Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance (CHARISMA)

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
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 (p0.043)
ASA
16
Clopidogrel
12
Cumulative event rate ()
8
4
0
0
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 (n19,185)
CAPRIE Steering Committee. Lancet 1996 348
13291339.
4
CAPRIE Clopidogrel Superior to ASA in
Sub-Population with Prior CABG1, 2
RRR 36.3
p0.004
10
RRR 8.7
9.1
p0.043
ASA
8
Clopidogrel
5.8
6
5.8
5.3
Event rate/year ()
4
2
0
All CAPRIE (n19,185)1
Prior CABG (n1480)2
MI, ischemic stroke, vascular death
1. CAPRIE Steering Committee. Lancet 1996 348
13291339. 2. Bhatt DL et al. Circulation 2001
103 363?368.
5
CAPRIE Clopidogrel Provided Amplified Benefit in
Patients with Diabetes1
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
p0.045
12
10.2
RRR 8.7
8.8
10
ASA
p0.043
Clopidogrel
8
5.8
Event rate/year ()
5.3
6
4
2
0
All CAPRIE patients (n19,099)
Prior history of major acute event (MI or
ischemic stroke) (n4496)
MI, ischemic stroke or vascular deathmean
duration of treatment was 1.6 years
1. Ringleb PA et al. Stroke 2004 35 528532.
7
CURE Early and Long-Term Benefits of Clopidogrel
in ACS Patients1
Placebo(n6303)
0.14
20 RRR p lt0.001
0.12
0.10
Clopidogrel (n6259)
0.08
Cumulative hazard rate
0.06
0.04
0.02
0
0
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 494502.
8
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 ()
Clopidogrel
1.9
2.0
1.0
0
101199 mg (n3109)
200 mg (n4110)
100 mg (n5320)
ASA dose (range 75325 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 P0.02
10
8.5
Combined endpoint occurrence ()
5
0
0
3
6
9
12
Months from randomization
Plus ASA and other standard therapies.
Steinhubl S, Berger P, Tift Mann III J et al.
JAMA. 2002Vol 288,No 192411-2420.
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 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
263268. 2. GUSTO Investigators. N Engl J Med
1993 329 673682.
12
CHARISMA Trial Design
Clopidogrel 75 mg/day (n7802)
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
(n15603)
Low dose ASA 75?162 mg/day
Placebo 1 tablet/day (n7801)
Final visit (Fixed study end date)
Visits every 6 months
1-month visit
3-month visit
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
263268.
13
Inclusion Criteria
Patients aged 45 years with at least one of
the following 1) Documented coronary
disease and/or 2) Documented cerebrovascular
disease and/or 3) Documented symptomatic
PAD and/or 4) Two major or one major and two
minor or three minor risk factors With written
informed consent Without exclusion criteria
Bhatt DL, Topol EJ, et al. Am Heart J 2004 148
263268.
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.)

Bhatt DL, Topol EJ, et al. Am Heart J 2004 148
263268.
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 lt0.9
Asymptomatic carotid stenosis ?70
Presence of at least one carotid plaque
Minor risk factors
SBP ?150 mm Hg (despite therapy)
Primary hypercholesterolemia
Currently smoking (gt15 cigarettes per day)
Male aged ?65 years or female aged ?70 years
ABI Ankle Brachial Index
Bhatt DL, Topol EJ, et al. Am Heart J 2004 148
263268.
16
Exclusion Criteria

• Requirement for clopidogrel such as
• recent acute coronary syndrome without ST-segment
  elevation
• investigators assessment clopidogrel required
  long-term
• Need for chronic therapy with high dose (gt 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, Topol EJ, et al. Am Heart J 2004 148
263268.
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)

Bhatt DL, Topol EJ, et al. Am Heart J 2004 148
263268. 1GUSTO Investigators. N Engl J Med 1993
329 673682.
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

Bhatt DL, Topol EJ, et al. Am Heart J 2004 148
263268. 1GUSTO Investigators. N Engl J Med 1993
329 673682.
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

GUSTO Investigators. N Engl J Med 1993 329
673682.
20
Time Since Qualifying Event1
Ischemic event Median duration (months)
MI Stroke TIA PAD 23.3 3.5 2.7 23.3
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
(n7802) (n7801) Age Median (range) 64.0
(39-95) 64.0 (45?93) Female 29.7
29.8 Ethnicity Caucasian 80.4 79.9 Hispanic
10.0 10.7 Asian 5.0 5.0 Black 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 1.1 Smoking Status Current 20.1
20.3 Former 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.
23
Overall Population Prior Medical History
Clopidogrel ASA () Placebo ASA
() Characteristic (n7802) (n7801)
Hypertension 73.3 73.9 Hypercholesterolemia
73.7 74.2 Congestive heart failure 6.0
5.9 Prior MI 34.2 34.9 Atrial fibrillation 3.8
3.7 Prior stroke 24.9 24.3 TIA 12.0
11.9 Diabetes 42.3 41.7 PAD 22.6 22.7 PCI 22.4
23.1 CABG 19.5 19.9 Carotid endarterectomy 5.4
5.2 Peripheral angioplasty or bypass 11.3
11.0 Diabetic nephropathy 12.9 12.9
Bhatt DL, Fox KA, Hacke W, et al. 2006, in press.
24
Overall Population Concomitant Medications
Clopidogrel ASA () Placebo ASA
() Medication (n7802) (n7801)
ASA 99.7 99.7 Open-label clopidogrel 9.9 10.4 Diu
retics 48.2 47.1 Nitrates 23.2 24.1 Calcium
antagonists 36.7 36.9 Beta blockers 55.0 55.7 Angi
otensin 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. 2006, in press.
25
Overall Population Primary Efficacy Outcome (MI,
Stroke, or CV Death)
Placebo ASA 7.3
Clopidogrel ASA 6.8
Cumulative event rate ()
RRR 7.1 95 CI -4.5, 17.5 P0.22
0
6
12
18
24
30
Months since randomization
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 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
Overall Population Principal Secondary Efficacy
Outcome (MI/Stroke/CV Death/Hospitalization)
Placebo ASA 17.9
Clopidogrel ASA 16.7
RRR 7.7 95 CI 0.5, 14.4 p 0.04
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
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 () (n7802) (n7801) 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 Hospita
lization 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
Bhatt DL, Fox KA, Hacke W, et al. 2006, in press.
28
Overall Population Safety Results
Clopidogrel Placebo ASA ASA Safety
Outcome - N () (n7802) (n7801) 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) lt0.001
Adjudicated outcomes by intention to treat
analysis ICH Intracranial Hemorrhage
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 0.88 (0.77, 0.998) 0.046 (n12,153)
Multiple Risk Factors 1.20 (0.91, 1.59) 0.20
(n3,284) Overall Population 0.93 (0.83,
1.05) 0.22 (n15,603)
1.4
1.2
1.6
0.6
0.8
0.4
Clopidogrel Better
Placebo Better
A statistical test for interaction showed
marginally significant heterogeneity (p0.045) 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
All patients received ASA 75-162 mg/day
Bhatt DL. Presented at ACC 2006.
31
Documented CV Disease Population Safety Results
Clopidogrel Placebo ASA ASA Safety
Outcome - N () (n6062) (n6091) 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) lt0.001
Adjudicated outcomes by intention to treat
analysis
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 PADCAPRIE-like Cohort
N9,478
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!!!