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