Unresolved issues with Drug-eluting Stents Stent Thrombosis Advanced Angioplasty 2007 Dan Blackman Yorkshire Heart Centre

Conflicts of Interest Speakers Honoraria –Boston Scientific –St Jude –Nycomed Advisory Boards –St Jude –Nycomed –Lilly

Investigator-led meta-analyses ‘The ESC Firestorm’ Camenzind 5 Taxus and 4 Cypher RCTs. All published data to latest available f/up P=0.03 P=0.68

Investigator-led meta-analyses ‘The ESC Firestorm’ Nordman 16 RCTs (5 Taxus, 4 Cypher, 2 Cook, 5 independent*) Increased non-cardiac mortality with Cypher alone No difference in cardiac mortality or stent thrombosis * BASKET-LATE, ASPECT, SES-SMART, DIABETES, SCANDSTENT Eur Heart J 2006;27:

TCT Response Independent patient-level meta-analysis

ARC Definition patient level meta-analyses Definite or probable 1.5% 0.9% 1.5% 1.8% 0.7% 1.4% BMS (n=1397) BMS (n=870) BMS (n=594)

Off-label/Real-world DES thrombosis Washington Hospital Data 12 month outcome with ‘on-label’ (n=1773, 55%) vs ‘off-label’ (n=1365, 45%) DES use Off-label = >33mm, ISR, SVG, AMI, LMS, CTO Waksman R. FDA Hearing 12/06

Off-label/Real-world DES thrombosis Rotterdam/Bern Registry 8,146 consecutive (ALL) DES cases in Bern/Rotterdam Angiographically proven ST 90% of all DES patients complete clinical follow-up Wenaweser FDA Hearing 12/06 Lancet in press

Off-label/Real-world DES outcome BASKET-LATE 746 patients; 1133 lesions Randomised 2:1 DES:BMS in BASKET trial Event-free patients at 6/12 followed up to 18/12 ‘Real-world’ population –84% of all PCIs included –67% MVD; 58% STEMI/UA –27% ≤2,5mm; 2 stents/pt Increased late death/MI, though not all due to ST Overall death/MI equivalent J Am Coll Cardiol 2006;

Off-label/Real-world DES outcome Swedish PCI Registry 13,738 BMS DES implanted in Complete long-term f/up from National registry of MI, CABG, and death DES use in Sweden 62% → 26% from Jan 06 to Oct 06 Wallentin. FDA Hearing 12/06 Absolute excess mortality 0.3%

Off-label/Real-world DES outcome Duke Registry 3165 BMS implanted DES implanted Median follow-up 3.1 years Eisenstein. FDA Hearing. 12/06

Independent predictors of DES thrombosis OR 1 OR 2 OR 3 ST incidence PATIENT FACTORS Premature d/c antiplatelets STEMI7.53.8% Renal failure Reduced LVEF3.3 (<30%) 1.1/10%  Diabetes3.7 LESION FACTORS Bifurcation % (Crush) Vein graft6.3 In-stent restenosis4.5 LAD3.9  Stent length 1.06/mm PROCEDURAL FACTORS  Final atmospheres 0.28 Stent underexpansionp=0.03 Incomplete lesion coveragep=0.02

Reduced Aspirin and clopidogrel responsiveness are associated with stent thrombosis and worse outcome after PCI Study Platelet functionClinical Outcome 1.Barragan  P2Y 12 reactivity ratioStent thrombosis Cathet Cardiovasc Interven Ajzenberg  shear-induced platelet aggregationStent thrombosis J Am Coll Cardiol Gurbel  P2Y 12 reactivity ratio J Am Coll Cardiol 2005  ADP-induced aggregationStent thrombosis 4.Matzesky  ADP-induced aggregationMACE post PCI Circulation Gurbel  peri-procedural platelet aggregationMyonecrosis post PCI J Am Coll Cardiol Bliden  platelet aggregation pre-PCI1 year MACE post PCI J Am Coll Cardiol in press 7.Cuisset  platelet aggregation30 day MACE post PCI J Thromb Haemost LevClopidogrel/aspirin resistanceMyonecrosis post PCI J Am Coll Cardiol Hochholzer  platelet aggregation30 day MACE post PCI J Am Coll Cardiol 2006

How long should patients have clopidogrel after DES? Milan/Siegburg/Naples registry 3021 patients with 5389 lesions treated with DES Incidence of definite stent thrombosis assessed according to whether patient was on or off clopidogrel

Conclusions DES are associated with a small increase in very late stent thrombosis ‘On-label’ this increased risk of stent thrombosis is not associated with an increased risk of death or MI In more complex patients data are limited, but indicate that the risk of stent thrombosis is higher, and may be associated with an increase in death/MI The balance between restenosis risk and thrombosis risk should be considered when determining treatment, and stent, choice in individual patients Optimising stent expansion and lesion coverage is essential to minimise risk Ensuring compliance with clopidogrel for 12 months is vital. Longer-term clopidogrel is not supported by the evidence, but may be justified in the highest risk patients Platelet aggregation studies ± an increase in the dose of clopidogrel to 150mg/day should be considered in the highest risk patients Further studies are underway which will provide more information to guide future strategies