Table 2 - uploaded by Filippo Maria Sarullo
Content may be subject to copyright.
Exercise Capacity, Anaerobic Threshold, Resting Heart Rate, NT-proBNP Value, and NYHA Functional Class at Baseline and After 3 Months a
Source publication
epidemiologic studies indicate that elevated heart rate (HR) is an independent risk factor for mortality and morbidity in patients (pts) with chronic heart failure (CHF). Clinical trials with β-blockers suggest that HR reduction is an important mechanism of their benefit in pts with stable CHF. Pharmacologic inhibition of the I(f) current now provi...
Contexts in source publication
Context 1
... was a significant increase in exercise endurance compared with baseline at 3 months for the ivabra- dine group (28.2 + 3.5 min; P < .0001). No significant differ- ence was found in the control group at 3 months (15.4 + 2.6 min; P ¼ ns; Table 2). In addition, the ivabradine group showed a significant reduction of HR (76 + 5 to 63 + 3 bpm, P < .0001) ...
Context 2
... No significant difference was found in the control group at 3 months (P ¼ ns, respectively; Table 2). ...
Context 3
... group showed a significant reduction in NT-proBNP levels compared with baseline at 3 months (1434 + 1273 pg/mL; P ¼ .045). No significant difference was found in the control group at 3 months (2285 + 1998 pg/mL; P ¼ ns; Table 2), and t the com- parison between the 2 groups at 3 months did not show a sig- nificant difference, P ¼ .054. ...
Context 4
... criterion was chosen by us to avoid effects of exer- cise training on the studied parameters. Aside from the first benefits mentioned, we also had noticed an improvement in neurohormonal modulation in the ivabra- dine group (significant reduction in NT-proBNP baseline ver- sus 3 months), while in the placebo group no difference was observed (Table 2). In addition, Peak VO 2 is a valid parameter to measure the exercise capacity in patients with CHF, and it has also been found to correlate with prognosis. ...
Similar publications
A 12 week exercise program was evaluated for its effect on aerobic fitness, anaerobic threshold, physical activity and sedentary behavior levels in obese insulin resistant adolescents post intervention and at follow up. 111 obese insulin resistant 10-17 year olds were recruited to a 12 month lifestyle intervention, known as RESIST. From months 4 to...
Citations
... One RCT was removed from the analysis due to the use of carvedilol, the established standard treatment for heart failure, in the control group [29]. Finally, nine RCTs were determined to be eligible [30][31][32][33][34][35][36][37][38]. Figure 2 illustrates the study quality assessment results using RoB2. ...
... A total of 18,972 HFrEF patients from nine RCTs [30][31][32][33][34][35][36][37][38], including 9,517 patients in the ivabradine group and 9,455 patients in the placebo group, were involved in this systematic review and meta-analysis. They were all in sinus rhythm, with LVEF ,40%. ...
... The total ivabradine daily doses ranged from 5-15 mg. The shortest follow-up period was 2 months, while the longest was 22.9 months [30][31][32][33][34][35][36][37][38]. Table 1 summarises the baseline characteristics of the RCTs involved. ...
... Esto se traduce en una notable elevación en la calidad de vida, abarcando el bienestar físico y emocional. Además, los pacientes experimentan un mejor rendimiento físico y capacidad de ejercicio (21). Es crucial reconocer que los cambios observados en nuestro estudio no son atribuibles únicamente a la introducción de ivabradina. ...
Introducción y objetivos
: La insuficiencia cardíaca (IC) es una preocupación creciente de salud pública. Si bien los betabloqueantes (BB) son la base del tratamiento, lograr reducciones objetivo de frecuencia cardíaca puede ser difícil debido a los efectos secundarios y la tolerancia limitada. La ivabradina, un inhibidor único de la corriente If, ofrece un enfoque complementario para controlar la frecuencia cardíaca sin afectar la contractilidad. El objetivo de este estudio fue evaluar la eficacia de agregar ivabradina a la terapia BB en pacientes con IC.
Métodos:
Se realizó un estudio observacional retrospectivo en un hospital privado en San José, Costa Rica se analizaron 7 casos de pacientes tratados con BB a los cuales posteriormente se les adicionó ivabradina. Se recopilaron datos demo- gráficos, las características clínicas, la frecuencia cardíaca previa y posterior a la ivabradina, la clase funcional NYHA y los valores de laboratorio seleccionados.
Resultados:
La ivabradina redujo significativamente la frecuencia cardíaca en reposo en un promedio de 26,87 latidos por minuto. El 42,86% alcanzó la dosis meta de su BB inicial después de agregar ivabradina. La clase funcional NYHA se mantuvo estable o mejoró en todos los casos.
Conclusiones:
Estos resultados sugieren que agregar ivabradina a la terapia BB puede ser una estrategia eficaz para optimizar el control de la frecuencia cardíaca en pacientes con IC. Este enfoque puede mejorar la tolerabilidad de BB, lo que lleva a un mayor manejo de la dosis meta y posiblemente mejores resultados clínicos.
... In the pooled analysis for SHIFT and BEAUTIFUL, 11897 patients were studied. Most studies included patients with heart rate ≥70 bpm [18,21,22,27,30,34,37,41,48], ≥75 bpm [19,23,24,28,38,40], or ≥80 bpm [20], except Potapenko et al. (2011) [29], in which patients with heart rate ≥60 bpm were included. The majority of the included studies analyzed patients with baseline LVEF ≤40% [17,20,22,26,28,29,[32][33][34]49] or ≤35% [19,21,23,27,30,35,37,40]. The mean age of patients ranged from 42 years to 74 years [20,50]. ...
... Most studies included patients with heart rate ≥70 bpm [18,21,22,27,30,34,37,41,48], ≥75 bpm [19,23,24,28,38,40], or ≥80 bpm [20], except Potapenko et al. (2011) [29], in which patients with heart rate ≥60 bpm were included. The majority of the included studies analyzed patients with baseline LVEF ≤40% [17,20,22,26,28,29,[32][33][34]49] or ≤35% [19,21,23,27,30,35,37,40]. The mean age of patients ranged from 42 years to 74 years [20,50]. ...
... Six trials compared ivabradine with placebo on top of background therapy [17,20,23,[34][35][36], and 16 trials evaluated ivabradine on top of background therapy [18,19,21,22,24,[26][27][28][29][31][32][33]37,38,41,49], including various beta-blockers, ARBs, ACEIs, and MRAs, either with or without placebo. One study compared ivabradine and pyridostigmine [41], and one trial compared ivabradine alone and placebo [39]. ...
Background: Heart failure is a chronic disease linked with significant morbidity and mortality, and uncontrolled resting heart rate is a risk factor for adverse outcomes. This systematic literature review aimed to assess the efficacy, safety, and patient-reported outcomes (PROs) of ivabradine in patients with heart failure (HF) with reduced ejection fraction (HFrEF) in randomized controlled trials (RCTs) and observational studies.
Methods: We searched electronic databases from their inception to July 2021 to include studies that reported on efficacy, safety, or PROs of ivabradine in patients with HFrEF.
Results: Of 1947 records screened, 51 RCTs and 6 observational studies were identified. Ivabradine on top of background therapy demonstrated a significant reduction in composite outcomes including hospitalization for HF or cardiovascular death. In addition, observational studies suggested that ivabradine was associated with a significant reduction in mortality. Across all studies, ivabradine use on top of background therapy was associated with greater reductions in heart rate, improved EF, and improved health-related quality of life (QoL) and comparable risk of total adverse events compared to those treated with background therapy alone.
Conclusions: Ivabradine on top of background therapy is beneficial for heart rate, hospitalization risk for HF, mortality, EF, and patients’ QoL. Moreover, these benefits were achieved with no significant increase in the overall risk of total adverse events.
... Based on previous research, 8 we assumed that the effect size in this study would be ≥0.8. To determine the target sample size, an effect size of 0.83 in a meta-analysis 11 was used as a reference value. ...
Background: A high resting heart rate is an independent risk factor for mortality and morbidity in patients with cardiovascular diseases. Ivabradine selectively inhibits the funny current (If) and decreases heart rate without affecting cardiac conduction, contractility, or blood pressure. The effect of ivabradine on exercise tolerance in patients with heart failure with reduced ejection fraction (HFrEF) on standard drug therapies remains unclear.
Methods and Results: This multicenter interventional trial of patients with HFrEF and a resting heart rate ≥75 beats/min in sinus rhythm treated with standard drug therapies will consist of 2 periods: a 12-week open-label, randomized, parallel-group intervention period (standard drug treatment+ivabradine group and standard drug treatment group) to compare changes in exercise tolerance between the 2 groups; and a 12-week open-label ivabradine treatment period for all patients to evaluate the effect of adding ivabradine on exercise tolerance. The primary endpoint will be the change in peak oxygen uptake (V̇O2) during the cardiopulmonary exercise test from Week 0 (baseline) to Week 12. Secondary endpoints will be time-dependent changes in peak V̇O2from Week 0 to Weeks 12 and 24. Adverse events will also be evaluated.
Conclusions: The EXCILE-HF trial will provide meaningful information regarding the effects of ivabradine on exercise tolerance in patients with HFrEF receiving standard drug therapies and suggestions for the initiation of ivabradine treatment.
... The flowchart of search and selection process is shown in Fig. 1. Based on the inclusion criteria and full text selection, a total number of 24 studies were included in the meta-analysis (Fox et al. 2008(Fox et al. , 2014Sarullo et al. 2010;Swedberg et al. 2010;Mansour 2011;Rayan et al. 2011;Volterrani et al. 2011;Cocco and Jerie 2013;Kosmala et al. 2013;Riccioni et al. 2013;Sargento et al. 2013;Abdel-Salam et al. 2015;Bagriy et al. 2015;Ordu et al. 2015;Pal et al. 2015;Simantirakis et al. 2015;Darabantiu 2016;Sisakian et al. 2016;Tsutsui et al. 2016;Cacciapuoti et al. 2017;Hidalgo and Anguita 2017;Komajda et al. 2017;Jirak et al. 2018;Villacorta et al. 2019). Among these articles there were only two studies in the HFrEF group (Fox et al. 2008;Swedberg et al. 2010), and one in the HFpEF group (Fox et al. 2014) that reported outcomes of hospital admission for worsening HF, all-cause mortality, and cardiovascular mortality. ...
... Risk of bias was assessed in 9 non-RCT studies Riccioni et al. 2013;Sargento et al. 2013;Bagriy et al. 2015;Ordu et al. 2015;Simantirakis et al. 2015;Darabantiu et al. 2016;Cacciapuoti et al. 2017;Jirak et al. 2018) and 15 RCTs Fox et al. 2008;Mansour 2011;Cocco and Jerie 2013;Kosmala et al. 2013;Pal et al. 2015;Sisakian et al. 2016;Komajda et al. 2017;Tsutsui et al. 2016;Villacorta et al. 2019;Volterrani et al. 2011;Hidalgo and Anguita 2017;Sarullo et al. 2010;Abdel-Salam et al. 2015;Fox et al. 2014). Results of the Cochrane Risk of Bias Assessment Tool for RCTs and the results of the Newcastle-Ottawa quality assessment scale for cohort studies are shown in Fig. 8 and Fig. 9 in both populations. ...
In clinical trials of heart failure reduced ejection fraction (HFrEF), ivabradine seemed to be an effective heart rate lowering agent associated with lower risk of cardiovascular death. In contrast, ivabradine failed to improve cardiovascular outcomes in heart failure preserved ejection fraction (HFpEF) despite the significant effect on heart rate. This meta-analysis is the first to compare the effects of ivabradine on heart rate and mortality parameters in HFpEF versus HFrEF. We screened three databases: PubMed, Embase, and Cochrane Library. The outcomes of these studies were mortality, reduction in heart rate, and left ventricular function improvement. We compared the efficacy of ivabradine treatment in HFpEF versus HFrEF. Heart rate analysis of pooled data showed decrease in both HFrEF (-17.646 beats/min) and HFpEF (-11.434 beats/min), and a tendency to have stronger bradycardic effect in HFrEF (p = 0.094) in randomized clinical trials. Left ventricular ejection fraction analysis revealed significant improvement in HFrEF (5.936, 95% CI: [4.199-7.672], p < 0.001) when compared with placebo (p < 0.001). We found that ivabradine significantly improves left ventricular performance in HFrEF, at the same time it exerts a tendency to have improved bradycardic effect in HFrEF. These disparate effects of ivabradine and the higher prevalence of non-cardiac comorbidities in HFpEF may explain the observed beneficial effects in HFrEF and the unchanged outcomes in HFpEF patients after ivabradine treatment.
... Several other studies have also reached inconsistent conclusions. [21][22][23][24] Accordingly, this meta-analysis was designed to evaluate the safety and efficiency of Ivabradine added to the standard HF treatment in patients with chronic HFrEF. ...
... High heterogeneity investigation in the resting HR was stratified into two subgroups based on age and follow-up duration. First, included studies were grouped based on the age < 60 years old 21,23,24 and ≥ 60 years old, 20,22,27 and revealed that the results were consistent in the two different age groups (MD = −11.40; 95%CI -13.08, ...
... 95%CI -10.24, −6.68, respectively). However, substantial heterogeneity presented in the subgroup of ≥60 years old (I 2 = 65%), but not in the <60 years old group (I 2 = 0%), thus indicating aging was one of the reasons for the high heterogeneity.Second, subgroup analysis was performed based on the duration of Ivabradine treatment for HR reduction with distinction <6 months21,23,24,27 and ≥ 6 months.20,22 In the <6 months subgroup, four RCTs demonstrated high heterogeneity (MD -9.84; 95%CI -13.11, −6.58; ...
Elevated resting heart rate in chronic heart failure (HF) patients has been associated with higher mortality and poor prognosis. Ivabradine is a new pure bradycardic agent that has been used to treat angina or heart failure reduced ejection fraction (HFrEF) with sinus heart rate above 70 beats per minute. However, the effect of ivabradine for chronic HF patients on rehospitalization and cardiac function is still inconsistent. Thus, this meta-analysis aimed to elucidate the effect of Ivabradine in chronic HFrEF patients. We systematically searched PubMed, Medline, Clinical Trials.gov, and The Cochrane Central Register of Controlled Trials for randomized controlled trials (RCTs) of ivabradine with search terms Ivabradine (MeSH Terms), chronic heart failure and beta-blocker. The primary endpoints of the study include the impact of Ivabradine on heart rate, left ventricle ejection fraction (LVEF), left ventricular remodeling, exercise capacity, and quality of life (QoL) in patients with chronic HFrEF. Secondary endpoints were safety analysis of Ivabradine including cardiovascular mortality, worsening HF readmission, visual disturbances, and asymptomatic bradycardia. The analysis was done by Review Manager 5.4 Analyzer, to analyze the mean differences (MD) for continuous data and risks ratio (RR) for dichotomous data. A total of six RCTs and one subgroup analysis showed add of Ivabradine to standard HF therapy was associated with greater resting heart rate reduction (MD = -9.57; 95% CI -11.15, -8.00), improved LVEF (MD = 3.89; 95% CI 2.61, 5.17), left ventricular reverse remodeling improvement (MD = -3.73; 95% CI -4.25, -3.21, LVESV; MD = -17.00, 95%CI -29.65, -4.35, LVEDD; MD = -1.43, 95%CI -2.78, -0.08, LVEDV; MD = -14.75, 95%CI -34.36, 4.87), increased exercise capacity (exercise duration; MD = 8.52; 95%CI 0.09, 16.94), and significant reduction on rehospitalization due to worsening HF (RR = 0.76, 95%CI 0.69, 0.84). However, Ivabradine has no significant effect on the quality of life (MD = 0.65; 95%CI -10.52, 11.82), and cardiovascular mortality (RR = 0.92; 95%CI 0.82, 1.03). Moreover, there were some events of visual disturbances and asymptomatic bradycardia observed in the Ivabradine group compared to the placebo group (RR = 4.76; 95%CI 3.03, 7.48; RR = 3.78; 95%CI 2.77, 5.15, respectively). Addition of Ivabradine to standard HF therapy is associated with cardiac function improvement, reduction on worsening HF readmission, greater HR reduction, and better exercise capacity in chronic HFrEF patients, although it cannot reduce cardiovascular mortality or improve the quality of life.
... Characteristics of the included studies on HFpEF are summarized in Table 1 [15][16][17], and those on HFrEF in Table 2 [18][19][20][21][22][23][24][25][26][27]. A total of 821 patients were enrolled in the 13 included RCTs with duration of follow-up ranging from 7 days to 6 months. ...
Background:
Ivabradine is a heart rate-lowering drug that selectively inhibits the funny (If) current of the sinoatrial node. It is currently recommended in patients with heart failure (HF) with reduced ejection fraction (HFrEF) in sinus rhythm and a heart rate of ≥ 70 beats per minute (bpm) at rest. To investigate whether ivabradine has an effect on diastolic dysfunction, exercise tolerance and quality of life (QOL), we conducted a systemic review and meta-analysis of randomized controlled trials (RCTs).
Methods:
We searched PubMed, EMBASE and Cochrane Central Register of Clinical Trials for studies on the effect of ivabradine on left ventricular (LV) diastolic dysfunction, exercise tolerance, QOL, readmission for worsening HF and mortality in both patients with HF with preserved ejection fraction (HFpEF) and HFrEF.
Results:
Thirteen RCTs with 881 patients met the inclusion criteria. According to the pooled analysis, for the HFpEF subgroup, treatment with ivabradine resulted in a decrease in early diastolic mitral inflow to late diastolic flow ratio (E/A) (standardized mean difference (SMD): -0.53; 95% confidence interval (CI): -0.99, -0.07; P < 0.000) and increase in peak oxygen uptake during exercise (VO2) (SMD: 0.05; 95% CI: -0.35, 0.45; P < 0.00; I2 = 95.1%). Similar effect was seen in the HFrEF subgroup with decrease in E/A ratio (SMD: -0.33; 95% CI: -0.59, -0.06; P < 0.000) and early diastolic mitral inflow to annular velocity ratio (E/e') (SMD: -1.01; 95% CI: -1.49, -0.54; P < 0.012). Ivabradine therapy increased peak VO2 and 6-min walk test (6MWT) in HFrEF patients (SMD: 0.83; 95% CI: 0.35, 1.32; P < 0.00; I2 = 97.5% and SMD: 1.11; 95% CI: 0.82, 1.41; P < 0.000, respectively). There was also significant reduction in Minnesota Living with Heart Failure Questionnaire (MLHFQ) score (SMD: -0.68; 95% CI: -0.91, -0.45; P < 0.000). However, there was no significant difference in readmission for worsening HF and all-cause mortality between ivabradine and control (risk ratio (RR): 1.44; 95% CI: 0.73, 2.16; P < 0.148 and RR: 0.76; 95% CI: 0.19, 1.33; P < 0.907, respectively).
Conclusions:
Ivabradine therapy is associated with improved LV diastolic function, increases exercise tolerance and hence QOL, but it has no significant effect on readmission for worsening HF and all-cause mortality.
... 10 Recently, Ivabradine, a novel sinus node inhibitor, has shown attenuating effects for hemodynamic with promising ability and with minimal side effects. 11 Ivabradine binds to hyperpolarization voltage-gated channels which carry the I (h) current in the eye, leading to transient, dose-dependent changes of the electroretinogram. 12 Considering the promising hemodynamic effect of Ivabradine, we were encouraged to evaluate its impact on rise of intraocular pressure among patients scheduled to undergo laryngoscopy and endotracheal intubation under succinylcholine. ...
... Most of the effects of ivabradine on functional capacity are related to the haemodynamic improvements provided by ivabradine in HF and not only through heart rate reduction. [13][14] In fact ivabradine provides an anti-remodelling effect, improves left ventricular structure and function, and reduces N-terminal pro-brain natriuretic peptide levels. When compared to beta-blockers, ivabradine, for the same degree of heart rate reduction, does not impair the neuro-muscular junction thereby affecting skeletal muscular contraction. ...
The novel first-in-class If channel antagonist, Ivabradine, is effective in improving clinical outcomes and functional capacity, in patients with HF, as well as demonstrating useful anti-anginal and protective anti-ischaemic effects. It can help improve heart rate control and can be usefully co-administered with beta blockers on HFrEF patients with residually elevated resting sinus rhythm heart rate. We review the clinical trial evidence for the benefits of Ivabradine in the treatment of heart failure.
... After primary screening by two researchers, 128 studies met the inclusion criteria. Finally, a total of 22 studies, 12 studies [14][15][16][17][18][19][20][21][22][23][24][25] with 6526 systematically reviewed patients and 10 studies 13,[26][27][28][29][30][31][32][33][34] with 18,036 patients, were subjected to metaanalysis. The characteristics of the component trials and study patients are shown in Tables I, II, respectively. ...
To systematically review and conduct a meta-analysis of the ivabradine-induced improvement in cardiopulmonary function, exercise capacity, and primary composite endpoints in patients with chronic heart failure (CHF).
This study was a systematic review and meta-analysis.
Databases, including PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and Clinical Trials and European Union Clinical Trials, were searched for randomized placebo-controlled trials. The efficacy and safety of ivabradine treatment in patients with CHF were assessed and compared to those of the standard anti-heart failure treatment. Review Manager 5.3 software was used to analyze the relative risk (RR) for dichotomous data and the mean difference (MD) for continuous data.
In total, 22 studies with 24,562 patients were included. Cardiopulmonary function analysis showed that treatment with added ivabradine reduced the heart rate (MD = −17.30, 95% confidence interval (CI): 19.52-−15.08, P < 0.00001), significantly increased the left ventricular ejection fraction (LVEF) (MD = 3.90, 95% CI: 0.40-7.40, P < 0.0001), and led to a better New York Heart Association (NYHA) classification. Ivabradine significantly reduced the minute ventilation/carbon dioxide production (VE/VCO2) (MD = −2.68, 95% CI: −4.81-−0.55, P = 0.01) and improved the peak VO2 (MD = 2.80, 95% CI: 1.05-4.55, P = 0.002) and the exercise capacity, including the exercise duration with a submaximal load (MD = 7.82, 95% CI: −2.57-−18.21, P < 0.00001) and the 6-minute walk distance. The RR of cardiovascular death or worsening heart failure was significantly decreased (RR = 0.93, 95% CI: 0.87-−0.98, P = 0.01) in the patients treated with ivabradine. Additionally, the RRs of heart failure and hospitalization also decreased (RR = 0.91, 95% CI: 0.85-−0.97, P = 0.006; RR = 0.86, 95% CI: 0.79-−0.93, P = 0.0002). Safety analysis showed no significant difference in the RR of severe adverse events between the ivabradine group and the standard anti-heart failure treatment group (P = 0.40). However, ivabradine significantly increased the RR of visual symptoms in CHF patients (RR = 3.82, 95% CI: 1.80-−8.13, P = 0.0005).
Existing evidence showed that adding ivabradine treatment significantly improved the cardiopulmonary function and increased the exercise capacity of patients with CHF. Adding ivabradine to the standard anti-heart failure treatment reduced the mortality and hospitalization risk and improved the quality of life. Finally, ivabradine significantly increased the RR of visual symptoms in CHF patients.
This is the first systematic review and meta-analysis to focus on the efficacy of ivabradine, which improved the cardiac function and increased the exercise capacity in patients with chronic heart failure (CHF). Therefore, this study will help evaluate the quality of life after adding ivabradine to the treatment of patients with CHF, even though there are differences in the standard for resting heart rate, left ventricular ejection fraction (LVEF), and New York Heart Association (NYHA) class in the included studies. This hybrid effect might be smaller when analyzed separately but might have a higher heterogeneity when analyzed in multiple studies.
