The Role of Platelets in Atherothrombosis

1
The Role of Platelets in Atherothrombosis
Adhesion
Aggregation (GP IIb/IIIa Inhibitors)
1
3
Activated Gpllb/llla
Fibrinogen
Platelets
von Willebrand Factor/Gplb bind
Collagen Gpla/lla bind
Lipid core
Platelet Plug
Activation (Clopidogrel)
2
4
Thrombin
PF4
ADP
CD 40 ligand
5 HT
thrombospondin
TXA2
TGF-B
Kumar A et al. Exp Opin Invest Drugs.
1997612571267.
2
IV Gp IIb/IIIa Inhibitors in ACS Death or MI at
30 Days (N31,402)
95 CI
Placebo
IV Gp IIb/IIIa
Study
Odds Ratio
PRISM 7.1 5.8 0.80
0.60-1.06 PRISM-PLUS 12.0 ()
8.7 0.70 0.50-0.98
(
) 13.6 1.17 0.80-1.70 PARAGON-A
11.7 (l) 10.3 0.87
0.58-1.29
(h) 12.3 1.06
0.72-1.55 PURSUIT 15.7 (l)
13.4 0.83 0.70-0.99

(h) 14.2 0.89 0.79-1.00 PARAGON-
B 11.4 10.6 0.92
0.77-1.09 GUSTO-IV 8.0 (24h) 8.2
1.02 0.83-1.24
(48h) 9.1
1.15 0.94-1.39 Overall 11.8
10.8 0.91 0.85-0.99
0.0
1.0
2.0
P.015
Placebo Better
Gp IIb/IIIa Better
without heparin, with/ without heparin (l)
low dose, (h) high-dose Boersma, E. et al.
Lancet. 2002359189-198.
Odds Ratio (95 CI)
srm
3
IV GP IIb/IIIa Inhibitors in ACS Death or MI
(at 30 d) Subgroup Results
Boersma, E. et al. Lancet. 2002359
4
IV GP IIb/IIIa Antagonists in ACSDeath or MI (at
30d) by PCI/CABG lt 5 days
P0.001
PNS
Interaction p lt 0.02
N25,555
N5847
Boersma et al. Lancet 2002 359 189b
5
IV Gp IIb/IIIa Inhibitors in ACS Major Bleeding
at 30 Days
Odds Ratio
95 CI
Study
Placebo
IV Gp IIb/IIIa

• PRISM 1.2
  1.7 1.36 0.76-2.43
• PRISM-PLUS 2.0 3.0
  1.50 0.78-2.86
• PARAGON-A 0.7 1.3
  2.02 0.58-7.03
• PURSUIT 0.9
  1.1 1.33 0.75-2.34
• PARAGON-B 1.0 1.7
  1.79 1.10-2.93
• GUSTO-IV 2.8
  4.7 1.72 1.28-2.32
• Overall 1.4
  2.4 1.62 1.36-1.94

without heparin, with/ without heparin major
bleeding for all low dose treatment Boersma, E.
et al. Lancet. 2002359189-198.
srm
6
Death During Follow-up Period
Odds Ratio 95 CI
Placebo
Fiban
N
Trial
7,232
EXCITE
0.3
0.7
2.14
Xemilofiban
OPUS
1.4
2.0
10,302
1.40
Orbofiban
9,169
SYMPHONY
1.8
2.0
1.14
Sibrafiban
2nd SYMPHONY
1.3
2.1
6,637
1.55
Sibrafiban
Pooled
1.3
1.7
33,340
p 0.002
1.37
0.5
1
1.5
2
0
Fiban Worse
Fiban Better
p 0.588 Breslow-Day heterogeneity
Chew DP, Bhatt DL, Sapp S, and Topol EJ.
Circulation. 2001103201-206.
Chew DP, Bhatt DL, Sapp S, and Topol EJ.
Circulation. 2001103201-206.
7

Synergistic Antithrombotic Effect of Clopidogrel
Plus Aspirin in Humans
Ex vivo study of collagen-induced thrombus
formation in 18 healthy volunteers at day 10
6
Baseline
ASA 325mg
5
C 75mg ASA 325mg
4
C 300mg ASA 325mg
3
Platelet deposition (x10-7/cm2)
2


1
0
Baseline
ASA
C75ASA
C300ASA
p lt0.01 vs ASA.
Cadroy et al. Circulation. 20001012823-2828.
8
Rapid Platelet Inhibition ofClopidogrel 375 mg
Loading Dose
100
91
85
80
80
79
80
68
55
60
Percent () Inhibition (5 mcM ADP)
40
19
20
0
0
Day 1,
Day 1,
Day 1,
Day 1,
Day 1,
Day 2
Day 3
Day 5
Day 10
0hr
0.5hr
1.0hr
2.0hr
5.0hr
Clopidogrel 75mg/d given on days 2-10. Bachmann
F et al. Eur Heart J. 199617(suppl)263.
Abstract.
9
Efficacy of Dual Antiplatelet Therapy vs ASA
alone in Reducing Coronary Events after Stenting
Death or MI
Study
Odds Ratio
95 CI
HALL (1996)
0.17 0.25 0.23
0.01-0.72 0.10-0.63 0.11-0.49
STARS (1998)
Total
P0.0001
0.1
1.0
10.0
ASA alone Better
ASA Ticlopidine Better
Test for heterogeneity P0.66 STARS was a 3 arm
trial. Data for aspirin ticlopidine vs aspirin
alone were used for this analysis. Mehta et
al. for The CURE Study Investigators. Eur. Heart
J. 21 24, 2000.
10
Efficacy of Dual Antiplatelet Therapy vs Warfarin
and ASA in Reducing Coronary Events after Stenting
Death or MI
Study
Odds Ratio
95 CI
ISAR (1996)
0.31 0.32 0.61 0.66 0.51
0.11-0.91 0.11-0.91 0.26-1.43 0.33-1.30 0.33-0.78
STARS (1998)
MATTIS (1998)
FANTASTIC (1998)
Total
P0.002
0.1
1.0
10.0
ASA Oral Anticoagulation Better
ASA Ticlopidine Better
Test for heterogeneity P0.51 STARS was a 3 arm
trial. Data for aspirin ticlopidine vs aspirin
Mehta et al. for The CURE Study
Investigators. Eur. Heart J. 21 24, 2000.
11
MI/Stroke/CV Death/Severe Ischemia
Within 24 hrs of Randomization
Cumulative Hazard Rates
0.025
Placebo ASA
0.020
34 Relative RiskReduction
0.015
Clopidogrel ASA
0.010
0.005
RR 0.66
0.003
p
0.0
0
2
4
6
8
10
12
14
16
18
20
22
24
Hours After Randomization
Mehta SR et al. AHA, 2002
12
Interventions Associated with Refractory Ischemia
in Hospital
13
Benefit of Clopidogrel stratified by TIMI Risk
Score
ARR 1.6 1.6 4.8
P0.003
P0.02
P0.03
N3276
N7297
N1989
Budaj et .al Circulation, In Press
14
CV Death/MI/Stroke by Revascularization
15
Type of MI
16
Prevention of large MI, thrombolytic use and new
onset CHF after randomizaton
Relative Risk Reduction
Placebo ASAN 6303
Clopidogrel ASAN 6259
P value
Outcome

• Q-wave MI 3.1 1.9 40 lt0.001
• Thrombolytics 2.0 1.1 43 lt 0.001
• Heart Failure 4.4 3.7 18 0.03

In addition to other standard therapies
Radiologically confirmed
17
During Initial Hospitalization
18
CV Death/MI Among Patients Undergoing Early PCI
(lt 72 Hrs)
RRR 38
RRR 29
N544
N2114
Mehta, SR. et al for the CURE Trial
Investigators. Lancet. August 2001212033-41.
19
CV Death or MI at Various Intervals

• PCI-CURE

RRR 31 32 34 21

P0.002
Mehta, SR. et al for the CURE Trial
Investigators. Lancet. August 2001212033-41.
20
Benefit/Risk Ratio
Yusuf, Mehta. N Eng J Med 2002 correspondence
21
CURE Study Definition of Bleeding

• Bleeding was defined as Major or Minor
• Major bleeding was defined as follows
• requiring at least 2 units of blood,
  substantially disabling, or intraocular bleeding
  leading to vision loss
• Major Bleeding was sub-categorized as
  life-threatening if it was fatal, symptomatic
  intracranial hemorrhage, leading to a drop in
  hemoglobin of at least 5 g/dL, significant
  hypotention requiring IV inotropes, requiring
  surgical intervention, or requiring transfusion
  of 4 or more units of blood
• Minor
• any other bleeds that led to interruption of
  study medication

The CURE Trial Investigators. N Engl J Med.
2001345494-502.
22
TIMI Major Bleeding / GUSTO Severe-Life-Threateni
ng Bleeding Criteria
23
Life Threatening Bleeding
24
All Major/LT Bleeding in Pts with CABG Surgery
25
Major/Life-Threatening Bleeds within 7 Days of
CABG Surgery
26
Bleeding by GP IIb/IIIa Use
Events
27
Number and Proportion of Patients Undergoing
Cardiac Procedures in ACS Trials
SMR
28
Relative Benefits of Different Interventions in
ACS By Time (Death/MI)
Long term benefits from lipid lowering and
ACE-inhibitor therapy
29
Risk-Benefit Analysis of Clopidogrel versus IV GP
IIb/IIIa in ACS
Active Placebo ARR P value


Yusuf S, Mehta SR. N Engl J Med 2002
(correspondence). Boersma, E. et al. Lancet.
2002359189-198
30
Benefit-Risk Comparison of Antithrombotic
Therapies vs Placebo in UA/NSTEMI
Treatment Major
Duration N Death or MI Bleeding
1. Antithrombotic Trialists Collaboration. BMJ
200232471-86 2. The CURE Trial Investigators.
NEJM 2001345494-502. 3. Frisc Investigators.
Lancet 1996347561-568. 3..4. Boersma E, et
al. Lancet 2002359189-198.
In addition to aspirin reported death or MI
at 150 days
Mehta SR. JACC 2002, In Press
31
Major Bleeding in IV GP IIb/IIIa Antagonists ACS
Trials vs CURE Within 30 Days
Active
Diff
Trial
N
Placebo

• CURE 12562 1.5 2.0 0.5
• IV GP IIb/ IIIa Trials
• PRISM-PLUS 1915 0.8 1.4 0.6
• PURSUIT 9375 9.1 10.6 1.5
• CAPTURE 1265 1.9 3.8 1.9

In addition to other standard therapies
including aspirin and heparin.
The CURE Trial Investigators. N Engl J Med.
2001345494-502. The PRISM-PLUS Study
Investigators. N Engl J Med. 19983381488-97.Th
e PURSUIT Trial Investigators. N Engl J Med.
1998339436-443.The CAPTURE Investigators.
Lancet. 19973491429-1435.
Mehta S. J Am Coll Cardiol. In Press
32
Role Of Antiplatelet Therapies In ACS

• Both ASA (RR of 40) and clopidogrel (RR of addl
  20) should be initiated early and continued long
  term, and are effective in addition to standard
  therapies (heparin, GP IIb/IIIa inhibitors and
  interventions)
• GP IIb/IIIa inhibitors (RR of 9 at 30 days) is
  best reserved for patients undergoing PCI
• All antiplatelet agents increase the risk of CABG
  related bleeds. Therefore an individualized
  approach (to the timing of CABG, continuation or
  discontinuation of the antiplatelet agents, the
  need for platelet transfusion) depending on the
  urgency of CABG and severity of CAD is needed
• Pre-treatment of patients with ASA and
  clopidogrel and periprocedural (PCI) use of IV GP
  IIb/IIIa inhibitors substantially reduces the
  risk of Death/MI

33
State of the Art Management ofnon-ST ? ACS

• Acute
• ASA Clopidogrel
• LMWH/UFH
• IV GP IIb/IIIa inhibitor during PCI for those
  undergoing an invasive strategy (moderate to high
  risk patients)
• Long Term
• ASA Clopidogrel for at least one year
• Planned program of secondary risk factor
  modification including smoking cessation, lipid
  lowering therapy, ACE inhibitor, BP and diabetic
  control, weight reduction

34
Implications of CURE and PCI CURE

• The results from both CURE and PCI CURE suggest
  that a broad range of patients with non-ST
  elevation ACS who present with ischemic ECG
  changes or positive enzymes will benefit with
  treatment with ASA and clopidogrel, in addition
  to other standard therapies, regardless of their
  baseline risk or management strategy