Disclosure Dr. Bhatt has received honoraria from: Astra Zeneca, Bristol-Myers Squibb, Eli Lilly, Millennium, Schering Plough, sanofi aventis, The Medicines

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


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

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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

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ven

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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


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


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)


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)


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)


Cu

mu

lati

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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

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ven

t ra

te (

%)

0

5

10

15

20

Months since randomization§

0 6 12 18 24 30


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


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


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)†


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


Multiple Risk Factor Population: Safety Results




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


Patients with Qualifying CV Disease (CAD, CVD, PAD): Safety Results




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


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

Documents

Disclosure Dr. Bhatt has received honoraria from: Astra Zeneca, Bristol-Myers Squibb, Eli Lilly, Millennium, Schering Plough, sanofi aventis, The Medicines