pci - a prospective, randomized, double- blind substudy of patients undergoing pci in the cure trial
TRANSCRIPT
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)
ClopidogrelClopidogrel
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
Mehta SR et al. Lancet 2001:358:527-33
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
Mehta SR et al. Lancet 2001:358:527-33
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
Mehta SR et al. Lancet 2001:358:527-33
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
Mehta SR et al. Lancet 2001:358:527-33
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
Mehta SR et al. Lancet 2001:358:527-33
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
ClopidogrelClopidogrel
PlaceboPlacebo
A=median time to PCIB=30 days after PCI
Overall Results: Overall Results: CV Death or MICV Death or MI
Mehta SR et al. Lancet 2001:358:527-33
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
Mehta SR et al. Lancet 2001:358:527-33
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
Mehta SR et al. Lancet 2001:358:527-33
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
Mehta SR et al. Lancet 2001:358:527-33
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
Mehta SR et al. Lancet 2001:358:527-33
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
Mehta SR et al. Lancet 2001:358:527-33
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-