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BEAUTIFUL: The impact of achieved heart rate and reduction in heart rate on cardiovascular outcomes - an analysis of the Ivabradine arm of the BEAUTIFUL trial

Clinical Trial Update I

Chronic Ischaemic Heart Disease (IHD)

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The BEAUTIfUL trial was a double-blind, placebo-controlled randomized trial on 10917 patients with documented coronary artery disease and left ventricular dysfunction (ejection fraction, EF <40%). Patients were randomized to ivabradine or placebo on top of evidence based treatments. In the overall population of BEAUTIfUL, heart rate reduction by ivabradine did not reduce the primary composite endpoint of cardiovascular death, admission to hospital for acute myocardial infarction or admission to hospital for new onset or worsening of heart failure. Interestingly, 28% of patients on ivabradine discontinued drug treatment mainly due to bradycardia and there was only a 5,6 bpm difference in heart rate between placebo and ivabradine at the end of the study in the total population. Therefore, the present subanalysis of the BEAUTIfUL data aimed at investigating whether heart rate response evaluated by heart rate change from baseline to one month and heart rate achieved at one month was predictive to evaluate outcomes in this patient population. Heart rate difference and heart rate achieved were evaluated as quartiles in those patients with a baseline heart rate above 70 bpm and on treatment with ivabradine.

The major strength of the analysis and the BEAUTIfUL programme in general is the clear physiological rationale of heart rate reduction. Heart rate is associated with cardiovascular outcomes in patients with vascular disease and chronic heart failure. Furthermore, the BEAUTIfUL population offers an opportunity to observe high rates of vascular re-events as well as a progression of impaired left ventricular function to overt heart failure. The subanalysis of BEAUTIfUL asked a clear question, because the high rate of discontinuations (28%) and a small difference between placebo and ivabradine (5,6 bpm) in the total population of BEAUTIfUL might have represented one cause of missing the primary composite. Thus, there was need to further analyze the effects of certain degrees of heart rate lowering in this population.

The analysis was performed in the subgroup in which a clear association of outcomes to a heart rate above 70 bpm was shown in BEAUTIfUL. This analysis could have been hampered by selection bias. It has to be pointed out that a subgroup of the whole BEAUTIfUL population (> 70 bpm) was further divided into a subgroup of ivabradine treatment and finally further divided of four subgroups of quartiles of different heart rates achieved and in quartiles of different heart rate changes. Therefore, the study formed subgroups in a stepwise manner, which might introduce a selection bias. Heart rate response at one month was related to cardiovascular outcomes over the whole study period. The open question remains here what is the risk in patients with long lasting heart rate reduction or fading heart rate reduction later.

Interestingly, there was a clear association of achieved heart rates and heart rate response at one month to vascular endpoints like hospitalization for acute myocardial infarction as well as progression to heart failure, as evidenced by admission to hospital for new onset or worsening of heart failure. This contrasts to the total BEAUTIfUL population in which the heart failure-related endpoints were not significantly associated with heart rate. However, this rigorous and more detailed analysis has raised the hypothesis that heart rate reduction in patients with higher heart rates might be beneficial also in the heart failure population, which is currently investigated in the SHIfT trial. However, it remains open whether outcome is better in those patients who are able to respond to heart rate lowering with ivabradine or whether the reduced event rate is due indeed to pharmacological effect of heart rate lowering by ivabradine itself. Therefore, the subanalyis of the BEAUTIfUL data is a very strong and clear hypothesis generating analysis. It has to be verified prospectively in trials on patients with heart failure and coronary artery disease taking into account the achieved heart rates and the amount of heart rate reduction.




The impact of achieved heart rate and reduction in heart rate on cardiovascular outcomes: an analysis of the Ivabradine arm of the BEAUTIFUL trial

Notes to editor

This congress report accompanies a presentation given at the ESC Congress 2009. Written by the author himself/herself, this report does not necessarily reflect the opinion of the European Society of Cardiology.

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.