A 67-year-old man with a past medical history significant for insulin-dependent diabetes mellitus, hypertension, and coronary artery disease was admitted with typical angina (Canadian Cardiovascular Society [CCS] class III) for 1 month. The patient had a history of acute non–ST-segment elevation myocardial infarction (NSTEMI) 12 months prior to his presentation and was treated with a total of 5 drug-eluting stents in the left anterior descending (LAD), left circumflex (LCx), and right coronary (RCA) arteries. The patient was compliant with dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI). During the current admission, the patient had dynamic electrocardiogram (ECG) changes in anterolateral leads with elevated troponin I. Echocardiography revealed a hypokinetic left ventricular (LV) apex with estimated left ventricular ejection fraction (LVEF) of 45%. The patient underwent coronary angiogram that showed severe diffuse in-stent restenosis (ISR) in the proximal LAD stent and moderate ISR in the diagonal stent (bifurcation lesion) along with significant ostial disease in the LAD extending from the upper edge of the LAD stent. Kissing balloon inflations were performed using a 2.5 × 15 mm sapphire noncompliant (NC) balloon in the LAD and a 2 × 10 mm sapphire balloon in the diagonal branch. Keeping the guidewire in the LAD, the LCx was wired using a BMW guidewire. A Xience V (Abbott, Chicago, IL) 2.75 × 12 mm stent was positioned in the ostioproximal LAD overlapping the distal stented segment (see Figure 17-3, red arrow) and deployed at 18 atm, keeping an uninflated 2 × 10 mm sapphire balloon in the distal left main and ostial LCx. The overlapped segment was postdilated using the same in-stent balloon at 20 atm. Thrombolysis in Myocardial Infarction (TIMI) grade 3 flow was achieved in the LAD without any compromise of ostial LCx.

Over the course of the past 3 decades, PCI with stent implantation transformed the practice of cardiology as it became the most widely performed procedure for the treatment of symptomatic coronary artery disease (CAD).¹ The most common complication of metallic stents is in-stent restenosis (ISR), which results in renarrowing of the arterial lumen and can lead to serious clinical events such as the need for reintervention and onset of acute coronary syndrome, including myocardial infarction. Since the introduction of metallic stents to clinical practice, clinicians, scientists, and engineers have studied the mechanism of ISR and searched for solutions to minimize or eliminate it. The development of drug-eluting stents (DES) was a breakthrough because they had a reduced ISR rate compared with bare metal stents (BMS).² As a result, DES became the default stent for the treatment of CAD, and research efforts were shifted to prevention and treatment of DES-related ISR. The problem of late restenosis as a result of neoatherosclerosis has also emerged, adding to the complexity and challenge of the treatment of ISR. In 2017, the focus is now targeted on reducing the rate of DES restenosis and finding treatments for it. This book covers the characterization of DES-ISR, the mechanisms that cause it, and the therapies and strategies to combat it. This chapter includes case studies to illustrate and better understand the phenomenon of ISR.

Many definitions have been proposed for ISR. In general, ISR is defined as the gradual renarrowing of a stented coronary artery lesion due to arterial damage with subsequent neointimal tissue proliferation.^3,4

Angiographically, ISR is a binary event defined as recurrent diameter stenosis at the stent segment more than 50% of the vessel diameter as determined by coronary angiography.⁴ The angiographic definition remains the main definition since it allows determination of ISR severity and morphologic pattern.

The clinical definition of ISR requires the presence of >50% diameter in-stent stenosis and 1 of the following: clinical symptoms of recurrent angina, objective signs of ischemia (ECG changes), positive coronary hemodynamic assessment with fractional flow reserve <0.80, intravascular ultrasonography minimum cross-sectional area <4 mm² (6 mm² for left main), or restenosis with ≥70% reduction in lumen diameter even in the absence of clinical symptoms or signs.

The main mechanism of ISR following stent implantation is neointimal tissue proliferation as a result of arterial wall damage.^3,4 Neointimal tissue proliferation could be focal or distributed uniformly along the length of the stent (Figure 17-1). The mechanism of ISR also depends on the duration after which it occurs. ISR, which happens early within days of stent deployment, is due to elastic recoil and relocation of axially transmitted plaque. The causes of late (weeks to months) ISR commonly are reorganization of thrombus, neointima formation, and remodeling.⁵

Neoatherosclerosis is another contributing factor to ISR. Injury to the vessel during the PCI and stent deployment stimulates neointima formation. A cascade of events are triggered by the intimal and medial damage, leading to proliferation and migration of vascular smooth muscle cells and extracellular matrix formation, which ultimately activates the coagulation-fibrinolysis system.⁶ The local inflammation can lead to the development of neoatherosclerosis characterized by accumulation of lipid-laden foamy macrophages within the neointima with or without a necrotic core formation and calcification, which can occur years after stent placement.⁷ Neoatherosclerosis is associated with a higher proportion of in-stent atherosclerotic plaque, which could explain unstable symptoms and myocardial infarction presentation of patients with ISR years after PCI. The incidence of neoatherosclerosis was significantly greater in DES compared with BMS (31% vs. 16%; P <.001).⁸ Younger age, longer implant durations, sirolimus-eluting stent usage, paclitaxel-eluting stent usage, and underlying unstable plaques are independent risk factors for neoatherosclerosis.^8,9

Stent underexpansion is another contributing factor for ISR after either DES or BMS placement. This is proposed to be due to underexpansion of the stent, which may occur as a result of undersizing, low deployment pressures, or underlying heavily calcified lesions.¹⁰ There are significant histopathologic differences between ISR that occurs after BMS compared with DES-related ISR.^11,12 Neointimal hyperplasia follows a diffuse pattern in BMS-ISR with rich smooth muscle cellularity and occasional peri-strut fibrin and inflammation, and the time observed for neointimal accumulation is 6 to 8 months after PCI.¹³ DES-ISR, however, is associated with focal neointimal hyperplasia affecting the stent edges and frequent peri-strut fibrin and inflammation, and the time observed for neointimal accumulation could be as late as 5 years after PCI. Moreover, compared with BMS, DES stents have been shown to have many technical difficulties during implantation, which can lead to ISR. Among these difficulties are stent overexpansion, stent fracture, nonuniform distribution of struts, geographic miss phenomenon, and malapposition.¹⁴ Due to these differences and the time course of neointimal accumulation, the clinical presentation of BMS-ISR differs from DES-ISR.¹⁵

The Mehran system¹⁶ is a morphologic classification of ISR lesions: pattern I (focal) is an ISR (≤10 mm in length) lesion within the stent; pattern II (diffuse) is ISR >10 mm within the stent; pattern III (proliferative) is ISR >10 mm extending outside the stent; and pattern IV (occlusion) is totally occluded ISR. This classification system predicts the need for repeat revascularization after intervention (19%, 35%, 50%, and 98% for patterns I, II, III, and IV, respectively).¹⁶ American College of Cardiology/American Heart Association classification also has been validated in patients with ISR.¹⁷ B2-C lesions have been reported to be frequently associated with suboptimal acute results with a higher restenosis rate and poorer long-term clinical outcomes.¹⁸

Different factors contribute to ISR, which makes the incidence of the complication difficult to predict. In general, the rate of ISR ranges from 3% to 20% with DES and 16% to 44% with BMS. This occurs typically between 3 and 20 months after stent placement.^3,19 The incidence of ISR depends on the definition used, stent type, location, patient comorbidities, and lesion complexity (ie, lesion length, vessel size, and bifurcation lesions).

The introduction of DES has significantly reduced the occurrence of neointimal proliferation, which is considered the main mechanism for ISR. The decrease in ISR was translated into decreased clinical need for subsequent repeat revascularization.^9,20,21 A meta-analysis of 38 randomized controlled trials with more than 18,000 patients showed that there was significant reduction in target lesion revascularization (TLR) with both sirolimus-eluting stents (SES) and paclitaxel-eluting stents (PES) compared with BMS.⁹ However, since ISR is a complex phenomenon that involves additional factors beyond device and stent design, the rate of complications with both BMS and DES is still relatively high.¹⁰ In a contemporary report on a large cohort (n = 10,004), routine angiographic surveillance 6 to 8 months after stent implantation revealed ISR rates of 30.1%, 14.6%, and 12.2% for BMS, first-generation DES, and second-generation DES, respectively.²²

BMS-ISR

Despite relatively high restenosis rates, BMSs are still frequently used in clinical practice during PCI.²³ This is in part due to the high price of DES and, more importantly, the lower risk of bleeding due to the shorter duration of DAPT that is required after BMS compared with DES. BMS-ISR causes a significant therapeutic burden in current clinical practice. One pooled analysis reported 1-year TLR and target vessel revascularization (TVR) rates after BMS of 12% and 14.1%, respectively.^24,25 Clinical restenosis was evident within 6 to 12 weeks after BMS implantation.²⁵ Beyond 1 year, the rate of BMS restenosis is negligible, and most stenting events are related to disease progression in vessel segments other than the stented lesion.²⁵

DES-ISR

The restenosis rate with DES has increased in recent years due to expanded use of DES in high-risk patients with complex coronary lesions. The DES-ISR rate has been reported to be between 3% and 20%, depending on DES type, the duration of follow-up, and the complexity of the lesions in which the stents were placed.³ Compared with BMS, DES is associated with less ISR. At 1-year follow-up, the TLR rate with sirolimus DES was 4.1% compared with 16.6% with BMS.²⁶ For first-generation DES, an analysis using the j-Cypher registry of 12,812 patients who received SES found the TLR rate was 7.3% at 1 year and 15.9% at 5 years.²⁷ 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.²⁸ Second-generation stents have been associated with a lower risk of death and myocardial infarction compared with first-generation DES. However, zotarolimus-eluting stent (ZES) was found to be noninferior to PES for TVR at 1 and 5 years.²⁹ In a pooled analysis of multiple studies comparing everolimus-eluting stents with ZESs, the rates of TVR at the 5-year follow-up were 6.3% and 5.0 %, respectively.³⁰

The predictors of ISR are divided into 3 main factors: patient characteristics and comorbidities, lesion characteristics, and procedural characteristics.

Patient characteristics and comorbidities that are associated with a higher rate of ISR include metal allergy, local hypersensitivity reactions with immunologic and inflammatory response to the drug or the polymer, advanced age, female sex, diabetes mellitus, chronic kidney disease (including hemodialysis), and multivessel CAD.^3,31,32

LESION CHARACTERISTICS

Lesion characteristics associated with ISR include lesion length, smaller reference artery diameter, ostial lesion, initial plaque burden, and residual plaque after implantation. In contrast to BMSs, DESs tend to have a more focal pattern of ISR, except in diabetics, where the ISR tends to be more confined to the stent edges.^33,34 Focal ISR (Mehran pattern I) has been associated with a lower rate of ISR recurrence than nonfocal ISR (Mehran pattern >I).³⁴

PROCEDURAL CHARACTERISTICS

Procedural characteristics are divided into technique and design properties. Operator- and technique-dependent characteristics associated with increased ISR rate include stent undersizing, incomplete lesion coverage, stent underexpansion, and malapposition. Mechanical properties of stents that may lead to recoil because of loss of radial force, stent fractures, and increase in shear stress are all associated with higher rates of ISR. Every 10 mm of excess stent length beyond the end of the lesion has been independently associated with increased postprocedural percent diameter stenosis by 4% and increased TLR at 9 months (odds ratio [OR], 1.12; 95% confidence interval [CI], 1.02-1.24).^35-38

Stent fracture can trigger focal ISR or thrombosis,^39-41 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 and with overlapping stents, longer stents, SES (because of the ridged closed cell structure), and excessively tortuous, angulated vessels.³

Malapposition, also known as incomplete stent apposition, is defined as the absence of contact between stent struts and the vessel wall not overlying a side branch. Stent malapposition has been associated with stent thrombosis and ISR.³ However, the evidence for this association is still controversial.⁴² Malapposition seems to be related to procedural technique due to undersizing the stent, use of low deployment pressures, and severely calcified lesions, which do not allow for homogenous stent expansion.⁴³ Oversized stents can also lead to extensive trauma to the vessel wall and increased proliferative reaction.⁴⁴

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 <0.9 or >1.3 (longitudinal miss). Geographic miss is associated with increased risk of TLR and myocardial infarction at 1 year.⁷ DES decreases neointimal growth. As a result, geographic miss or strut fracture may be more important factors of ISR in DES compared with BMS.¹⁰

Nonuniform drug delivery can also predispose to ISR and can be influenced by local blood flow alterations, strut overlap, and polymer damage. Difficult stent delivery may cause alterations to the stent composition and prevent optimal drug distribution.

Due to the gradual and slow progression of ISR compared with stent thrombosis, the majority of patients with ISR present with symptoms of progressive recurrent angina.⁸ Symptoms of DES-ISR typically develop 3 to 12 months after stent placement.¹¹ Symptoms of ISR related to BMS, on the other hand, develop sooner, with a reported average of 6 months after PCI.¹²

Patients with ISR sometimes present with unstable symptoms with elevated cardiac markers, fulfilling the diagnostic criteria for myocardial infarction (MI).^13,22 An estimated 3.5% to 20% of patients with BMS-ISR present as MI.¹⁵ DES-ISR is similar, with approximately 16% to 66% of patients presenting with unstable angina and 1% to 20% with MI.^15,45

ROUTINE SURVEILLANCE

Routine angiographic surveillance is not recommended because it has been shown to increase the rate of oculostenotic revascularization. In one study, the rate of TLR at 5 years was 18% in patients assigned to routine angiographic follow-up versus 11% in those assigned to clinic follow-up alone (P <.001).⁴⁶ The increased TLR rate was driven by treatment of more intermediate lesions (40%-70% stenosis). However, there was no reduction in rates of cardiac death or MI (8.9% vs. 8.8%; P = .93).

INTRAVASCULAR ULTRASONOGRAPHY

Intravascular ultrasonography (IVUS) is considered a fundamental intracoronary imaging modality to assess ISR. The stent and procedures characteristics can be readily assessed as contributing mechanisms of ISR using IVUS.⁴⁴ IVUS delineates external elastic lamina behind the stent struts very well, providing valuable insights on vessel sizing for optimization of stent expansion (Figure 17-2, F and G). IVUS also helps 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 17-2, K and L). However, IVUS has limited axial resolution (150 μm), which makes the neointimal interface difficult to distinguish.¹⁰