Follow-up Clinico e Trattamento Post- Rivascolarizzazione Percutanea Giuseppe Biondi Zoccai University of Turin, Turin, Italy Marrakesh, 24 April SIROLIMUS-ELUTING STENTS FOR THE TREATMENT OF SIROLIMUS-ELUTING STENTS FOR THE TREATMENT OF BARE-METAL IN-STENT RESTENOSIS

DISCLOSURE Consultant: Boston Scientific, Cordis, genae, Invatec, Mediolanum Cardio Research Lecture fees: Bristol Myers Squibb

BARE SOME BARE FACTS BARE METAL STENT (BMS) IN-STENT RESTENOSIS (ISR) DRUG-ELUTING STENT (DES)

LEARNING GOALS What is the scope of BMS ISR? What are the early and mid-term results of DES treatment for BMS ISR? What are the long-term results of DES treatment for BMS ISR?

LEARNING GOALS What is the scope of BMS ISR? What are the early and mid-term results of DES treatment for BMS ISR? What are the long-term results of DES treatment for BMS ISR? How can we further improve current results?

SCOPE OF THE PROBLEM ISR following BMS implantation remains a relatively common occurrence, especially given the recently renewed interest in BMS ISR rates are even higher in diabetics, small vessels, long lesions, saphenous vein grafts and bifurcations The most effective treatment of ISR has been investigated for many years, but until recently PTCA and brachytherapy were the only recommended strategies, yet with largely disappoiting results

Articulation or gap Margin Focal body Multifocal FOCAL Intra-stentProliferative Total occlusion DIFFUSE Mehran R et al. Circulation 1999;100: PATTERNS OF RESTENOSIS VBTPTCA

PTCAELCARTBSTENT CUTTING BALLOON VBT DIABETES (%) LESION LENGTH (MM) FINAL %DS YEAR (%) SCOPE OF THE PROBLEM WHC Registry, RESCUT trial, and Gamma One trial

PTCAELCARTBSTENT CUTTING BALLOON VBT DIABETES (%) LESION LENGTH (MM) FINAL %DS YEAR (%) DIFFUSE OR HIGH- RISK ISR SCOPE OF THE PROBLEM WHC Registry, RESCUT trial, and Gamma One trial FOCAL OR LOW- RISK ISR

BRACHYTHERAPY: A NUCLEAR BOMB? Edge effects / recurrent restenosis Stent thrombosis

LEARNING GOALS What is the scope of BMS ISR? What are the early and mid-term results of DES treatment for BMS ISR? What are the long-term results of DES treatment for BMS ISR? How can we further improve current results?

DES REVOLUTION – EARLY REGISTRY DATA ON ISR TREATED WITH DES

SELECTION OF REGISTRIES StudyJournalYearNFollow- up (m) Death (%) MACE (%) MI (%) TVR (%) TLR (%) ST (%) BAR (%) German Cypher Registry Clin Res Cardiol Li et alChin Med J (Engl) Airoldi et alAm J Cardiol TRUEJ Am Coll Cardiol Ruchin et alHeart Lung Circ Bellandi et alItal Heart J Suppl Brambilla et alJ Cardiovasc Med Anderson et alInt J Cardiovasc Intervent ISR IICatheter Cardiovasc Interv Lee et alAm J Cardiol

ISAR-DESIRE Kastrati et al, JAMA 2005

ISAR-DESIRE 12-month follow-up Kastrati et al, JAMA 2005 IN-STENT LATE LOSS 0.10 mm in SES vs 0.26 mm in PES P=0.004 IN-SEGMENT LATE LOSS 0.32 mm in SES vs 0.55 mm in PES P=0.02

488 patients (40 sites) Beta-source VBT TAXUS-SR stent A Prospective, Randomized Trial Evaluating the Slow-Release Formulation TAXUS™ Paclitaxel-Eluting Coronary Stent in the Treatment of In-Stent Restenosis Primary endpoints: TVF at 9 months Angiographic: all patients at 9 months IVUS: 250 patients at 9 months Inclusion: Lesion length < 46 mm RVD > 2.5 mm and < 3.75 mm Randomized TAXUS V - ISR Stone et al, JAMA 2006

TAXUS V – ISR 9-month follow-up Stone et al, JAMA 2006

Primary 9 months Angiographic: all 6 months IVUS: 5-7 center 6 months Inclusion: Lesion length < 45 mm RVD > 2.75 mm and < 3.5 mm A Multicenter, Randomized Study of the Sirolimus-Eluting Bx Velocity ® Balloon Expandable Stent vs. Intravascular Brachytherapy in the Treatment of Patients with In-Stent Restnotic Coronary Artery Lesions SISR 400 patients (30 sites) Beta or gamma VBT Sirolimus- eluting Bx Randomized Holmes et al, JAMA 2006

SISR 9-month follow-up Holmes et al, JAMA 2006

RIBS II Aflsono et al, JACC 2006

RIBS II Alfonso et al, JACC 2006

ISR META-ANALYSIS – TARGET LESION REVASCULARIZATION Dibra et al, JACC 2007

ISR META-ANALYSIS – DEATH OR MYOCARDIAL INFARCTION Dibra et al, JACC 2007

ISR META-ANALYSIS – STENT THROMBOSIS Dibra et al, JACC 2007

LEARNING GOALS What is the scope of BMS ISR? What are the early and mid-term results of DES treatment for BMS ISR? What are the long-term results of DES treatment for BMS ISR? How can we further improve current results?

StudyJournalYearNFollow- up (m) Death (%) MACE (%) MI (%) TVR (%) TLR (%) ST (%) BAR (%) German Cypher Registry Clin Res Cardiol Li et alChin Med J (Engl) Airoldi et alAm J Cardiol TRUEJ Am Coll Cardiol Ruchin et alHeart Lung Circ Bellandi et alItal Heart J Suppl Brambilla et alJ Cardiovasc Med Anderson et alInt J Cardiovasc Intervent ISR IICatheter Cardiovasc Interv Lee et alAm J Cardiol SELECTION OF REGISTRIES

StudyJournalYearNFollow- up (m) Death (%) MACE (%) MI (%) TVR (%) TLR (%) ST (%) BAR (%) German Cypher Registry Clin Res Cardiol Li et alChin Med J (Engl) Airoldi et alAm J Cardiol TRUEJ Am Coll Cardiol Ruchin et alHeart Lung Circ Bellandi et alItal Heart J Suppl Brambilla et alJ Cardiovasc Med Anderson et alInt J Cardiovasc Intervent ISR IICatheter Cardiovasc Interv Lee et alAm J Cardiol SELECTION OF REGISTRIES

StudyJournalYearNFollow- up (m) Death (%) MACE (%) MI (%) TVR (%) TLR (%) ST (%) BAR (%) German Cypher Registry Clin Res Cardiol Li et alChin Med J (Engl) Airoldi et alAm J Cardiol TRUEJ Am Coll Cardiol Ruchin et alHeart Lung Circ Bellandi et alItal Heart J Suppl Brambilla et alJ Cardiovasc Med Anderson et alInt J Cardiovasc Intervent ISR IICatheter Cardiovasc Interv Lee et alAm J Cardiol SELECTION OF REGISTRIES

LONG-TERM EFFICACY - YES Lee et al, CCI 2008

LONG-TERM EFFICACY - YES Lee et al, CCI 2008 TLR MACE

LONG-TERM EFFICACY – NO? Sheiban et al, JCM 2008

LONG-TERM EFFICACY – NO? Sheiban et al, JCM 2008 Design: prospective multicenter (Turin, Milan) study of patients with in-stent restenosis treated with sirolimus-eluting stents Primary endpoint: freedom from major adverse cardiovascular events Follow-up: ≥24 months, with 6-month angiography planned for all patients N=271 – Average follow-up 28.3 months

LONG-TERM EFFICACY – NO? Sheiban et al, JCM 2008

LONG-TERM EFFICACY – NO? Sheiban et al, JCM 2008

LEARNING GOALS What is the scope of BMS ISR? What are the early and mid-term results of DES treatment for BMS ISR? What are the long-term results of DES treatment for BMS ISR? How can we further improve current results?

POSSIBLE MECHANISMS OF RECURRENT FAILURE Asymmetric strut distribution Drug failure or resistance Incomplete re-endothelialization Polymer disruption Polymer (or drug) hypersensitivity Peri-stent vessel wall injury Stent fracture Stent under-expansion

GEOGRAPHY MATTERS

IMPACT OF IVUS EJVES 2007

IMPACT OF IVUS

3,535 patients (5,046 lesions) treated with DES Roy et al, AJC 2007

DRUG-ELUTING BALLOON: THE PEPCAD-2 ISR STUDY Unverdorben. ACC 2008 End points Paclitaxel-coated balloon Taxus stent p Intention-to-treat analysis n=66n=65 Late lumen loss (mm) Binary in-segment restenosis (%) TLR (%) MACE (%) Per-protocol analysis n=66n=60 Late lumen loss (mm) Binary in-segment restenosis (%) TLR (%) MACE (%)

ANY ROLE FOR ORAL ANTI- RESTENOTIC DRUG THERAPY? Review:Cilostazol in patients treated with drug-eluting stents Comparison:Cilostazol versus control in patients treated with drug-eluting stents Outcome:Binary angiographic restenosis Study Cilostazol Control Peto OR or sub-category n/N 95% CI DECLARE-Long 14/250 23/ [0.30, 1.16] CIDES 9/113 20/ [0.22, 1.02] DECLARE-DIABETES 13/200 26/ [0.25, 0.93] Total (95% CI) [0.34, 0.77] Total events: 36 (Cilostazol), 69 (Control) Test for heterogeneity: P = 0.87, I² = 0% Test for overall effect: P = Favours cilostazol Favours control Biondi-Zoccai et al, AHJ 2008

IN CASE OF RECURRENT FAILURE? GISE-CROSS Costa, AHJ 2007

TAKE HOME MESSAGES

Currently available studies (including RCTs) indicate that DES provide favorable results for the treatment of ISR at both short and mid- term Long-term data are preliminary, with some studies suggesting the presence of a late catch-up phenomenon long after DES implantation, especially in higher risk patients (eg diabetics or post-VBT) These issues will have to be addressed by long-term follow-up of RCTs

TAKE HOME MESSAGES In the meanwhile, technique remains paramount: a) sizing appropriately the stent, b) avoiding inter-stent gaps, c) aiming for full lesion coverage, d) high pressure dilation IVUS proves essential to identify the mechanism of restenosis and ensure adequate stenting Additional treatments, eg drug-eluting balloons or oral anti-restenotic therapy, could be envisioned in the future

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