Management of Restenosis in Drug-Eluting Stents: Still a Challenge!

Drug-eluting stents (DES) are currently implanted in > 3 million patients worldwide undergoing percutaneous coronary intervention (PCI) each year. With better equipment and understanding of the needs of prolonged dual-antiplatelet therapy with DES, they have been proven to be superior to bare-metal stents (BMS) in terms of reducing the incidence of restenosis.^1–3 Randomized, controlled trials (RCTs) and observational studies have shown varying results. In RCTs, treatment with DES was associated with no detectable differences in death or myocardial infarction (MI), with a significant 55% reduction in target vessel revascularization (TVR). In observational studies, the nonrandomized use of DES versus BMS was associated with significant 22% and 13% reductions in all-cause mortality and MI, respectively, and a significant 46% reduction in TVR. ⁴ In both types of studies, however, the consensus is that DES are associated with a significant reduction in TVR as compared to BMS. The initial approval of DES from the U.S. Food and Drug Administration was based on evidence consisting of RCTs enrolling patients with stable coronary artery disease and noncomplex, single, de novo coronary artery lesions. On the contrary, DES are currently being used “off label” in high-risk patients with more complex lesions, and concerns have arisen about the performance of DES in the “real world.” These off-label uses of DES are associated with a higher rate of in-stent restenosis (ISR) or stent thrombosis, which is still a challenge to treat. SES restenosis is believed to occur due to a variety of mechanisms such as stent underexpansion, stent fracture, uneven distribution or inadequate local delivery of sirolimus and intrinsic resistance to sirolimus. ⁵ The treatment options described in the literature include the “homo stent sandwich technique” (re-stenting with the same DES), “hetero-stent sandwich” (with a different DES), standalone angioplasty with a noncompliant balloon, cutting-balloon angioplasty, atherectomy, insertion of a BMS or brachytherapy. ^5,6 Given the relatively high major adverse cardiac events (MACE) rate in the DES ISR population, coronary artery bypass surgery is also a viable treatment alternative for complex DES restenosis. The study performed by Levisay et al, ⁷ which is published in the current issue of the Journal, evaluates the long-term clinical outcomes after an initial strategy of paclitaxel-eluting stent (PES) implantation for de novo sirolimus-eluting stent (SES) restenosis. A total of 130 patients (mean age 66.4 ± 11 years) undergoing PES implantation for SES restenosis were identified. The inclusion criteria for this study were: 1) initial target lesion for SES was de novo; 2) the SES restenotic lesion had not been previously treated; and 3) at least 1 year had passed since the PES implantation. Over a median follow up of 453 days, out-of-hospital MACE occurred in 33 (25.4%) patients. Death occurred in 2 patients (due to non-cardiac causes – septic shock and bronchogenic carcinoma), non-ST-elevation MI (not related to the target vessel) in 1 patient (0.8%) and target lesion revascularization (TLR) in 30 patients (23.8%). There were no episodes of stent thrombosis. There was no difference in freedom from TLR between patients treated for focal versus non-focal SES restenosis (p = 0.52). However, among the lesions which had recurrent restenosis after PES implantation, a non-focal pattern of initial SES restenosis was associated with a significantly shorter time to recurrence than a focal pattern (216 ± 23 days versus 323 ± 27 days; p = 0.02). The present study is a nonrandomized, retrospective analysis and does not compare the efficacy of PES implantation with that of other possible therapies. Several studies have compared the efficacy of “hetero-stent” with “homo-stent” techniques and have reported varying results. The ISAR-DESIRE 2 (Intracoronary Stenting and Angiographic Results: Drug-Eluting Stents for In-Stent Restenosis 2) study⁸ reports a comparable degree of antirestenotic efficacy and clinical safety between SES and PES in cases of SES restenosis. Cosgrave et al⁹ also reported that DES implantation for DES restenosis is feasible and safe, but found no differences between implantation of the same or a different DES. Mishkel et al⁶ showed the “hetero-stent” treatment to have more favorable outcomes (although not statistically significant) at 12 months than the other groups, probably due to differences in tissular response to the different DES, such that an initially poor response to one drug would be a signal to implant a DES that delivers another drug with a different mechanism of action. Levisay et al also make an important point by recommending optimization of post-procedural minimum luminal diameter and minimizing post-procedure percent diameter stenosis. To summarize, this is an important study highlighting the safety of PES implantation for SES restenosis at more than 1-year follow up in complex “real-world” coronary anatomy. However, the quest for an effective therapy still continues, and large RCTs with long-term angiographic follow up are required to compare the efficacy of PES and SES in patients with DES restenosis. Although results with drug-eluting balloon therapy show promise in cases of BMS restenosis, ¹⁰ the place of this therapy in cases of DES restenosis awaits definition and will be the subject of future investigation. Also, if the drug resistance mechanism in particular patients is identified, this might conceivably be used to guide future therapy.

References

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________________________________________________________________ From the Los Angeles Biomedical Research Institute at Harbor UCLA Medical Center, Torrance, California. The authors report no conflicts of interest regarding the content herein. Address for correspondence: Matthew J. Budoff, MD, Associate Professor of Medicine, Los Angeles Biomedical Research Institute, 1124 West Carson Street, Torrance, CA 90502. E-mail: mbudoff@labiomed.org