PCI in the patient with in stent restenosis

In-stent restenosis (ISR) is the most frequent late complication of stent implantation and occurs when there is a reoccurrence of stenosis in a lesion that was previously treated with a stent. In stent restenosis results from exaggerated neointimal formation. The lesion is primarily composed of smooth muscle cells and extracellular matrix. Intravascular ultrasound studies demonstrate that in stent restenosis is not due to extrinsic compression of the stent by scar tissue (i.e. there is not compression of the stent).

In the drug-eluting stent era the mechanisms of in-stent restenosis are recognized to be multiple rather than single. Neointimal hyperplasia remains one mechanism, but neoatherosclerosis developing within the stented segment, stent underexpansion and stent fracture each account for a substantial share of cases, and these mechanisms cannot be distinguished from one another on angiography. Intracoronary imaging with intravascular ultrasound or optical coherence tomography is therefore used to establish the mechanism before the lesion is treated, and the treatment selected follows from what the imaging shows. Repeat implantation of a drug-eluting stent is the reference percutaneous treatment. Drug-coated balloon angioplasty, which leaves no additional metal in the vessel, became available in the United States for this indication in 2024 and is an alternative where further stent layers are undesirable. Coronary artery bypass grafting and intracoronary brachytherapy have defined roles in recurrent, diffuse and multilayer disease.

Although ISR has traditionally occurred in 30-40% of treated lesions, its incidence has been dramatically reduced by the development of drug-eluting stents.

• Restenosis accounts for approximately 10% of all percutaneous coronary intervention procedures performed today.^[1]
• After drug-eluting stent implantation, in-stent restenosis and the resulting need for repeat revascularization continue to occur at a rate of 1% to 2% per year.^[2]
• With second-generation drug-eluting stents the restenosis rate is 5.7% in patients without diabetes and 8.7% in patients with diabetes, and the 5-year restenosis rate is 9% to 12% in non-complex lesions.^[1]
• In-stent restenosis should not be regarded as a benign process: approximately one quarter of cases present as acute myocardial infarction, with a 30-day mortality of 10% to 25%.^[1]

• The angiographic pattern of restenosis should be recorded, because it predicts recurrence: pattern I is focal disease 10 mm or less in length, pattern II is disease longer than 10 mm confined within the stent, pattern III is disease longer than 10 mm extending beyond the stent margins, and pattern IV is a totally occluded stent.^[3]
• The need for repeat target lesion revascularization rises steeply from the focal to the occlusive pattern, so diffuse and occlusive patterns should prompt consideration of a strategy other than repeat balloon angioplasty alone.^[3]
• Restenosis within a drug-eluting stent should additionally be classified by mechanism on intracoronary imaging as mechanical (stent underexpansion or stent fracture), biological (neointimal hyperplasia, or non-calcified or calcified neoatherosclerosis), mixed, occlusive, or occurring in a segment already carrying more than two stent layers, because each mechanism calls for a different treatment.^[4][1]

• Diabetes
• Chronic kidney disease

• Longer lesion length
• Smaller caliber vessel
• Greater plaque burden
• Ostial lesion location
• The presence of a chronic total occlusion
• Left anterior descending coronary artery location
• Saphenous vein graft lesion
• Stent underexpansion^[1][2]
• Stent fracture^[1][4]
• Neoatherosclerosis within the stented segment^[2]
• More than one layer of stent already present at the lesion site^[1]

• A residual stenosis >30%
• A residual pressure gradient > 20 mmHg
• An increased number, overlap, and length of stents
• Implantation without intracoronary imaging guidance; image-guided stenting at the index procedure should be used to minimize the occurrence of stent failure^[1]

The major goal of treating in-stent restenosis is to minimize the chance of recurrent restenosis. If a bare metal stent develops ISR, then a drug eluting stent should be placed. If ISR develops in a drug eluting stent, there is no data to suggest that a different type of drug eluting stent will prevent a recurrence (e.g. switching from sirolimus to paclitaxel). While use of a cutting balloon may improve acute angiographic results, there is no data to suggests that the use of a cutting balloon reduces the risk of a recurrence. Radiation treatment or brachytherapy was used in the past to treat ISR, but this procedure was associated with a higher rate of late stent thrombosis, and had fallen out of favor.

• Intravascular ultrasound or optical coherence tomography is reasonable before treating in-stent restenosis, because the mechanism of stent failure cannot be established from angiography alone and determines which treatment is appropriate.^[5][2]
• Imaging should be used to separate stent underexpansion and stent fracture from neointimal hyperplasia and from neoatherosclerosis, and to establish how many stent layers are present at the lesion.^[1][4]
• Where imaging demonstrates underexpansion, the stent should be expanded before any antiproliferative treatment is delivered, because an antiproliferative device does not correct a mechanical problem.^[1]

• An underexpanded stent should first be treated with an appropriately sized high-pressure non-compliant balloon.^[1]
• Where a non-compliant balloon fails to expand the segment, cutting or scoring balloons, rotational atherectomy, orbital atherectomy, excimer laser coronary atherectomy or intravascular lithotripsy may be used to modify the underlying calcified plaque or calcified neoatherosclerosis.^[1]
• Neointimal modification with a scoring balloon before drug-coated balloon angioplasty improves the angiographic antirestenotic result compared with predilatation using a standard balloon, although the randomised evidence was not powered for clinical events.^[6]

• A drug-eluting stent should be used when repeat percutaneous coronary intervention is planned for clinical in-stent restenosis, provided the anatomy is suitable and the patient is able to comply with dual antiplatelet therapy.^[5]
• Repeat stenting adds a further layer of metal, and the number of layers already present should be weighed before restenting, since accumulating layers reduce the available lumen and are associated with a higher rate of further recurrence.^[1][2]

• A paclitaxel drug-coated balloon reduces target lesion failure, target vessel myocardial infarction and stent thrombosis compared with uncoated balloon angioplasty in coronary in-stent restenosis, and has been approved for this indication in the United States since 2024.^[7]
• A drug-coated balloon should not be delivered until predilatation has produced a satisfactory result, taken as a residual stenosis of 50% or less.^[7]
• Because it leaves no additional metal behind, drug-coated balloon angioplasty is favoured where several stent layers are already present, where a side branch would be jailed by a further stent, or where prolonged dual antiplatelet therapy is undesirable.^[1]
• For restenosis occurring within a drug-eluting stent, repeat drug-eluting stenting is moderately more effective than paclitaxel-coated balloon angioplasty at preventing target lesion revascularization to three years, while death, myocardial infarction and target lesion thrombosis occur at similar rates with the two strategies.^[8]
• * On this basis European guidance recommends a drug-eluting stent in preference to a drug-coated balloon for restenosis within a drug-eluting stent.^[9]
• The evidence is not uniformly one-sided. At ten years, the randomised comparison of paclitaxel-coated balloon against paclitaxel-eluting stent for drug-eluting stent restenosis showed broadly comparable clinical outcomes, so the choice between the two strategies remains unsettled and should be made lesion by lesion.^[10]

• Intracoronary brachytherapy may be considered for recurrent in-stent restenosis to improve symptoms, and is used in particular where the lesion already carries several stent layers.^[5][1]

• Coronary artery bypass grafting can be useful in preference to repeat percutaneous coronary intervention in patients with symptomatic recurrent diffuse in-stent restenosis who have an indication for revascularization.^[5]

Step 1: Confirm that the restenosis is responsible for ischemia^[1]

• Symptoms or objective ischemia attributable to the stented segment → proceed to Step 2
• No symptoms and no demonstrable ischemia → continue medical therapy

Step 2: Image the lesion with intravascular ultrasound or optical coherence tomography^[5]

• Establish whether the mechanism is mechanical, biological, or mixed, and count the stent layers present
• Routine intracoronary imaging is strongly recommended for every ISR lesion, since angiography alone cannot reliably distinguish stent underexpansion from neointimal hyperplasia or neoatherosclerosis; imaging is used both to select the treatment strategy and to confirm an effective result after treatment.^[1]
• Target an IVUS-optimized minimal stent area >5.0 mm² or an OCT-optimized minimal stent area >4.5 mm², since a suboptimal minimal stent area is a major predictor of subsequent stent failure.^[1]

Step 3: Correct the mechanism identified^[1]

• Stent underexpansion → high-pressure non-compliant balloon; if a waist persists, cutting or scoring balloon, rotational atherectomy, orbital atherectomy, excimer laser coronary atherectomy or intravascular lithotripsy
• Neointimal hyperplasia → lesion preparation, then an antiproliferative treatment
• Calcified neoatherosclerosis → calcium modification before any antiproliferative treatment
• For focal neointimal hyperplasia, a high-pressure or scoring/cutting balloon alone may be sufficient, with excimer laser coronary atherectomy or atherectomy reserved for selected cases; for diffuse neointimal hyperplasia, atherectomy or scoring/cutting balloon angioplasty followed by repeat drug-eluting stent implantation is typically advised.^[1]
• Any major edge dissection (>60°, >3 mm in length, or penetrating the media) should be treated with additional stenting.^[1]
• When imaging identifies a peri-stent calcium arc >270° or >0.67 mm in thickness, atherectomy vessel preparation should be considered to optimize lesion and stent expansion.^[1]
• If underexpansion is due to significant peri-stent calcium (arc >90°), rotational atherectomy, orbital atherectomy, or excimer laser coronary atherectomy may disrupt the calcified plaque behind the stent, and intravascular lithotripsy may also be useful; these should be followed by high-pressure inflation, and coronary artery bypass grafting may be necessary if unsuccessful.^[1]
• If underexpansion is not due to calcification, atheroablative techniques (rotational atherectomy, orbital atherectomy, or excimer laser coronary atherectomy) should be used only if significant neointimal hyperplasia is also present.^[1]

Step 4: Deliver an antiproliferative treatment^[5][7]

• Suitable anatomy with few existing stent layers → repeat drug-eluting stent
• Several stent layers, a jeopardized side branch, or a need to limit dual antiplatelet therapy → drug-coated balloon
• Repeat drug-eluting stent implantation is recommended (Class I, Level of Evidence A) when the anatomy is suitable and the patient can comply with prolonged dual antiplatelet therapy.^[5]
• Drug-coated balloon angioplasty and repeat drug-eluting stent implantation produce similar outcomes for restenosis of a bare-metal stent, but repeat drug-eluting stent implantation is more effective than drug-coated balloon angioplasty for restenosis of a drug-eluting stent.^[11]
• More recent comparative meta-analyses report broadly similar clinical outcomes between drug-coated balloon angioplasty and repeat drug-eluting stent implantation, although guideline recommendations continue to favor repeat drug-eluting stent implantation where anatomy and dual antiplatelet therapy tolerance permit.^[12]
• Adverse events with drug-coated balloon angioplasty are increased when treating a segment with more than two existing stent layers, but not with one or two prior stents.^[1]

Step 5: Manage recurrence after repeated failure^[5]

• Symptomatic recurrent diffuse restenosis with suitable anatomy and acceptable operative risk → coronary artery bypass grafting
• Repeated recurrence not amenable to surgery → intracoronary brachytherapy
• Multilayer (more than two stents) underexpanded ISR is particularly recalcitrant to standard treatment; intracoronary brachytherapy is often reserved for this setting.^[1]
• Surgical revascularization should be considered in discussion with the patient once several interventional procedures have failed.^[1]

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