“Elevation of heart rate predicts fatal and non-fatal MI and revascularisation,” said Kim Fox, Chairman of the BEAUTIFUL Executive Committee. “Intuitively we thought this to be the case, but it has never been shown before.”
The study was prompted by the introduction of ivabradine - approved by the EMEA in 2005 – which specifically inhibits the If current in the sinoatrial node; this offers an opportunity to assess the effect of lowering heart rate without otherwsie directlyaltering cardiac function. “It causes pure heart rate reduction without any effect on catecholamines, so for the first time allowed us to explore pure heart rate reduction,” explained Fox.
In the double blind placebo controlled trial - initiated in December 2004 - 10,917 stable coronary artery disease patients with left ventricular ejection fractions less than 40% were randomised to receive 5 mg ivabradine (with the intention of increasing target dose to 7.5 mg twice daily) or placebo. The patients, recruited from 781 centres in 33 countries, continued to receive optimum conventional cardiovascular medical treatment throughout the study.
Results showed that ivabradine had no effect on the primary composite endpoint (p=0.94) – a composite of death, admission to hospital for heart attack, or admission to hospital for new or worsening heart failure. However, in a pre-specified subgroup of patients with heart rates of 70 bpm or greater, ivabradine reduced the secondary endpoints of admission to hospital for fatal and non-fatal MI (p=0.001) and coronary revascularisation (p=0.016).
In a separate study (also reported online by the Lancet) the investigators analysed the association of baseline resting heart rate with cardiovascular outcomes using the Cox proportional hazard model. Results showed that for every increase of 5 bpm there were increases in cardiovascular death of 8% (p=0.0005), admission to hospital for heart failure of 16% (p <0.0001) and admission to hospital for myocardial infarction of 7% (p=0.052).
One explanation for the absence of an effect in heart failure, suggest the authors, might be that the required reduction in heart rate differs according to underlying disease.
In an accompanying comment, Dr Jan-Christian Reil and Professor Michael Bohm, Universitatsklinikum des Saarlandes, Germany, said: “The BEAUTIFUL study has valuable lessons for clinical practice and illustrates the importance of individual decision-making. It remains to be seen whether or not the concept of the slower the better holds true.”
In the Hot Line session, discussant Sidney Smith (Chapel Hill, US) cautioned that the results were “hypothesis generating”, and that ivabradine should not be incorporated into guidelines until prospective trials have been undertaken. “Studies have shown
that as the number of subgroups increase, so the probability of false positives increases,” he warned.
View the ESC Congress Report for the BEAUTIFUL study here