Among patients with systolic heart failure and reduced left ventricular function who were stable on beta blocker treatment, reducing heart rate with ivabradine (Procoralan) significantly reduced death and heart failure hospitalizations compared with placebo, researchers reported here.
In the ivabradine group 24% of patients reached the primary endpoint of heart failure hospitalization or death versus 29% of placebo patients (hazard ratio 0.82, 95% confidence interval 0.75 to 0.90, P<0.001), over a median follow-up period of 22.9 months, said Michel Komajda, MD, of Pitié Salpetrière Hospital in Paris. He presented findings from the SHIFT (Systolic Heart Failure Treatment with the If Inhibitor Ivabradine Trial) study at the European Society of Cardiology meeting. The findings were simultaneously published online by The Lancet. Ivabradine specifically inhibits the If current in the sinoatrial node to reduce heart rate, considered a risk factor for death and other adverse outcomes in heart failure patients. The trial randomized 3,268 patients to ivabradine at a maximum dose of 7.5 mg twice daily or to matched placebo on top of beta blocker therapy. All patients had symptomatic heart failure and left ventricular function of less than 35%. Three-quarters of the patients were men and about 30% had diabetes. Half of the patients had class III NYHA heart failure and half had mild (Class II) heart failure. But while the reductions were statistically significant, the absolute numbers were small: 151 deaths in the placebo arm versus 113 in ivabradine arm, and 514 hospitalizations in the treatment arm versus 672 in the control group. Nonetheless, after the drug failed to reduce myocardial infarctions, hospitalizations or death in the BEAUTIFUL trial, which was reported at ESC in 2008, SHIFT was considered a clear win by its investigators. In 2008, the ivabradine investigators said they believed that the treatment would be effective in select groups. The SHIFT results appear to pinpoint one such group: patients with systolic heart failure. But finding that select population was a limiting factor, so the authors wrote that they could not "generalize the effect of ivabradine to the overall population with chronic heart failure." They did, however, conclude that the SHIFT results supported "the importance of heart-rate reduction with ivabradine for improvement of clinical outcomes in heart failure and confirm the important role of heart rate in the pathophysiology of heart failure." The SHIFT investigators also analyzed cardiovascular outcomes in the placebo group and reported those findings here and in a second paper, also published by Lancet. The placebo analysis found that patients with heart rates of 87 beats a minute or more had more than a two-fold higher risk for death or hospitalization than patients with heart rates of 70 to 72 beats a minute (P<0.0001). In the placebo group the "rate of the primary composite endpoint events increased by 3% with every beat increase from baseline heart rate and 16% for every 5 bpm increase," they wrote. Ivabradine is approved by the European Medicines Agency for treatment of angina but is not FDA approved. In a commentary published along with the two SHIFT papers, John R. Teerlink, MD, of the University of California San Francisco, said that still more trials are needed before a benefit of ivabradine is confirmed. He noted that only 23% of the SHIFT patients were at target dose for beta-blocker therapy and "under half (49%) were receiving 50% or more of the targeted beta-blocker dose." Without an active comparator arm at maximally tolerated beta-blocker dosing, it was difficult to assess the results and he warned against a rush to judgment. The authors said that excluding patients with sustained atrial fibrillation was a limitation of the overall study, as was a low proportion of elderly patients in the trial -- the median age was 60. source: Lancet