HR-lowering Agent Research Articles

The Role of Ivabradine in Managing Symptomatic Patients with Chronic Coronary Syndromes: A Clinically Oriented Approach

Angina is a significant contributor to disability and impairment in quality of life in patients with chronic coronary syndromes (CCS). An elevated heart rate (HR) may trigger myocardial ischemia by increasing oxygen consumption and decreasing the diastolic time, compromising the coronary flow. HR-lowering strategies offer symptom control and prevent cardiovascular events in subgroups of patients with CCS. However, the best therapeutic approach to achieve the desired HR in patients with CCS can be challenging based on efficacy and tolerability. Guidelines usually propose β-blockers and/or non-dihydropyridine calcium channel blockers (CCB) for angina patients with elevated HR. Nonetheless, there is no clear evidence of greater antianginal efficacy of this strategy versus an alternative HR-lowering agent. Ivabradine reduces the HR by blocking the If current in the sinoatrial node without affecting myocardial contractility or vascular tone. The magnitude of the HR reduction by ivabradine is proportional to the initial HR, which decreases the risk of significant bradycardia. Ivabradine increases the diastolic time and the coronary flow reserve to a greater extent than β-blockers and favors collateralization, improving the regional blood flow. We present two clinical cases of patients with symptomatic CCS in whom HR control with ivabradine was fundamental for symptom control and improvement in left ventricular (LV) function. An earlier combination of ivabradine plus β-blockers would have provided more rapid symptom control and improved LV function in the first case. In the second case, the primary mechanism responsible for angina was most likely a coronary vasomotor abnormality, in which the use of β-blockers aggravated the discomfort. The combination of a dihydropyridine CCB plus ivabradine was highly influential in symptom control. Due to its effects beyond HR reduction and good tolerability, ivabradine should be considered an essential ally in managing patients with angina and high HR with or without LV dysfunction. Talking Head Video (MP4 77394 kb)Supplementary InformationThe online version contains supplementary material available at 10.1007/s40119-021-00247-1.

Ivabradine Ameliorates Cardiac Diastolic Dysfunction in Diabetic Mice Independent of Heart Rate Reduction.

Cardiac fibroblast (CF) proliferation and activation play important roles in cardiac fibrosis and diastolic dysfunction (DD), which are involved in fibrosis-associated cardiovascular diseases. A previous study showed that ivabradine, a specific heart rate (HR)-lowering agent, significantly ameliorated DD in diabetic db/db mice by reducing HR. Herein, we attempted to determine whether ivabradine has antifibrotic and cardioprotective effects in diabetic mice by directly suppressing CF proliferation and activation, independent of a reduction in HR. We found that knockdown of c-Jun N-terminal kinase (JNK) or p38 mitogen-activated protein kinase (MAPK), or treatment with ivabradine, reduced JNK and p38 MAPK phosphorylation and the protein expression of proliferating cell nuclear antigen, collagen I, collagen III, tissue inhibitor of matrix metalloproteinase 2, and α-smooth muscle actin, accompanied with upregulation of matrix metalloproteinase 2 both in high glucose-treated neonatal rat CFs and left ventricular CFs isolated from db/db mice. However, zatebradine (a HR-lowering agent) did not have these effects in vitro or in vivo. In addition, cardiac fibrosis and DD were ameliorated in db/db mice that were intravenously administered lentiviruses carrying short hairpin RNAs targeting JNK and p38 MAPK or administered ivabradine. Taken together, these findings demonstrate that the ivabradine-induced amelioration of cardiac fibrosis, and DD in db/db mice may be at least in part attributable to the suppression of CF proliferation and activation, through the inhibition of JNK and p38 MAPK.

Ivabradine in Postural Orthostatic Tachycardia Syndrome: A Review of the Literature.

Postural orthostatic tachycardia syndrome (POTS) is an autonomic disorder characterized by symptoms such as palpitations, dyspnea, chest discomfort, and lightheadedness affecting various systems. The pathophysiology of POTS is not completely understood due to a variety of symptoms showing that the disease is multifactorial. There is no approved uniform management strategy for POTS and hence, no drug has been approved by the United States (US) Food and Drug Administration (FDA) for it. Ivabradine is an FDA-approved drug for stable symptomatic heart failure (HF) and patients with an ejection fraction (EF) of ≤35%. Previous studies have depicted improvement in symptoms of POTS with the use of ivabradine. It is a selective inhibitor of funny sodium channels (If) in the sinoatrial (SA) node cells resulting in the prolongation of the slow diastolic depolarization (phase IV) and reduction in the heart rate (HR). Although beta-adrenoceptor blockers are commonly used to lower HR in patients with POTS, they are less ideal due to numerous adverse effects. This review aims to provide a comprehensive and up-to-date picture of all the studies and case reports that utilized ivabradine for the treatment of POTS along with a precise overview of epidemiology, pathophysiology, and types of POTS. To conclude, we recommend further research on the effectiveness of ivabradine in patients who experience symptoms of POTS. Other than stable chronic angina pectoris, its application in this setting has been proven to be effective and safe. Further evaluation by means of randomized control trials is required to encourage use of this HR-lowering agent in common disorders other than HF and stable angina, i.e. POTS.

Novel drugs for heart rate control in heart failure.

In patients with heart failure, increased sympathetic activity is associated with a positive chronotropic stimulation leading to accelerated resting heart rate. Elevated heart rate (HR) is a risk factor for cardiovascular events, both in the general population and in patients with heart failure. Ivabradine is a pure HR-lowering agent, and it does not affect myocardial contractility, blood pressure, intracardiac conduction, or ventricular repolarization. In clinical trials such as BEAUTIFUL, CARVIVA HF, SHIFT, and INTENSIFY in patients with systolic left ventricular dysfunction, heart rate reduction with ivabradine brought positive outcomes. However, the results of the recent meta-analysis are rather neutral. In a diabetes mouse model of heart failure with preserved ejection fraction (HFpEF), selective heart rate reduction by If inhibition improved vascular stiffness, left ventricular (LV) contractility, and diastolic function. However, EDIFY (Effect of ivabradine in patients with heart rate with preserved ejection fraction) trial show that the use of ivabradine in patients with HFpEF is not supported. The further clinical trials investigating the use of ivabradine in heart failure should be carried out.

Ivabradine in Patients with ST-Elevation Myocardial Infarction Complicated by Cardiogenic Shock: A Preliminary Randomized Prospective Study.

An elevated heart rate (HR) is an independent risk factor for mortality and morbidity in patients with acute heart failure (HF). The purpose of this study was to evaluate the impact of ivabradine, a selective HR-lowering agent, in patients with cardiogenic shock (CS) complicating ST-elevation acute myocardial infarction (AMI). Patients with post-AMI CS were randomized to standard treatment (SDT, 28 patients) or to standard treatment plus ivabradine (I+SDT, 30 patients). In the presence of orotracheal intubation (OTI), ivabradine was administered by nasogastric intubation. HR, BP, New York Heart Association (NYHA) class, NT-proBNP, left ventricular ejection fraction (LVEF) and diastolic function (LVDF) were monitored at specific times after the onset of AMI. The primary (surrogate) end-point was the in-hospital halving of plasma NT-proBNP levels. The secondary end-points were cardiovascular death, hospital re-admission for worsening HF, and clinical and haemodynamic improvement. Treatment groups were statistically similar with regard to age, gender distribution, cardiovascular risk factors, number of diseased vessels and overall treated lesions, AMI site and occurrence of OTI. In-hospital mortality was double in the SDT group in comparison with the I+SDT group (14.3 vs. 6.7%), but the difference was not statistically significant. HR, BP, NT-proBNP and LVEF favorably changed in both groups, but the change was more relevant in the I+SDT group. LVDF significantly changed only in the I+SDT group (p<0.01). Patients in the I+SDT group did not experience adverse effects. Ivabradine in CS complicating AMI is safe, is associated with a short-term favourable outcome and can be effectively administered by nasogastric intubation.

Heart rate as a possible therapeutic guide for the prevention of cardiovascular disease

Epidemiologic evidence indicates that an elevated heart rate (HR) is an independent predictor of all-cause and cardiovascular (CV) mortality. Ivabradine, a pure HR-lowering agent, reduces CV events in patients with coronary artery disease (CAD) and chronic heart failure, and indicate that an HR greater than 70 b.p.m. is hazardous. These findings demonstrate not only that an elevated HR is an epiphenomenon of CV risk status but also that an elevated HR itself should be a therapeutic target. In addition, recent epidemiologic evidence demonstrates that the in-treatment HR or HR change predicts subsequent all-cause and CV mortality, independent of the HR-lowering strategy. Characteristics of the in-treatment HR or HR change are also important as possible therapeutic guides for risk management. However, there have been concerns regarding deleterious effects on CV event prevention owing to β-blocker-derived pharmacologic HR reduction. The potential role of HR and its modulation should be considered in future guidance documents.

Ivabradine: an intelligent drug for the treatment of ischemic heart disease.

Heart rate (HR) is a precisely regulated variable, which plays a critical role in health and disease. Elevated resting HR is a significant predictor of all-cause and cardiovascular mortality in the general population and patients with cardiovascular disease (CVD). β-blocking drugs exert negative effects on regional myocardial blood flow and function when HR reduction is eliminated by atrial pacing; calcium channel antagonists (CCAs) functionally antagonize coronary vasoconstriction mediated through α-adreno-receptors and are thus devoid of this undesired effect, but the compounds are nevertheless negative inotropes. From these observations derives the necessity to find alternative, more selective drugs to reduce HR through inhibition of specific electrical current (If). Ivabradine (IVA) is a novel specific HR-lowering agent that acts in sinus atrial node (SAN) cells by selectively inhibiting the pacemaker If current in a dose-dependent manner by slowing the diastolic depolarization slope of SAN cells, and by reducing HR at rest during exercise in humans. Coronary artery diseases (CAD) represent the most common cause of death in middle–aged and older adults in European Countries. Most ischemic episodes are triggered by an increase in HR, that induces an imbalance between myocardial oxygen delivery and consumption. IVA, a selective and specific inhibitor of the If current which reduced HR without adverse hemodynamic effects, has clearly and unequivocally demonstrated its efficacy in the treatment of chronic stable angina pectoris (CSAP) and myocardial ischemia with optimal tolerability profile due to selective interaction with If channels. The aim of this review is to point out the usefulness of IVA in the treatment of ischemic heart disease.

Heart Rate-Lowering Efficacy and Respiratory Safety of Ivabradine in Patients with Obstructive Airway Disease

There is substantial evidence that heart rate (HR) is a powerful predictor of mortality in both normal individuals and in patients with cardiovascular disease. The use of β-adrenoceptor antagonists (β-blockers) has confirmed the importance of lowering elevated HR in a patient's prognosis. However, these agents can have undesirable adverse effects (AEs) and due to the risk of bronchoconstriction are contraindicated in patients with obstructive airway disease. A selective bradycardic agent, without such undesirable effects, could be of therapeutic interest. Ivabradine, a new I(f) inhibitor that acts specifically on the sino-atrial node, is a pure HR-lowering agent. The objective of this study was to assess HR-lowering efficacy and respiratory safety of ivabradine in patients with asthma and chronic obstructive pulmonary disease (COPD). This was a randomized, single-center, double-blind, placebo-controlled, crossover trial. Enrolment began in May 2009, and the last patient completed the study in January 2011. The study was conducted in an ambulatory setting. A total of 40 patients completed the study (20 asthmatic patients and 20 COPD patients). Inclusion criteria were: documented diagnosis of asthma or COPD according to international guidelines, age 18-75 years, and mean HR on Holter ECG recording of ≥60 beats/min. Exclusion criteria included disease exacerbation in a previous month or inability to understand instructions on the study procedures. All patients received ivabradine 7.5 mg twice daily for 5 days and placebo twice daily for 5 days in a crossover manner, in one of the two arms of the study, with at least 2 days of washout between treatments. The main outcome measures included the difference in HR between ivabradine and placebo treatment and change in HR in comparison with baseline. Other evaluated outcomes were differences in the peak expiratory flow rate (PEFR), the daily symptom score, rescue medication consumption, and AEs. Ivabradine produced significantly lower mean HR than placebo in both groups of patients: asthma 67.4 ± 8.38 versus 82.85 ± 11.19 beats/min (p < 0.001) and COPD 69.75 ± 8.9 versus 81.05 ± 9.75 beats/min (p < 0.001). Similar results were observed for the minimal HR as well as for the maximal noted HR. In comparision with baseline, ivabradine significantly reduced HR in both groups of studied patients (all p < 0.05), whereas placebo did not have such an effect. No significant difference, in either the asthma or the COPD group, was found between ivabradine and placebo in morning and evening peak expiratory flow rate, peak expiratory flow diurnal variability, daily symptom scores, and rescue medication usage (all p > 0.05). Both treatments were well tolerated. The incidence of AEs was low and generally similar in both periods of treatment, except for visual symptoms during treatment with ivabradine, which was reported by 5% of the patients. Our study demonstrated that selective HR reduction with ivabradine is effective in patients with asthma and COPD, with no alteration in respiratory function or symptoms over the duration of the study. Ivabradine offers an interesting alternative, as an HR-lowering agent, in patients with respiratory disease and contraindications to β-blockers. Registered at www.clinicaltrials.gov (NCT01365286).

Ivabradine Versus Metoprolol for Heart Rate Reduction Before Coronary Computed Tomography Angiography

Several studies have demonstrated the correlation of heart rate (HR) and image quality in coronary computed tomography angiography. Beta-blocker administration is critical because of its negative inotropic effect. Ivabradine is a selective HR-lowering agent that exclusively inhibits the I(f) current in sinoatrial node cells without having any effect on cardiac contractility or atrioventricular conduction. A total of 120 patients were randomized to oral premedication with ivabradine 15 mg or metoprolol 50 mg. HR and blood pressure (BP) were measured before the administration of premedication and immediately before coronary computed tomographic angiography. The mean time between premedication administration and follow-up was 108 ± 21.5 minutes for ivabradine and 110 ± 22.2 minutes for metoprolol (p = NS). When comparing groups, there were no significant differences in reduction of HR (-11.83 ± 8.6 vs -13.20 ± 7.8 beats/min, p = NS) and diastolic BP (-5.05 ± 14.2 mm Hg vs -4.08 ± 10.8 mm Hg, p = NS), whereas the decrease of systolic BP was significantly lower in patients who received ivabradine compared to those in the metoprolol group (-3.95 ± 13.6 vs -13.65 ± 17.3 mm Hg, p <0.001). In the subgroup of patients who were receiving long-term β-blocker therapy, significantly stronger HR reduction was achieved with ivabradine (-13.19 ± 5.4 vs -10.04 ± 6.0 beats/min, p <0.05), while the decrease in systolic BP was less (-2.00 ± 13.6 vs -15.04 ± 20.8 mm Hg, p <0.05) compared to metoprolol. In conclusion, ivabradine decreases HR before coronary computed tomographic angiography sufficiently, with significantly less depression of systolic BP compared to metoprolol.

Reducing elevated heart rate in patients with multiple organ dysfunction syndrome by the I f (funny channel current) inhibitor ivabradine

Heart rate (HR) is of relevant prognostic value not only in the general population and patients with cardiovascular disease, but also in critically ill patients with multiple organ dysfunction syndrome (MODS). An elevated HR in MODS patients is associated with a worse prognosis. Beta-blocker (BB) administration has been shown to reduce mortality in MODS. In most cases, negative inotropic effects prevent administration of BBs in MODS patients. In this trial we investigate, whether the "funny current" (I (f)) channel inhibitor ivabradine is able and apt to reduce pathologically elevated HR in MODS patients. We hypothesize that critically ill patients could derive particular benefit from the specific HR-lowering agent ivabradine. MODI (f)Y is a prospective, single centre, open label, randomized, controlled two arms, phase II-trial to evaluate the potential of ivabradine to reduce an elevated HR in MODS patients. The primary end point is the proportion of patients with a reduction of HR by at least 10 beats per minute (bpm) within 4days. This trial will randomize 70 patients (men and women, aged ≥18years) with newly diagnosed MODS, with an elevated HR (sinus rhythm with HR ≥90bpm) and contraindications to BB therapy. Treatment period will last for 4days. All patients will be followed for 6months. The first patient was randomized on May 21, 2010. The MODI (f)Y trial is the first application of ivabradine as a pure heart rate reducing agent in MODS patients.

Increased heart rate and atherosclerosis: Potential implications of ivabradine therapy

Despite all the therapeutic advances in the field of cardiology, cardiovascular diseases, and in particular coronary artery disease, remain the leading cause of death and disability worldwide, thereby underlining the importance of acquiring new therapeutic options in this field. A reduction in elevated resting heart rate (HR) has long been postulated as a therapeutic approach in the management of cardiovascular disease. An increased HR has been shown to be associated with increased progression of coronary atherosclerosis in animal models and patients. A high HR has also been associated with a greatly increased risk of plaque rupture in patients with coronary atherosclerosis. Endothelial function may be an important link between HR and atherosclerosis. An increased HR has been shown experimentally to cause endothelial dysfunction. Inflammation plays a significant role in the pathogenesis and progression of atherosclerosis. In the literature, there is data that shows an association between HR and circulating markers of vascular inflammation. In addition, HR reduction by pharmacological intervention with ivabradine (a selective HR-lowering agent that acts by inhibiting the pacemaker ionic current I(f) in sinoatrial node cells) reduces the formation of atherosclerotic plaques in animal models of lipid-induced atherosclerosis. The aim of this editorial is to review the possible role of ivabradine on atherosclerosis.

Role of Heart Rate in Cardiovascular Diseases

The BEAUTIFUL (morBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary artery disease and left ventricULar systolic dysfunction) study assessed the morbidity and mortality benefits of the HR-lowering agent ivabradine. The placebo arm of the BEAUTIFUL trial was a large cohort of patients with stable coronary artery disease (CAD) and left ventricular systolic dysfunction. A subanalysis in the placebo group tested the hypothesis that elevated resting HR at baseline was a marker for subsequent cardiovascular death and morbidity. The primary aim of the study was to test whether lowering the HR with ivabradine reduced cardiovascular death and morbidity in patients with CAD and left ventricular systolic dysfunction. In the overall analysis, reduction in HR with ivabradine did not improve cardiac outcomes compared with placebo. The most important finding of the study was that patients with high baseline HR had an increase in serious cardiovascular events including death (34%), hospital admission secondary to congestive heart failure (53%), acute myocardial infarction (46%), or revascularization procedure (38%). In addition, in the subset analysis focusing on patients with baseline HR > or =70 bpm and left ventricular ejection fraction <40% the agent resulted in a 36% decrease in hospital admissions secondary to fatal and nonfatal myocardial infarction and a 30% decrease in coronary revascularization. The first practical implication from the study includes that baseline HR should be recorded in addition to other risk factors such as BP and lipid profile, in the follow-up of patients with CAD. Attempts should be made to achieve HR <70 bpm by cardiac rehabilitation and routine use of appropriately dosed beta-blockers. Despite the neutral results obtained in the BEAUTIFUL study, ivabradine could be administered to the subgroup of patients in whom HR <70 bpm is not achieved despite proper dosing of beta-blockers and in those in whom beta-blockers are contraindicated. Furthermore, in clinical practice, ivabradine may be helpful for patients with stable CAD who have a high HR while receiving beta-blockers. Future studies are needed to confirm the hypothesis that single reduction of HR can improve cardiovascular prognosis.

Ivabradine: Beyond heart rate control

Chronic stable angina pectoris (CSAP) usually occurs in patients with coronary artery disease (CAD) that affects one or more large epicardial arteries. It results when myocardial perfusion is insufficient to meet cardiac metabolic demand. Elevated heart rate (HR) is an important factor in the development of myocardial ischemia and angina pectoris. The pharmacologic agents most commonly administered in the treatment of CSAP are beta-blockers and calcium channel blockers (CCBs). However, the use of beta-blockers is limited by poor compliance related to contraindications and comorbidities, especially in elderly patients. Ivabradine is a new selective HR-lowering agent that selectively inhibits the pacemaker current I (f) in the sinus atrial node. In several randomized controlled trials, ivabradine 5-10 mg twice daily has demonstrated equivalent anti-ischemic and anti-anginal activity to beta-blockers and CCBs, with a good safety and tolerability profile. Although ivabradine has been shown not to improve cardiac outcomes in patients with stable CAD and left ventricular systolic dysfunction, it may be used to reduce the incidence of CAD outcomes in a subgroup of patients with HR > or =70 bpm. The aim of this short review is to summarize the use of ivabradine in the treatment of CSAP, and its potential utility in atherosclerosis, primitive and dilatative cardiomyopathy, and arrhythmias, such as postural tachycardia syndrome and inappropriate sinus tachycardia, where exclusive lowering of elevated HR may prove beneficial.

Rationale and design of a randomized, double-blind, placebo-controlled trial of ivabradine in patients with stable coronary artery disease and left ventricular systolic dysfunction: the morBidity-mortality EvAlUaTion of the I f inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction (BEAUTIFUL) Study

Raised resting heart rate (HR) is associated with increased cardiovascular and total mortality. Ivabradine is a new specific HR-reducing agent, which has been shown to have antianginal and anti-ischemic properties in patients with stable angina. Because patients with coronary artery disease and left ventricular dysfunction are at high risk of cardiac events and death, we hypothesized that they could derive particular benefit from a specific HR-lowering agent such as ivabradine. BEAUTIFUL is a multicenter, randomized, international, double-blind placebo-controlled trial to evaluate the superiority of ivabradine over placebo in reducing cardiovascular events in patients with stable coronary artery disease and left ventricular systolic dysfunction (ejection fraction < or = 39%). The primary end point is the composite of cardiovascular mortality and hospital admission for acute myocardial infarction or new onset or worsening of heart failure. This event-driven study will randomize 9650 patients and continue until 950 primary end points have occurred, providing 90% power to detect a 19% reduction in relative risk. In approximately 660 centers, men and women aged > or = 55 years if nondiabetic and > or = 18 years if diabetic are randomized to placebo or oral ivabradine (5 mg twice daily for 2 weeks then target dose of 7.5 mg twice daily). Follow-up is expected to last between 18 and 36 months. The first patient was randomized in January 2005. BEAUTIFUL will be the first major outcome trial of a specific HR-reducing agent. The study results are expected in 2008.