Vascular wall biology with current generation stents

Professor Martin BennettBHF Professor of Cardiovascular Sciences, Cambridge

NO CONFLICT OF INTEREST TO DECLARE

Late stent thrombosis - the extent of the problem

Outcome SES BMS RRR /

p value

PES BMS RR

p value

Late Loss1 0.17 1.0 0.001% 0.39 0.92 <0.001

TLR1 4.1% 16.6% 75%

<0.001

3.0% 11.3% 73%

<0.001

Death/MI2 11.65 10.4% NS 12.4% 11.8% NS

VLST3 0.9% 0.4% NS 0.9% 0.6% NS

1. Data from SIRIUS and TAXUS 4 randomised trials2. Data from 4-year patient level pooled analysis3. ARC definite or probable at 1-4 years

Malik, 2000

Effects of stent implantation on human arteries

Lumen

Stent

Plaque

IntimaMedia

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

Rabbit Human

Joner et al ATVB, 2007

Dis

tal

Mid

dle

(ove

rlapp

ing)

Pro

xim

al

28-day

Bx Velocity Cypher Express Taxus Cypher Taxus

90-day

Pe

rce

nta

ge

en

do

the

lialis

atio

n

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