Heart rate as a risk factor in chronic heart failure (SHIFT): the association between heart rate and outcomes in a randomised placebo-controlled trial

BACKGROUND: Raised resting heart rate is a marker of cardiovascular risk. We postulated that heart rate is also a risk factor for cardiovascular events in heart failure. In the SHIFT trial, patients with chronic heart failure were treated with the selective heart-rate-lowering agent ivabradine. We aimed to test our hypothesis by investigating the association between heart rate and events in this patient population. METHODS: We analysed cardiovascular outcomes in the placebo (n=3264) and ivabradine groups (n=3241) of this randomised trial, divided by quintiles of baseline heart rate in the placebo group. The primary composite endpoint was cardiovascular death or hospital admission for worsening heart failure. In the ivabradine group, heart rate achieved at 28 days was also analysed in relation to subsequent outcomes. Analysis adjusted to change in heart rate was used to study heart-rate reduction as mechanism for risk reduction by ivabradine directly. FINDINGS: In the placebo group, patients with the highest heart rates (>or=87 beats per min bpm, n=682, 286 events) were at more than two-fold higher risk for the primary composite endpoint than were patients with the lowest heart rates (70 to <72 bpm, n=461, 92 events; hazard ratio HR 2.34, 95% CI 1.84-2.98, p<0.0001). Risk of primary composite endpoint events increased by 3% with every beat increase from baseline heart rate and 16% for every 5-bpm increase. In the ivabradine group, there was a direct association between heart rate achieved at 28 days and subsequent cardiac outcomes. Patients with heart rates lower than 60 bpm at 28 days on treatment had fewer primary composite endpoint events during the study (n=1192; event rate 17.4%, 95% CI 15.3-19.6) than did patients with higher heart rates. The effect of ivabradine is accounted for by heart-rate reduction, as shown by the neutralisation of the treatment effect after adjustment for change of heart rate at 28 days (HR 0.95, 0.85-1.06, p=0.352). INTERPRETATION: Our analysis confirms that high heart rate is a risk factor in heart failure. Selective lowering of heart rates with ivabradine improves cardiovascular outcomes. Heart rate is an important target for treatment of heart failure. FUNDING: Servier, France.