Weekly Intervention with Zithromax for Atherosclerosis and its Related Disorders - WIZARD
The goal of the trial was to assess the association of 12 weeks of azithromycin treatment and clinical events in patients with stable coronary artery disease, prior MI, and known C pneumoniae exposure.
Treatment with azithromycin would results in a reduction in coronary heart disease events in patients with stable coronary artery disease, prior MI, and known C pneumoniae exposure.
Patients Screened: 11451
Patients Enrolled: 7747
Mean Follow Up: Mean: 2.1 years
Mean Patient Age: Mean age 62 years
Patients greater than 6 weeks post-MI who had elevated Chlamydia pneumoniae titers.
Coronary artery bypass graft surgery or percutaneous coronary intervention in the preceding 6 months, chronic antibiotic therapy, or use of antibiotics in the previous 3 months.
A composite endpoint of all-cause mortality, recurrent MI, revascularization procedures, and hospitalization for angina.
Components of the primary end point; noncoronary atherosclerotic event (stroke, transient ischemic attack, or intervention for peripheral vascular disease, whichever occurred first), cardiovascular death, and hospitalization for congestive heart failure.
The study population included 7,747 patients greater than 6 weeks post-MI (median 2.6 years) who had elevated Chlamydia pneumoniae titers (1:16 or more). Patients were randomized to therapy with azithromycin (n=3879) or placebo (n=3868). Azithromycin was given as 600 mg/day for 3 days followed by 600 mg weekly for 11 weeks. A composite endpoint of all-cause mortality, recurrent MI, revascularization procedures, and hospitalization for angina was measured at a mean of 2.1 years following randomization.
There was no significant difference in the primary endpoint with azithromycin vs placebo (14% vs 15%, relative risk reducion [RRR] 7%, 95% confidence interval -5% to 17%, p=0.23). Hazard ratio analysis showed early benefits of azithromycin on the primary event and on death or reinfarction, but the differences decreased over time. There were no significant risk reductions for any of the components of the primary endpoint including death (4% vs 5%, RRR 8%, p=0.42), recurrent MI( 4% vs 4%, RRR 7%, p=0.55), revascularization procedures (8% vs 9%, RRR 5%, p=0.51), or hospitalizations for angina (3% vs 3%, RRR -1%, p=0.94). Adverse events related to study drug occurred in 13.2% of patients in the azithromycin arm, predominantly a result of diarrhea, compared with 4.6% of placebo patients. Discontinuation of drug occurred in 1.6% in the azithromycin group and 0.4% in the placebo group. There was no relationship between baseline Chlamydia titer and treatment effect. Subgroup analysis showed a reduction in the primary endpoint with azithromycin in men (14% vs 15%, RRR 11%, p=0.06), current smokers (14% vs 18%, RRR 24%, p=0.05), and diabetics (17% vs 20%, RRR 19%, p=0.07).
Among post MI patients with known C pneumoniae exposure, treatment with azithromycin was not associated with a significant reduction in the primary composite endpoint of all-cause mortality, recurrent MI, revascularization procedures, and hospitalization for angina. Despite the lack of benefit in the overall population, there were several provocative subgroups that showed benefit, including diabetics and smokers. Given the substudy nature of the analysis, further prospective validation would be required to draw conclusions on treatment effect in these populations. The WIZARD trial is the largest antibiotic treatment trial to date in patients with stable coronary artery disease. Longer treatment may be required to show an effect, given the data in the present trial that suggest an early reduction in events that diminishes over time. Longer antibiotic treatment is being studied in the on-going Azithromycin and Coronary Events (ACES) study.
O'Connor CM, et al. Azithromycin for the secondary prevention of coronary heart disease events: the WIZARD study: a randomized controlled trial. JAMA. 2003 Sep 17;290(11):1459-66.
Keywords: Coronary Artery Disease, Myocardial Infarction, Pyridinolcarbamate, Risk Reduction Behavior, Diarrhea, Azithromycin, Chlamydophila pneumoniae, Confidence Intervals, Diabetes Mellitus
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