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Azithromycin for the secondary prevention of coronary eventsGrayston JT, Kronmal RA, Jackson LA, et al. N Engl J Med 2005; 352:1637-45 Reviewer: KW Tim Park, MD Background: Seroepidemiological studies have suggested an association between Chlamydia pneumoniae and atherosclerosis, especially coronary artery disease (CAD) and acute coronary events in the smokers.1,2 In addition, the microorganism has been found in atherosclerotic plaques.3,4 In the absence of clinical studies that treatment of C. pneumoniae has an impact on either prevention or treatment of CAD, some clinicians have gone ahead with treating CAD with antimicrobials.5 The present study, along with another study ("PROVE IT" trial) reported in the same issue of N Engl J Med,6 attempts to clarify the role of antimicrobials in the long-term treatment of CAD. Methods: This is a randomized, double-blind, placebo-controlled, multi-center trial of patients of either gender, 18 years of age or older, who had documented, stable CAD. Exclusion criteria included MI, coronary revascularization, or hospitalization for unstable angina within the preceding three months, NYHA class III or IV congestive heart failure (CHF), stage III or IV angina, allergy to macrolide antibiotics, significant renal or hepatic dysfunction, cancer, ongoing antibiotic therapy, or immunosuppression. Patients were randomized to receive azithromycin 600 mg or a placebo once weekly for one year. Follow-up occurred at three and six weeks and three, six, nine, and 12 months after enrollment and then every 6 months until the end of the follow-up. The primary end point was a composite of the first occurrence of death due to CAD, MI, percutaneous or surgical coronary revascularization, or hospitalization for unstable angina. Secondary end points were stroke, cardiac collapse followed by resuscitation, carotid endarterectomy, peripheral revascularization, and death from any cause. Participants were tested for IgG and IgA antibodies to C. pneumoniae and measured for total cholesterol, HDL, and LDL fractions at enrollment. With an assumed event rate of 6.5% per year in the placebo group, a sample size of 4,000 with an average follow-up of four years was planned to achieve 98% power to detect a 25% reduction and 85% power to detect a 20% reduction at a two-sided significance level of 0.05. Results: A total of 4,012 patients were enrolled, with 2004 randomized to the treatment group. Baseline characteristics of the treatment and placebo groups were similar with 80% males, 87% Caucasians, 80+% with hypercholesterolemia, 67 % with hypertension, and 22% with diabetes mellitus. Prior to enrollment, 87% were on aspirin, 76% on statins, 35% on ACE inhibitors, and 60% on beta-blockers. 2% either withdrew consent or were lost to follow-up. The median length of follow-up was 3.91 years in the treatment group and 3.92 years in the placebo group. The primary end point was realized in 22.3% of the treatment group and 22.4% in the placebo group (P=NS) and was not significantly different in subgroup analyses according to baseline characteristics. The presence of IgG or IgA antibody to C. pneumoniae at enrollment was not a risk factor for the primary end point in either the treatment or placebo group. None of the secondary end points were significantly different between the groups. Hearing loss as well as nausea and abdominal pain was reported more commonly in the treatment group (38/2004 vs. 20/2008, P <0.02), but the number seeking treatment because of hearing loss was similar. Discussion & Comments: There have now been 11 published studies on the use of antibiotics in the secondary prevention of CAD.6 The first 8 studies were inconclusive because of small sample sizes and very limited courses of antibiotic treatment. The life cycle of Chlamydia requires a long-term therapy. The infectious, nonreplicating form of the organism is not susceptible to antibiotics and may remain viable in the body for weeks to months. The intracellular replicating form is susceptible to antibiotics, but may enter a "persistent" phase for an indeterminate time and may then be resistant to antibiotics. Thus any trial of antibiotics against Chlamydia in the secondary prevention of CAD requires protracted treatment. Including the current study, there are now three trials with sample sizes large enough to achieve adequate power. These are the WIZARD (Weekly Intervention with Zithromycin for Atherosclerosis and its Related Disorders) trial,8 the PROVE IT (Pravastatin Or atorVastatin Evaluation and Infection Therapy - Thrombolysis In Myocardial Infarction 22) trial,6 and the present ACES (Azithromycin and Coronary Events Study) trial. The sample sizes all exceeded 4,000 and the antibiotic course ranged from three months (WIZARD) to two years (PROVE IT). None of these trials demonstrated any benefit of the antibiotics, at least in the way they were used, although in the WIZARD trial there was some benefit of azithromycin against death or reinfarction in the first six months of enrollment; but the benefit did not persist after six months. Whether the results of these trials indicate lack of a role of C. pneumoniae in the progression of CAD is not certain even with the negative results of the trials. First, the trials assume that the antibiotic course used was adequate against C. pneumoniae. This assumption might or might not have been true, since the dose or duration might have been inadequate or the antibiotic might not have reached the organism in the chronic lesions of atherosclerosis. Although the investigators checked serology at enrollment, they did not measure any change in the frequency of IgA or IgG with treatment vs. placebo. Second, the trials do not tell anything about a possible role of the microorganism in the initiation or acceleration of atherosclerosis. In rabbit and murine models, inoculation of C. pneumoniae is associated with acceleration of atherosclerosis and antibiotics may prevent this.9-11 The magnitude of the antibiotic effect depended on how early after inoculation the treatment was given.11 It may be that the antibiotic therapy is most effective in the early stages of C. pneumoniae-induced atherosclerotic process.
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