PCI complications: restenosis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Muhammad Saad, M.B.B.S.[2]

Overview

In-stent restenosis (ISR) is a common complication following percutaneous coronary intervention (PCI), defined by the Academic Research Consortium (ARC) as either ≥50% diameter stenosis with evidence of functional significance (ischemic symptoms or abnormal fractional flow reserve) or ≥70% stenosis without ischemic symptoms, occurring within 5 mm proximal or distal to the implanted stent.[1] PCI for ISR constitutes approximately 10% of all PCI procedures performed in the United States.[1]

The principal mechanism underlying ISR is neointimal hyperplasia, although neoatherosclerosis has been increasingly recognized as a major contributor to late stent failure.[1][2] ISR after drug-eluting stent (DES) implantation is generally more focal than following bare metal stent (BMS) placement.[3][4]

The risk of ISR has decreased substantially with successive generations of stent technology. In the pre-stent era, restenosis after balloon angioplasty occurred in 32%–55% of cases; with bare metal stents, rates were 17%–41%; and with contemporary second-generation DES, rates have fallen to less than 10%, with an ongoing incidence of approximately 1%–2% per year.[5][1]

Treatment options for ISR include repeat PCI with drug eluting stents, drug-coated balloons, plain balloon angioplasty, scoring or cutting balloons, atheroablative therapies, vascular brachytherapy, and coronary artery bypass surgery (CABG). The 2021 ACC/AHA/SCAI Guideline for Coronary Artery Revascularization recommends DES as the preferred strategy for repeat PCI of ISR (Class 1, Level of Evidence A).[6] The 2023 SCAI Expert Consensus Statement strongly recommends routine intravascular imaging (IVUS or OCT) to determine the mechanism of ISR, inform therapeutic strategy, and confirm effective treatment.[7]

Classification

The Mehran classification is the most widely used angiographic classification system for ISR and has important prognostic implications:[8]

Pattern Description Target Lesion Revascularization Rate
I: Focal (≤10 mm in length)

Ia: Restenosis within the body of the stent

Ib: Restenosis at the margin (edge) of the stent

Ic: Restenosis at the articulation or gap

Id: Multifocal restenosis

19%
II: Diffuse intrastent ISR >10 mm confined within the stent 35%
III: Diffuse proliferative ISR >10 mm extending beyond the stent margins 50%
IV: Total occlusion Complete stent occlusion (TIMI flow grade 0) 83%

The need for recurrent target lesion revascularization (TLR) increases significantly with increasing ISR class (P <0.001).[8] In the setting of ISR after bare metal stent implantation, the pattern of restenosis is predictive of recurrence risk.[8]

Pathophysiology

Neointimal Hyperplasia

The predominant mechanism of ISR is neointimal hyperplasia, a process involving smooth muscle cell activation, proliferation, migration from the media to the intima, and excessive extracellular matrix production within the stented segment.[8][9][10][11]

Low endothelial shear stress at the stented site promotes this process by creating a self-reinforcing cycle: flow disturbance activates smooth muscle cells, which produce neointimal tissue that further narrows the lumen and worsens flow disturbance.[12]

The temporal pattern of neointimal growth differs between stent types. With bare metal stents, neointimal hyperplasia is maximal by 6–8 months and then stabilizes. With drug eluting stents, neointimal growth is initially suppressed but continues with ongoing late lumen loss extending out to 5 years.[13]

Neoatherosclerosis

Neoatherosclerosis is increasingly recognized as a major cause of late stent failure and is characterized by the accumulation of lipid-laden foamy macrophages within the neointima, with or without necrotic core formation and calcification. Neoatherosclerosis occurs more frequently and at an earlier time point in DES compared with BMS. In-stent plaque rupture from neoatherosclerotic lesions likely accounts for most thrombotic events associated with late stent failure.[2][1]

Optical coherence tomography (OCT) can classify neoatherosclerotic lesions into subtypes: thin-cap neoatheroma, thick-cap neoatheroma, peristrut neoatheroma, and preexisting fibroatheroma. In very late DES-ISR, thin-cap fibroatheroma has been identified in 52% of cases, neointimal rupture in 58%, and thrombus in 58%.[1]

Mechanical Causes

The pathophysiology of ISR can also be anticipated based on the time period of occurrence:[6]

Early stent failure is usually due to residual target-lesion thrombus, stent underexpansion, or nonadherence to dual antiplatelet therapy.

Late stent failure is usually associated with inadequate neointimal coverage, incomplete healing, or neoatherosclerosis.

Suboptimal stent deployment (including underexpansion, malapposition, and geographic miss) occurs in 31%–58% of ISR cases and confers increased risk of adverse events, underscoring the importance of intravascular imaging at the time of ISR evaluation.[7][14]

Epidemiology and Demographics

ISR is found in 5% to 10% of patients undergoing PCI overall.[15][13] With contemporary second-generation DES, the annual incidence of ISR is approximately 1%–2% per year.[1]

Risk Factors

A large registry study of 10,004 patients with surveillance angiography identified the following independent predictors of ISR:[16]

Risk Factor Odds Ratio (95% CI)
Smaller vessel size (per 0.5 mm decrease) 1.59
Total stented length (per 10 mm increase) 1.27
Complex lesion morphology (type B2/C) 1.35
Diabetes mellitus 1.32
History of bypass surgery 1.38
Use of first-generation DES vs. BMS 0.35 (0.31–0.39)
Use of second-generation DES vs. first-generation DES 0.67 (0.58–0.77)

Additional predictors of DES-ISR include chronic total occlusions, ostial lesions, saphenous vein graft lesions, and stent underexpansion.[15][17][18]

A Swedish nationwide registry study found that stent diameter was the most important factor influencing ISR risk; for stents <3 mm, the absolute restenosis reduction with DES versus BMS was 3.6 percentage points (NNT 22). The highest ISR incidence was observed in diabetic patients with long, small-diameter BMS (NNT 10 for DES benefit).[19]

Diagnosis

Clinical Presentation

ISR typically presents with recurrent angina or evidence of ischemia on noninvasive testing. The presentation may range from stable angina to acute coronary syndrome, particularly when neoatherosclerosis with in-stent plaque rupture is the underlying mechanism.[1]

Intravascular Imaging

Evaluation of the underlying mechanism of ISR with intracoronary imaging (IVUS and OCT) is essential for planning appropriate treatment.[15][14] The 2023 SCAI Expert Consensus Statement strongly recommends routine intravascular imaging for ISR, as angiography alone is usually inadequate to determine the mechanism.[7]

IVUS is preferred for in-depth vessel wall characterization, assessment of stent expansion, and detection of stent underexpansion or malapposition.

OCT provides superior resolution for differentiating stent-related mechanisms including neointimal hyperplasia, neoatherosclerosis, stent fracture, and tissue prolapse.[6][1]

Differential Diagnosis of Recurrent Symptoms After PCI

Diagnosis Key Distinguishing Features
In-stent restenosis Gradual symptom onset; neointimal hyperplasia or neoatherosclerosis on imaging; ≥50% diameter stenosis with ischemic significance or ≥70% stenosis
Stent thrombosis Acute presentation (often STEMI or sudden cardiac death); thrombus on angiography; associated with antiplatelet nonadherence or stent malapposition
Progression of native coronary artery disease New lesions outside the stented segment; de novo stenosis in non-treated arteries
Stent fracture Visible discontinuity on fluoroscopy or OCT; may cause focal ISR or thrombosis
Incomplete revascularization Residual stenosis in untreated vessels; persistent ischemia in non-stented territories
Non-cardiac chest pain Normal coronary angiography; absence of ischemia on functional testing

Treatment

Initial Management

The initial evaluation of a patient presenting with suspected ISR should include:

Assessment of symptom severity and ischemic burden

Review of dual antiplatelet therapy compliance

Coronary angiography to confirm ISR and characterize the pattern (Mehran classification)

Intravascular imaging (IVUS or OCT) to determine the mechanism of ISR (e.g., neointimal hyperplasia, neoatherosclerosis, stent underexpansion, stent fracture)[7][6]

Medical Therapy

Guideline-directed medical therapy should be optimized in all patients with ISR, including antiplatelet therapy, high-intensity statin therapy, blood pressure control, and glycemic management in diabetic patients. Medical therapy alone may be appropriate for patients with mild symptoms and limited ischemic burden.[6]

Procedural / Surgical Therapy

Drug-Eluting Stents

Among all percutaneous treatment options, drug eluting stents appear to provide the most benefit for ISR. The 2021 ACC/AHA/SCAI guideline recommends DES for repeat PCI of ISR (Class 1, Level of Evidence A), provided anatomic factors and dual antiplatelet therapy compliance are considered.[6][20][21]

Everolimus-eluting stents have shown the best efficacy among drug eluting stent types for ISR treatment in network meta-analyses.[22][23]

However, a third stent layer should generally be avoided in patients who already have 2-layer ISR, as additional stent layers are associated with diminishing returns and increased risk.[1]

Drug-Coated Balloons

Drug-coated balloons (DCB) represent an important alternative to repeat stenting, particularly when avoiding additional stent layers is desirable.

The DAEDALUS individual patient data meta-analysis (10 randomized trials) compared DCB with DES for ISR and found:[24]

For BMS-ISR: DCB and DES had similar efficacy with no significant difference in TLR or major adverse cardiac events.

For DES-ISR: DES outperformed DCB with a 37% risk decrease in 3-year TLR.

No significant differences in safety endpoints (death, myocardial infarction, target lesion thrombosis) were observed in either setting.

A mixed treatment comparison meta-analysis of 18 randomized trials (3,820 patients) confirmed that both DCB and DES significantly reduced MACE compared with plain old balloon angioplasty (POBA) (OR 0.34 and 0.37, respectively), driven by TLR reduction (OR 0.28 and 0.21). No significant difference in clinical outcomes was observed between DCB and DES.[25]

A large German population-based cohort study (3,942 propensity-matched patients) found that DCB was associated with lower all-cause death or myocardial infarction versus DES at 1 year (10.4% vs. 12.9%; HR 0.77), lower all-cause mortality (6.3% vs. 8.1%; HR 0.75), and lower bleeding (2.5% vs. 4.2%; HR 0.65).[26] However, a Swedish registry long-term analysis (10,561 lesions) found that DCB was associated withless TLR compared with POBA (RR 0.69) but higher TLR compared with DES (HR 1.20; 95% CI 1.06–1.37), with no difference in death, cardiovascular death, or myocardial infarction between DCB and DES.[27]

A meta-analysis of 6 randomized controlled trials (1,038 patients) comparing limus-coated balloons with paclitaxel-coated balloons for ISR found that paclitaxel-coated balloons were associated with lower clinically driven TLR (RR 1.48 for limus-coated vs. paclitaxel-coated balloons; 95% CI 1.02–2.14), with no differences in mortality, myocardial infarction, stent thrombosis, or MACE.[28]

Vascular Brachytherapy

Vascular brachytherapy can be used as an additional tool to aid revascularization among patients with multiple stent layers or in those who have recurrent ISR with an artery that is not suitable to receive another DES or undergo bypass surgery.[29] If chosen properly, vascular brachytherapy can bypass the need to implant another stent in patients with challenging circumstances. The 2021 ACC/AHA/SCAI guideline states that brachytherapy may be considered for recurrent ISR (Class 2b, Level of Evidence B-NR).[6]

Coronary Artery Bypass Grafting

CABG is recommended as an effective treatment for patients with ISR in the following circumstances:[6]

When a patient experiences recurrent restenosis despite repeat PCI with DES

When a patient experiences recurrent restenosis with diffuse ISR in large vessels

When a patient experiences recurrent restenosis with a complex presentation such as chronic total occlusion with multivessel disease

CABG is the preferred treatment in those with suitable anatomy (Class 2a, Level of Evidence C-EO)

Atheroablative Therapies

Scoring or cutting balloons and atheroablative techniques (e.g., rotational atherectomy, excimer laser) may be considered as adjunctive strategies, particularly in cases of heavily calcified ISR or stent underexpansion that cannot be adequately treated with balloon dilation alone.[1][7]

Long-Term Management

Long-term recurrent revascularization remains a significant concern after treatment of ISR. A 10-year follow-up study of patients treated for DES-ISR demonstrated ongoing risk of recurrent revascularization over the long term, highlighting the need for sustained clinical surveillance.[1]

Long-term management includes:

Continued guideline-directed medical therapy including antiplatelet therapy, statins, and risk factor modification

Clinical follow-up with attention to recurrent symptoms

Noninvasive ischemia testing if recurrent symptoms develop

Consideration of CABG for patients with recurrent ISR despite multiple percutaneous interventions

Special Populations

Diabetes mellitus: Diabetic patients have a significantly higher risk of ISR (OR 1.32) and represent a population in which the absolute benefit of DES over BMS is greatest (NNT 10 for long, small-diameter stents). CABG should be strongly considered in diabetic patients with recurrent multivessel ISR.[16][19][6]

Small vessel disease: Patients with small coronary arteries (<3 mm) are at highest risk for ISR. DCB may be particularly useful in this population to avoid additional stent layers in already small lumens.[16][1]

Chronic kidney disease: Patients with renal insufficiency have accelerated neointimal hyperplasia and higher ISR rates. Careful attention to contrast volume and hydration is required during repeat procedures.[15]

Patients with multiple stent layers: A third stent layer should generally be avoided. Vascular brachytherapy, DCB, or CABG should be considered as alternatives to additional stenting.[1][6]

Algorithm for Management of In-Stent Restenosis

Step Action
1 Confirm ISR: coronary angiography demonstrating ≥50% diameter stenosis with ischemic significance or ≥70% stenosis within or adjacent to the stent
2 Perform intravascular imaging (IVUS or OCT) to determine the mechanism of ISR (neointimal hyperplasia, neoatherosclerosis, stent underexpansion, stent fracture, malapposition)
3 Classify ISR pattern using the Mehran classification (I–IV)
4a If mechanical cause identified (underexpansion, fracture): Address with high-pressure balloon dilation, scoring/cutting balloon, or atheroablative therapy; consider additional DES if needed
4b If single-layer ISR (first episode): Repeat PCI with DES (preferred, Class 1) or DCB (alternative, especially for BMS-ISR or to avoid additional stent layers)
4c If 2-layer ISR (second episode): Avoid third stent layer; consider DCB, vascular brachytherapy, or CABG
4d If recurrent diffuse ISR or complex anatomy: CABG preferred over repeat PCI (Class 2a)
5 Optimize guideline-directed medical therapy; ensure dual antiplatelet therapy compliance; long-term clinical surveillance

2021 ACA Guideline Recommendations

Class 1 Recommendation, Level of Evidence: A[6]
If another PCI is planned for a patient with clinical in-stent restenosis (ISR), drug eluting stent (DES) is recommended with goal of outcome improvement (if anatomic factors and dual antiplatelet therapy (DAPT) compliance are considered).
Class 2a Recommendation, Level of Evidence: C-EO[6]
If a patient with recurrent symptomatic diffuse in-stent restenosis (ISR) has a revascularization indication, planning CABG is preferred over repeat PCI to lower recurrent events.
Class 2a Recommendation, Level of Evidence: B-NR[6]
In patients with ISR, intravascular imaging with IVUS or OCT is useful to evaluate the mechanism of ISR and guide treatment strategy.
Class 2b Recommendation, Level of Evidence: B-NR[6]
In a patient with recurrent in-stent restenosis (ISR), brachytherapy could be helpful to improve symptoms.

References

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