Ivabradine BEAUTIFUL in Subset of Patients With Angina and Heart Rates 70 bpm or Higher

Fran Lowry

September 11, 2009

September 10, 2009 (Barcelona, Spain) — Ivabradine (Procoralan, Servier) may be helpful in reducing major cardiovascular events in patients with stable CAD and LV dysfunction who present with limiting angina, especially if they have a heart rate of 70 beats per minute or more, a post hoc analysis from the Morbidity-Mortality Evaluation of the If Inhibitor Ivabradine in Patients With Coronary Artery Disease and Left Ventricular Dysfunction (BEAUTIFUL) trial suggests. The findings were met with some skepticism when presented at the European Society of Cardiology (ESC) 2009 Congress last week; however, senior author Dr Roberto Ferrari (University of Ferrara, Italy), who presented the subgroup analysis at a clinical-trials-update session, noted that a large-scale clinical trial is ongoing, which will formally test this hypothesis. The results of the BEAUTIFUL subgroup analysis were simultaneously published online August 31, 2009 in the European Heart Journal [1]. "Use ivabradine in patients with angina. It is safe, and these patients do benefit from a reduction of heart rate that is often a further reduction of heart rate than that obtained with beta blockers," Ferrari, who is the current ESC president, told heartwire. As reported in heartwire, the BEAUTIFUL results were presented last year at the European Society of Cardiology Congress 2008 and simultaneously published in the Lancet [2]. Somewhat less stellar than the results of the current subgroup analysis, the trial failed to meet its primary composite end point of reduced cardiovascular death or admission to the hospital for acute MI or new-onset or worsening heart failure in patients with CAD and LV dysfunction, although patients with a heart rate of 70 beats per minute or higher did appear to derive some benefit from ivabradine [3]. At the time, lead author Dr Kim Fox (Brompton Hospital, UK) conceded that the trial failed its primary end point and that any conclusions that might be drawn regarding the reduction in fatal and nonfatal MI were hypothesis generating. Post hoc analysis shows significant benefit When the BEAUTIFUL investigators went back to the drawing board to have another look at their data, they noticed that a sizable number of patients--13.8%, or 1507 out of 10 917 patients--in their study who had limiting angina symptoms at baseline did indeed benefit from ivabradine treatment. The primary end point, a composite of cardiovascular death or hospitalization for MI or heart failure, was significantly reduced in the 734 patients who were randomized to ivabradine, compared with the 773 patients who were randomized to placebo. BEAUTIFUL: Hazard ratio in patients with limiting angina End point Hazard ratio p Primary composite end point 0.76 0.05 Cardiovascular death 0.88 0.51 Hospitalization for heart failure 0.84 0.45 Hospitalization for MI 0.58 0.021 The benefit was more pronounced in the patients who had a resting heart rate >70 bpm. Of these patients, 349 received ivabradine and 363 received placebo. BEAUTIFUL: Hazard ratio in patients with limiting angina and heart rate >70 bpm End point Hazard ratio p Primary composite end point 0.69 0.06 Cardiovascular death 0.90 0.66 Hospitalization for heart failure 0.96 0.91 Hospitalization for MI 0.27 0.002 "Ivabradine, by reducing the heart rate, should logically reduce angina, this is well-known. But whether by this reduction ivabradine also would improve the prognosis of the patients was not so well known, and this was the most surprising result," Ferrari told heartwire. "Because it did significantly modify the primary end point of cardiovascular death and hospitalization for heart failure and for myocardial infarction. And when we went to look at the component of this composite end point, it was clear that ivabradine, mainly by reducing ischemic attacks, also reduces the occurrence of myocardial infarction." Ferrari added that plans are in the works to continue with a larger study "called SIGNIFY," which will be done in patients with angina but without left ventricular dysfunction. Subgroup analysis confirms original trial Dr Gerd Heusch (Universitätsklinikum Essen, Essen, Germany) commented in his discussion as well as in an accompanying commentary published online in the European Heart Journal [4] that it was surprising that the investigators failed to discuss "critically" their choice of limiting angina as the entry criterion for their subgroup analysis. Nevertheless, he said, the current subgroup analysis confirms the findings of the original BEAUTIFUL trial, in that ivabradine protects from ischemia but not from heart failure and that protection is more pronounced in patients with a heart rate >70/min. Heusch confessed that he found it difficult to reconcile the fact that a heart rate >70 bpm "was a stronger discriminator for heart failure than ischemia and then there was no protection from heart-failure but only from ischemia end points with heart-rate reduction." He went on to ask if there was protection from ischemia by ivabradine beyond that of heart-rate reduction and provided a potential answer: "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. . . . This pleiotropic protective action of ivabradine beyond its bradycardic effect puts ivabradine into the context of cardioprotection," he stated, adding that the mechanism or mechanisms underlying the pleiotropic protection by ivabradine are largely unclear and that experimental studies are required to elucidate such a potential "pleiotropic protective mechanism of ivabradine." Data under duress Commenting on the study for heartwire, Dr Franz Messerli (St Luke's Roosevelt Hospital, New York) cast a rather negative view on the post hoc results. Messerli said the subanalysis of the BEAUTIFUL study "is a classic example of torturing the data until they confess. The study failed the primary end point, and therefore all secondary analyses are a priori suspicious and most likely motivated by wishful thinking of either the sponsor and/or the investigators." He added: "In patients with a heart rate 70 bpm or higher, heart-rate lowering by a meager seven beats per minute by ivabradine was associated with a stunning 73% reduction in hospitalization for MI and a 59% reduction in coronary revascularization. Of note, a heart rate >70 bpm was a stronger discriminator for heart failure than for ischemia, but heart-rate reduction protected only against ischemia and not against heart failure." Messerli also took issue with the hypothetical mechanism of benefit. "The accompanying editorial hypothesizes that some of these findings could be due to a pleiotropic protective action of ivabradine beyond its bradycardic effect. Do we really need to involve findings in pigs and resort to pleiotropism to explain such a post hoc data set in less than 15% of the total study population, which seems to make it look PITIFUL rather than BEAUTIFUL?" Ferrari has received fees, honoraria, and research grants from Servier. Heusch has received funding for experimental studies and honoraria for educational lectures from Servier. Messerli declares no conflicts of interest.

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