Keith A A Fox

Royal Infirmary & University of Edinburgh

CURE and PCI-CURECURE and PCI-CURE

12

3

17

13

3

20

8

1.5

20

0

10

20

30

Death Stroke Urgentreadmission for

cardiac event

Pat

ien

ts (

%)

STEMI (4074)NSTEMI (3526)UA (5065)

Total outcomes: Total outcomes: admission to 6 monthsadmission to 6 months

Largest multinational registry covering the full spectrum of ACS

ESC 2001ESC 2001

• Randomized, double-blind trial: clopidogrel vs placebo in patients with ACS

• All patients receive ASA (75-325 mg)

• International trial (28 countries), 12,562 patients

• Central randomization

• Primary outcome: -CV death, MI, strokes

Study DesignCURECURE

CURE Study

3 months > double-blind treatment < 12 months

Aspirin 75-325mg

Clopidogrel75mg o.d.

(~6,250 patients)

Placebo1 tab o.d.

(~6,250 patients)

Aspirin 75-325mgD

ay 1

6 m

. Vis

it

9 m

. Vis

it

12 m

.

or F

inal

Vis

it

300m

g load

ing

dose

3 m

. Vis

it

1 m

. Vis

it

Patients withAcute Coronary

Syndrome

(UA or MI Without STelevation)

R

load

ing

dose

CURECURE

CV Death: Excludes clear non-CV deaths

MI: Two of three standard criteria: (Chest Pain, ECG, enzyme changes)

Stroke: Neurological deficit 24 hrs (CT/MRI)

Outcome Definitions CURECURE

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 RFA, but no intervention

Recurrent Angina*: All other ischemic CP in hospital

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

Clopidogrel

Placebo

Cum

ulat

ive

Haz

ard

Rat

es

Months of Follow-up0 3 6 9 12

6203

6259

5778

5864

4660

4780

3599

3640

2378

2414

Plac

Clop

No of Pts

6303

6259

P = 0.00005

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

6097

6093

5994

6027

5954

5981

No. Plac

No. Clop

CURECURE

Very Early Events

Placebo vs Clopidogrel

Day 1 Day 2 Day 3

CVD, MI, Stroke

(RR)

48 v 38

(0.80)

80 v 65

(0.82)

102 v 86

(0.85)Above + RFA

(RR)

86 v 65

(0.76)

140 v 104

(0.75)*

178 v 142

(0.80)*Severe

(RR)

103 v 65

(0.63)**

174 v 114

(0.66)***

211 v 153**

(0.73)Primary + Severe

(RR)

149 v 100 (0.67)***

247 v 173 (0.70)***

302 v 228

(0.75)****p<0.05 **<0.01 *** <0.002

CURECURE

Events During Initial HospitalizationEvents During Initial Hospitalization

Plac Clop RR (95% CI) P

% %

Refract Ang 2.1 1.4 0.69 (0.53-0.91) 0.008

Other Severe Ischemia

3.7 2.8 0.74 (0.61-0.90) 0.0028

Other Recurrent Angina

22.9 21.0 0.92 (0.86-0.98) 0.01

Heart Failure 4.4 3.7 0.83 (0.70-0.98) 0.029

CURECURE

CURE: Who Benefits and When?

• Similar benefits across all major treatment groups• On or off lipid lowering treatment, beta-blockers, heparin,

ACE inhibitors• Irrespective of revascularization or not • RR 0.81 with and RR 0.78 without, both significant

• Higher and lower risk groups show similar risk reduction

• Curves separate early and remain separated• Primary outcome at 24hrs: • 143 vs 93 clopidogrel (RR 0.65 CI 0.50 – 0.85)

Life Threatening Bleed

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 0.1 0.1

• 4+ Blood Units 1.0 1.2

CURECURE

Bleeds With CABG

Placebo Clopidogrel

% % 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 0.90-0.83

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

CURE: Magnitude of Benefit

• Primary Outcome:• MI, stroke or CV death: 11.4% placebo, • 9.2%** clopidogrel (22 per 1000 absolute difference)• (Non-CV death 0.7 vs 0.7%)

Treating 1000 patients for 9 months: prevents 28 vascular events with 6 individuals requiring transfusion

TIMI bleeding criteria: 68 clopidogrel,73 placebo RR 0.94 (CI 0.68-1.30)TIMI bleeding criteria: 68 clopidogrel,73 placebo RR 0.94 (CI 0.68-1.30)GUSTO criteria: 78 clopidogrel, 70 placebo RR 1.11 (CI 0.81-1.55)GUSTO criteria: 78 clopidogrel, 70 placebo RR 1.11 (CI 0.81-1.55)

Study Design

RandomizePCIPCIPCIPCI

PLACEBOPLACEBO + ASA+ ASAPLACEBOPLACEBO + ASA+ ASA

CLOPIDOGRELCLOPIDOGREL+ ASA+ ASACLOPIDOGRELCLOPIDOGREL+ ASA+ ASA

30 d. post PCI30 d. post PCI30 d. post PCI30 d. post PCIEnd of follow-up:End of follow-up:

12 months12 monthsEnd of follow-up:End of follow-up:

12 months12 months

Open-label thienopyridineOpen-label thienopyridine

Pretreatment

PretreatmentN=2,658 patients undergoing PCI

N = 1345

N = 1313

CURE PCI-CURE

PCI-

Open-label thienopyridineOpen-label thienopyridine

Baseline CharacteristicsBaseline Characteristics

43.2%42.4%ST depression

12.0%13.0%Prior CABG

13.4%13.8%Prior PCI

27.3%26.0%Previous MI

19.0%19.0%Diabetes

30.3%30.1%Sex (%F)

61.661.4Age (yrs)

Clopidogrel

n=1254

Placebo

n=1272

PCI-

0.0

0.0

50

.10

0.1

5

0 40 100 200 300 40010 100 200 300 400

A B Days following PCI

Cu

mu

lati

ve H

aza

rd R

ate

P=0.002P=0.002

ClopidogrelClopidogrel

PlaceboPlacebo

A=median time to PCIB=30 days after PCI

Overall Results: CV Death or MI

Lancet 2001: 358:527-33

PCI-

Events Before PCI

Placebo

N=1345

Clop.

N=1313

RR 95% CI P

MI or Refract. Ischemia

15.3% 12.1% 0.76 0.62-0.93 0.008

MI 5.1% 3.6% 0.68 0.47-0.99 0.04

PCI-

Lancet 2001: 358:527-33

Events Placebo

N=1345

Clopid.

N=1313

RR 95% CI P

CV death, MI, urg. revasc.*

6.4% 4.5% 0.70 0.50-0.97 0.03

CV death, MI 4.4% 2.9% 0.66 0.44-0.99 0.04

CV death 1.0% 1.1% 1.10 0.52-2.35

MI 3.8% 2.1% 0.56 0.35-0.89

Q wave MI 2.4% 0.8% 0.35 0.18-0.70

Urg Rev. 2.8% 1.9% 0.67 0.41-1.11

Major Outcomes:Major Outcomes: From PCI to 30 days From PCI to 30 daysPCI-

Lancet 2001: 358:527-33 *Primary endpoint

Other OutcomesPCI-

Placebo+ ASA*

N = 1345

Clopidogrel +ASA*

N=1313

RRR PValue

GP IIb/IIIa Inhibitior 26.6% 20.9% 81% 0.001

Need for secondrevascularization

17.1% 14.2% 18% 0.049

Mehta SR et. al. Lancet 2001: 358:527-33

Events Placebo N = 1345

Clopid N = 1313

RRR 95% CI P

From PCI to End of Followup

CV death, MI, any revasc

21.7% 18.3% 17% 0.56-0.99 0.03

CV Death or MI 8.1% 6.0% 26% 0.56-1.00 0.047

From >30 after PCI to end of follow-up

CV death, MI, any rehosp

28.9% 25.3% 14% 0.74-1.00 0.05

CV Death or MI 3.9% 3.1% 21% 0.53-1.20

Before and After PCI

CV death or MI 12.6% 8.8% 32% 0.54-0.87 0.002

Major Outcomes: Long Term Treatment

PCI-

Lancet 2001: 358:527-33

Clinical Suspicion of ACS:Physical examination, ECG

Blood samples

No persistent STelevation

Aspirin-blocker“heparin”

clopidogrel

Persistent STelevation

Thrombolysisor

Primary PCI

Stress TestPre- or post-

discharge

GP IIb/IIIacoronary

angio

High Riskrecurrent ischaemia

elevated troponinhaemodynamic instabilityarrhythmia with ischaemia

early post-MI unstable angina

Low Riskstable

normal troponin