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

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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

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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

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** 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

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5

10

15

20

% o

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atie

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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 !