Treatment of In-Stent Restenosis









Introduction


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.




FIGURE 13-1


Schematic of relative contributions of acute gain and late loss to restenosis after coronary intervention.

BMS, Bare-metal stent; BX, balloon expandable; DES, drug-eluting stent; LL, late loss; PCI, percutaneous coronary intervention. *Compared with balloon angioplasty alone.




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:



  • 1.

    acute or subacute prolapse of the disrupted plaque


  • 2.

    elastic recoil of the vessel wall


  • 3.

    constrictive vascular remodeling


  • 4.

    neointimal hyperplasia (due to extracellular matrix deposition and smooth muscle cell hyperplasia)


  • 5.

    de novo in-stent atherosclerosis (so-called neoatherosclerosis)

While implantation of a metal stent after balloon dilatation largely negates the impact of the first three processes on restenosis, the additional vessel injury imposed by stent implantation increases the extent of neointimal tissue formation during vessel healing. Moreover, although DES have reduced the incidence of restenosis dramatically, the delayed vessel healing seen with these stents may contribute to an increased incidence or accelerated course of de novo atherosclerotic disease within the stent in the months and years after intervention. Indeed, from a clinicopathological standpoint it appears that there are considerable differences between the restenosis that occurs after bare-metal versus after drug-eluting stenting ( Table 13-1 , Figure 13-2 ). In addition the availability of high-resolution intravascular imaging modalities such as optical coherence tomography (OCT) permits more detailed characterization of intravascular tissue and recognition of neoatherosclerotic changes in vivo ( Figure 13-3 ; ).

TABLE 13-1

Comparison of Principle Features of Bare-Metal and Drug-Eluting Stent Restenosis
















































CHARACTERISTIC BARE-METAL STENT RESTENOSIS DRUG-ELUTING STENT RESTENOSIS
Imaging Features
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
Histopathological Features
Smooth muscle cellularity Rich Hypocellular
Proteoglycan content Moderate High
Peri-strut fibrin and inflammation Occasional Frequent
Complete endothelialization 3-6 months Up to 48 months
Thrombus present Occasional Occasional
Neoatherosclerosis Relatively infrequent, late after stenting Relatively frequent, accelerated course



FIGURE 13-2


Histopathology of restenosis after drug-eluting and bare-metal stents.

Low-power (2.5×) magnification of a Movat Pentachrome stained section of a Cypher sirolimus-eluting stent (A) showing severe in-stent restenosis with almost complete occlusion. There is postmortem clot in the lumen. Higher magnification (10×) section shows a stent strut with surrouding proteoglycan-rich neointimal tissue and presence of foam cells and neovascularization (B) . Low-power (2.5×) magnification of a Multilink bare-metal stent (C) with severe in-stent restenosis and (D) high-power (10×) magnification shows predominance of smooth muscle cells with neovascularization and chronic inflammation in the surrounding stent struts.



FIGURE 13-3


Diffuse in-stent restenosis showing features of in-stent neoatherosclerosis by optical coherence tomography.

In-stent restenosis 9 years after long-segment DES implantation showing features of in-stent neoatherosclerosis. Angiography shows diffuse in-stent restenosis ( ). Optical coherence tomography shows distal high-grade layered pattern in-stent restenosis (A) with an area of attenuated signal intensity 10-15 mm more proximally (B), which likely represents lipid-core atherosclerotic plaque. More proximally still an area of possible in-stent plaque erosion/rupture is visible ( C; at 10 o’clock). The proximal stent edge is free of restenosis with a thin layer of neointima covering stent struts (D) . Punctate areas of low signal intensity likely represent neovascularization. Predilatation with noncompliant balloon angioplasty and treatment with drug-coated balloon ( ) and additional distal stent implantation ( ) result in satisfactory acute appearance ( ).


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.


FIGURE 13-4


Angiographic classification of restenosis following bare-metal and drug-eluting stenting.





A, Distribution of patterns of restenosis after bare-metal stenting.

(Adapted from Mehran R, Dangas G, Abizaid AS, et al: Angiographic patterns of in-stent restenosis: classification and implications for long-term outcome. Circulation 100:1872–1878, 1999.)


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 .




E-TABLE 13-1

Summary Characteristics of Principal Randomized Clinical Trials on Local Treatment of In-Stent Restenosis



























































































































































































































































































































































































































































































































































































































































































































































































































































































































































































TRIAL YEAR STENT THERAPY PATIENTS TIME BAR LL ST LL SEG MLD DS TIME MACE DEATH MI TLR TVR
Months (%) (mm) (mm) (%) Months (%) (%) (%) (%) (%)
Teirstein 1997 BMS * BT 26 6 17 0.38 2.43 17 12 15.0 0 4 12.0
BA/BMS 29 6 54 1.03 1.85 37 12 48.0 3 0 45.0
WRIST 2000 BMS BT 65 6 22 0.22 2.03 30 12 35.3 6.2 9.2 23.0 33.8
PCI 65 6 60 1.00 1.24 57 12 67.3 6.2 9.2 63.1 67.6
Leon 2001 BMS BT 131 6 32 0.73 1.78 46 9 28.2 3.1 9.9 24.4 31.3
PCI 121 6 55 1.14 1.37 53 9 43.8 0.8 4.1 42.1 46.3
ARTIST 2002 BMS BA 146 6 51 0.67 1.20 56 6 20.4
ROTA 152 6 64 0.91 0.99 63 6 9.9
RESCUT 2003 BMS CB 214 7 30 0.56 1.61 39.0 7 16.4 1.4 1.4 13.5
BA 214 7 31 0.62 1.55 40.0 7 15.4 0.9 1.4 13.1
RIBS1 2003 BMS BMS 224 6 38 1.12 1.06 1.63 45 12 23 4 2.2 19.6
BA 226 6 39 0.73 0.72 1.52 46 12 29 3 5.3 24.3
Long WRIST 2003 BMS PCI 60 4-8 73 0.99 0.85 0.93 65 12 63.3 1.7 18.3 61.7
BT 60 4-8 45 0.67 0.65 1.23 54 12 42.2 6.8 23.7 39.0
Ragosta 2004 BMS BA 29 9 21 0 7.2 17
BMS 29 9 7 3.6 3.6 3.6
ROTA 30 9 43 6.6 3.3 40
BMS 25 9 32 0 4 32
ROSTER 2004 BMS ROTA 100 9 42 12 38 2.0 3.0 32.0
BA/BMS 100 9 56 12 52 2.0 3.0 45.0
ISAR-DESIRE 2005 BMS SES 100 6-8 14 0.10 2.12 23.1 12 11.0 2.0 1.0 8.0
PES 100 6-8 22 0.26 2.02 26.6 12 22.0 1.0 2.0 19.0
BA 100 6-8 45 1.40 45.8 12 36.0 3.0 0.0 33.0
PACCOCATH-ISR 2006 BMS DEB 26 6 5 0.09 0.03 2.31 12 4.0 4.0 4.0 0.0
BA 26 6 43 0.76 0.74 1.60 12 31.0 0.0 8.0 23.0
RIBS2 2006 BMS DES 76 9 11 0.13 2.52 8 12 11.8 3.9 2.6 10.5
BA 74 9 39 0.69 1.54 40 12 31.1 4.1 2.7 29.7
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
BT 125 6 30 0.27 0.33 1.52 40.97 9 19.2 0.0 0.0 19.2 21.6
TAXUS V-ISR 2006 BMS BT 201 9 31 0.27 1.55 31.2 9 20.1 0.5 4.6 20.1 23.7
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
BT 64 6 21 0.55 0.40 1.76 32.61 12 18.8 0.0 0.0 18.8
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
DES 65 6 12 0.45 0.38 2.11 34.2 12 16.9 0.0 1.5 15.4
ISAR-DESIRE-2 2010 DES PES 225 6-8 21 0.38 0.25 2.16 25.4 12 19.6 4.5 1.8 13.8
SES 225 6-8 19 0.40 0.26 2.14 26.6 12 20.4 3.4 2.7 14.3
Habara 2011 DES DEB 25 6 9 0.18 0.18 1.82 34.2 6 4.3 0.0 0.0 4.34
BA 25 6 63 0.72 0.72 1.28 58 6 41.7 0.0 0.0 41.7
Wiemer 2011 DES 44 6 4 0.09 2.66 7.78 12 4.0 2.0 0.0 2.0 2.0
BT 47 6 23 0.39 1.75 36.9 12 27.0 2.0 6.0 16.0 19.0
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
BA 38 6 58 1.03 0.72 1.10 51.1 6 50.0 10.5 2.6 36.8
Song 2012 DES CB 48 9 21 0.30 0.25 2.08 16.5 12 6.3 0.0 0.0 6.3 6.3
SES 48 9 3 0.02 0.06 2.57 12.5 12 6.3 0.0 6.3 0.0 0.0
SES 32 9 5 0.13 0.13 2.58 25 12 9.6 3.1 3.1 3.1 3.1
EES 34 9 14 0.07 0.07 2.71 18 12 8.8 2.9 2.9 5.8 5.8
CRISTAL 2012 DES SES 136 12 11 0.37 2.14 21.0 2.2 2.9 5.9 2.2
BA 61 12 14 0.41 1.71 29.8 1.6 1.6 13.1 0
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
PES 131 6-8 24 0.34 1.82 37.4 19.3 4.6 2.4 13.5 16.6
BA 134 6-8 57 0.70 1.26 54.1 46.2 5.3 1.5 43.5 45.1
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
BA 71 6 31.9 0.49 0.72 1.42 44.1 6 31.0 0 0 31 31
RIBS V 2014 BMS DEB 95 9.5 0.14 2.03 24 12 8 4 3 6 6
EES 94 4.7 0.04 2.44 13 12 6 0 4 1 2

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Mar 21, 2019 | Posted by in CARDIAC SURGERY | Comments Off on Treatment of In-Stent Restenosis
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