Interpreting clinical trials: the ‘Beautiful’ case

Abstract

Sirs, The BEAUTIFUL study was a fantastic study including almost 11 000 patients with coronary heart disease and a left-ventricular ejection fraction of <40% [1]. There are a lot of data supporting that a high resting heart rate is a potentially modifiable cardiovascular risk factor [2,3] and this was also confirmed in the substudy of the placebo-group in the BEAUTIFUL study [4]. The design and pre-specified end-points (Table I) have previously been described [5]. During the course of the study, other results were published which showed that heart rate was only important as a predictor of outcome when increased above 70–75 bpm and therefore the authors pre-specified that they would analyse the effects of ivabradine in a subgroup of patients with a heart rate of 70 bpm or greater. In the whole study population the 1676 patients experienced a primary endpoint: 844 (15AE4%) in the ivabradine group and 832 (15AE3%) in the placebo group [hazard ratio (HR) 1AE00, 95% CI 0AE91–1AE1, P = 0AE94). The effect of ivabradine was similar in all pre-specified subgroups. Furthermore, none of the secondary endpoints differed in the two treatment groups. The prespecified tertiary endpoints were not presented in the present paper. Neither in the subgroup of patients with heart rate of 70 bpm or more, there was a difference in the primary endpoint between the ivabradine group and the placebo group. The only significant effect of ivabradine was a lower coronary event rate in this subgroup with heart rate of 70 bpm or more. This difference was driven by a lower incidence of non-fatal myocardial infarction in the ivabradin group. The authors finish the discussion by saying; ivabradine can be given safely to patients with coronary artery disease and impaired left-ventricular systolic function, and that it can be used in conjunction with b blockers. Furthermore, a combination of ivabradine with b blockade was not only safe, but also improved coronary artery disease outcomes in patients with heart rates of 70 bpm or more. We are concerned about this conclusion since this is a negative study. No effect was shown on the primary end-point and it is not enough that the drug is safe. Furthermore, the positive effect on coronary event in the subgroup with heart rate of 70 bpm or more necessarily means that the drug ivabradin might cause harm in patients with a lower heart rate than 70, since there were no effect on coronary event in the whole study population.