Modern Treatment of Myocardial Infarction
AMI : Saving More Muscle
S W Davies C&W Oct 02
Historical Development : AMI Treatment
c 1960
adrenaline, lignocaine
E C massage
DC cardioversion
CCUs
Historical Development : AMI Theory
Heberden 1786
Herrick
1912
Falk, Davies
1980s
Historical Development : AMI Theory
Historical Development : AMI Treatment
c 1960
adrenaline, lignocaine
E C massage
DC cardioversion
c 1985
thrombolytics
CCUs
AMI Thrombolytic Treatment
aspirin + fibrinolytic
SK
tPA and developments
ISIS – 2
GISSI
Angios in Acute Ischaemia
after iv thrombolysis
AMI Thrombolytic Treatment
aspirin + fibrinolytic
SK
tPA and developments
1. novel agents
TNK - tPA
vampire bat !
2. adjunctive therapy
GpIIb / IIIa antiplatelets
hirudin
3. process
door-to-needle time, etc.
AMI Fibrinolytic Treatment
tPA - variations on molecular structure
Reteplase
Alteplase
Kringle 1
Kringle 2
EGF
Finger
Signal
Protease
Protease
527 amino acids MW 65,000
Mammalian cells (glycosylated)
Pennica et al. Nature. 1983;301;214-221.
Kohnert et al. Protien Eng. 1992;5:93-100.
355 amino acids MW 39,000
E coli cells (nonglycosylated)
Tebbe et al. Am J Cardiol. 1993;72:518-524.
Martin et al. Cardiovasc Drug Rev. 1993;11
Angios in Acute Ischaemia
after iv thrombolysis
Historical Development : AMI Treatment
c 1960
adrenaline, lignocaine
E C massage
c 1985
CCUs
angio
DC cardioversion
CABG
thrombolytics
PTCA
Historical Development : AMI Treatment
c 1960
adrenaline, lignocaine
E C massage
CCUs
angio
DC cardioversion
CABG
c 1985
thrombolytics
PTCA
1990s
primary PCI
new antiplatelet agents
PTCA with stent (PCI)
PCI in Acute Ischaemia
reperfusion → myocardial salvage
 acute risk HF, arrhythmia,
mechanical complications
 CHF
 re-infarction ??
rapid restoration of good flow (TIMI 3 at 60min.)
PCI in Acute Ischaemia
AMI trials PCI
Zwolle, Amsterdam
PAMI series → PAMI-Stent
CADILLAC, ADMIRAL
UA trials PCI
(ACS = UA + NSTEMI)
Fox KF et al
EurHJ 2001; 22: 192-195
PCI in Chronic Ischaemia
better perfusion → myocardial function
? ischaemic dysfunction
e.g.
? prevent future infarction
? hibernating myocardium
better flow / better flow reserve
on exercise
Is PCI getting better ??
 the rise of stents
 adjunctive drug therapy
? intravascular brachytherapy
? coated stents
? drug-eluting stents
niche devices :
DCA, X-ciser, cutting balloon
embolisation protection
The Problem of Restenosis
The Cell Cycle
Cytostatic v. Cytotoxic
Sirolimus inhibits Cell Cycle
→ blocks Neointimal Proliferation
Sirolimus Actions
• reduces inflammation after injury (1).
• inhibits VSMC migration (2).
• inhibits VSMC proliferation (3).
• inhibits extracellular matrix production (4).
• allows re-endothelialisation (1,5).
1. Suzuki T et al. Circulation 2001;104:1188-1193.
2. Sun J et al. Circulation 2001;103:2967-2972.
3. Marx SO et al. Circ. Res. 1995;76:412-417.
4. Buerke M et al. Eur Heart J. 2001;22:P1566(Abstr),280.
5. Gregory CR et al. Transplantation 1995;59(5):655-661.
Sirolimus - Coated Bx VELOCITY Stents
Stent Platform
With Sirolimus Coating
Drug – Eluting Polymer Coat
•
•
•
retain drug during implantation
achieve local therapeutic levels
continued elution through time
of peak cell proliferation
Sirolimus Coating Modulates Neointima
in 30 Day Porcine Coronary Model
Control
+ Sirolimus
Re-endothelialization of Sirolimus Stent
in 30-day Porcine Coronary Model
Endothelial Monolayer
lumen
vessel
40x
SIRIUS – Study Procedure
Pre-dilation
(balloons only)
Single de novo
native coronary
lesion
n = 1100 pts
Bx –
Sirolimus vs. non-coated
Post-dilation
(high pressure balloons)
SIRIUS Interim 400: Evolution of Events
SIRIUS Interim 400: Peri-stent restenosis @ 9m
P <0.001
CYPHER
Control
Restenosis Rate (%)
40
31.1
30
20
P = 1.00
10
5.7
P <0.001
5.8
5.5
2.0
2.0
0
Proximal
In-stent
Distal
RAVEL & SIRIUS Interim 400 : Key Outcomes
RAVEL (12m)
CYPHER™ Control
SIRIUS (9m)

CYPHER™
Control

Death
1.7
1.7
0
0.5
0.5
0
MI
3.4
3.4
0
3.7
3.3
-0.4
Clinical
TLR
0.8
13.6
12.8
4.7
16.7
12.0
0
26
26
2.0
31.1
29.1
1.4
28.6
27.2
2.1
31.0
28.9
In-stent
restenosis
Volume
Obstruction
All data as %
Current Trials of Drug – Eluting Stents
SIRIUS
randomized sirolimus-eluting stent in de novo coronary lesions
E-SIRIUS
randomized sirolimus-eluting stent in de novo coronary lesions
SIRIUS Bifurcations
randomized sirolimus-eluting stent in bifurcation lesions
SECURE
evaluation of sirolimus-eluting stent in end-stage disease (compassionate)
TAXUS-2
randomized slow-release and moderate-rate release polymer-based
taxol-eluting stents in de novo coronary lesions
TAXUS-4
randomized slow-release polymer-based taxol-eluting stent in de novo lesions
WISDOM
international transitional study of slow-release taxol stent
PATENCY
evaluation of nonpolymer-based taxol-eluting stent in de novo lesions
EASTER
evaluation of estradiol-eluting stent in de novo coronary lesions
( ORBIT
randomized oral rapamycin to prevent restenosis )
Saphenous Vein Grafts
• SVGs degenerate over time
– over 50% develop severe
stenosis within 10 years
• Repeat surgery is difficult
– high mortality rates
• Challenges for PCI
– embolization
– restenosis
– progression of disease
Distal Embolisation : AngioGuard
Covered Stent : Symbiot™
Cross-Section
self-expanding nitinol stent
sandwiched between 2 layers of ePTFE tubing
ultra-thin soft polymer 16μm
Symbiot™ Deployment Technique
Friable material
trapped behind cover
Symbiot™ Healing Response
neo-intima
Cross-Section
Porcine Carotid at 30 days
Lumen SEM
C-PORT - Primary Endpoint at 6 months
25
% of Patients
20
15
p = 0.03
19.9
Accel. t-PA (n=226) PCI (n=225)
Median Door to Needle Time =
46 min
p = 0.04
Median Door
to Balloon Time =
102 min
12.4
p = NS
10
7.1
6.2
10.6
5.3
5
0
Combined*
Death
Reinfarction
p = NS
4.0
2.2
Disabling
Stroke
JAMA 2002; 287:1943-51
Intention to Treat
Historical Development : AMI Treatment
c 1960
adrenaline, lignocaine
E C massage
CCUs
angio
DC cardioversion
CABG
c 1985
thrombolytics
PTCA
1990s
primary PCI
new antiplatelet agents
cardioprotective agents
Plaque → thrombosis → AMI
inactive & active platelets
(S.E.M.)
coronary artery
(L.M.)
necrotic myocardium
(L.M.)
Acute Myocardial Infarction : LV
apical infarct with clot
anterior aneurysm with clot
(P.M.)
(echo)
Reperfusion Therapy + ??
saving more muscle
 necrosis, apotosis
 stunning
 hibernation
 ischaemic injury + reperfusion injury
adjunctive therapy
Nicorandil - IONA trial
▪ stable angina + high risk features
▪ oral anti-anginal drugs (βblocker / LA nitrate / CCB)
▪ not currently for revascularisation
usual anti-anginals + nicorandil
10mg bd → 20mg bd
usual anti-anginals + placebo
UK
n=5126
mean 1.6 y
CHdeath + nonfatal MI + unplanned admission chest pain
Fox K et al
Lancet 2002
0.98
Nicorandil
0.94
0.96
(RRR = 21%, P=0.068)
0.92
Placebo
0.9
Proportion event free
1
IONA : CHD death or non-fatal MI
0
0.5
1
1.5
Years
2
2.5
3
Historical Development : AMI Treatment
c 1960
adrenaline, lignocaine
E C massage
CCUs
angio
DC cardioversion
CABG
c 1985
thrombolytics
PTCA
1990s
primary PCI
new antiplatelet agents
cardioprotective agents
Historical Development : AMI Treatment
c 1960
SUPPORTIVE THERAPY
adrenaline, lignocaine, frusemide. opiates
E C massage, DC cardioversion, temporary pacing wires, CCUs
c 1985
2002
REPERFUSION THERAPY
thrombolytics, aspirin
( rehab
PCI
( β-blockers, ACE-inhibitors
PCI coated stents ?
new antiplatelet ?
cardioprotective agents? statins ?