1. 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

2. CHARISMA: Rationale

3. CAPRIE: Superior Efficacy of Clopidogrel versus ASA
Patients with recent ischemic stroke, recent MI or symptomatic PAD 20
8.7%† RRR (p=0.043)
ASA 16
Clopidogrel 12
Cumulative event rate* (%) 8 4
The efficacy and safety of clopidogrel was compared with ASA in the Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial. This trial was a randomized, double-blind study in 19,185 patients with a wide spectrum of atherothrombotic disease
Clopidogrel was found to be significantly more effective than ASA, with a relative risk reduction (RRR) of 8.7% in the combined risk of MI, ischemic stroke or vascular death (p=0.043)1
The cumulative event rate curves for clopidogrel and ASA diverged early during the follow-up period and continued to diverge throughout the full treatment period of 3 years1
Reference
1. CAPRIE Steering Committee. Lancet 1996; 348: 1329–1339. 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.

4. CAPRIE: Clopidogrel Superior to ASA in Sub-Population with Prior CABG1, 2
RRR 36.3%
p=0.004 10
RRR 8.7%
9.1%
p=0.043
ASA 8
Clopidogrel 6
5.8%
5.8%
5.3%
Event rate/year* (%) 4 2
In those patients in the CAPRIE trial with a history of CABG, the event rate per year of vascular death, MI, stroke or hospitalization for ischemia/bleeding was 22.3% in the ASA group versus 15.9% in the clopidogrel group (p=0.001)1
A risk reduction was also seen in each of the individual end points examined, including a 42.8% RRR in vascular death in patients in the clopidogrel group versus the ASA group (p=0.030)1
Reference
1. Bhatt DL et al. Circulation 2001; 103: 363368.
All CAPRIE (n=19,185)1
Prior CABG (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: 363368.

5. CAPRIE: Clopidogrel Provided Amplified Benefit in Patients with Diabetes1
ASA
Clopidogrel
12.7%
17.7%
21.5%
11.8%
15.6% 5 10 15 20 25
Patients without diabetes (n=15,233)
Patients with diabetes (n=3866)
Patients treated with insulin (n=1134)
Event rate*/year (%) 9†
21†
38†
p=0.096
p=0.042
p=0.106
In the CAPRIE study, 3866 patients had co-existing diabetes1
Patients without diabetes treated with clopidogrel were at lower risk of MI, ischemic stroke, vascular death or rehospitalization for ischemic events/bleeding than those treated with ASA (11.8 vs 12.7%; p=0.096; 9 events prevented per 1000 patients per year with clopidogrel versus ASA)1
Similarly, patients with diabetes treated with clopidogrel were at lower risk of MI, ischemic stroke, vascular death or rehospitalization for ischemic events/bleeding than those treated with ASA (15.6 vs 17.7%; p=0.042)1
The benefits of clopidogrel over ASA were even further amplified in the higher risk, insulin-dependent patients (17.7 vs 21.5%; p=0.106; 38 events prevented per 1000 patients per year with clopidogrel versus ASA)1
Reference
1. Bhatt DL et al. Am Heart J 2002; 148: 67–73.
*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: 625628.

6. CAPRIE: Clopidogrel Provides Amplified Benefit in Patients with High Vascular Risk1
RRR 14.9%
p=0.045 12
RRR 8.7%
10.2% 10
8.8%
p=0.043
ASA 8
Clopidogrel
5.8%
Event rate/year* (%) 6
5.3% 4 2
Of the 19,099 patients in the CAPRIE trial who received study treatment, 4496 patients had a prior history of a major acute event (MI or ischemic stroke)1
Overall, the annual event rate was lower with clopidogrel versus ASA (5.3 vs 5.8%) with a RRR of 8.7%1
Similarly, in patients who had a prior history of a major acute event, the annual event rate was lower in the clopidogrel group versus the ASA group (8.8 vs 10.2%) with a RRR of 14.9%1
Thus, the benefits of clopidogrel over ASA were amplified in the higher vascular risk group1
References
1. Ringleb PA et al. Stroke 2004; 35: 528–532.
All CAPRIE patients (n=19,099)
Prior history of major acute event (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.

7. CURE: Early and Long-Term Benefits of Clopidogrel in ACS Patients1
0.14
Placebo† (n=6303)
20% RRR
p <0.001
0.12
0.10
Clopidogrel† (n=6259)
0.08
Cumulative hazard rate*
0.06
0.04
0.02
The CURE (Clopidogrel in Unstable angina to prevent Recurrent Events) trial compared clopidogrel on a background of standard therapy with standard therapy alone. A total of 12,562 patients with UA/non-ST-segment elevation MI (NSTEMI) were randomized to receive either clopidogrel 75 mg once daily plus ASA 75–325 mg/day or placebo plus ASA 75–325 mg/day and followed for 12 months
Clopidogrel demonstrated a highly significant 20% RRR in the primary endpoint of major vascular events (MI, stroke or vascular death; 95% confidence intervals [CI] 0.72–0.90; p <0.001)1
Overall, there were 719 (11.4%) vascular events experienced for the first time in the placebo group versus 582 (9.3%) in the clopidogrel group. The hazard rate curves began to diverge within the first few hours after the initiation of therapy and continued to diverge over the entire 12-month follow-up period1
A significant RRR of approximately 20% was observed during the first 30 days, with this reduction being similar to the value observed during the chronic phase (from 30 days until the end of follow-up at 12 months). Thus, clopidogrel provides both an early and long-term clinical benefit when given on a background of standard therapy (including ASA)1
The combination of clopidogrel and ASA was as well tolerated as ASA alone in the CURE trial. There was no statistically significant difference between the two treatment groups in terms of life-threatening bleeds (p=0.13). There were significantly more major bleedings in the clopidogrel plus ASA group versus the placebo plus ASA group (3.7 vs 2.7%; p=0.001), although this was dependent on ASA dosage1
Reference
1. The CURE Investigators. N Engl J Med 2001; 345: 494–502. 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.

8. Incidence of major bleeding (%)
CURE: Relationship Between Major Bleeding and ASA Dose in ACS Patients1
4.9%
5.0
3.7%
4.0
3.4%
3.0%
2.8%
3.0
Placebo*
Incidence of major bleeding (%)
1.9%
Clopidogrel*
2.0
1.0
The incidence of reported bleeding increased proportionally to the increasing dose of ASA. Major bleeding occurred less frequently in patients who received low-dose ASA either alone or with clopidogrel in comparison to high-dose ASA1
A multivariate analysis demonstrated that the efficacy of clopidogrel was not dependent on the dosage of ASA used, suggesting that in relation to major bleeding, the use of low-dose ASA and clopidogrel was better than the use of high-dose ASA and clopidogrel1
Reference
Peters RJG et al. Circulation 2003; 108: 16821687.
≤100 mg (n=5320)
101–199 mg (n=3109)
≥200 mg (n=4110)
ASA dose (range 75–325 mg)
*On a background of standard therapy (including ASA)
1. Peters RJG et al. Circulation 2003; 108: 16821687.

9. CREDO: Long-Term (1 Year) Benefits of Clopidogrel in PCI Patients
MI, stroke, or death – ITT population 15
Placebo*
Clopidogrel*
11.5%
27% RRR
P=0.02 10
8.5%
Combined endpoint occurrence (%) 5
The CREDO results demonstrate the benefits of long-term (1 year) administration of clopidogrel plus ASA and other standard therapies in patients undergoing PCI, with or without stent.
For the entire study population, long-term clopidogrel treatment was associated with a 27% reduction in the relative risk of the combined endpoint of death, MI, and stroke at 1 year.
This result was statistically significant (8.5% clopidogrel vs. 11.5% placebo, 95% CI, , p=0.02).
Reference:
Steinhubl S, Berger P, Tift Mann III J, et al. JAMA. 2002;Vol 288,No 19: 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:

10. CHARISMA: Design

11. 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 intent-to-treat population was used for all efficacy and safety analyses1
This consisted of all randomized patients irrespective of whether the patient actually received study drug or the patient’s compliance with the study protocol1
A patient was to be considered as randomized as soon as a treatment number was assigned by Interactive Voice Response System (IVRS)1
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
References
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
1. Bhatt DL et al. Am Heart J 2004; 148: 263–268.
2. GUSTO Investigators. N Engl J Med 1993; 329: 673–682.

12. Final visit (Fixed study end date)
CHARISMA Trial Design
Clopidogrel 75 mg/day
(n=7802)
Patients age ≥ 45 years at high risk of atherothrombotic events
Low dose ASA 75162 mg/day R
Double-blind treatment up to 1040 primary efficacy events*
(n=15603)
Low dose ASA 75162 mg/day
Placebo 1 tablet/day (n=7801)
CHARISMA was a multicenter, multinational, randomized, two-parallel group, double-blind trial of clopidogrel versus placebo
A total of 15, 603 patients with documented atherothrombosis (symptomatic) or multiple risk factors (asymptomatic patients) were randomized to clopidogrel (75 mg per day) or placebo in a double-blind manner, both in addition to background therapy including low-does ASA ( mg/day, the exact dose left to the discretion of the individual treating physician), and followed for a median of 28 months. 2
The randomization was centralized using an IVRS1
CHARISMA was an event-driven trial, meaning that it was planned to end after at least 1,040 blinded, primary events had accrued 2
Since 1,040 primary efficacy events had been reached, the fixed study end date was 29 August
Final visits occurred within the month following the fixed study end date1
During the trial each patient had follow-up visits scheduled at 1 month, 3 months, 6 months, 12 months and every 6 months thereafter until a common study end date 2
All patients were followed from randomization until study end date, with the last patient followed for at least 3 months1
Reference
Bhatt DL, Topol, EJ, et al. Am Heart J 2004; 148: 263–268.
1-month
visit
3-month
visit
Visits every 6 months
Final 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.

13. Inclusion Criteria Patients aged ≥45 years with
at least one of the following:
1) Documented coronary disease
and/or
2) Documented cerebrovascular disease
3) Documented symptomatic PAD
4) Two major or one major and two minor or three minor risk factors
With written informed consent
Without exclusion criteria
Patients aged ≥45 years with at least one of the following four categories of criteria (one or more may apply) could be randomized:1
Combination of two major or three minor or one major and two minor atherothrombotic risk factors
Documented cerebrovascular disease
Documented coronary disease
Documented symptomatic PAD
Reference
1. Bhatt DL, Topol EJ, et al. Am Heart J 2004; 148: 263–268.
Bhatt DL, Topol EJ, et al. Am Heart J 2004; 148: 263–268.

14. 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.)
To fulfill the documented coronary disease criteria, patients were required to have one of the following:1
Stable angina with documented multivessel coronary disease
History of multivessel percutaneous coronary intervention (PCI)
History of multivessel CABG
Previous MI
To fulfil the documented cerebrovascular disease criteria, patients must have had one or more of the following:1
Previous TIA within the past 5 years
Previous ischemic stroke within the past 5 years
To fulfil the documented symptomatic PAD criteria, patients must have had either:1
Current intermittent claudication with an ABI ≤0.85
A history of intermittent claudication together with a previous related intervention (amputation, peripheral bypass, angioplasty, etc.)
Reference
Bhatt DL, Topol EJ, et al. Am Heart J 2004; 148: 263–268.
Bhatt DL, Topol EJ, et al. Am Heart J 2004; 148: 263–268.

15. 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
In CHARISMA, major atherothrombotic risk factors were as follows:1
Type 1 or 2 diabetes currently under drug therapy
Diabetic nephropathy
ABI 0.9
Asymptomatic carotid stenosis 70%
Presence of at least one carotid plaque evidenced by intima–media thickness
In CHARISMA, minor atherothrombotic risk factors were as follows:1
SBP 150 mmHg, despite therapy for at least 3 months
Primary hypercholesterolemia
Currently smoking 15 cigarettes per day
Male aged 65 years or female aged 70 years
Reference
1. Bhatt DL, Topol EJ, et al. Am Heart J 2004; 148: 263–268.
ABI= Ankle Brachial Index
Bhatt DL, Topol EJ, et al. Am Heart J 2004; 148: 263–268.

16. 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)
Use of chronic oral antithrombotic medications (such as warfarin, high-dose ASA and nonsteroidal anti-inflammatory drugs* likely to:1
Interfere with efficacy assessment by decreasing trial sensitivity
Increase the risk of bleeding
If the patient requires prolonged clopidogrel therapy according to the investigator’s judgment, such as patients who have had a recent NSTEMI, they would not be eligible for enrollment1
If a revascularization procedure is planned, the patient cannot be randomly assigned until after the procedure has been completed and provided no prohibited concomitant medication such as open-label clopidogrel is still administered1
*cyclo-oxygenase-2 [COX-2] inhibitors were permitted
Reference
1. Bhatt DL, Topol EJ, et al. Am Heart J 2004; 148: 263–268.
Bhatt DL, Topol EJ, et al. Am Heart J 2004; 148: 263–268.

17. 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)
The intent-to-treat population will be used for all efficacy and safety analyses. This population will consist of all randomized patients irrespective of whether the patient actually received the study drug or the patient’s compliance with the study protocol1
Primary efficacy endpoint1
The first occurrence of any component of the following cluster:
Non-fatal MI
Non-fatal stroke (from any cause)
Cardiovascular death (including hemorrhagic death) 
Primary safety endpoint1
Severe bleeding (GUSTO definition)2, including fatal bleeding and primary ICH
References
1. Bhatt DL, Topol EJ, et al. Am Heart J 2004; 148: 263–268.
2. GUSTO Investigators. N Engl J Med 1993; 329: 673–682.
Bhatt DL, Topol EJ, et al. Am Heart J 2004; 148: 263–268.
1GUSTO Investigators. N Engl J Med 1993; 329: 673–682.

18. 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
The intent-to-treat population will be used for all efficacy and safety analyses. This population will consist of all randomized patients irrespective of whether the patient actually received the study drug or the patient’s compliance with the study protocol1
Secondary efficacy endpoint1
The first occurrence of cardiovascular death, MI, stroke or hospitalization for UA, TIA or revascularization
The GUSTO definition for severe and moderate bleeding were employed. Severe bleeding includes intracerebral bleeding or bleeding complications resulting in substantial hemodynamic compromise requiring treatment2. Moderate bleeding is defined by the need for transfusion, but without hemodynamic compromise
References
1. Bhatt DL, Fox KA, Hacke W, et al. 2006, in press.
GUSTO Investigators. N Engl J Med 1993; 329: 673–682.
Bhatt DL, Topol EJ, et al. Am Heart J 2004; 148: 263–268.
1GUSTO Investigators. N Engl J Med 1993; 329: 673–682.

19. 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
Bleeding was defined using the GUSTO Criteria1:
Severe bleeding:
Fatal
Primary or post-traumatic intracerebral hemorrhage
Substantial hemodynamic compromise requiring treatment
Moderate:
Need for transfusion, but without hemodynamic compromise
Minor bleeding:
Other bleeding, not requiring transfusion or causing hemodynamic compromise
1GUSTO Investigators. N Engl J Med 1993; 329: 673–682.
GUSTO Investigators. N Engl J Med 1993; 329: 673–682.

20. Time Since Qualifying Event1
Ischemic event
Median duration (months) MI
Stroke
TIA
PAD
23.3
3.5
2.7
The median time since qualifying event for patients with:1
MI was 23.3 months
PAD was 23.3 months
Stroke was 3.5 months
TIA was 2.7 months
Reference
1. Bhatt DL, Fox K, Hacke W, et al. Am Heart J 2005; 150: 401.
1. Bhatt DL, Fox K, Hacke W, et al. Am Heart J 2005; 150: 401.

21. CHARISMA: Results

22. Overall Population: Baseline Characteristics
Clopidogrel + ASA Placebo + ASA
Characteristic (n=7802) (n=7801)
Age
Median (range)* (39-95) (4593)
Female
Ethnicity
Caucasian
Hispanic
Asian
Black
Other
Inclusion group
Documented cardiovascular disease
Multiple risk factors
Neither criterion
Smoking Status
Current
Former
The median age of the overall population was 64 years; 30% of the subjects were female. More than three-quarters of the participants had documented cardiovascular disease, as defined by the enrollment criteria, while most of the remaining patients had multiple atherothrombotic risk factors.
Approximately half (50.5%) of patients were aged <65 years and approximately one-third (33.4%) were aged ≥65 and <75 years1
The majority (80.1%) of patients were white; 10.3% of patients were Hispanic, 5.0% were Asian and 3.1% were black1
Over three-quarters of patients were overweight (42.2%) or obese (33.4%)1
69.0% of the population are current or former smokers1
Reference
1. Bhatt DL, Fox KA, Hacke W, et al. 2006, in press.
*Data for age are in years, all other data expressed as percent
Bhatt DL, Fox KA, Hacke W, et al. 2006, in press.

23. Overall Population: Prior Medical History
Clopidogrel + ASA (%) Placebo + ASA (%)
Characteristic (n=7802) (n=7801)
Hypertension
Hypercholesterolemia
Congestive heart failure
Prior MI
Atrial fibrillation
Prior stroke
TIA
Diabetes
PAD
PCI
CABG
Carotid endarterectomy
Peripheral angioplasty or bypass
Diabetic nephropathy
The treatment groups in the overall population were well balanced with respect to prior medical history
Three quarters of the patients had a history of hypertension and hypercholesterolemia at baseline, and 42.0% had a history of diabetes1;
More than one third had prior MI, approximately one quarter of the patients had prior PCI, prior stroke, and/or documented PAD, and approximately 20% had prior CABG.
Reference
1. Bhatt DL, Fox KA, Hacke W, et al. 2006, in press.
Bhatt DL, Fox KA, Hacke W, et al. 2006, in press.

24. Overall Population: Concomitant Medications*
Clopidogrel + ASA (%) Placebo + ASA (%)
Medication (n=7802) (n=7801)
ASA
Open-label clopidogrel
Diuretics
Nitrates
Calcium antagonists
Beta blockers
Angiotensin II receptor blockers
ACE inhibitors
Other antihypertensives
Statins
Antidiabetic medications
The treatment groups in the overall population were also well matched with respect to concomitant medications.
These figures indicate the maximal frequency of usage of each agent at any time during the trial (assessed at baseline and at every follow-up visit). All of the subjects took aspirin and the study drug (excluding those who died or dropped out), while a few also took open-label clopidogrel. Three-quarters took a statin, and more than half took a beta-blocker. Nearly two-thirds took an ACE inhibitor, and a quarter took ARBs.
Reference
1. Bhatt DL, Fox KA, Hacke W, et al. 2006, in press.
*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.

25. Overall Population: Primary Efficacy Outcome (MI, Stroke, or CV Death)†
Placebo + ASA*
7.3% 8
Clopidogrel + ASA*
6.8% 6
Cumulative event rate (%) 4
RRR: 7.1% [95% CI: -4.5%, 17.5%]
P=0.22 2 6 12 18 24 30
The primary efficacy endpoint in CHARISMA was a cluster of the first occurrence of fatal or nonfatal MI, or fatal or nonfatal stroke (of any cause), or cardiovascular death (including haemorrhagic death)
With a median of 28 months of follow-up, the primary event rate was 6.8% in the clopidogrel plus aspirin arm and 7.3% in the placebo plus aspirin arm (p=0.22, relative risk [RR] 0.93, 95% confidence interval [CI] 0.83, 1.05) (Figure 1). This reduction was not statistically significant (p=0.217) 1
The yearly primary outcome events rates were 3.12% and 3.36% for clopidogrel plus ASA vs. placebo plus ASA, respectively
Clopidogrel plus ASA prevented 39 primary events overall during the study follow-up1
The Kaplan-Meier curve of the primary endpoint shows that the curves separate very early after randomization, and continue diverging over time, which indicates a continuous trend in favor of the clopidogrel and ASA treatment arm. 1
Bhatt DL, Fox KA, Hacke W, et al. 2006, in press.
Months since randomization§
† First Occurrence of MI (fatal or non-fatal), stroke (fatal or non-fatal), or cardiovascular death
*All patients received ASA 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.

26. Cumulative event rate (%) Months since randomization§
Overall Population: Principal Secondary Efficacy Outcome (MI/Stroke/CV Death/Hospitalization)†
Placebo + ASA*
17.9%
Cumulative event rate (%) 5 10 15 20
Months since randomization§ 6 12 18 24 30
Clopidogrel + ASA*
16.7%
RRR: 7.7% [95% CI: 0.5%, 14.4%] p = 0.04
The secondary efficacy endpoint in CHARISMA was a cluster of the first occurrence of MI, stroke, cardiovascular death (including haemorrhagic death), (of any cause), hospitalization for unstable angina, TIA, or a revascularization procedure.
There was a statistically significant risk reduction in the clopidogrel plus ASA arm in the rate of the principal secondary efficacy end point. The rate of the secondary efficacy outcome was 16.7% in the clopidogrel arm versus 17.9% in the placebo arm (p=0.037, RR 0.92, 95% CI: 0.86, 0.995)
The yearly secondary events rates were 8.07% vs. 8.76% for clopidogrel plus ASA vs. placebo plus ASA
The secondary endpoint result was driven by the statistically significant relative risk reduction in hospitalization for unstable angina, TIA, or a revascularization procedure (see next slide)
Bhatt DL, Fox KA, Hacke W, et al. 2006, in press.
*All patients received ASA mg/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.

27. Overall Population: Secondary Efficacy Results
Clopidogrel Placebo
+ ASA + ASA
Endpoint* - N (%) (n=7802) (n=7801) RR (95% CI) p value
Principle Secondary Endpoint† (16.7) 1395 (17.9) 0.92 (0.86, 0.995) 0.04
All Cause Mortality (4.8) 374 (4.8) 0.99 (0.86, 1.14) 0.90
Cardiovascular Mortality (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) (0.65, 0.997) 0.05
Hospitalization‡ (11.1) 957 (12.3) 0.90 (0.82, 0.98) 0.02
The secondary endpoint result was driven by the statistically significant relative risk reduction in hospitalization for unstable angina, TIA, or a revascularization procedure
The results of the other efficacy endpoints in CHARISMA were as follows:
Total deaths: a 0.99 [0.86, 0.995] relative risk in favor of the clopidogrel plus ASA arm, non-significant
CV death: a 1.04 [0.87, 1.25] non-significant increase in relative risk in the clopidogrel plus ASA arm
MI (fatal or not): a 0.92 [0.74, 1.16] relative risk in favor of the clopidogrel plus ASA arm, non-significant
IS (fatal or not): a 0.82 [0.66, 1.04] relative risk in favor of the clopidogrel plus ASA arm, non-significant
Stroke (fatal or not): a 0.80 [0.65, 0.997] relative risk in favor of the clopidogrel plus ASA arm, non-significant
Hospitalization for unstable angina, TIA, or a revascularization procedure: a statistically significant 0.90 [0.82, 0.98] relative risk in favor of the clopidogrel plus ASA arm (p=0.020)
Bhatt DL, Fox KA, Hacke W, et al. 2006, in press.
*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.

28. 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
The primary safety endpoint in CHARISMA was severe bleeding using the GUSTO definition (documented intracranial haemorrhage or bleeding that causes hemodynamic compromise requiring blood or fluid replacement, inotropic support, ventricular assist devices, surgical intervention, or CPR to maintain a sufficient cardiac output, which included fatal bleeding
At the end of follow-up, the rate of the primary safety end point (severe GUSTO bleeding) was 1.7% in the clopidogrel plus ASA group versus 1.3% in the placebo plus ASA group (p=0.087, 0.33% risk difference, 95% CI: -0.05%, 0.71%).
The rate of moderate bleeding was 2.1% in the clopidogrel plus ASA group versus 1.3% in the placebo plus ASA group (p<0.001, 0.81% risk difference, 95% CI: 0.40%, 1.21%).
The rates of fatal bleeding and intracranial hemorrhage were similar in both treatment groups
The yearly severe bleeding rates were respectively 0.75% vs. 0.60% for clopidogrel plus ASA arm vs. placebo plus ASA
Bhatt DL, Fox KA, Hacke W, et al. 2006, in press.
Bhatt DL, Fox KA, Hacke W, et al. 2006, in press.

29. Primary Efficacy Results (MI/Stroke/CV Death) by Pre-Specified Entry Category
Population RR (95% CI) p value
Qualifying CAD, CVD or PAD (0.77, 0.998) 0.046
(n=12,153)
Multiple Risk Factors (0.91, 1.59) (n=3,284)
Overall Population* 0.93 (0.83, 1.05) (n=15,603)
The primary efficacy endpoint in CHARISMA was a cluster of the first occurrence of cardiovascular death (including haemorrhagic death), fatal or nonfatal MI, or fatal or nonfatal stroke (of any cause)
There was no statistical difference in the primary endpoint between the two treatment arms.
Analysis of symptomatic (documented atherothrombotic disease) and asymptomatic (multiple atherothrombotic risk factors) groups was pre-specified in the CHARISMA statistical analysis plan.
Among 3284 asymptomatic patients, there was a 20% increase in primary events with clopidogrel (RR 1.20 [0.91, 1.59], p=0.20), while among 12,153 symptomatic patients, there was a marginally significant reduction in the primary end point with clopidogrel (6.9% versus 7.9% in the placebo group, RR 0.88, p=0.046, 95% CI: 0.77, 0.998).
The interaction term for this analysis, examining the differential treatment response in asymptomatic and symptomatic patients, was marginally significant (p=0.045). Of note, there was an increase in all cause mortality (5.4% versus 3.8%, p=0.04), and an increase in cardiovascular death (3.9% versus 2.2%, p=0.01), among the asymptomatic patients assigned to clopidogrel compared with placebo, respectively.
There were 166 patients originally randomized which were found later to have not met any of the inlclusion criteria.
Bhatt DL, Fox KA, Hacke W, et al. 2006, in press..
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.

30. Primary Efficacy Outcome (MI/Stroke/CV Death) by Category of Inclusion
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
Primary outcome event rate (%) 2 4 6 8 10
Months since randomization 12 18 24 30
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
Primary outcome event rate (%) 2 4 6 8 10
Months since randomization 12 18 24 30
The primary efficacy endpoint in CHARISMA was a cluster of the first occurrence of fatal or nonfatal MI, or fatal or nonfatal stroke (of any cause), or cardiovascular death (including haemorrhagic death).
There was no statistical difference in the primary endpoint between the two treatment arms.
An analysis of the population with documented atherothrombotic disease (symptomatic) and that with multiple atherothrombotic risk factors (asymptomatic) was pre-specified in the CHARISMA statistical analysis plan.
In the 12,153 patients with documented atherothrombosis, there was a significant 12.5% RRR in the primary endpoint (CV death/MI/stroke) from 7.9% in the placebo + ASA group to 6.9% clopidogrel+ ASA group (p=0.046, 95% CI: 0.2%, 23.2%).
At the end of follow-up, the event rate in the multiple risk factor population (N=3284) for the primary outcome in the clopidogrel plus ASA arm was 6.57% as compared to 5.48% in the placebo plus ASA arm (RRR -20.0% [-58.8%, 9.3%])
*All patients received ASA mg/day
Bhatt DL. Presented at ACC 2006.

31. 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
There was a non-significant absolute risk increase of 0.19 (p=0.39, 95% CI: -0.24%, 0.62%) in the rate of severe GUSTO bleeding, from 1.4% in the placebo + ASA group to 1.6% in the clopidogrel + ASA group.
There was a significant (p=.001) absolute increase in GUSTO moderate bleeding (requiring transfusion) in the clopidogrel +ASA arm; equating to 50 more bleeding episodes
Adapted from Bhatt DL, Fox KA, Hacke W, et al. 2006, in press.

32. 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
Primary outcome event rate (%) 2 4 6 8 10
Months since randomization 12 18 24 30
Clopidogrel + ASA
7.3 %
Placebo + ASA
8.8 %
N=9,478
A post-hoc analysis of patients (n=9478) with a previous MI, stroke, or PAD (similar to the entry criteria for the CAPRIE trial) showed a significant 17.1% RRR in favor of clopidogrel plus ASA over ASA alone
Bhatt DL. Presented at ACC 2006.

33. 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

34. 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

35. 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

36. THANK YOU!!!