Vascular wall biology with current generation stents Professor Martin Bennett BHF Professor of Cardiovascular Sciences, Cambridge

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Late stent thrombosis - the extent of the problem OutcomeSESBMSRRR / p value PESBMSRR p value Late Loss % <0.001 TLR 1 4.1%16.6%75% < %11.3%73% <0.001 Death/MI %NS12.4%11.8%NS VLST 3 0.9%0.4%NS0.9%0.6%NS 1.Data from SIRIUS and TAXUS 4 randomised trials 2.Data from 4-year patient level pooled analysis 3.ARC definite or probable at 1-4 years

Malik, 2000 Effects of stent implantation on human arteries Lumen Stent Plaque

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

Processes needed to heal the plaque 1.Re-endothelialisation 2.Resolution of inflammation 3.Thrombus reorganisation 4.Smooth muscle cell proliferation 5.Smooth muscle cell matrix synthesis 6.Return of vasomotor regulation + Foreign body reaction due to polymers -giant cell inflammation Drug eluting stents can inhibit all these processes = LST

Re-endothelialisation in DES vs BMS cases Joner et al. JACC, 2006 BMS DES RabbitHuman Joner et al ATVB, 2007 Distal Middle (overlapping) Proximal 28-day Bx Velocity Cypher Express TaxusCypherTaxus 90-day Percentage endothelialisation Duration in months

Healing of DES and BMS at different times Joner et al. JACC, 2006; 48:193–202

Mechanism of LST in ostial and bifurcation stenting Joner et al. JACC, 2006; 48:193– 202

LAD Taxus stent 6m before death Joner et al. JACC, 2006; 48:193–202

What else is on the horizon ? 1.Antibody-CD31 coated stents to attracts ECs/EPCs (Genous stent) 2.Nanoparticle predisone stents to reduce inflammation 3.Biodegradable stents to reduce inflammation (BIOLIMUS) 4.Less potent anti-proliferatives 5.New / longer anti-platelets 6.Stents coated with anti-platelets / anticoagulants 7.Stent polymers mimicking EC matrix

So do second generation stents show less LST ? Genous stent - Healing 2 registry - 0.3% at 12M (TCT 2008) - TRIAS HR pilot - 0% vs 2% (PES) (Euro PCR 2008) Biolimus stent - LEADERS trial - 2.2% vs 2.6% SES (Lancet 2008) Everolimus stent - SPIRIT III trial 1.0% vs 1.7% PES at 2 yr (TCT 2008) Zotarolimus stent - SORT OUT III 1.2% vs 0.3%* SES (TCT 2008) - Endeavor IV 0.5% vs 0.9% PSE at 2 yr (TCT 2007/8)

Conclusions Stenting causes significant damage to the plaque - mechanism of efficacy Plaque repair uses multiple processes, all of which are inhibited by DES Next generation DES may reduce the impaired healing, but will not eradicate it. Considerable scope for DES development