CURECURE (OASIS-4)Clopidogrel in Unstable

Angina to preventRecurrent ischemic Events

CURECUREAtherothrombosis: a Generalized and

Progressive Process

NormalNormalFattyFattystreakstreak

FibrousFibrousplaqueplaque

Athero-Athero-scleroticscleroticplaqueplaque

PlaquePlaquerupture/rupture/fissure &fissure &

thrombosisthrombosis MIMI

IschemicIschemicstroke/TIA stroke/TIA

Critical leg Critical leg ischemiaischemia

Clinically silentClinically silent

CardiovascularCardiovasculardeathdeath

Increasing ageIncreasing age

Stable anginaStable anginaIntermittent claudicationIntermittent claudication

UnstableUnstableanginaangina}}ACSACS

ACS, acute coronary syndrome; TIA, transient ischemic attack

CURECURE

Based on data from the Atherosclerotic Risk in Communities study (ARIC) of the National Heart, Lung, and Blood Institute, 1987–94. Includes Americans hospitalized with definite or probable MI or fatal CHD, not including silent MIs.

American Heart Association, 2001, Heart and Stroke Statistical Update

Epidemiology of MI and Angina

in the USA • Single largest cause of death

– 459 000 deaths in the USA in 1998

– 1 in every 5 deaths

• Incidence

– 1 100 000 Americans will have a new or recurrent coronary attack each year. Over 40% of people who experience a coronary attack in a given year will die of it in the same year

– 400 000 new cases of stable angina and about 150 000 new cases of unstable angina per year

• Prevalence

– 12 400 000 with a history of MI, angina, or both

CURECUREHospitalizations in the USA

Due to ACS

Acute Coronary SyndromesAcute Coronary Syndromes

1.5 million hospital admissions per year1.5 million hospital admissions per year

Unstable anginaUnstable angina Myocardial infarctionMyocardial infarction(Q-wave and non-Q-wave)(Q-wave and non-Q-wave)

Cairns J et al Cairns J et al Can J CardiolCan J Cardiol 1996;12:1279–1292 1996;12:1279–1292

750 000 admissions750 000 admissions 750 000 admissions750 000 admissions

CURECURE

Théroux P et al Circulation 1998; 97:1195–1206

The Role of Antiplatelet Therapy in Unstable Angina and Non-Q-wave MI

• Atherothrombosis is a generalized disease affecting the coronary, cerebral and peripheral circulations

• Unstable angina/non-Q-wave MI is one of the classic examples of the progression of atherothrombotic disease

• Platelets play a key role in thrombus formation associated with rupture of an unstable atherosclerotic plaque

• Angioscopic findings show that unstable angina is due to the formation of a platelet-rich thrombus

• Consequently, antiplatelet therapy is recognized as the foundation of long-term management

CURECURE Efficacy of Antiplatelet Therapy:Antiplatelet Trialists’ Collaboration

Antiplatelet Trialists’ Collaboration BMJ 1994;308:81–106

Prior MIPrior MI 1111 1331/96771331/9677 1693/99141693/9914 25% (4)25% (4)

Acute MIAcute MI 99 992/9388992/9388 1348/93851348/9385 29% (4)29% (4)

Prior stroke/Prior stroke/ 1818 1076/58371076/5837 1301/58701301/5870 22% (4)22% (4)TIATIA

Unstable angina Unstable angina 77 182/1991182/1991 285/2027285/2027

CategoryCategoryof trialof trial

No. ofNo. oftrialstrialswithwithdatadata

Anti-Anti-plateletplatelet

AdjustedAdjustedcontrolscontrols

Odds ratio andOdds ratio andconfidence intervalconfidence interval

(Antiplatelet:(Antiplatelet:control)control)

% odds% oddsreductionreduction

(SD)(SD)

MI, stroke, orMI, stroke, orvascular deathvascular death

00 0.50.5 1.01.0 1.51.5 2.02.0

AntiplateletAntiplatelettherapytherapybetterbetter

AntiplateletAntiplatelettherapytherapyworseworse

TIA, transient ischemic attack

CURECURE UA: CV Death or MI - ASA vs Placebo%

of

Pat

ient

s w

ith E

vent

Cairns et al NEJM 1985;313:1369-1375

Efficacy: Cardiac Death or Non-Fatal MI

At RiskASA (263)

No ASA (274)(174)(180)

(137)(144)

(107)(115)

(73)(80)

Time

CURECURE The Role of an ADP Receptor Antagonist

• Clopidogrel is an advanced ADP receptor antagonist and inhibits platelet aggregation by antagonizing the effects of ADP

• Clopidogrel is indicated for the reduction of atherothrombotic events in patients with a history of stroke, MI or peripheral arterial disease.

• Clopidogrel is at least as safe as ASA• Combining clopidogrel with ASA may potentially lead to

greater benefit

Jarvis B et al Drugs 2000;60:347–377Antiplatelet Trialists’ Collaboration BMJ 1999;308:81–106CAPRIE Steering Committee Lancet 1996:348:1329–1339

CURECUREComplementary Mode of Action between

Clopidogrel and ASA

COX, cyclooxygenase; ADP, adenosine diphosphate; TxACOX, cyclooxygenase; ADP, adenosine diphosphate; TxA2, 2, thromboxane Athromboxane A2 2

Schafer AI Am J Med 1996;101:199–209

CURECURETrials of ADP-receptor Antagonists vs

Placebo in Patients with Atherosclerosis

Trial, Year Setting Primary Outcome Odds Ratio 95% CI

Definition Thieno-pyridine

(n/N)

Comparator (n/N)

Thienopyridine versus Placebo or Control

CATS 1989 (Ticlopidine vs Placebo

Recent Stroke

Death, MI,

Stroke

106/525 134/528 0.74 0.56-0.99

Balsano 1990 (Ticlopidine vs Control)

Unstable Angina

Death, MI 23/314 46/338 0.52 0.31-0.85

STIMS 1990 (Ticlopidine vs Placebo)

Intermittent Claudication

Death, MI,

Stroke

89/346 99/341 0.85 0.61-1.18

TOTAL 218/1185 279/1207 0.73 0.60-0.90CURE Study Investigators Eur Heart J 2000; 21: 2033-41.

CURECURE Trials of ADP-receptor Antagonists vs ASA

in Patients with Atherosclerosis

Trial, Year Setting Primary Outcome Odds Ratio 95% CI

Definition Thieno-pyridine

(n/N)

Comparator (n/N)

Thienopyridine versus ASA

TASS, 1989 (Ticlopidine vs ASA)

Cerebral Ischemia

Death, Stroke

306/1529 349/1540 0.85 0.82-0.97

CAPRIE, 1996 (Clopidogrel vs ASA)

Recent Stroke,

Previous MI or PVD

Death, MI,

Stroke

939/9599 1021/9586 0.91 0.83-1.00

TOTAL 1245/11128 1370/11126 0.90 0.83-0.97

CURE Study Investigators Eur Heart J 2000; 21: 2033-41.

CURECURE

StudyStudy

HALL, 1996HALL, 1996

STARS, 1998*STARS, 1998*

TOTALTOTAL

0.10.1 1.01.0 10.010.0

Odds RatioOdds Ratio 95% CI95% CI

0.170.17 0.01-0.720.01-0.72

0.250.25 0.10-0.630.10-0.63

0.230.23 0.11-0.490.11-0.49

PP==0.00010.0001Test for heterogeneity Test for heterogeneity PP=0.66=0.66

ASA + Ticlopidine versus ASA after ASA + Ticlopidine versus ASA after Coronary Artery StentingCoronary Artery Stenting

Death or MIDeath or MI

CURE Study Investigators Eur Heart J 2000; 21:2033-41

Combination Better ASA Alone Better

StudyStudy

ISAR, 1996ISAR, 1996

MATTIS, 1998MATTIS, 1998

TOTALTOTAL

0.10.1 1.01.0 10.010.0

Odds RatioOdds Ratio 95% CI95% CI

0.310.31 0.11-0.910.11-0.91

0.610.61 0.26-1.430.26-1.43

0.510.51 0.33-0.780.33-0.78

P=0.002P=0.002Test for heterogeneity Test for heterogeneity PP=0.51=0.51

ASA + Ticlopidine vs ASA + Oral ASA + Ticlopidine vs ASA + Oral Anticoagulation after StentingAnticoagulation after Stenting

FANTASTIC, 1998FANTASTIC, 1998 0.660.66 0.33-1.300.33-1.30

STARS, 1998STARS, 1998 0.320.32 0.11-0.910.11-0.91

Death or MIDeath or MI

Combination Better ASA Alone Better

CURE Study Investigators Eur Heart J 2000; 21:2033-41

CURECURE

CURECUREEffect of Clopidogrel Alone or in Combination

with ASA on Thrombus Formation: Animal Model

-100

-80

-60

-40

-20

0

0 5 10 15 20 25 30 35 40 45 50

Time (min)

Clopidogrel + ASA (10 + 10 mg/kg)

Clopidogrel (10 mg/kg)

ASA (10 mg/kg) Placebo

Herbert JM et al Thromb Haemost 1998;80:512–518

Blood flow(% decrease)

CURECURERapid and Synergistic Effect of Clopidogrel

on top of ASA (Healthy Volunteers)

Mean reduction of platelet deposition compared with ASA alone

Cadroy Y et al Circulation 2000;101:2823–2828

C75+ASA vs ASA aloneC300+ASA vs ASA alone

-10

0

10

20

30

40

50

60

70

80

Day 1 1.5 hrs

Day 1 6 hrs

Day 10 6 hrs

Mean reduction (%)

p=0.03vs ASA

p<0.001vs ASA

p=0.04vs ASA

p<0.001vs ASA

p<0.001vs ASA

p=0.03

p=0.01

p=NS

n=18 for all comparisons

CURECURE

•Randomized, double-blind, parallel group, clinical trial of clopidogrel vs placebo in patients with ACS

•All patients receive ASA (75-325 mg)

•International trial (28 countries)

•12,562 patients (482 Hospitals)

•Central randomization

•3-12 month Rx and follow-up

•Main outcomes: -CV death/MI, stroke

-Above + refractory ischemia

Study Design

CURECURE Study Objectives

To evaluate if clopidogrel is superior to placebo in preventing

a) CV death, MI, stroke (Primary at 0.045)

b) Above and refractory ischemia (Co-primary at 0.01)

CURECURE Inclusion Criteria

• Ischemic symptoms, suspected to represent UA or MI without ST segment elevation

• Randomized within 24 hours of onset of CP

• and ECG evidence of ischemia at inclusion or already elevated cardiac enzymes or Troponin I or T to at least 2 x ULN*

* Prior to June 1999, pts > 60 yrs with normal ECG allowed

Revised July, 1999

CURECURE Outcome Definitions (1/2)

CV Death: Excludes clear non-CV deaths

MI: Two of three usual criteria (CP, ECG or enzyme changes)

Stroke: Neurological deficit 24 hrs (CT/MRI encouraged)

Refractory Ischemia: Inhosp*: recurrent ischemia on max med Rx + ECG changes + intervention 1 day

After discharge: Rehosp for UA with ECG changes

Severe Ischemia*: Changes similar to in hospital Refractory Ischema, but no intervention

Recurrent Angina*: All other ischemic CP in hospital

CURECURE Outcome Definitions (2/2)

Major Bleeds: Significantly disabling, intraocular (vision loss), or transfusion of 2 units

Classified as Life Threatening if:

Hb > 5g/dl, hypotension needing IV inotropes, surgery to stop bleeding, symptomatic ICH or transfusion or 4 units of blood

CURECURE Patient Schedule

3 months double-blind treatment 12 months

Aspirin 75-325mg

Clopidogrel(~6,250 patients)

Placebo1 tab o.d.

(~6,250 patients)

Aspirin 75-325mgD

ay 1

6 m

. Vis

it9

m. V

isit

12 m

.

or F

inal

Vis

it

3 m

. Vis

it

Dis

char

ge V

isit

1 m

. Vis

it

Patients withAcute Coronary

Syndrome

(UA or MI Without STelevation)

R

load

ing

dose

300 mg loading + 75 mg o.d. dose

CURECURESample Size (12,500) and

Power Calculations

Main Endpoints Control Event Rate

80% Power

90% Power

CV Death/MI/Stroke 10% 14.7% 16.9%

=0.045 (two-sided) 12% 13.3% 15.3%

Above + Refractory ischemia

14% 14.6% 16.4%

=0.01 (two-sided) 16% 13.6% 15.3%

2463

1110831

5036

3122

CURE: 12,562 from 482 centres in 28 countries

CURECURE Baseline Characteristics (1)

Placebo Clopidogrel

N=6303

%

N=6259

%

Male 61.7 61.3

Female 38.3 38.7

Unstable Angina 74.9 74.9

MI w/o ST Elevation 25.1 25.1

Abnormal ECG 93.9 93.7

Elevated enzymes/marker 25.3 25.3

CURECURE Baseline Characteristics (2)

Placebo Clopidogrel

N=6303

Mean (SD)

N=6259

Mean (SD)

Age 64.2 (11.3) 64.2 (11.3)

Heart rate 73.0 (14.6) 73.2 (14.8)

Systolic BP 134.1 (22.0) 134.4 (22.5)

Symptom onset to randomization (hrs) 14.1 (7.1) 14.2 (7.2)

CURECUREMedications After Randomization

in Hospital

Placebo Clopidogrel

% %

IV Heparin 46.9 46.0

LMW Heparin 56.0 56.1

Beta-blocker 78.4 78.7

Any CCB 36.0 36.0

ACE-I 49.9 50.9

Lipid-lowering 47.0 46.3

CURECURETemporary Interruptions by

Procedure

Any Procedure

(PTCA + CABG + Other Surgery)Plac Clop

With procedure

No. pts 2430 2359

% interruptions (84%) (84%)

Without procedure

No. pts 3873 3900

% interruptions (21%) (23%)

CURECURE ASA at Each Visit

Placebo

N = 6303

Clopidogrel

N = 6259

% on ASA Median Dose % on ASA Median Dose

Pre-Rand 65.6 150 66.6 150

Since-Rand 99.8 150 99.8 150

1-Month 94.1 150 94.0 150

3-Month 96.2 150 96.0 150

6-Month 95.8 125 95.4 125

9-Month 94.7 100 94.6 100

CURECURE Outcomes 1 /2

Plac Clop

% % RR CI p

# Patients 6303 6259

1st Co-Primary 11.41 9.30 0.80 0.72-0.90 < 0.001

•CV Death 5.47 5.08 0.93 0.79-1.08

•MI 6.65 5.18 0.77 0.67-0.89

•Stroke 1.38 1.20 0.86 0.63-1.18

Non CV death 0.71 0.66 0.91 0.60-1.39

CURECURE

Months of Follow-up

Cu

mu

lative

Ha

za

rd R

ate

s

0.0

0.0

20

.04

0.0

60

.08

0.1

00

.12

0.1

4

0 3 6 9 12

Cumulative Hazard Rates for CV Death/MI/Stroke

P < 0.001

Clopidogrel

Placebo

Cum

ulat

ive

Haz

ard

Rat

es

Months of Follow-up0 3 6 9 12

6303

6259

5780

5866

4664

4779

3600

3644

2388

2418

Plac

Clop

No of Pts

CURECURE

Days of Follow-up

Cu

mu

lative

Ha

za

rd R

ate

s

0.0

0.0

10

.02

0.0

30

.04

0.0

50

.06

0 10 20 30

Cumulative Hazard Rates for CV Death/MI/Stroke up to 30 Days

P = 0.003

Clopidogrel

Placebo

Cum

ulat

ive

Haz

ard

Rat

es

Days of Follow-up0 10 20 30

6303

6259

6108

6103

5998

6035

5957

5984

No. Plac

No. Clop

CURECURE Outcomes 2/2

Plac Clop

% % RR CI p

# Patients 6303 6259

2nd Co-Primary 18.83 16.54 0.86 0.79-0.94 < 0.001

Refract.Ischemia 9.31 8.69 0.93 0.82-1.04

In hospital 2.00 1.36 0.68 0.52-0.90

After Discharge 7.59 7.57 0.99 0.87-1.13

Severe Ischemia 5.03 3.80 0.75 0.63-0.89 < 0.001

CURECURECumulative Hazard Rates for CV

Death/MI/Stroke/RFA

Months of Follow-up

Cu

mu

lative

Ha

za

rd R

ate

s

0.0

0.0

50

.10

0.1

50

.20

0.2

5

0 3 6 9 12

P < 0.001

Clopidogrel

Placebo

Cum

ulat

ive

Haz

ard

Rat

es

Months of Follow-up0 3 6 9 12

6303

6259

5441

5542

4322

4438

3295

3346

2159

2201

Plac

Clop

No of Pts

CURECURE Events During Initial Hospitalization

Plac Clop RR (95% CI) P

% %

Refract Isch 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) < 0.003

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) < 0.027

CURECURE CV Death/MI/Stroke in Subgroups: (1)

Subgroup

2N Placebo%

Clopidogrel%

RR CI

• Major ST Dev 6275 14.3 11.5 0.79 0.69-0.91

Others 6287 8.6 7.0 0.81 0.68-0.97

• With Enzyme

Elevation 3176 13.0 10.7 0.81 0.66-0.99

Without Enzyme

Elevation 9386 10.9 8.8 0.80 0.70-0.91

CURECURECV Death/MI/Stroke by Revascularization: (2)

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 + 4577 13.9 11.5 0.82 0.69-0.96

Post Rand Revasc - 7985 10.0 8.1 0.80 0.69-0.92

CURECUREThrombolytic & GP IIb/IIIa Inhib

use after Randomization

Plac

N=6303

Clop

N=6259

RR CI p

(%) (%)

Thrombolytics 2.0 1.1 0.57 0.43-0.76 <0.001

IV GP IIb/IIIa Inhib 7.2 5.9 0.82 0.72-0.93 0.003

CURECURE Bleeding Complications

Placebo Clopidogrel RR 95% CI p

# Patients 6303 6259

Major 2.7% 3.7% 1.38 1.13-1.67 0.001

•Life Threatening

1.8% 2.2% 1.21 0.95-1.56 0.13

•Other Major 0.9% 1.5% 1.70 1.22-2.35 < 0.002

Minor 2.4% 5.1% 2.12 1.75-2.56 < 0.001

Transfusion (2+Units)

2.2% 2.8% 1.30 1.04-1.62 0.02

CURECURETIMI 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

CURECUREMajor/Life-Threatening Bleeds within 7

Days of CABG Surgery

Plac Clop RR p

Stopped < 5 days prior to CABG

N = 476 N = 436

Pts with Maj/LT Bleeds 6.3% 9.6% 1.53 0.06

Stopped > 5 days prior to CABG

N = 454 N = 456

Pts with Maj/LT Bleeds 5.3% 4.4% 0.83 0.53

CURECUREThrombocytopenia and

Neutropenia

Plac Clop

# Rand 6303 6259

Thrombocytopenia 28 (0.44%) 26 (0.42%)

Neutropenia 5 (0.1%) 8 (0.13%)

CURECURE Conclusions

Clopidogrel significantly reduces the risk of:

a) CV Death, MI, Stroke by about one-fifth (p < 0.001)

b) CV Death, MI, Stroke, and Refractory Ischemia by about one-sixth (p < 0.001)

c) Early revascularization, severe and recurrent ischemia and heart failure by about one-fifth to one-quarter in hospital

There is a small (absolute 1%) significant excess of major, but not life threatening, bleeds

CURECURE Clinical Implications

Clopidogrel is beneficial both early and long term in patients with ACS, with a small excess in bleeds. The benefits are consistently observed in various subgroups examined and in addition to other established therapies.

Treating 1000 patients for 9 months prevents about 27 major events in 23 patients at a cost of 4 life threatening bleeds (+ 2 other transfusions).

CURECURE Public Health Implications

USA: 1.5 million MI per year 0.5 mill non-fatal non-Q MI

1.5 million UA pts per year

Potential eligible for clopidogrel is about 2 millionMajor vascular events (CV death/MI/Stroke) reduced from about

250,000 to 200,000 (i.e. 12.5% to 10%) at one year.

If patients are treated longer (e.g. 3 yrs)500,000 reduced to 400,000 (i.e. 25% to 20%)

Therefore 50,000 to 100,000 individuals will avoid a major vascular eventin the USA per year

Global impact: if one-fifth of eligible pts receive clopidogrel, 250,000–500,000 individuals could benefit