What has the SIGNIFY trial shown?

Increased resting heart rate (HR) is an independent marker of increased cardiovascular risk, both in the general population and in patients

with various cardiovascular diseases. Pharmacological reduction of HR (e.g., with beta-blockers) reduces the cardiovascular risk. Ivabradine,

a selective sinus node If channel inhibitor, reduces HR without having other effects, such as haemodynamic ones. In the SHIFT trial, HR reduction

with ivabradine has been shown to reduce the rate of cardiovascular events in patients with systolic heart failure. A post hoc subgroup

analysis in the otherwise neutral BEAUTIFUL trial has suggested that ivabradine also can significantly improve the prognosis in patients with

chronic ischaemic heart disease (IHD) whose HR is > 70 bpm, particularly if they have concurrent angina pectoris. In order to confirm this

hypothesis, the SIGNIFY trial was designed and conducted. It included 19,102 patients with chronic IHD and normal left ventricular systolic

function who had a sinus rhythm and a resting HR ≥ 70 bpm. However, the results of this trial were surprising. Ivabradine did reduce the

resting HR by 10 bpm on average, but this reduction failed to result in a reduced incidence of the primary clinical endpoint – the sum of

cardiovascular deaths and non-fatal myocardial infarction (6.8% vs. 6.4%; HR = 1.08; CI = 0.96–1.20; p = 0.20). In a large subgroup of more

than 12,000 patients with angina pectoris, ivabradine even significantly increased the incidence of the primary endpoint (7.6% vs. 6.5%; HR =

1.18; CI = 1.03–1.35; p = 0.02). Treatment with ivabradine was also associated with a significantly higher rate of severe bradycardias and atrial

fibrillation. The unexpected results of the SIGNIFY trial have not been explained in a satisfactory manner. A higher daily dose of ivabradine

than previously used, or in part drug-drug interactions with verapamil and diltiazem could have played a role. Current recommendations

for treatment with ivabradine in systolic heart failure remain fully valid. When using ivabradine in stable angina pectoris, it is necessary to

respect the European Medicines Agency recommendations that, in this country, are in full compliance with the valid indication restriction.

Keywords: stable angina pectoris, ivabradine, chronic ischaemic heart disease, chronic heart failure, SIGNIFY trial