The role of heart rate may differ according to pathophysiological setting: from SHIFT to SIGNIFY

The results of the SIGNIFY (study assessing the morbidity–mortality benefits of the If inhibitor ivabradine in patients with coronary artery disease) trial, which were recently published in the New England Journal of Medicine,1 raise an important pathophysiological question regarding the relationship between elevated heart rate and outcomes in cardiovascular disease. Why did heart rate reduction with ivabradine improve prognosis in patients with chronic heart failure and left ventricular (LV) systolic dysfunction in the SHIFT (systolic heart failure treatment with the If inhibitor ivabradine trial) study,2 but not in patients with stable coronary artery disease (CAD) without heart failure and LV systolic dysfunction in SIGNIFY? The 19 102 patients recruited in SIGNIFY presented with stable CAD plus additional cardiovascular risk factors and resting heart rate ≥70 bpm.1 The SIGNIFY investigators deliberately recruited patients with no symptoms of heart failure or LV systolic dysfunction: the population had a mean left ventricular ejection fraction (LVEF) at baseline of 56.5 ± 8.6%.3 All were receiving guideline-based background therapy for their condition. In this stable CAD population, ivabradine had no effect on the primary endpoint, a composite of cardiovascular death or non-fatal myocardial infarction (MI), with annual event rates of 3.0% with ivabradine and 2.8% with placebo (hazard ratio [HR] 1.08, 95% confidence interval [CI], 0.96–1.20, P = 0.20).1 There were no significant differences between the groups in terms of any of the secondary endpoints including cardiovascular death (HR 1.10, P = 0.25), non-fatal MI (HR 1.04, P = 0.60), or all-cause death (HR 1.06, P = 0.35). Treatment with ivabradine was associated with an increase in primary composite endpoint in a sub-group of 12 049 patients with angina Canadian Cardiovascular Society (CCS) 2 and higher (63% of the whole population) vs. those on placebo (HR 1.18, P = 0.018, in patient with CCS class 2 angina or higher; P = 0.02 for interaction). There was no significant effect of ivabradine on the components of the primary endpoint or the main secondary endpoints in this angina population. There was no interaction between the use of ivabradine and outcomes in seven other pre-specified sub-groups, which were defined according to age, β-blocker use at baseline, sex, heart rate at baseline, history of diabetes, previous MI, or previous coronary revascularization.