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Clopidogrel for High Atherothrombotic
Risk and Ischemic Stabilization,
Management and Avoidance
(CHARISMA)
Deepak L. Bhatt M.D., Keith A. A. Fox M.B.Ch.B., Werner Hacke M.D., Peter B.
Berger M.D., Henry R. Black M.D., William E. Boden M.D., Patrice Cacoub M.D.,
Eric A. Cohen M.D., Mark A. Creager M.D., J. Donald Easton M.D., Marcus D.
Flather M.D., Steven M. Haffner M.D., Christian W. Hamm M.D., Graeme J. Hankey
M.D., S. Claiborne Johnston M.D., Koon-Hou Mak M.D., Jean-Louis Mas M.D.,
Gilles Montalescot M.D., Ph.D., Thomas A. Pearson M.D., P. Gabriel Steg M.D.,
Steven R. Steinhubl M.D., Michael A. Weber M.D., Danielle M. Brennan M.S., Liz
Fabry-Ribaudo M.S.N., R.N., Joan Booth R.N., Eric J. Topol M.D., on behalf of the
CHARISMA Investigators
The Cleveland Clinic Foundation
CHARISMA: Rationale
CAPRIE: Superior Efficacy of Clopidogrel
versus ASA
Patients with recent ischemic stroke, recent MI or symptomatic PAD
20
8.7%† RRR
Cumulative event rate* (%)
ASA (p=0.043)
16
Clopidogrel
12
8
4
0
0 3 6 9 12 15 18 21 24 27 30 33 36
Months of follow-up
*MI, ischemic stroke or vascular death
†Intent-to-treat analysis (n=19,185)
CAPRIE Steering Committee. Lancet 1996; 348: 1329–1339.
CAPRIE: Clopidogrel Superior to ASA in
Sub-Population with Prior CABG1, 2
RRR 36.3%
p=0.004
10 RRR 8.7% 9.1%
Event rate/year* (%)
8 p=0.043 ASA
Clopidogrel
6 5.8% 5.8%
5.3%
4
2
0
All CAPRIE Prior CABG
(n=19,185)1 (n=1480)2
*MI, ischemic stroke, vascular death
1. CAPRIE Steering Committee. Lancet 1996; 348: 1329–1339.
2. Bhatt DL et al. Circulation 2001; 103: 363368.
CAPRIE: Clopidogrel Provided Amplified
1
Benefit in Patients with Diabetes
38†
21†
p=0.106
9†
25 p=0.042
21.5%
Event rate*/year (%)
p=0.096 ASA
20 17.7% 17.7%
15.6% Clopidogrel
15 12.7%
11.8%
10
5
0
Patients without Patients with Patients treated
diabetes (n=15,233) diabetes (n=3866) with insulin (n=1134)
*MI, stroke, vascular death or rehospitalization
for ischemic events/bleeding
†Number of events prevented per 1000 patients
per year compared with ASA
1. Bhatt DL et al. Am J Cardiol 2002; 90: 625628.
CAPRIE: Clopidogrel Provides Amplified
1
Benefit in Patients with High Vascular Risk
RRR 14.9%
p=0.045
12 10.2%
RRR 8.7%
Event rate/year* (%)
10 8.8% ASA
p=0.043
8 Clopidogrel
5.8%
6 5.3%
4
2
0
All CAPRIE Prior history of
patients major acute event
(n=19,099) (MI or ischemic stroke)
(n=4496)
*MI, ischemic stroke or vascular death;
mean duration of treatment was 1.6 years
1. Ringleb PA et al. Stroke 2004; 35: 528–532.
CURE: Early and Long-Term Benefits of
1
Clopidogrel in ACS Patients
0.14 Placebo†
(n=6303) 20% RRR
0.12
Cumulative hazard rate*
p <0.001
0.10
0.08 Clopidogrel†
(n=6259)
0.06
0.04
0.02
0
0 3 6 9 12
Months of follow-up
*MI, stroke or cardiovascular death
†On a background of standard therapy (including ASA)
1. The CURE Investigators. N Engl J Med 2001; 345: 494–502.
CURE: Relationship Between Major
Bleeding and ASA Dose in ACS Patients1
4.9%
5.0
3.7%
4.0
Incidence of major
3.4%
bleeding (%)
3.0% 2.8%
3.0 Placebo*
1.9% Clopidogrel*
2.0
1.0
0
≤100 mg 101–199 mg ≥200 mg
(n=5320) (n=3109) (n=4110)
ASA dose (range 75–325 mg)
*On a background of standard therapy (including ASA)
1. Peters RJG et al. Circulation 2003; 108: 16821687.
CREDO: Long-Term (1 Year) Benefits
of Clopidogrel in PCI Patients
MI, stroke, or death – ITT population
15
Placebo*
Clopidogrel*
11.5%
Combined endpoint
27% RRR
occurrence (%)
10 P=0.02
8.5%
5
0
0 3 6 9 12
Months from randomization
* Plus ASA and other standard therapies.
Steinhubl S, Berger P, Tift Mann III J et al. JAMA. 2002;Vol 288,No 19:2411-2420.
CHARISMA: Design
Study Objectives1
Primary objective:
• To assess whether clopidogrel 75 mg daily is superior to placebo
in preventing the occurrence of major ischemic complications
(stroke, MI, cardiovascular death) in high-risk patients aged ≥45
years, receiving a background of standard therapy including low-
dose ASA
Secondary objective:
• To evaluate the safety of clopidogrel, in terms of the incidence of
fatal or severe bleeding (GUSTO definition*)
*The Global Use of Strategies To Open occluded coronary Arteries (GUSTO)
definition for severe bleeding includes intracerebral bleeding or bleeding
complications resulting in substantial hemodynamic compromise requiring
treatment2
1. Bhatt DL et al. Am Heart J 2004; 148: 263–268.
2. GUSTO Investigators. N Engl J Med 1993; 329: 673–682.
CHARISMA Trial Design
Clopidogrel
75 mg/day
(n=7802)
Patients age ≥ 45
years at high risk of Low dose ASA 75162 mg/day
atherothrombotic
events
R Double-blind treatment up to 1040
(n=15603) primary efficacy events*
Low dose ASA 75162 mg/day
Placebo
1 tablet/day
(n=7801)
1-month 3-month Visits every 6 months Final visit
visit visit (Fixed study
end date)
* MI (fatal or non-fatal), stroke (fatal or non-fatal), or cardiovascular death;
event-driven trial
Bhatt DL, Topol EJ, et al. Am Heart J 2004; 148: 263–268.
Inclusion Criteria
Patients aged ≥45 years
with
at least one of the following:
1) Documented coronary disease
and/or
2) Documented cerebrovascular disease
and/or
3) Documented symptomatic PAD
and/or
4) Two major or one major and two minor or three minor risk factors
With written informed consent
Without exclusion criteria
Bhatt DL, Topol EJ, et al. Am Heart J 2004; 148: 263–268.
Inclusion Criteria: Patients with
Documented CV Disease
• One or more of the following primary criteria must be satisfied:
– Documented cerebrovascular disease:
Previous TIA within the past 5 years
Previous ischemic stroke within the past 5 years
– Documented coronary disease:
Stable angina with documented multivessel coronary disease
History of multivessel percutaneous coronary intervention (PCI)
History of multivessel CABG
Previous MI
Documented symptomatic PAD
Current intermittent claudication with an ABI ≤0.85
A history of intermittent claudication together with a previous
related intervention (amputation, peripheral bypass, angioplasty,
etc.)
Bhatt DL, Topol EJ, et al. Am Heart J 2004; 148: 263–268.
Inclusion Criteria: Patients with Multiple
Risk Factors Only
• For the risk factor only population, two major or one major and two
minor or three minor atherothrombotic risk factors must be present
Major risk factors
Type 1 or 2 diabetes (treated with medications)
Diabetic nephropathy
ABI <0.9
Asymptomatic carotid stenosis 70%
Presence of at least one carotid plaque
Minor risk factors
SBP 150 mm Hg (despite therapy)
Primary hypercholesterolemia
Currently smoking (>15 cigarettes per day)
Male aged 65 years or female aged 70 years
ABI= Ankle Brachial Index
Bhatt DL, Topol EJ, et al. Am Heart J 2004; 148: 263–268.
Exclusion Criteria
• Requirement for clopidogrel such as:
– recent acute coronary syndrome without ST-segment elevation
– investigator’s assessment clopidogrel required long-term
• Need for chronic therapy with high dose (> 162 mg/day) ASA or
non-steroidal anti-inflammatory drug (except COX-2 inhibitors)
• Current use of other oral anti-thrombotic medications with
intention for long term treatment (e.g. OAC)
• Planned revascularization procedure (OK after the procedure if no
open-label clopidogrel is needed)
Bhatt DL, Topol EJ, et al. Am Heart J 2004; 148: 263–268.
Primary Study Endpoints
Primary efficacy endpoint:
• The first occurrence of any component of the following cluster:
– MI (Fatal or Non-fatal)
– Stroke (Fatal or Non-fatal stroke from any cause)
– Cardiovascular death (including hemorrhagic death)
Primary safety endpoint:
• Severe bleeding (GUSTO definition1), including fatal bleeding or
intracranial hemorrhage (ICH)
Bhatt DL, Topol EJ, et al. Am Heart J 2004; 148: 263–268.
1GUSTO Investigators. N Engl J Med 1993; 329: 673–682.
Other Study Endpoints
Principal Secondary Efficacy Endpoint:
• First occurrence of MI (fatal or non-fatal), stroke (fatal or non-
fatal), cardiovascular death, or hospitalization for UA, TIA or
revascularization
Other Efficacy Endpoints:
• Individual components of the primary and secondary endpoints
Other Safety Endpoints:
• Fatal bleeding
• Primary intracranial hemorrhage
• Moderate bleeding (GUSTO definition) 1
Bhatt DL, Topol EJ, et al. Am Heart J 2004; 148: 263–268.
1GUSTO Investigators. N Engl J Med 1993; 329: 673–682.
Bleeding Definitions: GUSTO Criteria
Severe bleeding:
• Fatal bleeding
• Primary or post-traumatic intracranial hemorrhage
• Substantial hemodynamic compromise requiring treatment
to sustain cardiac output
Moderate:
• Bleeding that required transfusion, but did not result in
hemodynamic compromise or meet definition for GUSTO
severe bleeding
Minor bleeding:
• Other bleeding, not requiring transfusion or causing
hemodynamic compromise
GUSTO Investigators. N Engl J Med 1993; 329: 673–682.
Time Since Qualifying Event1
Ischemic event Median duration
(months)
MI 23.3
Stroke 3.5
TIA 2.7
PAD 23.3
1. Bhatt DL, Fox K, Hacke W, et al. Am Heart J 2005; 150: 401.
CHARISMA: Results
Overall Population: Baseline Characteristics
Clopidogrel + ASA Placebo + ASA
Characteristic (n=7802) (n=7801)
Age
Median (range)* 64.0 (39-95) 64.0 (4593)
Female 29.7 29.8
Ethnicity
Caucasian 80.4 79.9
Hispanic 10.0 10.7
Asian 5.0 5.0
Black 3.2 3.0
Other 1.5 1.4
Inclusion group
Documented cardiovascular disease 77.7 78.1
Multiple risk factors 21.3 20.8
Neither criterion 1.0 1.1
Smoking Status
Current 20.1 20.3
Former 48.8 48.7
*Data for age are in years, all other data expressed as percent
Bhatt DL, Fox KA, Hacke W, et al. 2006, in press.
Overall Population: Prior Medical History
Clopidogrel + ASA (%) Placebo + ASA (%)
Characteristic (n=7802) (n=7801)
Hypertension 73.3 73.9
Hypercholesterolemia 73.7 74.2
Congestive heart failure 6.0 5.9
Prior MI 34.2 34.9
Atrial fibrillation 3.8 3.7
Prior stroke 24.9 24.3
TIA 12.0 11.9
Diabetes 42.3 41.7
PAD 22.6 22.7
PCI 22.4 23.1
CABG 19.5 19.9
Carotid endarterectomy 5.4 5.2
Peripheral angioplasty or bypass 11.3 11.0
Diabetic nephropathy 12.9 12.9
Bhatt DL, Fox KA, Hacke W, et al. 2006, in press.
Overall Population: Concomitant Medications*
Clopidogrel + ASA (%) Placebo + ASA (%)
Medication (n=7802) (n=7801)
ASA 99.7 99.7
Open-label clopidogrel 9.9 10.4
Diuretics 48.2 47.1
Nitrates 23.2 24.1
Calcium antagonists 36.7 36.9
Beta blockers 55.0 55.7
Angiotensin II receptor blockers 25.5 25.9
ACE inhibitors 60.1 60.7
Other antihypertensives 12.4 12.4
Statins 76.8 76.9
Antidiabetic medications 41.8 41.5
*Maximal frequency of usage of each agent at any time during
the trial (assessed after baseline and at every follow-up visit)
Bhatt DL, Fox KA, Hacke W, et al. 2006, in press.
Overall Population: Primary Efficacy Outcome
(MI, Stroke, or CV Death)†
8 Placebo + ASA*
7.3%
Cumulative event rate (%)
6 Clopidogrel + ASA*
6.8%
4
RRR: 7.1% [95% CI: -4.5%, 17.5%]
2 P=0.22
0
0 6 12 18 24 30
Months since randomization §
† FirstOccurrence of MI (fatal or non-fatal), stroke (fatal or non-fatal), or cardiovascular death
*All patients received ASA 75-162 mg/day
§The number of patients followed beyond 30 months decreases rapidly to
zero and there are only 21 primary efficacy events that occurred beyond
this time (13 clopidogrel and 8 placebo)
Bhatt DL, Fox KA, Hacke W, et al. 2006, in press.
Overall Population: Principal Secondary Efficacy
Outcome (MI/Stroke/CV Death/Hospitalization)†
Placebo + ASA*
20 17.9%
Cumulative event rate (%)
Clopidogrel + ASA*
15 16.7%
10
RRR: 7.7% [95% CI: 0.5%, 14.4%]
5
p = 0.04
0
0 6 12 18 24 30
Months since randomization§
*All patients received ASA 75-162mg/day
†First Occurrence of MI, Stroke, CV Death, or Hospitalization for UA, TIA, or Revascularization
§The number of patients followed beyond 30 months decreases rapidly to
zero and there are only 38 primary efficacy events that occurred beyond
this time (23 clopidogrel and 15 placebo)
Bhatt DL, Fox KA, Hacke W, et al. 2006, in press.
Overall Population: Secondary Efficacy
Results
Clopidogrel Placebo
+ ASA + ASA
Endpoint* - N (%) (n=7802) (n=7801) RR (95% CI) p value
Principle Secondary Endpoint† 1301 (16.7) 1395 (17.9) 0.92 (0.86, 0.995) 0.04
All Cause Mortality 371 (4.8) 374 (4.8) 0.99 (0.86, 1.14) 0.90
Cardiovascular Mortality 238 (3.1) 229 (2.9) 1.04 (0.87, 1.25) 0.68
Myocardial Infarction 147 (1.9) 159 (2.0) 0.92 (0.74, 1.16) 0.48
Ischemic Stroke 132 (1.7) 160 (2.1) 0.82 (0.66, 1.04) 0.10
Stroke 149 (1.9) 185 (2.4) 0.80 (0.65, 0.997) 0.05
Hospitalization‡ 866 (11.1) 957 (12.3) 0.90 (0.82, 0.98) 0.02
*Intention to treat analysis
†First occurrence of MI (fatal or not), stroke (fatal or not), cardiovascular death
(including hemorrhagic death), or hospitalization for UA, TIA, or a
revascularization procedure
‡For UA, TIA, or revascularization
Bhatt DL, Fox KA, Hacke W, et al. 2006, in press.
Overall Population: Safety Results
Clopidogrel Placebo
+ ASA + ASA
Safety Outcome* - N (%) (n=7802) (n=7801) RR (95% CI) p value
GUSTO Severe Bleeding 130 (1.7) 104 (1.3) 1.25 (0.97, 1.61) 0.09
Fatal Bleeding 26 (0.3) 17 (0.2) 1.44 (0.79, 2.63) 0.23
Primary ICH 26 (0.3) 27 (0.4) 0.93 (0.54, 1.58) 0.78
GUSTO Moderate Bleeding 164 (2.1) 101 (1.3) 1.62 (1.27, 2.08) <0.001
*Adjudicated outcomes by intention to treat analysis
ICH= Intracranial Hemorrhage
Bhatt DL, Fox KA, Hacke W, et al. 2006, in press.
Primary Efficacy Results (MI/Stroke/CV
Death) by Pre-Specified Entry Category
Population RR (95% CI) p value
Qualifying CAD, CVD or PAD 0.88 (0.77, 0.998) 0.046
(n=12,153)
Multiple Risk Factors 1.20 (0.91, 1.59) 0.20
(n=3,284)
Overall Population* 0.93 (0.83, 1.05) 0.22
(n=15,603)
0.4 0.6 0.8 1.2 1.4 1.6
Clopidogrel Better Placebo Better
* A statistical test for interaction showed marginally significant
heterogeneity (p=0.045) in treatment response for these pre-specified
subgroups of patients
Adapted from Bhatt DL, Fox KA, Hacke W, et al. 2006, in press.
Primary Efficacy Outcome (MI/Stroke/CV
Death) by Category of Inclusion
Qualifying CAD, CVD or PAD (N=12,153) Multiple Risk Factor (N=3,284)
10 RRR: -20% [95% CI: -58.8%, 9.3%]
Primary outcome event rate (%)
10 RRR: 12.5% [95% CI: 0.2%, 23.2%]
p=0.20
Primary outcome event rate (%)
p=0.046
8 Clopidogrel + ASA*
8 Placebo + ASA* 6.6%
7.9%
6 6
Clopidogrel +ASA* 4
4 Placebo + ASA*
6.9%
5.5%
2 2
0 0
0 6 12 18 24 30 0 6 12 18 24 30
Months since randomization Months since randomization
*All patients received ASA 75-162 mg/day
Bhatt DL. Presented at ACC 2006.
Documented CV Disease Population: Safety
Results
Clopidogrel Placebo
+ ASA + ASA
Safety Outcome* - N (%) (n=6062) (n=6091) RR (95% CI) p value
GUSTO Severe Bleeding 95 (1.6) 84 (1.4) 1.14 (0.85, 1.52) 0.39
Fatal 19 (0.3) 13 (0.2) 1.47 (0.73, 2.97) 0.28
Primary ICH 19 (0.3) 21 (0.3) 0.87 (0.47, 1.60) 0.65
GUSTO Moderate Bleeding 128 (2.1) 79 (1.3) 1.63 (1.23, 2.15) <0.001
*Adjudicated outcomes by intention to treat analysis
Adapted from Bhatt DL, Fox KA, Hacke W, et al. 2006, in press.
Primary Endpoint (MI/Stroke/CV Death) in
Patients with Previous MI, IS, or PAD
“CAPRIE-like Cohort”
10 N=9,478 Placebo + ASA
Primary outcome event rate (%)
8.8 %
8 Clopidogrel + ASA
7.3 %
6
4
RRR: 17.1 % [95% CI: 4.4%, 28.1%]
p=0.01
2
0
0 6 12 18 24 30
Months since randomization
Bhatt DL. Presented at ACC 2006.
Conclusions
• 7.1% RRR for the primary endpoint (MI/Stroke/CV
Death) in the overall population did not reach statistical
significance
• 7.7% RRR for the secondary endpoint which included
hospitalizations was significant
• The overall outcome was influenced by divergent
findings in the two main sub-groups enrolled in the trial
Conclusions
• In patients with multiple risk factors only, without
clearly established CV disease, dual antiplatelet was
not beneficial - excess in CV mortality as well as an
increase in bleeding
• In patients with documented CV disease (CAD, CVD, or
PAD) long-term clopidogrel plus ASA resulted in a
significant 12.5% RRR in MI/Stroke/CV Death with no
significant increase in severe bleeding compared to
ASA alone
Clinical Implications
• In acute setting, prior studies have shown the benefit of dual antiplatelet
therapy for 1 year post ACS or PCI
• For stable patients, CHARISMA suggests differential long-term effects by
patient type:
– NOT Recommended for Primary Prevention
– Benefit in Secondary Prevention (CAD, CVD, or PAD)
• CV death/MI/stroke - 10 events prevented per 1000 patients treated
• Balanced by 2 severe GUSTO bleeds per 1000 patients treated
• These data and future trials will help physicians decide which non-
acute/stable patients should receive long-term dual antiplatelet therapy
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