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

Linda Brookes, MSc

Disclosures

July 20, 2006

Editorial Collaboration

Medscape &

Presenter: Deepak L Bhatt, MD (The Cleveland Clinic Foundation, Cleveland, Ohio)

Combination antiplatelet therapy may be useful in patients with established cardiovascular disease, but offers no benefit -- and may even cause harm -- in patients having only risk factors for developing vascular disease, according to the results of the large international CHARISMA trial.[1] In CHARISMA, addition of clopidogrel to standard, low-dose aspirin was not significantly more effective than aspirin alone in reducing the rate of myocardial infarction (MI), stroke, or death from cardiovascular causes in patients with stable cardiovascular disease or multiple cardiovascular risk factors.

Some potential benefit of dual antiplatelet therapy was detected when the patients with established cardiovascular disease were analyzed separately, but increased bleeding and higher mortality rates were revealed when the patients with multiple risk factors alone were analyzed. The CHARISMA investigators conclude that dual antiplatelet therapy should not be used in patients without a history of established vascular disease.

The results of the CHARISMA trial were published simultaneously online in The New England Journal of Medicine.[2]

Background

The CHARISMA trial was set up to investigate whether a clinical benefit of clopidogrel might be achieved in a broad population of high-risk patients receiving low-dose aspirin therapy, including patients with:

  • Previously documented cardiovascular, neurovascular, or peripheral arterial manifestations of atherothrombosis; and

  • Combinations of recognized risk factors for atherosclerosis.[3]

The trial was carried out in 32 countries within Africa, Australasia, Europe, and North and South America.

CHARISMA was largely based on the Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) study, which reported that long-term administration of clopidogrel to patients with atherosclerotic vascular disease was more effective than aspirin in reducing ischemic stroke, MI, infarction, or vascular death (relative risk reduction, 8.7%).[4]

Patients and Methods

Patients enrolled in CHARISMA had to be aged ≥ 45 years and at high risk of atherothrombotic events, defined as:

  • Established cardiovascular disease

    • Documented coronary disease and/or

    • Documented cerebrovascular disease and/or

    • Documented symptomatic peripheral arterial disease (PAD)

    or

  • Multiple atherothrombotic risk factors

    • 2 major risk factors or

    • 1 major and 2 minor risk factors or

    • 3 minor risk factors

Patients with requirements for clopidogrel or chronic therapy with high dose-aspirin or nonsteroidal anti-inflammatory drugs, other than COX-2 inhibitors, were excluded from the study, as were patients already on other oral antithrombotic drugs, potentially long term, and those about to undergo revascularization.

The CHARISMA trial randomized 15,603 patients, average age 64 years, of whom about 30% were female and 80% white. Approximately 78% of the enrolled patients had documented cardiovascular disease and about 20% had multiple risk factors only; the remaining patients (who were included in the intention-to-treat analyses) had neither. Of the patients enrolled with coronary disease, the predominant entry criterion was previous MI (31%); for those with cerebrovascular disease it was previous ischemic stroke (27%); and for the patients enrolled with multiple risk factors the predominant risk factor (80%) was type 1 or 2 diabetes.[5] Almost all patients were on aspirin and the study drug, 10% on open-label clopidogrel; among other medications, 55% were on beta-blockers, 60% on an angiotensin-converting enzyme inhibitor, 26% on an angiotensin receptor blocker, and 77% on a statin.

All patients received low-dose aspirin (75-162 mg/day) and were randomized to additional clopidogrel (75 mg/day) or placebo and then followed for a median of 28 months.

Primary and Secondary Efficacy Endpoints

At the end of follow-up, there was no significant difference in the study's primary efficacy endpoint, first occurrence of either fatal or nonfatal MI, fatal or nonfatal stroke from any cause, or cardiovascular death (including hemorrhagic death), between the 2 treatment groups (7.3% in the placebo plus aspirin group vs 6.8% in the clopidogrel plus aspirin group; P =.22) (Table 1). However, the principal secondary endpoint of the study, a composite of the primary endpoint plus hospitalization for unstable angina, transient ischemic attack, or a revascularization procedure, was significantly lowered by 7.7% in the clopidogrel plus aspirin group.

Table 1. Primary and Secondary Efficacy Endpoints
Endpoint (%) Clopidogrel
+ Aspirin
Placebo
+ Aspirin
RR 95% CI P
Primary efficacy endpoint 6.8 7.3 0.93 0.83-1.05 .22
Principal secondary endpoint 16.7 17.9 0.92 0.86-0.995 .04
CI = confidence interval; RR = relative risk

No statistically significant differences were seen in the individual components of the primary and secondary endpoints, except for all-cause stroke and hospitalization (Table 2).

Table 2. Individual Endpoints
Endpoint (%) Clopidogrel
+ Aspirin
Placebo
+ Aspirin
RR 95% CI P
All-cause death 4.8 4.8 0.99 0.86-1.14 .90
Cardiovascular death 3.1 2.9 1.04 0.87-1.25 .68
Myocardial infarction 1.9 2.0 0.92 0.74-1.16 .48
Ischemic stroke 1.7 2.1 0.82 0.66-1.04 .10
Stroke 1.9 2.4 0.80 0.65-0.997 .05
Hospitalization 11.1 12.3 0.90 0.82-0.98 .02
CI = confidence interval; RR = relative risk
Safety Endpoints

The clopidogrel plus aspirin group showed a trend toward more severe bleeding (GUSTO [Global Utilization of Strategies To Open Occluded Arteries] definition: fatal bleeding or intracranial hemorrhage, or bleeding resulting in hemodynamic compromise requiring treatment),[6] but a significant increase in moderate bleeding (GUSTO definition: the need for transfusion, not meeting criteria for severe bleeding) (Table 3).

Table 3. Safety Endpoints
Endpoint (%) Clopidogrel
+ Aspirin
Placebo
+ Aspirin
RR 95% CI P
GUSTO severe bleeding 1.7 1.3 1.26 0.97-1.61 .09
Fatal bleeding 0.3 0.2 1.53 0.83-2.82 .17
Primary intracranial hemorrhage 0.3 0.3 0.96 0.56-1.65 .89
GUSTO moderate bleeding 2.1 1.3 1.62 1.27-2.10 <.001
CI = confidence interval; GUSTO = Global Utilization of Strategies To Open Occluded Arteries; RR = relative risk
Subgroup Analyses

Prespecified analysis by study entry criteria revealed divergent results in the patients who entered the study with cardiovascular disease vs those who entered with multiple risk factors. Analysis limited to the 12,153 patients with established cardiovascular disease showed a significant 12.5% relative reduction in the risk of primary events, from 7.9% in the placebo plus aspirin group to 6.9% in the clopidogrel plus aspirin group (RR 0.88, 95% CI 0.77-0.998; P =.046). Analysis by inclusion of criteria for cardiovascular disease showed no significant differences between the 2 treatments in patients with coronary disease, PAD, or cerebrovascular disease.

In the 3284 patients with multiple risk factors only, there was a slight trend in favor of placebo plus aspirin, and analysis of individual endpoints in these patients showed significantly higher rates of cardiovascular death and all-cause death in the patients on clopidogrel plus aspirin. GUSTO severe and moderate bleeding rates were both increased in the clopidogrel plus aspirin group compared with aspirin plus placebo in this population (2.0% vs 1.2% and 2.2% vs 1.4%, respectively); there were no increases in fatal or primary intracranial hemorrhage. This contrasted with the cardiovascular disease population, which showed no increase in severe bleeding, but a significant increase in moderate bleeding in the clopidogrel plus aspirin group (2.1% vs 1.3%, P <.001)

Interpretation

In answer to the "million-dollar question" -- ie, what are the clinical implications of CHARISMA? -- Dr. Bhatt stressed that although prespecified, the results of the subgroup analyses should be interpreted with caution. Since the primary endpoint was negative, any kind of subgroup comparison can only be hypothesis generating. However, he and his fellow investigators believe that such a large study must carry a message, and it is in the primary prevention cohort. "We have established a basement, that is, an area below which dual antiplatelet therapy is not efficacious and may just carry bleeding hazards," he said. "Don't use dual antiplatelet therapy for primary prevention, even though it may have seemed logical to do so in certain patients," he said.

Dr. Bhatt and colleagues believe that there may be a gradient from highest-risk patients, such as those who present with an acute MI in the emergency room and where mortality benefit has been shown for dual antiplatelet therapy, down to primary prevention, where it is not efficacious. The CHARISMA data will allow practicing physicians to make more informed decisions, but they need to be individualized decisions, Dr. Bhatt said. "We cannot make recommendations based on subgroup analyses. Physicians must weigh each individual patient's ischemic and bleeding risks, and then view the totality of data and reach a conclusion."

In a commentary accompanying publication of the CHARISMA results in The New England Journal of Medicine,[7] Marc A. Pfeffer, MD, PhD (Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts), and John A. Jarcho, MD, a deputy editor of The New England Journal of Medicine (Boston), criticize some of the statistical analyses carried out by the CHARISMA investigators. Although they found "the overall point estimate and 95 percent confidence limits for the entire population convincing," they suggest that, "for investigators, the massive effort of a major international clinical trial seems to warrant more than one hypothesis-testing P value."

They note that, "Unfortunately, this exploration of the data, generally termed subgroup analysis, is notoriously fraught with multiple hazards, especially the play of chance and uncontrollable confounders." And they further assert that "numerous" hypotheses generated by randomized trials that reported an apparently important differential response to therapy revealed by subgroup analysis have been subsequently refuted in studies specifically testing those hypotheses.

Drs. Pfeffer and Jarcho reiterate that the CHARISMA data show "no significant benefit associated with long-term clopidogrel therapy in addition to aspirin. More homogeneous genotypic and phenotypic (pathophysiological) characterization of patients will be required before clinical trials can be 'personalized.' " "Until then, the charisma of extracting favorable P values from subgroups should be resisted and dual antiplatelet therapy avoided in these patients with stable disease," they conclude.

Cardiology Organizations React

Following the release of the CHARISMA results, major cardiology societies in the United States and Europe issued statements urging patients currently taking clopidogrel, aspirin, or both drugs not to make their own decisions to stop their medications, but to talk with their physicians about any concerns raised by the new data.

The American College of Cardiology (ACC) itself issued a public health alert warning that media reports of the CHARISMA data could be misinterpreted by patients with coronary stents and other conditions, causing them to inappropriately stop taking clopidogrel.[8] The ACC statement stressed that the CHARISMA trial does not invalidate use of clopidogrel for approved indications, such as stenting, and noted that other patients may be given clopidogrel after hospitalization for MI or stroke.

A spokesperson for the American Heart Association/American Stroke Association, Ralph L. Sacco, MS, MD (Columbia University College of Physicians and Surgeons, New York, NY), said that the CHARISMA trial "does not support the addition of clopidogrel to aspirin therapy in patients with stable cardiovascular disease or, in the case of prevention, those at high risk for cardiovascular disease."[9] He added, "It is important to remember, however, that previous trials have documented the benefits of combined treatment with clopidogrel and aspirin for other groups of patients -- those with heart attack or unstable angina (also called unstable coronary syndromes) and those who have had coronary angioplasty with stent placement."

The European Society of Cardiology (ESC) seeks to remind patients that "While the CHARISMA trial results have shown no benefit overall of the combination of Clopidogrel and aspirin in the long term in stable vascular patients, and some indication of harm in patients in primary prevention... dual antiplatelet therapy is an essential, approved and recommended therapy for one year in patients post ACS without ST-segment elevation, and for at least 6 months post stenting."[10] Prof. Freek WA Verheugt, MD (Radboud University Medical Center, Nijmegen, The Netherlands), ESC spokesperson on acute coronary syndromes (ACS), warned that "Patients who stop taking clopidogrel without seeking the advice of their doctor may be putting themselves in grave danger."

Although clopidogrel plus aspirin is recommended over aspirin for ACS, with most guidelines advocating for up to 12 months of treatment, the results of recent studies such as Management of ATherothrombosis with Clopidogrel in High-Risk Patients with Recent Transient Ischemic Attack or Ischemic Stroke (MATCH)[11] have not suggested a similar risk/benefit ratio for stroke and transient ischemic attack survivors.[12]

References
  1. Bhatt DL, Topol EJ, for the CHARISMA Study Group. The Main Results of the CHARISMA trial. Program and abstracts from the American College of Cardiology 55th Annual Scientific Session. Late Breaking Clinical Trials I. Abstract 402-10.

  2. Bhatt DL, Fox KAA, Hacke W, et al; for the CHARISMA Investigators. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med. 2006;354. [Published online before print March 12, 2006]

  3. Bhatt DL, Topol EJ; Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance Executive Committee. 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. Am Heart J. 2004;148:263-268. Abstract

  4. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet. 1996;348:1329-1339. Abstract

  5. Bhatt DL, Fox KA, Hacke W, et al. CHARISMA Investigators. A global view of atherothrombosis: baseline characteristics in the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial. Am Heart J. 2005;150:401.

  6. The GUSTO investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med. 1993;329:673-682. Abstract

  7. Pfeffer MA, Jarcho JA. The charisma of subgroups and the subgroups of CHARISMA. N Engl J Med 2006;354. [Published online before print March 12, 2006]

  8. American College of Cardiology. Dangers of stopping clopidogrel (Plavix®) for patients with stents and certain other conditions. A public health alert from the American College of Cardiology. Issued March 16, 2005, Available online at www.acc.org.

  9. American Heart Association. American Heart Association Statement: Patient Guidance Based on Results of the CHARISMA Trial. Issued march 15, 2006. Available online at www.americanheart.org.

  10. ESC statement on the CHARISMA Trial on Clopidogrel (Plavix®): Patients should continue treatment as advised by their physicians. Issued March 17, 2006. Available online at www.escardio.org.

  11. Diener HC, Bogousslavsky J, Brass LM, et al; MATCH investigators. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet. 2004;364:331-337. Abstract

  12. Furie K, Goldstein LB, Gorelick P, et al. Guidelines for prevention of stroke in patients with ischemic stroke or transient ischemic attack : a statement for healthcare professionals from the American Heart Association/American Stroke Association Council On Stroke. Stroke. 2006;37;577-617. Abstract

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