up-to-date : antiplatelet therapy for acute coronary syndrome · acute coronary syndrome and er...

UpUp--toto--date : date : AntiplateletAntiplatelet

Therapy for Acute Therapy for Acute Coronary Coronary SyndromeSyndrome

นพนพ.. ภาภาวิทยวิทย เพียรวิจิตรเพียรวิจิตรหนวยโรคหัวใจหนวยโรคหัวใจ

คณะแพทยศาสตรโรงพยาบาลรามาธิบดีคณะแพทยศาสตรโรงพยาบาลรามาธิบดีมหาวิทยาลัยมหิดลมหาวิทยาลัยมหิดล

Acute Coronary Acute Coronary Syndrome and Syndrome and

ER ManagementER Management

นพนพ.. ภาภาวิทยวิทย เพียรวิจิตรเพียรวิจิตรหนวยโรคหัวใจหนวยโรคหัวใจ

คณะแพทยศาสตรโรงพยาบาลรามาธิบดีคณะแพทยศาสตรโรงพยาบาลรามาธิบดีมหาวิทยาลัยมหิดลมหาวิทยาลัยมหิดล

Increasing CV MortalityIncreasing CV Mortality

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CVDAccidentCancerAIDSPneumoniaDiarrhea

Bureau of Health Policy and Plan and Division of Epidemiology, MOPH

Top Ten Causes of Death in Top Ten Causes of Death in ThailandThailand

Per 100,000 population

Bureau of Health Policy and Plan and Division of Epidemiology, MOPH

CAD: 2 Major PresentationsCAD: 2 Major Presentations

Stable anginaStable angina

Unstable angina / ACSUnstable angina / ACS

Case # 1: Case # 1: อาการคงที่อาการคงที่ (stable angina)(stable angina)

AgeAge: 55: 55SexSex: Male: MalePast HistoryPast History: HTN: HTNOccupationOccupation: High stress: High stressComplaintComplaint::

Chest pain when he runs Chest pain when he runs about 500 meters.about 500 meters.Relieved with rest in 3 Relieved with rest in 3 minutes.minutes.Occasional chest pain Occasional chest pain with stresswith stress

‘‘StableStable’’ Angina: Predictable DiseaseAngina: Predictable Disease

ไขมัน พังผืด เซล

AgeAge: 50: 50SexSex: Male: MaleHabitHabit: non: non--smokersmokerPast HistoryPast History: : --

ComplaintComplaint::Sudden onset of chest pain Sudden onset of chest pain while restingwhile restingNo improvement after No improvement after 15minutes15minutes

What causes What causes ‘‘unstableunstable’’ symptom?symptom?

?

Acute Coronary SyndromeAcute Coronary Syndrome

Plaque RupturePlaque Rupture

‘‘ActiveActive’’ Platelet Platelet

Scanning electron micrograph of dormant platelets

Activated, aggregating platelets with fibrin strands

Lip GYH et al. Circulation 1996; 94: 425-431. Lip GYH et al. Am Heart J 1996; 131: 724-730.

ลิ่มเลอืด

Truths about Plaque RuptureTruths about Plaque Rupture

No warning.No warning.

Can occur after Can occur after ‘‘normalnormal’’ EST.EST.

No precipitating cause: ?No precipitating cause: ?↑↑BP, BP, ??activitiyactivitiy

Spectrum of ACSSpectrum of ACS

Accelerating/ New onset AnginaAccelerating/ New onset Angina

Unstable Angina, EKGUnstable Angina, EKG--, Trop, Trop--

UA with Trop+UA with Trop+ / NSTEMI / NQWMINSTEMI / NQWMI

STEMI / QWMI

ST Elevation MI

Non ST Elevation MI

Difference in Mortality

16.7

7

16.6

54.1

3

0

2

4

6

8

10

12

14

16

18

%

STEMI NSTEMI UA

Mortality of ACS in hospital (Thai ACSR : 2002)

Thai

US

แนวทางการรักษาคนไขแนวทางการรักษาคนไข ACSACS

Prevent plaque rupturePrevent plaque ruptureStatinsStatins

Decrease ODecrease O22 needneed

DecreaseDecrease platelet activation and platelet activation and aggregationaggregation

Open blocked vesselOpen blocked vessel

ยาที่ควรใหในยาที่ควรใหใน ACS ACS (NSTEMI and STEMI)(NSTEMI and STEMI)

ยาตานเกลด็เลอืดยาตานเกลด็เลอืดBB--blockers* blockers* (? mode of administration)(? mode of administration)

Ca blockers as alternativesCa blockers as alternativesNitratesNitratesOO22MorphineMorphineAntiAnti--coagulationcoagulationACEI*ACEI*

If no contra-indications!

Class I Class I

RecommendationRecommendation

AspirinAspirin

Mechanism of actionMechanism of action::Irreversible COX inhibitorCOX inhibitorPrevents thromboxane A2 formation Diminishing platelet aggregation

IndicationIndication:: Class IAClass IA

Dosage:Dosage: 160160--300mg300mg

Efficacy of ASA: Reduction of Efficacy of ASA: Reduction of Death or MI in Death or MI in Unstable AnginaUnstable Angina

0.25

Placebo

ASA 75 mg

Risk ratio after 1 year 0.5295% Cl 0.37–0.72 (p=0.0001)

Prob

abili

ty o

f dea

th o

r MI

0.20

0.15

0.10

0.05

0.000 3 6 9 12

Months

Wallentin LC et al JACC 1991;18:1587–1593

LyticsLytics & ASA in STEMI: ISIS& ASA in STEMI: ISIS--22

12.0%

9.2% 9.4%

11.8%13.2%

8.0%

Placebo versusstreptokinase

Placebo versusASA 162 mg

Neitherversus both

5-w

eek

mor

talit

y (%

)

25%*p <0.00001

23%*p <0.00001

42%*p <0.00001

0

2

4

6

8

10

12

14

*Odds reduction1. ISIS-2 Collaborative Group. Lancet 1988; 2: 349−360.

AntiplateletAntiplatelet and Cardiovascular Eventsand Cardiovascular Events

Category of trial

Prior MIAcute MIAcute MIPrior stroke/TIAOther high riskAll high risk(all the above)All low risk (primary prevention)

All trials

1199

18104142

3

145

MI/Stroke or Vascular DeathAnti-platelet adjusted controls

13.5 % 17.1%10.6 % 14.4%10.6 % 14.4%18.4% 22.2%6.9% 9.2%

4,183/36 536 5,400/36 711(11.4%) (14.7%)

652/14,608 708/14,604(4.46%) (4.85%)

4 835/51,144 6,108/51,315(9.5%) (11.19%)

0 0.5 1.0 1.5 2.0

25(4)29(4)22(4)32(4)27(2)

10(6)

25(2)

%OR(SD)

OR&CI

better worse2p <0.00001

No.of trials

AntiplateletAntiplatelet TrialistTrialist Collaboration BMJ. 1994Collaboration BMJ. 1994

ADP AntagonistADP Antagonist

ThienopyridineThienopyridine derivativederivative

Mechanism of action:Mechanism of action:

ADP receptor antagonistADP receptor antagonist

Mode of ActionMode of Action

COX, cyclooxygenase; ADP, adenosine diphosphate; TxA2, thromboxane A2

Schafer AI Am J Med 1996;101:199–209

PLAVIX is a selective and potent inhibitor of platelet PLAVIX is a selective and potent inhibitor of platelet aggregation aggregation PLAVIX binds to a receptor and blocks ADPPLAVIX binds to a receptor and blocks ADP--induced induced aggregation aggregation Blocking ADP binding results in a coupled biochemical Blocking ADP binding results in a coupled biochemical reaction that inhibits binding of fibrinogen to the reaction that inhibits binding of fibrinogen to the GPIIb/IIIaGPIIb/IIIa receptor on the platelet surface receptor on the platelet surface The end result is an irreversible modification of the The end result is an irreversible modification of the platelet, rendering it unable to aggregate platelet, rendering it unable to aggregate

ClopidogrelClopidogrel in Atherosclerotic in Atherosclerotic Disease (CAPRIE)Disease (CAPRIE)

Patient population:Recent ischemic strokeRecent MISymptomatic peripheral arterial disease

ASA 325mg vs Clopidogrel 75mg

Follow-up: 1 to 3 years

>> Confidential <<

ClopidogrelClopidogrel in Unstable Angina to Prevent in Unstable Angina to Prevent Recurrent Events : CURE DesignRecurrent Events : CURE Design

Double-blind treatment 3 to 12 months

ASA 75–325 mg

ASA 75–325 mg

6 mon

th vi

sit9 m

onth

visit

12 m

onth

or fi

nal v

isit

3 mon

th vi

sit

Disc

harg

e visi

t

1 mon

th vi

sit

ACSwithout ST elevation

R

N ≈12 50028 countries

Double-blind treatment 3 to 12 months

Day 1

Clopidogrel 300 mg loading dose

R

Plac

ebo

load

ing

dose

•Presented within 24hrs•Clinical symptoms•Ischemic EKG change

Clopidogrel75 mg o.d.

(~6250 patients)

Placebo1 tab o.d.

(~6250 patients)

CURE Study Investigators Eur Heart J 2000;21:2033–2041

CURE : Primary EndpointCURE : Primary Endpoint

20% RRRp=0.00009n=12,562

Benefits were seen within hours and continued to increase over the 12 months

% of patients with recurrent ischemic event (cardiovascular death, MI, or stroke)*

0

10

14

12

4

8

6

2

Standard therapy‡

Clopidogrel + standard therapy‡

9.3%

11.4%

0 1 2 3 4 5 6 7 8 9 10 11 12Months of follow-up‡including ASA

The CURE Investigators. N Eng J Med August 2001

Primary Outcome : SubgroupsPrimary Outcome : Subgroups

Overall 12 562 11.4 9.3

ST deviation + 6275 14.3 11.5ST deviation - 6287 8.6 7.0

Entry enzymes elevated + 3176 13.0 10.9Entry enzymes elevated - 9386 10.9 8.8

Diabetes + 2840 16.7 14.2Diabetes - 9722 9.9 7.9

Risk Low 4187 6.7 5.1Intermediate 4185 9.4 6.5High 4184 18.0 16.3

Rev after randomization + 4577 13.9 11.5Rev after randomization - 7985 10.0 8.1

History of rev + 2246 14.4 8.4History of rev - 10 316 10.7 9.5

Patient characteristics

0.4 0.6 0.8 1.0 1.2

RR (95% CI)

+ with condition - without condition Rev, revascularization

The CURE Investigators. N Eng J Med August 2001

‡including ASA

2N % eventsStandard therapy‡

Clopidogrel + Standard therapy‡

PCIPCI--CURECURECV death, MI or urgent TVR at 30d post PCI

•30% risk reduction•Absolute reduction 1.9%•P=0.03

PCIPCI--CURE :CURE :LongLong--term Efficacyterm Efficacy

Composite of CV-death or MI from randomization to end of follow-up†

0.15

0.10

0.05

0.0100

040

a b

Placebo‡

ClopidogrelClopidogrel‡‡

The CURE Investigators. Lancet August 2001

a = median time from randomization to PCI (10 days)b = 30 days after median time of PCI†up to 12 months ‡on top of standard therapy including ASA

100 200 300 400

Cum

ulat

ive

haza

rd ra

tes

31% RRR31% RRRp=0.002p=0.002n=2658n=2658

12.6%

8.8%

Days of follow-up

CURE: Major Bleeding by ASA CURE: Major Bleeding by ASA DoseDose

Peters RJ et al. Circulation 2003;108:1682

2002 ACC/AHA UA/NSTEMI 2002 ACC/AHA UA/NSTEMI Guidelines UpdateGuidelines Update

Class I:Class I:•• ASA should be administered as soon as possible after ASA should be administered as soon as possible after

presentation and continued indefinitely (IA)presentation and continued indefinitely (IA)•• ClopidogrelClopidogrel 75 mg daily (in the absence of 75 mg daily (in the absence of

contraindications) when ASA is not tolerated (IA)contraindications) when ASA is not tolerated (IA)•• If early If early nonnon--interventional approachinterventional approach is planned, is planned,

clopidogrel should be added to ASA as soon as clopidogrel should be added to ASA as soon as possible on admission and administered for at least 1 possible on admission and administered for at least 1 month (IA) and for up to 9 months (IB)month (IA) and for up to 9 months (IB)

•• If If PCI plannedPCI planned, clopidogrel should be started and , clopidogrel should be started and continued for at least 1 month (IA) and up to 9 months in continued for at least 1 month (IA) and up to 9 months in patients who are not at high risk for bleeding (IB)patients who are not at high risk for bleeding (IB)

1. Braunwald E et al.FOR INTERNAL USE ONLY


Class I:Class I:•• In patients taking clopidogrel in whom elective CABG is planned,In patients taking clopidogrel in whom elective CABG is planned,

the drug should be withheld for 5the drug should be withheld for 5−−7 days (IB)7 days (IB)

•• Anticoagulation with subcutaneous low molecular weight heparin Anticoagulation with subcutaneous low molecular weight heparin (LMWH) or intravenous (iv) (LMWH) or intravenous (iv) unfractionatedunfractionated heparin (UFH) should be heparin (UFH) should be added to antiplatelet therapy with ASA and/or clopidogrel (IA)added to antiplatelet therapy with ASA and/or clopidogrel (IA)

•• A platelet A platelet GPIIb/IIIaGPIIb/IIIa antagonist should be administered, in addition antagonist should be administered, in addition to ASA and heparin, to patients in whom catheterization and PCI to ASA and heparin, to patients in whom catheterization and PCI are planned. The are planned. The GPIIb/IIIaGPIIb/IIIa antagonist may also be administered antagonist may also be administered just prior to PCI (IA)just prior to PCI (IA)

*Also known as non-Q-wave MI

FOR INTERNAL USE ONLY1. Braunwald E et al.


Class I:Class I:•• For longFor long--term medical therapy, the combination of ASA and term medical therapy, the combination of ASA and

clopidogrel is recommended for 9 months after UA/NSTEMI (B)clopidogrel is recommended for 9 months after UA/NSTEMI (B)

*Also known as non-Q-wave MI

FOR INTERNAL USE ONLY1. Braunwald E et al.

ALBIONALBIONAssessment of best Loading dose of Assessment of best Loading dose of clopidogrelclopidogrel to Blunt to Blunt platelet activation, Inflammation and Ongoing Necrosisplatelet activation, Inflammation and Ongoing Necrosis

103 patients aged 18 to 85 years103 patients aged 18 to 85 yearsUA NSTEMI within the 48 hours prior to UA NSTEMI within the 48 hours prior to randomisationrandomisation. . 300mg, 600mg and 900mg300mg, 600mg and 900mgBlood monitored every hour during the first 6 hours then Blood monitored every hour during the first 6 hours then at 24 hours to determine the kinetics of inhibition of at 24 hours to determine the kinetics of inhibition of platelet aggregation.platelet aggregation.Within the first 24 hours, higher loading doses of Within the first 24 hours, higher loading doses of clopidogrelclopidogrel induced faster onset of action and higher induced faster onset of action and higher levels of inhibition of platelet aggregation than the levels of inhibition of platelet aggregation than the indicated loading dose of 300mg, in patients with ACSindicated loading dose of 300mg, in patients with ACSSimilar safety profile among different dosage groups.Similar safety profile among different dosage groups.

EuroPCREuroPCR Congress in Paris on May 24Congress in Paris on May 24

Faster Onset of Action and Faster Onset of Action and Higher Level of Platelet InhibitionHigher Level of Platelet Inhibition

Maximum Inhibition of Platelet Aggregation (5 µM ADP)

0

5

10

15

20

25

30

35

40

45

1 2 3 4 5 6 24

Time (h)

(%)

Inh

ibit

ion

300 mg LD600 mg LD900 mg LD

p< 0.05 vs. 300 mg LD

Shortened time to reach the highest level of inhibition of the 300 mg LD

Faster Onset of Action and Higher Level of Platelet Inhibition

Maximum Inhibition of Platelet Aggregation (20 µM ADP)

0

5

10

15

20

25

30

35

40

1 2 3 4 5 6 24

Time (h)

(%)

Inhi

biti

on

300 mg LD600 mg LD900 mg LD

p< 0.05 vs. 300 mg LD

Major Adverse CardiacEvents

300 mg300 mgn = 35n = 35

600 mg600 mgn = 34n = 34

900 mg900 mgn = 34n = 34

Death (n)Death (n)

NonNon--fatal MI*(n)fatal MI*(n)

Unplanned PCI (n)Unplanned PCI (n)

Hospitalization for recurrent angina (n)Hospitalization for recurrent angina (n)

00

11

11

22

00

22

00

00

00

00

00

00

TOTAL TOTAL –– n (%)n (%) 4 (11.4)4 (11.4) 2 (5.9)2 (5.9) 00

* New Q wave or CK > 3 times the ULN

Safety

300 mg 300 mg n = 35n = 35

600 mg600 mgn = 34n = 34

900 mg900 mgn = 34n = 34

Bleeding* Day 1Bleeding* Day 1-- Discharge (n)Discharge (n)

SevereSevere

ModerateModerate

MildMild

TOTALTOTAL

00

11

1010

1111

00

00

1010

1010

00

11

1313

1414

*GUSTO Classification

Summary

In patients with NSTEMI, 600 and 900 mg LDs compared to 300-mg LD provided:

More rapid and higher levels of IPA during the first 24 h

Potential favorable trends on ischemic events and troponin release

Greater reductions in some markers of platelet activation (PAC-1 and VASP) during the first 24 hours

Comparable safety profiles

IPA: Inhibition of Platelet Aggregation

Study DesignStudy DesignDouble-blind, randomized, placebo-controlled trial inpatients aged 18−75 years with STEMI ≤12 hours

Study treatment until angiography (2−8 days) or

hospital discharge (maximum 8 days)

n=1752

n=1739

Clopidogrel 300 mg loading dose / 75 mg QD†

Placebo†

RClinical

Follow-upat 30 days

Thrombolysis, heparin and ASA*

Primary endpoint: occluded artery (TIMI flow grade [TFG] 0/1), death/MI by time of angiography

*ASA=150–325 mg (if no ASA within prior 24 hours) as loading dose. Patients received heparin if they received a fibrin specific thrombolytic†All patients received ASA 75–162 mg/day plus other standard care1. Sabatine MS et al. New Engl J Med 2005; 352 (available at www.nejm.org)

Inclusion/Exclusion CriteriaInclusion/Exclusion Criteria

•• Inclusion criteriaInclusion criteria•• Age 18Age 18−−75 years75 years•• STEMI within 12 hoursSTEMI within 12 hours•• Planned treatment with fibrinolyticPlanned treatment with fibrinolytic

•• Major exclusion criteriaMajor exclusion criteria•• Clopidogrel within 7 daysClopidogrel within 7 days•• Planned clopidogrel or Planned clopidogrel or GPIIb/IIIaGPIIb/IIIa before angiographybefore angiography•• Contraindications to thrombolysis (stroke, ICH, brain tumor)Contraindications to thrombolysis (stroke, ICH, brain tumor)•• Cardiogenic shockCardiogenic shock•• Intention of angiography within 48 hoursIntention of angiography within 48 hours•• CABG, creatinine >2.5 mg/dL, hepatic insufficiency, CABG, creatinine >2.5 mg/dL, hepatic insufficiency, ↓↓ plateletsplatelets•• ≤≤67 kg and 67 kg and >4000 U bolus UFH; >67 kg and >5000 U bolus >1.1 >4000 U bolus UFH; >67 kg and >5000 U bolus >1.1

mg/kg subcutaneous of mg/kg subcutaneous of enoxaparinenoxaparin

FOR INTERNAL USE ONLY

Angiographic Outcomes and Angiographic Outcomes and LongLong--term Mortalityterm Mortality

0

2

4

6

8

10

12

14

16

0

2

4

6

8

10

12

14

16

TFG 0/1

2-ye

ar m

orta

lity

(%)

14.5%

TFG 2/3 TMPG 0/1 TMPG 2/3

6.4%4.8%

9.1%

HR: 0.41 (p=0.001) HR: 0.51 (p=0.038)

TIMI flow grade TIMI myocardial perfusion grade*

*90 minute angiogram in TIMI 10b trial; HR=hazard ratio1. Gibson CM et al. Circulation 2002; 105: 1909−1913.

Primary endpoint:Primary endpoint:•• CompositeComposite

•• % of occluded infarct related artery (TFG 0/1) on pre% of occluded infarct related artery (TFG 0/1) on pre--discharge angiogramdischarge angiogram

•• Death or MI before CAGDeath or MI before CAG•• Death or MI by hospital discharge (maximum 8 days) if no Death or MI by hospital discharge (maximum 8 days) if no

angiography performedangiography performed

Study EndpointsStudy Endpoints

*CV death, MI, stroke or recurrent ischemia leading to urgent target vessel revascularization

1. Sabatine MS et al. New Engl J Med 2005; 352 FOR INTERNAL USE ONLY

Clopidogrel Improved PerfusionClopidogrel Improved Perfusion

*Based on odds of an occluded infarct-related artery (TFG 0/1), death or MI by angiography for clopidogrel versus placebo (OR: 0.64 [0.53 to 0.76]; p <0.001)

Placebo(n=1739)

Clopidogrel(n=1752)

21.7

15.0

36% reduction*p <0.001

25Pr

imar

y en

dpoi

nt* (

%)

20

15

10

5

1. Sabatine MS et al. New Engl J Med 2005; 352 (available at www.nejm.org)

CLARITY: CLARITY: Reduction of Primary Endpoint by 36%Reduction of Primary Endpoint by 36%

ClopidogrelClopidogrel PlaceboPlacebo Odds ratioOdds ratio(n=1752) (n=1752) (n=1739)(n=1739) (95% CI)(95% CI) p valuep value

Primary endpoint (%)Primary endpoint (%)TFG 0/1, MI/deathTFG 0/1, MI/death 15.015.0 21.721.7 0.64 (0.530.64 (0.53−−0.76)0.76) <0.001<0.001

Components (%)Components (%)TFG 0/1TFG 0/1 11.711.7 18.418.4 0.59 (0.480.59 (0.48−−0.72)0.72) <0.001 <0.001 Recurrent MIRecurrent MI 2.52.5 3.63.6 0.70 (0.470.70 (0.47−−1.04)1.04) 0.080.08DeathDeath 2.62.6 2.22.2 1.17 (0.751.17 (0.75−−1.82)1.82) 0.490.49

1. Sabatine MS et al. New Engl J Med 2005; 352FOR INTERNAL USE ONLY

Primary Endpoint: SubgroupsPrimary Endpoint: SubgroupsNumber of Odds Event rates (%)

Characteristic patients reduction Clopidogrel Placebo

OVERALL 3491 36 15.0 21.7Age

<65 years 2466 42 13.2 21.0≥65 years 1015 22 19.0 23.1

GenderMale 2796 35 14.5 20.8Female 685 38 16.9 24.7

Infarct locationAnterior 1416 33 15.0 20.7Non-anterior 2065 38 15.0 22.2

FibrinolyticFibrin-specific 2397 31 14.7 20.1Non-fibrin specific 1084 44 15.7 24.9

Predominant heparinLMWH 1429 31 11.4 15.7UFH 1431 42 17.8 27.1None 621 26 17.1 21.9

1.00.4 0.6 0.8 1.2 1.6Clopidogrel better Placebo better

1. Sabatine MS et al. New Engl J Med 2005; 352

Clopidogrel Improved Clopidogrel Improved Angiographic OutcomesAngiographic Outcomes11

ClopidogrelClopidogrel PlaceboPlacebo Odds ratioOdds ratio

(n=1752) (n=1752) (n=1739)(n=1739) (95% CI)(95% CI)p valuep value

Angiographic outcomes (%)Angiographic outcomes (%)

TFG 3*TFG 3* 67.867.8 60.860.8 1.36 1.36 (1.18(1.18−−1.57)1.57) <0.001<0.001

TMPG 3TMPG 3†† 55.855.8 51.251.2 1.21 1.21 (1.05(1.05−−1.40)1.40) 0.0080.008

ThrombusThrombus 43.043.0 50.850.8 0.73 0.73 FOR INTERNAL USE ONLY

*TFG= TIMI Flow Grade†TPMG= TIMI Myocardial Perfusion Grade


CLARITY :CLARITY :Clinical Events at 30 DaysClinical Events at 30 Days

CV death, MI or recurrent ischemia leading to urgent revascularization

Time (days)

Inci

denc

e of

clin

ical

end

poin

ts (%

)

0

5

10

15

0 5 10 15 20 25 30

PlaceboClopidogrel 20%*

p=0.03

1. Sabatine MS et al. New Engl J Med 2005

Endpoints at 30Endpoints at 30--DayDayOdds

reduction Clopidogrel Placebo

CV death 3 4.4 4.5Recurrent MI 31 4.1 5.9

Recurrent ischemialeading to urgent 24 3.5 4.5 revascularizationStroke 46 0.9 1.7

CV death or MI 17 8.4 9.9

CV death, MI or stroke 18 9.1 10.9CV death, MI or recurrentischemia leading to urgent 20 11.6 14.1 revascularizationCV death, MI, stroke orrecurrent ischemia leading

21 12.3 15.0to urgent revascularization

Percentage ofpatients with event

Endpoint Odds ratio(95% CI)

1.00.4 0.6 0.8 1.2Clopidogrel better Placebo better

1.6


SafetySafetyClopidogrelClopidogrel PlaceboPlacebo(n=1733) (n=1733) (n=1719)(n=1719) p valuep value

Primary bleeding endpointPrimary bleeding endpoint (%)(%)TIMI major TIMI major 23 (1.3)23 (1.3) 19 (1.1)19 (1.1) 0.640.64

Secondary bleeding endpointsSecondary bleeding endpoints (%)(%)TIMI minor TIMI minor 17 (1.0)17 (1.0) 9 (0.5)9 (0.5) 0.170.17TIMI major or minor TIMI major or minor 40 (2.3)40 (2.3) 28 (1.6)28 (1.6) 0.180.18Intracranial hemorrhageIntracranial hemorrhage 8 (0.5)8 (0.5) 12 (0.7)12 (0.7) 0.380.38

Bleeding through 30 daysBleeding through 30 days (%)(%)TIMI major TIMI major 33 (1.9)33 (1.9) 30 (1.7)30 (1.7) 0.800.80TIMI minor TIMI minor 27 (1.6)27 (1.6) 16 (0.9)16 (0.9) 0.120.12TIMI major or minor TIMI major or minor 59 (3.4)59 (3.4) 46 (2.7)46 (2.7) 0.240.24

1. Sabatine MS et al. New Engl J Med 2005; 352 FOR INTERNAL USE ONLY

CLARITY: SummaryCLARITY: Summary

•• For STEMI, ASA + For STEMI, ASA + LyticsLytics + loading dose (300mg) + loading dose (300mg) clopidogrelclopidogrel followed by 75mg OD:followed by 75mg OD:

•• 36% reduction in the odds of an occluded infarct36% reduction in the odds of an occluded infarct--related artery, or death or MI by time of prerelated artery, or death or MI by time of pre--discharge discharge angiography or hospital discharge (maximum 8 days)angiography or hospital discharge (maximum 8 days)

•• Consistent across all major subgroupsConsistent across all major subgroups•• At 30 days, a 20% reduction (p=0.03) in CV death, MI At 30 days, a 20% reduction (p=0.03) in CV death, MI

or recurrent ischemia leading to urgent or recurrent ischemia leading to urgent revascularizationrevascularization

•• No significant excess in TIMI major bleeding or ICHNo significant excess in TIMI major bleeding or ICH


57

30 3225

18.411.7

0

10

20

30

40

50

60

SK vs TPA P vs ASA ASA vsCombo

47%RR;P<0.001

36%RR;P<0.001

22%RR;P=0.25

APRICOT ClarityTIMI 1

COMMIT/CCSCOMMIT/CCS--2: 2: CCllOOpidogrel pidogrel and and MMetoprolol in etoprolol in MMyocardial yocardial

IInfarction nfarction TTrialrial

1. Chen ZM et al. ACC 2005.

Study DesignStudy Design

Double-blind treatment until hospital discharge or for a maximum of 4 weeks

(n ~ 23,000)

R

Clopidogrel 75 mg QD*

(n ~ 23,000)

Patients with acute STEMI ≤ 24 hours

n=~46,000

Placebo*

(2 × 2 Factorial with metoprolol)

* All patients received a background of ASA 162mg/day during the study


Inclusion/Exclusion CriteriaInclusion/Exclusion CriteriaInclusion Criteria:Inclusion Criteria:

•• Suspected acute MI (with definite ECG changes: ST Suspected acute MI (with definite ECG changes: ST Elevation or LBBB)Elevation or LBBB)

•• 24 h since the onset of symptoms24 h since the onset of symptoms

•• No clear indication/contraindication to trial treatmentsNo clear indication/contraindication to trial treatments

Exclusion Criteria:Exclusion Criteria:•• High risk of adverse drug reactions:High risk of adverse drug reactions:

–– Allergy to aspirin or any trial drugAllergy to aspirin or any trial drug

–– Active bleeding or haematologic disorder Active bleeding or haematologic disorder

–– Persistent hypotension or Persistent hypotension or bradycardiabradycardia

–– HighHigh--degree AV block, pacemaker, cardiogenic shockdegree AV block, pacemaker, cardiogenic shock

•• Small likelihood of potential benefits:Small likelihood of potential benefits:–– Low risk of MI death (nonLow risk of MI death (non--typical MI, primary PCI)typical MI, primary PCI)

FOR INTERNAL USE ONLY1. Chen ZM et al. ACC 2005.

ClopidogrelClopidogrel PlaceboPlaceboCharacteristic Characteristic (n=22,960)(n=22,960) (n=22,891)(n=22,891)

Female (%)Female (%) 27.727.7 27.927.9Mean age (yrs)Mean age (yrs) 61.361.3 61.461.4Age >70 (%)Age >70 (%) 26.026.0 26.026.0Time from symptom onsetTime from symptom onset

to randomization (hrs)to randomization (hrs) 10.310.3 10.310.3Time from symptom onset <6 h (%)Time from symptom onset <6 h (%)

33.833.8 33.733.7Killip class II/III (%)Killip class II/III (%) 24.124.1 24.024.0STEMI/LBBBSTEMI/LBBB 93.193.1 93.193.1Prior MI history (%)Prior MI history (%) 8.68.6 8.18.1Fibrinolytic (%)Fibrinolytic (%) 49.749.7 49.849.8

Patient characteristicsPatient characteristics


0 7 14 21 280123456789

10

Days since randomization(up to 28 days)

Clopidogrel(9.3%)

Placebo (10.1%)

Even

ts (%

)RRR=9%

P=0.002

COMMIT: Composite EndpointCOMMIT: Composite Endpoint(Death, MI, or Stroke)(Death, MI, or Stroke)


COMMIT: MortalityCOMMIT: Mortality

0 7 14 21 280

1

2

3

4

5

6

7

8

9

Days since randomization (up to 28 days)

Clopidogrel(7.5%)

Placebo(8.1%)

RRR=7%p=0.03

Mor

talit

y (%

)


Clopidogrel Decreased ReClopidogrel Decreased Re--InfarctionInfarction

Odds ratio & 95% CIClopi better Placebo better

Outcome Clopidogrel Placeboafter Re-MI (n=22,958) (n=22,891)

Fatal MI 209 (0.9%) 223 (1.0%)

Non-Fatal MI 273 (1.2%) 330 (1.4%)

ALL 482 (2.1%) 553 (2.4%) 13% SE 6Reduction

p=0.02

0.4 0.6 0.8 1.0 1.2 1.4 1.6


Effects of Clopidogrel on StrokeEffects of Clopidogrel on Stroke


Clopidogrel PlaceboType (n=22,958) (n=22,891)

Ischemic 162 (0.7%) 192 (0.8%)

Hemorrhagic 55 (0.2%) 55 (0.2%)

ALL 216 (0.9%) 249 (1.1%) 14% SE 9ReductionP>0.1, NS

0.4 0.6 0.8 1.0 1.2 1.4 1.6


Effects of Clopidogrel on NonEffects of Clopidogrel on Non--Cerebral BleedingCerebral Bleeding


Clopidogrel PlaceboType (n=22,958) (n=22,891)

Major Bleed* 82 (0.4%) 73 (0.3%)

Other Bleed 831 (3.6%) 721 (3.1%)

ALL 896 (3.9%) 777 (3.4%) 16% SE 5IncreaseP=0.004

0.4 0.6 0.8 1.0 1.2 1.4 1.6

*Fatal or transfused


Consistent Effects of Clopidogrel Consistent Effects of Clopidogrel on Death,on Death,

ReRe--MI or Stroke by Age and MI or Stroke by Age and GenderGender Odds ratio & 95% CI

Clopi better Placebo betterBaseline Clopidogrel PlaceboFeatures (n=22,958) (n=22,891)

Gender

Male 1276 (7.7%) 1416 (8.6%)Female 849 (13.3%) 895 (14.0%)

Age<60 487 (5.1%) 513 (5.4%)60-69 747 (10.2%) 835 (11.2%)70+ 891 (14.9%) 963 (16.2%)

ALL 2125 (9.3%) 2311 (10.1%)9% SE 3

ReductionP=0.002

0.4 0.6 0.8 1.0 1.2 1.4 1.6


Outcomes by Time Delay and Outcomes by Time Delay and Fibrinolytic UseFibrinolytic Use


Baseline Clopidogrel PlaceboFeatures (n=22,958) (n=22,891)

Time Delay (hrs)

0-6 776 (9.3%) 904 (10.9%)7-12 672 (9.7%) 735 (10.7%)13-24 666 (8.8%) 666 (8.7%)

Lytic GivenYes 1005 (8.8%) 1123 (9.9%)No 1120 (9.7%) 1188 (10.3%)

ALL 2125 (9.3%) 2311 (10.1%) 9% SE 3Reduction

P=0.0020.4 0.6 0.8 1.0 1.2 1.4 1.6


COMMIT: SummaryCOMMIT: Summary

•• For STEMI, ASA + For STEMI, ASA + clopidogrelclopidogrel 75mg OD + 75mg OD + LyticLytic::•• 7% reduction mortality7% reduction mortality•• No significant excess in TIMI major bleeding or No significant excess in TIMI major bleeding or

ICHICH


GP GP IIb/IIIaIIb/IIIa Receptor AntagonistsReceptor Antagonists

EptifibatideEptifibatideTirofibanTirofibanAbciximabAbciximab

A murine monoclonalantibody that completely blocks the binding

of fibrinogen to platelets producesa thrombasthenic-like state in normal platelets and binds to glycoproteinsIIb and/or IIIa. J Clin Invest 1983

Coller BS, Peerschke EI, Scudder LE, Sullivan CA.

Fc fragment of murine monoclonal antibody against Gp2b3a, 7E3, was removed to prevent immunogenicity and Fab fragments joined with the constant regions of human immunoglobulin, forming a chimeric compound (abciximab, or c7E3).

RGD sequence

GpGp IIb/IIIaIIb/IIIa in ACSin ACS

GpGp IIb/IIIaIIb/IIIa blockers are recommended blockers are recommended (Class I) for UA/NSTEMI treated with (Class I) for UA/NSTEMI treated with

interventional approach.interventional approach.

For nonFor non--interventional patients with interventional patients with ongoing ischemia (Class II)ongoing ischemia (Class II)

ISARISAR--REACT:REACT:3030--d adverse reactions in lowd adverse reactions in low--toto--moderate risk undergoing moderate risk undergoing

PCI after 600mg PCI after 600mg ClopidogrelClopidogrel loading doseloading dose

เมื่อหลอดเลือดตันเมื่อหลอดเลือดตัน……

Medical solution

Mechanical solution

Percutaneous Coronary Percutaneous Coronary Intervention (PCI)Intervention (PCI)

Angioplasty Volume in Thailand Angioplasty Volume in Thailand (Approximate figures)(Approximate figures)

0

1000

2000

3000

4000

5000

6000

2001 2002 2003 2004

27 Cath Labs

* Projected for 2004

Problems with AngioplastyProblems with Angioplasty

Balloon-inducedDissection/ Plaque

rupture

Blood-Exposed Non-Intimal Surface (BENIS)

EfficacyEfficacy ofof DrugDrug RegimensRegimens in in CoronaryCoronary StentingStenting

Even

t rat

es (%

dea

th, M

I, re

vasc

.)

0

4

8

12

ISARN=517

FANTASTICN=485

STARSN=1653

MATTISN=350

Ticlopidine + ASACoumadin + ASA

6.2

1.6

8.3

5.7

2.7

0.5

11

5.6

3.6

ASA

CLASSICSN=1020

1.5 1.20.9

Clopidogrel + ASA

Clopidogrel LD + ASA

0

5

10

15

20

25

30

Ticlopidine Clopidogrel 75 mg Clopidogrel 300/75

Others

Skin disorders

GI disorders

Allergy

28 (8.2%)

17 (5.1%)

7 (2%)

EarlyEarly Discontinuation Discontinuation ofof StudyStudyDrugDrug

No.

ofp

atie

nts

disc

ontin

uing

CREDOCREDO

Symptomatic CAD with objective evidence of ischemiaSymptomatic CAD with objective evidence of ischemiasymptoms of angina pectoris symptoms of angina pectoris positive stress testpositive stress testdynamic ECG changesdynamic ECG changes

referred for elective or urgent PCIreferred for elective or urgent PCIRandomized to Randomized to clopidogrelclopidogrel loading (300mg) and long loading (300mg) and long term maintenance.term maintenance.

JAMA, November 20, 2002 – Vol 288, No 19: 2411 – 2420

CREDOCREDODouble-blind, comparison between two regimens

2000 patients, 100 centres in the US

1 MONTH 1 YEAR

Placebo+ aspirin

Clopidogrel75 mg + aspirin Placebo + aspirin

Clopidogrel 75 mg + aspirinClopidogrel300 mg LD+ aspirin

Group 1

Group 2

PTCA ± stent

6-24 h before PTCA ± stent

CREDOCREDO300mg 300mg clopidogrelclopidogrel vsvs placebo 3placebo 3--24hr prior to PCI24hr prior to PCI

From day 29 to 12months randomized to long term From day 29 to 12months randomized to long term clopidogrelclopidogrel vsvs placeboplacebo

1 year result : 1 year result : 29% reduction29% reduction in death, MI, stroke with in death, MI, stroke with loading and longloading and long--term term clopidogrelclopidogrel..

GpGp IIb/IIIaIIb/IIIa antagonist had relative benefits in the group antagonist had relative benefits in the group with >6with >6--24hr of 24hr of clopidogrelclopidogrel pretreatment.pretreatment.

LongLong--term Benefits of Clopidogrel term Benefits of Clopidogrel in PCI Patientsin PCI Patients

Clopidogrel*Placebo*

CO

MB

INE

D E

ND

POIN

T O

CC

UR

RE

NC

E (%

)

MONTHS FROM RANDOMIZATION

0 3 6 9 12

8.5%

11.5%

(MI, Stroke, or Death)1 year results

27% RRRp = 0.02

* Standard therapy including ASAJAMA, November 20, 2002 – Vol 288, No 19: 2411 – 2420

CREDO: Results by SubgroupsCREDO: Results by Subgroups(MI, Stroke, or Death at 1 year)

Placebo BetterClopidogrel Better RRR

0.6 1.20.4Hazard ratio (95% CI)

GPIIb/IIIa InhibitorYes (N=826) No (N=1289)

ACSYes (N=1407)No (N=694)

DiabetesYes (N=560)No (N=1556)

StentYes (N=1616)No (N=500)

Male (N=1510)

Female (N=606)

Overall (N=2116)

28.826.5

27.622.7

11.232.8

28.819.0

24.5

32.1

26.9

0.8 1.0

JAMA, November 20, 2002 – Vol 288, No 19: 2411 – 2420

ConclusionsConclusions

AntiplateletAntiplatelet therapy is essential in the management of therapy is essential in the management of patients with ACSpatients with ACS

Medically treatedMedically treatedPercutaneous interventionPercutaneous interventionNew studies support expanding role of ADP New studies support expanding role of ADP antagonists in the management of STEMIantagonists in the management of STEMI


Thank you for your Thank you for your attention.attention.

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