Predictors for major cardiovascular outcomes in stable ischaemic heart disease (PREMAC): statistical analysis plan for data originating from the CLARICOR (clarithromycin for patients with stable coronary heart disease) trial

BACKGROUND: The purpose of the predictors for major cardiovascular outcomes in stable ischaemic heart disease (PREMAC) study is exploratory and hypothesis generating. We want to identify biochemical quantities which—conditionally on the values of available standard demographic, anamnestic, and biochemical data—may improve the prediction of cardiovascular outcomes and/or death in patients suffering from stable ischaemic heart disease. The candidate biochemical quantities include N-terminal pro-B-type natriuretic peptide, YKL-40, osteoprotegerin, high-sensitive assay cardiac troponin T (hs-cTnT), pregnancy-associated plasma protein-A (PAPP-A), cathepsin B, cathepsin S, soluble TNF receptor 1 and 2, neutrophil gelatinase-associated lipocalin, endostatin, and calprotectin. As an extra objective, we also want to assess if skewness in these predictors may explain why the clarithromycin for patients with stable coronary heart disease (CLARICOR) trial found increased all-cause and cardiovascular (CV) mortality on a brief clarithromycin regimen compared with placebo. METHODS: Baseline data were obtained from the hospital files at five cardiology clinics covering the Copenhagen area. The CLARICOR trial included data from 4372 stable coronary artery disease patients recruited among such patients alive and diagnosed with acute myocardial infarction or unstable angina pectoris during 1993 to 1999 in Copenhagen and randomised during October 1999 to April 2000 to the CLARICOR trial of 14 days clarithromycin versus placebo. Initial follow-up lasted for 2.6 years, during which outcomes were collected through hospital and death registries and assessed by an adjudication committee. Corresponding register data later showed to produce similar results. The adjudicated outcomes were therefore replaced and augmented by register data on outcomes to cover 10 years of follow-up. Biochemical marker data were obtained from analysis of serum from the CLARICOR bio-bank collected at randomisation and stored at −80° C. Using Cox proportional hazard method, we will identify among the candidate biochemical quantities those which are significant predictors when used alone and in combination with the standard predictors as defined in the present study. DISCUSSION: Patients who became stable during the period 1993 to 1999 and died before October 1999 are missing. The data from the placebo patients are nevertheless useful to identify new prognostic biomarkers in patients with stable coronary artery disease, and data from both trial groups are useful to assess important potential skewness between randomised groups. However, due to the potential selection bias, we do not feel that it is advisable to try to rank identified biochemical predictors relative to each other nor to use the results for predictive purposes. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00121550 Date of registration 13 July 2005 Date of enrolment of first participant 12 October 1999