Ivabradine benefits patients with high heart rates, two studies say
Use of the heart-rate lowering drug ivabradine can reduce the incidence of cardiovascular disease and death in patients with coronary artery disease (CAD) and those who have a high heart rate, according to two studies presented this week at the European Society of Cardiology (ESC) Congress in Munich, Germany.

The studies on the BEAUTIFUL trial were published online Aug 31. in the Lancet. The second study also concluded that a higher resting heart rate in patients with CAD is a strong independent risk factor for death, heart attack and heart failure.

Ivabradine (Procolan from Servier) specifically inhibits electric currents on the pacemaker activity in the sinoatrial node (if inhibitor), which controls heart rate, but does not affect other aspects of cardiac function, according to the researchers.

Ivabradine was the first selective and specific if inhibitor to receive marketing authorization from the European Medicines Evaluation Agency (EMEA) for the symptomatic treatment of chronic stable angina pectoris in patients with normal sinus rhythm who have a contraindication or intolerance to beta-blockers.

Kim Fox, MD, from Royal Brompton Hospital in London, and colleagues from the BEAUTIFUL investigation team conducted a randomized, controlled trial to test whether lowering heart rate with the drug reduces cardiovascular death and disease in 10,917 patients with CAD and left-ventricular dysfunction. All patients received regular cardiovascular medicine, and in addition to this 5,479 patients received 5 mg ivabradine, with the intention of increasing to 7.5 mg twice a day, while 5,438 received matched placebo. The trial’s primary endpoint was a composite of death, admission to hospital for heart attack or admission to hospital for new or worsening heart failure.

Fox and colleagues found that patients had a mean heart rate of about 70 beats per minute (bpm). Ivabradine reduced heart rate by six bpm at 12 months. Most patients (87 percent) received ß blockers in addition to the study drugs, which did not cause any safety issues, according to the authors. Ivabradine had no effect on the primary endpoint for patients, and serious adverse events were as likely in both Ivabradine (22.5 percent) and placebo (22.8 percent) patients.

In a sub-group of patients with a heart rate above 70 bpm, Ivabradine again had no effect on the primary outcome, but did reduce coronary secondary outcomes, such as admission to hospital for fatal and non-fatal heart attack (36 percent reduced risk) and coronary revascularization percent (30 percent reduced risk). Both of these risk reductions were statistically significant, the authors wrote.

“Reduction in heart rate with ivabradine does not improve cardiac outcomes in all patients with stable coronary artery disease and left-ventricular systolic dysfunction, but could be used to reduce the incidence of coronary artery disease outcomes in a subgroup of patients who have heart rates of 70 bpm or greater,” Fox and colleagues concluded.

In the second study, the researchers analyzed a sub-group of the placebo group of the BEAUTIFUL study to test the hypothesis that raised resting heart rate at the start of the study was a marker for subsequent cardiovascular death and disease. Mathematical modeling was used to work out the likelihood of these outcomes for patients with a heart rate of above 70 bpm (2,693 patients) and below 70 bpm (2,745).

They found that in the above 70 bpm group, 34 percent had increased risk of cardiovascular death, 53 percent admission to hospital for heart failure, 46 percent admission to hospital for heart attack and 38 percent coronary revascularization. Analysis revealed that for every increase of 5 bpm, there were increases in cardiovascular death (8 percent), admission to hospital for heart failure (16 percent), admission to hospital for heart attack (7 percent) and coronary revascularization (8 percent).

The authors of the sub-group concluded that “elevated heart rate was a strong independent risk factor in patients with coronary artery disease and left-ventricular dysfunction. This was observed on top of a high level of background treatment, including ß blockers, in our patient population. Heart rate should be assessed as a prognostic marker and to guide optimum medical treatment in this patient population.”

“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,” said Jan-Christian Reil, MD, and Michael Böhm, MD, Universitätsklinikum des Saarlandes in Germany, in an accompanying Lancet commentary.