Restenosis and in-stent restenosis

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Chapter 13 Restenosis and in-stent restenosis

NEZAR M. FALLUJI, MD, MPH, DAVID J. MOLITERNO, MD

KEY POINTS

Percutaneous coronary intervention (PCI) has become the dominant revascularization modality for obstructive coronary artery disease while restenosis is the ‘Achilles heel’ of balloon angioplasty.

Restenosis occurs at a rate of 40–50% angiographically and 20–30% clinically following balloon angioplasty.

The use of bare metal stents (BMS) reduced the incidence of acute vessel closure and restenosis substantially.

A new form of restenosis, namely in-stent restenosis (ISR) following BMS implantation, is responsible for a large proportion of repeat PCI procedures.

The use of drug-eluting stents (DES) has lowered the incidence of ISR further, with clinical restenosis rates less than 10% in contemporary practice.

PATHOPHYSIOLOGY

Vascular injury during coronary intervention, leads to a complex reparative process that may become excessive and cause restenosis. Renarrowing after PCI develops over weeks to months post-procedure, in contrast to de novo coronary lesions, which develop over years, likely reflecting the difference in the underlying mechanisms and the extent of inflammation involved with each lesion type. The process of restenosis can be broadly categorized into four interrelated facets:

1. Vascular elastic recoil occurs within minutes to hours following balloon angioplasty. The underlying mechanism is related to a ‘spring-like’ rebound of the arterial segment, or it may simply reflect the persistence of a temporarily displaced atherosclerotic plaque. Elastic recoil is reduced with atherectomy and eliminated with stent placement.

2. Thrombus formation, before or after angioplasty, contributes to restenosis by lumen occupation. Furthermore, activated platelets within the thrombus secrete a host of substances from their alpha-granules (Fig. 13.1), which promote vasoconstriction, chemotaxis, mitogenesis, and activation of neighboring platelets, mediating the growth of fibromuscular tissue (neointima). Use of proper antiplatelet agents and anticoagulation therapy during PCI should limit this mechanism of restenosis, though no supportive data exist to establish a role for anti-thrombotics to reduce restenosis.

3. Neointimal hyperplasia predominates the luminal narrowing beyond the acute phase after PCI and is the major underlying mechanism of restenosis following coronary stent placement. Following PCI-mediated vascular injury a reparative process is orchestrated by coagulation and inflammatory factors and cells, which results in smooth muscle cell proliferation and extracelluar matrix formation.

4. Arterial remodeling during the reparative process can result in an increase, decrease, or no change in the cross-sectional area of the artery lumen. This so-called Glagov phenomenon (Fig. 13.2)^1, combined with neointimal hyperplasia, represents the final wave of the restenotic process. The restenotic process is usually complete within 3–6 months after balloon angioplasty and atherectomy, but can extend up to 6–12 months following stent placement. As such, the time course for restenosis after stents is delayed, relative to that for balloon angioplasty, by 1–3 months. Hence, patients who are free of restenosis at nine months after coronary stent placement are likely to have long-term patency within the index lesion. DES contain a polymeric coating that allows sustained (several weeks) release of anti-inflammatory and antiproliferative drugs, which inhibit neointimal growth.

Figure 13.1 Mechanisms of restenosis following PCI.

Source: Chan AW and Moliterno DJ, Clinical Evaluation of Restenosis. In Atherothrombosis and Coronary Artery Disease, edited by V. Fuster, EJ Topol, and EG Nabel, p. 1416 (Figure 93.2).

Figure 13.2 Vascular remodeling following PCI.

Source: Chan AW and Moliterno DJ, Clinical Evaluation of Restenosis. In Atherothrombosis and Coronary Artery Disease, edited by V. Fuster, EJ Topol, and EG Nabel, p. 1417 (Figure 93.3).

While elastic recoil and thrombus formation can lead to acute vessel closure and acute restenosis, the concept of restenosis primarily refers to neointimal hyperplasia and vascular remodeling over months, which result from an inflammatory reparative processes following PCI-induced vascular injury.

DEFINITIONS OF RESTENOSIS

Angiographic restenosis

Various definitions for angiographic restenosis have been used. 50% or greater dichotomous diameter stenosis at follow-up angiography is a widely used criterion in clinical trials. However, reporting of the minimum luminal diameter (MLD) may avoid variation of restenosis rates reported in clinical trials due to inconsistent definitions of angiographic restenosis. The difference between pre-procedural MLD and immediate post-procedural MLD is defined as acute gain, and the difference between post-procedural MLD and MLD at follow-up is termed to late loss. Acute gain is lowest with PTCA, followed by atherectomy, and stenting (highest acute gain). Late loss is usually proportional to acute gain, such that the late loss index, defined as late loss divided by the acute gain, is similar after revascularization with PTCA, atherectomy, or stents (Fig. 13.3).

Figure 13.3 Late Loss Index for various PCI devices. The loss index for DES is compared to that of other PCI devices. DES has an almost ideal profile that would produce a large immediate gain and have a low loss index. Balloon angioplasty has the lowest loss index but produces a relatively smaller immediate gain. Atherectomy produces a large immediate gain but has the highest loss index. BMS = bare metal stents, DCA = directional coronary atherectomy, DES = drug-eluting stents, ELCA = excimer laser coronary angioplasty, PTCA = percutaneous transluminal coronary angioplasty.

Source: updated with permission Moliterno DJ and Topol EJ, Restenosis: Epidemiology and Treatment. In Textbook of Cardiovascular Medicine, 2d ed., edited by EJ Topol, p. 1719 (Figure 83.5).

While visual methods of assessing angiographic stenosis severity are prone to interobserver and intraobserver variability, the use of quantitative coronary angiography (QCA) is highly reproducible, and is the standard technique employed in most contemporary research trials. QCA is usually unreliable for assessing bifurcation lesions and in the absence of disease-free reference segments.