LongTerm Antiplatelet Therapy in HighRisk Patients

1
Long-Term Antiplatelet Therapy in High-Risk
Patients

• Deepak L. Bhatt MD, FACC, FSCAI, FESC
• Cardiac, Peripheral, and Carotid Intervention
• Cleveland Clinic Foundation
  
• Cleveland, OH

2
CAPRIE Study

• A comparative study of clopidogrel vs. aspirin,
  not placebo 19,185 patients
• Combined endpoint ischemic stroke, MI, vascular
  death
• 8.7 relative risk reduction with clopidogrel
  over aspirin (P0.043)

CAPRIE Steering Committee. Lancet 19963481329.
3
CAPRIE Patients With CABG
Outcome vascular death, stroke, MI,
rehospitalization for ischemia or bleeding
50
Aspirin (n705) Clopidogrel (n775)
46.1
40
36.7
30
Cumulative event rate ()
20
Risk reduction29 P0.001
10
0
0
6
12
18
24
30
36
Months
Bhatt et al. Circulation 2001103363.
4
CAPRIE Clopidogrel in Diabetes
38
21
9
Annual event rate ()
Events prevented/1000 patients over aspirin
IS, MI, VD hospitalization for ischemic
events/bleeding overall benefit P.032
multivariate analysis Bhatt et al. Am J Cardiol
200290625.
5
Clopidogrel Provides Amplified Benefit in
Patients With High Vascular Risk
RRR 14.9
P0.045
RRR 8.7
P0.043
Event rate/year ()
All CAPRIE patients (n19,185)
Prior history of major acute event (MI or
stroke n4,496)
ASA
Clopidogrel
MI, ischemic stroke, or vascular death average
follow-up was 2 years Ringleb et al. Stroke
200435528.
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Clopidogrel for High Atherothrombotic Risk and
Ischemic Stabilization, Management, and
Avoidance(CHARISMA)
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Study Objectives

• 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, on 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) including primary ICH, thus
  allowing the global benefit of clopidogrel to be
  estimated in this patient population.

Bhatt et al. Am Heart J 2004140263.
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CHARISMA Study Design
Clopidogrel75 mg daily (n7800)
Patients (n15,603)at high risk of
atherothrombotic events
On a background of standard therapy, including
low-dose ASA 75-162 mg/day
Double-blind treatment up to 1040 primary
efficacy events
R
Placebo 1 tablet daily (n7800)
Visits every 6 months
36-monthor final visit
3-month visit
1-month visit
Cardiovascular death, nonfatal MI, or nonfatal
stroke event-driven trial Rrandomization
Bhatt et al. Am Heart J 2004140263.
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Inclusion Criteria

• Patients aged 45 years with at least 1 of the
  following
• Established cardiovascular disease
• Documented cerebrovascular diseaseand/or
• Documented coronary diseaseand/or
• Documented symptomatic PADand/or
• Multiple risk factors
• 2 major or 1 major, and 2 minor or 3 minor risk
  factors

Bhatt et al. Am Heart J 2004140263.
10
Inclusion CriteriaHistory of Ischemic Events

• 1 or more of the following primary criteria must
  be satisfied
• Cerebrovascular disease
• Previous TIA
• Previous ischemic stroke
• Coronary disease
• Stable angina with documented multivessel
  coronary disease
• History of multivessel percutaneous coronary
  intervention (PCI)
• History of multivessel CABG
• Previous MI
• Symptomatic PAD
• Current intermittent claudication
• A history of intermittent claudication

Bhatt et al. Am Heart J 2004140263.
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Inclusion Criteria Major and Minor
Atherothrombotic Risk Factors
Bhatt et al. Am Heart J 2004140263.
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Study Endpoints

• Primary efficacy endpoint
• The first occurrence of any component of the
  following cluster
• Nonfatal or fatal MI
• Nonfatal or fatal stroke
• Cardiovascular death  
• Primary safety endpoint
• Fatal or severe bleeding (GUSTO definition),
  including primary ICH
• Secondary efficacy endpoint
• First occurrence of cardiovascular death, MI,
  stroke, or hospitalization for UA, TIA, or
  revascularization

Bhatt et al. Am Heart J 2004140263. GUSTO
Investigators. N Engl J Med 1993329673.
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Planned Substudies

• Inflammatory marker substudy
• Genomics substudy
• ABI substudy
• Aspirin resistance substudy
• Pharmacoeconomic analysis
• Antiplatelet therapy impact on stroke severity

Bhatt et al. Am Heart J 2004140263.
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CHARISMA Baseline Data
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Patient Recruitment
A total of 15,603 patients were enrolled
Argentina Australia Austria Belgium Brazil Canada
Chile Czech Republic Denmark Finland France Germa
ny Greece Hong Kong Hungary Italy
Malaysia Mexico The Netherlands
Norway Poland Portugal Russia Singapore South
Africa Spain Sweden Switzerland Taiwan Turkey UK U
S
768 sites in 32 countries on 6 continents
Bhatt et al. Am Heart J 2005150401.
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Geographic Distribution of Patients by Region
The largest number of patients were recruited
in Western Europe (28), the US (27), and Canada
(14)
3
8
US
4
27
Canada
5
Western Europe
Northern/Central Europe
12
Australia
Asia
14
Latin America
South Africa
28
Bhatt et al. Am Heart J 2005150401.
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Demographic Characteristics
Bhatt et al. Am Heart J 2005150401.
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Prior Medication
Percentage of patients on selected medications
within 10 days of study entry Bhatt et al. Am
Heart J 2005150401.
19
80 of Patients Had a History of Documented
Ischemic Events CAD Patients
40
37.4
30
24.7
Incidence ()
20
11.4
10
9.4
5.4
0
Documented CAD
History of multivessel PCI
History of multivessel CABG
Previous MI
Angina with documented multivessel CAD
Bhatt et al. Am Heart J 2005150401.
20
80 of Patients Had a History of Documented
Ischemic Events CerebrovascularDisease Patients
40
30
27.7
20.8
Incidence ()
20
10
7.9
0
Documented cerebrovascular disease
Previous ischemic stroke
Previous TIA
Bhatt et al. Am Heart J 2005150401.
21
80 of Patients Had a History of Documented
Ischemic Events Symptomatic PAD Patients
40
30
Incidence ()
20
18.2
11.4
10.5
10
0
Documented symptomatic PAD
Current intermittent claudication ABI 0.85
History of intermittent claudication
intervention
Bhatt et al. Am Heart J 2005150401.
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20 of Patients Had Multiple Risk Factors
Major Risk Factors
Minor Risk Factors
100
100
80.8
80
80
61.6
60
60
51.6
Incidence ()
42.7
42.7
40
40
16.6
20
20
12.5
7.8
5.7
0
0
Currently smoking gt15 cigarettes/day
Male age 65 years or female age 70 years
Type 1 or 2 diabetes
Presence of at least 1 carotid plaque
ABI lt0.9
Primary hypercholesterolemia
Diabetic nephropathy
Asymptomatic carotid stenosis 70
SBP 150 mm Hg
Bhatt et al. Am Heart J 2005150401.
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Conclusions

• The CAPRIE trial demonstrated that clopidogrel is
  more effective than ASA in the secondary
  prevention of vascular events, particularly in
  high-risk patients.
• The CHARISMA study will evaluate the specific
  value of long-term clopidogrel therapy on a
  background of standard therapy, including
  low-dose ASA, in secondary and primary
  prevention.
• Beyond the question of optimal antiplatelet
  therapy, CHARISMA will enable detailed study of
  patients with CAD, CVD and PAD, as well as those
  with multiple risk factors, in a geographically
  diverse population.