6. AngioClub: A Multimodality Approach to Recalcitrant In-Stent Restenosis

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CathMasters (Drs. Amit Goyal, Daniel Ambinder, Nazli Okumus, and Salman Allana) discuss a challenging case of recalcitrant focal in-stent restenosis (ISR) within two layers of stent in a right coronary artery. The panel walks through a systematic approach to ISR: guide selection and access strategy; the role of intracoronary imaging in classifying ISR using the Waksman mechanistic classification; and a stepwise lesion-modification algorithm using cutting balloons, excimer laser coronary atherectomy (ELCA), and intravascular lithotripsy (IVL). The discussion concludes with the contemporary role of drug-coated balloons (DCB) versus vascular brachytherapy (VBT), and when to consider rotational atherectomy (RA) for stent ablation in refractory cases.

CathMasters is for educational purposes only.

CathMasters is for educational purposes only. Music by Elijah K from Pixabay

Media

Coronary Angiography
OCT – First Run
OCT – Second Run
Final Angiography

Pearls

  1. Always image before you intervene. Intravascular imaging (OCT or IVUS) is essential for classifying ISR using the Waksman mechanistic classification (Type I: mechanical; Type II: biologic; Type III: mixed; Type IV: CTO; Type V: multilayer) because the mechanism dictates the treatment strategy.
  2. “Watermelon seeding” does not equal neointimal hyperplasia. While balloon slippage is classically associated with neointimal hyperplasia, it also occurs with calcified lesions that resist expansion. Do not assume the mechanism without imaging.
  3. ELCA with contrast is not the same as ELCA with saline. Contrast infusion amplifies the photomechanical effect by generating cavitating microbubbles producing shockwaves equivalent to ~100 atm, enabling ablation of calcified neoatherosclerosis — but at the cost of increased risk of no-reflow and dissection. Use saline for predominantly biologic (NIH) lesions; consider adding contrast when calcium is present.
  4. Recalcitrant ISR often requires multimodality lesion preparation. A single tool rarely suffices for Waksman Type III (mixed) ISR. In this case, cutting balloon addressed tissue disruption, ELCA ablated neointimal hyperplasia, and IVL cracked the calcified neoatherosclerosis — each targeting a different component of the disease.
  5. Know your shelf and know your off-ramp. Not every lab has every tool. If adequate lesion modification cannot be achieved, have a plan to refer to a center with additional capabilities (e.g., brachytherapy, rotational atherectomy for stent ablation) rather than leaving a suboptimal result.

Notes

  1. How should ISR be classified, and why does it matter?
  • The Waksman ISR Classification is an imaging-based mechanistic classification that guides treatment. It identifies 5 types: Type I — mechanical (IA: underexpansion; IB: stent fracture); Type II — biologic (IIA: neointimal hyperplasia; IIB: noncalcified neoatherosclerosis; IIC: calcified neoatherosclerosis); Type III — mixed mechanical and biologic; Type IV — chronic total occlusion; Type V — multilayer (>2 stent layers).
  • OCT is preferred over IVUS for characterizing the neointimal tissue (NIH vs. neoatherosclerosis vs. calcium), though IVUS provides complementary information on stent expansion and persistent calcium.
  • In this case, OCT revealed Waksman Type III ISR: a combination of neointimal hyperplasia and calcified neoatherosclerosis within two layers of stent that were reasonably well expanded — meaning both biologic and mechanical components required treatment.
  1. What is the stepwise approach to lesion modification in recalcitrant ISR?

Steps will vary based on lesion characteristics, operator experience, and availability of cath lab devices. The following is specific to the case discussed in this podcast.

  • Step 1 — Noncompliant (NC) balloon: Start with a small NC balloon (2.0–2.5 mm) to predilate and create a path for imaging catheters. This also provides initial diagnostic information about lesion compliance.
  • Step 2 — Cutting/scoring balloon: If the NC balloon watermelon seeds or fails to expand, use a cutting balloon (e.g., Wolverine) or scoring balloon (e.g., AngioSculpt, ScoreFlex) to anchor and disrupt tissue. Sizing strategies vary by operator:
    • One-to-one sizing at nominal to moderate pressures (12–14 atm)
    • Undersizing by 0.5 mm and going to higher pressures (up to 18–20 atm) with slow inflation/deflation
  • Step 3 — Atheroablative therapy (ELCA or RA): If persistent waist remains after cutting balloon + NC:
    • ELCA is preferred for predominantly biologic (NIH) ISR. For the 1.4 mm catheter, max settings are 60 mJ/mm² fluence and 40 Hz repetition rate. Advance slowly at 0.5–1 mm/sec. Use saline flush for NIH; 50/50 contrast/saline for calcified neoatherosclerosis.
    • RA is preferred for calcified neoatherosclerosis or underexpanded stents. Start with a 1.5-mm burr at 160,000–180,000 RPM for calcific disease (treat as de novo). For underexpanded stents, longer runs at 200,000–220,000 RPM may be needed — advance very slowly to avoid burr entrapment.
  • Step 4 — Intravascular lithotripsy (IVL): Size 1:1 to the reference vessel. IVL is particularly effective for calcium behind stent struts, causing underexpansion. A meta-analysis of 354 patients showed an 88.7% strategy success rate for IVL in stent underexpansion. IVL may be less effective for calcified neoatherosclerosis (calcium within the stent lumen) compared to peri-stent calcium.
  • Step 5 — High-pressure NC or OPN balloon: After calcium modification, follow with aggressive NC balloon postdilation. OPN (ultra-high-pressure) balloons are an option, but are bulky and may be difficult to deliver.
  1. What is the role of ELCA in ISR, and how does contrast flush change the game?
  • ELCA produces monochromatic UV light (308 nm wavelength) that ablates tissue via three mechanisms: photochemical (direct molecular bond disruption), photothermal (heat generation), and photomechanical (acoustic shockwave from vapor bubble formation).
  • Contrast flush amplifies the photomechanical effect by generating cavitating microbubbles that produce shockwaves equivalent to ~100 atm, enabling disruption of calcified tissue that saline-only ELCA cannot address.
  • Available catheter sizes: 0.9, 1.4, 1.7, and 2.0 mm. For ISR, 1.4 mm is typically the starting size. The 0.9 mm catheter is reserved for very tight or balloon-uncrossable lesions. Catheter size should not exceed two-thirds of the vessel diameter.
  • The ROLLER COASTR trial (171 patients) randomized patients with calcified coronary stenosis to RA, IVL, or ELCA. IVL was noninferior to RA for stent expansion, but ELCA narrowly failed to meet the noninferiority margin versus RA in the intention-to-treat analysis — suggesting that for heavily calcified de novo lesions, RA and IVL may be superior to ELCA.
  • However, for ISR specifically, ELCA combined with DCB may offer advantages. The ELDISR trial (110 patients) randomized patients with ISR to ELCA + balloon angioplasty vs. balloon angioplasty alone and showed benefits with ELCA. Smaller studies have shown ELCA + DCB yields lower TLR than DCB alone (~10% vs. 20% at 1 year).
  1. DCB vs. brachytherapy — what is the contemporary approach to antiproliferative therapy in ISR?
  • Drug-coated balloons (DCB): The AGENT IDE trial randomized ~600 patients with coronary ISR to paclitaxel-coated balloon (Agent DCB) vs. uncoated balloon. DCB significantly reduced 12-month target lesion failure (TLF), driven by lower ischemia-driven TLR and target-vessel MI. Notably, zero cases of stent thrombosis occurred in the DCB arm vs. 6 cases (3.2%) in the control arm. Approximately 60% of enrolled patients had single-layer ISR, so the applicability to multilayer ISR was initially uncertain. A subsequent subgroup analysis showed consistent DCB benefit in both single-layer and multilayer ISR, with particularly striking absolute risk reduction in the multilayer cohort (TLF ~24% vs. ~40%).
  • Vascular brachytherapy (VBT): Remains a viable option, particularly for recurrent ISR after DCB failure. TLR rates with brachytherapy are approximately 29–30% at 2 years in single-center series. Logistical challenges include the need for a radiation source, radiation oncologist, and radiation physicist in the lab, making it an elective/scheduled procedure.
  • Contemporary practice: DCB is increasingly used as first-line antiproliferative therapy for ISR, given ease of use and strong trial data. VBT is reserved as a backup for recurrent ISR after DCB failure. No high-quality randomized data directly compare DCB to VBT. The longest available DCB is 30 mm, so diffuse ISR lesions exceeding this length may favor VBT. 
  • ELCA + DCB combination: Emerging data suggest that combining ELCA with DCB may be superior to DCB alone, particularly for debulking neointimal tissue before drug delivery. This combination is supported by the ELDISR trial and smaller observational studies.
  1. When and how to use rotational atherectomy for ISR and stent ablation
  • RA ablates both neointimal tissue and metallic stent struts via differential cutting (preferentially ablating hard, inelastic material).
  • For calcified neoatherosclerosis: treat similarly to de novo calcified disease. Start with a 1.5 mm burr at 160,000–180,000 RPM.
  • For underexpanded/dog-boning stents refractory to other modalities, prolonged RA runs at 200,000–220,000 RPM may be required. Advance very slowly to minimize the risk of burr entrapment. May need to upsize to 1.75 or 2.0 mm burr.
  • The ROSTER trial (200 patients, BMS-ISR) showed RA reduced TLR vs. balloon angioplasty at 12 months (32% vs. 45%). The ARTIST trial (298 patients) showed no benefit — likely because stent underexpansion was not excluded by IVUS, and RA is less effective for radial expansion of an underexpanded stent without calcium.
  • After RA for stent ablation, consider DCB rather than adding a third stent layer. The threshold for implanting a third stent layer should be very high.
  1. Practical tips for guide selection and access in complex ISR
  • Femoral access is preferred for complex RCA ISR in post-CABG patients to maximize guide support.
  • A 7-French system is recommended to accommodate larger devices (ELCA, IVL, RA).
  • AL 1.0 or AL 0.75 guides provide excellent support for the RCA.
  • Longer sheaths (e.g., 45 cm) provide additional backup support.
  • A GuideLiner may be needed for device delivery in long, fully stented segments.
  • Wire choice is critical: use a supportive wire for device delivery, but be cautious about distal wire perforation in small, diseased branches.

References

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