ATLANTA, March 12 - In patients at high risk for atherothrombotic events, the combination of Plavix (clopidogrel) and aspirin proved no better than aspirin alone at reducing rates of myocardial infarctions, stroke, or cardiovascular-related deaths.
In addition to finding no significant benefit for the combination in a randomized trial in more than 15,000 patients, Plavix plus aspirin for patients with multiple risk factors was associated with increased risk for moderate and serious bleeding, investigators reported the American College of Cardiology meeting here.
Action Points
- Explain to interested patients that the CHARISMA trial of aspirin alone vs. aspirin plus Plavix (clopidogrel) showed no benefit over aspirin alone at preventing major cardiovascular events or death.
- Be aware that the combination was associated with a higher risk for moderate-to-serious bleeding events but lower risk of death among patients with clinically evident atherothrombotic disease.
What's more, Plavix-aspirin nearly doubled the risk for death from cardiovascular causes for these high-risk asymptomatic patients compared with humble aspirin alone, said Deepak Bhatt, M.D., of the Cleveland Clinic, speaking for colleagues in the CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance) trial.
The findings do not support the use of dual antiplatelet therapy across the broad population tested, Dr. Bhatt said. Along with presentation at the ACC, the CHARISMA trial results were published in the online edition of the New England Journal of Medicine.
Although there was harm found for asymptomatic patients, the investigators found a suggestion of benefit for Plavix-aspirin in patients who were symptomatic and had established vascular disease.
"It's fascinating, I think, this dichotomous result both in terms of efficacy and bleeding in these two major subgroups," Dr. Bhatt said. "The secondary prevention population appeared to have a modest benefit of dual antiplatelet therapy with no increase in severe bleeding (1.6% in combination versus 1.4% in aspirin alone; P=0.39), while the primary prevention population had no benefit, an excess in cardiovascular mortality, and an increase in severe bleeding (2.0% in combination versus 1.2% in aspirin alone; P=0.07)."
In this trial, 15,603 patients at risk for atherothrombotic events, because of either evident cardiovascular disease or multiple risk factors, were randomly assigned to receive either Plavix at 75 mg per day or placebo, plus all patients were given low-dose aspirin (75 to 162 mg per day).
The patients were followed for a median of 28 months. The primary efficacy endpoint was a composite of myocardial infarction, stroke, or death from cardiovascular causes. The secondary endpoint was a composite of hospitalization for unstable angina, transient ischemic attack, or revascularization.
The investigator found that the primary endpoint occurred in 534 of 7,802 patients (6.8%) on the combination, and in 573 of 7,801 patients (7.3%) who took aspirin alone (relative risk, 0.93; 95% confidence interval, 0.83 to 1.05; P = 0.22).
Hospitalizations for ischemic events occurred in 16.7 % of those on the combination, and 17.9 % of those on aspirin only (relative risk, 0.92; 95 % CI, 0.86 to 0.995; P = 0.04).
The analysis of adverse events showed that patients taking Plavix plus aspirin had a severe bleeding rate of 1.7 %, compared with 1.3 % for the aspirin only group (relative risk, 1.25; 95 % CI, 0.97 tο 1.61%; P = 0.09).
Among patients who were asymptomatic but had multiple risk factors (e.g., diabetes, diabetic nephropathy, carotid artery stenosis > 70% lumen diameter) the rate of the primary endpoint was 6.6% for the combination, and 5.5% for aspirin (relative risk, 1.2; 95 % CI, 0.91 to 1.59; P = 0.20) and the rate of death from cardiovascular causes also was higher with Plavix (3.9 % vs. 2.2 %, P = 0.01).
"The risk associated with dual antiplatelet therapy in the asymptomatic group was not anticipated," the investigators noted. "The excess fatalities in this subgroup and the heightened risk of bleeding complications suggest that we should be cautious about too quickly dismissing this unexpected finding as the play of chance."
Among the subgroup of patients with clinically evident (symptomatic) atherothrombosis, the rate was 6.9 % with clopidogrel and 7.9 % with placebo (relative risk, 0.88; 95 % CI, 0.77 to 0.998; P = 0.046).
Although a subgroup analysis suggested the addition of Plavix might benefit patients with symptomatic (clinically evident) atherothrombotic disease, the benefit was only marginally significant, "suggesting that this observation should be interpreted with caution, especially since this subgroup analysis was only one of several such analyses performed," the researchers cautioned.
This subgroup was also at greater risk for moderate or severe bleeding on the combination, although there was no significant increase in intracranial or fatal bleeding, they added.
In a NEJM accompanying editorial, Marc A. Pfeffer, M.D., Ph.D., of Brigham and Women's Hospital and Harvard Medical School, and John A. Jarcho, M.D., of the NEJM, agreed with the authors that "we find the overall point estimate and 95% confidence limits for the entire population convincing."
They added, "The data how no significant benefit associated with long-term clopidogrel therapy in addition to aspirin. Admittedly, this 'one size fits all' approach leaves much to be desired. However, 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."
Primary Source
American College of Cardiology 2006 Annual Meeting
Source Reference: Bhatt DL et al. The Main Results of the CHARISMA Trial. Late-breaking clinical trial presented March 12.