Trial designClopidogrel added to aspirin versus aspirin alone in secondary prevention and high-risk primary prevention: Rationale and design of the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial☆
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Study design
A total of 15,603 patients 45 years of age or older with atherothrombosis have been randomly assigned to one of two treatments, either clopidogrel or placebo, on top of standard of care, including low-dose aspirin (Figure 1). The exact dose of aspirin is left to the discretion of the individual treating physician, though the range is restricted to 75 to 162 mg of aspirin daily.22, 23 Patients will be followed until a fixed study end date, allowing at least 1040 primary efficacy end points. The
End points
The primary efficacy end point is the first occurrence of cardiovascular death (including hemorrhagic death), MI, or stroke (of any cause). MI will follow the American College of Cardiology (ACC) definition.24 Stroke will be diagnosed if there is the acute onset of focal neurologic symptoms or signs lasting 24 hours or longer that are considered to be of vascular origin. A nonvascular cause must have been excluded by computed tomography or magnetic resonance imaging. The primary safety end
Inclusion criteria
The inclusion criteria for CHARISMA are meant to enable enrollment of a representative sample of patients that cardiologists, neurologists, internists, and vascular medicine specialists see every day, both in the hospital and outpatient settings. There are four broad categories of inclusion criteria: high-risk asymptomatic patients, or symptomatic patients with established coronary artery disease, cerebrovascular disease, or peripheral arterial disease. The inclusion criteria for the high-risk
Exclusion criteria
The major exclusion criteria include chronic oral antithrombotic medications likely to interfere with efficacy assessment by decreasing trial sensitivity and to increase the risk of bleeding. Chronic medications, such as warfarin, high-dose aspirin, or nonsteroidal anti-inflammatory drugs, are exclusion criteria. Concomitant use of cyclooxygenase-2 inhibitors is not prohibited. If the patient requires prolonged clopidogrel therapy according to the investigator's judgment, such as patients who
Sample size
A total of 15,200 patients (7600 per group) is the minimum required to detect a 20% relative risk reduction (RRR) in the risk of a primary outcome with 90% power, assuming a yearly event rate of 3.1% in the control group and 18 to 42 months of follow-up (2-sided test, α = 5%). The assumption of 3.1% for a yearly primary event rate in the control group is derived from the Heart Outcomes Prevention Evaluation (HOPE) trial, which displayed a similar event rate in patients receiving ramipril (on
Study organization
CHARISMA is a worldwide trial and has recruited patients from 6 continents, 32 countries, and 768 active sites. The leadership for the trial is provided by an executive committee that is multidisciplinary, comprised of senior clinical investigators from interventional cardiology, preventive cardiology, neurology, endocrinology, vascular medicine, and internal medicine. The sponsor and cosponsor of the trial have only nonvoting input in the executive committee. Auditing at sites is performed by
Timeline
The first patient was enrolled in October 2002. The study population (planned to be at least 15,200 patients) and the follow-up duration will be adapted according to the primary event rate (as this is an event-driven trial), with follow-up visits planned at 1 month, 3 months, 6 months, 12 months, and every 6 months thereafter until common study end date, to be determined when the projected number of 1040 primary efficacy end points is about to be reached.
Inflammation
The concept of arterial inflammation is gaining widespread acceptance in the scientific community.27 In a manner analogous to aspirin, it appears that clopidogrel may have its greatest clinical benefit in patients in the highest quartile of high-sensitivity C-reactive protein (CRP).28, 29 Clopidogrel also appears to have a role in lowering CRP.30 There is also evidence that clopidogrel may lower CD40 expression, a property not shared by aspirin.31, 32
To test these observations prospectively,
Genetics
High-throughput genomic technology should enable the discovery of single nucleotide polymorphisms and haplotypes associated with disease states, such as premature MI, allowing better identification of patients at high risk of atherothrombotic events and ultimately facilitating the discovery of new therapeutics.33, 34, 35
In CHARISMA, DNA samples will be obtained in a large number of patients at baseline. This large DNA bank will allow subsequent determination of candidate genes associated with
Discussion
The CHARISMA trial is global in every sense of the word, with patients and physician-investigators from all around the world. Patients are enrolled if they are at risk for or have any manifestation of atherothrombosis, again representing a global approach to vascular disease. The principal clinical manifestations of atherothrombosis are MI, stroke, critical leg ischemia, and limb amputation, as well as their respective precursors, unstable angina, transient ischemic attack, and peripheral limb
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The Future of Aspirin Therapy in Cardiovascular Disease
2021, American Journal of CardiologySpontaneous Micro-Aggregation of Platelets Predicts Clinical Outcome in Acute Ischemic Stroke
2018, Journal of Stroke and Cerebrovascular DiseasesCitation Excerpt :The prophylactic use of antiplatelet agents, low-dose aspirin, is widely recommended, but aspirin alone is insufficient to prevent thrombosis.14 Clinical results shown by the combination therapy in the MATCH and CHARISMA trials also failed to demonstrate a convincing benefit compared with antiplatelet monotherapy for the secondary prevention of major cardiovascular events.15,16 Cilostazol was shown to attenuate SMAP formation in type 2 diabetic patients.5
A systematic review of the efficacy of aspirin monotherapy versus other antiplatelet therapy regimens in peripheral arterial disease
2018, Journal of Vascular SurgeryCitation Excerpt :The Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial examined the efficacy of using clopidogrel and aspirin DAPT in patients with high risk of atherothrombotic events.46,47 In a subanalysis34 of the CHARISMA trial,46,47 those with PAD had a higher rate of MACEs compared with those without PAD (8.2% vs 6.8%; P = .002). Patients with PAD had higher rates of all-cause death (7.1% vs 4.2%; P < .001), hospitalization for ischemic events (18.3% vs 10.1%; P < .001), and MI (3.0% vs 2.3%; P = .017) than those without PAD.
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