Coronary stent implantation has significantly improved percutaneous coronary intervention and enabled the management of early complications of plain balloon angioplasty. However, a new complication has accompanied these improvements: in-stent restenosis (ISR) arising from neointimal hyperplasia. ISR after coronary angioplasty is currently one of the main limitations of this method, leading to the recurrence of exertional angina pectoris or acute coronary syndromes. The clinical incidence of ISR after bare-metal stent (BMS) implantation is approximately 20%-35%. The use of drug-eluting stents (DES) has led to a further decrease in the occurrence of ISR to 5%-10%. Evidence resulting from controlled clinical studies suggests that DES and drug-eluting balloon catheters (DEB) provide the best clinical and angiographic results in the treatment of ISR. We undertook a systematic review of the pathophysiology, diagnostics and treatment options for BMS- and DES-ISR. We discuss recent randomised studies, comparing different DES or DEB used for BMS or DES-ISR treatment, as well as the use of new biovascular scafolds and the topic of scafold restenosis.

Department of Cardioangiology St Anne's University Hospital and Faculty of Medicine Masaryk University Brno CZ Czech Republic

Department of Cardiovascular Diseases University Hospital Ostrava Czech Republic

International Clinical Research Center St Anne's University Hospital Brno CZ Czech Republic

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Kim MS, Dean LS. In-stent restenosis. Cardiovasc Ther. 2011;29:190–198. PubMed

Scott NA. Restenosis following implantation of bare metal coronary stents: Pathophysiology and pathways involved in the vascular response to injury. Adv Drug Deliv Rev. 2006;58:358–376. PubMed

Byrne RA, Joner M, Massberg S, et al. Restenosis in bare metal and drug-eluting stents. In: Escaned J, Serruys PW, editors. Coronary stenosis, imaging, structure and physiology. 1st Edition. Toulouse, France: Europa Edition; 2010. pp. 475–496.

Mehran R, Dangas G, Abizaid AS, et al. Angiographic patterns of in-stent restenosis classification and implications for long-term outcome. Circulation. 1999;100:1872–1878. PubMed

Farooq V, Räber L, Gogas BD, et al. In-stent restenosis. In: Eeckhout E, Serruys PW, Wijns W, et al., editors. Percutaneous interventional cardiovascular medicine, the PCR-EAPCI textbook. 1st Edition. Toulouse, France: Europa Edition; 2012. pp. 785–826.

Morice MC, Serruys PW, Sousa JE, et al. A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization. N Engl J Med. 2002;346:1773–1780. PubMed

Morice MC, Serruys PW, Barragan P, et al. Long-term clinical outcomes with sirolimus-eluting coronary stents: five-year results of the RAVEL trial. J Am Coll Cardiol. 2007;50:1299–1304. PubMed

Holmes DR, MB, Moses JW, et al. Analysis of 1-year clinical outcomes in the SIRIUS trial a randomized trial of a sirolimus-eluting stent versus a standard stent in patients at high risk for coronary restenosis. Circulation. 2004;109:634–640. PubMed

Weisz G, Leon MB, Holmes DR, et al. Five-year follow-up after sirolimus-eluting stent implantation results of the SIRIUS (Sirolimus-Eluting Stent in De-Novo Native Coronary Lesions) Trial. J Am Coll Cardiol. 2009;53:1488–1497. PubMed

Stone GW, Ellis SG, Cox DA, et al. One-year clinical results with the slow-release, polymer-based, paclitaxel-eluting TAXUS stent the TAXUS-IV trial. Circulation. 2004;109:1942–1947. PubMed

Ellis SG, Stone GW, Cox DA, et al. Long-term safety and efficacy with paclitaxel-eluting stents 5-year final results of the TAXUS IV clinical trial. J Am Coll Cardiol Intv. 2009;2:1248–1259. PubMed

Serruys PW, Ong ATL, Piek JJ, et al. A randomized comparison of a durable polymer everolimus-eluting stent with a bare metal coronary stent: the SPIRIT first trial. EuroInterv. 2005;1:58–65. PubMed

Beijk MA, Neumann FJ, Wiemer M, et al. Two-year results of a durable polymer everolimus-eluting stent in de novo coronary artery stenosis (The SPIRIT FIRST Trial) EuroInterv. 2007;3:206–212. PubMed

Fajadet J, Wijns W, Laarman GJ, et al. Randomized, double-blind, multicenter study of the Endeavor zotarolimus-eluting phosphorylcholine-encapsulated stent for treatment of native coronary artery lesions: clinical and angiographic results of the ENDEAVOR II trial. Circulation. 2006;114:798–806. PubMed

Mauri L, Massaro JM, Jiang S, et al. Long-term clinical outcomes with zotarolimus-eluting versus bare-metal coronary stents. J Am Coll Cardiol Intv. 2010;3:1240–1249. PubMed

Cosgrave J, Melzi G, Biondi-Zoccai GGL, et al. Drug-eluting stent restenosis the pattern predicts the outcome. J Am Coll Cardiol. 2006;47:2399–2404. PubMed

El-Hayek G, Bangalore S, Casso Dominguez A, et al. Meta-analysis of randomized clinical trials comparing biodegradable polymer drug-eluting stent to second-generation durable polymer drug-eluting stents. JACC Cardiovasc Interv. 2017;10:462–473. PubMed

Nakazawa G, Otsuka F, Nakano M, et al. The Pathology of neoatherosclerosis in human coronary implants bare-metal and drug-eluting stents. J Am Coll Cardiol. 2011;57:1314–1322. PubMed PMC

Alfonso F, Byrne RA, Rivero F, et al. Current treatment of in-stent restenosis. JACC. 2014;63:2659–2673. PubMed

Kastrati A, Mehilli J, Dirschinger J, et al. Restenosis after coronary placement of various sent types. Am J Cardiol. 2001;87:34–39. PubMed

Yoshitomi Y, Kojima S, Yano M, et al. Does stent design affect probability of restenosis? A randomized trial comparing multilink stents with GFX stents. Am Heart J. 2001;142:445–451. PubMed

Pache J, Kastrati A, Mehilli J, et al. Intracoronary stenting and angiographic results: Strut thickness effect on restenosis outcome (ISAR-STEREO-2) trial. J Am Coll Cardiol. 2003;41:1283–1288. PubMed

Kastrati A, Schomig A, Elezi S, et al. Predictive factors of restenosis after coronary stent placement. J Am Coll Cardiol. 1997;30:1428–1436. PubMed

Jukema JW, Verschuren JJ, Ahmed TA, et al. Restenosis after PCI. Part 1: pathophysiology and risk factors. Nat Rev Cardiol. 2012;9:53–62. PubMed

Elezi S, Kastrati A, Pache J, et al. Diabetes mellitus and the clinical and angiographic outcome after coronary stent placement. J Am Coll Cardiol. 1998;32:1866–1873. PubMed

Kastrati A, Dibra A, Mehilli J, et al. Predictive factors of restenosis after coronary implantation of sirolimus- or paclitaxel-eluting stents. Circulation. 2006;113:2293–2300. PubMed

Kobayashi Y, De Gregorio J, Kobayashi N, et al. Stented segment length as an independent predictor of restenosis. J Am Coll Cardiol. 1999;34:651–659. PubMed

Jones GT, Tarr GP, Phillips LV, et al. Active matrix metalloproteinases 3 and 9 are independently associated with coronary artery in-stent restenosis. Atherosclerosis. 2009;207:603–607. PubMed

Tarr GP, Williams GT, Wilkins VHT, et al. Intra-individual changes of active matrix metalloproteinase-9 are associated with clinical in-stent restenosis of bare metal stents. Cardiology. 2013;124:28–35. PubMed

Katsaros KM, Kastl SP, Zorn G, et al. Increased restenosis rate after implantation of drug-eluting stents in patients with elevated serum activity of matrix metalloproteinase-2 and -9. J Am Coll Cardiol Intv. 2010;3:90–97. PubMed

Sampietro ML, Pons D, de Knijff P, et al. A genome wide association analysis in the GENDER study. Neth Heart J. 2009;17:262–264. PubMed PMC

Verschuren JJW, Trompet S, Postmus I, et al. Systematic testing of literature reported genetic variation associated with coronary restenosis: results of the GENDER Study. PLoS One. 2012;7:e42401. PubMed PMC

Pocock SJ, Lansky AJ, Mehran R, et al. Angiogaphic surrogate end points in drug-eluting stent trials. JACC. 2008;51:23–32. PubMed

Cutlip DE, Windecker S, Mehran R, et al. Clinical end points in coronary stent trials. A case for standardized definitions. Circulation. 2007;115:2344–2351. PubMed

Mauri L, Orav EJ, Kuntz RE. Late loss in lumen diameter and binary restenosis for drug-eluting stent comparison. Circulation. 2005;111:3435–3442. PubMed

Garcia-Garcia HM, Shen Z, Piazza M. Study of restenosis in drug eluting stents: new insights from greyscale intravascular ultrasound and virtual histology. EuroInterv. 2009;5(Suppl D):D84–D92. PubMed

Kasaoka S, Tobis JM, Akiyama T, et al. Angiographic and intravascular ultrasound predictors of in-stent restenosis. J Am Coll Cardiol. 1998;32:1630–1635. PubMed

Sonoda S, Morino Y, Ako J, et al. Impact of final stent dimensions on long-term results following sirolimus-eluting stent implantation: serial intravascular ultrasound analysis from the SIRIUS trial. J Am Coll Cardiol. 2004;43:1959–1963. PubMed

Gonzalo N, Serruys PW, Okamura T, et al. Optical coherence tomography patterns of stent restenosis. Am Heart J. 2009;158:284–293. PubMed

Rixe J, Achenbach S, Ropers D, et al. Assessment of coronary artery stent restenosis by 64-slice multi-detector computed tomography. Eur Heart J. 2006;27:2567–2572. PubMed

Andreini D, Pontone G, Mushtaq S, et al. Coronary in-stent restenosis: assessment with CT coronary angiography. Radiology. 2012;265:410–417. PubMed

Mahnken AH. CT imaging of coronary stents: past, present, and future. ISRN Cardiol. 2012;2012:139823. PubMed PMC

Sun Z, Davidson R, Lin CHS. Multi-detector row CT angiography in the assessment of coronary in-stent restenosis: A systematic review. Eur J Radiol. 2009;69:489–495. PubMed

Sun Z, Almutairi AMD. Diagnostic accuracy of 64 multislice CT angiography in the assessment of coronary in-stent restenosis: A meta-analysis. Eur J Radiol. 2010;73:266–273. PubMed

Kumbhani DJ, Ingelmo CP, Schoenhagen P, et al. Meta-analysis of diagnostic efficacy of 64-slice computed tomography in the evaluation of coronary in-stent restenosis. Am J Cardiol. 2009;103:1675–1681. PubMed

Bainey KR, Norris CM, Graham MM, et al. Clinical in-stent restenosis with bare metal stents: Is it truly a benign phenomenon? Int J Cardiol. 2008;128:378–382. PubMed

Alfonso F, Zueco J, Cequier A, et al. A randomized comparison of repeat stenting with balloon angioplasty in patients with in-stent restenosis. J Am Coll Cardiol. 2003;42:796–805. PubMed

Albiero R, Silber S, Di Mario C, et al. Cutting balloon versus conventional balloon angioplasty for the treatment of in-stent restenosis: Results of the restenosis cutting balloon evaluation trial (RESCUT) J Am Coll Cardiol. 2004;43:943–949. PubMed

vom Dahl J, Dietz U, Haager PK, et al. Rotational atherectomy does not reduce recurrent in-stent restenosis results of the angioplasty versus rotational atherectomy for treatment of diffuse in-stent restenosis trial (ARTIST) Circulation. 2002;105:583–588. PubMed

Holmes DR, Jr, Teirstein P, Satler L, et al. Sirolimus-eluting stents vs vascular brachytherapy for in-stent restenosis within bare-metal stents: the SISR randomized trial. JAMA. 2006;295:1264–1273. PubMed

Stone GW, Ellis SG, O'Shaughnessy CD, et al. Paclitaxel-eluting stents vs. vascular brachytherapy for in-stent restenosis within bare-metal stents: The TAXUS V ISR Randomized Trial. JAMA. 2006;295:1253–1263. PubMed

Kastrati A, Mehilli J, von Beckerath N, et al. A. Sirolimus-eluting stent or paclitaxel-eluting stent vs balloon angioplasty for prevention of recurrences in patients with coronary in-stent restenosis: A randomized controlled trial. JAMA. 2005;293:165–171. PubMed

Alfonso F, Pérez-Vizcayno MJ, Hernandez R, et al. A Randomized comparison of sirolimus-eluting stent with balloon angioplasty in patients with in-stent restenosis results of the restenosis intrastent: balloon angioplasty versus elective sirolimus-eluting stenting (RIBS-II) trial. J Am Coll Cardiol. 2006;47:2152–2160. PubMed

Belkacemi A, Agostoni P, Voskuil M, et al. Drug-eluting balloons in coronary artery disease– current and future perspectives. ICR. 2011;6:157–160.

Scheller B, Speck U, Abramjuk C, et al. Paclitaxel balloon coating, a novel method for prevention and therapy of restenosis. Circulation. 2004;110:810–814. PubMed

Cortese B, Bertoletti A. Paclitaxel coated balloons for coronary artery interventions: A comprehensive review of preclinical and clinical data. Int J Cardiol. 2012;161:4–12. PubMed

Cremers B, Toner JL, Schwartz LB, et al. Inhibition of neointimal hyperplasia with a novel zotarolimus coated balloon catheter. Clin Res Cardiol. 2012;101:469–476. PubMed

Speck U, Scheller B, Abramjuk C, et al. Inhibition of restenosis in stented porcine coronary arteries: uptake of Paclitaxel from angiographic contrast media. Invest Radiol. 2004;39:182–186. PubMed

Chin K. In-stent restenosis: the gold standard has changed. EuroInterv. 2011;7:K43–K46. PubMed

Scheller B, Hehrlein C, Bocksch W, et al. Treatment of coronary in-stent restenosis with a paclitaxel-coated ballon catheter. N Engl J Med. 2006;355:2113–2124. PubMed

Scheller B, Hehrlein C, Bocksch W, et al. Two year follow-up after treatment of coronary in-stent restenosis with a paclitaxel-coated balloon catheter. Clin Res Cardiol. 2008;97:773–781. PubMed

Unverdorben M, Vallbracht C, Cremers B, et al. Paclitaxel-coated balloon catheter versus paclitaxel-coated stent for the treatment of coronary in-stent restenosis. Circulation. 2009;119:2986–2994. PubMed

Alfonso F, Fernandez C. Second-generation drug-eluting stents. Moving the field forward. J Am Coll Cardiol. 2011;58:26–29. PubMed

Lee MS, Yang T, Mahmud E, et al. Clinical outcomes in the percutaneous coronary intervention of in-stent restenosis with everolimus-eluting stents. J Invasive Cardiol. 2014;26:420–426. PubMed

Almalla M, Schröder JW, Pross V, et al. Everolimus-eluting versus paclitaxel-eluting stents for treatment of bare metal stent restenosis. Am J Cardiol. 2011;108:518–522. PubMed

Markovic S, Paliskyte R, Rottbauer W, et al. Everolimus-eluting stents compared with paclitaxel-eluting stents for treatment of coronary in-stent restenoses. Cardiovasc Revasc Med. 2012;13:307–310. PubMed

Alfonso F, Pérez-Vizcayno MJ, Cárdenas A, et al. A randomized comparison of drug-eluting balloon versus everolimus-eluting stent in patients with bare-metal stent in-stent restenosis. JACC. 2014;63:1378–1386. PubMed

Pleva L, Kukla P, Kusnierova P, et al. Comparison of the efficacy of paclitaxel-eluting balloon catheters and everolimus-eluting stents in the treatment of coronary in-stent restenosis. The treatment of in-stent restenosis study. Circ Cardiovasc Interv. 2016;9:e003316. PubMed

Latib A, Mussardo M, Ielasi A, et al. Long-term outcomes after the percutaneous treatment of drug-eluting stent restenosis. J Am Coll Cardiol Intv. 2011;4:155–164. PubMed

Mehilli J, Byrne RA, Tiroch K, et al. Randomized trial of paclitaxel-versus sirolimus-eluting stents for treatment of coronary restenosis in sirolimus-eluting stents: the ISAR-DESIRE 2 (Intracoronary Stenting and Angiographic Results: Drug Eluting Stents for In-Stent Restenosis 2) study. J Am Coll Cardiol. 2010;55:2710–2716. PubMed

Alfonso F, Pérez-Vizcayno MJ, Dutary J, et al. Implantation of a drug-eluting stent with a different drug (switch strategy) in patients with drug-eluting stent restenosis. Results from a prospective multicenter study (RIBS III [Restenosis Intra-Stent: Balloon Angioplasty Versus Drug-Eluting Stent]) J Am Coll Cardiol Intv. 2012;5:728–737. PubMed

Rittger H, Brachmann J, Sinha AM, et al. A randomized, multicenter, single-blinded trial comparing paclitaxel-coated balloon angioplasty with plain balloon angioplasty in drug-eluting stent restenosis: the PEPCAD-DES study. J Am Coll Cardiol. 2012;59:1377–1382. PubMed

Xu B, Gao R, Wang J, et al. A prospective, multicenter, randomized trial of paclitaxel-coated balloon versus paclitaxel-eluting stent for the treatment of drugeluting stent in-stent restenosis: results from the PEPCAD China ISR trial. J Am Coll Cardiol Intv. 2014;7:204–211. PubMed

Habara S, Iwabuchi M, Inoue N, et al. A multicenter randomized comparison of paclitaxel-coated balloon catheter with conventional balloon angioplasty in patients with bare-metal stent restenosis and drug-eluting stent restenosis. Am Heart J. 2013;166:527–533. PubMed

Byrne RA, Neumann FJ, Mehilli J, et al. Paclitaxel-eluting balloons, paclitaxel-eluting stents, and balloon angioplasty in patients with restenosis after implantation of a drug-eluting stent (ISAR-DESIRE 3): a randomised, open-label trial. Lancet. 2013;381:461–467. PubMed

Wöhrle J, Zadura M, Möbius-Winkler S, et al. SeQuent Please World Wide Registry: Clinical results of SeQuent please paclitaxel-coated balloon angioplasty in a large-scale, prospective registry study. JACC. 2012;60:1733–1738. PubMed

Stella PR, Belkacemi A, Waksman R, et al. The Valentines Trial: results of the first one week worldwide multicentre enrolment trial, evaluating the real world usage of the second generation DIOR paclitaxel drug-eluting balloon for in-stent restenosis treatment. EuroInterv. 2011;7:705–710. PubMed

Loh JP, Pieter R, Stella PR, et al. Paclitaxel-coated balloon for the treatment of drug-eluting stent restenosis: subanalysis results from the Valentines I trial. Cardiovasc Revasc Med. 2014;15:23–28. PubMed

Naganuma T, Latib A, Costopoulos C, et al. Drug-eluting balloon versus second-generation drug-eluting stent for the treatment of restenotic lesions involving coronary bifurcations. EuroInterv. 2016;11:989–995. PubMed

Kereiakes DJ, Meredith IT, Windecker S, et al. Efficacy and safety of a novel bioabsorbable polymer-coated, everolimus-eluting coronary stent: the EVOLVE II randomized trial. Circ Cardiovasc Interv. 2015;8:e002372. PubMed

Hong SJ, Ahn CM, Kim BK, et al. Prospective randomized comparison of clinical and angiographic outcomes between everolimus-eluting vs. zotarolimus-eluting stents for treatment of coronary restenosis in drug-eluting stents: intravascular ultrasound volumetric analysis (RESTENT-ISR trial) Eur Heart J. 2016;37:3409–3418. PubMed

Nijhoff F, Stella PR, Troost MS, et al. Comparative assessment of the antirestenotic efficacy of two paclitaxel drug-eluting balloons with different coatings in the treatment of in-stent restenosis. Clin Res Cardiol. 2016;105:401–411. PubMed PMC

Pleva L, Kukla P, Zapletalova J, et al. Efficacy of a seal-wing paclitaxel-eluting balloon catheters in the treatment of bare metal stent restenosis. BMC Cardiovasc Disor. 2017;17:168. PubMed PMC

Assadi-Schmidt A, Mohring A, Liebsch E, et al. SeQuent Please vs. Pantera Lux drug coated balloon angioplasty in real life: Results from the Düsseldorf DCB registry. Int J Cardiol. 2017;231:68–72. PubMed

Jamshidi P, Nyffenegger T, Sabti Z, et al. A novel approach to treat in-stent restenosis: 6- and 12-month results using the everolimus-eluting bioresorbable vascular scaffold. EuroInterv. 2016;11:1479–1486. PubMed

Moscarella E, Ielasi A, Granata F, et al. Long-term clinical outcomes after bioresorbable vascular scaffold implantation for the treatment of coronary in-stent restenosis a multicenter italian experience. Circ Cardiovasc Interv. 2016;9:e003148. PubMed

Capodanno D, Gori T, Nef H, et al. Percutaneous coronary intervention with everolimus-eluting bioresorbable vascular scaffolds in routine clinical practice: Early and midterm outcomes from the european multicenter GHOST-EU registry. EuroInterv. 2015;10:1144–1153. PubMed

Longo G, Granata F, Capodanno D, et al. Anatomical features and management of bioresorbable vascular scaffolds failure: a case series from the GHOST registry. Catheter and Cardiovas Interv. 2015;85:1150–1161. PubMed

Petretta M, Acampa W, Daniele S, et al. Long-term survival benefit of coronary revascularization in patients undergoing stress myocardial perfusion imaging. Circ J. 2016;80:485–493. PubMed

Baschet L, Bourguignon S, Marque S, et al. Cost-effectiveness of drug-eluting stents versus bare-metal stents in patients undergoing percutaneous coronary intervention. Open Heart. 2016:e000445. PubMed PMC