What is the management of in-stent restenosis?

Management of In-Stent Restenosis Using Mehran Classification

Drug-eluting stents (DES) are the preferred treatment for in-stent restenosis, with treatment intensity escalating based on Mehran classification severity—from simple DES implantation for focal Class I lesions to consideration of coronary artery bypass grafting for diffuse Class IV patterns with 80% target-lesion revascularization rates. 1

Understanding the Mehran Classification System

The Mehran classification stratifies in-stent restenosis into four prognostic categories that directly guide treatment decisions 1:

• Class I (Focal): Lesions ≤10 mm in length with 10% target-lesion revascularization rates 1
• Class II (Diffuse intrastent): Lesions >10 mm confined within the stent with 35% revascularization rates 2
• Class III (Proliferative): Lesions >10 mm extending beyond the stent margins with 50% revascularization rates 2
• Class IV (Total occlusion): Complete in-stent occlusion with 80-83% revascularization rates 2, 1

This classification system provides critical prognostic information, as target-lesion revascularization rates correlate directly with class severity 1.

Primary Treatment Algorithm by Mehran Class

Class I (Focal Lesions)

For focal in-stent restenosis ≤10 mm, implant a drug-eluting stent as first-line therapy 2, 1. Among DES options, everolimus-eluting stents demonstrate superior efficacy compared to other drug-eluting platforms 2. The 2022 ACC/AHA/SCAI guidelines provide Class I, Level A evidence that DES should be used for clinical in-stent restenosis when anatomic factors are appropriate and the patient can comply with dual antiplatelet therapy 2.

• Intravascular ultrasound (IVUS) is reasonable to determine the mechanism of stent restenosis before treatment 2
• Ensure optimal stent expansion to minimize recurrence risk 2
• Avoid plain balloon angioplasty alone, which results in unacceptably high restenosis rates of 44.6% 1

Class II-III (Diffuse and Proliferative Patterns)

Repeat DES implantation remains the treatment of choice for diffuse patterns, though outcomes progressively worsen with increasing lesion length 1. Network meta-analyses comparing various treatment options demonstrate that PCI with DES is associated with the lowest rates of restenosis and target-vessel revascularization 2.

• Drug-coated balloon angioplasty may reduce and delay in-stent re-restenosis in carotid applications, suggesting potential utility in coronary ISR 2
• Consider adjunctive debulking with rotational atherectomy for heavily calcified or fibrotic lesions before DES placement 3
• Sirolimus-eluting stents demonstrate superior outcomes to paclitaxel-eluting stents for focal ISR 1

Class IV (Total Occlusion)

Class IV ISR carries an 80% target-lesion revascularization rate and warrants serious consideration of coronary artery bypass grafting in addition to or instead of repeat PCI with DES 1. The 2022 ACC/AHA/SCAI guidelines recommend that in patients with recurrent episodes of restenosis despite repeat PCI with DES, or in patients with diffuse ISR in large vessels, CABG may be the preferred approach if the anatomy is suitable (Class IIa, Level C-EO) 2.

Critical Pre-Treatment Assessment

Before attributing ISR solely to neointimal hyperplasia, identify and address mechanical causes including stent underexpansion, fracture, and malapposition 1. This represents the most common error in ISR management and requires:

• IVUS or optical coherence tomography to assess stent expansion and apposition 4
• High-pressure balloon dilation for underexpanded stents before additional stent coverage 1
• Evaluation for stent fracture, which increases restenosis risk 3

Alternative and Adjunctive Therapies

Vascular Brachytherapy

In patients with multiple stent layers or recurrent ISR unfavorable for another DES who are not good candidates for bypass surgery, vascular brachytherapy provides an additional tool 2. The 2022 ACC/AHA/SCAI guidelines give this a Class IIb, Level B-NR recommendation 2. Gamma radiation reduces target-lesion revascularization from 42% to 24% in the GAMMA-1 trial 1.

Critical caveat: Late thrombosis occurs in up to 10% of patients treated with vascular gamma brachytherapy, requiring prolonged dual antiplatelet therapy and avoidance of new stent placement 5.

Drug-Coated Balloons

While drug-coated balloons avoid adding another metallic layer, the 2024 ESC guidelines for chronic coronary syndromes recommend DES over drug-coated balloons for treatment of in-DES restenosis (Class I, Level A) 2. This represents the most recent high-quality guideline evidence prioritizing DES.

Post-Intervention Medical Management

Antiplatelet Therapy

Following treatment of ISR with DES, continue dual antiplatelet therapy for 4-6 weeks if single-layer stents are used, and up to 3 months with mesh stents, then transition to single antiplatelet therapy 2. This differs from initial stent placement protocols.

Premature discontinuation of dual antiplatelet therapy dramatically increases thrombosis risk, particularly after brachytherapy or repeat DES implantation 1, 5.

Intensive Medical Therapy

Guideline-indicated medical therapy is essential and includes 2:

• Statin therapy: Target LDL-C <55 mg/dL with ezetimibe or PCSK9 inhibitor as needed 6
• Blood pressure control: Particularly with ACE inhibitors 6
• Glycemic optimization: Critical for diabetic patients to improve outcomes 6
• Smoking cessation: Smoking is a principal clinical risk factor for restenosis 2

Surveillance Protocol

Post-intervention surveillance should include clinical follow-up with formal neurologic examination (for carotid ISR) or symptom assessment at 1 month, 6 months, and then annually 2. For coronary ISR, routine periodic stress testing of asymptomatic patients is not indicated, as it has no proven benefit and a false-positive rate increasing from 37% to 77% 2.

When stress testing is clinically indicated for recurrent symptoms, stress imaging is preferred over exercise ECG alone, which is insensitive for detecting restenosis 2.

Key Clinical Pitfalls to Avoid

• Never use standard balloon angioplasty alone for in-stent restenosis—it has very high failure rates of 44.6% 1
• Do not assume mild symptoms will resolve spontaneously—20-30% of patients have persistent symptoms despite patent stents 6
• Avoid using velocity criteria for non-stented arteries when monitoring post-stent patients—this leads to significant overestimation of in-stent restenosis 2
• Do not fail to optimize medical therapy, particularly lipid management and antiplatelet therapy 6
• Never prematurely discontinue dual antiplatelet therapy, especially after brachytherapy 1, 5