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

2. 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

3. 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
This slide kit provides background information on ST-segment elevation myocardial infarction (STEMI) in the context of atherothrombosis
It examines where STEMI fits within the spectrum of acute coronary syndromes (ACS) and atherothrombosis, and provides information about current treatment, including antiplatelet therapy, in the management of STEMI patients
Background and results from the CLopidogrel as Adjunctive ReperfusIon TherapY (CLARITY) trial are presented. This trial investigated whether clopidogrel may produce angiographic and clinical benefits in MI patients (STEMI), on a background of standard therapy (including fibrinolysis and acetylsalicylic acid [ASA])
Background and results from the ClopidOgrel and Metoprolol in Myocardial Infarction Trial (COMMIT) follow. This trial evaluated the efficacy and safety of clopidogrel in MI patients (STEMI), on a background of standard therapy (including fibrinolysis and ASA)
Finally, an overview of the growing body of evidence showing the benefits of clopidogrel, including results from the CLARITY and COMMIT studies, is provided

4. Epidemiology and Background

5. Pathologic Progression to Atherothrombosis1
Unstable angina MI
Ischemic stroke/TIA
Critical leg ischemia
Intermittent
claudication
CV death
ACS
Atherosclerosis
Vascular disease is the common underlying disease process for myocardial infarction (MI), ischemia and vascular death1
ACS is a classic example of the progression of vascular disease to an ischemic event1
ACS (in common with ischemic stroke and critical leg ischemia) is typically caused by the rupture or erosion of an atherosclerotic plaque followed by the formation of a platelet-rich thrombus1,2
Atherosclerosis is an ongoing process affecting mainly large and medium-sized arteries. It can begin in childhood and progress throughout a person’s lifetime1
Stable atherosclerotic plaques may encroach on the lumen of the artery and cause chronic ischemia, resulting in (stable) angina pectoris or intermittent claudication, depending on the vascular bed affected3,4
Unstable atherosclerotic plaques may rupture, leading to the formation of a platelet-rich thrombus that partially or completely occludes the artery and causes acute ischemic symptoms3,4
References
Cannon CP. J Thromb Thrombolysis 1995; 2: 205218.
Yun DD et al. Cardiology 1997; 88: 223–237.
Davies MJ. Circulation 1990; 82(Suppl II): 1138–1146.
Fuster V. Circulation 1994; 94: 2126–2146.
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.

6. Major Role of Platelets in Atherothrombosis1
Adhesion 1
Platelets 2
Activation
Plaque
rupture
Activated platelets 3
Aggregation
TxA2
ADP
Fibrinogen
Platelets1
Platelets perform a very important biologic role in the vascular system. Interaction between the platelet and vessel wall is of crucial importance in the pathophysiology of atherothrombosis
Under normal circumstances, platelets do not adhere to healthy arterial walls nor are they activated by the vascular endothelium. However, at the site of injury, such as that caused by a ruptured atherosclerotic plaque, platelets will adhere to the endothelium, become activated and trigger the recruitment of more platelets forming a platelet plug
Platelet adhesion1
Within a few seconds of injury, platelets adhere to collagen fibrils in the vascular subendothelium via a specific platelet collagen receptor made up of glycoproteins (GPs). This interaction is stabilized by von Willebrand factor, an adhesive GP, which allows platelets to remain attached to the vessel wall despite the high shear forces generated within the vascular lumen. Platelet aggregation is mediated by fibrinogen, which links adjacent platelets on the platelet GP IIb/IIIa complex
Platelet activation1
Platelets can be activated by many mechanisms. Most of the substances released by these cells – in particular adenosine diphosphate (ADP), serotonin, thromboxane and others – can, in an autocrine and paracrine fashion, further enhance platelet activation and aggregation. Under these conditions, there is also activation of the coagulation cascade; therefore, thrombin is formed, which also markedly stimulates platelet activation
Platelet aggregation1
Activated platelets also change shape, resulting in cell membrane changes, which are important in further aggregation and coagulation
Reference
1. Cannon CP et al. Heart Disease: A Textbook of Cardiovascular Medicine. 6th ed. Philadelphia, PA: WB Saunders, 2001: 1232–1263.
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.

7. Major Manifestations of Atherothrombosis
Cerebrovascular disease
Coronary artery disease
Renal artery stenosis
Visceral arterial disease
Peripheral arterial disease (PAD)
Atherothrombosis is a progressive disorder that can be acute or chronic and may often affect multiple vascular beds in any single patient
Atherothrombosis in the coronary arteries is the major cause of ACS. In the cerebral arteries, atherothrombosis may result in transient ischemic attack (TIA) or ischemic stroke by a different mechanism (i.e. artery-to-artery embolism)
In the peripheral arteries, thrombosis superimposed on atherosclerosis can contribute to the progression of peripheral arterial disease (PAD), producing intermittent claudication as well as ischemic necrosis and, potentially, loss of the limb
Visceral artery disease is strongly associated with generalized atherosclerosis condition manifested by the presence of coronary artery disease (CAD), PAD and increasing age

8. Prevalence of Atherothrombotic Manifestations is Increasing Worldwide
Populations aged >50 years
205.0 million
(5.1% since 1997)
222.2 million
(13.9% since 1997)
9.1 million
(12.8% since 1997) MI
10.7 million
(32.7% since 1997)
Ischemic stroke
7.1 million
(11.8% since 1997)
8.4 million
(31.6% since 1997)
The burden of atherothrombosis is growing. As such, the leading cause of death of the estimated 55,694,000 people worldwide who died in 2000 was atherothrombosis, manifested as cardiovascular disease, ischemic heart disease and stroke (52% of deaths)1
Other main causes of death were1:
AIDS (5%)
Violent death (12%)
Pulmonary diseases (14%)
Infectious diseases (19%)
Cancer (24%)
It been estimated that the prevalence of MI and ischemic stroke has risen by approximately one-third from 1997 to 2005
The increases in the prevalence of these conditions is growing faster than the elderly population and, therefore, cannot be entirely explained by changing population demographics. Increased survival after a first event and secondary prevention contribute to this increase in prevalence
Reference
1. The World Health Report Geneva: WHO, Available at: URL: Accessed February 2005.
*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).

9. Increased Risk in Other Vascular Beds After an Atherothrombotic Event1–4
Increased risk of MI
Increased risk of stroke
Post-MI
5–7 X greater risk (includes death)
34 X greater risk (includes TIA)
Post-stroke
23 X greater risk (includes angina and sudden death)
9 X greater risk
PAD
4 X greater risk (includes only fatal MI and other CHD death)
23 X greater risk (includes TIA)
Data on this slide showing the increased risk of various events were taken from different sources, but show that the risk of a second vascular event can increase by up to 9-fold1–4
Patients with an atherothrombotic event (MI, stroke or PAD) are at an increased risk of experiencing a further atherothrombotic event1–4:
Patients with a history of MI have a 5–7-fold greater risk of having a further MI or dying, and a 3–4-fold greater risk of having a stroke or TIA
Patients with a history of stroke have a 2–3-fold greater risk of having a MI, angina or dying, and a 9-fold greater risk of having a stroke
Patients with a history of PAD have a 4-fold greater risk of experiencing a fatal MI or dying from other CHD death, and a 2–3-fold greater risk of experiencing a stroke or TIA
References
Adult Treatment Panel II. Circulation 1994; 89: 1333–1363.
Kannel WB. J Cardiovasc Risk 1994; 1: 333–339.
Wilterdink JI, Easton JD. Arch Neurol 1992; 49: 857–863.
Criqui MH et al. N Engl J Med 1992; 326: 381–386.
CHD=coronary heart disease
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.

10. ACS is an Important Manifestation of Atherothrombosis1
Plaque rupture
Stable UA
Non- Q-wave MI
Q-wave
Old term
angina MI
New term
Atherothrombosis
UA/NSTEMI
STEMI
Days–
weeks
Minutes– hours
Our current understanding of unstable coronary syndromes is that they include a spectrum of disease and begin with coronary plaque rupture1
The degree of thrombus occlusion determines the severity of the clinical syndrome, with total occlusion in STEMI or severe stenosis in patients with non-ST-segment elevation MI (NSTEMI) or unstable angina (UA)1
In addition, it is worthwhile to note that almost all plaque ruptures are clinically silent. A small degree of rupture leads to a small thrombus, which heals over, leading to the progression of a plaque1
This current understanding of how atherosclerosis progresses emphasizes the key role that acute and chronic antithrombotic therapy plays in all patients with unstable coronary syndromes1
Reference
1. Cannon CP. J Thromb Thrombolysis 1995; 2: 205218.
Antithrombotic
Thrombolysis
primary PCI
therapy
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.

11. Incidence of ACS in the US
Number of patients with ACS discharged from US hospitals in (including secondary discharges)
ACS can be classified as either UA or MI. The Heart Disease and Stroke Statistics 2005 Update showed that in the US over 50% of patients with ACS were diagnosed with MI; of these patients, 30–45% were diagnosed with STEMI1
The National Registry of Myocardial Infarction-4 (NRMI-4) is an observational study of the demographics, practice patterns and health outcomes among patients with MI in the United States (US; 1272 hospitals; July 2000 to October 2002)2
References
1. American Heart Association. Heart Disease and Stroke Statistics 2005 Update.
2. NRMI-4. J Am Coll Cardiol 2003; 41: 365A–366A.
*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.

12. 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
The common link between UA/NSTEMI and STEMI is that thrombus formation occurs secondary to the rupture or fissuring of an atherosclerotic plaque in the coronary arteries1
Under normal circumstances, platelets do not adhere to healthy arterial walls nor are they activated by the vascular endothelium. However, at the site of injury, such as that caused by a ruptured atherosclerotic plaque, platelets will adhere to the endothelium, become activated and trigger the recruitment of more platelets leading to the formation of a platelet plug2
This leads to thrombotic occlusion of the coronary artery with interruption of blood flow, resulting in myocardial ischemia and/or necrosis (death of myocardial cells)3,4
Patients with ACS are at high risk of subsequent life-threatening atherothrombotic events such as MI, stroke or vascular death5
References
1. Yun DD et al. Cardiology 1997; 88: 223–237.
2. Ferguson JJ. The Physiology of Normal Platelet Function. In: Ferguson JJ, Chronos N, Harrington RA, eds. Antiplatelet Therapy in Clinical Practice. London: Martin Dunitz, 2000: 15–35.
3. Davies MJ. Circulation 1990; 82(Suppl 3): 1138–1146.
4. Fuster V. Circulation 1994: 94: 2126–2146.
5. Hamm CW et al. N Engl J Med 1992; 327: 146–150.
RBC=red blood cell
1. Antman EM. In: Califf RM, ed. Atlas of Heart Diseases, VIII. Philadelphia, PA: Current Medicine, 1996.

13. High Risk of Mortality Following Acute MI
Approximately 33% of patients with an MI will die before they reach the hospital1
12.3%
6.6%
18.7% –
NRMI 34
(n=81,679)*2
In-hospital mortality
Reperfused
Not reperfused
6-month† mortality
GRACE Registry
(n=5,476)3
7.8%
4.8%
*Patients with STEMI from the NRMI 34 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
This slide demonstrates the high risk of MI patients developing subsequent events
The NRMI 34 trial showed that 12.3% of the patients with STEMI experienced hospital death1
In the Global Registry of Acute Coronary Events (GRACE), 7.8% of patients experienced hospital death and 4.8% died with 6 months2
Despite advances in medical management, patients with STEMI are still at high risk of subsequent events
References
1. NRMI 3-4. J Am Coll Cardiol 2004; 44: 783–789.
2. Goldberg RJ et al. Am J Cardiol 2004; 93: 288–293.
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 ACC/AHA STEMI Guidelines. Available at:
Accessed February 2005.

14. Ischemic Heart Disease Has a Devastating Impact on Quality of Life15 4 3
Total DALY* loss (%) 2 1
Depression
Ischemic
heart
disease
Stroke
Schizophrenia
Lung
cancer
Breast
cancer
Disability-adjusted life years (DALY) lost can be thought of as ‘healthy years of life lost’. They indicate the total burden of a disease, as opposed to simply the resulting deaths1
The burden of coronary heart disease (CHD) is projected to rise from approximately 47 million DALY globally in 1990 to 82 million DALY in 20201
Reference
1. World Health Organization. The Atlas of Heart Disease and Stroke. Available at: URL: Accessed February 2005.
*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, Available at: URL: Accessed February 2005.

15. Current Treatments for the Acute Management of STEMI

16. 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
Because the benefits of fibrinolytic therapy are directly related to the time from symptom onset, treatment benefit is maximized by the earliest possible application of therapy1
Contraindications and cautions for fibrinolysis in patients with STEMI include1:
Any prior intracranial hemorrhage (ICH)
A known structural cerebral vascular lesion or malignant intracranial neoplasm
Ischemic stroke within 3 months EXCEPT acute ischemic stroke within 3 hours
Suspected aortic dissection
Active or recent bleeding or bleeding diathesis
Systolic blood pressure (SBP) >180 mm Hg or diastolic blood pressure (DBP) >110 mm Hg
Current use of anticoagulants
Traumatic or prolonged cardiopulmonary resuscitation (CPR) or major surgery
Reference
1. Antman EM et al. Circulation 2004; 110: 588–636.
*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.

17. 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
Although the frequency of primary percutaneous coronary intervention (PCI) has recently increased, thrombolytics remain a frequent method of reperfusion in patients with acute STEMI worldwide, as illustrated by GRACE, the EuroHeart Survey and the NRMI 34 study
References
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.
*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.

18. Common Thrombolytic Regimens for STEMI1
Initial treatment Co-therapy Contraindications
Streptokinase (SK) 1.5 million U in 100 mL None or iv Prior SK or
5% dextrose or 0.9% saline heparin x 2448 hours anistreplase over 3060 min
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 iv heparin x 2448 hours
30 min apart
Tenecteplase Single iv bolus iv heparin x 2448 hours
(TNK-tPA) 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
More than 150,000 patients have been randomized in trials of thrombolysis versus control, or one fibrinolytic regimen compared with another1
For patients within 12 hours of the onset of MI symptoms, the overall evidence for the benefit of fibrinolytic treatment is overwhelming1
Dosages for the current fibrinolytic agents and the need for antithrombin co-therapy are outlined in this slide
Reference
1. Van de Werf F et al. Eur Heart J 2003; 24: 2866.
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.

19. Thrombolysis and ASA in Acute STEMI: ISIS-21
42%*
p <
23%*
p <
25%*
p < 14
13.2%
12.0%
11.8% 12 10
9.2%
9.4%
8.0% 8
5-week mortality (%) 6 4 2
In the Second International Study of Infarct Survival (ISIS-2) study, 17,187 patients entering 417 hospitals ≤24 hours (median 5 hours) after the onset of suspected acute MI were randomized (with placebo control) to receive one of the following treatments1:
A 1-hour intravenous (iv) infusion of streptokinase (SK) 1.5 MU
One month of enteric-coated ASA 160 mg/day
Both active treatments
Neither active treatments
The results demonstrated the benefits of antiplatelet therapy; in addition, the benefits of SK and ASA appear to be additive1
Reference
1. ISIS-2 Collaborative Group. Lancet 1988; 2: 349360.
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.

20. Other Routine Therapies in Acute STEMI1
ASA 150325 mg (non-enteric coated)
Beta-blockers
Angiotensin-converting enzyme (ACE) inhibitors
Oxygen
Nitrates
ASA now forms part of the early management of all patients with suspected STEMI. It is recommended to be given promptly, and certainly within the first 24 hours of an event, at a dose between 150 and 325 mg, and continued indefinitely at a daily dose of 75162 mg. Although some trials have used enteric-coated ASA for initial dosing, more rapid buccal absorption occurs with non-enteric coated formulations1
There is overwhelming evidence of the benefits of early beta-blockade in patients with STEMI, in whom their use is not contraindicated. Benefits of both early and late therapy have been demonstrated for patients with and without concomitant fibrinolytic therapy, after STEMI2
The proportional benefit of angiotensin-converting enzyme (ACE) inhibitor therapy is largest in higher-risk subgroups, including those with previous MI, heart failure, depressed left ventricular ejection fraction (LVEF) and tachycardia1
Oxygen should be administered early in acute MI by mask or intranasally; however, caution is necessary in the presence of chronic pulmonary disease. Monitoring blood oxygen saturation is recommended1
Oral nitrates doses should be titrated while monitoring blood pressure to avoid hypotension2
References
Antman EM et al. ACC/AHA STEMI Guidelines Available at: URL: Accessed February 2005.
Van de Werf F et al. Eur Heart J 2003; 24: 2866.
1. Van de Werf F et al. Eur Heart J 2003; 24: 2866.

21. 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
Sabatine M et al. New Eng J Med 2005; 352: 1179–1189.
Goldberg RJ et al. Am J Cardiol 2004; 93: 288–293.
Antman EM et al ACC/AHA STEMI Guidelines. Available at: Accessed February 2005.

22. Rationale for Antiplatelet Therapy in Acute MI

23. Antiplatelet Therapy is Beneficial1
Odds reduction Category of vascular events (%)*
Acute MI
Acute stroke
Prior MI
Prior stroke/TIA
Other high risk
All trials
30%
11%
25%
22%
26%
22%
The Antithrombotic Trialists’ Collaboration was a meta-analysis of 287 studies, including over 200,000 patients, which aimed to determine the effects of antiplatelet therapy among patients at high risk of occlusive vascular events1
Overall, a consistent benefit across all patient groups occurred with a mean odds reduction in vascular events of 22%1
This slide compares risk reduction in a number of high risk subgroups with this overall result
A stratified odds ratio of vascular events in the treatment groups versus the control groups was plotted for each group of trials (shown as yellow diamonds), along with a 99% confidence interval (CI; shown as a horizontal line)
Reference
1. Antithrombotic Trialists’ Collaboration. BMJ 2002; 324: 71–86.
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.

24. Potent, Specific and Complementary Mode of Action of Clopidogrel1
ADP
ADP
GPllb/llla
(fibrinogen receptor)
Collagen thrombin
TXA
Activation
Clopidogrel is a potent, non-competitive inhibitor of ADP-induced platelet aggregation, irreversibly inhibiting the binding of ADP to its platelet membrane receptors
Consequently, platelets exposed to clopidogrel are affected for the remainder of their lifespan (approximately 7–10 days)
The inhibition is specific and does not significantly affect cyclo-oxygenase (COX) or arachidonic acid metabolism
Clopidogrel can also indirectly inhibit platelet aggregation induced by agonists other than ADP by blocking the amplification of platelet activation by released ADP – ADP binding is necessary for the activation of the GPIIb/IIIa receptor, which is the binding site for fibrinogen. Fibrinogen links different platelets together to form the platelet aggregate
Thus, clopidogrel ultimately inhibits the activation of the GPIIb/IIIa receptor, its binding to fibrinogen and further platelet aggregation
Reference
1. Jarvis B et al. Drugs 2000; 60: 347–377. 2
ASA
COX
TXA 2
COX=cyclo-oxygenase
1. Jarvis B et al. Drugs 2000; 60: 347–377.

25. Cumulative* hazard ratio
Early and Long-Term Benefits of Clopidogrel in UA/NSTEMI1
Placebo† (n=6,303)
0.14
20%
p <0.001
0.12
0.10
Clopidogrel† (n=6,259)
0.08
Cumulative* hazard ratio
0.06
0.04
0.02
The Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial compared clopidogrel on a background of standard therapy (including ASA) with standard therapy (including ASA) alone. A total of 12,562 patients with UA/NSTEMI were randomized to receive either clopidogrel 75 mg once daily plus ASA 75–325 mg/day or placebo plus ASA 75–325 mg/day and followed for 12 months
Clopidogrel demonstrated a highly significant 20% relative risk reduction (RRR) in the primary endpoint of major vascular events (MI, stroke or vascular death; 95% CI 0.72–0.90; p <0.001)1,2
Overall, in the placebo group there were 719 (11.4%) vascular events experienced for the first time versus 582 (9.3%) in the clopidogrel group. The hazard rate curves began to diverge within the first few hours after the initiation of therapy and continued to diverge over the entire 12-month follow-up period1
A significant RRR of approximately 20% was observed during the first 30 days, with this reduction being similar to the value observed during the chronic phase (from 30 days until the end of follow-up at 12 months). Thus, clopidogrel provides both an early and long-term clinical benefit when given on a background of standard therapy (including ASA)1
Clopidogrel 75 mg once daily on a background of standard therapy (including ASA) was well tolerated in the CURE trial. There was no statistically significant difference between the two treatment groups in terms of life-threatening bleeds (p=0.13). There were significantly more major bleedings in the clopidogrel plus ASA group (3.7 vs 2.7%; p=0.001), although this was dependent on ASA dosage1
References
1. The CURE Trial Investigators. N Engl J Med 2001; 345: 494–502.
2. Yusuf S on behalf of the CURE Trial Investigators. Circulation 2003; 107: 966–972. 3 6 9 12
Follow-up (months)
*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.

26. 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)
Recent guidelines have further recognized the role of clopidogrel as a key component of long-term therapy in UA/NSTEMI patients, supporting its use for at least one month and up to 9 months after the initial hospitalization1
This slide lists the key American College of Cardiology (ACC)/American Heart Association (AHA) recommendations for the use of antiplatelet and anticoagulant therapy in patients with UA/NSTEMI (also known as non-Q-wave MI)
References
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
1. Braunwald E et al. J Am Coll Cardiol 2002; 40: 1366–1374.

27. 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)
This slide lists the key ACC/AHA recommendations for the use of antiplatelet and anticoagulant therapy in patients with UA/NSTEMI (also known as non-Q-wave MI)
In patients planned for coronary artery bypass graft (CABG), it is recommended that clopidogrel be stopped 57 days before surgery1
Reference
1. Braunwald E et al. J Am Coll Cardiol 2002; 40: 1366–1374.
*Also known as non-Q-wave MI
1. Braunwald E et al. J Am Coll Cardiol 2002; 40: 1366–1374.

28. 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)
This slide lists the key ACC/AHA recommendations for the use of antiplatelet and anticoagulant therapy in patients with UA/NSTEMI (also known as non-Q-wave MI)
In patients with UA/NSTEMI, clopidogrel has the highest recommendation (class I) grade for early and long-term use (9 months)1
Reference
1. Braunwald E et al. J Am Coll Cardiol 2002; 40: 1366–1374.
*Also known as non-Q-wave MI
1. Braunwald E et al. J Am Coll Cardiol 2002; 40: 1366–1374.

29. 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)
This slide lists the key ACC/AHA recommendations for the use of clopidogrel therapy in patients with UA/NSTEMI (also known as non-Q-wave MI)
In patients with UA/NSTEMI, clopidogrel has the highest recommendation (class I) grade for early and long-term use (9 months)1
Reference
1. Braunwald E et al. J Am Coll Cardiol 2002; 40: 1366–1374.
*Also known as non-Q-wave MI
1. Braunwald E et al. J Am Coll Cardiol 2002; 40: 1366–1374.

30. 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
Low risk
Second troponin measurement
The management of patients with different manifestations of ACS is governed by different sets of guidelines, which take into account the exact nature of the event
Recent European Society of Cardiology (ESC) guidelines for the management of UA and NSTEMI are summarized on this slide1
These guidelines recommend to stop clopidogrel ≥5 days before CABG1
References
1. Bertrand ME et al. Eur Heart J 2002; 23; 18091840.
GPIIb/IIIa,
coronary angiography
Positive
Twice negative
PCI, CABG or medical management
depending upon clinical and angiographic features
Stress test,
coronary angiography
1. Adapted with permission from Bertrand ME et al. Eur Heart J 2002; 23; 18091840.

31. New Clopidogrel Clinical Trials in Acute STEMI

32. 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
Due to the limitations of fibrinolytic therapy, additional adjuvant therapies that improve outcomes and can be safely administered along with fibrinolytics and heparin are needed
Given the complementary antiplatelet effects of ASA and clopidogrel and the early benefit of clopidogrel seen in the CURE trial1, it was hypothesized that clopidogrel on a background of standard care (including ASA and fibrinolytics) would reduce reocclusion and improve infarct-related artery patency in patients with acute STEMI
Reference
1. The CURE Trial Investigators. N Engl J Med 2001; 345: 494–502.
1. Sabatine M et al. New Eng J Med 2005; 352: 1179–1189.

33. Thrombolysis, heparin and ASA*
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*
Study treatment until angiography (28 days) or hospital discharge (maximum 8 days)
Clinical
follow-up
at 30 days R
n=1,739
The design of the CLARITY (CLopidogrel as Adjunctive ReperfusIon TherapY) trial is shown in this slide
CLARITY was a randomized, double-blind, placebo-controlled trial that investigated whether clopidogrel may produce angiographic and clinical benefits in MI (STEMI) patients, on a background of standard therapy (including fibrinolysis and ASA)1
Patients with acute STEMI presenting within 12 hours of symptom onset received standard therapy, which included ASA, heparin (either UFH or LMWH) and a fibrinolytic agent (either tenecteplase [TNK], reteplase [rPA], alteplase [TPA] or SK)1
Patients were then randomized to receive either clopidogrel (a loading dose of 300 mg, followed by 75 mg once daily) or placebo. This was continued to the time of angiography or hospital discharge (maximum of 8 days) if angiography was not performed. Antiplatelet therapy could be continued on an open-label basis, post-angiography, at the discretion of the treating physician1
Prior to hospital discharge, patients underwent cardiac catheterization, specifically between 48192 hours or Days 381
The primary efficacy end point was the composite of an occluded infarct-related artery (TFG 0/1) on the angiogram, or death or recurrent MI by the start of coronary angiography. For patients who did not undergo angiography, the primary endpoint was death or recurrent MI by Day 8 or hospital discharge, whichever came first1
Reference
1. Sabatine M et al. New Eng J Med 2005; 352: 1179–1189.
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.

34. 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
The study population included patients aged 1875 years, who presented to the hospital with >20 minutes of ischemic symptoms consistent with acute MI, who had new ST-segment elevation on their ECG, who were randomized within 12 hours of the onset of symptoms, and in whom fibrinolysis was the planned reperfusion strategy1
Patients were ineligible for the study if1:
Clopidogrel was received within the previous 7 days
Clopidogrel or GPIIb/IIIa therapy was planned before angiography
Thrombolysis was contraindicated (stroke, ICH, brain tumor)
They were at high risk for cardiogenic shock
Angiography was intended within 48 hours
They experienced CABG, creatinine >2.5 mg/dL or hepatic insufficiency, or decreased platelet count
They had received large doses of heparin
Reference
1. Sabatine M et al. New Eng J Med 2005; 352: 1179–1189.
1. Sabatine M et al. New Eng J Med 2005; 352: 1179–1189.

35. Global Study Sites 319 sites in 23 countries
The CLARITY trial was an international, multicenter, randomized, double-blind, placebo-controlled trial involving 319 sites in 23 countries worldwide1
Operations Committee – E Braunwald (Study Chair), C Cannon (Principal Investigator), M Sabatine (Co-Principal Investigator) and members of the Data Coordinating Center and Sponsor, who are indicated below with an asterisk1
Steering Committee – Members of the Operations Committee and D Ardissino, P Aylward, M Bertrand, C Bode, A Budaj, M Claeys, M Dellborg, R Ferreira, A Gershlick, K Huber, M Keltai, N Kleiman, B Lewis, J Lopez-Sendon, J Marx, G Montalescot, J Nicolau, Z Ongen, E Paolasso, J Leiva Pons, M Ruda, P Theroux, F Van de Werf, F Verheugt, R Wilcox, U Zeymer1
TIMI Study Group – C McCabe (Project Director),*A McCagg (Project Manager)1
Sponsors: sanofi-aventis (Paris, France) – B Job, *C Gaudin*; Bristol-Myers Squibb (Princeton, NJ, USA) – M Blumenthal, *R Saini,*J Froehlich, I Delaet, *L Townes, *D Anhalt, *K van Holder, *A Pieters1
Data Coordinating Center (Nottingham Clinical Research Group, Nottingham, UK) – A Skene, *K Hill, *A Charlesworth, M Goulder, S Stead1
Reference
1. Sabatine M et al. New Eng J Med 2005; 352: 1179–1189.
319 sites in 23 countries

36. Study Endpoints1 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
Primary endpoint1
A composite of an occluded infarct-related artery (TFG 0/1) on the angiogram, or death or recurrent MI prior to angiography
Secondary endpoints1
An occluded infarct-related artery (defined as TFG 0/1) on the pre-discharge angiogram
Survival without recurrent MI or severe recurrent myocardial ischemia by the start of coronary angiography or by hospital discharge, whichever came first. For patients who did not undergo angiography, Day 8 or hospital discharge, whichever came first, was used
Clinical follow-up at 30 days
Safety endpoints1
The primary safety endpoint in CLARITY was the rate of TIMI major bleeding for clopidogrel versus placebo (on a background of standard care including fibrinolytics and ASA). The secondary safety endpoints included rates of ICH and TIMI minor bleeding
The TIMI definition for major bleeding included either ICH or any clinically overt sign of hemorrhage (including via an imaging study), which was associated with a fall in hemoglobin of >5 g/dL (or, when hemoglobin was not available, a fall in hematocrit of >15%). Bleeding episodes with clinically overt, non-intracranial signs of hemorrhage associated with smaller drops in hemoglobin were classified as TIMI minor (35 g/dL drop in hemoglobin) and minimal (<3 g/dL drop) bleeding. The occurrence of primary ICH was confirmed using computed tomography (CT), magnetic resonance imaging (MRI) or autopsy
Reference
1. Sabatine M et al. New Eng J Med 2005; 352: 1179–1189.
*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.

37. 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
The TFG classification scheme has been successfully used to assess coronary blood flow in ACS1
TFG is divided into four categories1:
TFG 0 means there is no penetration of the contrast dye past the clot during angiography
TFG 1 means that a small amount of contrast dye flows past the vessel occlusion but does not fill the vessel past the clot
TFG 2 means that the infarct-related vessel fills to full length; however, the rate of filling is slower than the adjacent normal vessels
TFG 3 means there is normal filling of the infarct-related artery during angiography
Reference
1. Gibson CM et al. Circulation 2004: 109: 30963105.
TFG 0 Occlusion
TFG 1 Penetration
TFG 2 Slow flow
TFG 3 Normal flow
1. Reproduced with permission from Gibson CM et al. Circulation 2004: 109: 30963105.

38. 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
The restoration of epicardial flow does not necessarily lead to the restoration of tissue level or microvascular perfusion1
The TIMI Myocardial Perfusion Grade (TMPG) assesses tissue-level perfusion using an angiogram and is a multivariate predictor of mortality in acute MI1
In the TMPG system1:
TMPG 0 represents minimal or no myocardial blush
TMPG 1 dye stains the myocardium, and this stain persists on the next injection
TMPG 2 dye enters the myocardium but washes out slowly so that dye is strongly persistent at the end of the injection
TMPG 3 means there is normal entrance and exit of the dye in the myocardium
Reference
1. Gibson CM et al. Circulation 2004: 109: 30963105.
TMPG 0
TMPG 1
TMPG 2
TMPG 3
1. Gibson CM et al. Circulation 2004: 109: 30963105.

39. Relationship Between Angiographic Outcomes and Long-term Mortality1
HR: p=0.001
HR: 0.51 p=0.038
14.6%
9.1%
2-year mortality (%)
6.4%
4.8%
Two-year mortality in a TIMI 10B sub-study was 14.6% for patients with TFG 0/1 versus 6.4% for patients with TFG 2/3 (hazard ratio [HR] 0.41; p=0.001)
Furthermore, 2-year mortality in this study was 9.1% for patients with TMPG 0/1 versus 4.8% for patients with TMPG 2/3 (HR 0.51; p=0.038)1
This demonstrates that the occlusion of a coronary artery (TFG 0/1) is independently associated with long-term mortality1
Reference
1. Gibson CM et al. Circulation 2002; 105: 19091913.
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.

40. Baseline Characteristics1
Clopidogrel Placebo
Characteristic (n=1,752) (n=1,739)
Age (years)
Male gender (%)
Hypertension (%)
Hyperlipidemia (%)
Current smoker (%)
Diabetes mellitus (%)
Prior MI (%)
Prior PCI (%)
Anterior MI (%)
Baseline characteristics in the CLARITY trial were similar in both treatment groups1
Patients had a mean age of 57 years and were predominantly male (80%)1
Overall, 43% of patients had hypertension, 33% were hyperlipidemic, 50% were current smokers and 16% had a history of diabetes1
In total, 41% of patients were diagnosed with an anterior MI upon study entry1
Reference
1. Sabatine M et al. New Eng J Med 2005; 352: 1179–1189.
1. Sabatine M et al. New Eng J Med 2005; 352: 1179–1189.

41. Concomitant Medications1
Clopidogrel Placebo
Characteristic (n=1,752) (n=1,739)
Fibrin-specific thrombolytic (%):
TNK-tPA
rPA
tPA
Non-fibrin specific thrombolytic (%): SK
No thrombolytic given (%)
ASA (%)
Heparin (%):
UFH
LMWH
Use of concomitant medications included fibrin-specific and non-fibrin specific thrombolytics as follows1:
TNK, 48%
rPA, 12%
TPA, 9%
SK, 31%
No thrombolytic was administered in only 0.25% of patients
ASA use occurred in >98% of patients1
Concomitant UFH and LMWH were administered to 46% and 30% of patients, respectively1
Reference
1. Sabatine M et al. New Eng J Med 2005; 352: 1179–1189.
1. Sabatine M et al. New Eng J Med 2005; 352: 1179–1189.

42. Patient Management1 Clopidogrel Placebo Parameter (n=1,752) (n=1,739)
Symptom onset to fibrinolytic (hours)
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
CABG
The mean time to fibrinolytic administration following the onset of symptoms was 2.65 hours with a mean time of 10 minutes to study drug administration (clopidogrel 300 mg loading dose followed by 75 mg once daily versus placebo)1
Patients received a median of four doses of study medication1
Angiography was performed in 94% of patients at a mean time of 84 hours (3.5 days) following randomization1
Coronary revascularization (PCI or CABG) was performed in 63% of patients1
Reference
1. Sabatine M et al. New Eng J Med 2005; 352: 1179–1189.
1. Sabatine M et al. New Eng J Med 2005; 352: 1179–1189.

43. Other Cardiac Medications During Index Hospitalization1
Clopidogrel Placebo
Characteristic (%) (n=1,752) (n=1,739)
Beta-blockers
Statins
ACE inhibitors/ARBs
After angiography*
Clopidogrel
Ticlopidine
Patients enrolled in the CLARITY trial received standard medical management for STEMI based on current guidelines1:
89% of patients received beta-blockers
81% of patients received a statin
72% of patients received an ACE inhibitor or angiotensin receptor blocker (ARB)
Following angiography, open-label ADP-receptor antagonist (clopidogrel or ticlopidine) use was permitted; use occurred in 58% of the total patient population1
Reference
1. Sabatine M et al. New Eng J Med 2005; 352: 1179–1189.
*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.

44. Clopidogrel Improved Coronary Perfusion125
36% reduction*
p <0.001
21.7 20
15.0 15
Primary endpoint* (%) 10 5
Clopidogrel
(n=1,752)
Placebo
(n=1,739)
The major finding of the Clarity trial, is that Clopidogrel improved coronary perfusion in STEMI patients
The primary endpoint for this study was the composite of occluded infarct-related artery (as defined by TFG 0/1), or death or MI by the time of pre-discharge angiogram or hospital discharge (maximum 8 days) if no angiography was performed1
For all randomized patients, the primary composite endpoint (TFG 0/1, death or MI) rate was 21.7% in the placebo group versus 15.0% in the clopidogrel group, reflecting an odds reduction of 36% (95% CI 2447%; p <0.001)1
Note:
Relative risk reduction and odds reduction are not interchangeable terms. The CLARITY trial calculated odds reductions for all comparisons. Instead of using ‘relative risk reduction’ for describing comparisons, differences between the groups should be described by using the odds ratio or by using terminology such as ‘reduced the odds of xxx by x%’.
Reference
1. Sabatine M et al. New Eng J Med 2005; 352: 1179–1189.
*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.

45. 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 (0.530.76) <0.001
Individual components of primary endpoint (%)
TFG 0/ (0.480.72) <0.001
Recurrent MI (0.471.04) 0.08
Death (0.751.82) 0.49
Primary composite endpoint
For all randomized patients, the rate of the primary composite endpoint (TFG 0/1, death or MI) was 21.7% in the placebo group and 15.0% in the clopidogrel group, reflecting an odds reduction of 36% (95% CI 2447%; p <0.001)1
Individual components of the primary endpoint
Among the individual components of the primary endpoint, clopidogrel had the greatest effect on reducing the rate of an occluded infarct-related artery (from 18.4% to 11.7%; 41% odds reduction; p <0.001) and reducing the rate of recurrent MI (from 3.6% to 2.5%; 30% odds reduction; p=0.08)1
The trial was not powered to detect a survival benefit, and none was seen. The use of protocol-driven angiography and its attendant high rate of revascularization may have attenuated the translation of the angiography benefit into an immediate benefit.
Reference
1. Sabatine M et al. New Eng J Med 2005; 352: 1179–1189.
CI=confidence interval
1. Sabatine M et al. New Eng J Med 2005; 352: 1179–1189.

46. Consistent Results for Primary Endpoint Across Subgroups1
Number of Odds Patients with event (%)
Characteristic patients reduction Clopidogrel Placebo
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
The benefit of clopidogrel on the primary endpoint was highly consistent across the pre-specified subgroups including1:
Gender
Type of fibrinolytic
Type of heparin
Infarct location
No significant heterogeneity was found across the various subgroups1
In addition, there was no significant excess risk of TIMI major bleeding with clopidogrel in any of the pre-specified subgroups defined by gender, type of fibrinolytic, type of heparin, age or weight (data not shown)1
Reference
1. Sabatine M et al. New Eng J Med 2005; 352: 1179–1189.
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.

47. Clopidogrel Improved Angiographic Outcomes1
Clopidogrel Placebo Odds ratio
(n=1,752) (n=1,739) (95% CI) p value
Angiographic outcomes (%)
TFG (1.181.57) <0.001
TMPG (1.051.40) 0.008
Thrombus (0.640.84) <0.001
Clopidogrel improved all angiographic measurements, including the odds of achieving optimal epicardial flow (TFG 3) by 36% (p <0.001) and the odds of achieving optimal myocardial reperfusion (TMPG 3) by 21% (p=0.008)1
Clopidogrel also reduced the odds of intracoronary thrombus by 27% (p <0.001)1
Reference
1. Sabatine M et al. New Eng J Med 2005; 352: 1179–1189.
1. Sabatine M et al. New Eng J Med 2005; 352: 1179–1189.

48. Clopidogrel Reduced Clinical Events by 20% at 30 Days1
Placebo
(14.1%) 15
20%*
p=0.03 10
Clopidogrel
(11.6%)
Patients with endpoint (%) 5
At 30 days, clopidogrel had a significant effect on reducing clinical endpoints1
Clopidogrel reduced the odds of cardiovascular death, recurrent MI or recurrent ischemia leading to urgent revascularization by 20% (odds ratio 0.80; 95% CI [0.65–0.97]; p=0.03)1
Reference
1. Sabatine M et al. New Eng J Med 2005; 352: 1179–1189. 5 10 15 20 25 30
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.

49. Consistent Results Across 30-day Endpoints1
Odds
reduction
Clopidogrel
Placebo
CV death 3
4.4
4.5
Recurrent MI 31
4.1
5.9
Recurrent ischemia
leading to urgent 24
3.5
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 recurrent
ischemia leading to urgent 20
11.6
14.1
CV death, MI, stroke or
recurrent ischemia leading 21
12.3
15.0
to urgent revascularization
Patients with event (%)
Endpoint
Odds ratio
(95% CI)
1.0
0.4
0.6
0.8
1.2
Clopidogrel better
Placebo better
1.6
In terms of the individual 30-day endpoints, there was no difference in cardiovascular mortality in the clopidogrel versus placebo groups (4.4 vs 4.5%)1
For clopidogrel versus placebo, there was a statistically significant 31% odds reduction in recurrent MI (p=0.02), a non-statistically significant 24% odds reduction in recurrent MI leading to urgent revascularization (p=0.11) and a non-statistically significant 46% reduction in the odds of having a stroke (p=0.052)1
Additional clinical endpoints at 30 days were consistently in favor of treatment with clopidogrel1
Reference
1. Sabatine M et al. New Eng J Med 2005; 352: 1179–1189.
1. Sabatine M et al. New Eng J Med 2005; 352: 1179–1189.

50. 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) NS
TIMI major or minor 40 (2.3) 28 (1.6) NS
ICH 8 (0.5) 12 (0.7) NS
Bleeding through 30 days, n (%)
TIMI major 33 (1.9) 30 (1.7) NS
TIMI minor 27 (1.6) 16 (0.9) NS
TIMI major or minor 59 (3.4) 46 (2.7) NS
Primary bleeding endpoint
The rate of TIMI major bleeding was similar in the placebo and clopidogrel groups (1.1 vs 1.3%; p=0.64)1
Secondary bleeding endpoints
The rates of TIMI minor bleeding were 0.5% in the placebo group and 1.0% in the clopidogrel group (p=0.17)
There was no significant difference in the rates of ICH between the two groups (0.7 vs 0.5%; p=0.38)1
Bleeding through 30 days
At 30 days, there was no statistically significant differences in the rates of TIMI major or minor bleeding between the two groups1
Note:
The TIMI definition for major bleeding included either ICH or any clinically overt sign of hemorrhage (including via an imaging study), which was associated with a fall in hemoglobin of >5 g/dL (or, when hemoglobin was not available, a fall in hematocrit of >15%). Bleeding episodes with clinically overt, non-intracranial signs of hemorrhage associated with smaller drops in hemoglobin were classified as TIMI minor (35 g/dL drop in hemoglobin) and minimal (<3 g/dL drop) bleeding. Occurrence of primary ICH was confirmed using CT, MRI or autopsy.
Reference
1. Sabatine M et al. New Eng J Med 2005; 352: 1179–1189.
NS=not statistically significant
1. Sabatine M et al. New Eng J Med 2005; 352: 1179–1189.

51. 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
Clopidogrel significantly improved coronary reperfusion in MI patients, on a background of standard therapy (including thrombolytics and ASA)1
Clopidogrel reduced the odds of atherothrombotic events at 30 days among STEMI patients, on a background of standard therapy (including thrombolytics and ASA)1
Clopidogrel demonstrates a favorable safety profile; there were no statistically significant differences in TIMI major bleedings and ICH1
Author's conclusions: “In conclusion, in patients with STEMI aged ≤75 years, who received fibrinolytic therapy, ASA and, when appropriate, weight-based heparin, our results demonstrate that clopidogrel offers an effective, simple, inexpensive and safe means by which to improve infarct-related artery patency and reduce ischemic complications1”
Reference
1. Sabatine M et al. New Eng J Med 2005; 352: 1179–1189.
1. Sabatine M et al. New Eng J Med 2005; 352: 1179–1189.

52. 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
The Antiplatelet Trialists’ Collaboration meta-analyses of previous trials have shown that ASA and ADP-receptor antagonists are effective in the secondary prevention of vascular disease, with proportional reductions in major vascular events of 25% for ASA and 33% for ADP-receptor antagonists1
In the ISIS-2 study in >17,000 patients with suspected acute MI, 1 month of ASA produced a highly significant 23% proportional reduction in vascular deaths2
Despite current treatments, the risk of another MI, stroke or vascular death is high in the first month following a MI1
The COMMIT study was designed to demonstrate whether clopidogrel, on a background of standard therapy including ASA, could produce greater benefits than placebo in the acute phase of MI
References
Antithrombotic Trialists’ Collaboration. BMJ 2002; 324: 71–86.
ISIS-2 Collaborative Group. Lancet 1988; 2: 349–360.
1. CCS-2 Collaborative Group. J Cardiovasc Risk 2000; 7: 435441.

53. Patients with acute STEMI 24 hours (2 X 2 factorial with metoprolol)
Study Design1
Clopidogrel 75 mg once daily*
(n=~23,000)
Patients with acute STEMI 24 hours
Double-blind treatment until hospital discharge or for a maximum of 4 weeks R
n=~46,000
(n=~23,000)
Placebo*
The design of the COMMIT trial is shown in this slide
This large scale (~46,000 patients), acute-phase study performed in China was designed to demonstrate whether clopidogrel could produce greater benefits than placebo in the acute phase of MI in reducing the composite risk of death, MI and stroke, on a background of standard therapy (ASA)1
Patients with suspected acute MI within the previous 24 hours received ASA 162 mg and either placebo or clopidogrel 75 mg once daily with no loading dose of clopidogrel1
The COMMIT trial included a 2 X 2 factorial design with independent comparisons of clopidogrel versus placebo (plus usual care) and metoprolol versus placebo (plus usual care)1
The two co-primary endpoints for the COMMIT trial were death and the composite of the first occurrence of death, MI or stroke during initial hospitalization (maximum 28 days follow-up)1
Reference
1. CCS-2 Collaborative Group. J Cardiovasc Risk 2000; 7: 435441.
(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.

54. 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)
The study population included patients with suspected acute MI (with definite ECG changes: ST-segment elevation or left bundle block branch [LBBB] within 24 hours of the onset of symptoms)1
Patients had no clear indication for, or contraindication to, any trial treatments and were required to give informed consent to participate1
Main exclusion criteria were high risk of an adverse drug reaction and small likelihood of clinical benefit1
Patients were ineligible for the study if1:
There was a high risk of adverse drug reactions consisting of:
Allergy to ASA or hematologic disorder
Persistent hypotension or bradycardia
High degree atrioventricular (AV) block or the presence of a pacemaker
Cardiogenic shock
Or a small likelihood of potential benefits:
Low risk of MI death (non-typical MI)
Patient undergoing primary PCI
Reference
1. CCS-2 Collaborative Group. J Cardiovasc Risk 2000; 7: 435441.
1. CCS-2 Collaborative Group. J Cardiovasc Risk 2000; 7: 435441.

55. 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
The COMMIT trial had two primary endpoints1:
Death
The composite of death, non-fatal MI or non-fatal stroke
The major safety endpoints were major bleeding (defined as fatal or transfused bleeding) and hemorrhagic stroke1
Reference
1. CCS-2 Collaborative Group. J Cardiovasc Risk 2000; 7: 435441.
1. CCS-2 Collaborative Group. J Cardiovasc Risk 2000; 7: 435441.

56. Patient Baseline Characteristics1
Clopidogrel Placebo
Characteristic (n=22,960) (n=22,891)
Female (%)
Age >70 (%)
Time delay <6 hours (%)
Killip class II/III (%)
STEMI/LBBB (%)
Fibrinolytic:
All patients (%)
STEMI <12 hours (%)
Patient characteristics were similar between the treatment groups at baseline1
At baseline, the overall population was1:
28% female
26% age >70 years
34% randomized within 6 hours of the onset of pain
24% classified as Killip class II/III
50% were given fibrinolytics
References
1. Chen ZM et al. Oral presentation, ACC Available at: URL: Accessed April 2005.
Chen ZM et al. Oral presentation, ACC Available at: URL: Accessed April 2005.

57. Concomitant Medications During Index Hospitalization1
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 therapies were similar between the treatment groups1
Concomitant therapies during index hospitalization included1:
75% anticoagulants
68% ACE inhibitors
94% oral or iv nitrates
23% diuretics
22% anti-arrhythmics
12% calcium antagonists
References
1. Chen ZM et al. Oral presentation, ACC Available at: URL: Accessed April 2005.
Chen ZM et al. Oral presentation, ACC Available at: URL: Accessed April 2005.

58. Clopidogrel Reduced the Composite of Death, MI or Stroke by 9%1
Placebo
(10.1%)
RRR=9%
p=0.002 10 9
Clopidogrel
(9.3%) 8 7 6
Events (%) 5 4 3 2 1
At 28 days after randomization (mean follow-up 16.5 days), the percentage of patients in the clopidogrel group with the composite endpoint of death, MI or stroke was 9.3% compared with 10.1% in the placebo group
Thus, the COMMIT trial demonstrated that clopidogrel reduced the relative risk of the primary composite endpoint of death, recurrent MI or stroke by 9% (p=0.002)
Reference
1. Chen ZM et al. Oral presentation, ACC Available at: URL: Accessed April 2005. 7 14 21 28
Days (up to 28 days)
RRR=relative risk reduction
Chen ZM et al. Oral presentation, ACC Available at: URL: Accessed April 2005.

59. Clopidogrel Reduced Mortality by 7%1
Placebo
(8.1%) 9
RRR=7%
p=0.03 8 7
Clopidogrel
(7.5%) 6 5
Mortality (%) 4 3 2
At 28 days after randomization (mean follow-up 16.5 days), mortality in the clopidogrel group was 7.5% compared with 8.1% in the placebo group
Thus, the COMMIT trial demonstrated that clopidogrel reduced mortality during the initial hospitalization by 7% (p=0.03)
Based on COMMIT, it can be concluded that clopidogrel (75 mg once daily) is beneficial, on a background of standard treatment including ASA, in patients with acute STEMI receiving medical management1
The results of the metoprolol arm of COMMIT are to be presented separately from the clopidogrel results. There was no significant interaction between the two active treatments in the trial. Therefore, all comparisons will be conducted separately (clopidogrel versus placebo and metoprolol versus placebo)
Reference
1. Chen ZM et al. Oral presentation, ACC Available at: URL: Accessed April 2005. 1 7 14 21 28
Days (up to 28 days)
Chen ZM et al. Oral presentation, ACC Available at: URL: Accessed April 2005.

60. Clopidogrel Decreased Re-Infarction1
Outcome Clopidogrel Placebo
after 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%)
Odds ratio & 95% CI
Clopidogrel better
Placebo better
13%
reduction
p=0.02
In patients treated with clopidogrel versus placebo, the combined rate of fatal MI and non-fatal MI (2.1 vs 2.4%; p=0.02) showed a significant and consistent reduction1
Reference
1. Chen ZM et al. Oral presentation, ACC Available at: URL: Accessed April 2005.
0.4
0.6
0.8
1.0
1.2
1.4
1.6
Chen ZM et al. Oral presentation, ACC Available at: URL: Accessed April 2005.

61. Effects of Clopidogrel on Stroke1
Clopidogrel Placebo
Type (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%)
Odds ratio & 95% CI
Clopidogrel better
Placebo better
14%
reduction
p=NS
Overall, the combined rate of ischemic and hemorrhagic stroke showed no significant excess in patients treated with clopidogrel versus placebo (0.9 vs 1.1%; p=not significant [NS])1
There was a trend towards a reduction in ischemic stroke (p=NS) with no significant increase in hemorrhagic stroke1
Reference
1. Chen ZM et al. Oral presentation, ACC Available at: URL: Accessed April 2005.
0.4
0.6
0.8
1.0
1.2
1.4
1.6
Chen ZM et al. Oral presentation, ACC Available at: URL: Accessed April 2005.

62. COMMIT: Fatal and Non-Fatal Major Bleeds1
Clopidogrel Placebo
Type (n=22,958) (n=22,891)
Cerebral
Fatal
Non-fatal 16 15
Non-cerebral
Fatal 36 37
Non-fatal 46 36
Any major bleed 134 (0.58%) (0.54%)
In patients treated with clopidogrel versus placebo, there was a similar incidence of fatal and non-fatal cerebral bleeding (39 vs 40 patients and 16 vs 15 patients, respectively)1
In patients treated with clopidogrel versus placebo, there was a similar incidence of fatal non-cerebral bleeding (36 vs 37 patients). In the clopidogrel group, 46 patients experienced non-fatal non-cerebral bleeding compared with 36 patients in the placebo group1
Overall, there was no statistically significant increase in major bleeding for clopidogrel versus the placebo group (0.58 vs 0.54%; p=NS)1
Therefore, it can be concluded that clopidogrel demonstrates a favorable safety profile in MI (STEMI), in terms of the incidence of major bleeding
Reference
1. Chen ZM et al. Oral presentation, ACC Available at: URL: Accessed April 2005.
Chen ZM et al. Oral presentation, ACC Available at: URL: Accessed April 2005.

63. Effects of Clopidogrel on Death, Re-MI or Stroke by Days to Event1
Clopidogrel Placebo
Events by day (n=22,958) (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 (1.3) 347 (1.5)
ALL 2125 (9.3%) 2311 (10.1%)
Odds ratio & 95% CI
Clopidogrel better
Placebo better
9% increase
p=0.002
The results for the composite endpoint were consistently seen throughout the study1
It should be noted that the results were consistent based on the day of the event as shown above1
There was a significant reduction in the primary endpoint seen on the day of randomization1
Reference
1. Chen ZM et al. Oral presentation, ACC Available at: URL: Accessed April 2005.
0.4
0.6
0.8
1.0
1.2
1.4
1.6
Chen ZM et al. Oral presentation, ACC Available at: URL: Accessed April 2005.

64. Consistent Effects of Clopidogrel on Death, Re-MI or Stroke by Age and Gender1
Baseline Clopidogrel Placebo
features (n=22,958) (n=22,891)
Gender
Male 1276 (7.7%) 1416 (8.6%)
Female 849 (13.3%) 895 (14.0%)
Age (years)
< (5.1%) 513 (5.4%)
60 (10.2%) 835 (11.2%)
≥ (14.9%) 963 (16.2%)
ALL 2125 (9.3%) 2311 (10.1%)
Odds ratio & 95% CI
Clopidogrel better
Placebo better
9% reduction
p=0.002
Of note, is the consistent benefit seen in the large population of patients aged >70 years in this study1
It should also be noted that the results were consistent by gender and age as shown above1
Reference
1. Chen ZM et al. Oral presentation, ACC Available at: URL: Accessed April 2005.
0.4
0.6
0.8
1.0
1.2
1.4
1.6
Chen ZM et al. Oral presentation, ACC Available at: URL: Accessed April 2005.

65. Effects of Clopidogrel on Death, Re-MI or Stroke by Time Delay and Fibrinolytic Use1
Baseline Clopidogrel Placebo
features (n=22,958) (n=22,891)
Time delay (hours)
06 776 (9.3%) 904 (10.9%)
7 (9.7%) 735 (10.7%)
13 (8.8%) 666 (8.7%)
Fibrinolytic used
Yes 1005 (8.8%) 1123 (9.9%)
No 1120 (9.7%) (10.3%)
ALL 2125 (9.3%) 2311 (10.1%)
Odds ratio & 95% CI
Clopidogrel better
Placebo better
9% reduction
p=0.002
Clopidogrel benefit was consistent whether fybrinolytics were used or not1
Reference
1. Chen ZM et al. Oral presentation, ACC Available at: URL: Accessed April 2005.
0.4
0.6
0.8
1.0
1.2
1.4
1.6
Chen ZM et al. Oral presentation, ACC Available at: URL: Accessed April 2005.

66. 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 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
COMMIT demonstrated that clopidogrel (75 mg once daily) is beneficial, on a background of ASA for a wide range of acute STEMI patients1
Clopidogrel reduced the relative risk of hospital mortality by 7% (p=0.03)
Clopidogrel reduced the risk of death, recurrent MI or stroke by 9% (p=0.002)1
Clopidogrel demonstrated a favorable safety profile; there were no significant differences in major bleedings and ICH1
Thus the COMMIT trials proved an advance in STEMI management since more than a decade
Reference
1. Chen ZM et al. Oral presentation, ACC Available at: URL: Accessed April 2005.
Chen ZM et al. Oral presentation, ACC Available at: URL: Accessed April 2005.

67. Incidence of ACS in the US
Number of patients with ACS discharged from US hospitals in (including secondary discharges)
The landmark CURE trial was performed in patients with UA/NSTEMI1
This study demonstrated that clopidogrel offers a highly significant 20% relative risk reduction on a background of standard therapy, in the early and long-term (up to 1 year) reduction of MI, stroke and cardiovascular death in patients with UA/NSTEMI1
Clopidogrel 75 mg once daily on a background of standard therapy (including ASA) was well tolerated in the CURE trial. There was no statistically significant difference between the two treatment groups in terms of life-threatening bleeds (p=0.13). There were significantly more major bleedings in the clopidogrel plus ASA group (3.7 vs 2.7%; p=0.001), although this was dependent on ASA dosage1
The CLARITY/COMMIT trials were performed in patients with STEMI24
These three trials combined ensure that the clopidogrel clinical trial program covers all manifestations of ACS
References
1. The CURE trial investigators. N Engl J Med 2001; 345: 494–502.
2. Sabatine M et al. New Eng J Med 2005; 352: 1179–1189.
3. CCS-2 Collaborative Group. J Cardiovasc Risk 2000; 7: 435441.
4. Chen ZM et al. Oral presentation, ACC Available at: URL: Accessed April 2005.
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.

68. Evolution of Pharmacologic Reperfusion1
2005; 3.5 days
TIMI 11
APRICOT2 3
1985; 90 minutes
1993; 3 months 60 57 50
47%
p <0.001 40
22%
p=0.26
Occluded infarct-related artery (%) 30 32 30
36%
p <0.001 25 20
18.4
Over the past few decades, improvements in pharmacologic therapies have led to increased reperfusion in patients with MI13
In 1985, the TIMI 1 trial demonstrated that TPA significantly improved coronary perfusion by 47% (p <0.001) compared with SK at 90 minutes1
In the 1993, the Antithrombotics in the Prevention of Reocclusion In COronary Thrombolysis (APRICOT) study demonstrated that ASA tended to improve coronary perfusion by 22% (p=0.26) compared with ASA at 3 months, although this was not statistically significant2
The CLARITY results show that clopidogrel significantly improved the odds of occluded infarct related artery (TIMI 0/1) on the predischarge angiogram, or death or MI prior to angiography by 36% (p <0.001) on a background of standard therapy (including fibrinolytics and ASA) compared with placebo3
Reference
1. TIMI Study Group. New Engl J Med 1985; 312: 932–936.
2. Meijer A et al. Circulation : 1524–1530.
3. Sabatine M et al. New Eng J Med 2005; 352: 1179–1189. 10
11.7 SK
TPA
Placebo
ASA
ASA
ASA + clopidogrel
1. TIMI Study Group. New Engl J Med 1985; 312: 932–936.
2. Meijer A et al. Circulation : 1524–1530.
3. Sabatine M et al. New Eng J Med 2005; 352: 1179–1189.
APRICOT=Antithrombotics in the Prevention of Reocclusion In COronary Thrombolysis

69. 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 CLARITY and COMMIT trials demonstrate1,2:
Significant reduction in mortality for patients receiving clopidogrel versus standard care alone (COMMIT)
Significant improvement in coronary perfusion and clinical outcomes versus standard care (CLARITY)
No significant increase in major bleeding or ICH (COMMIT and CLARITY)
Therefore, CLARITY and COMMIT are consistent with Plavix proven benefit in ACS1,2
References
1. Sabatine M et al. New Eng J Med 2005; 352: 1179–1189.
2. Chen ZM et al. Oral presentation, ACC Available at: URL: Accessed April 2005.

70. The Role of Clopidogrel in Improving Atherothrombosis Management

71. The Ongoing Clopidogrel Clinical Trial Program Covers All Manifestations of Atherothrombosis
CHARISMA CAPRIE1
MATCH2
ACTIVE
CARESS
Stroke
TIA 1
Cerebrovascular
Acute MI
UA Prior MI
PCI/stenting
Atrial fibrillation
CHARISMA
CAPRIE1
ACTIVE
COMMIT
CLARITY3
CURE4
CLASSICS5
CREDO6 2
Cardiovascular
Intermittent claudication
Peripheral vascular
intervention 3
Peripheral arterial
The clinical trial program for clopidogrel relates to the various manifestations of atherothrombosis, covering cardiovascular, cerebrovascular and peripheral artery disease
There is a two-pronged approach, with some trials taking a global view of atherothrombosis and enrolling patients with all manifestations (CAPRIE1, CHARISMA), and other trials focusing on the prevention of atherothrombotic events (MI, stroke and vascular death) in patients enrolled on the basis of one manifestation of atherothrombosis (e.g. NSTEMI [CURE2], acute STEMI (CLARITY3, COMMIT) or stroke/TIA (MATCH4). The CLASSICS5 and CREDO6 trials enrolled patients who had undergone successful stent placement and patients with symptomatic CAD undergoing PCI, respectively
The systematic trial program has been designed to investigate the major manifestations of atherothrombosis and also to provide greater insight into the long-term efficacy of clopidogrel on a background of standard therapy (including ASA)
References
1. CAPRIE Steering Committee. Lancet 1996; 348: 1329–1339.
2. The CURE trial investigators. N Engl J Med 2001; 345: 494–502.
3. Sabatine M et al. New Eng J Med 2005; 352: 1179–1189.
4. Diener HC et al. Lancet 2004; 364: 331–337.
5. Bertrand ME et al. Circulation 2000; 102: 624–629.
6. Steinhubl SR et al. JAMA 2002; 288: 2411–2420.
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.

72. 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
MI is a life-threatening atherothrombotic event. Despite current therapies, patients with MI are at both early and long-term risk of life-threatening atherothrombotic events and thus require maximal protection
Clopidogrel reduced mortality during the initial hospitalization in patients with STEMI that are being medically managed, as shown by the COMMIT results. The CLARITY results also showed that clopidogrel significantly improved coronary perfusion on a background of standard therapy (including fibrinolytics and ASA)
Clopidogrel demonstrates a favorable safety profile in MI, as shown by the CLARITY and COMMIT results
Clopidogrel offers benefits across a broad range of CAD patient populations (including UA, recent MI, NSTEMI and STEMI patients); the CLARITY and COMMIT trials further expand the proven benefit of clopidogrel in CAD
Clopidogrel is a cornerstone in the management of atherothrombosis