Intravenous ivabradine versus placebo in patients with low cardiac output syndrome treated by dobutamine after elective coronary artery bypass surgery: a phase 2 exploratory randomized controlled trial.

BACKGROUND: Low cardiac output syndrome (LCOS) is a severe condition which can occur after cardiac surgery, especially among patients with pre-existing left ventricular dysfunction. Dobutamine, its first-line treatment, is associated with sinus tachycardia. This study aims to assess the ability of intravenous ivabradine to decrease sinus tachycardia associated with dobutamine infused for LCOS after coronary artery bypass graft (CABG) surgery. METHODS: In a phase 2, multi-center, single-blind, randomized controlled trial, patients with left ventricular ejection fraction below 40% presenting sinus tachycardia of at least 100 beats per minute (bpm) following dobutamine infusion for LCOS after CABG surgery received either intravenous ivabradine or placebo (three ivabradine for one placebo). Treatment lasted until dobutamine weaning or up to 48 h. The primary endpoint was the proportion of patients achieving a heart rate (HR) in the 80- to 90-bpm range. Secondary endpoints were invasive and non-invasive hemodynamic parameters and arrhythmia events. RESULTS: Nineteen patients were included. More patients reached the primary endpoint in the ivabradine than in the placebo group (13 (93%) versus 2 (40%); P = 0.04). Median times to reach target HR were 1.0 h in the ivabradine group and 5.7 h in the placebo group. Ivabradine decreased HR (112 to 86 bpm, P <0.001) while increasing cardiac index (P = 0.02), stroke volume (P <0.001), and systolic blood pressure (P = 0.03). In the placebo group, these parameters remained unchanged from baseline. In the ivabradine group, five patients (36%) developed atrial fibrillation (AF) and one (7%) was discontinued for sustained AF; two (14%) were discontinued for bradycardia. CONCLUSION: Intravenous ivabradine achieved effective and rapid correction of sinus tachycardia in patients who received dobutamine for LCOS after CABG surgery. Simultaneously, stroke volume and systolic blood pressure increased, suggesting a beneficial effect of this treatment on tissue perfusion. TRIAL REGISTRATION: European Clinical Trials Database: EudraCT 2009-018175-14 . Registered February 2, 2010.

Duration of chronic heart failure affects outcomes with preserved effects of heart rate reduction with ivabradine: findings from SHIFT.

AIMS: In heart failure (HF) with reduced ejection fraction and sinus rhythm, heart rate reduction with ivabradine reduces the composite incidence of cardiovascular death and HF hospitalization. METHODS AND RESULTS: It is unclear whether the duration of HF prior to therapy independently affects outcomes and whether it modifies the effect of heart rate reduction. In SHIFT, 6505 patients with chronic HF (left ventricular ejection fraction of ≤35%), in sinus rhythm, heart rate of ≥70 b.p.m., treated with guideline-recommended therapies, were randomized to placebo or ivabradine. Outcomes and the treatment effect of ivabradine in patients with different durations of HF were examined. Prior to randomization, 1416 ivabradine and 1459 placebo patients had HF duration of ≥4 weeks and <1.5 years; 836 ivabradine and 806 placebo patients had HF duration of 1.5 years to <4 years, and 989 ivabradine and 999 placebo patients had HF duration of ≥4 years. Patients with longer duration of HF were older (62.5 years vs. 59.0 years; P < 0.0001), had more severe disease (New York Heart Association classes III/IV in 56% vs. 44.9%; P < 0.0001) and greater incidences of co-morbidities [myocardial infarction: 62.9% vs. 49.4% (P < 0.0001); renal dysfunction: 31.5% vs. 21.5% (P < 0.0001); peripheral artery disease: 7.0% vs. 4.8% (P < 0.0001)] compared with patients with a more recent diagnosis. After adjustments, longer HF duration was independently associated with poorer outcome. Effects of ivabradine were independent of HF duration. CONCLUSIONS: Duration of HF predicts outcome independently of risk indicators such as higher age, greater severity and more co-morbidities. Heart rate reduction with ivabradine improved outcomes independently of HF duration. Thus, HF treatments should be initiated early and it is important to characterize HF populations according to the chronicity of HF in future trials.

Chronic exposure to ivabradine reduces readmissions in the vulnerable phase after hospitalization for worsening systolic heart failure: a post-hoc analysis of SHIFT.

AIMS: During the post-discharge phase following a heart failure hospitalization (HFH), patients are at high risk of early readmission despite standard of care therapy. We examined the impact of chronic exposure to ivabradine on early readmissions in patients hospitalized for heart failure during the course of the SHIFT study (Systolic Heart Failure treatment with the If inhibitor ivabradine Trial). METHODS AND RESULTS: A total of 1186 of the 6505 randomized patients experienced at least one HFH during the study, and had a more severe profile than those without HFH. Of these 1186 patients, 334 patients (28%) were rehospitalized within 3 months for any reason, mostly for cardiovascular causes (86%), including HFH (61%). Ivabradine was associated with fewer all-cause hospitalizations at 1 month [incidence rate ratio (IRR) 0.70, 95% confidence interval (CI) 0.50-1.00, P < 0.05], 2 months (IRR 0.75, 95% CI 0.58-0.98, P = 0.03), and 3 months (IRR 0.79, 95% CI 0.63-0.99, P = 0.04). A trend for a reduction in cardiovascular and HF hospitalizations was also observed in ivabradine-treated patients. CONCLUSION: We demonstrate in this post-hoc analysis that chronic exposure to ivabradine reduces the incidence of all-cause hospitalizations during the vulnerable phase after a HFH. Further studies are needed to investigate if in-hospital or early post-discharge initiation of ivabradine could be useful to improve early outcomes in patients hospitalized for HF.