title: Clarithromycin for stable coronary heart disease increases all-cause and cardiovascular mortality and cerebrovascular morbidity over 10years in the CLARICOR randomised, blinded clinical trial.
abstract: BACKGROUND
  The 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 10years follow up.
  
  
  METHODS
  The CLARICOR trial is a randomised, placebo-controlled trial including 4373 patients with stable coronary heart disease. The interventions were 2weeks of clarithromycin 500mg a day versus placebo. 10year follow up was performed through Danish public registers and analysed with Cox regression.
  
  
  RESULTS
  Clarithromycin increased all-cause mortality (hazard ratio (HR): 1.10, 95% confidence interval (CI): 1.00-1.21) and cerebrovascular disease during 10years (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 10years 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 4years, cardiovascular death outside hospital was lower in the clarithromycin group (HR: 0.64, 95% CI: 0.46-0.88).
  
  
  CONCLUSIONS
  Clarithromycin 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.
authors.affiliation: The Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. Electronic address: pwinkel@ctu.dk.
authors.forename: Per
authors.initials: P
authors.lastname: Winkel
authors.affiliation: Department of Biostatistics, Institute of Public Health Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Jørgen
authors.initials: J
authors.lastname: Hilden
authors.affiliation: Department of Cardiology Y, Bispebjerg Hospital, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Jørgen Fischer
authors.initials: JF
authors.lastname: Hansen
authors.affiliation: Department of Cardiology B, The Heart Centre, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Jens
authors.initials: J
authors.lastname: Kastrup
authors.affiliation: Department of Clinical Microbiology, Odense University Hospital, Odense, Denmark.
authors.forename: Hans Jørn
authors.initials: HJ
authors.lastname: Kolmos
authors.affiliation: Department of Cardiology S, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark.
authors.forename: Erik
authors.initials: E
authors.lastname: Kjøller
authors.affiliation: Department of Cardiology, Hvidovre Hospital, Copenhagen University Hospital, Hvidovre, Denmark.
authors.forename: Gorm Boje
authors.initials: GB
authors.lastname: Jensen
authors.affiliation: The Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Maria
authors.initials: M
authors.lastname: Skoog
authors.affiliation: The Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. Electronic address: JL@ctu.dk.
authors.forename: Jane
authors.initials: J
authors.lastname: Lindschou
authors.affiliation: The Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. Electronic address: cgluud@ctu.dk.
authors.forename: Christian
authors.initials: C
authors.lastname: Gluud
mesh_terms: D000368:Aged; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000009:adverse effects; D002423:Cause of Death / Q000639:trends; D017291:Clarithromycin / Q000008:administration & dosage / Q000009:adverse effects*; D003324:Coronary Artery Disease / Q000188:drug therapy* / Q000401:mortality; D003718:Denmark / Q000453:epidemiology; D005260:Female; D005500:Follow-Up Studies; D005544:Forecasting; D006801:Humans; D008297:Male; D009017:Morbidity / Q000639:trends; D012189:Retrospective Studies; D016037:Single-Blind Method; D020521:Stroke / Q000139:chemically induced* / Q000453:epidemiology
chemical_list: D000900:Anti-Bacterial Agents; D017291:Clarithromycin
keywords: Adverse effects; Adverse events; Cardiovascular mortality; Clarithromycin; Stable coronary heart disease; Statin