High heart rate is a risk factor in heart failure (HF), and selective lowering of heart rates with ivabradine improves cardiovascular (CV) outcomes in HF, based on results from two arms of the SHIFT trial, presented at the European Society of Cardiology (ESC) congress this week in Stockholm, and simultaneously published in the Lancet. However, an accompanying editorial suggests that these findings do not yet warrant a paradigm shift.

Servier, drug manufacturer of ivabradine, funded two arms of SHIFT (Systolic Heart failure treatment with I inhibitor ivabradine Trials), which assessed 3,268 patients in the ivabradine group and 3,290 patients in the placebo group,

In one study, Michael Böhm, MD, director of the clinic for internal medicine and cardiology at the University Hospital of Saarland in Homburg/Saar, Germany, and colleagues hypothesized that heart rate also is a risk factor for CV events in HF. To this end, the researchers analyzed CV outcomes in this randomized, double-blind multinational trial, divided by quintiles of baseline heart rate in the placebo group. The primary endpoint was a composite of CV death or hospital admission for worsening HF.

Similarly, Karl Swedberg, MD, department of medicine at Göteborg Universityl in Göteborg, Sweden, and colleagues aimed to assess the effect of heart rate reduction by the selective sinus-node inhibitor ivabradine on outcomes in HF. The participants had symptomatic HF and a left ventricular ejection fraction of 35 percent or less; were in sinus rhythm with a heart rate of 70 beats per minute (bpm) or higher; had been admitted to the hospital for HF within the previous year; and were on stable background treatment including beta-blockers if tolerated.

Böhm and colleagues found that in the placebo group, patients with the highest heart rates (>87 bpm, 682 patients, 286 events) were at more than a two-fold higher risk for primary composite endpoint than patients with the lowest heart rates (70 to <72 bpm, 461 patients, 92 events). Also, the risk of primary composite endpoint events increased by 3 percent with every beat increase from baseline heart rate, and 16 percent for every 5 bpm increase.

In the ivabradine group, Böhm and colleagues noted a “direct association” between heart rate achieved at 28 days and subsequent CV outcomes. Patients with heart rates lower than 60 bpm at 28 days on treatment had fewer primary composite endpoint events during the study (1,192 patients, 17.4 event rate) than did patients with higher heart rates. “The effect of ivabradine is accounted for by heart rate reduction, as shown by the neutralization of the treatment effect after adjustment for change of heart rate at 28 days,” they wrote.

“[S]ince the lowest heart rates achieved on treatment are associated with the best outcomes, and because the incremental benefit of ivabradine was obtained by titration of the drug to heart rates lower than 60 bpm,” Böhm and colleagues recommended that this target, when tolerated, should be pursued in patients with chronic HF.

During a median follow-up of 22.9 months, Swedberg and colleagues found that 24 percent of patients in the ivabradine group and 29 percent of those taking placebo had a primary endpoint event. The effects were driven mainly by hospital admissions for worsening HF (21 percent placebo vs. 16 percent ivabradine) and deaths due to HF (5 percent placebo vs. 3 percent ivabradine).

However, Swedberg and colleagues discovered fewer serious adverse events in the ivabradine group (3,388 events) than in the placebo group (3,847 events). Five percent of the ivabradine patients had symptomatic bradycardia compared to 1 percent of the placebo group.

“Our results support the importance of heart rate reduction with ivabradine for improvement of clinical outcomes in HF and confirm the important role of heart rate in the pathophysiology of HF,” Swedberg and colleagues concluded.

In the accompanying Lancet editorial, John R. Teerlink, MD, from the University of Calfornia, San Francisco, wrote that despite the SHIFT investigators' efforts to enroll a population and stable background treatment for at least four weeks, only 23 percent of the patients were at target dose and 49 percent were receiving 50 percent or more of the targeted beta-blocker dose. Also, he said that their heart rates were similar to those of patients naïve to beta-blockers, “calling into question whether they were truly on maximally tolerated doses.”

Teerlink also noted that all patients in the trial potentially qualified for an implantable cardioverter-defibrillator, but only 3 percent had such devices and only 1 percent had cardiac resynchronization therapy.

Because the patient population didn’t adhere to guideline-recommended beta-blocker doses, Teerlink said it is “not clear” that SHIFT successfully tested the hypothesis that ivabradine provided additional benefit to patients with HF treated with contemporary optimal HF therapies.

Furthermore, he cautioned providers from substituting ivabradine for beta-blockers in patients with HF. Also, Teerlink wrote that ivabradine had “no significant benefit for the primary endpoint, although there was a modest reduction in HF hospitalizations, which raises the question of whether there would be any benefit even on hospitalizations with ivabradine in the context of beta-blocker therapy at or near target doses.”

In his conclusion, Teerlink wrote that “whether ivabradine can improve outcomes in addition to optimally managed HF therapies or its benefits relative to other therapies, especially beta-blockers, remains unknown,” and cautions providers “not [to] rush too quickly to embrace this new therapy.”