VBWG

CHARISMA

Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance trial

VBWG

CHARISMA: Background and hypothesis

• The combination of clopidogrel plus aspirin has been demonstrated to be superior to aspirin in the treatment of patients with ACS and after coronary stenting.

• When added to the current standard of care, does long-term treatment with clopidogrel plus aspirin provide greater vascular protection than aspirin alone in a broad population of high-risk patients?

Bhatt DL et al. Am Heart J. 2004;148:263-8.Bhatt DL et al. N Engl J Med. 2006;354:1706-17.

VBWG

*n = 166 not in either category, butincluded in overall analysis

†Coronary, cerebral, or peripheral

CHARISMA: Study design

Clopidogrel 75 mgASA 75-162 mg

n = 7802

PlaceboASA 75-162 mg

n = 7801

Symptomatic patients with coronary, cerebrovascular, or

peripheral arterial disease*n = 12,153

Follow-up until 1040 primary events

Primary end point:First occurrence of MI, stroke (any cause), CV death (including hemorrhagic)

Principal secondary end point:First occurrence of MI, stroke, CV death, hospitalization for UA, TIA, revascularization†

RandomizedDouble-blind

Bhatt DL et al. Am Heart J. 2004;148:263-8.Bhatt DL et al. N Engl J Med. 2006;354:1706-17.

Asymptomatic patients with multiple atherothrombotic

risk factors*n = 3284

N = 15,603

VBWG

CHARISMA: Baseline characteristics

Clopidogrel + ASA(n = 7802)

Placebo + ASA(n = 7801)

Age (years) Median Range

64.039.0–95.0

64.045.0–93.0

Female sex (%) 29.7 29.8

Race/ethnicity (%) White Hispanic Asian Black Other

80.49.95.03.21.5

79.910.75.03.01.4

Smoking status (%) Current Former

20.148.9

20.348.7

Bhatt DL et al. N Engl J Med. 2006;354:1706-17.

VBWG

CHARISMA: Baseline characteristics, cont’d

Clopidogrel + ASA(n = 7802)

(%)

Placebo + ASA(n = 7801)

(%)

Hypertension 73.3 73.9

Hypercholesterolemia 73.7 74.2

Diabetes 42.3 41.7

Prior MI 34.2 34.9

Prior stroke 24.9 24.3

PAD 22.6 22.7

PCI 22.4 23.1

CABG 19.5 19.9

Bhatt DL et al. N Engl J Med. 2006;354:1706-17.Other comorbidities each occurred in <15%

VBWG

CHARISMA: Concomitant medications

Clopidogrel + ASA(n = 7802)

(%)

Placebo + ASA(n = 7801)

(%)

Statins 76.8 76.9

Other lipid-lowering agents 14.3 14.0

ACEIs 64.0 64.6

ARBs 25.5 25.9

β-blockers 55.0 55.7

Diuretics 48.2 47.1

Calcium antagonists 36.7 36.9

Nitrates 23.2 24.1

Antidiabetics 41.8 41.5

Bhatt DL et al. N Engl J Med. 2006;354:1706-17.

VBWG

CHARISMA: Treatment effect on primary end point

Bhatt DL et al. N Engl J Med. 2006;354:1706-17.

Cumulative incidence of MI, stroke, CV death; N = 15,603

7% RRRRR 0.93 (0.83–1.05)P = 0.22

Months

10

8

6

4

2

00 6 12 18 24 30

PlaceboClopidogrel

Events (%)

VBWG

CHARISMA: Treatment effect on principal secondary end point

Bhatt DL et al. N Engl J Med. 2006;354:1706-17.

Cumulative incidence of MI, stroke, CV death, hospitalization for UA,

TIA, revascularization;* N = 15,603

*Coronary, cerebral, or peripheral

20

15

10

5

00 6 12 18 24 30

Months

PlaceboClopidogrel

8% RRRRR 0.92 (0.86-0.995)P = 0.04

Events (%)

VBWG

CHARISMA: Safety end points

Event ratenumber of patients (%)

Clopidogrel + ASA

Placebo + ASA P

Severe bleeding

Fatal bleeding

Intracranial hemorrhage

130 (1.7)

26 (0.3)

26 (0.3)

104 (1.3)

17 (0.2)

27 (0.3)

0.09

0.17

0.89

Moderate bleeding 164 (2.1) 101 (1.3) <0.001

Bhatt DL et al. N Engl J Med. 2006;354:1706-17.

GUSTO criteria; N = 15,603

GUSTO = Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries

VBWG

n = 3284

n = 12,153

N = 15,603

CHARISMA: Treatment effect by inclusion criteria

MI, stroke, CV death

*Multiple atherothrombotic risk factors†Documented coronary, cerebrovascular, or peripheral arterial disease

0.5 1.0 1.5Placebobetter

Clopidogrelbetter

Asymptomatic*

Symptomatic†

All patients

Hazard ratio RR (95% CI)

1.20 (0.91–1.59)

0.88 (0.77–0.998)

0.93 (0.83–1.05)

Bhatt DL et al. N Engl J Med. 2006;354:1706-17.

P = 0.20

P = 0.046

P = 0.22

VBWG

CHARISMA: Safety end points by inclusion criteria

Event rate (%)

Clopidogrel + ASA

Placebo + ASA P

Symptomatic

Severe bleeding

Moderate bleeding

1.6

2.1

1.4

1.3

0.39

<0.001

Asymptomatic

Severe bleeding

Moderate bleeding

2.0

2.2

1.2

1.4

0.07

0.08

Bhatt DL et al. N Engl J Med. 2006;354:1706-17.

GUSTO criteria

VBWG

CHARISMA: Summary

• Primary efficacy end point7% decrease in MI, stroke, CV death (nonsignificant)

• Principal secondary efficacy end point8% decrease in MI, stroke, CV death, hospitalization for UA, TIA, revascularization (significant)

• Primary safety end pointSevere bleeding was not significantly increased but a trend was noted

Bhatt DL et al. N Engl J Med. 2006;354:1706-17.

VBWG

CHARISMA: Summary, cont’d

• Symptomatic patients experienced a 12% reduction in the primary end point (significant) with no significant increase in severe bleeding

• Asymptomatic patients experienced a 20% increase in the primary end point (nonsignificant) with no significant increase in severe bleeding

• Overall, clopidogrel plus aspirin was not significantly more effective than aspirin alone in reducing the primary end point

Bhatt DL et al. N Engl J Med. 2006;354:1706-17.