Etiopathogenesis and Management of In-Stent Restenosis

In-stent restenosis (ISR) is ≥50% diameter stenosis within the stent or its 5 mm proximal or distal margins on follow-up angiography.

Clinical ISR means angiographic restenosis accompanied by symptoms or objective ischaemia, and is the clinically relevant entity.

ISR occurs in roughly 5–10% of DES implants and up to 20–30% of BMS implants.

Neointimal hyperplasia is the classical mechanism — vessel injury during stenting causes endothelial denudation, platelet deposition, and inflammation.

Released growth factors and cytokines drive smooth muscle cell proliferation and migration from the media into the intima, with extracellular matrix deposition.

Neoatherosclerosis is the second and increasingly dominant mechanism, especially with DES — new atheromatous plaque with lipid-laden foam cells forms inside the stent and may rupture, causing late ACS.

Mechanical factors: stent under-expansion, stent fracture, geographical miss (lesion not fully covered), and stent gap.

Biological factors: polymer hypersensitivity, drug resistance, and persistent chronic inflammation.

Patient factors: diabetes mellitus, chronic kidney disease, and ongoing smoking.

Lesion factors: long lesions, small vessel diameter (<2.5 mm), bifurcation lesions, ostial lesions, chronic total occlusions, and heavy calcification.

BMS restenosis is dominated by neointimal hyperplasia and presents early (6–12 months); DES restenosis is more often due to neoatherosclerosis and presents late (beyond 1–2 years).

Most present as recurrent stable angina; about 10–20% present as an acute coronary syndrome, particularly when neoatherosclerotic plaque ruptures.

In older people the presentation may again be atypical — exertional dyspnoea, fatigue, or reduced exercise tolerance.

Coronary angiography confirms the diagnosis and defines the Mehran classification — Type I focal, Type II diffuse intra-stent, Type III proliferative extending beyond the stent, Type IV occlusive.

Intravascular imaging is mandatory — IVUS best assesses stent under-expansion and vessel size; OCT best characterises neointimal morphology and detects neoatherosclerosis.

Imaging is what distinguishes mechanical failure (needs high-pressure dilatation) from biological failure (needs an antiproliferative strategy).

Lesion preparation first — non-compliant balloon at high pressure, cutting or scoring balloon, or intravascular lithotripsy/rotational atherectomy for underexpanded or calcified segments.

Drug-coated balloon (DCB) angioplasty is a first-line option — it delivers paclitaxel or sirolimus without adding another metal layer, which is a major advantage in a vessel that already has one or more stents.

Repeat DES implantation is the alternative first-line option, preferred when there is significant dissection, elastic recoil, or a suboptimal DCB result.

Plain balloon angioplasty alone is inadequate and has unacceptably high recurrence.

CABG is considered for recurrent, multi-layered, or diffuse ISR, especially with left main or multivessel involvement — but the risk–benefit must be weighed against frailty in older patients.

Aggressive secondary prevention is essential: high-intensity statin, glycaemic control, blood pressure control, smoking cessation, and appropriate antiplatelet therapy.