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

 -  Atherothrombosis is a progressive and generalized vascular disease resulting in events
 leading to myocardial infarction (heart attack), stroke, and vascular death.

 -  In patients at risk for this disease, it is characterized by an unpredictable, sudden
 disruption of atherosclerotic plaques, which may lead to total occlusion of artery due
 to formation of a clot. The use of aspirin (blood thinner agent) for reducing those
 major ischemic events is either indicated, or recommended by international guidelines.
 However, aspirin fails to prevent a high percentage of such life-threatening events.
 Therefore, more effective blood thinning therapy may provide additional clinical benefit
 to such patients.

 -  The results of the CURE trial in patients with unstable angina demonstrate the
 additional benefit of long-term treatment (up to one year) with clopidogrel, (a blood
 thinner agent), when administered in combination with standard therapy including
 aspirin. The purpose of CHARISMA is to investigate whether a similar clinical benefit of
 clopidogrel may apply to a broad population of high-risk patients receiving low-dose
 aspirin therapy. Such population includes patients with previous cardiovascular,
 neurovascular or peripheral arterial manifestations of atherothrombosis and patients
 with combinations of recognized risk factors for atherosclerosis.

 OBJECTIVES:

 -  To assess the efficacy of clopidogrel 75 mg once-daily by comparison with a placebo, in
 preventing cardiovascular morbidity/mortality. The study will compare the efficacy of
 the two regimens in preventing the occurrence of major cardiovascular complications
 (stroke, heart attack, cardiovascular death) in high-risk patients who are otherwise
 receiving low-dose aspirin therapy (75-162 mg daily).

 -  To evaluate the safety of clopidogrel in this population, and more specifically the
 incidence of fatal or severe bleeding (as per GUSTO definition), in order to estimate
 the global benefit of clopidogrel in this patient population.
TREATMENTS:

 -  Clopidogrel (Plavix® and/or Iscover®) is an agent inhibiting platelet aggregation
 involved in clot formation. Each tablet contains 75mg of clopidogrel. A matching placebo
 of clopidogrel is an inactive substance that looks similar to the active clopidogrel
 tablet.

 TREATMENT PLAN:

 -  There will be two treatment groups; one will receive clopidogrel 75 mg (1 tablet qd),
 the second matching placebo of clopidogrel (1 tablet qd). These study drugs will be
 administered on top of low-dose aspirin (75-162 mg qd) systematically prescribed to such
 patients. In addition, patients enrolled in CHARISMA will be managed as appropriate for
 their risk factors for atherosclerosis: eg. high blood pressure, high cholesterol,
 diabetes…etc.

 PRIMARY ENDPOINT:

 -  Combined endpoint of cardiovascular mortality, stroke, acute myocardial infarction.

 STUDY EXECUTION:

 -  Some 7,600 patients per group will be recruited within two years. Patients will be
 observed over a maximum of 3.5 years.

 STUDY TERRITORY:

 -  Approximately 900 sites throughout North/South America, Europe, Asia, Australia, and
 South Africa.
INCLUSION:

 Be at least 45 years old and comply with at least one of the four categories of inclusion
 criteria:

 -  Combination of atherothrombotic risk factors (2 major or 3 minor or 1 major + 2 minor
 risk factors among those listed below)

 Major atherothrombotic risk factors

 -  Type I or II diabetes (under drug therapy)

 -  Diabetic nephropathy

 -  Ankle brachial index (ABI) < 0.9

 -  Asymptomatic carotid stenosis >= 70%

 -  At least one carotid plaque as evidenced by intima-media thickness (IMT)

 Minor atherothrombotic risk factors

 -  Systolic blood pressure (SBP) >= 150 mmHg, despite appropriate therapy for at least 3
 months

 -  Primary hypercholesterolemia

 -  Current smoking > 15 cigarettes per day

 -  Male >= 65 years

 -  Female >= 70 years

 and/or

 -  Documented cerebrovascular disease (TIA or IS within 5 years) and/or

 -  Documented coronary artery disease (stable angina with documented multivessel coronary
 disease, previous documented MI, multivessel PCI or CABG within 1 year, multivessel
 CABG older than 1 year associated with current angina) and/or

 -  Documented symptomatic PAD

 EXCLUSION:

 -  Absolute indication for the use of clopidogrel, high-dose aspirin (>162 mg), NSAIDs,
 or oral anti-thrombotic drugs

 -  Absolute contraindication to the use of clopidogrel or aspirin

 -  Clinical conditions likely to interfere with follow-up leading to inability to
 complete the trial