CHARISMA slide set

1
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.
2
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
3
Study Organization
Investigators
National Coordinators
Data Safety Monitoring Board
Sponsors
C5
Clinical Event Adjudication Committee
Operations Committee
Executive Committee
C5The Cleveland Clinic Cardiovascular
Coordinating Center
Bhatt DL et al. Am Heart J 2004 148 263268.
4
Executive Committee

• Chairman
• 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

• Henry R Black
• Patrice Cacoub
• J Donald Easton
• Steven M Haffner
• Graeme J Hankey
• Koon-Hou Mak
• Gilles Montalescot
• P Gabriel Steg
• Michael Weber

Bhatt DL et al. Am Heart J 2004 148 263268.
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National Coordinators

• Argentina
• Sebastian F Ameriso
• Fernando A Cura
• Australia
• Phillip Aylward
• Graeme J Hankey
• Belgium
• Benoît J Boland
• Brazil
• Angelo Amato
• Vicenzo De Paola
• Canada
• Eric A Cohen
• André Roussin
• Phillip Teal
• Czech Republic
• Edvard Ehler
• Denmark
• Henrik Sillesen

• Germany and Austria
• Ulrich Hoffmann
• Franz-Josef Neumann
• Greece
• Alexios P Dimas
• Hungary
• Tamàs Forster
• Italy
• Diego Ardissino
• Mexico
• Ricardo Alvarado
• The Netherlands
• Harry Roger Büller
• Norway
• Bent Indredavik
• Poland
• Zbigniew A Gaciong
• Portugal
• Joao Morais

• Spain
• Amadeo Betriu
• Luis M Ruilope
• South Africa
• Anthony J Dalby
• Sweden
• Jan B Östergren
• Switzerland
• Thomas F Luscher
• Turkey
• Hakan Kultursay
• United Kingdom
• Marcus D Flather
• Keith AA Fox
• United States
• William E Boden
• J Donald Easton
• Steven M Haffner
• Thomas A Pearson

Bhatt DL, Fox K, Hacke W, et al. Am Heart J 2005
150 401.
6
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.
7
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.
8
CAPRIE Clopidogrel Reduced the Rate of
Rehospitalization
Patients with recent ischemic stroke, recent MI
or symptomatic PAD
Rehospitalization for ischemia (angina pectoris,
TIA, limb ischemia) or bleeding
(gastrointestinal, intracranial or
other) On-treatment analysis (n19,099)
Bhatt DL et al. Am Heart J 2000 140 67?73.
9
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 et al. Am Heart J 2004 148 263268.
10
Inclusion Criteria
Patients aged 45 years with at least one of
the following 1A) Documented coronary
disease and/or 1B) Documented cerebrovascular
disease and/or 1C) Documented symptomatic
PAD and/or 2) Two major or one major and two
minor or three minor risk factors With written
informed consent Without exclusion criteria
Bhatt DL et al. Am Heart J 2004 148 263268.
11
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 et al. Am Heart J 2004 148 263268.
12
Inclusion Criteria Patients with Multiple Risk
Factors

• 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
Bhatt DL et al. Am Heart J 2004 148 263268.
13
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 ( 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 et al. Am Heart J 2004 148 263268.
14
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
263268. 1GUSTO Investigators. N Engl J Med 1993
329 673682.
15
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
263268. 1GUSTO Investigators. N Engl J Med 1993
329 673682.
16
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.
17
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 9.9 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. NEJM 2006.
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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. NEJM 2006.
19
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 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. NEJM 2006.
20
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
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 to zero and
there are only 38 secondary efficacy events that
occurred beyond this time (23 clopidogrel and 15
placebo)

Bhatt DL, Fox KA, Hacke W, et al. NEJM 2006.
21
Overall Population Primary and Secondary
Efficacy Results (MI/Stroke/CV Death/
Hospitalization)
Clopidogrel Placebo ASA
ASA Endpoint - N () (n7802) (n7801) 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
Bhatt DL, Fox KA, Hacke W, et al. NEJM 2006.
22
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) 1.53 (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) Adjudicated outcomes by intention to treat
analysis ICH Intracranial Hemorrhage
Bhatt DL, Fox KA, Hacke W, et al. NEJM 2006.
23
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 ASA Better
Placebo ASA Better
A statistical test for interaction showed
marginally significant heterogeneity (p0.045) 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
24
Primary Efficacy Results (MI/Stroke/CV Death) by
Category of Inclusion Criteria
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
Bhatt DL. Presented at ACC 2006.
25
Patients with Qualifying CV Disease (CAD, CVD,
PAD) Primary and Secondary Efficacy Results
(MI/Stroke/CV Death/ Hospitalization)
Clopidogrel Placebo ASA
ASA Endpoint - N () (n7802) (n7801) RR
(95 CI) p value Primary Efficacy Endpoint 420
(6.9) 480 (7.9) 0.88 (0.77, 0.998) 0.046 All
Cause Mortality 278 (4.6) 306 (5.0) 0.91 (0.78,
1.07) 0.27 Cardiovascular Mortality? 172
(2.8) 191 (3.1) 0.90 (0.74, 1.11) 0.34
Myocardial Infarction (nonfatal)? 120
(2.0) 127 (2.1) 0.95 (0.74, 1.22) 0.67 Ischemic
Stroke (nonfatal) 114 (1.9) 140 (2.3) 0.82
(0.64, 1.05) 0.11 Stroke (nonfatal)? 128
(2.1) 162 (2.7) 0.79 (0.63, 0.999) 0.048 Principal
Secondary Endpoint 1066 (17.6) 1169
(19.2) 0.91 (0.83, 0.98) 0.02 Hospitalization
720 (11.9) 803 (13.2) 0.89 (0.81, 0.99) 0.03
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
Bhatt DL, Fox KA, Hacke W, et al. NEJM 2006.
26
Patients with Qualifying CV Disease (CAD, CVD or
PAD) Primary Efficacy Outcome (MI/Stroke/CV
Death)
N12,153
Placebo ASA 7.9
Clopidogrel ASA 6.9
RRR 12.5 95 CI 0.2, 23.2 p0.046
All patients received ASA 75-162 mg/day
Bhatt DL. Presented at ACC 2006.
27
Patients with Qualifying CV Disease (CAD, CVD,
PAD) Principal Secondary Efficacy Outcome
Placebo ASA 19.2
N12,153
Clopidogrel ASA 17.6
Cumulative Event Rate, ()
RRR 9.5 95 CI 1.7, 16.7 P0.02
Months from Randomization
All patients received ASA 75-162 mg/day
Bhatt DL. Presented at ACC 2006.
28
Multiple Risk Factor Population Primary and
Secondary Efficacy Results (MI/Stroke/CV Death/
Hospitalization)
Clopidogrel Placebo ASA ASA Endpoint
N () (n1659) (n1625) 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 Hospitali
zation 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
Bhatt DL, Fox KA, Hacke W, et al. NEJM 2006.
29
Multiple Risk Factor Subgroup Primary Efficacy
Outcome (MI/Stroke/CV Death)
Clopidogrel ASA 6.6
Placebo ASA 5.5
RRR -20 95 CI -58.8, 9.3 p0.20
All patients received ASA 75-162 mg/day
Bhatt DL. Presented at ACC 2006.
30
Multiple Risk Factor Population Principal
Secondary Efficacy Endpoint
Clopidogrel ASA 13.5
N3284
Placebo ASA 13.3
Cumulative Event Rate, ()
RRR -1.4 95 CI -22.2, 15.9 P0.88
Months from Randomization
All patients received ASA 75-162 mg/day
Bhatt DL. Presented at ACC 2006.
31
Multiple Risk Factor Population Safety Results
Clopidogrel Placebo ASA ASA Safety
Outcome - N () (n1659) (n1625) RR (95 CI)
p value GUSTO Severe Bleeding 34 (2.0) 20
(1.2) 1.67 (0.96, 2.88) 0.07 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
Bhatt DL, Fox KA, Hacke W, et al. NEJM 2006.
32
Patients with Qualifying CV Disease (CAD, CVD,
PAD) 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) 0.91 (0.49,
1.69) 0.76 GUSTO Moderate Bleeding 128 (2.1) 79
(1.3) 1.63 (1.23, 2.15) Adjudicated outcomes by intention to treat
analysis
Bhatt DL, Fox KA, Hacke W, et al. NEJM 2006.
33
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

34
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

35
THANK YOU!!!To all the CHARISMA Investigators
and CHARISMA Patients
36
Backup Slides
37
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

38
Primary Endpoint (MI/Stroke/CV Death) in Patients
with Previous MI, IS, or PADCAPRIE-like Cohort
N9,478
Post hoc analysis
Bhatt DL. Presented at ACC 2006.