Assessment of safety profile of ivabradine in real-world scenario using FDA adverse event reporting system database.

BACKGROUND: Ivabradine is primarily indicated for patients with sinus rhythm and a heart rate ≥ 75 beats/min, who have NYHA class II-IV chronic heart failure with systolic dysfunction. There is currently a lack of large-scale, real-world studies concerning its drug adverse reactions. RESEARCH DESIGN & METHODS: This research assesses the side effects of ivabradine by analyzing reports of adverse events (AEs) from the FDA's Adverse Event Reporting System (FAERS) database. To evaluate the importance of these AEs, four sequential analytic strategies were utilized. RESULTS: In total, 2,701 ivabradine-related AE reports were identified in the FAERS database. We identified 26 ivabradine-induced AEs, each with more than 20 reports, including some significant AEs not mentioned on the product label. The timing of AEs was also analyzed, with the majority of AEs occurring within the first month of ivabradine use. Gender-specific analysis indicates that female have a higher risk of AEs, such as off-label use, tachycardia, drug effectiveness for unapproved indications, and rash compared to male. CONCLUSION: This study provides important information for maximizing the usage of ivabradine, increasing its efficacy, and reducing any possible negative effects. The actual clinical use of the medication will be greatly aided by this knowledge.

Ivabradine and Milrinone-Bridge to Recovery in New HFrEF With Low-Output Heart Failure.

In patients with newly diagnosed heart failure with reduced ejection fraction (HFrEF) who are on a downward clinical trajectory, options are mostly limited to left ventricular assist device and transplantation. However, in those with factors favorable for reverse remodeling, every effort should be made to promote native myocardial recovery. We present three patients with newly diagnosed severe HFrEF, NYHA Class 3-4 symptoms, and low cardiac output with and without organ malperfusion. Ivabradine and/or home milrinone were used during their tenuous hemodynamic period as a bridge to optimize guideline-directed medical therapy (GDMT), device therapy, and eventual reverse remodeling. Evidence of structural heart improvement continued far beyond 1 year.

Effect of Optimal Heart Rate on Left Ventricular Remodeling in Patients with Systolic Heart Failure Following Acute Coronary Syndrome.

The optimal therapeutic approach to facilitate reverse remodeling is desired in patients with systolic heart failure following acute coronary syndrome (ACS). The association between heart rate (HR) and reverse remodeling in this cohort has remained elusive.Patients with left ventricular ejection fraction (LVEF) < 50% who received echocardiography assessments following ACS were retrospectively included. Theoretically ideal HR was calculated using a previously established formula: 93 - 0.13 × (deceleration time [msec]). Impacts of HR on echocardiographic left ventricular (LV) reverse remodeling during the 2-year observational period were compared between 2 groups stratified by the HR difference between theoretically ideal and actual values: optimal HR group (HR difference ≤ 10 bpm) versus sub-optimal HR group (HR difference > 10 bpm).A total of 27 patients (median 72 years old, 23 males) were included. There were no significant differences in the baseline characteristics including maximum serum creatinine kinase level and the dose of beta-blocker between the 2 groups. LV ejection fraction increased significantly only in the optimal HR group at follow-up (from 42% to 54%; P = 0.001). The optimal HR group exhibited a more pronounced decrease in LV end-diastolic diameter (from 57 to 52 mm) compared to the sub-optimal HR group (from 58 to 56 mm).Optimal HR, which was calculated using a previously proposed formula, was associated with more substantial post-infarct LV reverse remodeling. The implications of aggressive HR modulation targeting theoretically ideal HR among those with systolic heart failure following ACS are the focus of our investigation here.

Effects of Ranolazine and Ivabradine on Pulmonary Microhemodynamics in Experimental Model of Pulmonary Thromboembolism.

We studied changes of pulmonary microhemodynamics when modeling pulmonary artery thromboembolism on perfused isolated rabbit lungs after pretreatment with ranolazine and ivabradine. The increase in pulmonary artery pressure, pulmonary vascular resistance, and pre- and postcapillary resistance was less pronounced than in control animals, but was close to that in case of pulmonary thromboembolism after pretreatment with voltage-gated Na+ channel blockers lidocaine and ropivacaine. The increase of capillary filtration coefficient inversely correlated with values of capillary hydrostatic pressure. Thus, ranolazine and ivabradine exhibit the properties of voltage-gated Na+ channel blockers mainly in smooth muscles of pulmonary arterial vessels and promote the decrease in endothelial permeability.

Personalised perioperative dosing of ivabradine in noncardiac surgery: a single-centre, randomised, placebo-controlled, double-blind feasibility pilot trial.

BACKGROUND: Perioperative myocardial injury after noncardiac surgery is associated with postoperative mortality. Heart rate (HR) is an independent risk factor for perioperative myocardial injury. In this pilot trial we tested the feasibility of a randomised, placebo-controlled trial of personalised HR-targeted perioperative ivabradine. METHODS: This was a single-centre, randomised, placebo-controlled, double-blind, parallel group, feasibility pilot trial conducted at Geneva University Hospitals. We included patients ≥75 yr old or ≥45 yr old with cardiovascular risk factors planned for intermediate- or high-risk surgery. Patients were randomised to receive ivabradine (2.5, 5.0, or 7.5 mg) or placebo according to their HR, twice daily, from the morning of surgery until postoperative day 2. Primary outcomes were appropriate dosage and blinding success rates. RESULTS: Between October 2020 and January 2022, we randomised 78 patients (recruitment rate of 1.3 patients week-1). Some 439 of 444 study drug administrations were adequate (99% appropriate dosage rate). The blinding success rate was 100%. There were 137 (31%) administrations of Pill A (placebo in both groups for HR ≤70 beats min-1). Nine (11.5%) patients had a high-sensitive cardiac troponin T elevation ≥14 ng L-1 between any two measurements. The number of bradycardia episodes was eight in the placebo group and nine in the ivabradine group. CONCLUSIONS: This pilot study demonstrates the feasibility of, and provides guidance for, a future trial testing the efficacy of personalised perioperative ivabradine. Future studies should include patients at higher risk of cardiac complications. CLINICAL TRIAL REGISTRATION: NCT04436016.

A randomized controlled trial of ivabradine in patients with acute myocardial infarction related cardiogenic shock.

Objective: . Acute myocardial infarction-related cardiogenic shock (AMI-CS) is often accompanied by tachycardia, which, in turn, increases myocardial oxygen consumption and hinders the use of ventricular assist devices, such as intra-aortic balloon pump. Evidence suggests that ivabradine may reduce heart rate (HR) without affecting other hemodynamic parameters. The aim of the present study was to determine the effect of ivabradine on reducing HR and changes in other hemodynamic parameters such as cardiac index (CI), in patients with AMI-CS and tachycardia. Materials and methods: . A single-center, open label, randomized clinical trial included patients diagnosed with AMI-CS and tachycardia with >100 beats per minute (BPM). Heart rate, cardiac index, and other hemodynamic parameters measured by pulmonary flotation catheter were compared at 0, 6, 12, 24, and 48 hours after randomization. Results: . A total of 12 patients were randomized; 6 received standard therapy, and 6 received ivabradine in addition to standard therapy. Baseline clinical characteristics were similar at randomization. A statistically significant lower heart rate was found at 12 hours (p=0.003) and 48 hours (p=0.029) after randomization, with differences of -23.3 (-8.2 to -38.4) BPM and -12.6 (-0.5 to -25.9) BPM, respectively. No differences in cardiac index, or any other evaluated hemodynamic parameters, length of hospital stay, nor mortality rate were noted between both groups. Conclusions: . The use of ivabradine in patients with AMI-CS was associated with a significant reduction in heart rate at 12 and 48 h, without affecting other hemodynamic parameters.

Objetivo: . El choque cardiogénico relacionado con el infarto agudo de miocardio (AMI-CS, por sus siglas en inglés) suele ir acompañado de taquicardia, lo que, a su vez, aumenta el consumo de oxígeno miocárdico y dificulta el uso de dispositivos de asistencia ventricular, como la bomba de balón intraaórtico. La evidencia sugiere que la ivabradina puede reducir la frecuencia cardíaca (FC) sin afectar otros parámetros hemodinámicos. El objetivo del presente estudio fue determinar el efecto de la ivabradina en la reducción de la FC y los cambios en otros parámetros hemodinámicos como el índice cardíaco (CI) en pacientes con AMI-CS y taquicardia. Materiales y métodos: Se incluyeron pacientes diagnosticados con AMI-CS y taquicardia con >100 latidos por minuto (LPM) en un ensayo clínico aleatorizado de un solo centro. La frecuencia cardíaca, el índice cardíaco y otros parámetros hemodinámicos medidos mediante catéter de flotación pulmonar se compararon a las 0, 6, 12, 24 y 48 h después de la aleatorización. Resultados: Se aleatorizaron un total de 12 pacientes; 6 recibieron terapia estándar y 6 recibieron ivabradina además de la terapia estándar. Las características clínicas basales fueron similares en la aleatorización. Se encontró una frecuencia cardíaca significativamente más baja a las 12 h (p=0,003) y a las 48 h (p=0,029) después de la aleatorización, con diferencias de -23,3 (-8,2 a -38,4) LPM y -12,6 (-0,5 a -25,9) LPM, respectivamente. No se observaron diferencias en el índice cardíaco, en ningún otro parámetro hemodinámico evaluado; tampoco en la duración de la estancia hospitalaria, ni en la tasa de mortalidad entre ambos grupos. Conclusiones: El uso de ivabradina en pacientes con AMI-CS se asoció con una reducción significativa en la frecuencia cardíaca a las 12 y 48 h, sin afectar otros parámetros hemodinámicos.

[Research progress in the application of ivabradine in children with cardiovascular diseases]. / ä¼Šä¼å¸ƒé›·å®šåœ¨å„¿ç«¥å¿ƒè¡€ç®¡ç–¾ç— ä¸­çš„åº”ç”¨è¿›å±•.

Ivabradine, as a specific If current inhibitor, has been widely used in the treatment of chronic heart failure in adults due to its ability to reduce heart rate without affecting myocardial contractility and blood pressure. It has also shown good effects in various types of tachyarrhythmias. However, the application of ivabradine in pediatric cardiovascular diseases still faces many limitations. This article reviews the current research progress on the use of ivabradine in treating pediatric cardiovascular diseases both domestically and internationally, aiming to provide guidance for pediatric cardiologists. Citation:Chinese Journal of Contemporary Pediatrics, 2024, 26(7): 782-788.

Feasibility of Short-Term Use of Ivabradine in Critical Ill Patients Who Have Atrial Fibrillation and Tachycardia.

Background: Ivabradine is approved for heart rate reduction in patients with stable symptomatic heart failure (HF). The United States Food and Drug Administration and Taiwan Central Health Insurance Agency approved the use of ivabradine for patients with chronic stable HF with sinus rhythm, but it has not yet been approved for patients with acute decompensated HF or with atrial fibrillation (AF). Objectives: To investigate whether short-term ivabradine use is feasible in critically ill patients with AF and rapid ventricular response (RVR). Methods: This study retrospectively analyzed 23 patients admitted to an intensive care unit with acute HF and AF-RVR who received ivabradine. All patients initially received a slow IV of amiodarone. Other medications for HF were prescribed according to current HF guidelines. The time taken for ivabradine to reduce HR to 80 beats per minute, referred to as "Time to 80," was measured in each patient. Results: Overall, 69.6 % (16/23) of the patients had New York Heart Association functional class IV HF. In addition, 60.9% (14/23) of the patients required endotracheal intubation and ventilatory support, with more than half receiving vasopressor treatment to manage hypotension. Five patients died during the study period. The surviving patients had a significantly shorter "Time to 80" compared to those who did not survive (p = 0.037). Conclusions: Adding ivabradine to standard treatment might be feasible for critically ill patients with AF and tachycardia. The finding that surviving patients had a shorter "Time to 80" duration than those who did not survive may have clinical implications. However, further investigations are needed to assess its clinical utility.

Effect of the combined use of ivabradine and metoprolol in patients with acute myocardial infarction early after percutaneous coronary intervention: A randomized controlled study.

Objective: To investigate the effect and safety of the combined use of ivabradine and metoprolol in patients with acute myocardial infarction (AMI) after percutaneous coronary intervention (PCI). Methods: Eighty patients with AMI were randomly divided into the ivabradine group and the control group. The ivabradine group was treated with ivabradine combined with metoprolol after PCI, while the control group was treated with metoprolol only. Both groups were treated continuously for 1 year. Echocardiography-derived parameters, heart rate, cardiopulmonary exercise testing (CPET) data, major adverse cardiac events (MACE) and myocardial markers were analyzed. The primary endpoint was the left ventricular ejection fraction (LVEF). The safety outcomes were blood pressure, liver and kidney function. Results: The LVEF was significantly higher in the ivabradine group than in the control group at 1 week, 3 months and 1 year after PCI. The heart rate of the ivabradine group was significantly lower than that of the control group at 1 week and 1month after PCI. The VO2max, metabolic equivalents, anaerobic threshold heart rate, peak heart rate, and heart rate recovery at 8 min of the ivabradine group were significantly higher than those of the control group at 1 year after PCI. Kaplan-Meier analysis demonstrated the one-year total incidence of MACE in the ivabradine group was significantly lower than that in the control group. The B-type natriuretic peptide of the ivabradine group was significantly lower than that of the control group on Day 2 and Day 3 after PCI. The high-sensitivity cardiac troponin I level of the ivabradine group was significantly lower than that of the control group on Day 5 after PCI. Conclusion: Early use of ivabradine in patients with AMI after PCI can achieve effective heart rate control, reduce myocardial injury, improve cardiac function and exercise tolerance, and may reduce the incidence of major adverse cardiac events. (Clinical research registration number: ChiCTR2000032731).

Beyond quadruple therapy: the potential roles for ivabradine, vericiguat, and omecamtiv mecarbil in the therapeutic armamentarium.

Quadruple therapy is effective for patients with heart failure with reduced ejection fraction, providing significant clinical benefits, including reduced mortality. Clinicians are now in an era focused on how to initiate and titrate quadrable therapy in the early phase of the disease trajectory, including during heart failure hospitalization. However, patients with heart failure with reduced ejection fraction still face a significant "residual risk" of mortality and heart failure hospitalization. Despite the effective implementation of quadruple therapy, high mortality and rehospitalization rates persist in heart failure with reduced ejection fraction, and many patients cannot maximize therapy due to side effects such as hypotension and renal dysfunction. In this context, ivabradine, vericiguat, and omecamtiv mecarbil may have adjunct roles in addition to quadruple therapy (note that omecamtiv mecarbil is not currently approved for clinical use). However, the contemporary use of ivabradine and vericiguat is relatively low globally, likely due in part to the under-recognition of the role of these therapies as well as costs. This review offers clinicians a straightforward guide for bedside evaluation of potential candidates for these medications. Quadruple therapy, with strong evidence to reduce mortality, should always be prioritized for implementation. As second-line therapies, ivabradine could be considered for patients who cannot achieve optimal heart rate control (≥ 70 bpm at rest) despite maximally tolerated beta-blocker dosing. Vericiguat could be considered for high-risk patients who have recently experienced worsening heart failure events despite being on quadrable therapy, but they should not have N-terminal pro-B-type natriuretic peptide levels exceeding 8000 pg/mL. In the future, omecamtiv mecarbil may be considered for severe heart failure (New York Heart Association class III to IV, ejection fraction ≤ 30%, and heart failure hospitalization within 6 months) when current quadrable therapy is limited, although this is still hypothesis-generating and requires further investigation before its approval.

Novel Therapies for the Treatment of Cardiovascular Disease.

Over the last decade, randomized clinical trials of several pharmacologic agents have demonstrated a reduction in cardiovascular mortality and other important secondary outcomes. Angiotensin-Neprilysin Inhibitors and Sodium-Glucose Co-transporter 2 inhibitors have now become pillars in the treatment of heart failure. Ivabradine is a negative chronotropic agent used as an adjunctive therapy in patients with heart failure. Two new hypertension therapies, zilebresiran and aprocitentan, are currently in investigational stages. Finally, mavacamten has emerged as a pharmacologic treatment for hypertrophic obstructive cardiomyopathy. Practitioners must be familiar with the indications and side effects of newer therapies as they are now frequently prescribed.

Effect of ivabradine on structural and functional changes of myocardium and NT-proBNP levels in patients with stable coronary heart disease after coronary stenting.

OBJECTIVE: Aim: To investigate the effect of ivabradine on the hemodynamics and contractility of the myocardium and the features of NT-pro-BNP production in patients with stable ischemic heart disease after endovascular revascularization of the myocardium depending on the number of affected coronary arteries during 12 months of therapy. PATIENTS AND METHODS: Materials and Methods: The object of the study was 120 patients with stable coronary artery disease: angina pectoris of functional class III with heart failure IIA FC III with preserved and moderately reduced ejection fraction of the left ventricle, who underwent coronary artery stenting. The examined patients were randomized according to the number of affected coronary vessels and the method of treatment. RESULTS: Results: Ivabradine in patients with stable ischemic heart disease after 12 months of therapy had a significant beneficial effect on the structural and functional parameters of the myocardium (contributed to the reverse remodeling of the left ventricle), which did not depend on the number of stented coronary arteries (p<0.05). In patients with stented one coronary artery, all structural and functional indicators of the heart after 12 months of treatment reached the values of practically healthy individuals from the control group. The use of ivabradine in patients with stable ischemic heart disease with heart failure with preserved and intermediate ejection fraction of the left ventricle after coronary stenting made it possible to ensure the correction of a number of clinical and pathogenetic links of the disease, which generally contributed to the improvement of metric and volumetric parameters of the heart. CONCLUSION: Conclusions: Ivabradine made it possible to significantly increase the effectiveness of standard therapy, which was manifested by a faster recovery of the geometry and contractility of the left ventricle. Therefore, the use of ivabradine along with standard therapy was appropriate for such a contingent of patients. The management of patients with stable coronary heart disease should combine adequate (surgical and pharmacological) treatment of the underlying disease, further individual medication correction of symptoms and circulatory disorders inherent in coronary heart disease and heart failure.

Structural determinants of ivabradine block of the open pore of HCN4.

HCN1-4 channels are the molecular determinants of the If/Ih current that crucially regulates cardiac and neuronal cell excitability. HCN dysfunctions lead to sinoatrial block (HCN4), epilepsy (HCN1), and chronic pain (HCN2), widespread medical conditions awaiting subtype-specific treatments. Here, we address the problem by solving the cryo-EM structure of HCN4 in complex with ivabradine, to date the only HCN-specific drug on the market. Our data show ivabradine bound inside the open pore at 3 Å resolution. The structure unambiguously proves that Y507 and I511 on S6 are the molecular determinants of ivabradine binding to the inner cavity, while F510, pointing outside the pore, indirectly contributes to the block by controlling Y507. Cysteine 479, unique to the HCN selectivity filter (SF), accelerates the kinetics of block. Molecular dynamics simulations further reveal that ivabradine blocks the permeating ion inside the SF by electrostatic repulsion, a mechanism previously proposed for quaternary ammonium ions.

Novel Use of Ivabradine for Persistent Sinus Tachycardia in a Patient on Extracorporeal Life Support With Right Ventricular Dysfunction.

Persistent sinus tachycardia (pST) has been associated with adverse cardiovascular events in critically ill patients. Pharmacological control of heart rate with negative inotropic agents has proven to be safe but could be potentially dangerous in patients with concomitant right ventricular (RV) dysfunction. Ivabradine, a medication devoid of negative inotropy, could be a potentially safe solution for this patient population when adequate heart rate control is desired. A 17-year-old male with a history of vaping developed acute respiratory distress syndrome (ARDS) and RV dysfunction, requiring extra corporal life support (ECLS). He suffered from pST. Given his RV dysfunction, a beta-blocker was avoided, and ivabradine was used safely with improvement of his pST. This case demonstrates the efficacy of ivabradine to reduce heart rate and avoid the use of beta-blockers for patients with RV dysfunction, which could be detrimental. Ivabradine was shown to lower the heart rate without altering hemodynamic parameters.

A Systematic Review and Meta-Analysis of Randomised Controlled Trials Assessing Clinical and Haemodynamic Outcomes of Ivabradine in Heart Failure With Reduced Ejection Fraction Patients.

BACKGROUND: Ivabradine, a pure bradycardic agent, can be given to heart failure reduced ejection fraction (HFrEF) patients with a sinus rhythm of ≥70 bpm on a maximum beta blocker dose, or when beta blockers are contraindicated. This study aimed to see how ivabradine affects the clinical and haemodynamic outcomes of HFrEF patients. METHODS: This systematic review and meta-analysis searched ClinicalTrials.gov, OpenMD, ProQuest, PubMed, and ScienceDirect for potential articles. All relevant data were extracted. For all pooled effects, the random effect model was applied. RESULTS: A total of 18,972 heart failure (HF) patients from nine randomised clinical trials (RCTs) were involved in this study. Ivabradine decreased the risk of HF mortality (RR 0.79; 95% CI 0.64-0.98; p=0.03) and HF hospitalisation (RR 0.80; 95% CI 0.65-0.97; p=0.03). Ivabradine was related to a greater reduction in heart rate (MD -12.21; 95% CI -15.47 - -8.96; p<0.01) and left ventricular ejection fraction (LVEF) improvement (MD 3.24; 95% CI 2.17-4.31; p <0.01) compared with placebo. Asymptomatic bradycardia (RR 4.25; 95% CI 3.36-5.39; p<0.01) and symptomatic bradycardia (RR 3.99; 95% CI 3.17-5.03; p<0.01) were higher in the ivabradine group. CONCLUSION: Ivabradine can reduce the risk of HF mortality and HF hospitalisation in HFrEF patients. Ivabradine also effectively reduces resting heart rate and improves LVEF. However, ivabradine is associated with a greater risk of symptomatic and asymptomatic bradycardia.

Effect of Ivabradine on Left Ventricular Reverse Remodeling in Relatively Stable Heart Failure Outpatients With Reduced Ejection Fraction.

Background: Elevations of resting heart rate (HR) in patients with heart failure (HF) with reduced ejection fraction (HFrEF) are often missed, resulting in some patients with an indication for ivabradine reportedly being missed. Methods and Results: We studied 30 relatively stable HFrEF outpatients, and ivabradine was administered when regular follow-up echocardiography showed a resting HR ≥75 beats/min. Significant left ventricular reverse remodeling was observed 10.1±3.9 months after administration of ivabradine. Conclusions: This finding may well make this procedure a potential new approach for preventing worsening of HF for relatively stable patients with HFrEF.

Evaluating the role of ivabradine in acute decompensated heart failure: A systematic review and meta-analysis.

BACKGROUND: Acute decompensated heart failure (ADHF) presents a significant global health challenge, with high morbidity, mortality, and healthcare costs. The current therapeutic options for ADHF are limited. Ivabradine, a selective inhibitor of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, has emerged as a potential therapy for ADHF by reducing the heart rate (HR) without negatively affecting myocardial contractility. However, the evidence regarding the efficacy and safety of ivabradine in patients with ADHF is limited and inconsistent. This meta-analysis aimed to evaluate the efficacy and safety of ivabradine for ADHF based on observational studies. METHODS: A systematic literature search was conducted following PRISMA guidelines to identify relevant observational studies comparing ivabradine with placebo in adult patients with ADHF. Data were pooled using a random-effects model, and heterogeneity was assessed. The risk of bias was evaluated using the Newcastle-Ottawa Scale. RESULTS: Four observational studies comprising a total of 12034 patients. Meta-analysis revealed that ivabradine significantly reduced all-cause mortality (RR: 0.66, 95 % CI: 0.49-0.89, p < 0.01) and resting HR (MD: -12.54, 95 % CI: -21.66-3.42, p < 0.01) compared to placebo. However, no significant differences were observed in cardiovascular mortality, hospital readmission for all causes, changes in LVEF, or changes in LVEDD. Sensitivity and publication bias assessments were conducted for each outcome. CONCLUSION: Ivabradine may be beneficial for reducing mortality and HR in patients with ADHF. However, its impact on other clinical outcomes such as cardiovascular mortality, hospital readmission, and cardiac function remains inconclusive. Further research, particularly well-designed RCTs with larger sample sizes and longer follow-up durations, are warranted.