Transcript Disclosure

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.
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
Study Organization
Investigators
National
Coordinators
Data Safety
Monitoring Board
Sponsors
C5
Clinical Event
Adjudication
Committee
Operations
Committee
Executive
Committee
C5=The Cleveland Clinic Cardiovascular Coordinating Center
Bhatt DL et al. Am Heart J 2004; 148: 263–268.
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
• Steven R Steinhubl
•
•
•
•
•
•
•
•
•
Bhatt DL et al. Am Heart J 2004; 148: 263–268.
Henry R Black
Patrice Cacoub
J Donald Easton
Steven M Haffner
Graeme J Hankey
Koon-Hou Mak
Gilles Montalescot
P Gabriel Steg
Michael Weber
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
Finland
• Markku Nieminen
France
• P Gabriel Steg
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
Russia
• Viacheslav Mareev
Bhatt DL, Fox K, Hacke W, et al. Am Heart J 2005; 150: 401.
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
• Steven R Steinhubl
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.
CAPRIE: Superior Efficacy of Clopidogrel
versus ASA
Patients with recent ischemic stroke, recent MI or symptomatic PAD
Cumulative event rate* (%)
20
ASA
16
Clopidogrel
12
8
4
0
0
3
6
9
12
15
18
21
24
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.
27
30
33
36
8.7%† RRR
(p=0.043)
CAPRIE: Clopidogrel Reduced the Rate of
Rehospitalization
Patients with recent ischemic stroke, recent MI or symptomatic PAD
ASA
Cumulative event rate* (%)
20
9.1%† RRR
(p=0.018)
Clopidogrel
15
10
5
0
5
10
15
20
25
Months of follow-up
30
*Rehospitalization for ischemia (angina pectoris, TIA, limb
ischemia) or bleeding (gastrointestinal, intracranial or other)
†On-treatment analysis (n=19,099)
Bhatt DL et al. Am Heart J 2000; 140: 6773.
35
CHARISMA Trial Design
Clopidogrel
75 mg/day
(n=7802)
Patients age ≥ 45
years at high risk of
atherothrombotic
events
R
(n=15603)
Low dose ASA 75162 mg/day
Double-blind treatment up to 1040
primary efficacy events*
Low dose ASA 75162 mg/day
Placebo
1 tablet/day
(n=7801)
1-month
visit
3-month
visit
Visits every 6 months
* 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: 263–268.
Final visit
(Fixed study
end date)
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: 263–268.
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)
Bhatt DL et al. Am Heart J 2004; 148: 263–268.
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: 263–268.
1GUSTO Investigators. N Engl J Med 1993; 329: 673–682.
Other Study Endpoints
Principal Secondary Efficacy Endpoint:
• First occurrence of MI (fatal or non-fatal), stroke (fatal or nonfatal), 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: 263–268.
1GUSTO Investigators. N Engl J Med 1993; 329: 673–682.
Overall Population: Baseline Characteristics
Characteristic
Age
Median (range)*
Female
Ethnicity
Caucasian
Hispanic
Asian
Black
Other
Inclusion group
Documented cardiovascular disease
Multiple risk factors
Neither criterion
Smoking Status
Current
Former
Clopidogrel + ASA
(n=7802)
Placebo + ASA
(n=7801)
64.0 (39-95)
29.7
64.0 (4593)
29.8
80.4
9.9
5.0
3.2
1.5
79.9
10.7
5.0
3.0
1.4
77.7
21.3
1.0
78.1
20.8
1.1
20.1
48.8
20.3
48.7
*Data for age are in years, all other data expressed as percent
Bhatt DL, Fox KA, Hacke W, et al. NEJM 2006.
Overall Population: Concomitant Medications*
Medication
ASA
Open-label clopidogrel
Diuretics
Nitrates
Calcium antagonists
Beta blockers
Angiotensin II receptor blockers
ACE inhibitors
Other antihypertensives
Statins
Antidiabetic medications
Clopidogrel + ASA (%)
Placebo + ASA (%)
(n=7802)
(n=7801)
99.7
9.9
48.2
23.2
36.7
55.0
25.5
60.1
12.4
76.8
41.8
99.7
10.4
47.1
24.1
36.9
55.7
25.9
60.7
12.4
76.9
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.
Overall Population: Primary Efficacy Outcome
(MI, Stroke, or CV Death)†
Placebo + ASA*
7.3%
Cumulative event rate (%)
8
Clopidogrel + ASA*
6.8%
6
4
RRR: 7.1% [95% CI: -4.5%, 17.5%]
p=0.22
2
0
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. NEJM 2006.
Cumulative event rate (%)
Overall Population: Principal Secondary Efficacy
Outcome (MI/Stroke/CV Death/Hospitalization)†
20
Placebo + ASA*
17.9%
15
Clopidogrel + ASA*
16.7%
10
RRR: 7.7% [95% CI: 0.5%, 14.4%]
p = 0.04
5
0
0
†First
6
12
18
24
Months since randomization§
30
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.
Overall Population: Primary and Secondary
Efficacy Results (MI/Stroke/CV Death/ Hospitalization)†
Clopidogrel
+ ASA
(n=7802)
Placebo
+ ASA
(n=7801)
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
1301 (16.7)
1395 (17.9)
0.92 (0.86, 0.995)
0.04
866 (11.1)
957 (12.3)
0.90 (0.82, 0.98)
0.02
Endpoint* - N (%)
Principal Secondary Endpoint†
Hospitalization‡
†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.
Overall Population: Safety Results
Safety Outcome* - N (%)
Clopidogrel
+ ASA
(n=7802)
Placebo
+ ASA
(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)
1.53 (0.83, 2.82)
0.17
Primary ICH
26 (0.3)
27 (0.3)
0.96 (0.56, 1.65)
0.89
164 (2.1)
101 (1.3)
1.62 (1.27, 2.08) <0.001
GUSTO Moderate Bleeding
*Adjudicated outcomes by intention to treat analysis
ICH= Intracranial Hemorrhage
Bhatt DL, Fox KA, Hacke W, et al. NEJM 2006.
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
(n=12,153)
Multiple Risk Factors *
1.20 (0.91, 1.59)
0.20
0.93 (0.83, 1.05)
0.22
(n=3,284)
Overall Population†
(n=15,603)
0.4
0.6 0.8
Clopidogrel + ASA
Better
1.2
1.4 1.6
Placebo + ASA
Better
* A statistical test for interaction showed marginally significant heterogeneity (p=0.045) in treatment response for these prespecified 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
Primary Efficacy Results (MI/Stroke/CV
Death) by Category of Inclusion Criteria
Population
N
Qualifying CV Disease
RR (95% CI)
p value
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
0.4 0.6 0.8
Clopidogrel + ASA
Better
Bhatt DL. Presented at ACC 2006.
1.2 1.4 1.6
Placebo + ASA
Better
Multiple Risk Factor Population: Primary and Secondary
Efficacy Results (MI/Stroke/CV Death/ Hospitalization)†
Clopidogrel
+ ASA
(n=1659)
Placebo
+ ASA
(n=1625)
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
Hospitalization‡
140 (8.4)
147 (9.0)
0.93 (0.74, 1.18)
0.55
Endpoint* – N (%)
†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.
Multiple Risk Factor Population: Safety
Results
Safety Outcome* - N (%)
GUSTO Severe Bleeding
Clopidogrel Placebo
+ ASA
+ ASA
(n=1659) (n=1625)
RR (95% CI)
p value
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
36 (2.2)
22 (1.4)
1.60 (0.95, 2.71)
0.08
GUSTO Moderate Bleeding
*Adjudicated outcomes by Intention to treat analysis
Bhatt DL, Fox KA, Hacke W, et al. NEJM 2006.
Patients with Qualifying CV Disease (CAD,
CVD, PAD): Safety Results
Safety Outcome* - N (%)
GUSTO Severe Bleeding
Clopidogrel Placebo
+ ASA
+ ASA
(n=6062) (n=6091)
RR (95% CI)
p value
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
128 (2.1)
79 (1.3)
1.63 (1.23, 2.15) <0.001
GUSTO Moderate Bleeding
*Adjudicated outcomes by intention to treat analysis
Bhatt DL, Fox KA, Hacke W, et al. NEJM 2006.
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
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
THANK YOU!!!
To all the CHARISMA Investigators and
CHARISMA Patients
Backup Slides
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 nonacute/stable patients should receive long-term dual antiplatelet therapy
Primary Endpoint (MI/Stroke/CV Death) in
Patients with Previous MI, IS, or PAD*
“CAPRIE-like Cohort”
Primary outcome event rate (%)
10
N=9,478
Placebo + ASA
8.8%
8
Clopidogrel + ASA
7.3%
6
4
RRR: 17.1 % [95% CI: 4.4%, 28.1%]
p=0.01
2
0
0
6
12
18
24
Months since randomization
* Post hoc analysis
Bhatt DL. Presented at ACC 2006.
30