Drug Eluting Versus Bare Metal Stents Prof. Dr. Raouf Mahran ;MRCP Prof. of cardiovasc. Med National Heart Institute 2009

Evolution of PCI 1977: Balloon Angioplasty (POBA) 1994: Bare Metal Stent (BMS) 2003: Drug Eluting Stent (DES)

Coronary Angioplasty (PTCA) Andreas Gruntzig

Coronary Stenting Julio Palmaz

PCI Procedural refinements: Stents Expandable metal mesh tubes that buttresses the dilated segment, limit restenosis. Drug eluting stents: further reduce cellular proliferation in response to the injury of dilatation.

What is a Drug-Eluting Stent (DES)? DHHS/FDA/CDRH Example: Cordis’ Cypher™ Sirolimus-Eluting Coronary Stent Stent Platform & Delivery System Carrier(s)Drug Components

TAXUS Technology Binds tubulin Microtubular dynamics MulticellularMultifunctional Binds tubulin Microtubular dynamics MulticellularMultifunctional Paclitaxel Polymer Platform UniformityDurability Biphasic Controlled Release Kinetics UniformityDurability Express™ Stent Tandem Architecture Flexibility Maverick™ Balloon Deliverability Express™ Stent Tandem Architecture Flexibility Maverick™ Balloon Deliverability

Drug-Eluting Stents The “HOLY GRAIL” of interventional cardiology is a stent with optimal deliverability and scaffolding which is impervious to intimal hyperplasia

Reduced Restenosis - Efficacy –Goal = <10% restenosis frequency for all patient cohorts and all lesion subsets –Simulate normal wound healing with rapid endothelialization and minimal (? no) neointima formation Absence of Pathobiologic Responses - Safety –No early or late thrombosis –No “edge” hyperproliferative effects –No late aneurysms, delayed “catch-up” (late restenosis), accelerated atherosclerosis Clinical imperatives… Drug-Eluting Stents

Three Component System Stent design Pharmacologic agent Drug carrier vehicle Drug- Eluting Stent Drug-Eluting Stents

Neointimal Hyperplasia (30%) CausesCauses SolutionSolution 1.A stent to block recoil and remodeling 2.A therapeutic agent to prevent neointimal hyperplasia Why DES??- Coz of Restenosis - Causes & Solution Recoil & Negative Remodeling (70%)

Growth Factors / Cytokines Radiation Actinomycin D, (DNA) FKBP S G2G2 M cell cycle G0G0 Rapamycin and derivatives X Cell Division Smooth muscle cell Signal Transductio n Receptor TOR Activation p27, Cyclins/Cdks Paclitaxel, (microtubules) Therapeutic Mechanisms of Action G1G1

Stent Design… Optimized geometry for homogeneous drug distribution (closed vs. open cell designs, inter-strut distances) Circumferential stent-vessel wall contact (to insure drug delivery) - conformability Enhanced radiopacity for precise placement (avoid overlap regions and inter-stent gaps) Maintained side-branch access Advanced deliverability to complex anatomies Drug-Eluting Stents

Drug Carrier Vehicle…requirements Non-inflammatory and non-thrombogenic Predictable drug elution kinetics (timing and dose) Elastomeric without surface integrity changes (e.g. cracking, peeling) No alteration of incorporated drug activity No alteration of the structural and operational stent characteristics Logistic factors – sterilization, stability, shelf-life, and expense Drug-Eluting Stents

Methods of Stent-Mediated Delivery

RAVEL-Study (ESC, Stockholm, September 2001) Cypher stents Bare Metal stents N = 118 N = 120 Patients Results after 12 months 0 % 26%Restenosis

SIRIUS - Study Flow All Randomized Patients n = 1101 All Randomized Patients n = 1101 Sirolimus-eluting Bx VELOCITY TM n = 533 Sirolimus-eluting Bx VELOCITY TM n = 533 Control Bx VELOCITY TM n = 525 Control Bx VELOCITY TM n = 525 Angio FU at 8 Months = 85.4% Clinical FU at 9 Months = 95.7% Angio FU at 8 Months = 85.4% Clinical FU at 9 Months = 95.7% Angio FU at 8 Months = 84.7% Clinical FU at 9 Months = 95.8% Angio FU at 8 Months = 84.7% Clinical FU at 9 Months = 95.8% De-registered Sirolimus-eluting Bx VELOCITY TM (n=23) De-registered Sirolimus-eluting Bx VELOCITY TM (n=23) De-registered Control Bx VELOCITY TM (n=20) De-registered Control Bx VELOCITY TM (n=20)

FIM- Two Sites, 45 patients 0% Restenosis RAVEL Multicenter, Randomized 238 patients 0% Restenosis SIRIUS 400- Multicenter, Randomized 400 pts 9.2% Restenosis SIRIUS Final Results 1058 pts 8.9% Restenosis The Realism of Drug Eluting Stents Than NOW Than First MACE at 24 Months 5/45=11.1% 5/45=11.1%

Current Indications for Drug- eluting Stents: 1. Why do we need DES ? 2. Which DES should we use ? 3. Indications for DES ?

Restenosis Elastic recoil: after balloon deflation, the large number of elastic fibers in the tunica media cause a mechanical collapse. Neointimal proliferation (NI): formation of an inner layer at the site of injury, composed of cells and ECM on the intimal surface Negative remodeling: constriction of the vessel by the formation of a fibrotic scar within the adventitia.

Intervention 2003 Stents: the dominant strategy in interventional cardiology Improved procedural safety Predictable angiographic results Better late outcomes (lower restenosis) Stents: the dominant strategy in interventional cardiology Improved procedural safety Predictable angiographic results Better late outcomes (lower restenosis)

Current Indications for Drug-eluting Stents: 1. Why do we need DES ? 2. Which DES should we use ? 3. Indications for DES ?

Streptomyces hygroscopicus Sirolimus (Rapamycin) Streptomyces hygroscopicus

Paclitaxel Taxus brevifolia

DES ever received CE-Certificate !

100 randomised DES Studies in Patients ABSOLUTE, ACTION, APPLAUSE, ASPECT, AVELLINO, BASKET, BBK, BRADES, CACTUS, CARDIA, CHINA-1, CHINA-2, CHREDIT, CORPAL, CORPAL-Bif-1, CORPAL-Bif-2, COSTAR-II, C-SIRIUS, Cypher/ BeStent, Cypher/Vision, DEDICATION-DES, DECODE, DELIVER-I, DESSERT, DEXA, DEXAMET, DIABETES, EAGLE, ELUTES, ENDEAVOR-II, ENDEAVOR-III, ENDEAVOR-IV, E-SIRIUS, ESTRADIOL, ETHOS-I, EUROSTAR-II, FUTURE- I, FUTURE-II, GENESIS, GENOUS-STEMI, HAAMU, HORIZONS-AMI, ISAR- DESIRE, ISAR-DIABETICS, ISAR-LM, ISAR-PEACE, ISAR-SMART-3, ISAR- TEST, ISAR-TEST-3, JUPITER-II, LABEM, LEADERS, LONG-DES-II, MISSION, NOBORI-I Phase 1, NOBORI-I Phase 2, NORDIC-Bif-I, NORDIC- Bif-II, PAINT, PASSION, PATENCY, PISA-LAD, PRISON-II, PROSIT, RAPPAC, RAVEL, RIGA-LM, RRISC, REALITY, RIBS-II, SCANDSTENT, SCORE, SCORPIUS, SESAMI, SES-SMART, SEVILLA, SIRIUS, SIRIUS-Bif, SIRTAX, SISR, SORT-OUT-II, SORT- OUT-III, SOS, SPIRIT-I, SPIRIT-II, SPIRIT-III, STEALTH-I, STRATEGY, SYNTAX, TAXI, TAXUS-I, TAXUS-II, TAXUS-IV, TAXUS-V, TAXUS-V-ISR, TAXUS-VI, TYPHOON, ZEST, ZOOMAX-I, ZOOMAX-II

1. High Evidence (primary clinical endpoint reached)  Cypher Sirolimus  Taxus (Cordis / J&J) (Boston Scientific) Paclitaxel  Endeavor (Medtronic) Zotarolimus  Xience V / Promus (Abbott / Boston Sc.) Everolimus  Biomatrix (Biosensors/Krauth) Biolimus A9 2. Medium Evidence (primary surrogate reached)  Yukon (Translumina) Sirolimus  Nobori (Terumo) Biolimus A9

Current Indications for Drug-eluting Stents: 1. Why do we need DES ? 2. Which DES should we use ? 3. Indications for DES ?

NO Just Play it Smart Should We Use Drug-Eluting Stents in All Patients and in All Lesions?

Indications Anticipated Approval De-Novo Lesions Length mm Vessel sizes Not Approved (off label use)  Acute MI (Yes Recent data:Sirolimus), Acute Coronary Syndrome?  In-Stent Restenosis (ISAR 11 favours Sirolimus)  Bifurcations, long lesions>30 mm, small vessels< 2.5mm  SVG ??  Multivessel (Syntax approves LMS+1,2vessels).

DRUG COATED STENTS BETTER… Show me the Data ??? 1) Long lesion >18-50mm less Restenosis 2) Small vessel (<2.5mm) less Restenosis 3) Acute myocardial infarction Thrombosis? Sirolomus is safe(Recent publication!!).. Sirolomus is safe(Recent publication!!).. 10) Chronic occlusion No Data 4) Multi-vessel disease Syntax D/LMS+1.2,Vessels 5) Bifurcation less Restenosis 6) Main stem, settled following All Comapre!! 7) In-stent restenosis Mixed Results 8) Diabetes Restenosis less 9) Saphenous Vein Grafts No Data

Cypher sirolimus-eluting stent Primary Endpoint:  In-stent and late lumen loss at 9 months (determined by QCA) Secondary Endpoints:  MACE (cardiac death, MI, TLR) at 30 days, 9, 12, and 24 months  Mean in-stent and edge neointimal hyperplasia  Percent volume obstruction (determined by IVUS)  Complications Primary Endpoint:  In-stent and late lumen loss at 9 months (determined by QCA) Secondary Endpoints:  MACE (cardiac death, MI, TLR) at 30 days, 9, 12, and 24 months  Mean in-stent and edge neointimal hyperplasia  Percent volume obstruction (determined by IVUS)  Complications DIABETES trial Presented at TCT patients with type 2 diabetes (1/3 on insulin) and native coronary lesions appropriate for stent implantation Bare-metal stent

In Segment Restenosis Small Vessel Size and Diabetes

Secondary end points – Restenosis, TLR, MACE % TCT 2004 p=< p =<0.001 Angiographic restenosis, TLR, and overall MACE were significantly reduced. (Reduction in overall MACE was primarily due to the reduction in TLR – rates of cardiac death and MI were not significantly different between the two groups.)

In-stent and overall in-segment late lumen loss was significantly reduced in the drug eluting stent group. No significant difference was seen in the degree of late loss reduction between insulin- dependent patients (99% reduction) and patients on oral agents (72 % reduction.) Presented at ACC Scientific Sessions 2004 Primary End Point – Late Loss at 9 Months mm p=<0.0001

DIABETES trial – 9 month results Among patients with native coronary lesions and type 2 diabetes (insulin requiring and noninsulin requiring), treatment with a sirolimus-eluting stent was associated with a reduction in late loss (in-stent and in-segment) at 9 months compared with treatment with a bare stent Among patients with native coronary lesions and type 2 diabetes (insulin requiring and noninsulin requiring), treatment with a sirolimus-eluting stent was associated with a reduction in late loss (in-stent and in-segment) at 9 months compared with treatment with a bare stent Consistent with other drug-eluting stent trials, the sirolimus –eluting stent was not associated with a reduction in death or MI Consistent with other drug-eluting stent trials, the sirolimus –eluting stent was not associated with a reduction in death or MI A subanalysis of the SIRIUS trial showed that diabetics treated with a drug- eluting stent had significant reductions in TLR, MACE, late loss and restenosis compared with diabetics treated with bare stent, but the degree of improvement in diabetic patients was less than in nondiabetic patients, with no significant benefit in the insulin-dependent patients A subanalysis of the SIRIUS trial showed that diabetics treated with a drug- eluting stent had significant reductions in TLR, MACE, late loss and restenosis compared with diabetics treated with bare stent, but the degree of improvement in diabetic patients was less than in nondiabetic patients, with no significant benefit in the insulin-dependent patients The current trial showed no significant difference in late loss reduction between insulin-dependent and noninsulin-dependent diabetics, but the sample size of insulin-dependent patients (and the overall trial) was small The current trial showed no significant difference in late loss reduction between insulin-dependent and noninsulin-dependent diabetics, but the sample size of insulin-dependent patients (and the overall trial) was small Among patients with native coronary lesions and type 2 diabetes (insulin requiring and noninsulin requiring), treatment with a sirolimus-eluting stent was associated with a reduction in late loss (in-stent and in-segment) at 9 months compared with treatment with a bare stent Among patients with native coronary lesions and type 2 diabetes (insulin requiring and noninsulin requiring), treatment with a sirolimus-eluting stent was associated with a reduction in late loss (in-stent and in-segment) at 9 months compared with treatment with a bare stent Consistent with other drug-eluting stent trials, the sirolimus –eluting stent was not associated with a reduction in death or MI Consistent with other drug-eluting stent trials, the sirolimus –eluting stent was not associated with a reduction in death or MI A subanalysis of the SIRIUS trial showed that diabetics treated with a drug- eluting stent had significant reductions in TLR, MACE, late loss and restenosis compared with diabetics treated with bare stent, but the degree of improvement in diabetic patients was less than in nondiabetic patients, with no significant benefit in the insulin-dependent patients A subanalysis of the SIRIUS trial showed that diabetics treated with a drug- eluting stent had significant reductions in TLR, MACE, late loss and restenosis compared with diabetics treated with bare stent, but the degree of improvement in diabetic patients was less than in nondiabetic patients, with no significant benefit in the insulin-dependent patients The current trial showed no significant difference in late loss reduction between insulin-dependent and noninsulin-dependent diabetics, but the sample size of insulin-dependent patients (and the overall trial) was small The current trial showed no significant difference in late loss reduction between insulin-dependent and noninsulin-dependent diabetics, but the sample size of insulin-dependent patients (and the overall trial) was small

68 RECENT Recommendations for the use of stents in STEMI

69 Use of stents in STEMI NEW Recommendation It is reasonable to use a drug- eluting stent as an alternative to a bare-metal stent for primary PCI in STEMI * Consideration for the use of stents (DES or BMS) in STEMI should include the ability of the patient to comply with prolonged dual antiplatelet therapy, the bleeding risk in patients on chronic oral anticoagulation, and the possibility that the patient may need surgery during the ensuing year

70 Use of stents in STEMI MODIFIED Recommendation A DES may be considered for clinical and anatomic settings† in which the efficacy/safety profile appears favorable

Conclusions ● Progressive adoption of DES programmes is intuitively correct for physicians, patients and healthcare systems ● Changing referral patterns in favour of PCI/DES present a significant challenge to current and future resources ● Future developments seem unlikely to halt this advance ●Stent platforms – increased deliverability and decreased vascular injury ●Biodegradable polymers – no consequences of retained drug or polymer ●Pharmacokinetics – sustained drug release ●Combination therapy – directed luminal and abluminal release of vasculoprotective agents and cell cycle inhibitors

DES appears to have the edge over BMS in: 1-Diabetics: a)Less TLR, Less Restenosis rate, less Mace 2-In vessels 2.5 to 3.5mm up to 30 mm lenght: Less TLR,TVR,Mace. 3-In ISR: favouring Sirolimus in particular. 4-In LMS: In main Compare+Syntax Trials(growing Future Role)

Thank You 73

Intima Media Adventitia ANGIOPLASTY / STENT INSERTION Intimal and medial tears Acute stent-induced damage to the plaque Longitudinal translocation of plaque Embolisation of necrotic core Endothelial loss Necrotic core Fibrous cap Thrombosis

PCI Procedural refinements: Stents Expandable metal mesh tubes that buttresses the dilated segment, limit restenosis. Drug eluting stents: further reduce cellular proliferation in response to the injury of dilatation.

Stent releasing an antiproliferative drug