Clarithromycin for stable coronary heart disease increases all-cause and cardiovascular mortality and cerebrovascular morbidity over 10 years in the CLARICOR randomised, blinded clinical trial

BackgroundThe CLARICOR trial reported that clarithromycin compared with placebo increased all-cause mortality in patients with stable coronary heart disease. This study investigates the effects of clarithromycin versus placebo during 10 years follow up.MethodsThe CLARICOR trial is a randomised, placebo-controlled trial including 4373 patients with stable coronary heart disease. The interventions were 2 weeks of clarithromycin 500 mg a day versus placebo. 10 year follow up was performed through Danish public registers and analysed with Cox regression.ResultsClarithromycin increased all-cause mortality (hazard ratio (HR): 1.10, 95% confidence interval (CI): 1.00-1.21) and cerebrovascular disease during 10 years (HR: 1.19, 95% CI: 1.02-1.38). The increased mortality and morbidity were restricted to patients not on statin at entry (HR: 1.16, 95% CI: 1.04-1.31, and HR: 1.25, 95% CI: 1.03-1.50). The assumption of constant HR during the 10 years was violated for cardiovascular death (P = 0.01) and cardiovascular death outside hospital (P < 0.0005). Analyses of the effects over time showed that clarithromycin increased cardiovascular mortality during the first three years (HR: 1.42, 95% CI: 1.09-1.84) due to increased cardiovascular mortality outside hospital in patients not on statin (HR: 2.36, 95% CI: 1.60-3.50). During the last 4 years, cardiovascular death outside hospital was lower in the clarithromycin group (HR: 0.64, 95% CI: 0.46-0.88).ConclusionClarithromycin increased mortality due to cardiovascular death outside hospital and cerebrovascular morbidity in patients with stable coronary heart disease who were not on statin. The increased cardiovascular mortality was years later compensated, likely through frailty attrition.