BEAUTIFUL: Effect of ivabradine on cardiovascular outcomes in patients with stable CAD and LV dysfunction with limiting angina: a subgroup analysis of the BEAUTIFUL trial 

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	Presenter | see Discussant report
	Roberto Ferrari, FESC (Italy)

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	Discussant | see Presenter abstract
	Gerd Heusch, FESC (Germany)

Report:

The BEAUTIFUL investigators present a retrospective, subgroup analysis in 13.8% of the original patient population who had limiting symptomatic angina – as characterized by pain, fatigue, palpitations or dyspnoea – at baseline. The essential conclusions from the original BEAUTIFUL study were largely confirmed and further emphasized: now with a just borderline-significant reduction in the composite endpoint, ivabradine had no effect on mortality and hospitalization for heart failure, but significantly reduced the hospitalization for myocardial infarction and coronary revascularization, and this reduction was more pronounced in patients with heart rate above 70/min than in the entire population with limiting angina; the placebo-corrected heart rate reduction was only 4/min and 7/min in the entire population with limiting angina and in those with limiting angina and a heart rate above 70/min, respectively.

The investigators appropriately acknowledge the limitations of their retrospective approach to analyze a subgroup of a trial which was entirely negative in its primary endpoint and advocate their analysis as hypothesis-generating and in need of large-scale prospective testing. Unfortunately, they do not say precisely which hypothesis they generate from their subgroup analysis, possibly that ivabradine provides greater protection from ischemia in patients with coronary artery disease and limiting angina than in those without angina; to test such hypothesis would require a huge trial.

Somewhat surprisingly, the investigators fail to critically discuss their choice of limiting angina as the entry criterion for their subgroup analysis. While they expand in detail on the impact of angina on prognosis, this is obviously not true for the BEAUTIFUL patients with limiting angina who had a mortality of 10.0% with placebo as compared to 10.1% in the entire BEAUTIFUL population with placebo. The reasons for the lack of impact of angina on prognosis in this study population remain unclear: the excellent anti-anginal background medication or potential cardioprotective phenomena related to repeated episodes of reversible ischemia/reperfusion, such as ischemic preconditioning or – in conjunction with left ventricular dysfunction – myocardial hibernation, might have offset the otherwise adverse effects of angina on prognosis.

Notwithstanding the above limitations, the current subgroup analysis in patients with limiting angina confirms the original BEAUTIFUL trial, in that ivabradine protects from ischemia and not from heart failure and that protection is more pronounced in patients with heart rate above 70/min. However, the placebo-corrected heart rate reduction by no more than 7/min with ivabradine strikes me as modest and difficult to reconcile with the profound protection. Also difficult to reconcile are the facts that heart rate above 70/min was a stronger discriminator for heart failure than ischemia outcome, but then there was no protection from heart failure but only from ischemia endpoints with heart rate reduction.

So is there protection from ischemia by ivabradine beyond that by heart rate reduction ? Experimental studies in pigs clearly revealed a significant reduction in infarct size with ivabradine, not only when given before ischemia but also when given just at reperfusion, and such infarct size reduction was largely preserved when heart rate reduction was offset by atrial pacing. This pleiotropic protective action of ivabradine beyond its bradycardic effect puts ivabradine into the context of cardioprotection and its signal transduction, notably into the context of postconditioning since ivabradine is still protective when given just at reperfusion. The mechanism(s) underlying the pleiotropic protection by ivabradine are largely unclear; attenuation of damage by reactive oxygen species and reduced sodium influx through the If current with secondary reduction of sodium – calcium exchange and ultimate reduction in calcium overload have been suggested.

Experimental studies, e.g. with ivabradine on top of sodium-calcium exchange blockade or anti-oxidant regimes, are required to elucidate the potential pleiotropic protective mechanism of ivabradine. Clinical studies are required to confirm the experimental data on protection by ivabradine against reperfusion injury; a similar study design as in the most recent trial on cyclosporine A in patients with acute myocardial infarction would be most useful.

A detailed Editorial with references is available on the website of the European Heart Journal as of today.

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.