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