Prognostic and symptomatic benefits with ivabradine: lessons from the SHIFT trial

Ivabradine, a funny current (If) inhibitor, has been developed for symptomatic therapy of angina and in chronic heart failure (CHF) with low ejection fraction. A large outcome trial, SHIFT (Systolic Heart Failure Treatment with the If inhibitor ivabradine trial), was conducted in patients with EF ≤ 35% in sinus rhythm and increased heart rate ≥70 b.p.m. It demonstrated that the addition of this new compound to the best possible contemporary therapy, including beta-blockers, was associated with a 18% relative risk reduction in the occurrence of cardiovascular mortality or hospitalization for worsening heart failure (HF), 26% relative risk reduction in HF hospitalization, and in HF death. This beneficial effect was of greater magnitude in patients with heart rate ≥75 b.p.m. Ivabradine improved health-related quality of life significantly and reduced the number of recurrent hospitalizations for HF. Sub-studies conducted in subgroups with important co-morbidities, i.e. chronic obstructive pulmonary disease, renal dysfunction, diabetes mellitus and low systolic blood pressure, show that the efficacy and the safety of the drug are similar compared with those observed in patients without these comorbidities. The acute cardiac effect is characterized by a reversal of the abnormal force–frequency relationship, thus resulting in preserved contractile function and increased stroke volume despite heart rate reduction. The chronic cardiac effect is characterized by a reverse remodelling of the left ventricle with reduced cardiac dimensions which result from unloading of the left ventricle. Ivabradine is now indicated in CHF NYHA class II–IV with systolic dysfunction in patients in sinus rhythm and whose heart rate is ≥75 b.p.m. in combination with standard therapy including beta-blocker therapy or when beta-blocker therapy is contraindicated or not tolerated.