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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 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 3 6 9 12 15 18 21 24 27 30 33 36Months of follow-up

Clopidogrel

8.7%† RRR (p=0.043)

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

5.3% 5.8%

All CAPRIE (n=19,185)1

Prior CABG (n=1480)2

p=0.004

p=0.043RRR 8.7%

RRR 36.3%

ASAClopidogrel

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

ASAClopidogrel

17.7%21.5%

11.8%15.6%

Patients without diabetes (n=15,233)

Patients with diabetes (n=3866)

Patients treated with insulin (n=1134)

p=0.096

p=0.042p=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

All CAPRIE patients

(n=19,099)

Prior history of major acute event

(MI or ischemic stroke) (n=4496)

ASAClopidogrel

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 3 6 9 12Months of follow-up

Placebo†

(n=6303)

Clopidogrel† (n=6259)

20% RRRp <0.001

CURE: Relationship Between Major Bleeding and ASA Dose in ACS Patients1

ASA dose (range 75–325 mg)

3.0% 2.8%3.4%

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.

Months from randomizationMonths from randomization

27% RRR27% RRRPP=0.02=0.02

Placebo*Placebo*Clopidogrel*Clopidogrel*

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

(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

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.)

Inclusion Criteria: Patients with Multiple Risk Factors Only

Minor risk factorsSBP 150 mm Hg (despite therapy)

Primary hypercholesterolemiaCurrently smoking (>15 cigarettes per day)

Male aged 65 years or female aged 70 years

Major risk factorsType 1 or 2 diabetes (treated with medications)

Diabetic nephropathy ABI <0.9

Asymptomatic carotid stenosis 70%Presence of at least one carotid plaque

• 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)

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 EndpointsPrincipal 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)

MIStrokeTIAPAD

23.33.52.7

1. Bhatt DL, Fox K, Hacke W, et al. Am Heart J 2005; 150: 401.

CHARISMA: Results

Overall Population: Baseline CharacteristicsClopidogrel + ASA Placebo + ASA

Characteristic (n=7802) (n=7801) Age

Median (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 73.9Hypercholesterolemia 73.7 74.2Congestive heart failure 6.0 5.9Prior MI 34.2 34.9Atrial fibrillation 3.8 3.7Prior stroke 24.9 24.3TIA 12.0 11.9Diabetes 42.3 41.7PAD 22.6 22.7PCI 22.4 23.1CABG 19.5 19.9Carotid endarterectomy 5.4 5.2Peripheral angioplasty or bypass 11.3 11.0Diabetic nephropathy 12.9 12.9

Overall Population: Concomitant Medications*Clopidogrel + ASA (%) Placebo + ASA (%)

Medication (n=7802) (n=7801) ASA 99.7 99.7Open-label clopidogrel 9.9 10.4Diuretics 48.2 47.1Nitrates 23.2 24.1Calcium antagonists 36.7 36.9Beta blockers 55.0 55.7Angiotensin II receptor blockers 25.5 25.9ACE inhibitors 60.1 60.7Other antihypertensives 12.4 12.4Statins 76.8 76.9Antidiabetic 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)

Placebo + ASA*7.3%

Clopidogrel + ASA*6.8%

RRR: 7.1% [95% CI: -4.5%, 17.5%]P=0.22

Months since randomization§

0 6 12 18 24 30

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*

Clopidogrel + ASA*

RRR: 7.7% [95% CI: 0.5%, 14.4%] p = 0.04

Months since randomization§ 0 6 12 18 24 30

Overall Population: Secondary Efficacy Results

ClopidogrelPlacebo+ 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

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

Population RR (95% CI) p

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 1.41.2Clopidogrel 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

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

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

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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