Advances in the management of heart failure: the role of ivabradine

Abstract

A high resting heart rate (≥70–75 b.p.m.) is a risk factor for patients with heart failure (HF) with reduced ejection fraction (EF), probably in the sense of accelerated atherosclerosis, with an increased morbidity and mortality. Beta-blockers not only reduce heart rate but also have negative inotropic and blood pressure-lowering effects, and therefore, in many patients, they cannot be given in the recommended dose. Ivabradine specifically inhibits the pacemaker current (funny current, If) of the sinoatrial node cells, resulting in therapeutic heart rate lowering without any negative inotropic and blood pressure-lowering effect. According to the European Society of Cardiology guidelines, ivabradine should be considered to reduce the risk of HF hospitalization and cardiovascular death in symptomatic patients with a reduced left ventricular EF ≤35% and sinus rhythm ≥70 b.p.m. despite treatment with an evidence-based dose of beta-blocker or a dose below the recommended dose (recommendation class “IIa” = weight of evidence/opinion is in favor of usefulness/efficacy: “should be considered”; level of evidence “B” = data derived from a single randomized clinical trial or large nonrandomized studies). Using a heart rate cutoff of ≥ 75 b.p.m., as licensed by the European Medicines Agency, treatment with ivabradine 5–7.5 mg b.i.d. reduces cardiovascular mortality by 17%, HF mortality by 39% and HF hospitalization rate by 30%. A high resting heart rate is not only a risk factor in HF with reduced EF but also at least a risk marker in HF with preserved EF, in acute HF and also in special forms of HF. In this review, we discuss the proven role of ivabradine in the validated indication “HF with reduced EF” together with interesting preliminary findings, and the potential role of ivabradine in further, specific forms of HF.

Influences of Ivabradine treatment on serum levels of cardiac biomarkers sST2, GDF-15, suPAR and H-FABP in patients with chronic heart failure

“…In our study population, there were no significant differences in NYHA stage and cardiovascular risk factors between ICM, DCM, and HCM patients at baseline, representing a homogenous patient population. Confirming former studies, our analysis showed that Ivabradine treatment led to a significant decrease in resting heart rate in all patients with CHF, regardless of disease etiology 20 .…”

“…A high resting heart rate is of highest prognostic relevance in heart failure patients and is associated with increased morbidity and mortality in patients with reduced ejection fraction 20,21,22 . Myocardial oxygen consumption and energy demand increase due to higher resting heart rates while myocardial perfusion decreases due to a shortening of diastole, resulting in a decrease in oxygen supply despite the increased myocardial strain 29,30 .…”

“…A high resting heart rate is of highest prognostic relevance in heart failure and is associated with rapid disease progression, resulting in increased rates of morbidity and mortality in patients with reduced ejection fraction 20,21,22 . Ivabradine has been evaluated as being one of the most promising new therapeutic options for heart rate reduction 20,22 and specifically inhibits the hyperpolarization-activated cyclic nucleotide-gated funny current channel (I f ; located in pacemaker cells of the sinoatrial node), thereby leading to a reduction in heart rate 20,23 . In comparison to beta-blockers, Ivabradine has no effect on myocardial contractility, atrioventricular or ventricular conduction 24,25 and has been proven to reduce cardiovascular mortality and hospitalization due to heart failure 26,27 .…”

Inhibition of hyperpolarization‐activated cyclic nucleotide‐gated channels by β‐blocker carvedilol

“…Ivabradine was approved by the FDA for the treatment of CHF in 2015 (U.S. Food and Drug Administration, ). It is used in combination with β‐blockers in people with CHF with a left ventricular ejection fraction lower than 35% inadequately controlled by β‐blockers alone and whose heart rate exceeds 70 beats min −1 (Müller‐Werdan et al ., ). In patients not sufficiently managed with β‐blockers for their heart failure, adding ivabradine decreases the risk of hospitalization due to worsening CHF (McMurray et al ., ; Tse and Mazzola, ).…”

Ivabradine in Congestive Heart Failure: Patient Selection and Perspectives

“…HF is a major public health issue, with a prevalence of over 25 million cases worldwide. Hospitalization due to HF is rising in the United States, particularly in elderly populations [7]. Despite a notable improvement in consequences with medical treatment, rehospitalization remains high, with more than 50% of patients re-hospitalized within six months of discharge [5].…”