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 conclude.

Senior author of the CHARISMA study, Dr Eric Topol (Case Western Reserve University, Cleveland, OH), told heartwire: "The most stunning result was the suggestion of harm in the primary-prevention subgroup. Not one of the 600 investigators expected that this group would be harmed, and I don't believe it's a fluke."

The disappointing results of CHARISMA are a big blow for Sanofi Aventis—a positive trial would have had a huge clinical impact, massively expanding the patient population eligible for clopidogrel therapy and generating millions of dollars in revenue. The cost of long-term clopidogrel therapy for these patients would have been a thorny issue, however.

In an accompanying editorial [2], Drs Marc A Pfeffer (Brigham and Women's Hospital, Boston, MA) and John A Jarcho (New England Journal of Medicine) applaud the strength of the study and the fact that it ran to completion, but they question the wisdom of the subgroup analyses.

Bhatt et al say the benefits of adding clopidogrel to aspirin in patients with acute coronary syndromes or in those undergoing percutaneous coronary intervention have already been demonstrated in a number of studies. "CHARISMA represents the logical next step of the evaluation of the potential role of this approach in a broad population of patients" with more stable disease, they note.

They explain that aspirin alone, in many instances, is not sufficient to prevent ischemic events in patients at high risk. Aspirin inhibits only the cyclooxygenase pathway, leaving the adenosine diphosphate P2Y₁₂ receptor unaffected. Thus, the rationale behind CHARISMA was that adding clopidogrel, a P2Y₁₂-receptor antagonist, might provide greater protection against cardiovascular events than aspirin alone.

In the study, 15 603 patients with either clinically relevant cardiovascular disease or multiple risk factors were randomized to clopidogrel 75 mg/day plus low-dose aspirin (75-162 mg/day) or placebo plus low-dose aspirin. Roughly speaking, around 12 000 of these were secondary-prevention patients (symptomatic) while 3000 were primary-prevention patients (asymptomatic). They were followed for a median of 28 months. The primary end point was a composite of myocardial infarction, stroke, or death from cardiovascular causes.

Overall, clopidogrel plus aspirin was not significantly more effective than aspirin alone in reducing the primary end point. There was a suggestion of a benefit in symptomatic patients with established vascular disease (secondary prevention)—the rate of the primary end point among these patients was 6.9% with clopidogrel and 7.9% with placebo (p=0.046)—but "this finding requires further study," Bhatt et al say.

The rate of the primary end point in the asymptomatic, or primary-prevention, patients was 6.6% with clopidogrel and 5.5% with placebo (p=0.20). But it was the rate of death from cardiovascular causes that was most striking—3.9% among those receiving clopidogrel and 2.2% in those taking placebo (p=0.01).

We tested the boundaries and we found them. We hit the wall.

This suggestion of harm in asymptomatic patients means that "dual antiplatelet therapy should not be used in patients without a history of established vascular disease," Bhatt et al say in the paper.

Topol is less circumspect, however. He told heartwire that the excess deaths seen in this group were not due to bleeding events. "Most of them suffered sudden death or myocardial infarction. We think that these primary-prevention patients don't have such hyperactive platelets and that somehow clopidogrel is causing a hemorrhage in plaques.

"We tested the boundaries and we found them. We hit the wall," he adds.

In their editorial, Pfeffer and Jarcho say: "The trial was probing uncharted territory in determining whether long-term dual antiplatelet therapy would be of incremental clinical value in patients with vascular disease without an acute manifestation of injury."

"In CHARISMA, the absence of a clear benefit in terms of clinical outcome, coupled with the increased rate of bleeding (as well as the economic considerations related to the long-term use of clopidogrel) provides a robust answer to the central question of the trial and argues against the use of dual antiplatelet therapy in this patient population," they state.

However, the suggestion of benefit in the subgroup of "symptomatic" patients is worrisome, they say, adding that subgroup analyses are "notoriously fraught with multiple hazards."

"We are . . . concerned that the characteristics that differentiate patients in this subgroup are not sufficiently distinct. If anything, the subgroup analysis could be used to generate a hypothesis for a further study to help define the currently blurry distinction between the benefits and risks of dual antiplatelet therapy in patients with acute injury and those in patients with more stable vascular disease.

"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.

Topol says he is "bothered" by the editorial. "They basically accuse us of a fishing expedition for p values. It would have been irresponsible of us not to show the dichotomous results. I totally disagree with their conclusions," he says.