CHARISMA: Aspirin-clopidogrel no better than aspirin-placebo

Patients who already had atherosclerosis experienced benefit, but some experts caution the data came from subgroup analysis.

ATLANTA – A combination of clopidogrel plus aspirin showed no overall benefit compared to aspirin alone among patients with either clinically evident cardiovascular disease or multiple risk factors.

Among symptomatic patients, however, there was a 1% absolute risk reduction and a 12% relative risk reduction in the primary composite outcome of MI, stroke or cardiovascular death.

Deepak L. Bhatt, MD, associate director of the Cleveland Clinic Cardiovascular Coordinating Center, presented results of CHARISMA (Clopidogrel for High Atherothrombotic Risk, Ischemic Stabilization, Management, and Avoidance) trial at the American College of Cardiology 55th Annual Scientific Session.

Bhatt said the results of CHARISMA were provocative. The primary outcome was negative, yet a subgroup that represented about 80% of the entire cohort showed some evidence of benefit with the combination treatment.

“From the standpoint of a statistical purist, if the primary endpoint is negative any subgroup analysis can only be hypothesis generating,” Bhatt said. “Having said that, we are talking about 12,000 out of 15,000 patients, and it would be a shame to throw the baby out with the bathwater.”

Eligible patients

Results of CHARISMA were published simultaneously in the New England Journal of Medicine. In an editorial accompanying the results, Marc A. Pfeffer, MD, Brigham and Women’s Hospital, and John A. Jarcho, MD, said reliance on subgroups is best avoided.

“These data show 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 homogenous genotypic and phenotypic (physiological) characterization will be required before trials can be ‘personalized,’” Pfeffer and Jarcho wrote.

Results of the CHARISMA trial were widely reported following its release and officials at the ACC were concerned that patients might stop taking clopidogrel (Plavix, Sanofi-Aventis/Bristol-Myers Squibb) on their own.

In a written statement, the ACC said the CHARISMA trial did not invalidate clopidogrel for use during a stent procedure or following an MI or stroke.

In an interview with Cardiology Today, Udho Thadani, MD, professor of medicine at the University of Oklahoma Health Sciences Center and Editorial Board member of Cardiology Today’s Cardiovascular Pharmacology section, said he would still use clopidogrel with aspirin in patients with acute coronary syndromes or following stent procedures.

“One cannot recommend long-term clopidogrel-plus-aspirin therapy in patients with chronic-stable established CVD, and this combination therapy should be avoided in high-risk individuals for CVD but without established CVD,” Thadani said.

CHARISMA

CHARISMA enrolled 15,603 patients from 900 centers in Asia, Australia, Europe, North America, South America and South Africa. Mean age of the patient cohort was 64 years. Approximately 30% of the patients were women.

Patients had to have either documented vascular disease or multiple risk factors to be included in CHARISMA, and nearly 80% had documented disease.

All patients received low-dose aspirin at 75 mg to 162 mg per day. An active treatment group was given clopidogrel at 75 mg per day, while a control group received placebo. The trial was event driven and follow-up lasted a median of 28 months.

Researchers assessed a primary composite outcome of MI, stroke or death from cardiovascular causes. Patients taking clopidogrel plus aspirin had a 6.8% rate of events compared to 7.3% in the placebo-plus-aspirin group (RR=.93; 95% CI, 0.83-1.05; P=.22).

A composite secondary outcome, which added hospitalizations for ischemic events, was noted in 16.7% of the active treatment group compared to 17.9% of the controls (RR=.92; 95% CI, 0.86-0.995, P=.04).

Subgroup analysis

Researchers conducted a predefined subgroup analysis among those patients who presented with symptomatic disease (n=12,153) and those who were asymptomatic (n=3,284).

Among those with clinically evident atherosclerosis, patients treated with clopidogrel plus aspirin had a 6.9% rate of the primary outcome compared with 7.9% treated with placebo (RR=.88; 95% CI, 0.77-0.998; P=.046).

However, those who were asymptomatic had a slight increase in the primary composite outcome while taking clopidogrel (RR=1.2; 95% CI, 0.97-1.61, P=.2). Deaths from cardiovascular causes in the primary prevention subgroup were significantly higher in the clopidogrel-plus-aspirin group at 3.9% compared with 2.2% in the placebo group (P=.01).

“These findings present a clear contraindication against this treatment regimen for primary prevention, but its role in secondary prevention requires further study,” Bhatt said. – by Jeremy Moore

Bhatt has served as a paid consultant to both Sanofi-Aventis and Bristol-Myers Squibb in the past. He currently donates such honoraria to nonprofit organizations.

For more information:

• Bhatt DL, Fox KAA, Hacke W, et al. N Engl J Med. 2006; 354. The main results of the CHARISMA trial. Presented at the American College of Cardiology 55th Annual Scientific Session. March 11-14, 2006. Atlanta.