts and the vessel wall not overlying a side branch. Malapposition seems to be related to procedural technique due to under-sizing the stent, use of low deployment pressures, and severely calcified lesions, which do not allow for homogenous stent expansion[34]. Oversized stents can also lead to extensive trauma to the vessel wall and increased proliferative reaction[35]. Geographic miss occurs when the stent does not fully cover the injured or diseased segment of the artery (axial miss) or the ratio of balloon to artery size is less than 0.9 or greater than 1.3 (longitudinal miss). Geographic miss is associated with increased risk of TLR and MI at 1 year[36]. DESs decrease neointimal growth. As a result, geographic miss or strut fracture may be larger factors of ISR in DESs compared with BMSs[12].

Routine angiographic surveillance is not recommended because it has been shown to increase the rates of oculostenotic revascularization.

IVUS is considered a fundamental intracoronary imaging modality to assess ISR. The stent and procedures characteristics can be readily assessed as contributing mechanism of ISR using IVUS[35]. IVUS delineate external elastic lamina behind the stent struts very well, which provides valuable insights on vessel sizing for optimization of stent expansion (Figure 2F and G). IVUS does help detect the presence of neointimal hyperplasia obstructing the stent, stent underexpansion, stent fracture, or edge restenosis. In addition, it can provide insights into optimal vessel sizing for choosing the appropriate stent size (Figure 2K and L). However, IVUS has limited axial resolution (150 μm), which makes neointimal interface hard to define[12].

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Figure 2 Sixty-seven-year-old man presented with increasing chest pain at rest. He has past medical history significant for coronary artery disease with PCI and coronary artery bypass grafting. He had PCI with (3.0 mm × 12 mm) DES to LCx, (2.5 mm × 16 mm) DES to RI and (2.5 mm × 16 mm) DES to obtuse marginal a year prior to his presentation. The left internal mammary artery to LAD is patent, however, he is known to have occluded SVG to RI and SVG to first diagonal (D1). Given his increasing chest pain, coronary angiogram was done. A: Coronary stents before contrast injection in LAD (red arrow), LCx (blue arrow); B: Coronary angiogram of the same patient showing severe proximal LCx ISR (blue arrow) with no flow, severe proximal RI ISR (green arrow) with slow flow, and mid LAD severe ISR (red arrow); C: Dilation of the RI coronary artery with 2.5 mm × 22 mm NC balloon with 22 atm inflation pressures was done; D: Coronary angiogram showing the proximal RI ISR (green arrow) post balloon dilation. Red arrow shows severe proximal LAD stenosis with poor flow. LCx has completely occluded ISR (blue arrow); E: The left circumflex ISR lesion (red arrow) was wired and with balloon dilation the flow was restored in the LCx (green arrow); F: IVUS imaging of the underexpanded stent in the proximal LCx lesion. Left panel shows stent struts (red arrow) with evidence of neointimal hyperplasia (yellow star). The right panel shows small stent CSA of only 3.6 mm² which is below the target 5 mm² in asians and 6 mm² in non-asians; G: IVUS imaging of the underexpanded stent in the proximal ramus coronary artery. Left panel shows severely under-expanded stent (red arrow) with evidence of neointimal hyperplasia (yellow star). The right panel shows small stent CSA of only 2.9 mm²; H: Excimer Laser Coronary Angioplasty treatment of LCx (left panl - red arow) and ramus artery (right panel - green arrow) using 0.9 mm coronary laser and the heparinized flush technique. Laser catheter was advanced slowly at 0.2-0.5 m/s during laser emission with careful monitoring of heart rate and blood pressure. Vessel injury such as perforation, dissections and acute closure are the main side effects; I: Post laser balloon dilation with (3.5 mm × 20 mm) NC balloon of both LCx (red arrow) and ramus (green arrow) arteries; J: Sequential kissing stenting technique in the proximal LCx and ramus arties with DES 3.5 mm x 18 mm in Ramus and 3.5 mm × 15 mm in LCx; K: IVUS imaging of the stent in the proximal LCx coronary artery that shows good expansion of the stent with great increase in CSA to 5.9 mm²; L: IVUS imaging of the stent in the proximal ramus coronary artery that shows good expansion of the stent with great increase in CSA to 5.6 mm²; M: TIMI III flow was achieved in the LCx and Ramus coronary arteries without any compromise of LAD. PCI: Percutaneous coronary intervention; DES: Drug-eluting stents; LCx: Left circumflex; RI: Ramus intermedius; LAD: Left anterior descending artery; SVG: Saphenous vein graft; ISR: In-stent restenosis; NC: Non-compliant; IVUS: Intravascular ultrasound; CSA: Cross-sectional area.

Optical coherence tomography (OCT) provides better axial resolution (15 μm), allowing better resolution of the vessel lumen, neointimal tissue, and stent struts distribution. The morphology of ISR can be identified using OCT which could show macrophage infiltration, necrotic core, in-stent calcification and neoatherosclerotic plaque rupture[46,47]. The weakness of the OCT resides in the poor tissue penetration, which cause poor visualization of the residual plaque that is beyond the stent[12].

FFR has been validated for clinical decision making in patients with ISR. The clinical outcome of patients with ISR with deferred interventions based on a FFR > 0.75 is excellent[48]. This diagnostic strategy is useful in controversial cases with angiographically moderate or inconclusive ISR.

Balloon angioplasty (BA) is one of the earliest interventions that were used to treat ISR by displacing in-stent tissue from the lumen in axial and longitudinal direction to the outer portion of the vessel wall as well as further expanding the stent[49] (Figure 2). This intervention could be useful in focal ISR. The outcome of BA for focal ISR However, during balloon inflation, slippage or watermelon seeding can occur, leading to edge-related complications. Cutting or scoring balloons can help minimize this, but also have limitations in delivery through stented regions or distal areas[50]. Lateral blades or atherotomes anchor the balloon in the lesion and minimize slippage[51]. Progressive balloon dilations and small/short balloons can also prevent side effects from balloon slippage[52]. One of the limitations of BA is that subacute tissue re-intrusion back to the lumen tends to occur within minutes after the last balloon inflation. This explains the early lumen loss phenomenon detected in BA studies in this setting, a finding also associated with subsequent recurrent restenosis.

Brachytherapy inhibits neointimal formation within the stent, but not the stent edges, by delivering radiation to the areas of ISR. Brachytherapy effectively suppressed the proliferative response and significantly reduced clinical and angiographic restenosis rates (Figure 3C). Both beta and gamma radiation sources could achieve major reductions in the angiographic restenosis rates[53]. Gamma emitters had profound tissue penetration, whereas beta emitters had less tissue penetration (Figure 3E). Randomized clinical trials in patients with ISR demonstrated the superiority of brachytherapy compared with conventional BA or atheroablative techniques[53-55]. Adding an extra layer of metal to treat DES or BMS-ISR is not ideal and will continue to place patients at future risk for ISR. Therefore, DEB and vascular brachytherapy are better options compared with DES. Vascular brachytherapy is available in few centers in the United States and is used primarily for recurrence of DES-ISR, but logistic issues and lack of radiation oncology support impede its uses. Therefore, restenting with second-generation DES became the default therapy for DES-ISR.

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Figure 3 Fifty-five-years-old caucasian male with mantle cell radiation for Hodgkin's lymphoma complicated with radiation heart valve disease with severe aortic valve stenosis status post mehanical aortic valve replacement surgery. Few years later he presented with chest pain and had PCI to the proximal LAD and LCx with DES. However, both few months later he developed ISR and underwent another PCI with DES to the proximal LAD and LCx. Patient was referred for vascular brachytherapy for the treatment of ISR of the LCx due to increased chest pain at rest and recurrent ISR of proximal LCx. A: Coronary angiogram showing 90% focal proximal LCx ISR (red arrow); B: Balloon angioplasty of the proximal LCx lesion (red arrow) to prepare the lesion before brachytherapy delivery; C: Coronary angiogram showing the Novoste Beta-Cath™ System that was used to deliver a source train that contains 12 individual radioactive seeds blue arrow to red arrow). Once properly positioned, 23 Gy from the center of the source center was prescribed. The patient was monitored during the dwell time which required 4 min and 49 s; D: Another balloon angioplasty was done after the radioactive seeds are pulled from LCx; E: Final TIMI-III flow in the LCx. PCI: Percutaneous coronary intervention; LAD: Left anterior descending artery; LCx: Left circumflex; DES: Drug-eluting stents; ISR: In-stent restenosis.

Excimer laser angioplasty (ELA) produces monochromatic light energy, which generates heat and shock waves that disrupt plaque (Figure 2H). Mehran et al[56] compared results of ELA vs rotational atherectomy (RA), both followed by percutaneous transluminal coronary angioplasty (PTCA). 119 patients with 158 ISR lesions were treated with ELA plus PTCA and 130 patients with 161 ISR lesions were treated with RA plus PTCA. Volumetric IVUS analysis showed a greater reduction in intimal hyperplasia volume after RA than after ELA (43 mm³vs 19 mm³, P < 0.001). However, the 1-year TLR rates were similar: 26% with ELA plus PTCA vs 28% with RA plus PTCA (P = nonsignificant). ELA is not currently a well-accepted treatment for ISR, but the ultimate role of this therapy is still unclear.

It was proposed that repeat stenting for ISR raises concerns for creating multiple stent layers. Therefore, the use of DEB angioplasty should minimize the metal layer and eventually decrease future ISR. For that purpose, multiple randomized studies have been done to evaluate the efficacy and durability of DEB compared with DES in treating BMS or DES-ISR. Few studies have shown that DEB is non-inferior to DES for BMS and DES-ISR[52-61]. However, none of these studies have been powered for clinical endpoints. DEB is currently not available for use in the United States. In addition, their use has been associated with issues that may limit their use mostly related to the use of paclitaxel and potential of particulates showering to the distal vessel bed, as well as the high profile of the device. Comparison of DEB with DES for treatment of ISR will be discussed in the following section.

Balloon angioplasty alone carries a high risk of recurrent stenosis, especially in diffuse and/or severe ISR[44,62,63]. The randomized trials Paclitaxel-eluting Stents vs Brachytherapy for In-stent Restenosis (TAXUS V ISR) and Sirolimus-eluting Stents vs Vascular brachytherapy (SISR) trial showed better outcomes for DES compared with brachytherapy[64,65]. Two major randomized trials compared DES with DEB for patients with ISR. The ISAR-DESIRE 3 trial randomized 402 patients with ISR in DES to paclitaxel-eluting balloon (PEB) vs first generation DES (PES) vs balloon angioplasty[52]. At a median follow-up of 3 years, the risk of TLR was similar with PEB vs PES (HR = 1.46, 95%CI: 0.91-2.33, P = 0.11) and lower with PEB vs balloon angioplasty (HR = 0.51, 95%CI: 0.34-0.74, P < 0.001). The risk of death/MI was lower, but not statistically significant, with PEB vs PES (HR = 0.55, 95%CI: 0.28-1.07, P = 0.08). This finding was driven by a lower risk of death (HR = 0.38, 95%CI: 0.17-0.87, P = 0.02). The risk of death/MI was similar with PEB vs balloon angioplasty (HR = 0.96, 95%CI: 0.46-2.0, P = 0.91). Using the second generation DES, Restenosis Intra-Stent of Drug-Eluting Stents: Drug-Eluting Balloon vs Everolimus-Eluting Stent (RIBS IV) trial, evaluated the comparative efficacy of DEB and EES in patients presenting with DES-ISR[66,67]. A total of 309 patients with DES-ISR were randomly allocated to DEB, or second generation DES (EES) patients in the EES arm had a significantly larger minimal lumen diameter (2.03 ± 0.7 mm vs 1.80 ± 0.6 mm, P < 0.01) net lumen gain (1.28 ± 0.7 mm vs 1.01 ± 0.7 mm, P < 0.01), and lower percent diameter stenosis (23% ± 22% vs 30% ± 22%, P < 0.01) and binary restenosis rate (11% vs 19%, P = 0.06), compared with patients in the DEB arm. At the 1-year clinical follow-up (100% of patients), the main clinical outcome measure (composite of cardiac death, myocardial infarction, and target vessel revascularization) was significantly reduced in the EES arm (10% vs 18%, P = 0.04, HR = 0.58, 95%CI: 0.35-0.98), mainly driven by a lower need for target vessel revascularization (8% vs 16%, P = 0.035).

A meta-analysis looked into treatment of ISR comparing DEB, DES, and BA reported that treatment with DEB had a trend toward better outcomes than with DES[68-72]. The risk of TLR was lower in patients treated with DEB (OR = 0.22, 95%CI: 0.10-0.42) or DES (OR = 0.24, 95%CI: 0.11-0.47) than in those treated with BA. In a comparison of DEB and DES, the risk of TLR (OR = 0.92, 95%CI: 0.43-1.90) was similar. The risk of major adverse cardiac events, which was mainly driven by TLR, was also significantly lower in the DEB and DES groups (OR = 0.28, 95%CI: 0.14-0.53) than in the BA group, but it was similar between the DEB and DES groups (OR = 0.84, 95%CI: 0.45-1.50). For TLR, the probability of being ranked as the best treatment was 59.9% (DEB), 40.1% (DES), and 0.1% (BA).

There is no clear evidence on which type of DES should be used to treat ISR of a DES. Some experts argue that using a different type of DES helps to overcome drug resistance, but no strong data support this practice. A recently published network meta-analysis addressed the question of which strategy is preferred for the treatment of ISR, with the primary outcome defined as the percent diameter stenosis at angiographic follow-up[73]. This analysis suggested that PCI with second-generation DES (EES) was the most effective treatment, whereas percutaneous coronary intervention with DEB was ranked as the second most effective treatment but without significant differences from first-generation DES. Two additional similar design meta-analyses have reported similar findings suggesting second generation DES as treatment of choice for BMS and DES-ISR[74,75]. As a result, the 2009 update of the American College of Cardiology/American Heart Association/Society for Cardiovascular Angiography and Interventions guideline update for PCI and the 2005 European Society of Cardiology Task Force recommend DES for ISR whether the initial stent was BMS or DES[76-78].

A recently published pooled analysis of the RIBS V and RIBS IV compared the efficacy of EES in patients with BMS-ISR and DES-ISR[79-82]. The study detected clinical and morphological differences of ISR in BMS vs DES, including for the later more focal ISR pattern and delayed onset of presentation. Nevertheless, the outcome of the patients with DES restenosis was less favorable with regard to the angiographic indices, including lumen diameter post procedure and at follow-up. DES-ISR group treated with EES had both increased mortality and need for target vessel revascularization as compared with BMS-ISR group at one year follow up. The authors conclude that EES provides favorable outcomes in patients with ISR and that the results of EES are less satisfactory in patients with DES-ISR than in those with BMS-ISR.