Elsevier

American Heart Journal

Volume 148, Issue 2, August 2004, Pages 263-268
American Heart Journal

Trial design
Clopidogrel 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

https://doi.org/10.1016/j.ahj.2004.03.028Get rights and content

Abstract

Background

Clopidogrel is a more potent antiplatelet agent than aspirin, resulting in greater clinical efficacy in patients with atherothrombotic disease. Furthermore, the combination of clopidogrel plus aspirin has been demonstrated to be superior to aspirin alone in the treatment of patients with acute coronary syndromes and after coronary stenting. Whether dual antiplatelet therapy is superior to aspirin monotherapy for high-risk primary prevention and secondary prevention is unknown.

Methods and results

The Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) study was designed to evaluate the efficacy and safety of clopidogrel plus aspirin versus placebo plus aspirin in patients with established coronary, cerebral, or peripheral arterial disease or in patients with multiple risk factors for atherothrombosis who have not yet sustained an ischemic event. This randomized, international, multicenter, double-blinded, placebo-controlled study has finished enrolling patients worldwide. A total of 15,603 patients will be followed long term. The primary end point will be the composite of vascular death, myocardial infarction, or stroke. Rates of severe bleeding will also be compared between the two arms of the study.

Conclusions

This large-scale trial of patients at high risk for atherothrombotic events will allow determination of the value of a strategy of adding clopidogrel to the current standard of care, including low-dose aspirin, for a wide spectrum of patients with atherothrombosis.

Section snippets

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

References (45)

  • S. Yusuf et al.

    Global burden of cardiovascular diseases, IIvariations in cardiovascular disease by specific ethnic groups and geographic regions and prevention strategies

    Circulation

    (2001)
  • S.C. Smith et al.

    AHA Conference Proceedings. Prevention conference Vbeyond secondary prevention: identifying the high-risk patient for primary prevention: executive summary. American Heart Association

    Circulation

    (2000)
  • S.M. Haffner et al.

    Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction

    N Engl J Med

    (1998)
  • Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction...
  • P.S. Sanmuganathan et al.

    Aspirin for primary prevention of coronary heart diseasesafety and absolute benefit related to coronary risk derived from meta-analysis of randomised trials

    Heart

    (2001)
  • Aspirin for the primary prevention of cardiovascular events: recommendation and rationale. Ann Intern Med 2002...
  • M. Hayden et al.

    Aspirin for the primary prevention of cardiovascular eventsa summary of the evidence for the US Preventive Services Task Force

    Ann Intern Med

    (2002)
  • F.M. Sacks et al.

    The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levelsCholesterol and Recurrent Events Trial Investigators

    N Engl J Med

    (1996)
  • J.C. LaRosa et al.

    Effect of statins on risk of coronary diseasea meta-analysis of randomized controlled trials

    JAMA

    (1999)
  • S. Yusuf et al.

    Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patientsthe Heart Outcomes Prevention Evaluation Study Investigators

    N Engl J Med

    (2000)
  • A.W. Chan et al.

    Early and sustained survival benefit associated with statin therapy at the time of percutaneous coronary intervention

    Circulation

    (2002)
  • A.W. Chan et al.

    Relation of inflammation and benefit of statins after percutaneous coronary interventions

    Circulation

    (2003)
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    Supported by Sanofi-Synthelabo and Bristol-Myers Squibb.

    *

    See Appendix for a complete list of the CHARISMA Executive Committee.

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