Pharmacoeconomics of ivabradine in the treatment of CHF in the context of “Quadruple Therapy” / 中国药房

OBJECTIVE To evaluate the cost-effectiveness of ivabradine in the treatment of chronic heart failure （CHF） in the context of “Quadruple Therapy” from the perspective of the health system. METHODS Based on real-world cohort data， the Markov model was constructed according to the natural progression of CHF， with a cycle time of 3 months， a study timeframe of 20 years， and a discount rate of 5%. Using quality-adjusted life year （QALY） and incremental cost-effectiveness ratios （ICER） as the output indexes， the cost-utility analysis was used to evaluate the cost-effectiveness of ivabradine in combination with the “Quadruple Therapy” regimen， compared with the “Quadruple Therapy” regimen for the treatment of CHF， and the robustness of the results of the base analysis was verified by univariate sensitivity analysis and probabilistic sensitivity analysis. RESULTS The results of the base analysis showed that the ICER of ivabradine combined with the “Quadruple Therapy” regimen was 165 065.54 yuan/QALY， compared with the “Quadruple Therapy” regimen， which was lower than the willingness-to-pay （WTP） threshold （257 094 yuan/QALY） based on 3 times of China’s gross domestic product （GDP） per capita in 2022. The results of the univariate sensitivity analysis showed that the discount rate had the greatest impact on the robustness of the model. The probabilistic sensitivity analysis showed that the probability that the ivabradine combined with the “Quadruple Therapy” regimen was cost-effective under the WTP threshold in this study was 59.50%. CONCLUSIONS When using 3 times China’s 2022 GDP per capita （257 094 yuan/ QALY） as the WTP threshold， the combination of ivabradine and the “Quadruple Therapy” regimen for treating CHF is cost- effective.

Effect of ivabradine on ventricular arrhythmias in heart failure patients with reduced ejection fraction

SUMMARY BACKGROUND/INTRODUCTION: Heart failure patients with reduced ejection fraction are at high risk for ventricular arrhythmias and sudden cardiac death. Ivabradine, a specific inhibitor of the If current in the sinoatrial node, provides heart rate reduction in sinus rhythm and angina control in chronic coronary syndromes. OBJECTIVE: The effect of ivabradine on ventricular arrhythmias in heart failure patients with reduced ejection fraction patients has not been fully elucidated. The aim of this study was to investigate the effect of ivabradine use on life-threatening arrhythmias and long-term mortality in heart failure patients with reduced ejection fraction patients. METHODS: In this retrospective study, 1,639 patients with heart failure patients with reduced ejection fraction were included. Patients were divided into two groups: ivabradine users and nonusers. Patients presenting with ventricular tachycardia, the presence of ventricular extrasystole, and ventricular tachycardia in 24-h rhythm monitoring, appropriate implantable cardioverter-defibrillator shocks, and long-term mortality outcomes were evaluated according to ivabradine use. RESULTS: After adjustment for all possible variables, admission with ventricular tachycardia was three times higher in ivabradine nonusers (95% confidence interval 1.5-10.2). The presence of premature ventricular contractions and ventricular tachycardias in 24-h rhythm Holter monitoring was notably higher in ivabradine nonusers. According to the adjusted model for all variables, 4.1 times more appropriate implantable cardioverter-defibrillator shocks were observed in the ivabradine nonusers than the users (95%CI 1.8-9.6). Long-term mortality did not differ between these groups after adjustment for all covariates. CONCLUSION: The use of ivabradine reduced the appropriate implantable cardioverter-defibrillator discharge in heart failure patients with reduced ejection fraction patients. Ivabradine has potential in the treatment of ventricular arrhythmias in heart failure patients with reduced ejection fraction patients.

Short-Term Results of Ivabradine versus Metoprolol: The Effects on Atrial Fibrillation in Patients Undergoing Off-Pump Coronary Artery Bypass Grafting

ABSTRACT Introduction: Classic coronary artery bypass grafting (CABG) surgery involves diastolic cardiac arrest under cardiopulmonary bypass, while off-pump CABG (OPCABG) has become widespread in recent years. Methods: 174 patients who underwent OPCABG were included in the study. Patients were divided into two groups. Group I (n=90) received ivabradine and Group M (n=84) received metoprolol before surgery until postoperative day 10. Intraoperative arrhythmias and hypotension were recorded. Postoperative atrial fibrillation (AF) and arrhythmia, mortality and morbidity rates were assessed based on the 30-day postoperative follow-up. Results: There were no significant differences in the intraoperative amount of inotropic support and red blood cell transfusion between groups (P=0.87 and P=0.31). However, the rates of intraoperative arrhythmias and hypotension were not significantly higher in Group M (P=0.317 and P=0.47). Ventricular tachycardia/ventricular fibrillation (VT/VF) was observed in 2 patients in both groups. Postoperative AF occurred in 7 patients (7.7%) in Group I and in 10 patients (11.9%) in Group M. Although there was a trend towards a higher prevalence of AF in Group M patients, this did not reach statistical significance. In addition, mortality and morbidity rates were comparable between groups.

Observational study of new-onset atrial fibrillation inpatients treated with Ivabradine alone versus Ivabradine and?-blocker drug (The BetaBrad Study)

Introduction: Ivabradine is a heart rate lowering agent by inhibiting Iƒ current in sinus node. It is approved for use in patients with angina and heart failure for heart rate control. Recently, the concern has grown over increased incidence of atrial fibrillation in patients treated with Ivabradine. Aims: We observed critically ill patients in the intensive care unit, treated with Ivabradine alone versus Ivabradine plus a ?-blocking agent, and compared the incidence of new-onset atrial fibrillation. Settings and Design: This was an observational, single-center study. Materials and Methods: We observed 40 patients who were divided into two groups. One group of patients was treated with Ivabradine (no other heart rate-controlling agent) and the other group was treated with Ivabradine plus a ?-blocker drug. We studied the incidence of atrial fibrillation in an observation period of 7 days in the intensive care unit along with other patient characteristics. We used appropriate analytical protocol to compare the two groups. Statistical Analysis Used: Student’s unpaired t test and Fisher’s exact probability test were applied. The value of P < 0.05 was considered statistically significant. Results: Although one patient treated with Ivabradine (and no other rate/rhythm controlling drug) had new-onset atrial fibrillation, there was no statistically significant increase in the incidence of atrial fibrillation in critically ill patients (during the observation period) treated with Ivabradine versus Ivabradine plus ?-blocker drug. Conclusion: Our preliminary research suggests the use of Ivabradine for heart rate control in critically ill patients is not associated with an increased incidence of new-onset atrial fibrillation. However, we recommend a further larger study on this subject.

Efficacy and safety of ivabradine in dilated cardiomyopathy patients: a meta-analysis of randomized controlled trials / 中国医师杂志

Objective:This study aimed to systematically evaluate the efficacy and safety of ivabradine in patients with dilated cardiomyopathy, and to provide evidence-based reference for clinical treatment.Methods:We searched PubMed, Embase, Cochrane Library, Web of Science, CNKI, Wan Fang, VIP databases from inception to 1 September 2021 for randomized controlled trials (RCTs) that compared conventional therapies and ivabradine with conventional therapies in dilated cardiomyopathy patients. Studies meeting the inclusion criteria were included and analyzed. After data extraction and literature quality evaluation, we use the Review Manager 5.4 to perform the meta-analysis and publication bias test.Results:5 studies enrolling 494 patients were included. Compared with conventional therapies (control group), ivabradine and conventional therapies (observation group) significantly reduced resting heart rate [ MD=-7.58, 95% CI(-12.40, -2.76), Z=3.08, P=0.002], left ventricular end diastolic diameter (LVEDD) [ MD=-4.48, 95% CI(-7.33, -1.64), Z=3.09, P=0.002], left ventricular end systolic diameter (LVESD) [ MD=-4.94, 95% CI(-7.29, -2.59), Z=4.12, P<0.001], B-type natriuretic peptide (BNP) [ MD=-212.39, 95% CI(-230.55, -194.23), Z=22.92, P<0.001], New York Heart Association (NYHA) class [ MD=-0.36, 95% CI(-0.44, -0.27), Z=8.46, P<0.001] and Minnesota Questionnaire Score [ MD=-10.43, 95% CI(-15.72, -5.13), Z=3.86, P=0.001]. The left ventricular ejection fraction (LVEF) levels [ MD=1.31, 95% CI(0.64, 1.97), Z=3.85, P=0.001], 6-minute walk test level (6MWT) [ MD=54.83, 95% CI(40.58, 69.08), Z=7.54, P<0.001], systolic blood pressure [ MD=4.72, 95% CI(0.91, 8.54), Z=2.43, P=0.02], the incidence of visual symptoms (phosphene) [ OR=7.22, 95% CI(1.32, 45.00), P=0.02] and symptomatic bradycardia [ OR=8.90, 95% CI(1.21, 65.75), P=0.03] in the observation group were higher than those in the control group after treatment. In addition, there were no significant difference in the incidence of acute event between the two groups [ OR=0.72, 95% CI(0.12, 4.29), P=0.72]. Conclusions:Meta analysis showed that ivabradine combined β receptor blockers can effectively reduce resting heart rate and improve cardiac function in patients with dilated cardiomyopathy, but may increase the incidence of hallucinations and symptomatic bradycardia.

Uso de la ivrabadina para el tratamiento de la taquicardia ectópica de la unión congénita / Use of ivabradine for the treatment of congenital junctional ectopic tachycardia

Resumen La taquicardia ectópica de la unión en su variante congénita es una taquiarritmia pediátrica poco frecuente, que por su naturaleza incesante y su refractariedad a los agentes farmacológicos tradicio nales lleva asociada una alta morbimortalidad. Se presentan los casos clínicos de dos pacientes pediátricos con diagnóstico de taquicardia ectópica de la unión congénita, que mostraron respuesta inadecuada a las alternativas de tratamiento habituales y que, en consecuencia, desarrollaron miocardiopatía dilatada y disfunción ventricular secundaria a la taquicardia sostenida. En ambos se utilizó ivabradina como alternativa farmacológica innovadora pare el control de ésta con excelente respuesta clínica.

Abstract The congenial form of junctional ectopic tachycardia is a rare variant of pediatric tachyarrhythmia that due to its incessant nature and its refractoriness to the traditionally used antiarrhythmic agents has a high morbimortality The clinical cases of two patients with a diagnosis of congenital junctional ectopic tachycardia with inadequate response to the regular pharmacological options, who developed dilated cardiomyopathy and ventricular dysfunc tion secondary to sustained tachycardia, are presented. In both ivrabadine, a new innovative option was used with excellent clinical response.

Preparation and in vitro release of ivabradine hydrochloride elementary osmotic pump tablets / 中国药科大学学报

@#In this study, ivabradine hydrochloride (IVB) was prepared as elementary osmotic pump tablets whose administration frequency was reduced to once daily. The dissolution method was developed, and effects on drug release profiles were evaluated by single factor analysis involving suspending agents, osmotic active agents and aging process. Orthogonal test was carried out at 3 levels on 3 factors including the amount of polyoxyethylene (PEO) in the core, polyethylene glycol (PEG) percentage and weight increase of controlled-release film coatings. The final formulation consisted of IVB (16.25 mg), PEO N80 (60 mg), hypromellose E5 (10 mg), lactose (111.75 mg), magnesium stearate (2 mg); and the film coatings consisted of PEG (15%), cellulose acetate (85%), with a weight increase of 7.5%. In vitro drug release behaviors were investigated. Prepared tablets exhibited similar release profiles in different pH dissolution media, with no risk of dose dumping in 40% ethanol solutions. The osmotic pressure differences inside and outside the membrane drove drug release. IVB osmotic pump tablets could reduce the frequency of administration and improve patients'' compliance, thus with better application values.

Ivabradina como apoyo a la contrapulsación aórtica en pacientes con insuficiencia cardíaca avanzada

Introducción. Los pacientes con insuficiencia cardíaca (IC) avanzada bajo tratamiento con inotrópicos tienden a la taquicardia sinusal, principalmente, por: 1) efecto compensador neuroendocrino, 2) efecto farmacológico, 3) imposibilidad del uso de beta bloqueantes por interferir en el efecto inotrópico. Objetivos. Evaluar mediante cateterismo pulmonar el efecto hemodinámico de la ivabradina en la taquicardia sinusal durante el tratamiento de la IC avanzada bajo contrapulsación aórtica. Material y métodos. Entre el 1° de Enero de 2014 y el 1° de Mayo de 2020, se incluyeron prospectivamente todos los pacientes admitidos al área de cardiología crítica por IC aguda de etiología isquémico-necrótica refractaria al tratamiento farmacológico vía oral e indicación de inotrópicos y contrapulsación intra-aórtica, en ritmo sinusal con más de 110 latidos por minuto (lpm) de frecuencia cardíaca. Resultados. El estudio incluyó a 55 pacientes (33 hombres) con edad promedio de 61,9 años. Post tratamiento con ivabradina, la frecuencia cardíaca bajó de 118±5 lpm a 93±8 lpm (p=0,0002), el volumen minuto cardíaco aumentó de 4637±610 ml a 5176±527 ml (p=0,03) y el volumen sistólico promedio se incrementó significativamente de 39,29±5,2 a 55,65±7,7 ml (p=0,002). No se observaron diferencias significativas pre y post tratamiento en los registros de las presiones de la aurícula derecha ni en las presiones capilar pulmonar, así como en los cálculos de resistencias vasculares sistémicas y pulmonares. No se observaron efectos adversos de las drogas hasta transcurridas cinco vidas medias luego de suspenderla. Conclusiones. La ivabradina mejora la efectividad de la contrapulsación aórtica evaluada mediante catéter de Swan Ganz en paciente con IC avanzada tratada con agentes inotrópicos.

Background. Patients with advanced heart failure (HF) under inotropic treatment tend to sinus tachycardia, mainly due to: 1) neuroendocrine compensatory effect, 2) pharmacological effect, 3) impossibility of using beta-blockers because they interfere with the inotropic effect. Objectives. To evaluate the hemodynamic effect of ivabradine on sinus tachycardia during the treatment of advanced HF under aortic balloon pump using pulmonary catheterization. Material and methods. Between January 1, 2014 and May 1, 2020, all patients admitted to the critical cardiology area for acute HF of ischemic-necrotic etiology refractory to oral pharmacological treatment and indication of inotropic drugs and aortic balloon pump were prospectively included, in sinus rhythm with more than 110 beats per minute (bpm) of heart rate. Results. The study included 55 patients (33 men) with a mean age of 61.9 years. Post-treatment with ivabradine, the heart rate decreased from 118±5 bpm to 93±8 bpm (p=0.0002), the cardiac minute volume increased from 4637±610 ml to 5176±527 ml (p=0.03) and mean stroke volume increased significantly from 39.29±5.2 to 55.65±7.7 ml (p=0.002). No significant differences were observed before and after treatment in the recordings of the pressures of the right atrium or in the pulmonary capillary pressures, as well as in the calculations of systemic and pulmonary vascular resistance. No adverse effects of the drugs were observed until five half-lives after stopping it. Conclusions. Ivabradine improves the effectiveness of aortic balloon pump evaluated by means of a Swan Ganz catheter in patients with advanced HF treated with inotropic agents.

Introdução. Pacientes com insuficiência cardíaca (IC) avançada em tratamento inotrópico tendem a apresentar taquicardia sinusal, principalmente devido a: 1) efeito compensatório neuroendócrino, 2) efeito farmacológico, 3) impossibilidade de uso de betabloqueadores por interferirem no efeito inotrópico. Objetivo. Avaliar o efeito hemodinâmico da ivabradina na taquicardia sinusal durante o tratamento da IC avançada sob contrapulsação aórtica por cateterismo pulmonar. Material e métodos. Entre 1º de Janeiro de 2014 e 1º de Maio de 2020, foram incluídos prospectivamente todos os pacientes admitidos na área de cardiologia crítica por IC aguda de etiologia isquêmico-necrótica refratária ao tratamento farmacológico oral e indicação de inotrópicos e de balão de contrapulsação intra-aórtico, em ritmo sinusal com mais de 110 batimentos por minuto (bpm) de frequência cardíaca. Resultados. O estudo incluiu 55 pacientes (33 homens) com idade média de 61,9 anos. Após o tratamento com ivabradina, a frequência cardíaca caiu de 118±5 bpm para 93±8 bpm (p=0,0002), o volume minuto cardíaco aumentou de 4637±610 ml para 5176±527 ml (p=0,03) e o volume sistólico médio aumentou significativamente de 39,29±5,2 para 55,65±7,7 ml (p=0,002). Não foram observadas diferenças significativas antes e após o tratamento nos registros das pressões do átrio direito ou nas pressões capilares pulmonares, bem como nos cálculos da resistência vascular sistêmica e pulmonar. Nenhum efeito adverso dos medicamentos foi observado até cinco meias-vidas após a descontinuação. Conclusões. A ivabradina melhora a eficácia da contrapulsação aórtica avaliada por meio de um cateter de Swan Ganz em pacientes com IC avançada tratados com agentes inotrópicos.

Positive inotropic effect of Ivabradine in rats and its underlying mechanism / 医学研究生学报

ObjectiveIvabradine reduces heart rate by inhibiting If current of cardiomyocyte and is used clinically to treat stable angina pectoris and myocardial ischemia. However, the mechanism of positive inotropic effect by Ivabradine is still not well understood. This study aims to investigate the Ivabradine's positive inotropic effect both in vivo and in vitro and the underlying mechanism involved.Methods①A Millar catheter with double-pressure was inserted into the right carotid artery of general anesthesia rats. The pressure-volume of left ventricle, HR (heart rate) and aortic pressure were recorded as a blank group (n=7). The effect of Ivabradine (1 mg/kg) administrated via left external jugular vein was recorded as a drug treated group (n=7). The cardiac output, left ventricular and aortic pressure of the rats in the blank group A and the administration group A were compared, and the results were used to analyze the Ivabradine's inotropic effectin vivo.②Langendorff setup was used to analyze the left ventricular pressure of the isolated heart. The normal perfusion solution was used as the blank group (n=6), while the Ivabradine (10 μmol/L) perfusion was used as the treated group (n=6). In addition, the treatment of H89 (200 nmol/L) (a PKA inhibitor) was recorded as the blank group (n=6) and the combined use of H89 (200 nmol/L) and Ivabradine (10 μmol/L) was recorded as drug treated group (n=6). Following the above protocol, KN-93 (500 nmol/L) (a CaMKII inhibitor) or CA (10 nmol/L) (a protein phosphatase 1 and 2A inhibitor) was used to analyze the inhibitory effect on inotropic effect of Ivabradine (n=6 for each group). ③The field stimulation induced Ca2+ transient from cardiomyocyte was used to investigate the mechanism underlying the positive inotropic effect of Ivabradine (10 μmol/L).The perfusion orders and concentrations of Ivabradine or/and H89, KN-93 and CA were the same as that in isolated rat heart experiment (n= 6 for each group).Results① Ivabradine (1 mg/kg) significantly increased the left ventricular develop pressure (from 102.43±11.06 in blank group to 109.86±11.65 mmHg in ivabradine treated group, P<0.01, n=7) and cardiac output (from 33.72±1.96 in blank group to 36.27±2.22 mL/min in ivabradine treated group, P<0.01, n=7). It reduced the heart rate (from 348.56±10.02 in blank group to 324.17±11.33 beats/min in ivabradine treated group, P<0.01, n=7) and increased the systolic blood pressure (from 99.74±8.67 in blank group to 108.57±9.24 mmHg in Ivabradine treated group, P<0.01, n=7) without significant change in diastolic blood pressure. ② Ivabradine (1, 10 μmol/L) significantly increased the left ventricular developed pressure (LVDP) (P<0.05, n=6). The positive inotropic effect of Ivabradine was blocked by CaMKⅡ inhibitor of KN-93. ③ Ivabradine (10 μmol/L) significantly increased the amplitude of SR Ca2+ transient (P<0.01,n=6). The enhanced amplitude of Ca2+ transient was blocked by CaMKⅡ inhibitor of KN-93.ConclusionIvabradine shows a positive inotropic effect in rat hearts both in vivo and in vitro and its underlying mechanism involved the action which was mediated by CaMKⅡ.

A comparative study on efficacy of metoprolol and ivabradine in acute ST elevation myocardial infarction patients

Background: The ST-elevation myocardial infarction (STEMI), a fatal disease, is rapidly extending in patients, worldwide. Therefore, proper and timely diagnosis followed by appropriate management becomes necessary. The study aimed to compare the effectiveness of metoprolol and ivabradine in acute STEMI patients.Methods: This was an observational, comparative, in-hospital study carried out in patients admitted in the in-patient cardiac department, intensive cardiac care unit of a tertiary care centre in India. Total 60 patients diagnosed with acute ST-elevation MI were included in the study and were equally divided into two groups. Group 1 involved patients who were given metoprolol for treatment and group 2 involved patients who were given ivabradine. The patients were assessed in terms of heart rate, NYHA class, and ejection fraction. Follow-up of 30 days was taken in all patients.Results: Ivabradine reduced mean heart rate from 85.57 bpm at baseline to 78.23 bpm. Heart rate in the metoprolol group was reduced from 81.93 bpm to 76.47 bpm over the same time period. Metoprolol and ivabradine showed significant improvement in the ejection fraction volume during the in-hospitalization stay. Ivabradine showed a better improvement in ejection fraction when compared to metoprolol but the difference was not found to be statistically significant. Higher mortality was assessed in ivabradine group compared to metoprolol.Conclusions: The study gives the gold standard efficacy and mortality benefit of metoprolol, although ivabradine on the other hand gave better responses in heart rate reduction and improvements in ejection fraction.

Comparison of Oral Ivabradine, Oral Metoprolol and Placebo to Attenuate the Stress Response in Nasal and Laryngeal Surgeries: A Prospective, Randomized, Double Blind Study

Introduction: Nasal surgeries like septoplasty, polypectomyand laryngeal surgeries for removal of vocal nodule, cysts etcare commonly performed. Changes in haemodynamics due tolaryngoscopy and endotracheal intubation are likely to persistduring these procedures. These surgeries also require bloodless field. The present study was conducted to evaluate andcompare the efficacy of oral metoprolol tartrate versus oralivabradine versus placebo in attenuation of haemodynamicresponses during laryngoscopy, tracheal intubation andthroughout nasal and laryngeal surgeries.Methods: This was a prospective, randomized, comparative,double blind study. . Patients were randomly allocated bysimple randomization into 3 groups having 30 patients in each.Neither the patient nor the investigator was aware, whichpatient is allocated into which group and were unaware of thedrug being administered as it was given to the patient by aperson not involved in the study. Data collections were carriedout by investigator in a double blind manner. All the patientswere explained about the anesthesia technique and writteninformed consent was taken. Group 1: Oral Ivabradine 5mgtablet was given orally 2 hours before induction of anaesthesia.Group 2: Oral Metoprolol tartrate 50mg tablet was given orally2 hours before induction of anaesthesia. Group 3: Oral placebowas given 2 hours before induction of anaesthesia.Results and Conclusion: We concluded that both the drugscan be used as an effective premedication, to attenuate thesympathetic response to laryngoscopy, endotrachealintubation, extubation and throughout nasal and laryngealsurgeries. However Metopolol was found to have better controlthan Ivabradine in maintaining the vitals at all points andproviding a good hypotensive effect than ivabradine.

Pacientes elegibles para las nuevas terapias de la insuficiencia cardíaca en un policlínico especializado / Proportion of patients with heart failure in a specialized clinic eligible for novel therapies

Background: Pharmacological treatment improves survival in patients with heart failure with reduced ejection fraction. The use of sacubutril/valsartan and ivabradine has been recently approved and incorporated in the latest guidelines. Aim: To identify candidates eligible for these therapies among patients treated in a heart failure clinic, considering the inclusion criteria for the PARADIGM-HF and SHIFT trials. Material and Methods: Cross-sectional study on 158 patients aged 62 ± 11 years (67% male) with heart failure and reduced ejection fraction, with at least three months of follow-up and without decompensation. The percentage of patients complying for the inclusion criteria for the PARADIGM-HF y SHIFT trials was determined. Results: In 37%, the etiology of heart failure was ischemic, 49% were in functional class I, their ejection fraction was 33 ± 11% and their median Pro-brain natriuretic peptide was 800 pg/mL. Ninety five percent were treated with vasodilators, 97% with beta-blockers and 82% with aldosterone antagonists. Using PARADIGM-HF and SHIFT criteria, 11 patients (7%) were eligible for sacubitril / valsartan and 21 patients (13.3%) for ivabradine. Among the main causes of non-eligibility for sacubitril / valsartan were being functional class I (48.7%) and not achieving a stable dose of enalapril ≥ 20 mg / day or losartan ≥ 100 mg / day (24.7%). In the case of ivabradine, apart from those in functional class I, the absence of sinus rhythm and a heart rate < 70 / min when receiving a maximal tolerated dose of beta-blockers, were present in 22%. Conclusions: A low percentage of our patients were eligible for these therapies. Among the causes that explain these results were clinical stability, a high percentage of patients in functional class I and being in a disease modifying treatment.

Budget Effect Analysis of Ivabradine in the Treatment of Heart Failure on Medical Insurance Fund in China / 中国药房

OBJECTIVE： To evaluate the effects of ivabradine in the treatment of heart failure on medical insurance fund budget in China， and to provide support evidence of related economical evaluation for medical insurance department to solve the problem of reimbursement admission of the drug in hospital outpatient department and the establishment of drug list in hospital. METHODS： Excel decision tree model was used. Pharmacoeconomic analysis was conducted based on the data reported in domestic literatures over the years. Firstly， according to the prevalence rate of heart failure in China， the number of patients with heart failure was estimated， which accorded with NYHA cardiac function class Ⅱ-Ⅳ， systolic blood pressure dysfunction and ivabradine indication. Then the cost of ivabradine was estimated. Secondly， the total number of hospitalizations and the cost of hospitalization due to heart failure were estimated. Finally， the cost of ivabredine and the cost of treatment saved by avoiding re-hospitalization due to the use of ivabredine were considered comprehensively. Static budget impact analysis was conducted to evaluate the effects of the use of ivabredine on medical insurance fund budget. RESULTS： The prevalence rate of heart failure in China was raised to 1.3％ in 2013. It was estimated that the number of heart failure patients between 35-75 years old in China could be about 8.51 million and total hospitalization times was about 4.32 million per year. The economic burden of hospitalization in heart failure patients was about 168.940 billion yuan in whole country. Since 18％ of patients could be avoided re-hospitalization after treatment with ivabradine， the cost of hospitalization could be saved by about 30.410 billion yuan， while the total cost of taking ivabradine was about 17.525 billion yuan. Therefore， the use of ivabradine could save the hidden medical cost budget by about 12.886 billion yuan， which had obvious cost-effectiveness. Static budget impact analysis results showed that by 2019-2020， the expected proportion of patients with heart failure covered by ivabradine would increased to 8.70％， and the total consumption sum would reach about 1.797 billion yuan. The incremental cost savings ratio （ICSR） showed that the cost of hospitalization could be saved by about 11 951 yuan for each additional case of heart failure treated with ivabradine； there could be 5 711 yuan of balance by deducting drug cost 6 240 yuan of ivabradine. CONCLUSIONS： The cost savings of hospitalization treated by ivabradine is not only enough to offset the cost of ivabradine itself， but also has a premium effect. The drug is of certain economy for the treatment of heart failure in China.

Ivabradine use in patients with HFrEF in the heart failure multidisciplinary program (PIC) in a private hospital: first registration and 3-years follow up, Central American (CA) region / Uso de ivabradina en pacientes con insuficiencia cardíaca aguda en la insuficiencia cardíaca programa multidisciplinario (PIC) en un hospital privado: primer registro y seguimiento de 3 años, región de América Central (AC)

Abstract Introduction and objectives: Heart rate (HR) elevation in patients (p) with heart failure with reduced ejection fraction (HFrEF) is related to increased mortality and hospitalization for HF; its reduction improves the filling of the left ventricle, increases the myocardial oxygen supply and reduces its consumption, all of which is beneficial in p with impaired left ventricular systolic function. Use of ivabradine (IBRA) in p with HFrEF, in sinus rhythm (SR) and HR > 70 beats per minute (bpm), reduces hospitalizations for HF and mortality for HF. The management of p with advanced HF in PIC ensures a morbidity and mortality reduction with the highest levels of evidence. The first retrospective analysis in a PIC at a private hospital in CA, during 3 years of all case p with HFrEF who received treatments (tx) recommended by International Guidelines and maintained HR > 70 bpm at rest in SR, with the purpose of reducing it. The use of baseline clinical data, natriuretic peptides (NP) and LVEF at rest, compared with same variables in follow up, in a region where these PICs are borning. Methods: 26 p with HFrEF for 3 years of PIC. General data, tx, baseline clinical condition, BP, pulse, NYHA, quality of life (QoL), NP, LVEF by Doppler Echocardiography were registered, and IBRA tx response was compared baseline and end. 18 p completed data; 8 incomplete (baseline or follow-up data). Results: Ambulatory p, with HFrEF (<35%) and SR HR > 70 bpm; age 78 years, 17 men. Tx average time with IBRA 11 months, 53.5% more than 1 year. Baseline medications, 93% ACEIs or ARAs II; 85% beta-blockers and 74% MRA, maximum tolerated doses. No patient used IBRA prior baseline. 20% CRT. Variables behavior assessed: HR (baseline 89 bpm vs 62 bpm after IBRA 2 months); BP (baseline systolic 100 mmHg vs 123 mmHg end; baseline diastolic 55 mmHg vs 65 mmHg end); LVEF (baseline 29% vs 35% end); BNP baseline 7,550 pg/ml vs 1,935 pg/ml end. 5 p improved NYHA III to NYHA I, 5 p improved NYHA III to NYHA II, 3 had deterioration NYHA III; rest remained unchanged. 77% p no dose adjustment required (HR below 70 bpm). 6 p began with 2.5 mg every 12 hours and increased to 5 mg every 12 hours after 15 days. By KCCQ-12 increase 42 to 59 points. 1 discontinuation case of IBRA due to bradycardia (HR < 50 bpm). 2 p hospitalized, one pneumonia and one HF decompensation. 3 dead: 1 myocardial infarction, 2 HF progression. Conclusions: 26 p studied, registered and treated with IBRA in the PIC at private hospital in CA, most of them registered metric improvements identified as prognosis factors (HR, BP, LVEF, NP, NYHA and QoL). This assessment, registration and follow up of p with HFrEF with use of IBRA in a PIC, is the first one carried out in CA. Results reflect the usual clinical practice in a PIC, with cardiologists and nurses trained to support and follow-up p, and evidence the importance of PIC when using and prescribing drugs like IBRA, in a region where these PICs are rare.

Resumen Introducción y objetivos: La elevación de la frecuencia cardíaca (FC) en pacientes (p) con insuficiencia cardíaca (IC) con fracción de eyección reducida (ICFE) se relaciona con un aumento de la mortalidad y la hospitalización por IC; su reducción mejora el llenado del ventrículo izquierdo, aumenta el suministro de oxígeno al miocardio y reduce su consumo, todo lo cual es beneficioso en p con deterioro de la función sistólica del ventrículo izquierdo. El uso de ivabradina (IBRA) en p con ICFE, en ritmo sinusal (SR) y FC> 70 latidos por minuto (lpm), reduce las hospitalizaciones por insuficiencia cardíaca y la mortalidad por insuficiencia cardíaca. El manejo de p con FC avanzada en PIC asegura una reducción de la morbilidad y la mortalidad con los mayores niveles de evidencia. El primer análisis retrospectivo en un PIC en un hospital privado en centroamérica, durante 3 años de todos los casos p con ICFE que recibieron tratamientos (tx) recomendados por Interna tional Guidelines y mantuvieron FC> 70 lpm en reposo en SR, con el objetivo de reducirlo. El uso de datos clínicos basales, péptidos natriuréticos (NP) y FEVI en reposo, en comparación con las mismas variables en el seguimiento, en una región donde estos PIC están naciendo. Métodos: 26 p con ICFE durante 3 años de PIC. Se registraron datos generales, tx, estado clínico basal, presión arterial, pulso, NYHA, calidad de vida (QoL), NP, FEVI por ecocardiografía Doppler, y se comparó la respuesta de IBRA tx al inicio y al final. 18 p datos completados; 8 incompleto (datos iniciales o de seguimiento). Resultados: p ambulatorios, con ICFE (<35%) y SR FC> 70 lpm; 78 años de edad, 17 hombres. Tiempo promedio de Tx con IBRA 11 meses, 53.5% más de 1 año. Medicamentos de referencia, 93% IECA o IRA II; 85% de betabloqueantes y 74% de MRA, dosis máximas toleradas. Ningún paciente usó IBRA antes de la línea base. 20% de CRT. Comportamiento de las variables evaluado: FC (basal 89 lpm frente a 62 lpm después de IBRA 2 meses); BP (sistólica basal de 100 mmHg frente a 123 mmHg de extremo, línea diastólica basal de 55 mmHg frente a 65 mmHg de extremo); FEVI (línea de base 29% frente a 35% de final); BNP línea de base 7.550 pg / ml vs 1.935 pg / ml final. 5 p mejoró NYHA III a NYHA I, 5 p mejoró NYHA III a NYHA II, 3 sufrió deterioro NYHA III; el resto se mantuvo sin cambios. 77% p no se requiere ajuste de dosis (FC por debajo de 70 lpm). 6 p comenzó con 2.5 mg cada 12 horas y aumentó a 5 mg cada 12 horas después de 15 días. Por KCCQ-12 aumenta de 42 a 59 puntos. 1 caso de discontinuación de IBRA debido a bradicardia (FC <50 lpm). 2 p hospitalizados, una neumonía y una descompensación de FC. 3 muertos: 1 infarto de miocardio, progresión de 2 FC. Conclusiones: 26 p estudiados, registrados y tratados con IBRA en el PIC en un hospital privado en CA, la mayoría de ellas registraron mejorías métricas identificadas como factores pronósticos (FC, BP, FEVI, NP, NYHA y QoL). Esta evalua ción, registro y seguimiento de p con ICFE con uso de IBRA en un PIC, es la primera llevada a cabo en CA. Los resultados reflejan la práctica clínica habitual en un CFP, con cardiólogos y enfermeras capacitados para apoyar y dar seguimiento p, y evidencian la importancia del CFP al usar y prescribir fármacos como el IBRA, en una región donde estos PIC son raros.

Heart rate manipulation in dilated cardiomyopathy: Assessing the role of Ivabradine

Background Heart rate (HR) reduction is of benefit in chronic heart failure (HF). The effect of heart rate reduction using Ivabradine on various echocardiographic parameters in dilated cardiomyopathy has been less investigated. Methods Of 187 patients with HF (DCM, NYHA II–IV, baseline HR > 70/min), 125 patients were randomized to standard therapy (beta blockers, ACEI, diuretics, n = 62) or add-on Ivabradine (titrated to maximum 7.5 mg BD, n = 63). Beta-blockers were titrated in both the groups. Results At 3 months both groups had improvement in NYHA class, 6 min walk test, Minnesota Living With Heart Failure (MLWHF) scores and fall in BNP, however the magnitude of change was greater in Ivabradine group. Those on Ivabradine also had lower LV volumes, higher LVEF (28.8 ± 3.6 vs 27.2 ± 0.5, p = 0.01) and more favorable LV global strain (11 ± 1.7vs 12.2 ± 1.1, p = <0.001), MPI (0.72 ± 0.1 vs 0.6 ± 0.1, p = <0.001), LV mass (115.2 ± 30 vs 131.4 ± 35, p = 0.007), LV wall stress (219.8 ± 46 vs 238 ± 54) and calculated LV work (366 ± 101 vs 401 ± 102, p = 0.05). The benefit of Ivabradine was sustained at 6 months follow up. The % change in HR was significantly higher in Ivabradine group (−32.2% vs −19.3%, p = 0.001) with no difference in blood pressure. Resting HR < 70/min was achieved in 96.8% vs 27.9%, respectively in the two groups. Conclusion Addition of Ivabradine to standard therapy in patients with DCM and symptomatic HF and targeting a heart rate < 70/min improves symptoms, quality of life and various echocardiographic parameters.

Effects of Ivabradine on Left Ventricular Systolic Function and Cardiac Fibrosis in Rat Myocardial Ischemia-Reperfusion Model / 전남의대학술지

We evaluated the effects of Ivabradine on left ventricle (LV) ejection fraction (EF) and LV infarcted tissue in the rat myocardial ischemia-reperfusion model. Twenty rats were randomly assigned to group 1 (ischemia-reperfusion, no treatment, n=10) and group 2 (ischemia-reperfusion + Ivabradine 10 mg/kg, n=10). Ivabradine was administered for 28 days. Echocardiography was performed at 7 days and at 28 days after the induction of ischemia-reperfusion injury. Cardiac fibrosis induced by ischemia-reperfusion injury was evaluated by Masson's trichrome staining. The infarct size was quantified using the Image J program. At the 28-day follow-up, LVEF was significantly higher (36.02±6.16% vs. 45.72±2.62%, p<0.001) and fractional shortening was significantly higher (15.23±2.84% vs. 20.13±1.38%, p<0.001) in group 2 than group 1. Delta (28 day minus 7 day) EF was significantly higher in group 2 than group 1 (−4.36±3.49% vs. 4.31±5.63%, p<0.001). Also, heart rate (beats/min) was significantly lower in group 2 than group 1 (251.67±25.19 vs. 199.29±31.33, p=0.025). Group 2 had a smaller infarct size (40.70±8.94% vs. 30.19±5.89%, p<0.01) than group 1 at 28-day follow-up. Oral administration of Ivabradine could improve LV systolic function and reduce infarcted tissue area in rat myocardial ischemia-reperfusion model.

Heart rate control in chronic heart failure patients received cardiovascular implantable electronic device therapy: effects of optimized medication / 中华心血管病杂志

Objective@#To investigate the heart rate control situation of chronic heart failure (CHF) patients who received cardiovascular implantable electronic device (CIED) therapy, and to assess the heart rate control efficacy by optimized medication adjustment.@*Methods@#We performed a perspective study in heart failure with reduced left ventricular ejection fraction (HFrEF) patients who received CIED according to guideline recommendations, patients were enrolled from January 2012 to January 2017. Resting heart rate (RHR) recorded by electrocardiogram after 10 minutes' rest and medication usage within 1 month were recorded at baseline. RHR less than 70 beats per minute (bpm) was regarded as well controlled. β-receptor blockers and (or) ivabradine would be added in patients whose RHR were over 70 bpm. RHR after optimized medication adjustment was recorded during follow-up period.@*Results@#One hundred and fifty patients were included in this study with average RHR (80.6±11.9) bpm. RHR was<70 bpm in 27.3% (41/150) patients at baseline and β-receptor blockers was underused in 80.7% patients (88/109) whose RHR was>70 bpm. The overall RHR decreased to (73.1±10.4) bpm and percent of patients with RHR<70 bpm increased to 70.0% (105/150) after up-titration of β-receptor blockers compared to baseline (χ2=52.958, P<0.001). Ivabradine was added in the rest 45 patients and RHR was<70 bpm in 43 out of 45 patients after ivabradine use. The overall RHR decreased to (67.1±2.7) bpm and percent of RHR<70 bpm significantly increased to 98.7% (148/150) (χ2=44.504, P<0.001 vs. up-titration of β-receptor blockers only).@*Conclusion@#RHR in CHF patients who received CIED therapy is not ideally controlled in this patient cohort, individual up-titration ofβ-receptor blockers and ivabradine use may help to optimize RHR in these patients.

Current Treatments of Refractory Heart Failure / 医药导报

Although great progress has been made in the treatment of heart failure,refractory heart failure is still a difficult problem.It has high incidence and poor prognosis,which brings huge financial burden to patients, families and society. Recently,the clinical application of sacubitril/ valsartan and ivabradine,mechanical circulatory support,and heart transplantation have been greatly improved.This article reviews current treatments of refractory heart failure from aspects of new breakthroughs in drug treatment,mechanical circulatory support,and heart transplantation.

Ivabradina en el manejo de la falla cardiaca aguda por miocarditis / Ivabradine in acute heart failure due to myocarditis

Resumen Presentamos el caso de una paciente de 47 años de edad, remitida a nuestra institución por cuadro de la falla cardiaca aguda secundaria a la miocarditis viral, en quien se utilizó la ivabradina como terapia coadyuvante para el control de la frecuencia cardiaca en el contexto del choque cardiogénico.

Abstract The case of a 47 year-old female patient is presented. She was referred to our institution due to acute heart failure secondary to viral myocarditis, where ivabradine was used as an adjuvant therapy for controlling the heart rate in the context of a cardiogenic shock.

Efficacy and safety analysis of ivabradine hydrochloride treatment of Chinese patients with chronic heart failure: subgroup analysis of Chinese patients in the SHIFT study / 中华心血管病杂志

Objective@#To evaluate the efficacy and safety of ivabradine for the treatment of Chinese patients with chronic heart failure based on the Chinese subgroup data of the systolic heart failure treatment with the If inhibitor ivabradine trial (SHIFT).@*Method@#A total of 6 558 stable outpatients who presented symptoms of heart failure, with a left ventricular ejection fraction (LVEF) ≤35%, sinus rhythms with a heart rate ≥70 bpm participated in the randomized, double-blind, placebo-controlled, international multicenter clinical study.The subset of Chinese patients with heart rate ≥75 bpm was enrolled in the post-hoc subgroup analyses.Patients were randomly allocated by computer-generated assignment through a telephone interactive voice response system to ivabradine group (starting dose 5 mg bid, which was then uptitrated to the maximum 7.5 mg bid) or matched placebo group.The clinical baseline characteristics of participants were obtained and analyzed.The primary outcome endpoint was a composite endpoint of cardiovascular death or hospitalization resulting from worsening HF.The primary safety endpoint included total incidence of adverse events during the study, bradycardia, and adverse visual reaction (phosphenes).@*Results@#A total of 49 Chinese centers enrolled a total of 225 patients with chronic heart failure, of whom, 106 patients were randomized to the ivabradine group and the other 119 patients to the placebo group, and the mean follow-up time was (15.6±5.1) months.By the end of the study, mean heart rate (71.0 bpm vs. 80.3 bpm, P<0.05) and incidence of the primary endpoint events (18.9% (20/106) vs. 31.9%(38/119), HR=0.56, 95%CI 0.33-0.97, P=0.039) were significantly lower, while the percentage of patients with improvement in heart functional class NYHA (53.8% (56/106) vs. 34.5% (41/119), P=0.006 1) was significantly higher in the ivabradine group than in the placebo group.The total number of adverse events (129 events, 49.6% PY) in the ivabradine group was lower than that in the placebo group (203 events, 50.8% PY). In the ivabradine group and the placebo group, there were respectively 2 patients (1.9%) and 0 patients experienced bradycardia, 3 patients (2.9%) and 1 patient (0.8%) experienced adverse visual reaction (phosphenes).@*Conclusions@#Ivabradine significantly reduced heart rate and improved the clinical outcomes and NYHA function class in Chinese patients with chronic heart failure, these beneficial effects are achieved without inducing remarkable adverse reactions.The results of Chinese subgroup analysis were thus consistent with the overall results of the SHIFT study.@*Clinical Trial Registry@#International standard randomized controlled trials registry, ISRCTN 70429960.