Disclosure
Dr. Bhatt has received honoraria from: Astra Zeneca, Bristol-Myers Squibb, Eli Lilly, Millennium, Schering Plough, sanofi aventis, The Medicines Company.
This presentation discusses off-label uses of clopidogrel.
This study was funded by sanofi aventis and Bristol-Myers Squibb.
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
Study Organization
C5=The Cleveland Clinic Cardiovascular Coordinating Center
Investigators
National Coordinators
C5
Sponsors
Operations Committee
Executive Committee
Clinical Event Adjudication Committee
Data Safety Monitoring Board
Bhatt DL et al. Am Heart J 2004; 148: 263–268.
Executive CommitteeChairman• Eric J Topol
Co-Chairmen/Investigators• Keith AA Fox• Werner Hacke
Member/International Principal Investigator • Deepak L Bhatt
Members/Investigators• Peter B Berger• William E Boden• Eric Cohen• Marcus Flather• Christian W Hamm• S Claiborne Johnston• Jean-Louis Mas
• Thomas A Pearson • Steven R Steinhubl
• Henry R Black• Patrice Cacoub• J Donald Easton• Steven M Haffner• Graeme J Hankey• Koon-Hou Mak • Gilles Montalescot• P Gabriel Steg• Michael Weber
Bhatt DL et al. Am Heart J 2004; 148: 263–268.
National CoordinatorsArgentina• Sebastian F Ameriso• Fernando A CuraAustralia• Phillip Aylward• Graeme J HankeyBelgium• Benoît J BolandBrazil• Angelo Amato• Vicenzo De PaolaCanada• Eric A Cohen• André Roussin• Phillip TealCzech Republic• Edvard EhlerDenmark• Henrik SillesenFinland• Markku NieminenFrance• P Gabriel Steg
Germany and Austria• Ulrich Hoffmann• Franz-Josef NeumannGreece• Alexios P DimasHungary• Tamàs ForsterItaly• Diego ArdissinoMexico• Ricardo AlvaradoThe Netherlands• Harry Roger BüllerNorway• Bent IndredavikPoland• Zbigniew A GaciongPortugal• Joao MoraisRussia• Viacheslav Mareev
Spain• Amadeo Betriu• Luis M RuilopeSouth Africa• Anthony J DalbySweden• Jan B ÖstergrenSwitzerland• Thomas F LuscherTurkey• Hakan KultursayUnited Kingdom• Marcus D Flather• Keith AA FoxUnited States• William E Boden• J Donald Easton• Steven M Haffner• Thomas A Pearson• Steven R Steinhubl
Bhatt DL, Fox K, Hacke W, et al. Am Heart J 2005; 150: 401.
Trial Committees
Clinical Events Committee• A Michael Lincoff (Chairman) • Sorin J Brener (cardiology)• Cathy A Sila (neurology)
Data Safety Monitoring Board• Robert L Frye (Chairman)• Pierre Amarenco• Lawrence M Brass: A Great Doctor, A Great Investigator, A Great Friend• Marc Buyse • Lawrence S Cohen • David L DeMets• Valentin Fuster• Robert G Hart• John R Marler• Charles McCarthy• Albert Schömig
Bhatt DL, Fox K, Hacke W, et al. Am Heart J 2005; 150: 401.
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 Reduced the Rate of Rehospitalization
Bhatt DL et al. Am Heart J 2000; 140: 6773.
*Rehospitalization for ischemia (angina pectoris, TIA, limb ischemia) or bleeding (gastrointestinal, intracranial or other)†On-treatment analysis (n=19,099)
Patients with recent ischemic stroke, recent MI or symptomatic PAD
5 10 15 20 25 30 35
9.1%† RRR(p=0.018)
Months of follow-up
Cu
mu
lati
ve e
ven
t ra
te*
(%)
0
5
10
15
20ASA
Clopidogrel
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 et al. Am Heart J 2004; 148: 263–268.
Patients aged ≥45 years with
at least one of the following:
1A) Documented coronary diseaseand/or
1B) Documented cerebrovascular disease and/or
1C) Documented symptomatic PADand/or
2) Two major or one major and two minor or three minor risk factors
With written informed consentWithout exclusion criteria
Inclusion Criteria
Bhatt DL 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 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 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 et al. Am Heart J 2004; 148: 263–268.1GUSTO Investigators. N Engl J Med 1993; 329: 673–682.
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 9.9 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. NEJM 2006.
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. NEJM 2006.
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)
Bhatt DL, Fox KA, Hacke W, et al. NEJM 2006.
Cu
mu
lati
ve e
ven
t ra
te (
%)
0
2
4
6
8
Months since randomization
0 6 12 18 24 30
Placebo + ASA* 7.3%
Clopidogrel + ASA*6.8%
RRR: 7.1% [95% CI: -4.5%, 17.5%]p=0.22
Overall Population: Principal Secondary Efficacy Outcome (MI/Stroke/CV Death/Hospitalization)†
†First Occurrence of MI, Stroke, CV Death, or Hospitalization for UA, TIA, or Revascularization*All patients received ASA 75-162 mg/day§The number of patients followed beyond 30 months decreases rapidly tozero and there are only 38 secondary efficacy events that occurred beyond this time (23 clopidogrel and 15 placebo)
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
Bhatt DL, Fox KA, Hacke W, et al. NEJM 2006.
Overall Population: Primary and Secondary Efficacy Results (MI/Stroke/CV Death/ Hospitalization)†
Clopidogrel Placebo+ ASA + ASA
Endpoint* - N (%) (n=7802) (n=7801) RR (95% CI) p value
Primary Efficacy Endpoint 534 (6.8) 573 (7.3) 0.93 (0.83,1.05) 0.22
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 (nonfatal)∆ 146 (1.9) 155 (2.0) 0.94 (0.75, 1.18) 0.59
Ischemic Stroke (nonfatal) 132 (1.7) 163 (2.1) 0.81 (0.64, 1.02) 0.07
Stroke (nonfatal)∆ 150 (1.9) 189 (2.4) 0.79 (0.64, 0.98) 0.03
Principal Secondary Endpoint† 1301 (16.7) 1395 (17.9) 0.92 (0.86, 0.995) 0.04
Hospitalization‡ 866 (11.1) 957 (12.3) 0.90 (0.82, 0.98) 0.02
†First occurrence of MI (fatal or not), stroke (fatal or not), cardiovascular death (including hemorrhagic death), or hospitalization for UA, TIA, or revascularization*Intention to treat analysis∆Components of the primary efficacy endpoint. Patients that did not die from CV causes, are counted for the first non-fatal event of MI or stroke.‡For UA, TIA, or revascularization
Bhatt DL, Fox KA, Hacke W, et al. NEJM 2006.
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) 1.53 (0.83, 2.82) 0.17
Primary ICH 26 (0.3) 27 (0.3) 0.96 (0.56, 1.65) 0.89
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. NEJM 2006.
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 + ASA Better
Placebo + ASA 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† 166 patients did not meet any of the main inclusion criteria but were followed (intent-to-treat analysis)
Bhatt DL, Fox KA, Hacke W, et al. NEJM 2006
Population N RR (95% CI) p
value
Qualifying CV Disease 12,153 0.88 (0.77, 0.998) 0.046
Coronary 5,835 0.86 (0.71, 1.05) 0.13
Cerebrovascular 4,320 0.84 (0.69, 1.03) 0.09
PAD 2,838 0.87 (0.67, 1.13) 0.29
Multiple Risk Factors 3,284 1.20 (0.91, 1.59) 0.20
Overall Population 15,603 0.93 (0.83, 1.05) 0.22
Primary Efficacy Results (MI/Stroke/CV Death) by Category of Inclusion Criteria
0.6 0.8 1.41.2Clopidogrel + ASA
Better
Placebo + ASABetter
1.60.4
Bhatt DL. Presented at ACC 2006.
Multiple Risk Factor Population: Primary and Secondary Efficacy Results (MI/Stroke/CV Death/ Hospitalization)†
Clopidogrel Placebo+ ASA + ASA
Endpoint* – N (%) (n=1659) (n=1625) RR (95% CI) p value
Primary Efficacy Endpoint 109 (6.6) 89 (5.5) 1.20 (0.91, 1.59) 0.20
All Cause Mortality 89 (5.4) 62 (3.8) 1.41 (1.02, 1.95) 0.04
Cardiovascular Mortality∆ 64 (3.9) 36 (2.2) 1.74 (1.16, 2.62) 0.01
Myocardial Infarction (nonfatal)∆ 25 (1.5) 26 (1.6) 0.95 (0.55, 1.64) 0.84
Ischemic Stroke (nonfatal) 16 (1.0) 23 (1.4) 0.68 (0.36, 1.29) 0.24
Stroke (nonfatal)∆ 20 (1.2) 27 (1.7) 0.73 (0.41, 1.29) 0.27
Principal Secondary Endpoint† 224 (13.5) 216 (13.3) 1.01 (0.84, 1.22) 0.88
Hospitalization‡ 140 (8.4) 147 (9.0) 0.93 (0.74, 1.18) 0.55
†First occurrence of MI (fatal or not), stroke (fatal or not), cardiovascular death (including hemorrhagic death), or hospitalization for UA, TIA, or revascularization*Intention to treat analysis∆Components of the primary efficacy endpoint. Patients that did not die from CV causes, are counted for the first non-fatal event of MI or stroke.‡For UA, TIA, or revascularization
Bhatt DL, Fox KA, Hacke W, et al. NEJM 2006.
Multiple Risk Factor Population: Safety Results
Clopidogrel Placebo+ ASA + ASA
Safety Outcome* - N (%) (n=1659) (n=1625) RR (95% CI) p value
GUSTO Severe Bleeding 34 (2.0) 20 (1.2) 1.67 (0.96, 2.88) 0.07
Fatal 7 (0.4) 4 (0. 2) 1.71 (0.50, 5.84) 0.38
Primary ICH 7 (0.4) 6 (0.4) 1.14 (0.38, 3.39) 0.81
GUSTO Moderate Bleeding 36 (2.2) 22 (1.4) 1.60 (0.95, 2.71) 0.08
*Adjudicated outcomes by Intention to treat analysis
Bhatt DL, Fox KA, Hacke W, et al. NEJM 2006.
Patients with Qualifying CV Disease (CAD, CVD, PAD): 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) 0.91 (0.49, 1.69) 0.76
GUSTO Moderate Bleeding 128 (2.1) 79 (1.3) 1.63 (1.23, 2.15) <0.001
*Adjudicated outcomes by intention to treat analysis
Bhatt DL, Fox KA, Hacke W, et al. NEJM 2006.
Conclusions
• 7.1% RRR for the primary endpoint (first occurrence of
MI/Stroke/CV Death) in the overall population did not
reach statistical significance
• 7.7% RRR for the secondary endpoint which included
hospitalizations was statistically 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, without clearly
documented CV disease, dual antiplatelet therapy 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
THANK YOU!!!To all the CHARISMA Investigators and
CHARISMA Patients
Backup Slides
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 of
dual antiplatelet therapy by patient type:
– NOT Recommended for Primary Prevention
– Benefit in Secondary Prevention (CAD, CVD, or PAD)
• CV death/MI/stroke - 9 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
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 + ASA 8.8%
N=9,478
Bhatt DL. Presented at ACC 2006.
* Post hoc analysis