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The Pivotal Role of Platelets in The Pivotal Role of Platelets in Primary PCI Primary PCI
Paul Martin PhD
Senior Medical Affairs Scientist
Centocor/ Eli Lilly
UK/Eire/Nordic regions
Reperfusion…..by Design Reperfusion…..by Design Reperfusion…..by Design
No
. live
s s
aved
pe
r 10
00
pati
en
ts
tre
ate
d w
ithth
rom
bo
lyti
cs
(b
ase
d o
n 3
5-d m
ort
ality
ra
tes
)
Additional Lives Saved by Reducing Treatment Delay
Time from onset of symptoms (h) 0 - 1 1 - 2 2 - 3 3 - 6 6 - 12 12 - 24
Average delay (h) 0.75 1.60 2.17 4.03 8.37 18.00
Boersma E et al. Lancet. 1996;348:771-775.
70
60
50
40
30
20
10
0
Procoagulant Effects of Fibrinolytic TherapyProcoagulant Effects of Fibrinolytic Therapy
Adapted with permission from Moliterno DJ, Topol EJ. Thromb Haemost. 1997;78:214-219.
Fibrin-ThrombinPlateletsFibrin-Thrombin
FibrinolyticFibrinolyticThrombin increasesplatelet aggregationThrombin begets
thrombin
PlateletsActivated by fibrinolytic
Resistance tofibrinolysis PAI-1 Fibrinogen
Primary PCI2003 ESC AMI Guidelines
Evidence Level of Evidence
Recommendations
Class I APreferred treatment if performed by experienced team < 90 min after first medical contact.
Class I CIndicated for patients in shock and those with contraindications to fibrinolytic therapy
Class IClass IIa
AA
GP IIb/IIIa antagonists and primary PCI• no stenting• with stenting
European Heart Journal 2003;24:28-66.
Should the 90 min PCI window be Should the 90 min PCI window be extended?extended?
C o n s is t e n t A b i l i t y o f A b c ix im a b to C a u s e C o n s is t e n t A b i l i t y o f A b c ix im a b to C a u s e D e th r o m b o s is in A M I P a t ie n t sD e th r o m b o s is in A M I P a t ie n t s
D e th r o m b o s isD e th r o m b o s is
0
1 0
2 0
3 0
4 0
5 0
0 2 0 4 0 6 0 8 0 1 0 0
G o ld Z o r m a nG R A P E
T IM I-1 4
% T
IMI 3
Flo
w
*
** R e s u l ts w ith S t r e p to k in a s e f r o m M e ta -A n a ly s is (A H A 1 9 9 8 ; 9 8 : I - 7 8 4 A b s t r a c t N o . 4 1 0 8 )
A D M IR A L
S P E E D
S P E E D (6 0 m in )_C ir c . 2 0 0 0 ; 1 0 1 :2 7 8 8 -9 4 .
T IM I-1 4 (9 0 m in )C ir c . 1 9 9 9 ; 9 9 :2 7 2 0 -3 2 .
G R A P E (4 5 m in )J A C C 1 9 9 9 ; 3 3 :1 5 2 8 -3 2 .
Z o r m a n , e t a l. ( 3 8 m in )A J C 2 0 0 2 ; 9 0 :5 3 3 -3 6 .
A D M IR A L ( 3 6 m in )N E J M 2 0 0 1 ; 3 4 4 :1 8 9 5 -9 0 3 .
G o ld e t a l (1 0 m in )C ir c . 1 9 9 7 ; 9 5 : 1 7 5 5 -5 9 .
T im e to A n g io g r a p h y
30 Day Composite Endpoint Summary in 1° PCI30 Day Composite Endpoint Summary in 1° PCIDeath, MI or Urgent TVR
11.210.5
14.6
6.9
10.5
5.8 5.06.0
4.5 4.5
0
5
10
15
20
% o
f P
atie
nts
No AbciximabAbciximab
48%p = 0.03
52%p = 0.04
52%p = 0.01
30%p = 0.02
JACC 2000;35:915-21.
NEJM 2001;41:1895-03.
Circ 1998;98:734-41.
n = 401 n = 300 n = 2082n = 483ISAR-2 ADMIRAL CADILLAC*RAPPORT
57%p = 0.02
TCT 2002;Oral Pres.
n = 400ACE**
* CADILLAC includes ischemic stroke** ACE includes disabling stroke
High Risk PCI
adapted from NEJM 2002; 346:957-66
NNT ~20
FollowFollow--Up LV Function in Primary PCI TrialsUp LV Function in Primary PCI Trials
NEJM 2002; 346:957-66
Circ 98; 98: 2695-270155.9 57.0
60.562.2 61.1 61.6
50
55
60
65
70
75
80
ISAR-2 ADMIRAL CADILLAC
n = 72 n = 79 n = 151 n = 149 n = 109 n = 116
%
14 days 6 months 7 months
NEJM 2001; 41:1895-03Circ 1999; 98:2695-2601
No AbciximabAbciximab
High Risk PCI
p = 0.003 p = 0.05 p = 0.84
Mortality Outcomes through 1 YearACE
80
85
90
95
100
0 30 60 90 120 150 180 210 240 270 300 330 360
Su
rviv
al (
%)
p=.043
95 ± 2
89 ± 2
Stenting plus Abciximab
Stenting Alone
Time (days)
Dr Antonucci, Oral presentation, AHA 2003
5,6 %
Absolute
Reduction
NNT 18
Cardiogenic Shock Meta-analysis
Clinical Outcomes at 30 Days
43,4
19
1,7
25
35
4
0
10
20
30
40
50
All causeMortality
p<0.0001
Any Bleeding Major Bleeding
p=NSp<0.02
Control (n=226) Abciximab (n=240)
% o
f p
atie
nts
RR 42.4%AR 18.4%
Dr Phil Reid, Oral presentation, ESC 2003
NNT: 5
““Unless or until there are Unless or until there are new data available, we new data available, we should regard catheter-should regard catheter-based reperfusion with based reperfusion with adjunctive abciximab adjunctive abciximab
therapy as the preferred therapy as the preferred reperfusion therapy for reperfusion therapy for
acute MI.”acute MI.”
Topol, Neumann & Montalescot JACC 2003; Topol, Neumann & Montalescot JACC 2003; 42:1886-942:1886-9
Options for “Platelet” Facilitation
• Transfer + PCI – DANAMI 2 / FINESSE
• Lysis + PCI – GRACIA 1, 2
• Early ReoPro + PCI – ADMIRAL / FINESSE
• Early ReoPro Combo +PCI – BRAVE 1 / CARESS / FINESSE
SummarySummary
• Primary PCI with ReoPro remains the gold-standard
• Facilitated PCI strategy is a work in progress
• Pre-hospital/ early ReoPro …more data awaited from FINESSE
• The time-window of Primary PCI may be extended by ReoPro but Phase 3 data needed
• The platelet is pivotal to Prim. PCI outcomes !