Intracoronary stent restenosis

INTRODUCTION — Although intracoronary stent restenosis (ISR) is much less common with the use of drug-eluting stents (DES) than with bare-metal stents (BMS), the number of stents being implanted in interventional practice and the ongoing risk for restenosis over time means that the treatment of ISR remains an important clinical challenge. In a report from the National Cardiovascular Data Registry in 2020, percutaneous coronary intervention (PCI) for ISR represented 10.6 percent of all PCI procedures [1].

DEFINITIONS — After a successful procedure, coronary stents can fail to maintain vessel patency due to either restenosis or stent thrombosis. Restenosis is a gradual re-narrowing of the stented segment that occurs mostly between 3 to 12 months after stent placement. It usually presents as recurrent angina, but can present as acute myocardial infarction in approximately 10 percent of patients. It can usually be managed by repeat percutaneous revascularization.

In contrast, stent thrombosis is an abrupt thrombotic occlusion of a previously widely patent stent. It is a catastrophic complication that presents as sudden death or large myocardial infarction in most patients. Despite successful repeat revascularization, the six-month mortality is high. (See "Coronary artery stent thrombosis: Clinical presentation and management" and "Coronary artery stent thrombosis: Incidence and risk factors".)

In this topic, intracoronary stent restenosis (ISR) and in-stent restenosis refer to the same issue.

The following are widely agreed upon definitions related to ISR (table 1) [2]:

●Restenosis – A reduction in lumen diameter after percutaneous coronary intervention due to arterial damage and subsequent neointimal tissue proliferation.

●Binary angiographic restenosis – A ≥50 percent luminal narrowing at follow-up angiography.

●Clinical restenosis – The presence of both binary angiographic restenosis and clinical symptoms or signs of ischemia (either at rest or with stress) OR restenosis with a ≥70 percent reduction in lumen diameter even in the absence of clinical symptoms or signs.

INCIDENCE OF RESTENOSIS — The incidence of restenosis depends on the definition of restenosis (see 'Definitions' above), type of stent, and the complexity of the lesion(s) stented. Restenosis rates are considerably higher in more complex lesion subsets, such as small vessels, long lesions, and bifurcations. (See "Percutaneous coronary intervention of specific coronary lesions".)

●Bare metal stents – With decreasing use of bare metal stents (BMS) in favor of newer drug-eluting stents (DES), data for BMS restenosis are mostly from older studies, although the lessons learned regarding restenosis outcomes remain of interest. A pooled analysis of 6186 patients from six major clinical trials assessed frequency and predictors of restenosis among BMS. The frequency of clinical restenosis was defined as target lesion or target vessel revascularization (TVR) beyond 30 days, death, or myocardial infarction in the target vessel territory [3]. At one year, target lesion revascularization (TLR) was performed in 12 percent and TVR in 14.1 percent. These values were more than two-thirds higher than those at six months (6.9 and 8 percent). Clinically relevant restenosis occurred in only about one-half of patients with angiographic restenosis (defined as ≥50 percent diameter stenosis). This was mostly a matter of degree, since 50 to 70 percent angiographic stenosis is unlikely to cause symptoms. The incidence of TLR was much higher with more than 70 percent diameter stenosis (73 versus 26 percent for less than 60 percent diameter stenosis).

Clinical restenosis with BMS is a relatively early event, most often becoming clinically evident within the first 6 to 12 months after the procedure [4]. After one year, recurrent ischemia is more likely to be due to new or progressive disease at another site rather than restenosis. The magnitude of this difference was illustrated in a review of 1228 patients who were followed for five years [4]. After the first year, the annual hazard rate was 1.7 percent for target lesion events compared with 6.3 percent for nontarget lesion events.

●Drug-eluting stents – The rate of intracoronary stent restenosis (ISR) has been reported between 3 to 20 percent, depending on which DES is evaluated, the duration of follow-up, and the complexity of the lesions in which the stents were placed [2]. The following three studies provide representative outcomes:

•For first-generation DES (sirolimus or paclitaxel DES), the rate of restenosis is between 13 and 16 percent at five years [5,6]. (See "Intracoronary stents: Stent types", section on 'Early-generation drug-eluting stents'.)

In a 2020 meta-analysis of 19 trials in 25,032 patients who underwent PCI, very late stent-related events occurred between one and five years after PCI at a rate of approximately 2 percent per year; this was true for all stent types [7]. Target vessel revascularization occurred in 6.9 percent of participants at five years. In a prior pooled analysis of multiple studies comparing everolimus-eluting with zotarolimus-eluting stents, the rates of TVR at up to five years of follow-up were 6.3 and 5 percent, respectively [8]. (See "Intracoronary stents: Stent types", section on 'Zotarolimus-eluting stents'.)

Multiple trials have demonstrated that both first-generation sirolimus and paclitaxel DES and second-generation everolimus and zotarolimus DES markedly reduced the incidence of ISR and the rate of TLR by about 75 percent compared with BMS. The data supporting this conclusion are discussed in detail elsewhere. (See "Intracoronary stents: Stent types".)

PATHOGENESIS — Reduction in lumen diameter following stent implantation is the result of arterial damage with subsequent neointimal tissue proliferation. Typically, neointimal proliferation is distributed uniformly along the length of the stent [9-11], but may also be relatively focal. The neointimal proliferation occurs in association with macrophage accumulation and extensive neovascularization, suggesting a role for organization of mural thrombus [12].

Consistent with this hypothesis are the pathologic findings in 55 stents in 35 coronary arteries from patients who died, had repeat coronary artery bypass graft (CABG) surgery, or underwent transplantation. The mean duration of stent placement was 39 days [13]. The following abnormalities were noted:

●Fibrin, platelets, and neutrophils, indicating thrombus formation and acute inflammation, have been demonstrated at stent struts evaluated ≤11 days after placement. Inflammation was more pronounced in struts that were embedded in a lipid core and those in contact with damaged media.

●Stents evaluated at a later time showed neointimal growth that increased as the ratio of stent area to reference lumen area increased. Neointimal thickness was greater for struts associated with medial damage than for those in contact with plaque. Over time, extracellular matrix accumulation may play a greater role than cell proliferation in neointimal thickening [14].

Although there is an increase in neointimal tissue with subsequent reduction in the minimal luminal diameter during the first six months after stent placement, there may be no further reduction in luminal diameter or even regression at one year and a further increase in diameter at later time points [15-17]. Serial angiography and angioscopy found the following sequence of changes [16]. There was initial thickening of the neointima that became nontransparent at six months. Thereafter, the neointima became thin and transparent (ie, the majority of the stent was visible). This correlated with an increase in the luminal diameter.

Mechanisms — Mechanisms to explain the observations of inflammation, mural thrombus, and neointimal tissue growth include [2]:

●Biologic factors, such as resistance to the drug component of stents

●Hypersensitivity

●Mechanical factors such as stent underexpansion or stent fracture

●Technical factors such as barotrauma outside the stented segment

●Neoatherosclerosis has been increasingly recognized as an important factor in DES restenosis, especially in late restenosis (beyond one year) [18].

Patterns of restenosis — Patterns of intracoronary stent restenosis (ISR) have been described as focal or diffuse. However, in order to further classify the types of restenosis, an angiographic classification was developed in a study of 288 ISR lesions in 245 patients who had received BMS [19]:

●Pattern I describes a focal (<10 mm in length) lesion and was found in 42 percent of patients. Subsequent target lesion revascularization (TLR) was performed in 19 percent of patients.

●Pattern II describes ISR >10 mm within the stent and was present in 21 percent of patients; 35 percent required TLR.

●Pattern III describes ISR >10 mm extending outside the stent; TLR performed in 50 percent of patients.

●Pattern IV describes a totally occluded stent, which was found in 7 percent of patients; 83 percent underwent TLR.

PREDICTORS IN BMS — In a review of 1084 patients who underwent follow-up angiography six months after bare metal stent (BMS) placement, the incidence of restenosis is related to the number of risk factors present (as low as 16 percent in the absence of any risk factors [diabetes, multiple stents, and minimal luminal diameter after stenting <3 mm]) [20], and as high as 59 percent when at least three factors were present (figure 1) [21].

Angiographic factors — A number of angiographic risk factors have been identified for stent restenosis, mostly with BMS [3,21-30]. (See "Percutaneous coronary intervention of specific coronary lesions".)

●Restenotic target lesion [30].

●Longer stented stenosis length and stent length [3,24,31,32].

●Smaller vessel size.

●Ostial lesion location.

●Preinterventional lesion site plaque burden (plaque/total arterial area) and amount of residual plaque burden after stent implantation.

●Longitudinal straightening effect and post-stent changes in vessel angulation ≥9.1 degrees [29].

●Minimal lumen diameter <3 mm at the end of the procedure [27].

●Minimum stent area and in-stent diameter [3,32].

●Late lumen loss, which is due to in-stent neointimal hyperplasia, is defined as the difference between the minimum lumen diameter immediately after stenting and the minimum lumen diameter at six- to eight-month angiographic follow-up. It is an important predictor of the risk of clinical restenosis with both BMS and drug-eluting stents (DES) and appears to be more reliable than binary angiographic restenosis (>50 percent diameter stenosis at follow-up) [33-35].

●The morphology of the coronary lesion also may have predictive value (table 2) [36,37]:

•Type A lesions – High success and low restenosis rate.

•Type B lesions – Intermediate success and moderate risk of restenosis; this has been further modified to type B1 (one adverse type B characteristic) and type B2 (more than one type B characteristic).

•Type C lesions – Low success and high risk of restenosis.

Clinical factors — Studies of BMS identified a number of independent clinical predictors of stent restenosis and the need for target vessel revascularization (TVR), including female sex, diabetes, hypertension, weight and body mass index, multivessel disease, and the use of multiple stents [3,21-23,30].

Cigarette smokers require target lesion revascularization (TLR) significantly less frequently than nonsmokers (6.6 versus 10.1 percent in one study) [38,39]. Despite this difference in clinical restenosis, the angiographic restenosis rate does not differ between the groups [38,40], and the rates of subsequent death and myocardial infarction are significantly higher for smokers [39]. Explanations for this paradox include a reduced sensitivity to restenosis or a greater reluctance to seek medical attention for recurrent angina in smokers [38].

A contact allergy to metal compounds, particularly nickel, released from stainless steel stents may contribute to the development of stent restenosis, although the evidence for this is limited. Studies evaluating the association between metal allergy and stent restenosis are reviewed separately. (See "Nickel hypersensitivity and coronary artery stents".)

Strut thickness — Strut thickness may influence the development of stent restenosis [41-43]. This was evaluated in the ISAR-STEREO trial in which 651 patients with lesions in vessels >2.8 mm in diameter were randomly assigned to a BMS with a thin (50 micrometers) or thick (140 micrometers) strut [41]. At six months, the thin strut group had a significantly lower incidence of angiographic restenosis (15 versus 26 percent for the thick strut, relative risk [RR] 0.58) and a lesser likelihood of reintervention for clinical restenosis (8.6 versus 13.8 percent, RR 0.62).

The companion ISAR-STEREO-2 trial compared the same stent geometry, fabricated with either thin or thick (140 micrometers) struts in 611 patients [42]. Procedural success was ≥99 percent in both groups, but device success was lower with the thin stent (87 versus 99 percent with the thick stent). The thin stent was associated with significant reductions in angiographic restenosis at six months (18 versus 31 percent) and TVR at one year (12 versus 22 percent). There was no difference in the combined endpoint of death or MI at one year.

Continued improvement in stent engineering, including thinner struts, has been associated with improved safety and effectiveness.

Mechanical problems — Technical problems associated with stent deployment contribute to restenosis in a significant number of patients. In a review of 1090 patients with restenosis in BMS who underwent intravascular ultrasound (IVUS), mechanical complications were considered to contribute in 4.5 percent, while an additional 20 percent had stent underexpansion as a contributing factor [44]. These findings highlight the need for optimal stenting, as with the use of high pressure balloon dilation with or without IVUS. (See "Percutaneous coronary intervention with intracoronary stents: Overview".)

Stenting of multiple lesions — In patients who undergo stent placement in multiple lesions, the restenosis rate appears to be higher for a lesion when a companion lesion develops restenosis. One study evaluated 1244 patients who underwent stent placement in 1734 lesions. The restenosis rate for single, double, or ≥3 lesion stenting was 24, 29, and 34 percent, respectively, on a per lesion basis and 24, 44, and 63 percent, respectively, on a per patient basis [45]. The risk of a lesion developing restenosis was 2.5 times higher if a companion lesion had restenosis, an effect that was independent of all other clinical factors associated with restenosis. (See "Percutaneous coronary intervention of specific coronary lesions", section on 'Multivessel revascularization'.)

PREDICTORS IN DES — Although restenosis is significantly less common with drug-eluting stents (DES) than bare metal stents (BMS), it still occurs at a rate between 3 and 20 percent depending on the duration of follow-up and the complexity of the initial lesion. (See 'Incidence of restenosis' above.)

Predictors of target lesion revascularization (TLR) (an approximation of restenosis) in patients receiving zotarolimus- or everolimus-eluting stents were evaluated in the RESOLUTE All-Comers trial [46]. At four years, major predictors of TLR, which occurred in 8.6 percent of patients, included insulin-treated diabetes (odds ratio [OR] 1.97), treatment of saphenous vein grafts (OR 2.28), ostial lesions (OR 2.17), or intracoronary stent restenosis (ISR) (OR 2.24). (See "Intracoronary stents: Stent types", section on 'Everolimus- versus zotarolimus-eluting stents'.)

In an angiographic follow-up study of 238 patients who underwent sirolimus-eluting stent placement in complex lesions, the following characteristics were identified as independent multivariate predictors of angiographic restenosis: treatment of ISR (OR 4.16); ostial location (OR 4.84); diabetes (OR 2.63); total stented length (per 10 mm increase, OR 1.42); reference diameter (per 1 mm increase, OR 0.46); and left anterior descending artery (OR 0.30) [25].

In another angiographic follow-up study of 1845 patients who underwent implantation of either sirolimus-eluting stents or paclitaxel-eluting stents, the following were found to be independent multivariate predictors of angiographic restenosis: vessel size (per 0.5 mm decrease, OR 1.74, 95% CI 1.31-2.32); final diameter stenosis (per 5 percent increase, OR 1.30, 95% CI 1.15-1.47); and sirolimus-eluting stents compared with paclitaxel-eluting stent (0.60, 95% CI 0.44-0.81) [47].

CLINICAL PRESENTATION AND DIAGNOSIS OF ISR — For patients with prior placement of an intracoronary stent, recurrent symptoms of myocardial ischemia, usually in a stable pattern, may be due to restenosis, incomplete revascularization at the time of the initial stent placement, or disease progression elsewhere. The diagnosis of intracoronary stent restenosis (ISR) is confirmed by coronary angiography, usually performed as a prelude to repeat catheter-based therapy in the same sitting. (See "Approach to the patient with suspected angina pectoris", section on 'History'.)

An appreciable proportion of patients with bare metal stents (BMS) can present with an acute coronary syndrome (3 to 20 percent) [48-50]. A similarly high frequency of acute coronary syndrome (mostly unstable angina) has been noted with restenosis in drug-eluting stents (DES). In two small reports of patients with DES restenosis, 27 and 50 percent presented with a diagnosis of unstable angina pectoris and 5 and 11 percent presented with myocardial infarction [1,51,52]. (See "Coronary artery stent thrombosis: Incidence and risk factors".)

MANAGEMENT — The indications for coronary angiography and repeat revascularization in patients with prior stenting and stable angina are similar to those for patients without prior intervention. (See "Chronic coronary syndrome: Indications for revascularization", section on 'Indications'.)

Most patients who are diagnosed with intracoronary stent restenosis(ISR) and who undergo revascularization will undergo repeat stenting. Revascularization with coronary artery bypass graft (CABG) surgery should be considered in patients who are deemed to not be candidates for percutaneous intervention or who meet the established criteria for its use in patients with stable angina; this may include patients with recurrent, diffuse, or occlusive ISR involving a substantial myocardial territory. Patient preference plays an important role in decision-making at the time of symptomatic ISR. The relative benefits and risks of medical, percutaneous, and surgical treatments need to be discussed. In particular, the need for long-term dual antiplatelet therapy (aspirin and platelet P2Y₁₂ receptor blocker) with DES must be understood by the patient. (See "Revascularization in patients with stable coronary artery disease: Coronary artery bypass graft surgery versus percutaneous coronary intervention", section on 'Multivessel disease'.)

We place a newer generation DES within the original stent in most cases. Percutaneous coronary intervention using other techniques such as plain old balloon angioplasty placement of a BMS, or intracoronary radiation, is performed less often. The use of drug-eluting balloon (DEB) angioplasty, rather than placement of a newer generation DES may be reasonable in those locations where the device is available.

Specialized revascularization devices, such as rotational or directional atherectomy and laser angioplasty are used infrequently to treat ISR. These tools are discussed separately. (See "Specialized revascularization devices in the management of coronary heart disease" and "Coronary artery bypass graft surgery: Prevention and management of vein graft stenosis", section on 'Atherectomy'.)

Our recommendations for antiplatelet therapy after ISR are similar to the broad population of patients who receive intracoronary stents. (See "Long-term antiplatelet therapy after coronary artery stenting in stable patients", section on 'Summary and recommendations'.)

Role of imaging — We perform intravascular ultrasound or OCT imaging of the ISR region in all patients. These imaging techniques allow for identification of the most likely mechanism of restenosis, such as stent underexpansion of the original stent, and help guide management. For example, if underexpansion is found, high-pressure balloon dilation may be preferred rather than additional stenting. (See "Intravascular ultrasound, optical coherence tomography, and angioscopy of coronary circulation".)

Choice of device — Placement of a newer generation drug-eluting stent (DES), and in particular an everolimus-eluting stent, is the preferred treatment for patients with ISR, irrespective of whether the original stent was bare metal or drug-eluting. The various potential percutaneous coronary interventional (PCI) techniques of plain old balloon angioplasty, bare metal stenting, or older generation stenting, newer generation stenting (table 3), atherectomy, brachytherapy, and DEBs, have been compared in multiple studies [25,53-71].

These studies have established the superiority of newer generation DES to all other PCI devices. A 2015 well-performed network meta-analysis evaluated 27 trials (n = 5923) which compared everolimus-eluting stent with one or more of the other devices and noted the following [72]:

●The primary end point of percent diameter stenosis at angiographic follow-up occurred less often with everolimus-eluting stents: -9 percent (95% CI -15.8 to -2.2) compared with drug-coated balloon; -9.4 percent (95% CI -17.4 to -1.4 percent) compared with sirolimus-eluting stents; -10.2 percent (95% CI -18.4 to -2 percent) compared with paclitaxel-eluting stents; -19.2 (95% CI -28.2 to -10.4 percent) compared with vascular brachytherapy; -23.4 percent (95% CI –36.2 to -10.8 percent) compared with BMS; -24. 2 percent (95% CI -32.2 to -16.4 percent) compared with balloon angioplasty; and -31.8 percent (95% CI -44.8 to -18.6 percent) compared with a rotablator.

●PCI with everolimus-eluting stents was associated with a lower risk of target lesion revascularization (TLR) than all other strategies.

A 2015 meta-analysis evaluated patients at one year or shorter [72]. Three-year follow-up of the RIBS IV study (included in the 2015 meta-analysis), which compared EES with DEB, found that the combined clinical outcome of cardiac death, myocardial infarction, and target lesion revascularization was lower with EES (12.3 versus 20.1 percent; hazard ratio 0.57, 95% CI 0.34-0.96) [73].

Despite the apparent superiority of the everolimus-eluting stents compared with a DEB, we believe it has some role, particularly as the network meta-analysis discussed above suggests, that it may be superior to other devices. For example, patients who are not good candidates for long-term dual antiplatelet therapy, those in whom there is a concern about having too much metal (eg, three concentric stents) in one location, and when compromise of flow in a side branch is a concern may be reasonable candidates for a DEB. These devices are not approved in the United States. Assessing their role in the setting of intermediate effectiveness, as suggested in the meta-analysis above, and associated benefit of avoiding additional stenting will require thoughtful trial designs.

Occasionally, we use a scoring (cutting) balloon prior to stenting to increase the likelihood of achieving an optimal final internal luminal diameter. (See "Specialized revascularization devices in the management of coronary heart disease", section on 'Cutting balloon angioplasty'.)

RECOMMENDATIONS OF OTHERS — The 2014 European Society of Cardiology/European Association for Cardio-Thoracic Surgery guideline on myocardial revascularization recommends either drug-eluting stent (DES) or drug-coated balloons for the treatment of intracoronary stent restenosis (ISR) (bare metal stents [BMS] or DES) and consideration of CABG for recurrent episodes of diffuse ISR [74].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Percutaneous coronary intervention".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

●Beyond the Basics topics (see "Patient education: Angina treatment — medical versus interventional therapy (Beyond the Basics)" and "Patient education: Stenting for the heart (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Introduction – Restenosis is a gradual re-narrowing of the stented segment that occurs mostly between 3 and 12 months after stent placement. It usually presents as recurrent angina, but it can also present as acute myocardial infarction in approximately 10 percent of patients.

●Revascularization – We perform coronary artery revascularization in most patients diagnosed with clinically significant intracoronary stent restenosis (ISR) rather than a continuation of medical therapy in an attempt to control symptoms. Indications for repeat revascularization in patients with ISR are similar compared with patients without prior stent placement.

We perform percutaneous coronary intervention in most patients with ISR rather than coronary artery bypass grafting (CABG). (See 'Management' above.)

•Intracoronary imaging – Prior to percutaneous coronary intervention for restenosis, we perform intracoronary imaging in most cases to determine if the original stent is adequately expanded, to assess for other restenosis mechanisms, and to further evaluate the size of the reference vessel. (See 'Role of imaging' above.)

•Long-term antiplatelet therapy – Our recommendations for antiplatelet therapy are similar to the broad population of patients who receive intracoronary stents. (See "Long-term antiplatelet therapy after coronary artery stenting in stable patients", section on 'Summary and recommendations'.)

•Type of stent – In patients with ISR (bare metal stents [BMS] or drug-eluting stents [DES]) who require repeat revascularization, we recommend stenting using a current generation DES, and in particular, an everolimus-eluting stent, rather than treating with a BMS, balloon angioplasty, and intracoronary radiation (Grade 1B) [75]. The use of a drug-eluting balloon is also a reasonable option where available. (See 'Management' above.)

•Patients unlikely to adhere with long-term DAPT – In patients who are unlikely to adhere to a recommendation for long-term dual antiplatelet therapy, alternatives include continuation of medical therapy, balloon angioplasty or repeat BMS, or CABG surgery. (See 'Management' above.)