ATLANTA — The world's major cardiology organizations have had to scramble to issue public health alerts warning patients who take clopidogrel not to stop taking it on their own in response to confusing media reports on the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance trial.

CHARISMA was an ambitious 15,063-patient randomized trial aimed at expanding the indications for dual antiplatelet therapy with clopidogrel (Plavix) and low-dose aspirin. It was, overall, a negative study—and therein lay the misunderstanding, as many lay media reports failed to note that the existing applications for such therapy remain fully intact.

Situations in which clopidogrel plus aspirin is of proven benefit over aspirin alone include those in patients with ST-elevation MI, in whom it reduced mortality in clinical trials; in patients with acute coronary syndromes, in whom it decreased the composite of death, MI, or stroke; and in recently stented patients.

In the days following initial presentation of CHARISMA at the annual meeting of the American College of Cardiology in Atlanta, the ACC, the American Heart Association, and the European Society of Cardiology each issued public alerts. The impetus was feedback from member physicians who reported fielding queries from panicky patients, although prominent cardiologists contacted by this news organization indicated they were receiving few such calls.

In presenting the CHARISMA results at the ACC meeting, principal investigator Dr. Deepak L. Bhatt characterized the study as “a complex trial with somewhat unanticipated findings.”

The study comprised two distinct groups: roughly 12,000 enrollees with documented baseline stable coronary, cerebrovascular, and/or symptomatic peripheral arterial disease; and the remainder (the primary prevention cohort) who had multiple cardiovascular risk factors.

The primary efficacy end point—MI, stroke, or cardiovascular death—occurred in 7.3% of the dual antiplatelet therapy group and in 6.8% on aspirin alone during 28 months of follow-up, a nonsignificant difference.

The primary safety end point—the rate of severe bleeding—was also similar at 1.7% with dual therapy and 1.3% with aspirin, noted Dr. Bhatt of the Cleveland Clinic Foundation.

The prespecified subgroup analysis showed dichotomous results in the primary and secondary prevention subgroups. Among the 12,000 patients with documented atherothrombotic disease at baseline, the primary efficacy end point occurred in 6.9% on dual therapy and in 7.9% on aspirin, resulting in what Dr. Bhatt termed a “modest” but statistically significant 12.5% relative risk reduction favoring dual antiplatelet therapy, with no increase in serious bleeding.

In sharp contrast, there was a suggestion of harm with dual therapy in the primary prevention group. They had significant increases in both cardiovascular mortality (3.9% versus 2.2%) and bleeding.

One biologically plausible hypothesis for the disparate results is that patients in the secondary prevention category have hyperactive platelets, which mitigate the bleeding risk; the addition of clopidogrel to aspirin in such patients restores their platelets to a steady state, affording partial protection against atherothrombotic events.

In contrast, further reduction of platelet activity in asymptomatic patients without baseline platelet activation would expose them to increased risk of bleeding complications, the cardiologist speculated.

Discussant Dr. Matthew R. Wolff, chief of cardiovascular medicine at the University of Wisconsin, Madison, said, “I think the investigators and sponsors went for a home run and maybe got a broken-bat single.”

Dr. Bhatt said, “We like to think of it as a solid double,” adding that there will be much clinically useful data to come from planned future CHARISMA subanalyses.

In his own clinical practice, the cardiologist continued, he'll use the initial CHARISMA findings to better individualize secondary preventive therapy.

“If I had a patient in front of me who'd had multiple heart attacks in the past while taking aspirin but was tolerating aspirin well in terms of not having any bleeding problems, I would now consider adding clopidogrel. On the other hand, if I had a patient with an MI in the past but who has been rock-stable since, and last month while on aspirin had a bleeding ulcer, I don't think I'd add clopidogrel,” he explained.

Dr. Prakash Deedwania said in an interview that he won't change anything about how he uses clopidogrel, based on CHARISMA.

“I wasn't at all surprised at the results. There was no rationale to think that patients with no prior CAD events should benefit, as there is no evidence that clopidogrel should work when plaque is not disrupted,” said Dr. Deedwania of the University of California, San Francisco, and chief of cardiology at the Veterans Affairs Central California Health Care System, Fresno.

CHARISMA was funded by Sanofi Aventis and Bristol-Myers Squibb Co.

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In patients with atherothrombotic disease, a 12.5% relative risk reduction favored dual antiplatelet therapy. DR. BHATT

Initial CHARISMA Results Create Antiplatelet Anxiety