stents are not enough: recent clopidogrel data rob henderson nottingham city hospital rob henderson...
TRANSCRIPT
Stents Are Not Enough:Stents Are Not Enough:Recent Clopidogrel DataRecent Clopidogrel DataStents Are Not Enough:Stents Are Not Enough:Recent Clopidogrel DataRecent Clopidogrel Data
Rob HendersonRob Henderson
Nottingham City HospitalNottingham City Hospital
Rob HendersonRob Henderson
Nottingham City HospitalNottingham City Hospital
Stent thrombosis - ‘Thrombus Horribilis’Stent thrombosis - ‘Thrombus Horribilis’
• In early 1990’s stent thrombosis occurred in ~4% of elective cases within 2d to 4 weeks
• Associated with high risk of MI (60-90%) and death (12-17%)
• In early 1990’s stent thrombosis occurred in ~4% of elective cases within 2d to 4 weeks
• Associated with high risk of MI (60-90%) and death (12-17%)
Bittl JA, JACC 1996; 28:368-70Hasdai D, JACC 1996;28:361-7Mak KH, JACC 1996;27:494-503
Eur Heart J 2000;21:2033Eur Heart J 2000;21:2033
0.1 1 100.1 1 10
0.31 0.11-0.91
0.32 0.11-0.91
0.61 0.26-1.43
0.66 0.33-1.30
0.51 0.33-0.78
0.31 0.11-0.91
0.32 0.11-0.91
0.61 0.26-1.43
0.66 0.33-1.30
0.51 0.33-0.78
OR 95%CIOR 95%CI
ISAR, 1996
STARS, 1998
MATTIS, 1998
FANTASTIC, 1998
Total
ISAR, 1996
STARS, 1998
MATTIS, 1998
FANTASTIC, 1998
Total
StudyStudy
p=0.002, test for heterogeneity p=0.51p=0.002, test for heterogeneity p=0.51
Aspirin + ticlopidine vs aspirin + warfarinafter coronary stenting
Aspirin + ticlopidine vs aspirin + warfarinafter coronary stenting
Aspirin and ticlopidinebetter
Aspirin and ticlopidinebetter
Aspirin and warfarinbetter
Aspirin and warfarinbetter
Odds of death or MIOdds of death or MI
CLASSICS - clopidogrel versus ticlopidine after coronary stenting
CLASSICS - clopidogrel versus ticlopidine after coronary stenting
Circulation 2000;102:624Circulation 2000;102:624
9.1%
0.9%
4.5%
1.3%
0%
2%
4%
6%
8%
10%
Eve
nt r
ate
at 2
8 da
ys Ticlopidine + ASA (n=340)
Clopidogrel + ASA (n=680)
9.1%
0.9%
4.5%
1.3%
0%
2%
4%
6%
8%
10%
Eve
nt r
ate
at 2
8 da
ys Ticlopidine + ASA (n=340)
Clopidogrel + ASA (n=680)
Safety(major bleed, neutropenia,
thrombocytopenia,early drug discontinuation)
Safety(major bleed, neutropenia,
thrombocytopenia,early drug discontinuation)
Efficacy(Cardiac death,
MI, TVR)
Efficacy(Cardiac death,
MI, TVR)
P=0.005P=0.005
NSNS
Clopidogrel - thienopyridine of choiceClopidogrel - thienopyridine of choice
dose?
pre-treatment?
duration of treatment?
role with IIbIIIa receptor antagonists?
dose?
pre-treatment?
duration of treatment?
role with IIbIIIa receptor antagonists?
CURE: trial design CURE: trial design
12 562 Patients with non-ST-elevationacute coronary syndromes
Placebo + aspirinPlacebo + aspirin Clopidogrel (300mg +75mg daily) + aspirin
Clopidogrel (300mg +75mg daily) + aspirin
4946 no PCI4946 no PCI 1345 underwentPCI
1345 underwentPCI
1313 underwentPCI
1313 underwentPCI
4958 no PCI4958 no PCI
Thienopyridine for 2-4 weeks(344 open label drug before PCI)
Thienopyridine for 2-4 weeks(344 open label drug before PCI)
PCI -CURE
Thienopyridine for 2-4 weeks(329 open label drug before PCI)
Thienopyridine for 2-4 weeks(329 open label drug before PCI)
PCI-CUREPCI-CURE
NEJM 2001;345:494NEJM 2001;345:494
CURE: primary endpoint - CV death/MI/strokeCURE: primary endpoint - CV death/MI/stroke
Clopidogrel Clopidogrel + ASA+ ASA
Clopidogrel Clopidogrel + ASA+ ASA
3333 6666 9999
Placebo Placebo + ASA+ ASA
Placebo Placebo + ASA+ ASA
Months of Follow-UpMonths of Follow-UpMonths of Follow-UpMonths of Follow-Up
11.4%11.4%11.4%11.4%
9.3%9.3%9.3%9.3%
20% RRR20% RRRPP < 0.001 < 0.001
N = 12,562N = 12,562
20% RRR20% RRRPP < 0.001 < 0.001
N = 12,562N = 12,562
0000 121212120.000.00
0.020.02
0.040.04
0.060.06
0.080.08
0.100.10
0.120.12
0.140.14
Cu
mu
lati
ve H
azar
d R
ate
Cu
mu
lati
ve H
azar
d R
ate
Δ2.1%Δ2.1%
Excess of 1 life-threatening and 6 major bleeds per 1000 patients treated with clopidogrelExcess of 1 life-threatening and 6 major bleeds per 1000 patients treated with clopidogrel
Effect of aspirin dose in CUREEffect of aspirin dose in CURE
18.2%17.2%
20.7%
16.3% 15.7%17.4%
0%
5%
10%
15%
20%
25%
<100mgn=5320
101-199mgn=3109
>200mgn=4110
18.2%17.2%
20.7%
16.3% 15.7%17.4%
0%
5%
10%
15%
20%
25%
<100mgn=5320
101-199mgn=3109
>200mgn=4110
1.9%
2.8%
3.7%
3.0%3.4%
4.9%
0%
1%
2%
3%
4%
5%
6%
<100mgn=5320
101-199mgn=3109
>200mgn=4110
Aspirin + Placebo
Aspirin + Clopidogrel
1.9%
2.8%
3.7%
3.0%3.4%
4.9%
0%
1%
2%
3%
4%
5%
6%
<100mgn=5320
101-199mgn=3109
>200mgn=4110
Aspirin + Placebo
Aspirin + Clopidogrel
CV death, MI, stroke, refractory angina
CV death, MI, stroke, refractory angina
Major bleedingMajor bleeding
Aspirin doseAspirin dose
P<0.001P<0.001
Peters, Circulation 2003; 108: 1682Peters, Circulation 2003; 108: 1682
PCI-CURE: 30 day resultsEffect of pre-treatment with clopidogrel
PCI-CURE: 30 day resultsEffect of pre-treatment with clopidogrel
00 55 1010 1515 2020 2525 3030Days of follow-upDays of follow-up
0.00.0
0.020.02
0.040.04
0.060.06
0.080.08
30% RRRP = 0.03
N = 2658
30% RRRP = 0.03
N = 2658Cum
ulat
ive
Haz
ard
Rat
eC
umul
ativ
e H
azar
d R
ate
* Includes open label thienopyridine* Includes open label thienopyridine
6.4%6.4%
4.5%4.5%
Clopidogrel+ ASA*
Clopidogrel+ ASA*
Placebo + ASA*
Placebo + ASA*
Composite of cardiovascular death, MI, or urgent revascularizationComposite of cardiovascular death, MI, or urgent revascularization
Mehta, Lancet 2001; 21: 2033Mehta, Lancet 2001; 21: 2033
Δ1.9%Δ1.9%
PCI-CURE – long-term resultsPCI-CURE – long-term results
Mehta Lancet 2001;358:527Mehta Lancet 2001;358:527
Placebo + ASAPlacebo + ASA0.150.15
0.100.10
0.050.05
0.00.0
00 100100 200200 300300 400400Days of follow-upDays of follow-up
12.6%12.6%
8.8%8.8%
P = 0.002N = 2658
P = 0.002N = 2658
Cum
ulat
ive
Haz
ard
Rat
eC
umul
ativ
e H
azar
d R
ate
31% RRR31% RRR
Composite of cardiovascular death or MI from randomization to end of follow-upComposite of cardiovascular death or MI from randomization to end of follow-up
Clopidogrel + ASAClopidogrel + ASA
Caveat - PCI-CURE was not a randomised trialCaveat - PCI-CURE was not a randomised trial
Δ2.8%Δ2.8%
CREDO: Clopidogrel for the Reduction of Events During
Observation
CREDO: Clopidogrel for the Reduction of Events During
Observation
C lop id og re l 7 5 m g odu n til s tu d y en d
C lop id og re l 7 5 m g odfo r 2 8 d ays
C lop id og re l 3 0 0 m g load in g3 -2 4 h rs p re -p roced u re
P laceb ou n til s tu d y en d
C lop id og re l 7 5 m g odfo r 2 8 d ays
P laceb o load in g3 -2 4 h rs p re -p roced u re
2 1 1 6 p a tien ts sch ed u led fo r P C I
C lop id og re l 7 5 m g odu n til s tu d y en d
C lop id og re l 7 5 m g odfo r 2 8 d ays
C lop id og re l 3 0 0 m g load in g3 -2 4 h rs p re -p roced u re
P laceb ou n til s tu d y en d
C lop id og re l 7 5 m g odfo r 2 8 d ays
P laceb o load in g3 -2 4 h rs p re -p roced u re
2 1 1 6 p a tien ts sch ed u led fo r P C I
Aspirin in all patientsIIbIIIa antagonist in 45%
Aspirin in all patientsIIbIIIa antagonist in 45%
Com
bine
d E
ndpo
int
Occ
urre
nce
(%)
Com
bine
d E
ndpo
int
Occ
urre
nce
(%)
Days From RandomizationDays From Randomization
00
55
1010
00 77 1414 2121 2828
*Plus ASA and other standard therapies*Plus ASA and other standard therapies
Death, MI, UTVR - PP Population (N=1815)Death, MI, UTVR - PP Population (N=1815)
18.5% RRR, 95%CI -14.2 to 41.8, p=0.2318.5% RRR, 95%CI -14.2 to 41.8, p=0.23
99
88
11
44
33
22
77
66
8.3%8.3%
6.8%6.8%
Steinhubl, JAMA 2002; 288: 2411Steinhubl, JAMA 2002; 288: 2411
CREDO - Pre-treatment with clopidogrelCREDO - Pre-treatment with clopidogrel
Clopidogrel pre-treatmentClopidogrel pre-treatment
No pre-treatmentNo pre-treatment
Δ1.5%Δ1.5%
* Plus ASA and other standard therapies * Plus ASA and other standard therapies
CREDO: 12 month benefits of clopidogrel in PCI patients
CREDO: 12 month benefits of clopidogrel in PCI patients
Death, MI, or stroke – ITT PopulationDeath, MI, or stroke – ITT PopulationC
ombi
ned
End
poin
t O
ccur
renc
e (%
)C
ombi
ned
End
poin
t O
ccur
renc
e (%
)
Months From RandomizationMonths From Randomization
27% RRR, 95%CI 3.9 to 44.4, P=0.0227% RRR, 95%CI 3.9 to 44.4, P=0.020000
5555
10101010
15151515
8.5%8.5%8.5%8.5%
11.5%11.5%11.5%11.5%
0000 3333 6666 9999 12121212
ClopidogrelClopidogrel
PlaceboPlacebo
Steinhubl, JAMA 2002; 288: 2411Steinhubl, JAMA 2002; 288: 2411Steinhubl, JAMA 2002; 288: 2411Steinhubl, JAMA 2002; 288: 2411
Δ2.0%Δ2.0%
CREDO – loading dose timing and 28d MACE (D/MI/urgent TVR)
CREDO – loading dose timing and 28d MACE (D/MI/urgent TVR)
3.5%
8.0% 8.3%
0%
5%
10%
15%
Clopidogrel>15hrs N=202
Clopidogrel<15hrs N=545
Placebo N=915
% P
atie
nts
3.5%
8.0% 8.3%
0%
5%
10%
15%
Clopidogrel>15hrs N=202
Clopidogrel<15hrs N=545
Placebo N=915
% P
atie
nts
Steinhubl, TCT 2003
CREDO – clopidogrel loading dose timingand MACE at 28d in per protocol patients (n=1762)
CREDO – clopidogrel loading dose timingand MACE at 28d in per protocol patients (n=1762)
-2-2
-3-3
-4-4
-5-5
-6-6303055 1010 1515 2020 252500
Hours prior to PCI of study drug loading doseHours prior to PCI of study drug loading dose
Log odds of death, MI or urgent TVR at 28 daysLog odds of death, MI or urgent TVR at 28 days
PlaceboPlacebo
ClopidogrelClopidogrel
P=0.020for treatment / timing
interaction
P=0.020for treatment / timing
interaction
Steinhubl, TCT 2003
Clopidogrel loading dose – bigger is better?Clopidogrel loading dose – bigger is better?
Müller Heart 2001;85;92-3Müller Heart 2001;85;92-3Time after administration (hours)Time after administration (hours)
00 44 2424 484800
2020
4040
6060
8080
100100
20µmol ADP-inducedplatelet aggregation (%)20µmol ADP-induced
platelet aggregation (%)Ticlopidine 2x 500mg, then 250 bd (n=10)Ticlopidine 2x 500mg, then 250 bd (n=10)
Clopidogrel 300mg, then 75mg od (n=10)Clopidogrel 300mg, then 75mg od (n=10)
Clopidogrel 600mg, then 75mg bd (n=10)Clopidogrel 600mg, then 75mg bd (n=10)
ISAR-REACT - trial designISAR-REACT - trial design
2,159 low-risk patients undergoing elective stenting, excluding patients with:
Acute coronary syndrome Acute MI with 14 days ST-segment depression Positive biomarkers
Insulin-dependent diabetesChronic total occlusions
Lesions in bypass grafts Thrombus presence
EF <=30%
2,159 low-risk patients undergoing elective stenting, excluding patients with:
Acute coronary syndrome Acute MI with 14 days ST-segment depression Positive biomarkers
Insulin-dependent diabetesChronic total occlusions
Lesions in bypass grafts Thrombus presence
EF <=30%
Endpoints:
Primary – 30 day death / MI / urgent target vessel revascularization
Secondary –30 day bleeding complications
Endpoints:
Primary – 30 day death / MI / urgent target vessel revascularization
Secondary –30 day bleeding complications
Abciximab (n = 1,079)Abciximab (n = 1,079) Placebo (n = 1,080)Placebo (n = 1,080)
Aspirin at least 100mg od and
Clopidogrel (600 mg loading, 75 mg bd to discharge, 75 mg od for 4 weeks)
Aspirin at least 100mg od and
Clopidogrel (600 mg loading, 75 mg bd to discharge, 75 mg od for 4 weeks)
Kastrati, NEJM 2004; 350: 232Kastrati, NEJM 2004; 350: 232
ISAR-REACT: efficacy analysis at 30 daysISAR-REACT: efficacy analysis at 30 days
0.3% 0.4%
1.7%
3.7%
0.9%
0.3%0.5%
1.5%
3.8%
0.6%
0%
1%
2%
3%
4%
5%
Death Q MI Large MI Any MI Urgent TVR
AbciximabPlacebo
0.3% 0.4%
1.7%
3.7%
0.9%
0.3%0.5%
1.5%
3.8%
0.6%
0%
1%
2%
3%
4%
5%
Death Q MI Large MI Any MI Urgent TVR
AbciximabPlacebo
No significant differencesNo significant differences
Kastrati, NEJM 2004; 350: 232Kastrati, NEJM 2004; 350: 232
All patients had clopidogrel 600mg loading, then maintenance RxAll patients had clopidogrel 600mg loading, then maintenance Rx
ISAR-REACT: death, MI or urgent TVR at 30dISAR-REACT: death, MI or urgent TVR at 30d
00 55 1010 1515 2020 2525 303000
11
22
33
44
55
Days after randomizationDays after randomization
Cu
mu
lativ
e in
cid
enc
e (
%)
Cu
mu
lativ
e in
cid
enc
e (
%) AbciximabAbciximab
PlaceboPlacebo
Relative risk 1.05 (95%CI 0.69-1.59; p=082)Underpowered for triple endpoint at 30d
Relative risk 1.05 (95%CI 0.69-1.59; p=082)Underpowered for triple endpoint at 30d
Kastrati, NEJM 2004; 350: 232Kastrati, NEJM 2004; 350: 232
All patients had clopidogrel 600mg loading, then maintenance RxAll patients had clopidogrel 600mg loading, then maintenance Rx
N=2159N=2159
ISAR-REACT: safety analysisISAR-REACT: safety analysis
1.1%
2.5% 2.4%
0.9%0.7%
1.9%
0.9%
0.0%0%
1%
2%
3%
4%
5%
TIMI majorbleed
TIMI minorbleed
Transfusion Thrombo-cytopenia
Abciximab
Placebo
1.1%
2.5% 2.4%
0.9%0.7%
1.9%
0.9%
0.0%0%
1%
2%
3%
4%
5%
TIMI majorbleed
TIMI minorbleed
Transfusion Thrombo-cytopenia
Abciximab
Placebo
p=0.002p=0.002
Kastrati, NEJM 2004; 350: 232Kastrati, NEJM 2004; 350: 232
p=0.007p=0.007
All patients had clopidogrel 600mg loading, then maintenance RxAll patients had clopidogrel 600mg loading, then maintenance Rx
Thienopyridine use in drug-eluting stent trialsThienopyridine use in drug-eluting stent trials
TrialTrial StentStent Thienopyridine (mg)Thienopyridine (mg) IIbIIIaIIbIIIa FUFU NN Stent thrombosisStent thrombosis
DESDES ControlControl
RavelRavel Sirolimus Sirolimus (Cordis)(Cordis)
Clopidogrel 300 loading and 75 od, Clopidogrel 300 loading and 75 od, or Ticlopidine 250 bd for 2/12or Ticlopidine 250 bd for 2/12 9.8%9.8% 238238 00 00
E-SIRIUSE-SIRIUS Sirolimus Sirolimus (Cordis)(Cordis)
Clopidogrel 300 loading + 75 od, or Clopidogrel 300 loading + 75 od, or Ticlopidine 250 bd for 2/12Ticlopidine 250 bd for 2/12 15.9%15.9% 352352 1.1%1.1% 00
SIRIUSSIRIUS Sirolimus Sirolimus (Cordis)(Cordis)
Clopidogrel 300-375 loading, 75 od Clopidogrel 300-375 loading, 75 od for 3/12for 3/12 60%60% 10581058 0.4%0.4% 0.8%0.8%
ASPECTASPECT Paclitaxel Paclitaxel (Cook)(Cook)
Ticlopidine loading, then 1 or 6/12Ticlopidine loading, then 1 or 6/12
Clopidogrel loading, then 1 or 6/12Clopidogrel loading, then 1 or 6/12
CilostazolCilostazol1.1%1.1% 177177
00
00
2.7%2.7%
00
00
00
TAXUS2TAXUS2 Paclitaxel Paclitaxel (Boston)(Boston)
Clopidogrel 300 loading, then 75 od Clopidogrel 300 loading, then 75 od for 6/12for 6/12 NANA 402402 0.4%0.4%
TAXUS4TAXUS4 PaclitaxelPaclitaxel
(Boston)(Boston)
Clopidogrel 300 loading, then 75 od Clopidogrel 300 loading, then 75 od for 6/12for 6/12 57%57% 12/1212/12 13261326 0.6%0.6% 0.8%0.8%
TAXUS6TAXUS6 PaclitaxelPaclitaxel
(Boston)(Boston)
Clopidogrel 300 loading, then 75 od Clopidogrel 300 loading, then 75 od for 6/12for 6/12 NANA
446446NANA NANA
Randomised trial evidence for prolonged clopidogrel treatment after DES placementRandomised trial evidence for prolonged
clopidogrel treatment after DES placement
• Prodrug clopidogrel is metabolised to active metabolite by cytochrome P450 (?isozymes 3A4 and 3A5)
• Atorvastatin (and other statins) also metabolised by CP450 3A4
• Some ex-vivo evidence that co-administration of these drugs inhibits activation of clopidogrel
• Prodrug clopidogrel is metabolised to active metabolite by cytochrome P450 (?isozymes 3A4 and 3A5)
• Atorvastatin (and other statins) also metabolised by CP450 3A4
• Some ex-vivo evidence that co-administration of these drugs inhibits activation of clopidogrel
Does atorvastatin reduce the effect of clopidogrel on platelet aggregation?
Does atorvastatin reduce the effect of clopidogrel on platelet aggregation?
Clarke, Drug Metab Disp 2003; 31: 53Lau, Circulation 2003;107:32Clarke, Drug Metab Disp 2003; 31: 53Lau, Circulation 2003;107:32
CREDO – no clinically important interaction between statins and clopidogrel
CREDO – no clinically important interaction between statins and clopidogrel
7.4% 7.6%
5.4%
10.1%
11.9% 11.8%
13.6%
11.6%
0%
4%
8%
12%
16%
Statin usen=1172
CYP3A4 Metn=1001
Non-CYP3A4Met n=158
No statin usen=944
1 y
r d
ea
th /
MI
/ st
roke
(%
)
Clopidogrel
Placebo
7.4% 7.6%
5.4%
10.1%
11.9% 11.8%
13.6%
11.6%
0%
4%
8%
12%
16%
Statin usen=1172
CYP3A4 Metn=1001
Non-CYP3A4Met n=158
No statin usen=944
1 y
r d
ea
th /
MI
/ st
roke
(%
)
Clopidogrel
Placebo
Saw, Circulation 2003; 108: 921Saw, Circulation 2003; 108: 921
No statistical evidence of a clinically important interaction between statin use and effect of clopidogrel
No statistical evidence of a clinically important interaction between statin use and effect of clopidogrel
Clopidogrel resistanceClopidogrel resistance
• Several studies demonstrate marked inter-patient variability in response to clopidogrel
• No consistent definition of ‘resistance’ but reported incidence ranges from 4.8% to 31%
• Clinical significance of clopidogrel ‘resistance uncertain
• Aspirin resistance increases risk of death, MI or stroke 3-fold during 1-2 year follow-up
• Several studies demonstrate marked inter-patient variability in response to clopidogrel
• No consistent definition of ‘resistance’ but reported incidence ranges from 4.8% to 31%
• Clinical significance of clopidogrel ‘resistance uncertain
• Aspirin resistance increases risk of death, MI or stroke 3-fold during 1-2 year follow-up
Müller, Thromb Haemost 2003; 89: 783Gurbel, Circulation 2003; 107: 2908Gum, JACC 2003;41: 961
Müller, Thromb Haemost 2003; 89: 783Gurbel, Circulation 2003; 107: 2908Gum, JACC 2003;41: 961
Hollopeter, Nature 2001;409:202Fontana, Circulation 2003;108:989Hollopeter, Nature 2001;409:202Fontana, Circulation 2003;108:989
Normal platelet aggregation requires simultaneous activationof Gq and Gi pathways by ADP
Normal platelet aggregation requires simultaneous activationof Gq and Gi pathways by ADP
*Phosphoinositide 3-kinase pathway?*Phosphoinositide 3-kinase pathway?
P2Y12 ADP receptor is target of clopidogrelP2Y12 ADP receptor is target of clopidogrel
Transient
Ca2+
Transient
Ca2+
Platelet shape change and reversible aggregation
Platelet shape change and reversible aggregation
GqGq
GiGi
Adenylate cyclase inhibition
cAMP
Adenylate cyclase inhibition
cAMPP2Y12P2Y12
P2Y1P2Y1
ThienopyridineThienopyridine
ADPADP
ADPADPProgressive and
sustained platelet aggregation
Progressive and sustained platelet
aggregation
GPIIbIIIa activationGPIIbIIIa activation**
Maximal platelet aggregation in response to2µmol/L ADP for different P2Y12 haplotype
Maximal platelet aggregation in response to2µmol/L ADP for different P2Y12 haplotype
100100
5050
00
Mea
n m
axim
al a
ggre
gatio
n (%
)M
ean
max
imal
agg
rega
tion
(%)
H1/H1H1/H1 H1/H2H1/H2 H2/H2H2/H2
n=74n=74 n=21n=21 n=3n=3
34.7%34.7%
67.9%67.9%
82.4%82.4%
P2Y12 platelet receptor haplotypeP2Y12 platelet receptor haplotype
Fontana, Circulation 2003;108:989
Clopidogrel in PCI patients
• Pretreatment has a small but important beneficial effect on MACE rate
• Whenever possible start early (3-5 days) or give loading dose (600mg within 12-15h)
• Optimal duration of treatment uncertain– In ACS continue clopidogrel at least 3 months but
cost efficacy of longer-term treatment uncertain– DES trials used 3-6 months
• Combine with low-dose aspirin (75mg)
• Pretreatment has a small but important beneficial effect on MACE rate
• Whenever possible start early (3-5 days) or give loading dose (600mg within 12-15h)
• Optimal duration of treatment uncertain– In ACS continue clopidogrel at least 3 months but
cost efficacy of longer-term treatment uncertain– DES trials used 3-6 months
• Combine with low-dose aspirin (75mg)
Clopidogrel in PCI patients
• Combined use of clopidogrel and IIbIIIa antagonist may increase bleeding risk
• In low risk PCI abciximab may not add major benefit to clopidogrel 600mg loading at least 2h pre-procedure
• Currently no evidence of clinically important clopidogrel / statin interaction
• Clopidogrel ‘resistance’ occurs ex vivo but no data to support clinical relevance
• Combined use of clopidogrel and IIbIIIa antagonist may increase bleeding risk
• In low risk PCI abciximab may not add major benefit to clopidogrel 600mg loading at least 2h pre-procedure
• Currently no evidence of clinically important clopidogrel / statin interaction
• Clopidogrel ‘resistance’ occurs ex vivo but no data to support clinical relevance