The Role of Platelets in Atherothrombosis Kumar A et al. Exp Opin Invest Drugs. 1997;6:1257–1267....
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Transcript of The Role of Platelets in Atherothrombosis Kumar A et al. Exp Opin Invest Drugs. 1997;6:1257–1267....
The Role of Platelets in Atherothrombosis
Kumar A et al. Kumar A et al. Exp Opin Invest DrugsExp Opin Invest Drugs. 1997;6:1257–1267.. 1997;6:1257–1267.
AdhesionAdhesion Aggregation (GP IIb/IIIa Inhibitors)Aggregation (GP IIb/IIIa Inhibitors)
FibrinogenFibrinogen
Activated Gpllb/lllaActivated Gpllb/llla
Activation (Clopidogrel)Activation (Clopidogrel)
PlateletsPlatelets
LipidLipidcorecore
CollagenCollagenGpla/lla bindGpla/lla bind
von Willebrandvon WillebrandFactor/Gplb bindFactor/Gplb bind
ThrombinThrombin
ADPADP
5 HT5 HT
TXATXA22
Platelet PlugPlatelet Plug
1 3
2 4
PF4PF4
CD 40 ligandCD 40 ligandthrombospondinthrombospondin
TGF-BTGF-B
PRISMPRISM 7.1%7.1% 5.8% 5.8%†† 0.80 0.80 0.60-1.06 0.60-1.06
PRISM-PLUSPRISM-PLUS 12.0% 12.0% (*)(*) 8.7% 8.7% 0.70 0.70 0.50-0.98 0.50-0.98 ((† )) 13.6% 13.6%†† 1.17 1.17 0.80-1.70 0.80-1.70
PARAGON-APARAGON-A 11.7% 11.7% (l)(l) 10.3% 10.3% 0.87 0.87 0.58-1.29 0.58-1.29 (h)(h) 12.3% 12.3% 1.06 1.06 0.72-1.55 0.72-1.55
PURSUITPURSUIT 15.7% 15.7% (l)(l) 13.4% 13.4% 0.83 0.83 0.70-0.99 0.70-0.99 (h)(h) 14.2% 14.2% 0.89 0.89 0.79-1.00 0.79-1.00
PARAGON-BPARAGON-B 11.4%11.4% 10.6% 10.6% 0.92 0.92 0.77-1.09 0.77-1.09
GUSTO-IVGUSTO-IV 8.0% 8.0% (24h)(24h) 8.2% 8.2% 1.02 1.02 0.83-1.24 0.83-1.24 (48h)(48h) 9.1% 9.1% 1.15 1.15 0.94-1.39 0.94-1.39
OverallOverall 11.8%11.8% 10.8% 10.8%** 0.91 0.85-0.99 0.91 0.85-0.99
Odds RatioPlacebo IV Gp IIb/IIIa 95% CI
† without heparin, * with/ without heparin(l) = low dose, (h)= high-doseBoersma, E. et al. Lancet. 2002;359:189-198.
IV Gp IIb/IIIa Inhibitors in ACS: Death or MI at 30 Days (N=31,402)
Placebo BetterGp IIb/IIIa Better
Odds Ratio (95% CI)
0.0 1.0 2.0
Study
P=.015srm
CURECURE
Prevalence N=31,402
Placebo Event Rate
OR P
Age <60 35% 7.3% 0.86 0.10
60-69 30% 11.1% 0.91
70 35% 15.5% 0.96
Sex Male 65% 11.3% 0.81 0.001
Female 35% 11.1% 1.15
ST dep - 44% 8.9% 0.83 0.057
+ 56% 13.1% 0.98
CKMB <ULN 54% 9.6% 0.94 0.55
ULN 46% 14.1% 0.98
IV GP IIb/IIIa Inhibitors in ACS: Death or MI (at 30 d): Subgroup Results
Boersma, E. et al. Lancet. 2002;359
CURECURE IV GP IIb/IIIa Antagonists in ACSDeath or MI (at 30d) by PCI/CABG < 5 days
17.3
14.3
10.5 10.1
0
2
4
6
8
10
12
14
16
18
Dea
th o
r M
I
Intervention Medical Rx
Placebo
IV GP IIb/Iia
P=0.001
P=NS
N=5847 N=25,555 Boersma et al. Lancet 2002; 359: 189b
Interaction p < 0.02
CURECURE
Odds Ratio 95% CIStudy 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
IV Gp IIb/IIIa Inhibitors in ACS: Major Bleeding at 30 Days
† without heparin, * with/ without heparinmajor bleeding for all low dose treatmentBoersma, E. et al. Lancet. 2002;359:189-198. srm
CURECURE Death During Follow-up Period
p = 0.588 Breslow-Dayp = 0.588 Breslow-Dayheterogeneityheterogeneity
EXCITEEXCITE 0.3%0.3% 0.7%0.7%
Odds Ratio & 95% CIOdds Ratio & 95% CITrialTrial PlaceboPlacebo FibanFiban
Fiban WorseFiban WorseFiban BetterFiban Better
7,2327,232
NN
00 0.50.5 11 1.51.5 22
XemilofibanXemilofiban2.14
OPUSOPUS 1.4%1.4% 2.0%2.0%10,30210,302OrbofibanOrbofiban
1.40
SYMPHONYSYMPHONY 1.8%1.8% 2.0%2.0%9,1699,169SibrafibanSibrafiban
1.14
PooledPooled 1.3%1.3% 1.7%1.7%33,34033,340 p = 0.0021.37
2nd SYMPHONY2nd SYMPHONY 1.3%1.3% 2.1%2.1%6,6376,637SibrafibanSibrafiban
1.55
Chew DP, Bhatt DL, Sapp S, and Topol EJ. . Circulation. 2001;103:201-206.Chew DP, Bhatt DL, Sapp S, and Topol EJ. . Circulation. 2001;103:201-206.
CURECURE
Pla
tele
t d
epo
siti
on
(x
10-7/c
m2)
Ex vivo study of collagen-induced thrombus formation in 18 healthy volunteers at day 10
** **
Synergistic Antithrombotic Effect of Clopidogrel Plus Aspirin in Humans
** p <0.01 vs ASA.
Baseline ASA C75+ASA C300+ASA
0
1
2
3
4
5
6 Baseline
ASA 325mg
C 75mg+ ASA 325mg
C 300mg+ ASA 325mg
Cadroy et al. Circulation. 2000;101:2823-2828.
Rapid Platelet Inhibition ofClopidogrel* 375 mg Loading Dose
0
19
6880
8579 80
91
55
0
20
40
60
80
100
Day 1, 0hr
Day 1,0.5hr
Day 1,1.0hr
Day 1,2.0hr
Day 1,5.0hr
Day 2 Day 3 Day 5 Day 10
* Clopidogrel 75mg/d given on days 2-10.* Clopidogrel 75mg/d given on days 2-10.Bachmann F et al.Bachmann F et al. Eur Heart J. Eur Heart J. 1996;17(suppl):263. Abstract1996;17(suppl):263. Abstract..
Pe
rce
nt
(%)
Inh
ibit
ion
(5
P
erc
en
t (%
) In
hib
itio
n (
5 m
cM
AD
P)
AD
P)
P=0.0001P=0.0001
0.10.1 1.01.0 10.010.0ASA + TiclopidineASA + Ticlopidine
BetterBetterASA aloneASA alone
BetterBetter
HALL (1996)HALL (1996)
*STARS (1998)*STARS (1998)
TotalTotal
0.170.17
0.250.25
0.230.23
0.01-0.720.01-0.72
0.10-0.630.10-0.63
0.11-0.490.11-0.49
StudyStudy Odds RatioOdds Ratio 95% CI95% CI
Death or MI
Test for heterogeneity P=0.66*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.
Efficacy of Dual Antiplatelet Therapy vs ASA alone in Reducing Coronary Events after Stenting
Test for heterogeneity P=0.51*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.
StudyStudy Odds RatioOdds Ratio 95% CI95% CI
P=0.002P=0.002
0.10.1 1.01.0 10.010.0
ISAR (1996)ISAR (1996)
*STARS (1998)*STARS (1998)
MATTIS (1998)MATTIS (1998)
FANTASTIC (1998)FANTASTIC (1998)
TotalTotal
0.310.31
0.320.32
0.610.61
0.660.66
0.510.51
0.11-0.910.11-0.91
0.11-0.910.11-0.91
0.26-1.430.26-1.43
0.33-1.300.33-1.30
0.33-0.780.33-0.78
ASA + TiclopidineASA + Ticlopidine BetterBetter
ASA + Oral AnticoagulationASA + Oral AnticoagulationBetterBetter
Death or MI
Efficacy of Dual Antiplatelet Therapy vs Warfarin and ASA in Reducing Coronary Events after Stenting
CURECURE
Hours After Randomization
Cumulative Hazard Rates
0.0
0.005
0.010
0.015
0.020
0.025
0 2 4 6 8 10 12 14 16 18 20 22 24
Within 24 hrs of Randomization
RR= 0.66p=0.003
Placebo+ ASA
Clopidogrel+ ASA
MI/Stroke/CV Death/Severe IschemiaMI/Stroke/CV Death/Severe Ischemia
34%34%Relative RiskRelative Risk
ReductionReduction
Mehta SR et al. AHA, 2002
CURECURE Interventions Associated with Refractory Ischemia in Hospital
Plac Clop
# Patients 6303 6259
# RFAs 126 85
Thromb Therapy 5 3
Cath 40 35
PTCA 44 25
CABG 18 11
IABP 10 3
Transfer for Cath 21 14
Missing 2 0
5.7
11.4
20.7
4.1
9.8
15.9
0
5
10
15
20
25
LOW RISK MODERATERISK
HIGH RISK
CV
De
ath
/MI,
Str
ok
e
Placebo
Clopidogrel
Benefit of Clopidogrel stratified byTIMI Risk Score
N=3276 N=7297 N=1989
ARR 1.6% 1.6% 4.8%
P=0.03
P=0.02
P=0.003
Budaj et .al Circulation, In Press
CURECURE CV Death/MI/Stroke by Revascularization:
Subgroup
2N Plac%
Clop%
RR CI
• H/O Revasc 2246 14.4 8.4 0.56 0.43-0.72
Others 10316 10.7 9.5 0.88 0.78-0.99
• Post Rand Revasc +• Post Rand Revasc -
4577
7985
13.9
10.0
11.5
8.1
0.82
0.80
0.69-0.96
0.69-0.92
CURECURE Type of MI
Plac Clop RR CI
# Patients 6303 6259
% %
All MI 6.7 5.2 0.77 0.67-0.89
Q wave MI 3.1 1.9 0.60 0.48-0.76
Other MI 3.8 3.5 0.89 0.74-1.07
CURECURE Prevention of large MI, thrombolytic use and new onset CHF after randomizaton
Q-wave MI 3.1% 1.9% 40%<0.001
ThrombolyticsThrombolytics 2.0%2.0% 1.1%1.1% 43%43%< 0.001< 0.001
Heart FailureHeart Failure‡‡ 4.4%4.4% 3.7%3.7% 18%18%0.030.03
Relative Risk
Reduction P valueOutcome
Placebo + ASA*
N = 6303
Clopidogrel + ASA*
N = 6259
‡ ‡ Radiologically confirmed
* In addition to other standard therapies
CURECURE During Initial Hospitalization
Plac Clop RR (95% CI) P
% %
Refract Ang 2.0 1.4 0.68 (0.52-0.90) 0.007
Other Severe Ischemia
3.8 2.8 0.74 (0.61-0.90) 0.0028
Other Recurrent Angina
22.9 20.9 0.91 (0.85-0.98) 0.01
Heart Failure 4.4 3.7 0.82 (0.69-0.98) 0.026
CURECURE CV Death/MI Among Patients Undergoing Early PCI (< 72 Hrs)
0
2
4
6
8
10
12
14
16
PCI<72 Hours PCI>72 Hours
CV
Dea
th/M
I ASA + Placebo
ASA +Clopidogrel
N=544 N=2114
RRR 38% RRR 29%
Mehta, SR. et al for the CURE Trial Investigators. Lancet. August 2001;21:2033-41.
CURECURECV Death or MI at Various Intervals
12.6
5.1
4.43.9
3.12.93.6
8.8
0
2
4
6
8
10
12
14
Overall Before PCI PCI to 30 d. 30 d. to 1 yr
CV
dea
th o
r M
I (%
) PlaceboClopidogrel
RRR 31% 32% 34% 21%
*
*P=0.002 Mehta, SR. et al for the CURE Trial Investigators. Lancet. August 2001;21:2033-41.
• PCI-CURE
CURECURE Benefit/Risk Ratio
% Events
No.
Placebo
6303
Clop
6259
RR (95% CI) P
Primary + Life Threatening Bleed
12.45 10.61 0.84 (0.76, 0.93) 0.001
Primary + RFA + Major Bleeds
14.50 12.83 0.87 (0.79-0.96) 0.005
Yusuf, Mehta. N Eng J Med 2002; correspondence
CURECURE
The CURE Trial InvestigatorsThe CURE Trial Investigators. N Engl J Med. 2001;345:494-502.
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
CURECURE TIMI Major Bleeding / GUSTO Severe-Life-Threatening Bleeding Criteria
Plac Clop RR
(95% CI)
P
# Patients 6303 6259
TIMI Criteria 73
(1.2%)
68 (1.1%)
0.94 0.70
GUSTO Criteria 70
(1.1%)
78
(1.2%)
1.12 0.48
CURECURE Life Threatening Bleeding
Plac Clop
# Patients 6303 6259
Percent Percent
Life Threatening 1.8 2.2
•Fatal 0.2 0.2
•5 g/L Drop Hemoglobin 0.9 0.9
•Hypotension-inotropes 0.5 0.5
•Surgery Required 0.7 0.7
•Hemorrhagic Stroke
•4+ Blood Units
0.1
1.0
0.1
1.2
CURECURE All Major/LT Bleeding in Pts with CABG Surgery
Plac Clop
% % RR CI
# Patients 1061 1011
All Major 6.6 8.3 1.26 0.93-1.71
Life Threatening 5.0 6.4 1.29 0.90-1.83
Other Major 1.6 1.9 1.17 0.61-2.24
TIMI Major 3.1 2.6 0.83 0.50-1.37
GUSTO Severe/LT 3.6 4.5 1.24 0.81-1.90
CURECURE Major/Life-Threatening Bleeds within 7 Days of CABG Surgery
Plac Clop RR p
Stopped < 5 days prior to CABG or continued
N = 565 N = 519
Pts with Maj/LT Bleeds 5.7% 8.5% 1.50 0.07
Stopped > 5 days prior to CABG
N = 454 N = 456
Pts with Maj/LT Bleeds 5.3% 4.4% 0.83 0.53
CURECURE Bleeding by GP IIb/IIIa Use
Plac Clop RR
GP IIb/IIIa Use 454 369
All Major 4.63 4.88 1.05 (0.57-1.95)
Minor 3.52 4.88 1.38 (0.72-2.68)
No GP IIb/IIIa Use 5849 5890
All Major 2.53 3.62 1.43 (1.16-1.76)
Minor 2.34 5.16 2.20 (1.81-2.69)
% Events
CURECURE Number and Proportion of Patients Undergoing Cardiac Procedures in ACS Trials
Cath PCI CABG
CURE 5491
(44%)
2658
(21%)
2072
(16%)PURSUIT 5625
(59%)
2253
(24%)
1558
(14%)PRISM PLUS -- 475
(69%)
365
(23%)PRISM 2003
(62%)
698
(21%)
549
(17%)GUSTO IV 5036
(49%)
1509
(19%)
859
(11%)SMR
CURECURE Relative Benefits of Different Interventions in ACS By Time (Death/MI)
RRR
< 30 days > 30 days
ASA 35% 25%
Clopidogrel 21% 20%
Thrombin inhib 20% 0%
IV GP IIb/IIIa inhib 9% 0%
Invasive Strategy -35% 40%
Long term benefits from lipid lowering and ACE-inhibitor therapy
CURECURE Risk-Benefit Analysis of Clopidogrel versus IV GP IIb/IIIa in ACS
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EEEffffffiiicccaaacccyyy(((dddeeeaaattthhh,,,MMMIII,,,ssstttrrroookkkeee))) 999...333%%% 111111...444%%% ---222...111%%% 000...000000000000999
SSSaaafffeeetttyyy(((MMMaaajjjooorrr LLLTTT BBBllleeeeeedddsss))) 222...222%%% 111...888%%% +++000...444%%% 000...111333
EEEffffffiiicccaaacccyyy +++ SSSaaafffeeetttyyy 111111...555%%% 111333...222%%% ---111...777%%% 000...000000111
IIIVVV GGGPPP IIIIIIbbb///IIIIIIIIIaaa
EEEffffffiiicccaaacccyyy (((DDDeeeaaattthhh ooorrr MMMIII))) 111111...888%%% 111000...888%%% ---111%%% 000...000111444
SSSaaafffeeetttyyy (((MMMaaajjjooorrr BBBllleeeeeedddsss))) 111...444%%% 222...444%%% +++111%%% <<<000...000000111
EEEffffffiiicccaaacccyyy +++ SSSaaafffeeetttyyy 111333...222%%% 111333...222%%% 000%%% NNNSSS
Active Placebo ARR P value
*Yusuf S, Mehta SR. N Engl J Med 2002 (correspondence)*Yusuf S, Mehta SR. N Engl J Med 2002 (correspondence). † Boersma, E. et al. Lancet. 2002;359:189-198
*
†
CURECURE Benefit-Risk Comparison of Antithrombotic Therapies vs Placebo in UA/NSTEMI
ASA1 1-2 yrs 5,031 - 46% +60%
Clopidogrel2* Up to 1 yr 12,562 - 19% +38%
LMWH 42 days 1,506 - 10% +27%
IV GP IIb/IIIa Inhibitor4*
3 days 31,402 - 9% +62%
Treatment Major Duration N Death or MI Bleeding
1. Antithrombotic Trialists’ Collaboration. BMJ 2002;324:71-86 2. The CURE Trial Investigators. NEJM 2001;345:494-502. 3. Frisc Investigators. Lancet 1996;347:561-568. 3..4. Boersma E, et al. Lancet 2002;359:189-198.
* In addition to aspirin† reported death or MI at 150 days
Mehta SR. JACC 2002, In Press
CURECURE
Active* DiffTrial 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 InvestigatorsThe CURE Trial Investigators. N Engl J Med. 2001;345:494-502. The PRISM-PLUS Study Investigators. N Engl J Med. 1998;338:1488-97.
The PURSUIT Trial Investigators. N Engl J Med. 1998;339:436-443.The CAPTURE Investigators. Lancet. 1997;349:1429-1435.
Major Bleeding in IV GP IIb/IIIa Antagonists ACS Trials vs CURE: Within 30 Days
Mehta S. J Am Coll Cardiol. In Press
CURECURE Role Of Antiplatelet Therapies In ACS:
• Both ASA (RR of 40%) and clopidogrel (RR of add’l 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
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
CURECURE 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