The Role of Platelets in Atherothrombosis

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


% %

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


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


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


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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SSSaaafffeeetttyyy(((MMMaaajjjooorrr LLLTTT BBBllleeeeeedddsss))) 222...222%%% 111...888%%% +++000...444%%% 000...111333

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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

Documents

The Role of Platelets in Atherothrombosis