Up-to-date : Up-to-date : Antiplatelet Antiplatelet

Therapy for Acute Therapy for Acute Coronary Coronary SyndromeSyndrome

นพนพ. . ภาวิ�ทย์ เพ�ย์รวิ�จิ�ตรภาวิ�ทย์ เพ�ย์รวิ�จิ�ตรหน�วิย์โรคห�วิใจิหน�วิย์โรคห�วิใจิ

คณะแพทย์ศาสตรโรงคณะแพทย์ศาสตรโรงพย์าบาลรามาธิ�บดี�พย์าบาลรามาธิ�บดี�มหาวิ�ทย์าล�ย์มห�ดีลมหาวิ�ทย์าล�ย์มห�ดีล

Increasing CV MortalityIncreasing CV Mortality

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Accident

Cancer

AIDS

Pneumonia

Diarrhea

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

AgeAge: 55: 55 SexSex: Male: Male Past HistoryPast History: HTN: HTN OccupationOccupation: High stress: High stress ComplaintComplaint::

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

Case # 1: Case # 1: อาการคงท�#อาการคงท�# (stable (stable angina)angina)

ไขมั�น พั�งผืด เซล

‘‘Stable’ Angina: Predictable DiseaseStable’ Angina: Predictable Disease

AgeAge: 50: 50 SexSex: Male: Male HabitHabit: non-smoker: non-smoker Past HistoryPast History: -: -

ComplaintComplaint:: Sudden onset of chest pain Sudden onset of chest pain

while restingwhile resting No improvement after No improvement after

15minutes15minutes

What causes ‘unstable’ symptom?What causes ‘unstable’ symptom?

?

Acute Coronary SyndromeAcute Coronary Syndrome

ล�#มเล$อดี

Truths about Plaque RuptureTruths about Plaque Rupture

No warning.No warning.

Can occur after ‘normal’ EST.Can occur after ‘normal’ EST.

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

Spectrum of ACSSpectrum of ACS

Accelerating/ New onset AnginaAccelerating/ New onset Angina

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

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

STEMI / QWMI

Non ST Elevation MI

ST Elevation MI

แนวิทางการร�กษาคนไข้( แนวิทางการร�กษาคนไข้( ACSACS

Prevent plaque rupturePrevent plaque rupture StatinsStatins

Decrease ODecrease O22 need need

DecreaseDecrease platelet activation and platelet activation and aggregationaggregation

Open blocked vesselOpen blocked vessel

ย์าต(านเกล)ดีเล$อดีย์าต(านเกล)ดีเล$อดี B-blockers* B-blockers* (? mode of administration)(? mode of administration)

Ca blockers as alternativesCa blockers as alternatives NitratesNitrates OO22

MorphineMorphine Anti-coagulationAnti-coagulation ACEI*ACEI*

ย์าท�#ควิรให(ในย์าท�#ควิรให(ใน ACS ACS (NSTEMI and STEMI)(NSTEMI and STEMI)

Class I Class I

RecommendationRecommendation

If no contra-indications!

AspirinAspirin

Mechanism of actionMechanism of action:: Irreversible COX inhibitor COX inhibitor Prevents thromboxane A2 formation Diminishing platelet aggregation

IndicationIndication:: Class IA Class IA

Dosage:Dosage: 160-300mg 160-300mg

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

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

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Placebo

ASA 75 mg

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

Lytics & ASA in STEMI: ISIS-2Lytics & ASA in STEMI: ISIS-2

1. ISIS-2 Collaborative Group. Lancet 1988; 2: 349360.

12.0%

9.2% 9.4%

11.8%

13.2%

8.0%

Placebo versusstreptokinase

Placebo versus ASA 162 mg

Neitherversus both

5-w

eek

mo

rtal

ity

(%)

25%*p <0.00001

23%*p <0.00001

42%*p <0.00001

*Odds reduction

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ADP AntagonistADP Antagonist

Thienopyridine derivativeThienopyridine derivative

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

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

Double-blind treatment 3 to 12 months

ASA 75–325 mg

Clopidogrel75 mg o.d.

(~6250 patients)

Placebo1 tab o.d.

(~6250 patients)

ASA 75–325 mg

6 m

onth

vis

it9

mon

th v

isit

12 m

onth

or fi

nal v

isit

3 m

onth

vis

it

Dis

char

ge v

isit

1 m

onth

vis

it

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

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

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

CURE : Primary EndpointCURE : Primary Endpoint

20% RRRp=0.00009n=12,562

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

0 1 2 3 4 5 6 7 8 9 10 11 12

Months of follow-up

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

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Standard therapy‡

Clopidogrel + standard therapy‡

The CURE Investigators. N Eng J Med August 2001

‡including ASA

9.3%

11.4%

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

Primary Outcome : SubgroupsPrimary Outcome : Subgroups

‡including ASA

2N % eventsStandard therapy‡

Clopidogrel + Standard therapy‡

PCI-CURE :PCI-CURE :Long-term EfficacyLong-term Efficacy

0.15

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0.0100

040 100 200 300 400

Cum

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tive

ha

zard

rat

es

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

Days of follow-upa 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

12.6%

8.8%

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

Peters RJ et al. Circulation 2003;108:1682

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

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)• Clopidogrel 75 mg daily (in the absence of Clopidogrel 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 non-interventional approachnon-interventional approach is planned, is planned,

clopidogrel should be added to ASA as soon as possible clopidogrel should be added to ASA as soon as possible on admission and administered for at least 1 month (IA) on admission and administered for at least 1 month (IA) and for up to 9 months (IB)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 continued for at least 1 month (IA) and up to 9 months in patients who are not at high risk for bleeding (IB)in patients who are not at high risk for bleeding (IB)

1. Braunwald E et al.FOR INTERNAL USE ONLY

ALBIONALBION Assessment of best Loading dose of clopidogrel to Blunt Assessment of best Loading dose of clopidogrel 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 years UA NSTEMI within the 48 hours prior to randomisation. UA NSTEMI within the 48 hours prior to randomisation. 300mg, 600mg and 900mg300mg, 600mg and 900mg Blood 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 clopidogrel induced faster onset of action and higher clopidogrel 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 ACS

Similar safety profile among different dosage groups.Similar safety profile among different dosage groups.

EuroPCR Congress in Paris on May 24EuroPCR Congress 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)

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Time (h)

(%) I

nhib

ition

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

Maximum Inhibition of Platelet Aggregation (20 µM ADP)

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Time (h)

(%)

Inhi

bition

300 mg LD

600 mg LD

900 mg LD

Faster Onset of Action and Higher Level of Platelet Inhibition

p< 0.05 vs. 300 mg LD

Major Adverse Cardiac Events

300 300 mgmg

n = 35n = 35

600 mg600 mgn = 34n = 34

900 mg900 mgn = 34n = 34

Death (n)Death (n)

Non-fatal MI*(n)Non-fatal MI*(n)

Unplanned PCI (n)Unplanned PCI (n)

Hospitalization for recurrent Hospitalization for recurrent

angina (n)angina (n)

00

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22

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22

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00

00

00

00

TOTAL – n (%)TOTAL – n (%) 4 4

(11.4)(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 1- Discharge Bleeding* Day 1- Discharge (n)(n)

SevereSevereModerateModerateMildMild

TOTALTOTAL

00

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1010

1111

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1010

1010

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1313

1414

*GUSTO Classification

Study DesignStudy Design

*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 care

Study treatment until angiography (28 days) or

hospital discharge (maximum 8 days)

n=1752

n=1739

Thrombolysis, heparin and ASA*

Clopidogrel 300 mg loading dose / 75 mg QD†

Placebo†

R

Double-blind, randomized, placebo-controlled trial inpatients aged 1875 years with STEMI ≤12 hours

Clinical Follow-up at 30 days

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

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

Angiographic Outcomes and Angiographic Outcomes and Long-term MortalityLong-term Mortality

1. Gibson CM et al. Circulation 2002; 105: 19091913.

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TFG 0/1

2-ye

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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 ratio

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

FOR INTERNAL USE ONLY1. Sabatine MS et al. New Engl J Med 2005; 352

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

5

10

15

20

25P

rim

ary

end

po

int*

(%

)36% reduction*

p <0.001

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 value p 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 (0.530.76)0.76) <0.001<0.001

Components (%)Components (%) TFG 0/1TFG 0/1 11.711.7 18.418.4 0.59 (0.480.59 (0.480.72)0.72) <0.001 <0.001 Recurrent MIRecurrent MI 2.52.5 3.63.6 0.70 (0.470.70 (0.471.04)1.04) 0.080.08 DeathDeath 2.62.6 2.22.2 1.17 (0.751.17 (0.751.82)1.82) 0.490.49

FOR INTERNAL USE ONLY1. Sabatine MS et al. New Engl J Med 2005; 352

Number of Odds Event rates (%)Characteristic patients reduction Clopidogrel Placebo

OVERALL 3491 36 15.0 21.7Age

<65 years 2466 42 13.2 21.065 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

Primary Endpoint: SubgroupsPrimary Endpoint: Subgroups

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

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

CV death, MI or recurrent ischemia leading to urgent revascularization

Time (days)

Inci

den

ce o

f cl

inic

al e

nd

po

ints

(%

)

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

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) 0.170.17 TIMI major or minor TIMI major or minor 40 (2.3)40 (2.3) 28 (1.6)28 (1.6) 0.180.18 Intracranial 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) 0.800.80 TIMI minor TIMI minor 27 (1.6)27 (1.6) 16 (0.9)16 (0.9) 0.120.12 TIMI major or minor TIMI major or minor 59 (3.4)59 (3.4) 46 (2.7)46 (2.7) 0.240.24

FOR INTERNAL USE ONLY1. Sabatine MS et al. New Engl J Med 2005; 352

1. Chen ZM et al. ACC 2005.

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

IInfarction nfarction TTrialrial

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

(n ~ 23,000)

n=~46,000R

Patients with acute STEMI 24 hours

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

(2 2 Factorial with metoprolol)

Study DesignStudy DesignClopidogrel 75 mg QD*

Placebo*

(n ~ 23,000)

1. Chen ZM et al. ACC 2005.

0 7 14 21 280

1

2

3

4

5

6

7

8

9

10

Days since randomization(up to 28 days)

Clopidogrel(9.3%)

Placebo (10.1%)

Eve

nts

(%

)RRR=9%

P=0.002

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

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

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

Mo

rtal

ity

(%)

COMMIT: MortalityCOMMIT: Mortality

1. Chen ZM et al. ACC 2005.

COMMIT: SummaryCOMMIT: Summary

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

ICHICH

FOR INTERNAL USE ONLY

GP IIb/IIIa Receptor AntagonistsGP IIb/IIIa Receptor Antagonists

EptifibatideEptifibatide TirofibanTirofiban AbciximabAbciximab

A murine monoclonalantibody that completely blocks

the binding of fibrinogen to platelets produces

a 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

Gp IIb/IIIa in ACSGp IIb/IIIa in ACS

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

interventional approach.interventional approach.

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

ISAR-REACT:ISAR-REACT:30-d adverse reactions in low-to-moderate risk undergoing 30-d adverse reactions in low-to-moderate risk undergoing

PCI after 600mg Clopidogrel loading dosePCI after 600mg Clopidogrel loading dose

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

Medically treatedMedically treated Percutaneous interventionPercutaneous intervention New studies support expanding role of ADP New studies support expanding role of ADP

antagonists in the management of STEMIantagonists in the management of STEMI

ConclusionsConclusions

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

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