clopidogrel in patients with st-segment elevation myocardial infarction (stemi)

Clopidogrel in Patients with ST-Segment Elevation Myocardial Infarction (STEMI)

Disclaimer

This slide kit presents data that is not contained in the approved professional label for clopidogrel.

The slide kit has been prepared for internal medical education purposes only and should not be distributed to or used with physicians in promotional detailing.

Neither sanofi-aventis nor Bristol-Myers Squibb recommends the use of clopidogrel in any manner inconsistent with that described in the full prescribing information

Outline

Epidemiology and background

Current treatments for the acute management of STEMI

Rationale for antiplatelet therapy in STEMI

Results of new clopidogrel clinical trials CLARITY (CLopidogrel as Adjunctive ReperfusIon TherapY) COMMIT (ClopidOgrel and Metoprolol in Myocardial

Infarction Trial)

The growing body of evidence for clopidogrel

Summary and conclusions

Epidemiology and Background

Unstable angina MI

Ischemic stroke/TIA

Critical leg ischemiaIntermittentclaudication

CV death

ACS

Atherosclerosis

Stable angina/intermittent claudication

Thrombosis

1. Libby P. Circulation 2001; 104: 365–372.

Pathologic Progression to Atherothrombosis1

MI=myocardial infarction; ACS=acute coronary syndromes; TIA=transient ischemic attack; CV=cardiovascular

Major Role of Platelets in Atherothrombosis1

1. Cannon CP et al. Heart Disease: A Textbook of Cardiovascular Medicine. 6th ed. Philadelphia, PA: WB Saunders, 2001: 1232–1263.

Activated platelets

Adhesion1

Activation2

Aggregation3

Plaquerupture

Fibrinogen

TxA2

ADP

Platelets

ADP=adenosine diphosphate; TxA2=thromboxane A2

Cerebrovascular disease

Coronary artery disease

Renal artery stenosis

Visceral arterial disease

Peripheral arterial disease (PAD)

Major Manifestations of Atherothrombosis

Prevalence of Atherothrombotic Manifestations is Increasing Worldwide*1

1. Guillot F et al. Circulation 1998; 98: A1421 (Abstract).

*Projected populations of people aged >50 years and estimated prevalence of MI and ischemic stroke accumulated in 14 countries: Belgium, Canada, Denmark, Finland, France, Germany, Italy, The Netherlands, Norway, Spain, Sweden, Switzerland, the United Kingdom (UK) and the United States (US)

Prevalence 2000 2005

Populations aged >50 years

205.0 million(5.1% since 1997)

222.2 million(13.9% since 1997)

MI

Ischemic stroke





1. Adult Treatment Panel II. Circulation 1994; 89: 1333–1435.2. Kannel WB. J Cardiovasc Risk 1994; 1: 333–339.3. Wilterdink JI et al. Arch Neurol 1992; 49: 857–863.4. Criqui MH et al. N Engl J Med 1992; 326: 381–386.

Increased risk of MI

5–7 Xgreater risk

(includes death)

Post-MI

23 Xgreater risk

(includes anginaand sudden death)

Post-stroke

4 Xgreater risk

(includes only fatal MI and other CHD death)

PAD

Increased risk of stroke

34 Xgreater risk

(includes TIA)

9 Xgreater risk

23 Xgreater risk

(includes TIA)

Increased Risk in Other Vascular Beds After an Atherothrombotic Event1–4

CHD=coronary heart disease

ACS is an Important Manifestation of Atherothrombosis1

1. Adapted with permission from Cannon CP. J Thromb Thrombolysis 1995; 2: 205–218.

Antithrombotictherapy

Stable angina

UA Non-Q-wave MI

Thrombolysisprimary PCI

Q-wave MI

Minutes– hours

Days–weeks

STEMIUA/NSTEMIAtherothrombosisNew term

Old term

Plaquerupture

UA=unstable angina; NSTEMI=non-ST-segment elevation myocardial infarction; PCI=percutaneous coronary intervention

Incidence of ACS in the US

ACS1,673,0001

UA728,0001*

MI 973,0001*

NSTEMI55–70% of ACS patients2

STEMI30–45% of ACS patients2

1. American Heart Association. Heart and Stroke statistical update. Dallas, Texas: American Heart Association 2005. 2. NRMI-4. J Am Coll Cardiol 2003; 41: 365A–366A.

*28,000 hospitalizations received both diagnoses for UA and MI

Number of patients with ACS discharged from US hospitals in 2002 (including secondary discharges)

Pathophysiology of STEMI1

1. Antman EM. In: Califf RM, ed. Atlas of Heart Diseases, VIII. Philadelphia, PA: Current Medicine, 1996.

Results from stabilization of a platelet aggregate at the site of plaque rupture by fibrin mesh

Platelet

RBC

Fibrin mesh

GPIIb/IIIa

Generally caused by a completely occlusive

thrombus in a coronary artery

RBC=red blood cell

High Risk of Mortality Following Acute MI

12.3%

6.6%

18.7%

–

NRMI 34 (n=81,679)*2

In-hospital mortality

Reperfused

Not reperfused

6-month† mortality

GRACE Registry (n=5,476)3

7.8%

–

–

4.8%

Approximately 33% of patients with an MI will die before they reach the hospital1

1. Boersma E et al. Lancet 2003; 361: 847–858.2. NRMI 3-4. J Am Coll Cardiol 2004; 44: 783–789.3. Goldberg RJ et al. Am J Cardiol 2004; 93: 288–293.4. Antman EM et al. 2004 ACC/AHA STEMI Guidelines. Available at:www.accp.org/clinical/guidelines/stemi/index.pdf. Accessed February 2005.

*Patients with STEMI from the NRMI 34 database (n=153,486); †post-discharge; GRACE=The Global Registry of Acute Coronary Events; within 6 years 18% of men and 35% of women will suffer an additional heart attack4; NRMI=National Registry for Myocardial Infarction

http://www.accp.org/clinical/guidelines/stemi/index.pdf







Ischemic Heart Disease Has a Devastating Impact on Quality of Life1

*Disability-adjusted life years (DALY) combine years of potential life lost due to premature death with years of productive life lost due to disability

To

tal

DA

LY

* lo

ss (

%)

Depression Ischemicheart

disease

SchizophreniaStroke Lungcancer

Breastcancer

1. World Health Organization. The Atlas of Heart Disease and Stroke, 2004. Available at: URL: http://www.who.int/cardiovascular_diseases/resources/atlas/en/. Accessed February 2005.

0

1

2

3

4

5

http://www.who.int/cardiovascular_diseases/resources/atlas/en/

Current Treatments for the Acute Management of STEMI

Assessing Reperfusion Options for Patients with STEMI1

STEP 1: Assess time and risk (time from symptom onset, risk of STEMI, risk of thrombolysis, time for transport to PCI lab)

STEP 2: Determine whether fibrinolysis or invasive strategy is preferred*

1. Antman EM et al. Circulation 2004; 110: 588–636.

Fibrinolysis preferred if: Invasive strategy preferred if: Early presentation (<3 hours) Invasive strategy not an option Delay to invasive strategy

Skilled PCI lab with surgical backup available

High risk (i.e. cardiogenic shock) Contraindications to fibrinolysis Late presentation (>3 hours) Diagnosis of STEMI is in doubt

*If presentation is <3 hours from onset and there is no delay to an invasive strategy, there is no preference for either strategy

Thrombolysis Remains an Important Reperfusion Strategy Worldwide

1. Goldberg RJ et al. Am J Cardiol 2004; 93: 288–293.2. Hasdai D et al. Eur Heart J 2002; 23: 1190–1201.3. Wiviott SD et al. J Am Coll Cardiol 2004; 44: 783–789.

GRACE1

(n=5,476)

EHS2

(n=3,438)

NRMI 34*3

(n=81,679)

Thrombolytic agent (%) 45.0 35.1 52.0

Catheterization (%)

PCI

Primary PCI

61.0

44.4

–

53.0

40.4

20.7

–

–

48.0

CABG (%) 5.0 3.4 –

*Patients with STEMI from the NRMI 34 database (n=153,486); EHS=EuroHeart Survey; CABG=coronary artery bypass graft

Common Thrombolytic Regimens for STEMI1

Initial treatment Co-therapyContraindications

Streptokinase (SK) 1.5 million U in 100 mL None or iv Prior SK or5% dextrose or 0.9% saline heparin x 2448 hours

anistreplaseover 3060 min

Alteplase (tPA) 15 mg iv bolus, then iv heparin x 2448 hours0.75 mg/kg over 30 min,then 0.5 mg/kg iv over 60 minTotal dose not over 100 mg

Reteplase (rPA) 10 U + 10 U iv bolus given iv heparin x 2448 hours30 min apart

Tenecteplase Single iv bolus iv heparin x 2448 hours(TNK-tPA) 30 mg if <60 kg

35 mg if 60 kg to <70 kg40 mg if 70 kg to <80 kg45 mg if 80 kg to <90 kg50 mg if ≥90 kg

1. Van de Werf F et al. Eur Heart J 2003; 24: 2866.

Note: acetylsalicylic acid (ASA) should be given to all patients without contraindications; iv=intravenous

Thrombolysis and ASA in Acute STEMI: ISIS-21

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

12.0%

9.2% 9.4%

11.8%

13.2%

8.0%

Placebo versusSK

Placebo versus ASA 162 mg

Neitherversus both

5-w

eek

mo

rtal

ity

(%)

*Odds reduction; ISIS=Second International Study of Infarct Survival

0

2

4

6

8

10

12

14

25%*p <0.00001

23%*p <0.00001

42%*p <0.00001

Other Routine Therapies in Acute STEMI1

ASA 150325 mg (non-enteric coated)

Beta-blockers

Angiotensin-converting enzyme (ACE) inhibitors

Oxygen

Nitrates

1. Van de Werf F et al. Eur Heart J 2003; 24: 2866.

Current Limitations of Pharmacologic Reperfusion

Lack of initial reperfusion in 20% of patients1

– Associated with a 2 X increase in mortality

Reocclusion in 5–8% of patients1 – Associated with 3 X increase in mortality

Despite current therapy, 10% of STEMI patients die within one month after hospital discharge2

Within 6 years 18% of men and 35% of women will suffer another heart attack3

1. Sabatine M et al. New Eng J Med 2005; 352: 1179–1189. 2. Goldberg RJ et al. Am J Cardiol 2004; 93: 288–293.3. Antman EM et al. 2004 ACC/AHA STEMI Guidelines. Available at:

www.accp.org/clinical/guidelines/stemi/index.pdf. Accessed February 2005.







Rationale for Antiplatelet Therapyin Acute MI

Antiplatelet Therapy is Beneficial1

1. Antithrombotic Trialists’ Collaboration. BMJ 2002; 324: 71–86.

*Vascular events=MI, stroke or vascular death

Odds reduction Category of vascular events (%)*

Acute MI

Acute stroke

Prior MI

Prior stroke/TIA

Other high risk

All trials

1.00.50.0 1.5 2.0Control betterAntiplatelet better

30%

11%

25%

22%

26%

22%

COX=cyclo-oxygenase

CLOPIDOGREL

ASA COX

ADP

ADP

C

GPllb/llla(fibrinogen receptor)

Collagen thrombinTXA2

Activation

TXA2

Potent, Specific and Complementary Mode of Action of Clopidogrel1

1. Jarvis B et al. Drugs 2000; 60: 347–377.

Cu

mu

lati

ve*

haz

ard

rat

io

Follow-up (months)

0 3 6 9 120

0.02

0.04

0.06

0.08

0.10

0.12

0.14

Early and Long-Term Benefits of Clopidogrelin UA/NSTEMI1

1. CURE Trial Investigators. N Engl J Med 2001; 345: 494–502.

*Cumulative events: MI, stroke or CV death; †all patients received a background of ASA therapy

20%p <0.001

Placebo†

(n=6,303)

Clopidogrel†

(n=6,259)

2002 ACC/AHA UA/NSTEMI* Guidelines Update: Antiplatelet and Anticoagulant Therapy1

Class I: Antiplatelet therapy should be initiated promptly. ASA should

be administered as soon as possible after presentation and continued indefinitely (IA)

In hospitalized patients in whom an early non-interventional approach is planned, clopidogrel should be added to ASA as soon as possible on admission and administered for at least 1 month (IA) and for up to 9 months (IB)

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

1. Braunwald E et al. J Am Coll Cardiol 2002; 40: 1366–1374.

*Also known as non-Q-wave MI; ACC=American College of Cardiology; AHA=American Heart Association

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

planned, the drug should be withheld for 57 days (IB)

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

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

2002 ACC/AHA UA/NSTEMI* Guidelines Update: Antiplatelet and Anticoagulant Therapy (cont)1

*Also known as non-Q-wave MI


Class I: ASA 75–325 mg daily in the absence of contraindications (IA)

Clopidogrel 75 mg once daily (in the absence of contraindications) when ASA is not tolerated because of hypersensitivity or gastrointestinal intolerance (IA)

The combination of ASA and clopidogrel for 9 months after UA/NSTEMI (IB)

2002 ACC/AHA UA/NSTEMI* Guidelines Update: Antiplatelet and Anticoagulant Therapy (cont)1



Class I: In patients in whom an early noninterventional approach is

planned, clopidogrel should be added to ASA therapy as soon as possible on admission and administered for at least 1 month (A) and for up to 9 months (B)

In patients in whom a PCI is planned, clopidogrel should be started and continued for at least 1 month (A) and up to 9 months in patients who are not at high risk for bleeding (B)

For long-term medical therapy, the combination of ASA and clopidogrel is recommended for 9 months after UA/NSTEMI (B)

2002 ACC/AHA UA/NSTEMI* Guidelines Update: Key Recommendations for Clopidogrel Therapy1



Clinical suspicion of ACS

Physical examinationElectrocardiogram (ECG) monitoring, blood samples

Undetermineddiagnosis

Persistent ST-segment elevation

No persistent ST-segment elevation

ASA, LMWH,clopidogrel*, beta-blockers, nitrates

ThrombolysisPCI

High risk Low risk

GPIIb/IIIa,coronary angiography

Stress test,coronary angiography

1. Adapted with permission from Bertrand ME et al. Eur Heart J 2002; 23; 18091840.

Second troponin measurement

Positive Twice negative

ASA

PCI, CABG or medical managementdepending upon clinical and angiographic features

*Omit clopidogrel if the patient is likely to go to CABG within 5 days

ESC Recommended Strategy in ACS Patients1

New Clopidogrel Clinical Trials in Acute STEMI

CLopidogrel as Adjunctive ReperfusIon TherapY (CLARITY) – TIMI 28 Trial Results1

Purpose:This study investigated whether clopidogrel would produce greater angiographic and clinical benefits over placebo for patients with acute STEMI treated with fibrinolytics and other standard care

1. Sabatine M et al. New Eng J Med 2005; 352: 1179–1189.

Study Design1

*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=1,752

n=1,739

Thrombolysis, heparin and ASA*

Clopidogrel 300 mg loading dose/75 mg once daily†

Placebo†

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

Clinical follow-up

at 30 days

Primary endpoint: occluded artery (Thrombolysis In Myocardial Infarction [TIMI] flow grade [TFG] 0/1) on the angiogram or death/MI by time of angiography

R


Inclusion criteria Age 1875 years STEMI within 12 hours Planned treatment with fibrinolytic

Major exclusion criteria Clopidogrel within 7 days Planned clopidogrel or GPIIb/IIIa before angiography Contraindications to fibrinolysis (stroke, ICH [intracranial

hemorrhage], brain tumor) Cardiogenic shock Intention of angiography within 48 hours CABG, creatinine >2.5 mg/dL, hepatic insufficiency, platelets Patients 67 kg who had received >4000 U bolus UFH or >67 kg

who had received >5000 U bolus; or >1.1 mg/kg subcutaneous (sc) enoxaparin

Inclusion/Exclusion Criteria1


319 sites in 23 countries

Global Study Sites

Primary endpoint: Composite of occluded infarct-related artery (TFG 0/1) on pre-

discharge angiogram, or death or MI before angiography Death or MI by hospital discharge (maximum 8 days) if no

angiography performed

Secondary endpoints: Angiographic (TFG 0/1) Clinical (death, recurrent MI or recurrent ischemia) Clinical events* at 30 days

Safety endpoints: Primary: TIMI major bleeding Secondary: TIMI minor bleeding, ICH

Study Endpoints1

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


TIMI Flow Grade Definitions1

TIMI flow grade describes epicardial blood flow: Grade 0: complete occlusion Grade 1: penetration of obstruction with no distal perfusion Grade 2: perfusion of artery with delayed flow Grade 3: full perfusion with normal flow

TFG 0Occlusion

TFG 1Penetration

TFG 2Slow flow

TFG 3Normal flow

1. Reproduced with permission from Gibson CM et al. Circulation 2004: 109: 30963105.

TIMI Myocardial Perfusion Grade Definitions1

TIMI Myocardial Perfusion Grade (TMPG) or ‘blush score’ describes blood flow in the microvasculature: Grade 0: no dye enters Grade 1: dye slowly enters but fails to exit Grade 2: delayed entry and exit of dye Grade 3: normal entry and exit of dye

TMPG 3 TMPG 3 TMPG 2 TMPG 2 TMPG 1 TMPG 1 TMPG 0 TMPG 0

1. Gibson CM et al. Circulation 2004: 109: 30963105.

Relationship Between Angiographic Outcomes and Long-term Mortality1

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

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

ort

alit

y (%

)

14.6%

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

6.4%

4.8%

9.1%

HR: 0.41 p=0.001

HR: 0.51p=0.038

*Assessed on 90-minute angiogram in TIMI 10B trial; HR=hazard ratio

Baseline Characteristics1

Clopidogrel Placebo

Characteristic (n=1,752) (n=1,739)

Age (years) 57.7 57.2

Male gender (%) 79.9 80.7

Hypertension (%) 42.8 43.9

Hyperlipidemia (%) 32.2 33.0

Current smoker (%) 50.7 49.9

Diabetes mellitus (%) 16.5 16.4

Prior MI (%) 9.1 9.1

Prior PCI (%) 4.8 4.9

Anterior MI (%) 41.2 40.1


Concomitant Medications1

Clopidogrel PlaceboCharacteristic (n=1,752) (n=1,739)

Fibrin-specific thrombolytic (%):

TNK-tPA 47.8 47.3

rPA 11.9 12.3

tPA 9.1 8.9

Non-fibrin specific thrombolytic (%):

SK 30.9 31.2

No thrombolytic given (%) 0.2 0.3

ASA (%) 98.5 98.6

Heparin (%):

UFH 46.1 45.5

LMWH 30.1 29.1


Patient Management1

Clopidogrel Placebo

Parameter (n=1,752) (n=1,739)

Symptom onset to fibrinolytic (hours) 2.7 2.6

Fibrinolytic to study drug (minutes) 10 10

Median doses of study medication 4 4

Angiography performed (%) 94 94

Study drug to angiography (hours) 84 84

Coronary revascularization (%): 63 63

PCI 57.2 56.6

CABG 5.9 6.0


Other Cardiac Medications During Index Hospitalization1

Clopidogrel Placebo

Characteristic (%) (n=1,752) (n=1,739)

Beta-blockers 88.7 89.6

Statins 80.4 81.1

ACE inhibitors/ARBs 72.7 72.1

After angiography*

Clopidogrel 54.5 55.6

Ticlopidine 3.5 2.9

*Some patients received open-label ADP-receptor antagonists after angiography and primary endpoint ascertainment; ARB=angiotensin receptor blocker


Clopidogrel Improved Coronary Perfusion1

*Based on odds of an occluded infarct-related artery (TFG 0/1), death or MI by angiography for clopidogrel versus placebo (odds ratio: 0.64 [0.530.76]; p <0.001)

Placebo(n=1,739)

Clopidogrel(n=1,752)

21.7

15.0

5

10

15

20

25P

rim

ary

end

po

int*

(%

)36% reduction*

p <0.001


Clopidogrel Reduced Primary Endpoint by 36%1

Clopidogrel Placebo Odds ratio

(n=1,752) (n=1,739) (95% CI) p value

Primary composite endpoint (%)

TFG 0/1, MI or death 15.0 21.7 0.64 (0.530.76) <0.001

Individual components of primary endpoint (%)

TFG 0/1 11.7 18.4 0.59 (0.480.72) <0.001

Recurrent MI 2.5 3.6 0.70 (0.471.04) 0.08

Death 2.6 2.2 1.17 (0.751.82) 0.49

CI=confidence interval


Number of Odds Patients with event (%)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

Consistent Results for Primary Endpoint Across Subgroups1


Clopidogrel Improved Angiographic Outcomes1

Clopidogrel Placebo Odds ratio

(n=1,752) (n=1,739) (95% CI) p value

Angiographic outcomes (%)

TFG 3 67.8 60.8 1.36 (1.181.57) <0.001

TMPG 3 55.8 51.2 1.21 (1.051.40) 0.008

Thrombus 43.0 50.8 0.73 (0.640.84) <0.001


Clopidogrel Reduced Clinical Events by 20% at 30 Days1

*Odds ratio in CV death, MI or recurrent ischemia leading to urgent revascularization

Time (days)

Pat

ien

ts w

ith

en

dp

oin

t (%

)

0

5

10

15

0 5 10 15 20 25 30

20%*p=0.03

Clopidogrel(11.6%)

Placebo (14.1%)


Consistent Results Across 30-day Endpoints1

Oddsreduction Clopidogrel Placebo

CV death 3 4.4 4.5

Recurrent MI 31 4.1 5.9

Recurrent ischemialeading to urgent 24 3.5 4.5 revascularization

Stroke 46 0.9 1.7

CV death or MI 17 8.4 9.9

CV death, MI or stroke 18 9.1 10.9

CV death, MI or recurrentischemia leading to urgent 20 11.6 14.1 revascularization

CV death, MI, stroke orrecurrent ischemia leading

21 12.3 15.0

to urgent revascularization

Patients with event (%)Endpoint Odds ratio

(95% CI)

1.00.4 0.6 0.8 1.2Clopidogrel better Placebo better

1.6


Safety1

Clopidogrel Placebo(n=1733) (n=1719) p

value

Primary bleeding endpoint, n (%)TIMI major 23 (1.3) 19 (1.1) NS

Secondary bleeding endpoints, n (%) TIMI minor 17 (1.0) 9 (0.5) NSTIMI major or minor 40 (2.3) 28 (1.6) NSICH 8 (0.5) 12 (0.7) NS

Bleeding through 30 days, n (%)TIMI major 33 (1.9) 30 (1.7) NSTIMI minor 27 (1.6) 16 (0.9) NSTIMI major or minor 59 (3.4) 46 (2.7) NS


NS=not statistically significant

Summary1

In patients aged 75 years with STEMI, receiving ASA and standard fibrinolytic therapy, a loading dose of 300 mg of clopidogrel followed by clopidogrel 75 mg once daily resulted in:

A 36% reduction (p <0.001) in the odds of an occluded infarct-related artery, or death or MI by time of pre-discharge angiography or hospital discharge (maximum 8 days)

Consistent results across all major subgroups

At 30 days, a 20% reduction (p=0.03) in CV death, MI or recurrent ischemia leading to urgent revascularization

No significant excess in TIMI major bleeding or ICH


1. CCS-2 Collaborative Group. J Cardiovasc Risk 2000; 7: 435441.

COMMIT/CCS-2: ClOpidogrel and Metoprolol in Myocardial Infarction Trial

Purpose:To determine whether adding clopidogrel can produce a further reduction in mortality and the risk of vascular events in hospitalized patients admitted with acute STEMI1

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

(n=~23,000)

n=~46,000

Patients with acute STEMI 24 hours

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

(2 X 2 factorial with metoprolol)

Study Design1

Clopidogrel 75 mg once daily*

Placebo*

(n=~23,000)

R


Inclusion/Exclusion Criteria1

Inclusion criteria: Suspected acute MI (with definite ECG changes: ST elevation

or left bundle block branch [LBBB]) Within 24 hours of the onset of symptoms No clear indication/contraindication to trial treatments

Exclusion criteria: High risk of adverse drug reactions:

Allergy to ASA or any trial drug Active bleeding or hematologic disorder Persistent hypotension or bradycardia High-degree atrioventricular (AV) block, pacemaker,

cardiogenic shock Small likelihood of potential benefits:

Low risk of MI death (non-typical MI, primary PCI)


Study Endpoints1

Co-primary endpoints: Death Death, non-fatal MI or non-fatal stroke

Safety endpoints: Major non-cerebral bleeding (fatal or transfused) Hemorrhagic stroke


Clopidogrel Placebo

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

Female (%) 27.7 27.9

Age >70 (%) 26.0 26.0

Time delay <6 hours (%) 33.8 33.7

Killip class II/III (%) 24.1 24.0

STEMI/LBBB (%) 93.1 93.1

Fibrinolytic:

All patients (%) 49.7 49.8

STEMI <12 hours (%) 67.8 67.7

Patient Baseline Characteristics1

1. Chen ZM et al. Oral presentation, ACC 2005. Available at: URL: http://www.commit-ccs2.org. Accessed April 2005.

http://www.commit-ccs2.org/

Clopidogrel Placebo

Therapy (n=22,960) (n=22,891)

Anticoagulants 74.1% 75.0%

ACE inhibitors 68.2% 68.3%

Nitrates (oral or iv) 94.1% 94.3%

Diuretics 23.3% 23.3%

Anti-arrhythmics 22.4% 22.2%

Calcium antagonists 11.8% 11.8%

Concomitant Medications During Index Hospitalization1



Clopidogrel Reduced the Composite of Death, MI or Stroke by 9%1

0 7 14 21 280

1

2

34

5

67

8

910

Days (up to 28 days)

Clopidogrel(9.3%)

Placebo (10.1%)

Eve

nts

(%

)

RRR=9%p=0.002

RRR=relative risk reduction



Clopidogrel Reduced Mortality by 7%1

0 7 14 21 280

1

2

3

4

5

6

7

8

9

Days (up to 28 days)

Clopidogrel(7.5%)

Placebo(8.1%)

RRR=7%p=0.03

Mo

rtal

ity

(%)



Clopidogrel Decreased Re-Infarction1

Odds ratio & 95% CIClopidogrel 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%reduction

p=0.02

0.4 0.6 0.8 1.0 1.2 1.4 1.6



Effects of Clopidogrel on Stroke1


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%reduction

p=NS

0.4 0.6 0.8 1.0 1.2 1.4 1.6



COMMIT: Fatal and Non-Fatal Major Bleeds1

Clopidogrel Placebo

Type (n=22,958) (n=22,891)

Cerebral

Fatal 39 40

Non-fatal 16 15

Non-cerebral

Fatal 36 37

Non-fatal 46 36

Any major bleed 134 (0.58%) 124 (0.54%)



Effects of Clopidogrel on Death, Re-MI or Stroke by Days to Event1


Clopidogrel PlaceboEvents by day (n=22,958) (n=22,891)

0 463 (2.0) 523 (2.3)

1 486 (2.1) 527 (2.3)

23 449 (2.0) 451 (2.0)

47 432 (1.9) 463 (2.0)

828 295 (1.3) 347 (1.5)

ALL 2125 (9.3%) 2311 (10.1%)

0.4 0.6 0.8 1.0 1.2 1.4 1.6

9% increase

p=0.002



Consistent Effects of Clopidogrel on Death,Re-MI or Stroke by Age and Gender1


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

Gender

Male 1276 (7.7%) 1416 (8.6%)

Female 849 (13.3%) 895 (14.0%)

Age (years)

<60 487 (5.1%) 513 (5.4%)

6069 747 (10.2%) 835 (11.2%)

≥70 891 (14.9%) 963 (16.2%)

ALL 2125 (9.3%) 2311 (10.1%)

9% reduction

p=0.002

0.4 0.6 0.8 1.0 1.2 1.4 1.6



Effects of Clopidogrel on Death, Re-MI or Stroke by Time Delay and Fibrinolytic Use1


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

Time delay (hours)

06 776 (9.3%) 904 (10.9%)

712 672 (9.7%) 735 (10.7%)

1324 666 (8.8%) 666 (8.7%)

Fibrinolytic used

Yes 1005 (8.8%) 1123 (9.9%)

No 1120 (9.7%) 1188 (10.3%)

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

reductionp=0.002

0.4 0.6 0.8 1.0 1.2 1.4 1.6



Clopidogrel (75 mg once daily) on a background of standard therapy including ASA was beneficial at 4 weeks for a wide range of acute STEMI patients Clopidogrel reduced mortality* by 7% (p=0.03) Clopidogrel reduced the risk of death, non-fatal MI or

non-fatal stroke by 9% (p=0.002)

No significant increase in the risk of major (fatal or transfused) bleeding occurred with clopidogrel

*Death during initial hospitalization

Conclusions1



Incidence of ACS in the US

ACS1,673,0001

Unstable angina728,0001*

MI 973,0001*

NSTEMI55–70% of ACS patients2

STEMI30–45% of ACS patients2

1. American Heart Association. Heart and Stroke statistical update. Dallas, Texas: American Heart Association 2005. 2. NRMI-4. J Am Coll Cardiol 2003; 41: 365A–366A.

*28,000 hospitalizations received both diagnoses for UA and MI

Number of patients with ACS discharged from US hospitals in 2002 (including secondary discharges)

Scope of the CURE trial

Scope of the CLARITY/COMMIT trials

Evolution of Pharmacologic Reperfusion1

2005; 3.5 days

TPASK

TIMI 11

ASA +clopidogrel

ASA

APRICOT2

Placebo ASA

1985; 90 minutes 1993; 3 months

11.7

32

18.4

2530

57

0

10

20

30

40

50

60

Occ

lud

ed i

nfa

rct-

rela

ted

art

ery

(%)

47%p <0.001

22%p=0.26

36%p <0.001

APRICOT=Antithrombotics in the Prevention of Reocclusion In COronary Thrombolysis

1. TIMI Study Group. New Engl J Med 1985; 312: 932–936. 2. Meijer A et al. Circulation 1993 87: 1524–1530. 3. Sabatine M et al. New Eng J Med 2005; 352: 1179–1189.

3

Complementary Results of CLARITY and COMMIT for Patients with STEMI

Significant improvement in coronary perfusion and clinical outcomes versus standard care (CLARITY)

Significant reduction in mortality for patients receiving clopidogrel versus standard care alone (COMMIT)

No significant increase in major bleeding or ICH (COMMIT and CLARITY)

The Role of Clopidogrel in Improving Atherothrombosis Management

The Ongoing Clopidogrel Clinical Trial Program Covers All Manifestations of Atherothrombosis

1. CAPRIE Steering Committee. Lancet 1996; 348: 1329–1339. 2. Diener HC et al. Lancet 2004; 364: 331–337.3. Sabatine M et al. New Eng J Med 2005; 352: 1179–1189. 4. The CURE trial investigators. N Engl J Med 2001; 345: 494–502.5. Bertrand ME et al. Circulation 2000; 102: 624–629.6. Steinhubl SR et al. JAMA 2002; 288: 2411–2420.

StrokeTIA

Acute MIUA

Prior MIPCI/stenting

Atrial fibrillation

Intermittent claudication

Peripheral vascular

intervention

CHARISMACAPRIE1

ACTIVECOMMITCLARITY3

CURE4

CLASSICS5

CREDO6

CHARISMACAPRIE1

CASPAR

CHARISMACAPRIE1

MATCH2

ACTIVECARESS

© Teri J McDermott CMI 2003

Cerebrovascular1

Cardiovascular2

Peripheral arterial3

Conclusions

STEMI is a sudden and severe consequence of underlying atherothrombotic disease, which requires immediate reperfusion therapy

Clopidogrel reduced mortality and improved coronary perfusion and clinical outcomes for patients with STEMI receiving standard medical care (including thrombolytics and ASA)

Clopidogrel (including a loading dose) does not significantly increase major bleeding or ICH versus standard care alone

CLARITY and COMMIT complement the positive benefits of clopidogrel seen in other clinical trials and atherothrombosis populations

clopidogrel in patients with st-segment elevation myocardial infarction (stemi)

Documents

deathpostmi23 x greater

j cardiovasc risk

use of clopidogrel

fatal mi

myocardial infarction

myocardial infarction

estimated prevalence

coronary heart diseaseacs