The development of percutaneous coronary intervention (PCI) with stent implantation has revolutionized the practice of cardiology over the course of the past decades. However, despite considerable technological advancements, in-stent restenosis (ISR) remains the most common cause of treatment failure after PCI. Moreover the high efficacy with contemporary devices—primarily drug-eluting stents (DES)—has facilitated the expansion of PCI to broader and increasingly more complex lesion and patient subsets. Accordingly, despite low rates of ISR in relative terms the absolute numbers of patients presenting with stent failure remain considerable. Importantly the management of this condition remains challenging, with high rates of subsequent events at medium- to long-term follow-up.
The term restenosis is used in a variety of settings across the field of interventional cardiology. Angiographic restenosis is commonly adjudicated as a binary event defined as a re-narrowing of more than 50% of the vessel diameter as determined by coronary angiography. As this definition is based on two-dimensional parameters accurate measurements are critically dependent on the acquisition of worst-view projections. Typically visual estimation of restenosis is employed in routine clinical practice in the catheterization laboratory. This requires the operator to develop a sense of what comprises a 50% diameter stenosis. In adjudication of ISR the basic frame of reference is the body of the stent—this is known as an in-stent analysis. However, restenosis also shows a predilection for occurrence at stent margins. Accordingly a frame of reference including both the body of the stent and 5-mm margin proximal and distal to the stent edges is also usually assessed—this is known as an in-segment analysis. It is important to recognize that the use of 50% diameter stenosis as a cut-off for determination of restenosis as a binary event is rather arbitrary. For this reason continuous parameters are also commonly employed as surrogate markers of restenosis. These parameters also offer the advantage of superior statistical power for comparison between treatments, which makes them particularly attractive for clinical trials as they reduce the sample size required. The most commonly used continuous parameters are minimal lumen diameter (MLD) or percentage diameter stenosis at follow-up angiography and late lumen loss (which is the difference between the MLD immediately postprocedure and that at follow-up angiography). Of these, percentage diameter stenosis and late loss are the most well-studied markers in clinical trials and mean values of these parameters correlate reliably with incidence of angiographic and clinical restenosis.
Intravascular imaging modalities such as intravascular ultrasound (IVUS) or optical coherence tomography (OCT) acquire data in three dimensions. Using these modalities restenosis is defined as a re-narrowing of more than 75% of the reference vessel area in cross-section. Visual estimation of stenosis is not usually employed and rapid online quantitative measurements are routinely available in the catheterization laboratory. Similarly, in autopsy studies restenosis is usually defined as a pathological vessel re-narrowing of more than 75% of the vessel area in cross-section. The term clinical restenosis is sometimes used to refer to restenosis of the treated lesion accompanied by requirement for re-treatment, for example, due to symptoms or signs of ischemia. Rates of clinical restenosis are usually considerably lower than rates of restenosis detected by imaging as not all restenotic lesions cause ischemia or elicit symptoms.
The principles underpinning the management of ISR are not dissimilar to those underlying the treatment of de novo coronary atherosclerotic lesions. The basic tenet of interventional treatment is that efficacy is optimized by maximizing acute gain and/or by minimizing late loss ( Figure 13-1 ). However, the major difference with restenotic in comparison with de novo lesions is the presence of an existing stent scaffold in the diseased coronary segment. This may offer certain mechanical advantages, if its structural integrity is intact, but also provides a challenge due to the potential disadvantages of implanting multiple stent layers.
Mechanisms of In-Stent Restenosis
Restenosis after PCI is well characterized as a distinct pathophysiological process rather than merely an accelerated form of postintervention atherosclerosis. Broadly speaking the contributing factors to restenosis after vascular intervention may be divided into five categories as follows:
acute or subacute prolapse of the disrupted plaque
elastic recoil of the vessel wall
constrictive vascular remodeling
neointimal hyperplasia (due to extracellular matrix deposition and smooth muscle cell hyperplasia)
de novo in-stent atherosclerosis (so-called neoatherosclerosis)
|CHARACTERISTIC||BARE-METAL STENT RESTENOSIS||DRUG-ELUTING STENT RESTENOSIS|
|Angiographic appearance||Diffuse pattern more common||Focal pattern more common|
|Time course of late luminal loss||Late loss maximal by 6-8 months||Ongoing late loss out to 5 years|
|Optical coherence tomography tissue properties||Homogeneous, high-signal band typical||Layered structure or heterogeneous typical|
|Smooth muscle cellularity||Rich||Hypocellular|
|Peri-strut fibrin and inflammation||Occasional||Frequent|
|Complete endothelialization||3-6 months||Up to 48 months|
|Neoatherosclerosis||Relatively infrequent, late after stenting||Relatively frequent, accelerated course|
In terms of angiographic morphology of restenosis after stenting Mehran et al. developed the most widely accepted classification system for restenosis within bare-metal stents. This scheme is based on stenosis length (≤10 mm is classified as focal, >10 mm as diffuse), geographic localization of the neointima in relation to the stent and whether or not the restenosis is occlusive. Patterns are classified into 4 major groups: type I focal; type II diffuse within stent; type III diffuse within and beyond stent; and type IV occlusive (see case examples ). Importantly the pattern of restenosis at presentation is a predictor of subsequent outcome after re-intervention. In the original study target lesion revascularization rates were 19%, 35%, 50%, and 83% in groups I-IV, respectively (p < 0.001). While the majority of restenotic lesions within bare-metal stents are diffuse, in DES the majority are focal ( Table 13-1 , Figure 13-4 ). This may be because DES are generally very effective at suppressing neointimal overgrowth, which means that focal technical issues (e.g., stent fracture, local underexpansion) may play a relatively more important role in comparison with bare-metal stent restenosis.
The remainder of this chapter summarizes the spectrum of management options for patients presenting with restenosis following bare-metal or drug-eluting stent therapy. The principal randomized trials investigating outcomes of patients treated for ISR are summarized in E-Table 13-1 .
|TRIAL||YEAR||STENT||THERAPY||PATIENTS||TIME||BAR||LL ST||LL SEG||MLD||DS||TIME||MACE||DEATH||MI||TLR||TVR|
|Teirstein||1997||BMS *||BT||26||6||17 †||0.38 †||2.43 †||17 †||12||15.0 †||0||4||12.0 †|
|WRIST||2000||BMS||BT||65||6||22 †||0.22 †||2.03 †||30 †||12||35.3 †||6.2||9.2||23.0 †||33.8 †|
|Leon||2001||BMS||BT||131||6||32 †||0.73 †||1.78 †||46 †||9||28.2 †||3.1||9.9||24.4 †||31.3 †|
|ARTIST||2002||BMS||BA||146||6||51 †||0.67 †||1.20 †||56 †||6||20.4|
|BT||60||4-8||45 †||0.67 †||0.65 †||1.23||54 †||12||42.2 †||6.8||23.7||39.0 †|
|PACCOCATH-ISR||2006||BMS||DEB||26||6||5 †||0.09 †||0.03 †||2.31||12||4.0 †||4.0||4.0||0.0 †|
|RIBS2||2006||BMS||DES||76||9||11 †||0.13||2.52||8||12||11.8 †||3.9||2.6||10.5 †|
|SISR||2006||DES-BMS||DES||259||6||20||0.33||0.23||1.80||32.35||9||10.0 †||0.0||0.4||8.5 †||10.8 †|
|PES||195||9||15 †||0.25||0.11 †||1.99||14.5||9||11.5 †||0.0||3.7||7.9||12.0|
|INDEED||2008||BMS||DES||65||6||6 †||0.15 †||0.23||2.29||20.42||12||7.7||3.1||1.5||4.6 †|
|PEPCAD-II||2009||DES-BMS||DEB||66||6||4||0.19 †||0.17 †||2.08||29.4||12||7.6||1.5||0.0||6.3|
|Habara||2011||DES||DEB||25||6||9 †||0.18 †||0.18 †||1.82||34.2||6||4.3 †||0.0||0.0||4.34 †|
|Wiemer||2011||DES||44||6||4 †||0.09 †||2.66||7.78||12||4.0||2.0||0.0||2.0||2.0 †|
|PEPCAD-DES||2012||DES||DEB||72||6||17 †||0.43 †||0.18 †||1.75||29.6||6||16.7 †||1.4||0.0||15.3 †|
|SES||48||9||3||0.02 †||0.06 †||2.57||12.5||12||6.3||0.0||6.3||0.0||0.0|
|CRISTAL||2012||DES||SES||136||12||11||0.37||2.14 †||21.0 †||2.2||2.9||5.9||2.2|
|ISAR-DESIRE 3||2013||DES-S||DEB||137||6-8||27 †||0.37||1.79||38||23.5||2.2||2.1||22.1||24.2|
|Habara||2013||DES/BMS||DEB||137||6||4.3 †||0.11 †||0.18 †||1.87 †||28.1 †||6||6.6 †||0||0||6.6 †||6.6 †|
|EES||94||4.7||0.04||2.44 †||13 †||12||6||0||4||1||2|