PCI - A prospective, randomized, double- blind substudy of patients undergoing PCI in the CURE trial

PCI-A prospective, randomized, double-A prospective, randomized, double-

blind substudy of patients blind substudy of patients undergoing PCI in the CURE trialundergoing PCI in the CURE trial

PCI-

Background and HypothesisBackground and Hypothesis

Despite pretreatment and long term use of Despite pretreatment and long term use of ASA in patients undergoing PCI, there ASA in patients undergoing PCI, there remains a significant risk of major CV remains a significant risk of major CV events following PCIevents following PCI

Hypothesis:Hypothesis: in patients undergoing PCI in patients undergoing PCI receiving ASA, pretreatment with receiving ASA, pretreatment with clopidogrel, in addition to ASA, followed by clopidogrel, in addition to ASA, followed by long term therapy is superior to a strategy long term therapy is superior to a strategy of treating for only 4 weeks after PCIof treating for only 4 weeks after PCI

PCI-

ObjectivesObjectives

To determine whether:To determine whether:

1.1. Clopidogrel pretreatment, in addition to Clopidogrel pretreatment, in addition to aspirin, is superior to placebo in preventing aspirin, is superior to placebo in preventing major ischemic events 30 days after PCImajor ischemic events 30 days after PCI

2.2. Long term therapy with clopidogrel, in Long term therapy with clopidogrel, in addition to aspirin, for up to 1 year after addition to aspirin, for up to 1 year after PCI, is superior to placeboPCI, is superior to placebo

PCI-

PCI-CURE: PCI-CURE: Study DesignStudy Design

RPCIPCIPCIPCI

PLACEBOPLACEBO + ASA+ ASA

CLOPIDOGRELCLOPIDOGREL+ ASA+ ASA

30 d. post PCI*30 d. post PCI*30 d. post PCI*30 d. post PCI*Follow-up Follow-up (to 12 m(to 12 mafter rand.)after rand.)

Follow-up Follow-up (to 12 m(to 12 mafter rand.)after rand.)

Open-label thienopyridineOpen-label thienopyridine

Pretreatment

Open-label thienopyridineOpen-label thienopyridine

Pretreatment N=2,658 patients undergoing PCI

N = 1345

N = 1313

CURE PCI-CURE

*1o Outcome: CV Death, MI, Urg Revasc. Mehta SR et al. Lancet 2001:358:527-33

PCI-

StatisticsStatistics

Primary Outcome:Primary Outcome: CV death, MI, urgent CV death, MI, urgent revascularization 30 days after PCIrevascularization 30 days after PCI

Other Outcomes:Other Outcomes: CV death, MI from PCI to CV death, MI from PCI to end of long term followupend of long term followup

Primary Analysis:Primary Analysis: Intention to treatIntention to treat

Follow-up:Follow-up: 100%100%

PCI-

Procedural CharacteristicsProcedural CharacteristicsPlaceboPlacebo

N=1345N=1345

ClopidogrelClopidogrel

N=1313N=1313

Median Day of PCIMedian Day of PCI 1010 1010

During initial HospDuring initial Hosp 66 66

After initial HospAfter initial Hosp 4949 4949

StentStent 81.3%81.3% 82.4%82.4%

Open label thienopyridineOpen label thienopyridine

Before PCIBefore PCI 24.7%24.7% 26.4%26.4%

OverallOverall 84.1%84.1% 82.9%82.9%

PCI-

43.2%43.2%42.4%42.4%ST depressionST depression

12.0%12.0%13.0%13.0%Prior CABGPrior CABG

13.4%13.4%13.8%13.8%Prior PCIPrior PCI

27.3%27.3%26.0%26.0%Previous MIPrevious MI

19.0%19.0%19.0%19.0%DiabetesDiabetes

30.3%30.3%30.1%30.1%Sex (%F)Sex (%F)

61.661.661.461.4Age (yrs)Age (yrs)


n=1313n=1313

PlaceboPlacebo

N=1345N=1345

Baseline CharacteristicsBaseline Characteristics

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

PCI-

0.02

0.04

0.06

0.08

5 10 15 20 25 30

Clopidogrel

Placebo

0.0

RR 0.7095% CI 0.50-0.97P=0.03

Days following PCI

Cu

mu

lati

ve H

aza

rd R

ate

Primary Endpoint:Primary Endpoint: CV Death, MI, Urgent RevascularizationCV Death, MI, Urgent Revascularization


PCI-

EventsEvents PlaceboPlacebo

N=1345N=1345

Clopid.Clopid.

N=1313N=1313

RRRR 95% CI95% CI PP

CV death, MI, CV death, MI, urg. revasc.*urg. revasc.*

6.4%6.4% 4.5%4.5% 0.700.70 0.50-0.970.50-0.97 0.030.03

CV death, MICV death, MI 4.4%4.4% 2.9%2.9% 0.660.66 0.44-0.990.44-0.99 0.040.04

CV deathCV death 1.0%1.0% 1.1%1.1% 1.101.10 0.52-2.350.52-2.35

MIMI 3.8%3.8% 2.1%2.1% 0.560.56 0.35-0.890.35-0.89

Q wave MIQ wave MI 2.4%2.4% 0.8%0.8% 0.350.35 0.18-0.700.18-0.70

Urg Rev. Urg Rev. 2.8%2.8% 1.9%1.9% 0.670.67 0.41-1.110.41-1.11*Primary outcome

Major Outcomes: Major Outcomes: From PCI to 30 daysFrom PCI to 30 days


PCI- Events Prevented Within Events Prevented Within 30 Days of PCI30 Days of PCI

No. Days No. Days After PCIAfter PCI

PlacPlac ClopidClopid ARRARR RRRR 95% CI95% CI

22 3.03.0 2.42.4 -0.6-0.6 0.800.80 0.50-1.270.50-1.27

77 4.44.4 3.03.0 -1.4-1.4 0.690.69 0.46-1.030.46-1.03

1414 5.45.4 3.73.7 -1.7-1.7 0.670.67 0.47-0.960.47-0.96

3030 6.46.4 4.54.5 -1.9-1.9 0.700.70 0.50-0.970.50-0.97

CV Death, MI, Urgent Revascularization


PCI-

0 100 200 300 400

0.0

0.02

0.04

0.06

0.08

0.10

Clopidogrel

Placebo

RR 0.7595% CI 0.56-1.00P=0.047

Days following PCI

Cu

mu

lati

ve H

aza

rd R

ate

CV Death, MI:CV Death, MI:From PCI to End of FollowupFrom PCI to End of Followup


PCI-

Long Term OutcomesLong Term OutcomesEvents Placebo

N =1345

Clopid N

=1313

RR 95% CI P

PCI to End

CV Death, MI 8.0% 6.0% 0.75 0.56-1.00 0.0470.047MI 6.4% 4.5% 0.71 0.51-0.99

>30 days to End

CV Death, MI, Rehosp.

28.9% 25.3% 0.86 0.74-1.00 0.046

CV Death or MI

3.9% 3.1% 0.79 0.53-1.200.53-1.20


PCI-

0.0

0.0

50

.10

0.1

5

0 40 100 200 300 40010 100 200 300 400

A BDays following PCI

Cu

mu

lati

ve H

aza

rd R

ate

RR 0.69RR 0.6995% CI 0.54-0.8795% CI 0.54-0.87P=0.002P=0.002


PlaceboPlacebo

A=median time to PCIB=30 days after PCI

Overall Results: Overall Results: CV Death or MICV Death or MI


PCI- CV Death or MI at Various CV Death or MI at Various IntervalsIntervals

12.6

5.14.4

3.93.12.9

3.6

8.8

0

2

4

6

8

10

12

14

Overall BeforePCI

PCI to30 d.

30 d. to1 yr

CV

de

ath

or

MI (

%)

PlaceboClopidogrel

RRR 31% 32% 34% 21%

*

*P=0.002 Mehta SR et al. Lancet 2001:358:527-33

PCI-

Other OutcomesOther Outcomes

Placebo

N = 1345

Clopidogrel

N=1313

RRR P

Value

GP IIb/IIIa Inhibitor Use

26.6% 20.9% 21% 0.001

Need for secondrevascularization

17.1% 14.2% 18% 0.049


PCI-

Bleeding OutcomesBleeding OutcomesPlacebo Placebo N=1362N=1362

Clopidogrel Clopidogrel N=1362N=1362

RRRR PP

From PCI to 30 days

Major 1.4% 1.6% 1.13 0.69

Life threatening 0.7% 0.7% 0.92 0.86

Minor 0.7% 1.0% 1.33 0.49

From PCI to follow-up

Major 2.5% 2.7% 1.12 0.64

Life threatening 1.3% 1.2% 0.91 0.78

Minor 2.1% 3.5% 1.68 0.03


PCI- Bleeding and GP IIb/IIIa Bleeding and GP IIb/IIIa AntagonistsAntagonists

PlaceboPlacebo Clopidogrel Clopidogrel RRRR PP

At 30 DaysAt 30 Days

Major Major 2.2%2.2% 2.2%2.2% 0.980.98 0.970.97

Life threateningLife threatening 1.1%1.1% 1.1%1.1% 0.980.98 0.980.98


PCI- CV Death or MI from CV Death or MI from Randomization to EndRandomization to End

7.97.911.911.918541854Male Male

13.413.416.916.910421042Age >65Age >65

5.95.99.89.816161616Age Age 65 65

9.49.416.216.2486486No Stent No Stent

8.78.711.711.721722172Stent Stent

8.88.812.612.6OverallOverall

ClopidClopidPlacPlac2N2N

11.011.014.114.1804804FemaleFemale

0.2 1.21.00.80.60.4

Relative RiskRelative Risk

Clopidogrel betterClopidogrel better Placebo betterPlacebo better

26582658


PCI-

7.97.911.711.721542154No DiabetesNo Diabetes12.912.916.516.5504504DiabetesDiabetes

13.513.5

12.012.0

8.98.912.312.321142114PCI > 72 h RandPCI > 72 h Rand

8.58.5544544PCI PCI 72 h Rand 72 h Rand

8.38.317301730PCI in 1st Hosp.PCI in 1st Hosp.

13.813.8 9.89.8928928PCI After 1PCI After 1stst Hosp. Hosp.

21.721.7 9.69.6332332H/O CABGH/O CABG

11.211.2 8.78.723262326No H/O CABGNo H/O CABG

ClopidClopidPlacPlac2N2N

Clopidogrel betterClopidogrel better Placebo betterPlacebo better

0.2 1.21.00.80.60.4

Relative RiskRelative Risk

CV Death or MI from CV Death or MI from Randomization to EndRandomization to End


PCI-

PCI-CURE – PCI-CURE – ConclusionsConclusions

In patients with non-ST elevation ACS undergoing PCI:In patients with non-ST elevation ACS undergoing PCI:

Pretreatment with Clopidogrel followed by long term Pretreatment with Clopidogrel followed by long term therapy for up to 1 year after PCI demonstrated a therapy for up to 1 year after PCI demonstrated a significant reduction in major CV events, compared with significant reduction in major CV events, compared with placebo (overall death/MI P=0.002)placebo (overall death/MI P=0.002)

There were consistent reductions in events in the mutually There were consistent reductions in events in the mutually exclusive time periods before PCI, 4 weeks after PCI and exclusive time periods before PCI, 4 weeks after PCI and in the months thereafter up to one yearin the months thereafter up to one year

There was consistent benefit regardless of whether PCI There was consistent benefit regardless of whether PCI was performed during the initial hospital admission was performed during the initial hospital admission (including very early PCI <72 hrs) or more electively after (including very early PCI <72 hrs) or more electively after dischargedischarge

PCI-

PCI CURE PCI CURE ImplicationsImplications

All patients with non-ST elevation ACS All patients with non-ST elevation ACS should be routinely pretreated with should be routinely pretreated with clopidogrel before PCI with therapy clopidogrel before PCI with therapy continued long term after PCIcontinued long term after PCI

The results of and The results of and together suggest that clopidogrel should be together suggest that clopidogrel should be initiated as early as possible and continued initiated as early as possible and continued long termlong term in all appropriate non-ST in all appropriate non-ST elevation ACS patients regardless of elevation ACS patients regardless of management strategymanagement strategy

PCI-

Documents

PCI - A prospective, randomized, double- blind substudy of patients undergoing PCI in the CURE trial