Clarithromycin for 2 weeks for stable coronary heart disease: 6-year follow-up of the CLARICOR randomized trial and updated meta-analysis of antibiotics for coronary heart disease

Abstract

Objectives: We have reported increased 2.6-year mortality in clarithromycin- versus placebo-exposed stable coronary heart disease patients, but meta-analysis of randomized trials in coronary heart disease patients showed no significant effect of antibiotics on mortality. Here we report the 6-year mortality of clarithromycin- versus placebo-exposed patients and updated meta-analyses.

Methods: Centrally randomized, placebo controlled multicenter trial. All parties were blinded. Analyses were by intention to treat. Meta-analyses followed the Cochrane Collaboration methodology.

Results: We randomized 4,372 patients with stable coronary heart disease to clarithromycin 500 mg (n = 2,172) or placebo (n = 2,200) once daily for 2 weeks. Mortality was followed through public register. Nine hundred and twenty-three patients (21.1%) died. Six-year mortality was significantly higher in the clarithromycin group (hazard ratio 1.21, 95% confidence interval 1.06-1.38). Adjustment for entry characteristics (sex, age, prior myocardial infarction, center, and smoking) did not change the results (1.18, 1.04-1.35). Addition of our data to that of other randomized trials on antibiotics for patients with coronary heart disease versus placebo/no intervention (17 trials, 25,271 patients, 1,877 deaths) showed a significantly increased relative risk of death from antibiotics of 1.10 (1.01-1.20) without heterogeneity.

Conclusions: Our results stress the necessity to consider carefully the strength of the indication before administering antibiotics to patients with coronary heart disease.

Fig. 1.

Unadjusted Kaplan-Meier estimates of all-cause cumulative mortality in the clarithromycin group and in the placebo group during 2.6 years of follow-up. Figures below the diagram are the number of participants still at risk (followed by the cumulative number of deaths) in the clarithromycin and placebo groups.

Fig. 2.

Unadjusted Kaplan-Meier estimates of all-cause cumulative mortality in the clarithromycin group and in the placebo group during 6 years of follow-up. Figures below the diagram are the number of participants still at risk (followed by the cumulative number of deaths) in the clarithromycin and placebo groups. Until 5.7 years after randomization the graph is based on the full cohorts.

Fig. 3.

Cumulative difference in the estimated all-cause risk of death during 6 years of follow-up, with 95% confidence limits. A negative value indicates that placebo patients did better than clarithromycin patients. Until 5.7 years after randomization the graph is based on the full cohorts. The number of deaths and the number at risk are as shown in figure 2.

Fig. 4.

Intervention effect of different antibiotics versus placebo or no intervention on mortality of patients with coronary heart disease. CI = Confidence interval; n = number of patients with outcome; N = number of participants at risk; d.f. = degrees of freedom; I² = percentage of total variation across studies that is due to heterogeneity rather than chance. Relative risks are plotted (black squares with area proportional to the amount of statistical information in each trial) comparing outcome among participants allocated to antibiotic with those allocated to placebo or no intervention, alongside their 95% CI (horizontal lines). For totals, the result and its 95% CI are represented by a diamond with the relative risk and 95% CI given alongside. Squares or diamonds to the right of the solid vertical line indicate harm from antibiotics. This is conventionally significant (p < 0.05) only if the horizontal line or diamond does not overlap the solid vertical line.