Transcript Slide 1

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
Pathologic Progression to Atherothrombosis1
Thrombosis
Unstable
angina
MI
Atherosclerosis
ACS
Ischemic
stroke/TIA
Critical leg
ischemia
Intermittent
claudication
CV death
Stable angina/intermittent claudication
MI=myocardial infarction; ACS=acute coronary syndromes;
TIA=transient ischemic attack; CV=cardiovascular
1. Libby P. Circulation 2001; 104: 365–372.
Major Role of Platelets in Atherothrombosis1
1
Adhesion
Platelets
Plaque
rupture
2 Activation
Activated
platelets
3 Aggregation
TxA2
ADP
ADP=adenosine diphosphate; TxA2=thromboxane A2
1. Cannon CP et al. Heart Disease: A Textbook of Cardiovascular Medicine. 6th ed.
Philadelphia, PA: WB Saunders, 2001: 1232–1263.
Fibrinogen
Major Manifestations of Atherothrombosis
Cerebrovascular disease
Coronary artery disease
Renal artery stenosis
Visceral arterial disease
Peripheral arterial disease (PAD)
Prevalence of Atherothrombotic Manifestations
is Increasing Worldwide*1
Prevalence
2000
2005
Populations aged
>50 years
205.0 million
(5.1% since 1997)
222.2 million
(13.9% since 1997)
MI
9.1 million
(12.8% since 1997)
10.7 million
(32.7% since 1997)
Ischemic stroke
7.1 million
(11.8% since 1997)
8.4 million
(31.6% since 1997)
*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)
1. Guillot F et al. Circulation 1998; 98: A1421 (Abstract).
Increased Risk in Other Vascular Beds After an
Atherothrombotic Event1–4
Increased risk of MI
CHD=coronary heart disease
1.
2.
3.
4.
Adult Treatment Panel II. Circulation 1994; 89: 1333–1435.
Kannel WB. J Cardiovasc Risk 1994; 1: 333–339.
Wilterdink JI et al. Arch Neurol 1992; 49: 857–863.
Criqui MH et al. N Engl J Med 1992; 326: 381–386.
Increased risk of stroke
ACS is an Important Manifestation of
Atherothrombosis1
Plaque
rupture
Old term
Stable
angina
UA
New term Atherothrombosis
Days–
weeks
NonQ-wave MI
UA/NSTEMI
Antithrombotic
therapy
Q-wave
MI
STEMI
Minutes–
hours
Thrombolysis
primary PCI
UA=unstable angina; NSTEMI=non-ST-segment elevation
myocardial infarction; PCI=percutaneous coronary intervention
1. Adapted with permission from Cannon CP. J Thromb Thrombolysis 1995; 2: 205–218.
Incidence of ACS in the US
Number of patients with ACS discharged from US hospitals in 2002
(including secondary discharges)
ACS
1,673,0001
UA
728,0001*
MI
973,0001*
NSTEMI
55–70% of ACS patients2
STEMI
30–45% of ACS patients2
*28,000 hospitalizations received both diagnoses for UA and MI
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.
Pathophysiology of STEMI1
Generally caused by a
completely occlusive
thrombus in a coronary artery
Results from stabilization of a
platelet aggregate at the site of
plaque rupture by fibrin mesh
Platelet
RBC
Fibrin mesh
GPIIb/IIIa
RBC=red blood cell
1. Antman EM. In: Califf RM, ed. Atlas of Heart Diseases, VIII. Philadelphia, PA: Current
Medicine, 1996.
High Risk of Mortality Following Acute MI
 Approximately 33% of patients with an MI will die
before they reach the hospital1
NRMI 34
(n=81,679)*2
In-hospital mortality
GRACE Registry
(n=5,476)3
12.3%
7.8%
Reperfused
6.6%
–
Not reperfused
18.7%
–
6-month† mortality
–
4.8%
*Patients with STEMI from the NRMI 34 database (n=153,486); †postdischarge; 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
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.
Ischemic Heart Disease Has a Devastating
Impact on Quality of Life1
Total DALY* loss (%)
5
4
3
2
1
0
Depression
Ischemic
heart
disease
Stroke
Schizophrenia Lung
cancer
Breast
cancer
*Disability-adjusted life years (DALY) combine years of potential
life lost due to premature death with years of productive life lost
due to disability
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.
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*
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
1. Antman EM et al. Circulation 2004; 110: 588–636.
Thrombolysis Remains an Important
Reperfusion Strategy Worldwide
GRACE1
(n=5,476)
EHS2
(n=3,438)
NRMI 34*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 34 database (n=153,486);
EHS=EuroHeart Survey; CABG=coronary artery bypass graft
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.
Common Thrombolytic Regimens for STEMI1
Initial treatment
Streptokinase (SK) 1.5 million U in 100 mL
5% dextrose or 0.9% saline
over 3060 min
Co-therapy
Contraindications
None or iv
heparin x 2448 hours
Alteplase (tPA)
15 mg iv bolus, then
iv heparin x 2448 hours
0.75 mg/kg over 30 min,
then 0.5 mg/kg iv over 60 min
Total dose not over 100 mg
Reteplase (rPA)
10 U + 10 U iv bolus given
30 min apart
iv heparin x 2448 hours
Tenecteplase
(TNK-tPA)
Single iv bolus
30 mg if <60 kg
35 mg if 60 kg to <70 kg
40 mg if 70 kg to <80 kg
45 mg if 80 kg to <90 kg
50 mg if ≥90 kg
iv heparin x 2448 hours
Prior SK or
anistreplase
Note: acetylsalicylic acid (ASA) should be given to all patients without contraindications;
iv=intravenous
1. Van de Werf F et al. Eur Heart J 2003; 24: 2866.
Thrombolysis and ASA in Acute STEMI: ISIS-21
25%*
p <0.00001
23%*
p <0.00001
14
5-week mortality (%)
12
10
42%*
p <0.00001
13.2%
12.0%
11.8%
9.2%
9.4%
8.0%
8
6
4
2
0
Placebo versus
SK
Placebo versus
ASA 162 mg
Neither
versus both
*Odds reduction; ISIS=Second International Study of Infarct Survival
1. ISIS-2 Collaborative Group. Lancet 1988; 2: 349360.
Other Routine Therapies in Acute STEMI1
 ASA 150325 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: 2866.
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 Therapy
in Acute MI
Antiplatelet Therapy is Beneficial1
Category
Odds reduction
of vascular events (%)*
Acute MI
30%
Acute stroke
11%
Prior MI
25%
Prior stroke/TIA
22%
Other high risk
26%
22%
All trials
0.0
0.5
1.0
1.5
2.0
Antiplatelet better
Control better
*Vascular events=MI, stroke or vascular death
1. Antithrombotic Trialists’ Collaboration. BMJ 2002; 324: 71–86.
Potent, Specific and Complementary
Mode of Action of Clopidogrel1
CLOPIDOGREL
C
ADP
ADP
GPllb/llla
Activation
(fibrinogen receptor)
ASA
COX
TXA2
COX=cyclo-oxygenase
1. Jarvis B et al. Drugs 2000; 60: 347–377.
Collagen thrombin
TXA 2
Early and Long-Term Benefits of Clopidogrel
in UA/NSTEMI1
Placebo†
(n=6,303)
Cumulative* hazard ratio
0.14
20%
p <0.001
0.12
0.10
Clopidogrel†
(n=6,259)
0.08
0.06
0.04
0.02
0
0
3
6
Follow-up (months)
9
*Cumulative events: MI, stroke or CV death; †all patients received a
background of ASA therapy
1. CURE Trial Investigators. N Engl J Med 2001; 345: 494–502.
12
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)
*Also known as non-Q-wave MI; ACC=American College of
Cardiology; AHA=American Heart Association
1. Braunwald E et al. J Am Coll Cardiol 2002; 40: 1366–1374.
2002 ACC/AHA UA/NSTEMI* Guidelines Update:
Antiplatelet and Anticoagulant Therapy (cont)1
Class I:
 In patients taking clopidogrel in whom elective CABG is
planned, the drug should be withheld for 57 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)
*Also known as non-Q-wave MI
1. Braunwald E et al. J Am Coll Cardiol 2002; 40: 1366–1374.
2002 ACC/AHA UA/NSTEMI* Guidelines Update:
Antiplatelet and Anticoagulant Therapy (cont)1
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)
*Also known as non-Q-wave MI
1. Braunwald E et al. J Am Coll Cardiol 2002; 40: 1366–1374.
2002 ACC/AHA UA/NSTEMI* Guidelines Update:
Key Recommendations for Clopidogrel Therapy1
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)
*Also known as non-Q-wave MI
1. Braunwald E et al. J Am Coll Cardiol 2002; 40: 1366–1374.
ESC Recommended Strategy in ACS Patients1
Clinical suspicion of ACS
Physical examination
Electrocardiogram (ECG) monitoring, blood samples
Persistent
ST-segment elevation
No persistent
ST-segment elevation
Undetermined
diagnosis
Thrombolysis
PCI
ASA, LMWH,
clopidogrel*, beta-blockers, nitrates
ASA
*Omit clopidogrel if
the patient is likely
to go to CABG
within 5 days
High risk
GPIIb/IIIa,
coronary angiography
Low risk
Second troponin measurement
Positive
PCI, CABG or medical management
depending upon clinical and angiographic features
1. Adapted with permission from Bertrand ME et al. Eur Heart J 2002; 23; 18091840.
Twice negative
Stress test,
coronary angiography
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
Double-blind, randomized, placebo-controlled trial in
patients aged 1875 years with STEMI ≤12 hours
Clopidogrel 300 mg loading dose/75 mg once daily†
n=1,752
Thrombolysis,
heparin and ASA*
R
Study treatment until
angiography (28 days) or
hospital discharge
(maximum 8 days)
Clinical
follow-up
at 30 days
n=1,739
Placebo†
Primary endpoint: occluded artery (Thrombolysis In Myocardial Infarction [TIMI]
flow grade [TFG] 0/1) on the angiogram or 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 care
1. Sabatine M et al. New Eng J Med 2005; 352: 1179–1189.
Inclusion/Exclusion Criteria1
Inclusion criteria
 Age 1875 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
1. Sabatine M et al. New Eng J Med 2005; 352: 1179–1189.
Global Study Sites
319 sites in 23 countries
Study Endpoints1
Primary endpoint:
 Composite of occluded infarct-related artery (TFG 0/1) on predischarge 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
*CV death, MI, stroke or recurrent ischemia leading
to urgent target vessel revascularization
1. Sabatine M et al. New Eng J Med 2005; 352: 1179–1189.
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 0
Occlusion
TFG 1
Penetration
TFG 2
Slow flow
1. Reproduced with permission from Gibson CM et al. Circulation 2004: 109: 30963105.
TFG 3
Normal flow
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 0
TMPG 1
1. Gibson CM et al. Circulation 2004: 109: 30963105.
TMPG 2
TMPG 3
Relationship Between Angiographic Outcomes
and Long-term Mortality1
2-year mortality (%)
16
HR: 0.41
HR: 0.51
p=0.001
p=0.038
14.6%
14
12
9.1%
10
8
6.4%
6
4.8%
4
2
0
TFG 0/1
TFG 2/3
TMPG 0/1 TMPG 2/3
*Assessed on 90-minute angiogram in TIMI 10B trial;
HR=hazard ratio
1. Gibson CM et al. Circulation 2002; 105: 19091913.
Baseline Characteristics1
Characteristic
Age (years)
Male gender (%)
Hypertension (%)
Hyperlipidemia (%)
Current smoker (%)
Diabetes mellitus (%)
Prior MI (%)
Prior PCI (%)
Anterior MI (%)
1. Sabatine M et al. New Eng J Med 2005; 352: 1179–1189.
Clopidogrel
(n=1,752)
Placebo
(n=1,739)
57.7
79.9
42.8
32.2
50.7
16.5
9.1
4.8
41.2
57.2
80.7
43.9
33.0
49.9
16.4
9.1
4.9
40.1
Concomitant Medications1
Characteristic
Clopidogrel
(n=1,752)
Fibrin-specific thrombolytic (%):
TNK-tPA
rPA
tPA
Non-fibrin specific thrombolytic (%):
SK
No thrombolytic given (%)
ASA (%)
Heparin (%):
UFH
LMWH
1. Sabatine M et al. New Eng J Med 2005; 352: 1179–1189.
Placebo
(n=1,739)
47.8
11.9
9.1
47.3
12.3
8.9
30.9
0.2
98.5
31.2
0.3
98.6
46.1
30.1
45.5
29.1
Patient Management1
Parameter
Symptom onset to fibrinolytic (hours)
Fibrinolytic to study drug (minutes)
Median doses of study medication
Angiography performed (%)
Study drug to angiography (hours)
Coronary revascularization (%):
PCI
CABG
1. Sabatine M et al. New Eng J Med 2005; 352: 1179–1189.
Clopidogrel
(n=1,752)
Placebo
(n=1,739)
2.7
10
4
94
84
63
57.2
5.9
2.6
10
4
94
84
63
56.6
6.0
Other Cardiac Medications During Index
Hospitalization1
Characteristic (%)
Beta-blockers
Statins
ACE inhibitors/ARBs
After angiography*
Clopidogrel
Ticlopidine
Clopidogrel
(n=1,752)
Placebo
(n=1,739)
88.7
80.4
72.7
89.6
81.1
72.1
54.5
3.5
55.6
2.9
*Some patients received open-label ADP-receptor antagonists after angiography
and primary endpoint ascertainment; ARB=angiotensin receptor blocker
1. Sabatine M et al. New Eng J Med 2005; 352: 1179–1189.
Clopidogrel Improved Coronary Perfusion1
25
36% reduction*
Primary endpoint* (%)
p <0.001
21.7
20
15
15.0
10
5
Clopidogrel
(n=1,752)
Placebo
(n=1,739)
*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 [0.530.76]; p <0.001)
1. Sabatine M et al. New Eng J Med 2005; 352: 1179–1189.
Clopidogrel Reduced Primary Endpoint by 36%1
Clopidogrel Placebo
(n=1,752) (n=1,739)
Odds ratio
(95% CI)
p value
0.64 (0.530.76)
<0.001
Individual components of primary endpoint (%)
TFG 0/1
11.7
18.4
0.59 (0.480.72)
Recurrent MI
2.5
3.6
0.70 (0.471.04)
Death
2.6
2.2
1.17 (0.751.82)
<0.001
0.08
0.49
Primary composite endpoint (%)
TFG 0/1, MI or death
15.0
CI=confidence interval
1. Sabatine M et al. New Eng J Med 2005; 352: 1179–1189.
21.7
Consistent Results for Primary Endpoint
Across Subgroups1
Characteristic
Number of
patients
Odds
reduction
3491
36
15.0
21.7
2466
1015
42
22
13.2
19.0
21.0
23.1
2796
685
35
38
14.5
16.9
20.8
24.7
1416
2065
33
38
15.0
15.0
20.7
22.2
2397
1084
31
44
14.7
15.7
20.1
24.9
1429
1431
621
31
42
26
11.4
17.8
17.1
15.7
27.1
21.9
OVERALL
Age
<65 years
65 years
Gender
Male
Female
Infarct location
Anterior
Non-anterior
Fibrinolytic
Fibrin-specific
Non-fibrin specific
Predominant heparin
LMWH
UFH
None
0.4
0.6
0.8 1.0 1.2
Clopidogrel better
1.6
Placebo better
1. Sabatine M et al. New Eng J Med 2005; 352: 1179–1189.
Patients with event (%)
Clopidogrel Placebo
Clopidogrel Improved Angiographic Outcomes1
Clopidogrel Placebo
(n=1,752) (n=1,739)
Angiographic outcomes (%)
TFG 3
67.8
TMPG 3
55.8
Thrombus
43.0
1. Sabatine M et al. New Eng J Med 2005; 352: 1179–1189.
60.8
51.2
50.8
Odds ratio
(95% CI)
p value
1.36 (1.181.57)
1.21 (1.051.40)
0.73 (0.640.84)
<0.001
0.008
<0.001
Clopidogrel Reduced Clinical Events by 20%
at 30 Days1
Placebo
(14.1%)
Patients with endpoint (%)
15
20%*
p=0.03
Clopidogrel
(11.6%)
10
5
0
0
5
10
15
20
Time (days)
*Odds ratio in CV death, MI or recurrent ischemia
leading to urgent revascularization
1. Sabatine M et al. New Eng J Med 2005; 352: 1179–1189.
25
30
Consistent Results Across 30-day Endpoints1
Odds ratio
(95% CI)
Endpoint
Odds
reduction
Patients with event (%)
Clopidogrel Placebo
CV death
3
4.4
4.5
Recurrent MI
31
4.1
5.9
Recurrent ischemia
leading to urgent
revascularization
24
3.5
4.5
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 recurrent
ischemia leading to urgent
revascularization
20
11.6
14.1
21
12.3
15.0
CV death, MI, stroke or
recurrent ischemia leading
to urgent revascularization
0.4
0.6 0.8 1.0 1.2 1.6
Clopidogrel better Placebo better
1. Sabatine M et al. New Eng J Med 2005; 352: 1179–1189.
Safety1
Clopidogrel
(n=1733)
Placebo
(n=1719)
p value
Primary bleeding endpoint, n (%)
TIMI major
23 (1.3)
19 (1.1)
NS
Secondary bleeding endpoints, n (%)
TIMI minor
TIMI major or minor
ICH
17 (1.0)
40 (2.3)
8 (0.5)
9 (0.5)
28 (1.6)
12 (0.7)
NS
NS
NS
Bleeding through 30 days, n (%)
TIMI major
TIMI minor
TIMI major or minor
33 (1.9)
27 (1.6)
59 (3.4)
30 (1.7)
16 (0.9)
46 (2.7)
NS
NS
NS
NS=not statistically significant
1. Sabatine M et al. New Eng J Med 2005; 352: 1179–1189.
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 infarctrelated 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. Sabatine M et al. New Eng J Med 2005; 352: 1179–1189.
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
1. CCS-2 Collaborative Group. J Cardiovasc Risk 2000; 7: 435441.
Study Design1
Clopidogrel 75 mg once daily*
(n=~23,000)
Patients with
acute STEMI
24 hours
n=~46,000
R
Double-blind treatment until hospital
discharge or for a maximum of 4 weeks
(n=~23,000)
Placebo*
(2 X 2 factorial with metoprolol)
*All patients received a background of ASA 162 mg/day
during the study
1. CCS-2 Collaborative Group. J Cardiovasc Risk 2000; 7: 435441.
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)
1. CCS-2 Collaborative Group. J Cardiovasc Risk 2000; 7: 435441.
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
1. CCS-2 Collaborative Group. J Cardiovasc Risk 2000; 7: 435441.
Patient Baseline Characteristics1
Characteristic
Female (%)
Age >70 (%)
Time delay <6 hours (%)
Killip class II/III (%)
STEMI/LBBB (%)
Fibrinolytic:
All patients (%)
STEMI <12 hours (%)
Clopidogrel
Placebo
(n=22,960)
(n=22,891)
27.7
26.0
33.8
24.1
93.1
27.9
26.0
33.7
24.0
93.1
49.7
67.8
49.8
67.7
1. Chen ZM et al. Oral presentation, ACC 2005. Available at: URL: http://www.commit-ccs2.org. Accessed April 2005.
Concomitant Medications During Index
Hospitalization1
Therapy
Anticoagulants
ACE inhibitors
Nitrates (oral or iv)
Diuretics
Anti-arrhythmics
Calcium antagonists
Clopidogrel
(n=22,960)
Placebo
(n=22,891)
74.1%
68.2%
94.1%
23.3%
22.4%
11.8%
75.0%
68.3%
94.3%
23.3%
22.2%
11.8%
1. Chen ZM et al. Oral presentation, ACC 2005. Available at: URL: http://www.commit-ccs2.org. Accessed April 2005.
Clopidogrel Reduced the Composite of Death,
MI or Stroke by 9%1
Events (%)
Placebo
(10.1%)
10
9
8
7
6
5
4
3
2
1
0
RRR=9%
p=0.002
Clopidogrel
(9.3%)
0
7
14
21
28
Days (up to 28 days)
RRR=relative risk reduction
1. Chen ZM et al. Oral presentation, ACC 2005. Available at: URL: http://www.commit-ccs2.org. Accessed April 2005.
Clopidogrel Reduced Mortality by 7%1
Placebo
(8.1%)
9
RRR=7%
8
p=0.03
Mortality (%)
7
Clopidogrel
(7.5%)
6
5
4
3
2
1
0
0
7
14
21
28
Days (up to 28 days)
1. Chen ZM et al. Oral presentation, ACC 2005. Available at: URL: http://www.commit-ccs2.org. Accessed April 2005.
Clopidogrel Decreased Re-Infarction1
Outcome
after re-MI
Clopidogrel
(n=22,958)
Placebo
Odds ratio & 95% CI
(n=22,891) Clopidogrel better Placebo better
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
1. Chen ZM et al. Oral presentation, ACC 2005. Available at: URL: http://www.commit-ccs2.org. Accessed April 2005.
Effects of Clopidogrel on Stroke1
Clopidogrel
(n=22,958)
Placebo
(n=22,891)
Ischemic
162 (0.7%)
192 (0.8%)
Hemorrhagic
55 (0.2%)
55 (0.2%)
ALL
216 (0.9%)
249 (1.1%)
Type
Odds ratio & 95% CI
Clopidogrel better Placebo better
14%
reduction
p=NS
0.4 0.6 0.8 1.0 1.2 1.4 1.6
1. Chen ZM et al. Oral presentation, ACC 2005. Available at: URL: http://www.commit-ccs2.org. Accessed April 2005.
COMMIT: Fatal and Non-Fatal Major Bleeds1
Type
Clopidogrel
(n=22,958)
Placebo
(n=22,891)
39
16
40
15
36
46
134 (0.58%)
37
36
124 (0.54%)
Cerebral
Fatal
Non-fatal
Non-cerebral
Fatal
Non-fatal
Any major bleed
1. Chen ZM et al. Oral presentation, ACC 2005. Available at: URL: http://www.commit-ccs2.org. Accessed April 2005.
Effects of Clopidogrel on Death, Re-MI or
Stroke by Days to Event1
Clopidogrel
(n=22,958)
Placebo
(n=22,891)
0
463 (2.0)
523 (2.3)
1
486 (2.1)
527 (2.3)
23
449 (2.0)
451 (2.0)
47
432 (1.9)
463 (2.0)
828
295 (1.3)
347 (1.5)
ALL
2125 (9.3%)
2311 (10.1%)
Events by day
Odds ratio & 95% CI
Clopidogrel better Placebo better
9%
increase
p=0.002
0.4 0.6 0.8 1.0 1.2 1.4 1.6
1. Chen ZM et al. Oral presentation, ACC 2005. Available at: URL: http://www.commit-ccs2.org. Accessed April 2005.
Consistent Effects of Clopidogrel on Death,
Re-MI or Stroke by Age and Gender1
Baseline
features
Clopidogrel
(n=22,958)
Placebo
(n=22,891)
Male
Female
Age (years)
<60
6069
≥70
1276 (7.7%)
849 (13.3%)
1416 (8.6%)
895 (14.0%)
487 (5.1%)
747 (10.2%)
891 (14.9%)
513 (5.4%)
835 (11.2%)
963 (16.2%)
ALL
2125 (9.3%)
2311 (10.1%)
Odds ratio & 95% CI
Clopidogrel better Placebo better
Gender
9%
reduction
p=0.002
0.4 0.6 0.8 1.0 1.2 1.4 1.6
1. Chen ZM et al. Oral presentation, ACC 2005. Available at: URL: http://www.commit-ccs2.org. Accessed April 2005.
Effects of Clopidogrel on Death, Re-MI or
Stroke by Time Delay and Fibrinolytic Use1
Baseline
features
Clopidogrel
(n=22,958)
Odds ratio & 95% CI
Placebo
(n=22,891) Clopidogrel better Placebo better
Time delay (hours)
06
712
1324
776 (9.3%)
672 (9.7%)
666 (8.8%)
904 (10.9%)
735 (10.7%)
666 (8.7%)
Fibrinolytic used
Yes
No
1005 (8.8%)
1120 (9.7%)
1123 (9.9%)
1188 (10.3%)
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
1. Chen ZM et al. Oral presentation, ACC 2005. Available at: URL: http://www.commit-ccs2.org. Accessed April 2005.
Conclusions1
 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 nonfatal 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
1. Chen ZM et al. Oral presentation, ACC 2005. Available at: URL: http://www.commit-ccs2.org. Accessed April 2005.
Incidence of ACS in the US
Number of patients with ACS discharged from US hospitals in 2002
(including secondary discharges)
ACS
1,673,0001
Unstable angina
728,0001*
MI
973,0001*
NSTEMI
55–70% of ACS patients2
STEMI
30–45% of ACS patients2
Scope of the CURE trial
Scope of the CLARITY/COMMIT trials
*28,000 hospitalizations received both diagnoses for UA and MI
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.
Evolution of Pharmacologic Reperfusion1
Occluded infarct-related artery (%)
TIMI 11
1985; 90 minutes
3
APRICOT2
1993; 3 months
2005; 3.5 days
60
57
47%
p <0.001
50
40
30
22%
p=0.26
32
30
25
20
18.4
10
36%
p <0.001
11.7
0
SK
TPA
Placebo
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.
ASA
ASA
ASA +
clopidogrel
APRICOT=Antithrombotics in the Prevention
of Reocclusion In COronary Thrombolysis
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 Cerebrovascular
2 Cardiovascular
3 Peripheral arterial
CHARISMA
CAPRIE1
MATCH2
ACTIVE
CARESS
Stroke
TIA
Acute MI
UA
Prior MI
PCI/stenting
Atrial fibrillation
CHARISMA
CAPRIE1
ACTIVE
COMMIT
CLARITY3
CURE4
CLASSICS5
CREDO6
Intermittent
claudication
Peripheral
vascular
intervention
CHARISMA
CAPRIE1
CASPAR
© Teri J McDermott CMI 2003
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.
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