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Dr Deepak Bhatt
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Adding clopidogrel (Plavix, Sanofi Aventis) to long-term aspirin therapy in patients with established vascular disease or multiple risk factors was of no benefit in the study, the investigators reported.
As well as showing no added efficacy, the addition of clopidogrel to aspirin increased the risk of moderate to severe bleeding in the trial participants and appeared to be harmful in a subgroup of patients—the primary-prevention, or "asymptomatic," group. "Our findings do not support the use of dual antiplatelet therapy across the broad population tested," Bhatt and colleagues concluded in their paper.
But in the ACC press conference and late-breaking session, Bhatt made somewhat of a U-turn, arguing that there were certain stable patients who could benefit from long-term clopidogrel therapy. Others, however, disagreed.
Don't throw the baby out with the bathwater
Bhatt said the findings of CHARISMA were a logical follow-on to those of the CURE results, which showed a benefit of adding clopidogrel to aspirin in ACS patients.
In CHARISMA, the rate of the primary end point—a composite of MI, stroke, or death from cardiovascular causes—among the subgroup of patients with established vascular disease (secondary prevention) was 6.9% with clopidogrel and 7.9% with placebo (p=0.046).
"CURE found a 2% absolute risk reduction in the same primary end point. In CHARISMA, we saw around a 1% absolute risk reduction in this subgroup. This represents a much more modest degree of benefit than was seen in acute patients in CURE," Bhatt pointed out.
The primary end point was negative. I don't think it's even fair to look at secondary end points.
Moderator of the press conference, Dr Matthew Wolff (University of Wisconsin, Madison), said: "Many doctors have extrapolated from CURE to use clopidogrel in high-risk patients, so it is interesting to see these new results."
Bhatt added that further analyses of CHARISMA will attempt to tease out which patients in particular benefited from adding clopidogrel to aspirin. But in the meantime, he said it was up to doctors to make decisions about clopidogrel therapy in this group of patients, based on a person's individual characteristics and future risk of events.
"The data are what they are, and there's an important message for physicians. We need to weigh the ischemic risk against the risk of bleeding," Bhatt said. "If I had a patient who had had multiple MIs in the past despite taking aspirin, I would consider adding clopidogrel. But if a patient were stable and had a bleeding ulcer, I would avoid clopidogrel."
"We had 12 000 patients in the secondary-prevention subgroup, and there was a suggestion of a benefit. It would be a shame to throw the baby out with the bathwater," he commented.
But Dr Doug Weaver (Henry Ford Health System, Detroit, MI), one of the moderators of the late-breaking session, commented: "The primary end point was negative. I don't think it's even fair to look at secondary end points." He said he would conclude, "Our indications for clopidogrel should not change after this study."
Another moderator, Dr Paul Armstrong (University of Alberta, Edmonton), said he believed the CHARISMA results were "charismatic, because I don't have to use clopidogrel now, and that's cheaper."
No reason to use clopidogrel in primary prevention
Bhatt did reiterate, however, the potential dangers in giving clopidogrel as primary prevention in stable patients. "The bottom line, in primary prevention, is that there is no reason to use clopidogrel based on its lack of efficacy and the excess bleeding seen."
Even the aspirin data, for primary prevention, are checkered.
He added that they did not know exactly how the excess cardiovascular deaths seen in the primary-prevention subgroup taking clopidogrel had occurred, as it seemed they were not linked to the excess bleeding seen. (The rate of death from cardiovascular causes in the primary prevention subgroup was 3.9% among those receiving clopidogrel and 2.2% in those taking placebo [p=0.01]).
"We cannot rule out the statistical play of chance, but it seems that two blood thinners instead of one backfires," Bhatt said.
Meanwhile, advocates of aspirin lost no time in emphasizing that the CHARISMA results highlight the benefits of this drug.
"CHARISMA reaffirms the favorable benefit-to-risk and benefit-to-cost ratio of aspirin in the treatment and prevention of heart attack and stroke," said Dr Charles H Hennekens (University of Miami School of Medicine, FL) in a Bayer media release.
"These findings are particularly welcome news worldwide, with cardiovascular disease rising from the fifth to the leading cause of death. Aspirin is both effective and affordable for the millions of people worldwide who could benefit. Wider utilization is needed in both developing and developed countries, like the US," Hennekens concluded.
But Bhatt pointed out "even the aspirin data, for primary prevention, are checkered."
