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.

Clinical restenosis

Since angiographic definitions for restenosis are somewhat arbitrary, the importance of restenosis becomes clinically relevant only when it is linked to symptom(s) or functional parameter(s). Because the process of restenosis is usually gradual, and the newly formed lesion is ‘stabilized’ with fibrous tissue and smooth muscle cells, recurrent angina is the most common presenting feature, whereas myocardial infarction (MI) and sudden death are less frequent. Chest pain is reportedly present in 25–93% of patients six months following balloon angioplasty, with an average of approximately 50%.² The proportion of patients presenting with recurrent chest pain who have restenosis demonstrable at angiography ranges from 48–92%. Hence, the positive predictive value (PPV) of symptoms alone is only modest.

Clinical restenosis is roughly correlated with the need for repeat revascularization (repeat PCI or bypass surgery). Traditionally, target lesion revascularization (TLR) has been used in many of the interventional trials designed to test various pharmacology, while target vessel revascularization (TVR) has been used in device trials in which the effect of the device on the vessel beyond the target lesions also needs to be considered. More recently, the term target vessel failure (TVF) has also become popular, and it refers to TVR plus death or myocardial infarction due to restenosis or reocclusion of the target vessel.

PREDICTORS FOR RESTENOSIS

Many identifiable restenosis predictors were derived from large pharmacological trials related to PCI. Predictors for restenosis after balloon angioplasty, stenting, and brachytherapy modestly differ. Risk factors can be categorized into those related to the patient, the lesion, and the procedure, as summarized in Table 13.1.

TABLE 13.1 PREDICTORS FOR RESTENOSIS

PRESENTATION AND EVALUATION OF RESTENOSIS

Regardless of the PCI device used, most patients who have clinical restenosis experience return of angina. As mentioned, myocardial infarction or death due to restenosis per se is unusual.³ Atypical chest pain or pain different from the patient’s angina is unlikely to be secondary to restenosis. Similarly, early angina (that is, within the first couple months after PCI) is usually related to incomplete revascularization, whereas angina presenting much beyond nine months is usually due to lesions other than the index lesion.³ The incidence of silent restenosis is variable since the definition of angiographic restenosis is somewhat arbitrary. Absence of any symptom may be related to less severe coronary obstruction, diabetes, non-viable myocardium, or abundant collateralization. The importance of silent restenosis in clinical practice remains questionable, as the available data are limited and inconsistent.

Recurrent angina within nine months of PCI is an ACC/AHA Class I indication for repeat coronary angiography.⁴ In asymptomatic patients or those with atypical symptoms following PCI, use of non-invasive tests is the recommended evaluation method. A stress test (exercise or pharmacological) with nuclear scintigraphy or echocardiography carries relatively less risk, cost, and time (compared with routine coronary angiography), and it provides physiologic assessment of the restenotic lesion.⁵ When stress testing is believed to be unreliable and the myocardium at risk is large, angiography is preferable.

PREVENTION OF RESTENOSIS

Historically, and mostly prior to the development of DES, many classes of drugs were tested to prevent restenosis following PTCA, including antiplatelets, anticoagulants, calcium channel blockers, statins, corticosteriods, thromboxane antagonists, and prostacycline analogues. While animal studies were promising, these various classes of drugs failed to show a positive effect in clinical studies. Growth factor inhibitors (such as trapidil, angiopeptin and cilostazol) may be the exception as they have shown encouraging results that may warrant further investigation.

While pharmacological agents failed to reduce restenosis following PTCA, the use of coronary BMS resulted in significant reductions in both acute vessel closure and restenosis (when compared to PTCA), and the use of DES has further reduced the incidence of angiographic and clinical restenosis to less than 10%.

TREATMENT OF RESTENOSIS

For patients who develop restenosis, repeat revascularization is most often the best treatment for symptom relief. Intracoronary stent placement is the appropriate strategy for lesions not previously treated with stents, provided the anatomy is suitable. Most patients with single-vessel restenosis undergo a second PCI, whereas patients with restenosis in multiple vessels may undergo percutaneous or surgical revascularization. This is influenced by several factors including left ventricular function, history of primary CABG, and diabetes.

PTCA

Balloon angioplasty as a treatment for restenosis is associated with a particularly high rate (40–50%) of recurrent restenosis. In a multicenter randomized restenosis stent study, 383 patients with clinical and angiographic restenosis following prior balloon angioplasty were randomized to repeat PTCA versus Palmaz-Schatz stent placement. In this study of non-complete lesions, repeat PTCA was associated with a 32% rate of angiographic restenosis at six months.⁶ With ISR, repeat PTCA is effective when used for management of focal lesions with angiographic restenosis rates as low as 20% at six month.⁷^–⁸ For more diffuse restenotic lesions, however, repeat PTCA is associated with a six-month angiographic restenosis rate >50%.⁹

Atherectomy

Several small case series documented the safety of rotational atherectomy to treat restenosis. In a non-randomized registry of 304 patients, the combined use of atherectomy and balloon angioplasty was associated with a reduced rate of one-year clinical events (death, MI, TLR) when compared with balloon angioplasty or atherectomy alone (38% vs. 52% vs. 60%, respectively).¹¹ However, in the multicenter ARTIST trial, 298 patients with ISR were randomly assigned to PTCA or rotational atherectomy; atherectomy was associated with a higher rate of angiographic restenosis (65% vs. 51%) and incidence of composite clinical events (death, MI, TLR) (20% vs. 9%), primarily due to a greater rate of repeat revascularization at six months.¹² Similarly, the use of excimer laser and rotational atherectomy in treating in-stent restenotic lesions has been disappointing (one-year TLR rates of 26% and 28%, respectively). These debulking devices cause a greater late lumen loss, so-called device taxing, implying that remodeling or neointimal proliferation are not favorably reduced.¹³

Stenting

Bare metal stents

By reducing elastic recoil and vascular remodeling, and by compressing the plaque and scaffolding the vessel lumen, BMS has resulted in a significant reduction in acute vessel closure and restenosis. ISR secondary to neointimal hyperplasia remains a significant problem with BMS, however, with 20–30% angiographic and 10–15% clinical restenosis.^14,¹⁵

Drug-eluting stents

Sirolimus (rapamune) is a macrocyclic lactone with antibiotic, immunosuppressive, and anti-proliferative actions. Biologically it induces cell-cycle arrest and affects proliferation and migration of smooth muscle cells. In the RAVEL trial, which was the first randomized controlled trial of sirolimus-eluting stents (SES) versus BMS, SES reduced ISR at six months by more than 50% when compared to BMS (0 vs. 27%)^16, and at one-year follow up, the overall rate of cardiac events (mostly TVR) was lower with SES (6% vs. 29%).

Paclitaxel interferes with function of the microtubules responsible for proper chromosome segregation during cell division. In the TAXUS II trial, 536 low-risk patients were randomly assigned to a BMS or a paclitaxel-eluting stent (PES).¹⁷ At six months, PES were associated with significant reductions in ISR (3.5% vs. 19.1%) and TLR (3.9% vs. 13.3%). In a meta-analysis of all randomized clinical trials of sirolimus-versus paclitaxel-eluting stents the rate of angiographic restenosis in patients with SES was 9.3% and the rate of TLR was 5.1%. The rate of angiographic restenosis in patients with PES was 13.1% and the rate of TLR was 7.8%.¹⁸

TREATMENT OF ISR

The conventional, mechanical treatments of ISR (PTCA, cutting balloons, repeat stenting with a BMS, or atherectomy) have been disappointing, with recurrent rates of restenosis averaging 30–50% for focal disease and 50–70% for diffuse disease. The mainstay of treatment for ISR recently involved balloon angioplasty with intracoronary brachytherapy. More recently, the use of DES for ISR has emerged.

Brachytherapy

Gamma and beta radiotherapy have been studied for treatment of ISR. During spontaneous decay of nuclei of certain elements, radiation is emitted in the form of either gamma radiation (electromagnetic energy carried by photons which may penetrate more than 10 mm of human tissue) or beta particles (electrons carrying a wide range of energy and traveling within 2–3 mm of human tissue). By affecting DNA in the actively dividing cells, brachytherapy inhibits smooth muscle proliferation and neointima formation. Use of brachytherapy in management of restenosis and ISR has been evaluated in multiple clinical trials and registries, with both gamma (SCRIPPS, GAMMA-1, WRIST, SVG WRIST, and LONG WRIST) and beta (BETA WRIST, START, and INHIBIT) radiation. The effect of brachytherapy is not always consistent or curative. While infrequent, both thrombosis (perhaps due to inadequate re-endothelialization) and restenosis (possibly from paradoxical neointimal stimulation of an adjacent vessel segment) have been reported following brachytherapy. Overall, brachytherapy has reduced the rate of recurrent restenosis by about 40–50%. Figure 13.4 summarizes the results of the noted effects of beta and gamma radiation on TLR.

Figure 13.4 Brachytherapy. Cumulative incidence of target lesion revascularization required after intracoronary radiotherapy using gamma-radiation and beta-radiation. Percentages indicate percent reduction with therapy; all differences were statistically significant.

Source: Chan AW and Moliterno DJ, In-Stent Restenosis: Update on Intracoronary Radiotherapy, Cleveland Clinic Journal of Medicine 2001: 68; 796–803.

DES for ISR

Use of DES in the management of ISR was evaluated in small observational studies that suggested benefit. These were soon followed by the ISAR-DESIRE trial, which randomized 300 patients with ISR to treatment with SES, PES or PTCA.¹⁹ DES resulted in a significant reduction (≥50%) in the primary end point of angiographic restenosis at six months (14.3% SES, 21.7% PES, and 44.6% PTCA). TVR rate was reduced significantly as well (8% SES, 19% PES, and 33% PTCA).

When restenosis occurs with DES, it may often be a consequence of local vessel injury during the procedure, polymer peeling, non-homogeneous drug elution, gaps in stent coverage, or inadequate stent expansion. In addition to suboptimal stent placement technique, Table 13.2 lists the variables that have been associated with ISR in sirolimus-eluting stents.²⁰

TABLE 13.2 TVR PREDICTORS AMONG 1,726 PATIENTS FROM THE GERMAN CYPHER REGISTRY

VARIABLES	ADJUSTED OR (95% CI)	P-VALUE
Target vessel coronary bypass graft	2.43 (1.41–4.18)	0.001
2- or 3-vessel disease	1.69 (1.05–2.72)	0.030
Hypertension	1.66 (0.99–2.79)	0.056
Additional implantation of BMS	1.49 (0.71–3.13)	0.230
Renal insufficiency	1.41 (0.80–2.48)	0.230
Indication of in-stent restenosis	1.40 (0.94–2.07)	0.095
Chronic total occlusion	1.39 (0.73–2.68)	0.320
Ostial lesion	1.28 (0.79–2.07)	0.320
Diabetes mellitus	1.14 (0.76–1.71)	0.530
Total length of SES (per 10 mm)	1.07 (0.90–1.26)	0.450