August 31, 2008 (Munich, Germany) — Ivabradine (Procoralan, Servier) appears to safely lower heart rate, but doing so has no effect on cardiac death, need for PCI, or admission to the hospital for heart failure or MI in patients with CAD and LV dysfunction, results from the Morbidity-Mortality Evaluation of the I f Inhibitor Ivabradine in Patients With Coronary Artery Disease and Left Ventricular Dysfunction (BEAUTIFUL) trial suggest. But as investigators showed here at the European Society of Cardiology Congress 2008, patients with higher heart rates to begin with--70 beats per minute (bpm) or higher--appear to derive some benefit from the drug, even on top of beta-blocker therapy.
"This trial failed its primary end point in BEAUTIFUL, and the conclusions that we can draw regarding the reduction in fatal and nonfatal MI are to a great extent hypothesis generating," Dr Kim Fox (Brompton Hospital, UK) acknowledged in a morning press conference. "They're reassuring, but they're not definitive, I'm not going to argue with that."
Kim later presented the BEAUTIFUL results during the first hotline session of the meeting; they have also been published online today in the Lancet [ 1].
In the Eye of the Beholder
BEAUTIFUL enrolled 10 917 patients from 781 centers in 33 countries, randomizing them to 5-mg ivabradine (with the aim of titrating up to 7.5 mg twice per day) or matched placebo, on top of best medical therapy, including high rates of aspirin, ACE inhibitors, and beta blockers. At a median of 19 months of follow-up, ivabradine had reduced heart rate by roughly 6 bpm but had no effect on the primary composite end point of cardiovascular death or admission to the hospital for AMI or new-onset or worsening heart failure. Among patients identified at the study outset as having a heart rate higher than 70 bpm--a prespecified subgroup--ivabradine reduced the secondary end points of admission to the hospital for fatal and nonfatal MI and need for coronary revascularization but had no effect on the primary composite outcome.
Hazard Ratio in Prespecified >70 bpm Subgroup
|End Point||Hazard Ratio||p|
|Primary composite end point||0.91||0.17|
|Admission to the hospital: heart failure||0.97||0.76|
|Admission to the hospital: MI||0.64||0.001|
Apart from some instances of bradycardia, the drug was well-tolerated and, according to Fox, supports the safety of ivabradine as an antianginal agent in this population. Ivabradine is an I f current inhibitor, already on the market in Europe for the treatment of symptomatic chronic stable angina.
Reacting to BEAUTIFUL
Commenting on the study for heartwire , Dr Alfred Bove (Temple University, Philadelphia, PA) pointed out that beta-blocker use was slightly higher among patients with heart rates lower than 70 bpm (90% vs 84%), a finding that might account for the larger effect of ivabradine in the higher-heart-rate group. "One of the questions I would ask would be, What if you had 90% of both groups on beta blockers--would there still be a benefit of the new drug?" he asked.
Bove called the overall results of the trial somewhat "predictable," given the known effects of the drug on heart rate. But despite the trial's failure to meet its primary end point, he believes it supports a role for ivabradine in patients who can't tolerate beta-blocker therapy.
"The problem with beta blockers is they have side effects," he explained. "In older patients you get depression, in males you get impotence, and in anyone you can get bradycardia. So this drug is probably going to have a place; in patients in whom you can't get the heart rate down until you make the patients sick with the side effects, this may be a great addition."
That said, Bove continued, "It will always be your first choice to titer the beta blocker first."
Dr Sydney Smith (University of North Carolina, Chapel Hill), the discussant during the hotline session, pointed to research showing that the number of secondary end points in a study can increase the risk of false-positive results in subgroup analyses. The multiple secondary end points in BEAUTIFUL warrant careful statistical analysis before any "formal conclusions" can be drawn from the study, Smith suggested. For the time being, he concluded, "I see no reason to change our current guideline-recommended therapy for patients with LV dysfunction, but I do think a prospective study is needed to look at effects of ivabradine on CAD outcomes for patients with heart rates >70 bpm."
Drs Jan-Christian Reil and Michael Bhm (Universitä:tsklinikum des Saarlandes, Homburg/Saar, Germany) point out in a Lancet Comment [ color="blue">2] that while a direct comparison of ivabradine and beta blockers would be "useful," such a trial "might be ethically challenging to set up."
Instead, they note, more answers may come from the SHIFT trial of ivabradine in heart-failure patients. For now, they conclude, "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."
| Heart Rate and Prognosis
The BEAUTIFUL investigators also highlighted a subgroup analysis, published in the Lancet alongside the overall study results, showing the link between high heart rate and worse prognosis [ color="blue">3]. Conducted in the placebo group, the subanalysis looked specifically at patients with heart rates above 70 bpm as compared with those with heart rates below 70 bpm, showing that after adjustment for baseline characteristics, those with the higher heart rates had a significantly increased risk of cardiovascular death, admission to the hospital for heart failure, admission for MI, and coronary revascularization.
Adjusted Hazard Ratios for Heart Rate >70 bpm vs <70 bpm
"I'm not saying this is conclusive evidence, but I think it's very important, and certainly it is at least evidence that we should be paying more attention to heart rate," Fox commented to the press. "What manipulation of that elevated heart rate does in terms of improving that outcome--I think this study probably generates as many questions as it does answers."
All of the study authors disclosed receiving fees, research grants, or both from the study sponsor, Servier.
Fox K, Ford I, Steg PG, et al. Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a randomised, double-blind, placebo-controlled trial. Lancet 2008; DOI:10.1016/S0140-6736(08)61170-8. Available at: www.thelancet.com.
Reil JC, BÃ¶hm M. BEAUTIFUL results—the slower, the better? Lancet 2008; DOI:10.1016/S0140-6736(08)61172-1. Available at: www.thelancet.com.
Fox K, Ford I, Steg PG, et al. Heart rate as a prognostic risk factor in patients with coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a subgroup analysis of a randomised controlled trial. Lancet 2008; DOI:10.1016/S0140-6736(08)61171-X. Available at: www.thelancet.com.
face="Verdana" size="1">The complete contents of Heartwire , a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals.
Heartwire from Medscape © 2008 Medscape
Cite this: Shelley Wood. BEAUTIFUL For Some: No Overall Advantage of Ivabradine, But High-Heart-Rate Patients May Benefit - Medscape - Aug 31, 2008.