Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance...
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Transcript of Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance...
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 FoundationThe Cleveland Clinic Foundation
CHARISMA: Rationale
CAPRIE: Superior Efficacy of Clopidogrel versus ASA
*MI, ischemic stroke or vascular death†Intent-to-treat analysis (n=19,185)
CAPRIE Steering Committee. Lancet 1996; 348: 1329–1339.
0
4
8
12
16
0 3 6 9 12 15 18 21 24 27 30 33 36
Months of follow-up
Cu
mu
lati
ve e
ven
t ra
te*
(%)
ASA
Clopidogrel
8.7%† RRR (p=0.043)
20
Patients with recent ischemic stroke, recent MI or symptomatic PAD
CAPRIE: Clopidogrel Superior to ASA in Sub-Population with Prior CABG1, 2
1. CAPRIE Steering Committee. Lancet 1996; 348: 1329–1339.2. Bhatt DL et al. Circulation 2001; 103: 363368.
*MI, ischemic stroke, vascular death
10
5.8%
9.1%
5.3% 5.8%
0
2
4
6
8
All CAPRIE (n=19,185)1
Prior CABG (n=1480)2
Eve
nt
rate
/yea
r* (
%)
p=0.004
p=0.043
RRR 8.7%
RRR 36.3%
ASA
Clopidogrel
CAPRIE: Clopidogrel Provided Amplified Benefit in Patients with Diabetes1
1. Bhatt DL et al. Am J Cardiol 2002; 90: 625628.
*MI, stroke, vascular death or rehospitalization for ischemic events/bleeding†Number of events prevented per 1000 patients per year compared with ASA
ASA
Clopidogrel12.7%
17.7%
21.5%
11.8%
15.6%17.7%
0
5
10
15
20
25
Patients without diabetes (n=15,233)
Patients with diabetes (n=3866)
Patients treated with insulin (n=1134)
Eve
nt
rate
*/ye
ar (
%)
9†
21†
38†
p=0.096
p=0.042
p=0.106
CAPRIE: Clopidogrel Provides Amplified Benefit in Patients with High Vascular Risk1
1. Ringleb PA et al. Stroke 2004; 35: 528–532.
*MI, ischemic stroke or vascular death;mean duration of treatment was 1.6 years
5.8%
10.2%
5.3%
8.8%
0
2
4
6
8
10
All CAPRIE patients
(n=19,099)
Prior history of major acute event
(MI or ischemic stroke) (n=4496)
Eve
nt
rate
/yea
r* (
%)
ASA
Clopidogrel
12
p=0.043
RRR 8.7%
RRR 14.9%
p=0.045
CURE: Early and Long-Term Benefits of Clopidogrel in ACS Patients1
1. The CURE Investigators. N Engl J Med 2001; 345: 494–502.
*MI, stroke or cardiovascular death†On a background of standard therapy (including ASA)
0
0.02
0.04
0.06
0.08
0.10
0.12
0.14
0 3 6 9 12
Months of follow-up
Cu
mu
lati
ve h
azar
d r
ate*
Placebo†
(n=6303)
Clopidogrel† (n=6259)
20% RRR
p <0.001
CURE: Relationship Between Major Bleeding and ASA Dose in ACS Patients1
ASA dose (range 75–325 mg)
0
1.0
2.0
3.0
4.0
5.0
Inci
den
ce o
f m
ajo
r b
leed
ing
(%
)
1.9%
3.0% 2.8%
3.4%
3.7%
4.9%
101–199 mg (n=3109)
≥200 mg (n=4110)
≤100 mg (n=5320)
Placebo*
Clopidogrel*
*On a background of standard therapy (including ASA)
1. Peters RJG et al. Circulation 2003; 108: 16821687.
CREDO: Long-Term (1 Year) Benefits CREDO: Long-Term (1 Year) Benefits of Clopidogrel in PCI Patientsof Clopidogrel in PCI Patients
MI, stroke, or death – ITT populationMI, stroke, or death – ITT population
* Plus ASA and other standard therapies.* Plus ASA and other standard therapies.
Steinhubl S, Berger P, Tift Mann III J et al. Steinhubl S, Berger P, Tift Mann III J et al. JAMAJAMA. 2002;Vol 288,No 19:2411-2420.. 2002;Vol 288,No 19:2411-2420.
Co
mb
ined
en
dp
oin
t C
om
bin
ed e
nd
po
int
occ
urr
ence
(%
)o
ccu
rren
ce (
%)
Months from randomizationMonths from randomization
27% RRR27% RRRPP=0.02=0.02
Placebo*Placebo*Clopidogrel*Clopidogrel*
00
55
1010
1515
8.5%8.5%
11.5%11.5%
00 33 66 99 1212
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*)
1. Bhatt DL et al. Am Heart J 2004; 148: 263–268.2. GUSTO Investigators. N Engl J Med 1993; 329: 673–682.
*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
CHARISMA Trial Design
* MI (fatal or non-fatal), stroke (fatal or non-fatal), or cardiovascular death; event-driven trial
Clopidogrel
75 mg/day(n=7802)
Placebo 1 tablet/day
(n=7801)1-month
visitFinal visit
(Fixed study end date)
Patients age ≥ 45 years at high risk of atherothrombotic events
R Double-blind treatment up to 1040 primary efficacy events*
Low dose ASA 75162 mg/day
Low dose ASA 75162 mg/day
(n=15603)
Visits every 6 months3-month visit
Bhatt DL, Topol EJ, et al. Am Heart J 2004; 148: 263–268.
Patients aged ≥45 years with
at least one of the following:
1) Documented coronary diseaseand/or
2) Documented cerebrovascular disease and/or
3) Documented symptomatic PADand/or
4) Two major or one major and two minor or three minor risk factors
With written informed consentWithout exclusion criteria
Inclusion 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
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
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
Bhatt DL, Topol EJ, et al. Am Heart J 2004; 148: 263–268.
• For the risk factor only population, two major or one major and two minor or three minor atherothrombotic risk factors must be present
ABI= Ankle Brachial Index
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
Stroke
TIA
PAD
23.3
3.5
2.7
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 + ASACharacteristic (n=7802) (n=7801)
AgeMedian (range)* 64.0 (39-95) 64.0 (4593)
Female 29.7 29.8Ethnicity
Caucasian 80.4 79.9Hispanic 10.0 10.7Asian 5.0 5.0Black 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 1.1Smoking Status
Current 20.1 20.3Former 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 HistoryClopidogrel + 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)†
† First Occurrence 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 tozero and there are only 21 primary efficacy events that occurred beyond this time (13 clopidogrel and 8 placebo)
Placebo + ASA*7.3%
Clopidogrel + ASA*6.8%
RRR: 7.1% [95% CI: -4.5%, 17.5%]P=0.22
Months since randomization§
0
2
4
6
8
0 6 12 18 24 30
Cu
mu
lati
ve e
ven
t ra
te (
%)
Bhatt DL, Fox KA, Hacke W, et al. 2006, in press.
Overall Population: Principal Secondary Efficacy Outcome (MI/Stroke/CV Death/Hospitalization)†
*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 tozero 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.
Placebo + ASA*
17.9%
Clopidogrel + ASA*
16.7%
RRR: 7.7% [95% CI: 0.5%, 14.4%] p = 0.04
Cu
mu
lati
ve e
ven
t ra
te (
%)
0
5
10
15
20
Months since randomization§
0 6 12 18 24 30
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 analysisICH= Intracranial Hemorrhage
Bhatt DL, Fox KA, Hacke W, et al. 2006, in press.
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)
Primary Efficacy Results (MI/Stroke/CV Death) by Pre-Specified Entry Category
0.6 0.8 1.41.2
Clopidogrel Better Placebo Better
1.60.4
* 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
*All patients received ASA 75-162 mg/day
Placebo + ASA* 5.5%
Multiple Risk Factor (N=3,284)
Clopidogrel + ASA* 6.6%
RRR: -20% [95% CI: -58.8%, 9.3%]p=0.20
Pri
mar
y o
utc
om
e ev
ent
rate
(%
)
0
2
4
6
8
10
Months since randomization
0 6 12 18 24 30
Qualifying CAD, CVD or PAD (N=12,153)
Clopidogrel +ASA*6.9%
Placebo + ASA* 7.9%
RRR: 12.5% [95% CI: 0.2%, 23.2%]p=0.046
Pri
mar
y o
utc
om
e ev
ent
rate
(%
)
0
2
4
6
8
10
Months since randomization 0 6 12 18 24 30
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”
RRR: 17.1 % [95% CI: 4.4%, 28.1%]p=0.01
Pri
mar
y o
utc
om
e ev
ent
rate
(%
)
0
2
4
6
8
10
Months since randomization
0 6 12 18 24 30
Clopidogrel + ASA7.3 %
Placebo + ASA8.8 %
Bhatt DL. Presented at ACC 2006.
N=9,478
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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