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

Abstract

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.

10‐Year Associations Between Tumor Necrosis Factor Receptors 1 and 2 and Cardiovascular Events in Patients With Stable Coronary Heart Disease: A CLARICOR (Effect of Clarithromycin on Mortality and Morbidity in Patients With Ischemic Heart Disease) Trial Substudy

“…Model D was used as the standard model for primary analysis, as predefined in the study protocol. 16 The proportional hazards assumption for Cox regression was violated for age for the outcomes all-cause death and the composite outcome (ie, age at entry; Bonferroni adjusted P<0.00056 for the composite outcome, and P<0.0044 for allcause mortality). Accordingly, we choose to omit age from all Cox models for those 2 outcomes.…”

“…Improvement in prediction, relative to that obtained when standard predictors (available from routinely available clinical information model D [ Table S1]) were used, was calculated in accordance with the published statistical analysis plan. 16 We used curves (penalized splines) to see the potential nonlinearity of the associations between either TNFR and the outcome, where the hazard ratio was plotted against the circulating TNFR concentration.…”

“…Model C was adjusted for factors in model B and estimated glomerular filtration rate, because the TNFRs have been shown previously to be associated with both kidney function and incident chronic kidney disease, to rule out that the TNFRs mirror more than kidney function. Model D was adjusted for established risk factors, comorbidities and cardiovascular pharmacotherapies, and standard biochemical predictors, as shown in Table . Model D was used as the standard model for primary analysis, as predefined in the study protocol …”

“…Improvement in prediction, relative to that obtained when standard predictors (available from routinely available clinical information model D [Table ]) were used, was calculated in accordance with the published statistical analysis plan …”

Prognostic value of routinely available data in patients with stable coronary heart disease. A 10-year follow-up of patients sampled at random times during their disease course

“…The present analysis also serves as a background for a search for additional prognostic covariates which may be available in the biobank of the CLARICOR trial. A detailed account of methodology and statistical analysis was published before the analysis commenced 3…”