clopidogrel in patients with st-segment elevation myocardial infarction (stemi)
TRANSCRIPT
Clopidogrel in Patients with ST-Segment Elevation Myocardial Infarction (STEMI)
Disclaimer
This slide kit presents data that is not contained in the approved professional label for clopidogrel.
The slide kit has been prepared for internal medical education purposes only and should not be distributed to or used with physicians in promotional detailing.
Neither sanofi-aventis nor Bristol-Myers Squibb recommends the use of clopidogrel in any manner inconsistent with that described in the full prescribing information
Outline
Epidemiology and background
Current treatments for the acute management of STEMI
Rationale for antiplatelet therapy in STEMI
Results of new clopidogrel clinical trials CLARITY (CLopidogrel as Adjunctive ReperfusIon TherapY) COMMIT (ClopidOgrel and Metoprolol in Myocardial
Infarction Trial)
The growing body of evidence for clopidogrel
Summary and conclusions
Epidemiology and Background
Unstable angina MI
Ischemic stroke/TIA
Critical leg ischemiaIntermittentclaudication
CV death
ACS
Atherosclerosis
Stable angina/intermittent claudication
Thrombosis
1. Libby P. Circulation 2001; 104: 365–372.
Pathologic Progression to Atherothrombosis1
MI=myocardial infarction; ACS=acute coronary syndromes; TIA=transient ischemic attack; CV=cardiovascular
Major Role of Platelets in Atherothrombosis1
1. Cannon CP et al. Heart Disease: A Textbook of Cardiovascular Medicine. 6th ed. Philadelphia, PA: WB Saunders, 2001: 1232–1263.
Activated platelets
Adhesion1
Activation2
Aggregation3
Plaquerupture
Fibrinogen
TxA2
ADP
Platelets
ADP=adenosine diphosphate; TxA2=thromboxane A2
Cerebrovascular disease
Coronary artery disease
Renal artery stenosis
Visceral arterial disease
Peripheral arterial disease (PAD)
Major Manifestations of Atherothrombosis
Prevalence of Atherothrombotic Manifestations is Increasing Worldwide*1
1. Guillot F et al. Circulation 1998; 98: A1421 (Abstract).
*Projected populations of people aged >50 years and estimated prevalence of MI and ischemic stroke accumulated in 14 countries: Belgium, Canada, Denmark, Finland, France, Germany, Italy, The Netherlands, Norway, Spain, Sweden, Switzerland, the United Kingdom (UK) and the United States (US)
Prevalence 2000 2005
Populations aged >50 years
205.0 million(5.1% since 1997)
222.2 million(13.9% since 1997)
MI
Ischemic stroke
9.1 million(12.8% since 1997)
10.7 million(32.7% since 1997)
7.1 million(11.8% since 1997)
8.4 million(31.6% since 1997)
1. Adult Treatment Panel II. Circulation 1994; 89: 1333–1435.2. Kannel WB. J Cardiovasc Risk 1994; 1: 333–339.3. Wilterdink JI et al. Arch Neurol 1992; 49: 857–863.4. Criqui MH et al. N Engl J Med 1992; 326: 381–386.
Increased risk of MI
5–7 Xgreater risk
(includes death)
Post-MI
23 Xgreater risk
(includes anginaand sudden death)
Post-stroke
4 Xgreater risk
(includes only fatal MI and other CHD death)
PAD
Increased risk of stroke
34 Xgreater risk
(includes TIA)
9 Xgreater risk
23 Xgreater risk
(includes TIA)
Increased Risk in Other Vascular Beds After an Atherothrombotic Event1–4
CHD=coronary heart disease
ACS is an Important Manifestation of Atherothrombosis1
1. Adapted with permission from Cannon CP. J Thromb Thrombolysis 1995; 2: 205–218.
Antithrombotictherapy
Stable angina
UA Non-Q-wave MI
Thrombolysisprimary PCI
Q-wave MI
Minutes– hours
Days–weeks
STEMIUA/NSTEMIAtherothrombosisNew term
Old term
Plaquerupture
UA=unstable angina; NSTEMI=non-ST-segment elevation myocardial infarction; PCI=percutaneous coronary intervention
Incidence of ACS in the US
ACS1,673,0001
UA728,0001*
MI 973,0001*
NSTEMI55–70% of ACS patients2
STEMI30–45% of ACS patients2
1. American Heart Association. Heart and Stroke statistical update. Dallas, Texas: American Heart Association 2005. 2. NRMI-4. J Am Coll Cardiol 2003; 41: 365A–366A.
*28,000 hospitalizations received both diagnoses for UA and MI
Number of patients with ACS discharged from US hospitals in 2002 (including secondary discharges)
Pathophysiology of STEMI1
1. Antman EM. In: Califf RM, ed. Atlas of Heart Diseases, VIII. Philadelphia, PA: Current Medicine, 1996.
Results from stabilization of a platelet aggregate at the site of plaque rupture by fibrin mesh
Platelet
RBC
Fibrin mesh
GPIIb/IIIa
Generally caused by a completely occlusive
thrombus in a coronary artery
RBC=red blood cell
High Risk of Mortality Following Acute MI
12.3%
6.6%
18.7%
–
NRMI 34 (n=81,679)*2
In-hospital mortality
Reperfused
Not reperfused
6-month† mortality
GRACE Registry (n=5,476)3
7.8%
–
–
4.8%
Approximately 33% of patients with an MI will die before they reach the hospital1
1. Boersma E et al. Lancet 2003; 361: 847–858.2. NRMI 3-4. J Am Coll Cardiol 2004; 44: 783–789.3. Goldberg RJ et al. Am J Cardiol 2004; 93: 288–293.4. Antman EM et al. 2004 ACC/AHA STEMI Guidelines. Available at:www.accp.org/clinical/guidelines/stemi/index.pdf. Accessed February 2005.
*Patients with STEMI from the NRMI 34 database (n=153,486); †post-discharge; GRACE=The Global Registry of Acute Coronary Events; within 6 years 18% of men and 35% of women will suffer an additional heart attack4; NRMI=National Registry for Myocardial Infarction
Ischemic Heart Disease Has a Devastating Impact on Quality of Life1
*Disability-adjusted life years (DALY) combine years of potential life lost due to premature death with years of productive life lost due to disability
To
tal
DA
LY
* lo
ss (
%)
Depression Ischemicheart
disease
SchizophreniaStroke Lungcancer
Breastcancer
1. World Health Organization. The Atlas of Heart Disease and Stroke, 2004. Available at: URL: http://www.who.int/cardiovascular_diseases/resources/atlas/en/. Accessed February 2005.
0
1
2
3
4
5
Current Treatments for the Acute Management of STEMI
Assessing Reperfusion Options for Patients with STEMI1
STEP 1: Assess time and risk (time from symptom onset, risk of STEMI, risk of thrombolysis, time for transport to PCI lab)
STEP 2: Determine whether fibrinolysis or invasive strategy is preferred*
1. Antman EM et al. Circulation 2004; 110: 588–636.
Fibrinolysis preferred if: Invasive strategy preferred if: Early presentation (<3 hours) Invasive strategy not an option Delay to invasive strategy
Skilled PCI lab with surgical backup available
High risk (i.e. cardiogenic shock) Contraindications to fibrinolysis Late presentation (>3 hours) Diagnosis of STEMI is in doubt
*If presentation is <3 hours from onset and there is no delay to an invasive strategy, there is no preference for either strategy
Thrombolysis Remains an Important Reperfusion Strategy Worldwide
1. Goldberg RJ et al. Am J Cardiol 2004; 93: 288–293.2. Hasdai D et al. Eur Heart J 2002; 23: 1190–1201.3. Wiviott SD et al. J Am Coll Cardiol 2004; 44: 783–789.
GRACE1
(n=5,476)
EHS2
(n=3,438)
NRMI 34*3
(n=81,679)
Thrombolytic agent (%) 45.0 35.1 52.0
Catheterization (%)
PCI
Primary PCI
61.0
44.4
–
53.0
40.4
20.7
–
–
48.0
CABG (%) 5.0 3.4 –
*Patients with STEMI from the NRMI 34 database (n=153,486); EHS=EuroHeart Survey; CABG=coronary artery bypass graft
Common Thrombolytic Regimens for STEMI1
Initial treatment Co-therapyContraindications
Streptokinase (SK) 1.5 million U in 100 mL None or iv Prior SK or5% dextrose or 0.9% saline heparin x 2448 hours
anistreplaseover 3060 min
Alteplase (tPA) 15 mg iv bolus, then iv heparin x 2448 hours0.75 mg/kg over 30 min,then 0.5 mg/kg iv over 60 minTotal dose not over 100 mg
Reteplase (rPA) 10 U + 10 U iv bolus given iv heparin x 2448 hours30 min apart
Tenecteplase Single iv bolus iv heparin x 2448 hours(TNK-tPA) 30 mg if <60 kg
35 mg if 60 kg to <70 kg40 mg if 70 kg to <80 kg45 mg if 80 kg to <90 kg50 mg if ≥90 kg
1. Van de Werf F et al. Eur Heart J 2003; 24: 2866.
Note: acetylsalicylic acid (ASA) should be given to all patients without contraindications; iv=intravenous
Thrombolysis and ASA in Acute STEMI: ISIS-21
1. ISIS-2 Collaborative Group. Lancet 1988; 2: 349360.
12.0%
9.2% 9.4%
11.8%
13.2%
8.0%
Placebo versusSK
Placebo versus ASA 162 mg
Neitherversus both
5-w
eek
mo
rtal
ity
(%)
*Odds reduction; ISIS=Second International Study of Infarct Survival
0
2
4
6
8
10
12
14
25%*p <0.00001
23%*p <0.00001
42%*p <0.00001
Other Routine Therapies in Acute STEMI1
ASA 150325 mg (non-enteric coated)
Beta-blockers
Angiotensin-converting enzyme (ACE) inhibitors
Oxygen
Nitrates
1. Van de Werf F et al. Eur Heart J 2003; 24: 2866.
Current Limitations of Pharmacologic Reperfusion
Lack of initial reperfusion in 20% of patients1
– Associated with a 2 X increase in mortality
Reocclusion in 5–8% of patients1 – Associated with 3 X increase in mortality
Despite current therapy, 10% of STEMI patients die within one month after hospital discharge2
Within 6 years 18% of men and 35% of women will suffer another heart attack3
1. Sabatine M et al. New Eng J Med 2005; 352: 1179–1189. 2. Goldberg RJ et al. Am J Cardiol 2004; 93: 288–293.3. Antman EM et al. 2004 ACC/AHA STEMI Guidelines. Available at:
www.accp.org/clinical/guidelines/stemi/index.pdf. Accessed February 2005.
Rationale for Antiplatelet Therapyin Acute MI
Antiplatelet Therapy is Beneficial1
1. Antithrombotic Trialists’ Collaboration. BMJ 2002; 324: 71–86.
*Vascular events=MI, stroke or vascular death
Odds reduction Category of vascular events (%)*
Acute MI
Acute stroke
Prior MI
Prior stroke/TIA
Other high risk
All trials
1.00.50.0 1.5 2.0Control betterAntiplatelet better
30%
11%
25%
22%
26%
22%
COX=cyclo-oxygenase
CLOPIDOGREL
ASA COX
ADP
ADP
C
GPllb/llla(fibrinogen receptor)
Collagen thrombinTXA2
Activation
TXA2
Potent, Specific and Complementary Mode of Action of Clopidogrel1
1. Jarvis B et al. Drugs 2000; 60: 347–377.
Cu
mu
lati
ve*
haz
ard
rat
io
Follow-up (months)
0 3 6 9 120
0.02
0.04
0.06
0.08
0.10
0.12
0.14
Early and Long-Term Benefits of Clopidogrelin UA/NSTEMI1
1. CURE Trial Investigators. N Engl J Med 2001; 345: 494–502.
*Cumulative events: MI, stroke or CV death; †all patients received a background of ASA therapy
20%p <0.001
Placebo†
(n=6,303)
Clopidogrel†
(n=6,259)
2002 ACC/AHA UA/NSTEMI* Guidelines Update: Antiplatelet and Anticoagulant Therapy1
Class I: Antiplatelet therapy should be initiated promptly. ASA should
be administered as soon as possible after presentation and continued indefinitely (IA)
In hospitalized patients in whom an early non-interventional approach is planned, clopidogrel should be added to ASA as soon as possible on admission and administered for at least 1 month (IA) and for up to 9 months (IB)
In patients in whom a PCI is planned, clopidogrel should be started and continued for at least 1 month (IA) and up to 9 months in patients who are not at high risk for bleeding (IB)
1. Braunwald E et al. J Am Coll Cardiol 2002; 40: 1366–1374.
*Also known as non-Q-wave MI; ACC=American College of Cardiology; AHA=American Heart Association
Class I: In patients taking clopidogrel in whom elective CABG is
planned, the drug should be withheld for 57 days (IB)
Anticoagulation with subcutaneous low molecular weight heparin (LMWH) or iv unfractionated heparin (UFH) should be added to antiplatelet therapy with ASA and/or clopidogrel (IA)
A platelet GPIIb/IIIa antagonist should be administered, in addition to ASA and heparin, to patients in whom catheterization and PCI are planned. The GPIIb/IIIa antagonist may also be administered just prior to PCI (IA)
2002 ACC/AHA UA/NSTEMI* Guidelines Update: Antiplatelet and Anticoagulant Therapy (cont)1
*Also known as non-Q-wave MI
1. Braunwald E et al. J Am Coll Cardiol 2002; 40: 1366–1374.
Class I: ASA 75–325 mg daily in the absence of contraindications (IA)
Clopidogrel 75 mg once daily (in the absence of contraindications) when ASA is not tolerated because of hypersensitivity or gastrointestinal intolerance (IA)
The combination of ASA and clopidogrel for 9 months after UA/NSTEMI (IB)
2002 ACC/AHA UA/NSTEMI* Guidelines Update: Antiplatelet and Anticoagulant Therapy (cont)1
*Also known as non-Q-wave MI
1. Braunwald E et al. J Am Coll Cardiol 2002; 40: 1366–1374.
Class I: In patients in whom an early noninterventional approach is
planned, clopidogrel should be added to ASA therapy as soon as possible on admission and administered for at least 1 month (A) and for up to 9 months (B)
In patients in whom a PCI is planned, clopidogrel should be started and continued for at least 1 month (A) and up to 9 months in patients who are not at high risk for bleeding (B)
For long-term medical therapy, the combination of ASA and clopidogrel is recommended for 9 months after UA/NSTEMI (B)
2002 ACC/AHA UA/NSTEMI* Guidelines Update: Key Recommendations for Clopidogrel Therapy1
*Also known as non-Q-wave MI
1. Braunwald E et al. J Am Coll Cardiol 2002; 40: 1366–1374.
Clinical suspicion of ACS
Physical examinationElectrocardiogram (ECG) monitoring, blood samples
Undetermineddiagnosis
Persistent ST-segment elevation
No persistent ST-segment elevation
ASA, LMWH,clopidogrel*, beta-blockers, nitrates
ThrombolysisPCI
High risk Low risk
GPIIb/IIIa,coronary angiography
Stress test,coronary angiography
1. Adapted with permission from Bertrand ME et al. Eur Heart J 2002; 23; 18091840.
Second troponin measurement
Positive Twice negative
ASA
PCI, CABG or medical managementdepending upon clinical and angiographic features
*Omit clopidogrel if the patient is likely to go to CABG within 5 days
ESC Recommended Strategy in ACS Patients1
New Clopidogrel Clinical Trials in Acute STEMI
CLopidogrel as Adjunctive ReperfusIon TherapY (CLARITY) – TIMI 28 Trial Results1
Purpose:This study investigated whether clopidogrel would produce greater angiographic and clinical benefits over placebo for patients with acute STEMI treated with fibrinolytics and other standard care
1. Sabatine M et al. New Eng J Med 2005; 352: 1179–1189.
Study Design1
*ASA=150–325 mg (if no ASA within prior 24 hours) as loading dose. Patients received heparin if they received a fibrin specific thrombolytic†All patients received ASA 75–162 mg/day plus other standard care
Study treatment until angiography (28 days) or
hospital discharge (maximum 8 days)
n=1,752
n=1,739
Thrombolysis, heparin and ASA*
Clopidogrel 300 mg loading dose/75 mg once daily†
Placebo†
Double-blind, randomized, placebo-controlled trial inpatients aged 1875 years with STEMI ≤12 hours
Clinical follow-up
at 30 days
Primary endpoint: occluded artery (Thrombolysis In Myocardial Infarction [TIMI] flow grade [TFG] 0/1) on the angiogram or death/MI by time of angiography
R
1. Sabatine M et al. New Eng J Med 2005; 352: 1179–1189.
Inclusion criteria Age 1875 years STEMI within 12 hours Planned treatment with fibrinolytic
Major exclusion criteria Clopidogrel within 7 days Planned clopidogrel or GPIIb/IIIa before angiography Contraindications to fibrinolysis (stroke, ICH [intracranial
hemorrhage], brain tumor) Cardiogenic shock Intention of angiography within 48 hours CABG, creatinine >2.5 mg/dL, hepatic insufficiency, platelets Patients 67 kg who had received >4000 U bolus UFH or >67 kg
who had received >5000 U bolus; or >1.1 mg/kg subcutaneous (sc) enoxaparin
Inclusion/Exclusion Criteria1
1. Sabatine M et al. New Eng J Med 2005; 352: 1179–1189.
319 sites in 23 countries
Global Study Sites
Primary endpoint: Composite of occluded infarct-related artery (TFG 0/1) on pre-
discharge angiogram, or death or MI before angiography Death or MI by hospital discharge (maximum 8 days) if no
angiography performed
Secondary endpoints: Angiographic (TFG 0/1) Clinical (death, recurrent MI or recurrent ischemia) Clinical events* at 30 days
Safety endpoints: Primary: TIMI major bleeding Secondary: TIMI minor bleeding, ICH
Study Endpoints1
*CV death, MI, stroke or recurrent ischemia leading to urgent target vessel revascularization
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 0Occlusion
TFG 1Penetration
TFG 2Slow flow
TFG 3Normal flow
1. Reproduced with permission from Gibson CM et al. Circulation 2004: 109: 30963105.
TIMI Myocardial Perfusion Grade Definitions1
TIMI Myocardial Perfusion Grade (TMPG) or ‘blush score’ describes blood flow in the microvasculature: Grade 0: no dye enters Grade 1: dye slowly enters but fails to exit Grade 2: delayed entry and exit of dye Grade 3: normal entry and exit of dye
TMPG 3 TMPG 3 TMPG 2 TMPG 2 TMPG 1 TMPG 1 TMPG 0 TMPG 0
1. Gibson CM et al. Circulation 2004: 109: 30963105.
Relationship Between Angiographic Outcomes and Long-term Mortality1
1. Gibson CM et al. Circulation 2002; 105: 19091913.
0
2
4
6
8
10
12
14
16
0
2
4
6
8
10
12
14
16
TFG 0/1
2-ye
ar m
ort
alit
y (%
)
14.6%
TFG 2/3 TMPG 0/1 TMPG 2/3
6.4%
4.8%
9.1%
HR: 0.41 p=0.001
HR: 0.51p=0.038
*Assessed on 90-minute angiogram in TIMI 10B trial; HR=hazard ratio
Baseline Characteristics1
Clopidogrel Placebo
Characteristic (n=1,752) (n=1,739)
Age (years) 57.7 57.2
Male gender (%) 79.9 80.7
Hypertension (%) 42.8 43.9
Hyperlipidemia (%) 32.2 33.0
Current smoker (%) 50.7 49.9
Diabetes mellitus (%) 16.5 16.4
Prior MI (%) 9.1 9.1
Prior PCI (%) 4.8 4.9
Anterior MI (%) 41.2 40.1
1. Sabatine M et al. New Eng J Med 2005; 352: 1179–1189.
Concomitant Medications1
Clopidogrel PlaceboCharacteristic (n=1,752) (n=1,739)
Fibrin-specific thrombolytic (%):
TNK-tPA 47.8 47.3
rPA 11.9 12.3
tPA 9.1 8.9
Non-fibrin specific thrombolytic (%):
SK 30.9 31.2
No thrombolytic given (%) 0.2 0.3
ASA (%) 98.5 98.6
Heparin (%):
UFH 46.1 45.5
LMWH 30.1 29.1
1. Sabatine M et al. New Eng J Med 2005; 352: 1179–1189.
Patient Management1
Clopidogrel Placebo
Parameter (n=1,752) (n=1,739)
Symptom onset to fibrinolytic (hours) 2.7 2.6
Fibrinolytic to study drug (minutes) 10 10
Median doses of study medication 4 4
Angiography performed (%) 94 94
Study drug to angiography (hours) 84 84
Coronary revascularization (%): 63 63
PCI 57.2 56.6
CABG 5.9 6.0
1. Sabatine M et al. New Eng J Med 2005; 352: 1179–1189.
Other Cardiac Medications During Index Hospitalization1
Clopidogrel Placebo
Characteristic (%) (n=1,752) (n=1,739)
Beta-blockers 88.7 89.6
Statins 80.4 81.1
ACE inhibitors/ARBs 72.7 72.1
After angiography*
Clopidogrel 54.5 55.6
Ticlopidine 3.5 2.9
*Some patients received open-label ADP-receptor antagonists after angiography and primary endpoint ascertainment; ARB=angiotensin receptor blocker
1. Sabatine M et al. New Eng J Med 2005; 352: 1179–1189.
Clopidogrel Improved Coronary Perfusion1
*Based on odds of an occluded infarct-related artery (TFG 0/1), death or MI by angiography for clopidogrel versus placebo (odds ratio: 0.64 [0.530.76]; p <0.001)
Placebo(n=1,739)
Clopidogrel(n=1,752)
21.7
15.0
5
10
15
20
25P
rim
ary
end
po
int*
(%
)36% reduction*
p <0.001
1. Sabatine M et al. New Eng J Med 2005; 352: 1179–1189.
Clopidogrel Reduced Primary Endpoint by 36%1
Clopidogrel Placebo Odds ratio
(n=1,752) (n=1,739) (95% CI) p value
Primary composite endpoint (%)
TFG 0/1, MI or death 15.0 21.7 0.64 (0.530.76) <0.001
Individual components of primary endpoint (%)
TFG 0/1 11.7 18.4 0.59 (0.480.72) <0.001
Recurrent MI 2.5 3.6 0.70 (0.471.04) 0.08
Death 2.6 2.2 1.17 (0.751.82) 0.49
CI=confidence interval
1. Sabatine M et al. New Eng J Med 2005; 352: 1179–1189.
Number of Odds Patients with event (%)Characteristic patients reduction Clopidogrel Placebo
OVERALL 3491 36 15.0 21.7Age
<65 years 2466 42 13.2 21.065 years 1015 22 19.0 23.1
GenderMale 2796 35 14.5 20.8Female 685 38 16.9 24.7
Infarct locationAnterior 1416 33 15.0 20.7Non-anterior 2065 38 15.0 22.2
FibrinolyticFibrin-specific 2397 31 14.7 20.1Non-fibrin specific 1084 44 15.7 24.9
Predominant heparinLMWH 1429 31 11.4 15.7UFH 1431 42 17.8 27.1None 621 26 17.1 21.9
1.00.4 0.6 0.8 1.2 1.6Clopidogrel better Placebo better
Consistent Results for Primary Endpoint Across Subgroups1
1. Sabatine M et al. New Eng J Med 2005; 352: 1179–1189.
Clopidogrel Improved Angiographic Outcomes1
Clopidogrel Placebo Odds ratio
(n=1,752) (n=1,739) (95% CI) p value
Angiographic outcomes (%)
TFG 3 67.8 60.8 1.36 (1.181.57) <0.001
TMPG 3 55.8 51.2 1.21 (1.051.40) 0.008
Thrombus 43.0 50.8 0.73 (0.640.84) <0.001
1. Sabatine M et al. New Eng J Med 2005; 352: 1179–1189.
Clopidogrel Reduced Clinical Events by 20% at 30 Days1
*Odds ratio in CV death, MI or recurrent ischemia leading to urgent revascularization
Time (days)
Pat
ien
ts w
ith
en
dp
oin
t (%
)
0
5
10
15
0 5 10 15 20 25 30
20%*p=0.03
Clopidogrel(11.6%)
Placebo (14.1%)
1. Sabatine M et al. New Eng J Med 2005; 352: 1179–1189.
Consistent Results Across 30-day Endpoints1
Oddsreduction Clopidogrel Placebo
CV death 3 4.4 4.5
Recurrent MI 31 4.1 5.9
Recurrent ischemialeading to urgent 24 3.5 4.5 revascularization
Stroke 46 0.9 1.7
CV death or MI 17 8.4 9.9
CV death, MI or stroke 18 9.1 10.9
CV death, MI or recurrentischemia leading to urgent 20 11.6 14.1 revascularization
CV death, MI, stroke orrecurrent ischemia leading
21 12.3 15.0
to urgent revascularization
Patients with event (%)Endpoint Odds ratio
(95% CI)
1.00.4 0.6 0.8 1.2Clopidogrel better Placebo better
1.6
1. Sabatine M et al. New Eng J Med 2005; 352: 1179–1189.
Safety1
Clopidogrel Placebo(n=1733) (n=1719) p
value
Primary bleeding endpoint, n (%)TIMI major 23 (1.3) 19 (1.1) NS
Secondary bleeding endpoints, n (%) TIMI minor 17 (1.0) 9 (0.5) NSTIMI major or minor 40 (2.3) 28 (1.6) NSICH 8 (0.5) 12 (0.7) NS
Bleeding through 30 days, n (%)TIMI major 33 (1.9) 30 (1.7) NSTIMI minor 27 (1.6) 16 (0.9) NSTIMI major or minor 59 (3.4) 46 (2.7) NS
1. Sabatine M et al. New Eng J Med 2005; 352: 1179–1189.
NS=not statistically significant
Summary1
In patients aged 75 years with STEMI, receiving ASA and standard fibrinolytic therapy, a loading dose of 300 mg of clopidogrel followed by clopidogrel 75 mg once daily resulted in:
A 36% reduction (p <0.001) in the odds of an occluded infarct-related artery, or death or MI by time of pre-discharge angiography or hospital discharge (maximum 8 days)
Consistent results across all major subgroups
At 30 days, a 20% reduction (p=0.03) in CV death, MI or recurrent ischemia leading to urgent revascularization
No significant excess in TIMI major bleeding or ICH
1. Sabatine M et al. New Eng J Med 2005; 352: 1179–1189.
1. CCS-2 Collaborative Group. J Cardiovasc Risk 2000; 7: 435441.
COMMIT/CCS-2: ClOpidogrel and Metoprolol in Myocardial Infarction Trial
Purpose:To determine whether adding clopidogrel can produce a further reduction in mortality and the risk of vascular events in hospitalized patients admitted with acute STEMI1
Double-blind treatment until hospital discharge or for a maximum of 4 weeks
(n=~23,000)
n=~46,000
Patients with acute STEMI 24 hours
*All patients received a background of ASA 162 mg/day during the study
(2 X 2 factorial with metoprolol)
Study Design1
Clopidogrel 75 mg once daily*
Placebo*
(n=~23,000)
R
1. CCS-2 Collaborative Group. J Cardiovasc Risk 2000; 7: 435441.
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: 435441.
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: 435441.
Clopidogrel Placebo
Characteristic (n=22,960) (n=22,891)
Female (%) 27.7 27.9
Age >70 (%) 26.0 26.0
Time delay <6 hours (%) 33.8 33.7
Killip class II/III (%) 24.1 24.0
STEMI/LBBB (%) 93.1 93.1
Fibrinolytic:
All patients (%) 49.7 49.8
STEMI <12 hours (%) 67.8 67.7
Patient Baseline Characteristics1
1. Chen ZM et al. Oral presentation, ACC 2005. Available at: URL: http://www.commit-ccs2.org. Accessed April 2005.
Clopidogrel Placebo
Therapy (n=22,960) (n=22,891)
Anticoagulants 74.1% 75.0%
ACE inhibitors 68.2% 68.3%
Nitrates (oral or iv) 94.1% 94.3%
Diuretics 23.3% 23.3%
Anti-arrhythmics 22.4% 22.2%
Calcium antagonists 11.8% 11.8%
Concomitant Medications During Index Hospitalization1
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
0 7 14 21 280
1
2
34
5
67
8
910
Days (up to 28 days)
Clopidogrel(9.3%)
Placebo (10.1%)
Eve
nts
(%
)
RRR=9%p=0.002
RRR=relative risk reduction
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
0 7 14 21 280
1
2
3
4
5
6
7
8
9
Days (up to 28 days)
Clopidogrel(7.5%)
Placebo(8.1%)
RRR=7%p=0.03
Mo
rtal
ity
(%)
1. Chen ZM et al. Oral presentation, ACC 2005. Available at: URL: http://www.commit-ccs2.org. Accessed April 2005.
Clopidogrel Decreased Re-Infarction1
Odds ratio & 95% CIClopidogrel better Placebo better
Outcome Clopidogrel Placeboafter re-MI (n=22,958) (n=22,891)
Fatal MI 209 (0.9%) 223 (1.0%)
Non-fatal MI 273 (1.2%) 330 (1.4%)
ALL 482 (2.1%) 553 (2.4%) 13%reduction
p=0.02
0.4 0.6 0.8 1.0 1.2 1.4 1.6
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
Odds ratio & 95% CIClopidogrel better Placebo better
Clopidogrel PlaceboType (n=22,958) (n=22,891)
Ischemic 162 (0.7%) 192 (0.8%)
Hemorrhagic 55 (0.2%) 55 (0.2%)
ALL 216 (0.9%) 249 (1.1%) 14%reduction
p=NS
0.4 0.6 0.8 1.0 1.2 1.4 1.6
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
Clopidogrel Placebo
Type (n=22,958) (n=22,891)
Cerebral
Fatal 39 40
Non-fatal 16 15
Non-cerebral
Fatal 36 37
Non-fatal 46 36
Any major bleed 134 (0.58%) 124 (0.54%)
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
Odds ratio & 95% CIClopidogrel better Placebo better
Clopidogrel PlaceboEvents by day (n=22,958) (n=22,891)
0 463 (2.0) 523 (2.3)
1 486 (2.1) 527 (2.3)
23 449 (2.0) 451 (2.0)
47 432 (1.9) 463 (2.0)
828 295 (1.3) 347 (1.5)
ALL 2125 (9.3%) 2311 (10.1%)
0.4 0.6 0.8 1.0 1.2 1.4 1.6
9% increase
p=0.002
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
Odds ratio & 95% CIClopidogrel better Placebo better
Baseline Clopidogrel Placebofeatures (n=22,958) (n=22,891)
Gender
Male 1276 (7.7%) 1416 (8.6%)
Female 849 (13.3%) 895 (14.0%)
Age (years)
<60 487 (5.1%) 513 (5.4%)
6069 747 (10.2%) 835 (11.2%)
≥70 891 (14.9%) 963 (16.2%)
ALL 2125 (9.3%) 2311 (10.1%)
9% reduction
p=0.002
0.4 0.6 0.8 1.0 1.2 1.4 1.6
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
Odds ratio & 95% CIClopidogrel better Placebo better
Baseline Clopidogrel Placebofeatures (n=22,958) (n=22,891)
Time delay (hours)
06 776 (9.3%) 904 (10.9%)
712 672 (9.7%) 735 (10.7%)
1324 666 (8.8%) 666 (8.7%)
Fibrinolytic used
Yes 1005 (8.8%) 1123 (9.9%)
No 1120 (9.7%) 1188 (10.3%)
ALL 2125 (9.3%) 2311 (10.1%)9%
reductionp=0.002
0.4 0.6 0.8 1.0 1.2 1.4 1.6
1. Chen ZM et al. Oral presentation, ACC 2005. Available at: URL: http://www.commit-ccs2.org. Accessed April 2005.
Clopidogrel (75 mg once daily) on a background of standard therapy including ASA was beneficial at 4 weeks for a wide range of acute STEMI patients Clopidogrel reduced mortality* by 7% (p=0.03) Clopidogrel reduced the risk of death, non-fatal MI or
non-fatal stroke by 9% (p=0.002)
No significant increase in the risk of major (fatal or transfused) bleeding occurred with clopidogrel
*Death during initial hospitalization
Conclusions1
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
ACS1,673,0001
Unstable angina728,0001*
MI 973,0001*
NSTEMI55–70% of ACS patients2
STEMI30–45% of ACS patients2
1. American Heart Association. Heart and Stroke statistical update. Dallas, Texas: American Heart Association 2005. 2. NRMI-4. J Am Coll Cardiol 2003; 41: 365A–366A.
*28,000 hospitalizations received both diagnoses for UA and MI
Number of patients with ACS discharged from US hospitals in 2002 (including secondary discharges)
Scope of the CURE trial
Scope of the CLARITY/COMMIT trials
Evolution of Pharmacologic Reperfusion1
2005; 3.5 days
TPASK
TIMI 11
ASA +clopidogrel
ASA
APRICOT2
Placebo ASA
1985; 90 minutes 1993; 3 months
11.7
32
18.4
2530
57
0
10
20
30
40
50
60
Occ
lud
ed i
nfa
rct-
rela
ted
art
ery
(%)
47%p <0.001
22%p=0.26
36%p <0.001
APRICOT=Antithrombotics in the Prevention of Reocclusion In COronary Thrombolysis
1. TIMI Study Group. New Engl J Med 1985; 312: 932–936. 2. Meijer A et al. Circulation 1993 87: 1524–1530. 3. Sabatine M et al. New Eng J Med 2005; 352: 1179–1189.
3
Complementary Results of CLARITY and COMMIT for Patients with STEMI
Significant improvement in coronary perfusion and clinical outcomes versus standard care (CLARITY)
Significant reduction in mortality for patients receiving clopidogrel versus standard care alone (COMMIT)
No significant increase in major bleeding or ICH (COMMIT and CLARITY)
The Role of Clopidogrel in Improving Atherothrombosis Management
The Ongoing Clopidogrel Clinical Trial Program Covers All Manifestations of Atherothrombosis
1. CAPRIE Steering Committee. Lancet 1996; 348: 1329–1339. 2. Diener HC et al. Lancet 2004; 364: 331–337.3. Sabatine M et al. New Eng J Med 2005; 352: 1179–1189. 4. The CURE trial investigators. N Engl J Med 2001; 345: 494–502.5. Bertrand ME et al. Circulation 2000; 102: 624–629.6. Steinhubl SR et al. JAMA 2002; 288: 2411–2420.
StrokeTIA
Acute MIUA
Prior MIPCI/stenting
Atrial fibrillation
Intermittent claudication
Peripheral vascular
intervention
CHARISMACAPRIE1
ACTIVECOMMITCLARITY3
CURE4
CLASSICS5
CREDO6
CHARISMACAPRIE1
CASPAR
CHARISMACAPRIE1
MATCH2
ACTIVECARESS
© Teri J McDermott CMI 2003
Cerebrovascular1
Cardiovascular2
Peripheral arterial3
Conclusions
STEMI is a sudden and severe consequence of underlying atherothrombotic disease, which requires immediate reperfusion therapy
Clopidogrel reduced mortality and improved coronary perfusion and clinical outcomes for patients with STEMI receiving standard medical care (including thrombolytics and ASA)
Clopidogrel (including a loading dose) does not significantly increase major bleeding or ICH versus standard care alone
CLARITY and COMMIT complement the positive benefits of clopidogrel seen in other clinical trials and atherothrombosis populations