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Ivabradine has potent actions in reducing heart rate and improving clinical outcomes of chronic heart failure with reduced ejection fraction (HFrEF). At present, only the short-acting formulation of ivabradine is available that needs to be administered twice daily.This study sought to evaluate the role of ivabradine hemisulfate sustained release (SR), a novel long-acting formulation of ivabradine dosed once daily, in stable patients with HFrEF.Patients with stabilized HFrEF in New York Heart Association functional class II-IV were enrolled and randomized to receive placebo or ivabradine SR in addition to standard medications. The primary endpoint was the change of left ventricular (LV) end-systolic volume index from baseline to week 32.We randomly assigned 181 patients to placebo and 179 patients to ivabradine SR. After 32 weeks, a significant improvement of LV end-systolic volume index from baseline was observed in both arms with a greater effect in the ivabradine SR arm. Ivabradine SR therapy also exhibited superiority in improving LV end-diastolic volume index, LV ejection fraction, resting heart rate, the Kansas City Cardiomyopathy Questionnaire score, and hospital admission for heart failure worsening and cardiovascular disease in comparison to placebo. Overall adverse events showed no difference between the treatment arms. There were fewer occurrences of worsening heart failure in the ivabradine SR arm.The present study demonstrates that ivabradine SR once daily in addition to optimum standard therapy improved heart function in patients with HFrEF. (Clinical Trial of Systolic Heart Failure Treatment of IvabRadine Hemisulfate Sustained-release Tablets [FIRST]; NCT02188082).

Ivabradine increases stroke volume, but does not have a negative impact on blood pressure (BP). Thus, a patient with low BP can benefit from treatment with ivabradine. A 72-year-old Japanese woman with asthma and chronic bronchitis presented with dyspnea. Her heart rate (HR) was 126 beats per minute and an electrocardiogram showed sinus tachycardia. The chest X-ray showed cardiomegaly and pulmonary congestion. A transthoracic echocardiogram (TTE) showed reduced left ventricular ejection function (LVEF) and severe functional mitral regurgitation (MR). We diagnosed her with inappropriate sinus tachycardia (IST) and heart failure (HF) due to tachycardia-induced cardiomyopathy. After resolving the pulmonary congestion with diuretics, we administered a minimum dose of bisoprolol, which resulted in re-exacerbation of the HF. Because IST was persistent, we initiated treatment with ivabradine. As soon as ivabradine was started, the HR decreased, the BP gradually increased, and HF compensation was achieved. Bisoprolol was continued and losartan was started. In summary, we used ivabradine for a patient with tachycardia, low BP, a low LVEF, and severe MR. By optimizing the medical therapy, exercise tolerance improved and she was discharged. The serum brain natriuretic peptide was significantly reduced and TTE showed an improved LVEF and reduced MR.

Introduction and objectives Ivabradine reduces heart rate by blocking the I(f) current and preserves blood pressure and stroke volume through unknown mechanisms. Caveolin-3 protects the heart by forming protein complexes with several proteins, including extracellular matrix (ECM)-metalloproteinase-inducer (EMMPRIN) and hyperpolarization-activated cyclic nucleotide-gated channel 4 (HN4), a target of ivabradine. We hypothesized that ivabradine might also exert cardioprotective effects through inhibition of ECM degradation. Methods In a porcine model of cardiogenic shock , we studied the effects of ivabradine on heart integrity, the levels of MMP-9 and EMMPRIN , and the stability of caveolin-3/HCN4 protein complexes with EMMPRIN. Results Administration of 0.3 mg/kg ivabradine significantly reduced cardiogenic shock-induced ventricular necrosis and expression of MMP-9 without affecting EMMPRIN mRNA , protein, or protein glycosylation (required for MMP activation). However, ivabradine increased the levels of the caveolin-3/LG-EMMPRIN (low-glycosylated EMMPRIN) and caveolin-3/HCN4 protein complexes and decreased that of a new complex between HCN4 and high-glycosylated EMMPRIN formed in response to cardiogenic shock. We next tested whether caveolin-3 can bind to HCN4 and EMMPRIN and found that the HCN4/EMMPRIN complex was preserved when we silenced caveolin-3 expression, indicating a direct interaction between these 2 proteins. Similarly, EMMPRIN-silenced cells showed a significant reduction in the binding of caveolin-3/HCN4, which regulates the I(f) current, suggesting that, rather than a direct interaction, both proteins bind to EMMPRIN. Conclusions In addition to inhibition of the I(f) current, ivabradine may induce cardiac protection by inhibiting ECM degradation through preservation of the caveolin-3/LG-EMMPRIN complex and control heart rate by stabilizing the caveolin-3/HCN4 complex.

Hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels, expressed in a variety of cell types and in all tissues, control excitation and rhythm. Since their discovery in neurons and cardiac pacemaker cells, they attracted the attention of medicinal chemistry and pharmacology as novel targets to shape (patho)physiological mechanisms. To date, ivabradine represents the first-in-class drug as specific bradycardic agent in cardiac diseases; however, new applications are emerging in parallel with the demonstration of the involvement of different HCN isoforms in central and peripheral nervous system. Hence, the possibility to target specific isoforms represents an attractive development in this field; indeed, HCN1, HCN2 or HCN4 specific blockers have shown promising features in vitro and in vivo, with remarkable pharmacological differences likely depending on the diverse functional role and tissue distribution. Here, we show a recently developed compound with high potency as HCN2–HCN4 blocker; because of its unique profile, this compound may deserve further investigation.

Objectives This study sought to compare the efficacy of ivabradine and amiodarone in the management of postoperative junctional ectopic tachycardia (JET) after cardiac surgery in children. Background JET is a serious arrhythmia occurring in children after cardiac surgery and requires aggressive management. Amiodarone has been conventionally used in its treatment. Recent studies have reported the utility of ivabradine in this regard. Methods In this open-label randomized controlled trial, 94 children (age ≤18 years) who developed postoperative JET were allocated to receive either amiodarone or ivabradine. The primary endpoint was restoration of normal sinus rhythm. Results Sinus rhythm was achieved in 43 out of the 46 patients (93.5%) in the amiodarone group and 46 out of the 48 patients (95.8%) in the ivabradine group (mean difference of treatment effect: 2.3%; 95% confidence interval: −6.7% to 11.5%). The median (interquartile range) time taken to achieve sinus rhythm conversion was similar in both the groups: 21.5 (17–30.2) hours versus 22 (13.4–38.5) hours (p = 0.36)]. The time taken to rate control of JET was significantly less in the amiodarone group: median 7.0 (5.5–9.5) hours versus 8.0 (5.8–10.8) hours (p = 0.02)]. No drug-related adverse events were observed in the ivabradine group. Conclusions Oral ivabradine is not inferior to intravenous amiodarone in converting postoperative JET to sinus rhythm. There was no difference in time taken to sinus rhythm conversion between the groups, although the rate control was earlier in patients who received amiodarone. Monotherapy with ivabradine may be considered as an alternative to amiodarone in the management of postoperative JET. (Comparison of Two Drugs, Ivabradine and Amiodarone, in the Management of Junctional Ectopic Tachycardia, an Abnormality in Cardiac Rhythm in Patients Under 18 years Who Undergo Cardiac Surgery: CTRI/2018/08/015182 )

Since 1953, sinus tachycardia has been defined as a heart rate (HR) in sinus rhythm of >100 beats per minute (bpm). However, this number has never been formally evaluated, and no established threshold values for special groups, such as those with heart failure (HF) accompanied by a reduced ejection fraction (HFrEF). Herein, we provided evidence that lowering the HR of patients with HFrEF to

Coronary CT angiography (CCTA) is increasing seen as a first line investigation in patients with suspected coronary artery disease. Heart-rate control improves the image quality and diagnostic accuracy of CCTA. Typically, beta-blockers are administered to induce sinus bradycardia. Sinus bradycardia may also be induced by ivabradine. We hypothesized that in a real-world population ivabradine would be an effective alternative to metoprolol at heart rate lowering for CCTA.This was a retrospective analysis of consecutive patients who were exposed to an ivabradine-based (IB) versus a metoprolol-only (MO) protocol to achieve a target heart rate/ = 65bpm. Hemodynamic responses to both strategies were compared along with differences in cost and the time expired from medication administration to CCTA.5955 consecutive patients were included in the analysis: 3211 were imaged during an era of a metoprolol only strategy (MO) and 2744 CCTA following an ivabradine based (IB) strategy. 2676 patients had heart rates65 and received heart-rate lowering medication: 1958 patients had MO, and 718 received IB protocol. Target heart rate of/ = 65bpm was achieved in 77% of MO and 89% of IB patients (p 0.01). The time from initial medication administration to CCTA was longer in the IB versus MO patients (77 versus 48 min, p 0.01).Introduction of a novel single dose ivabradine-based protocol to control heart rate for CCTA was more successful in achieving target heart rate than a metoprolol-only strategy. The use of ivabradine however incurred a 1.6-fold increase in the time delay from medication administration and imaging compared to a metoprolol only protocol.

Objectives This study evaluated the impact of clinical and physiological factors limiting treatment optimization toward recommended medical therapy in heart failure (HF). Background Although guidelines aim to assist physicians in prescribing evidence-based therapies and to improve outcomes of patients with HF and reduced ejection fraction (HFrEF), gaps in clinical care persist. Methods Medical records of all patients with HFrEF followed for at least 6 months at the authors’ HF clinic (n = 511) allowed for drug optimization and were reviewed regarding the prescription rates of recommended pharmacological agents and devices (implantable cardioverter-defibrillator [ICD] or cardiac resynchronization therapy [CRT]). Then, an algorithm integrating clinical (New York Heart Association [NYHA] functional class, heart rate, blood pressure and biologic parameters (creatinine, serum potassium) based on the inclusion/exclusion criteria of landmark trials guiding these recommendations) was applied for each agent and device to identify potential explanations for treatment gaps. Results Gross prescription rates were high for beta-blockers (98.6%), mineralocorticoid receptor antagonist (MRA) (93.4%), vasodilators (90.3%), ICDs (75.1%), and CRT (82.1%) among those eligible, except for ivabradine (46.3%, n = 41). However, achievement of target physiological doses was lower (beta-blockers, 67.5%; MRA, 58.9%; and vasodilators, 63.4%), and one-fifth of patient dosages were still being up-titrated. Suboptimal doses were associated with older age (odds ratio [OR]: 1.221; p Conclusions Gaps in adherence to guidelines exist in specialized HF setting and are mostly explained by limiting physiological factors rather than inertia. Older age and history of stroke/TIA, potential markers of frailty, are associated with suboptimal doses of guideline-directed medical therapy, suggesting that an individualized rather than a “one-size-fits-all” approach may be required.

Introduction and objectives Ivabradine is an inhibitor of the If channel, the main determinant of the pacemaker function of the sinus node. The drug has been approved for the treatment of angina and heart failure. There is some evidence of its role as an inhibitor of atrial-ventricular node (AVN) conduction. The aim of the BRAKE-AF project is to assess ivabradine use for rate control in atrial fibrillation (AF). Methods A multicenter, randomized, parallel, open-label, noninferiority phase III clinical trial will be conducted to compare ivabradine vs digoxin in 232 patients with uncontrolled permanent AF despite beta-blockers or calcium channel blockers. The primary efficacy endpoint is the reduction in daytime heart rate measured by 24-hour Holter monitoring at 3 months. This clinical trial will be supported by an electrophysiological study of the effect of ivabradine on the action potential of the human AVN. To do this, an experimental model will be used with Chinese hamster ovarium cells transfected with the DNA encoding the expression of the t channels involved in this action potential and recording of the ionic currents with patch clamp techniques. Results New data will be obtained on the effect of ivabradine on the human AVN and its safety and efficacy in patients with permanent AF. Conclusions The results of the BRAKE-AF project might allow inclusion of ivabradine within the limited arsenal of drugs currently available for rate control in AF. Clinical trial registration: http://www.clinicaltrials.gov . Identifier: NCT03718273 .

Background Ivabradine is guideline-recommended to reduce heart failure (HF) hospitalization in patients with stable chronic HF with reduced ejection fraction (EF). Ivabradine initiation following acute HF has had limited evaluation, and there are few randomized data in US patients. The PredischaRge initiation of Ivabradine in the ManagEment of Heart Failure (PRIME-HF) study was conducted to address predischarge ivabradine initiation in stabilized acute HF patients. Methods PRIME-HF was an investigator-initiated, randomized, open-label study of predischarge initiation of ivabradine versus usual care. Eligible patients were hospitalized for acute HF but stabilized, with EF ≤35%, on maximally tolerated β-blocker and in sinus rhythm with heart rate ≥70 beats/min. Ivabradine was acquired per routine care. The primary end point was the proportion of patients on ivabradine at 180 days. Additional end points included heart rate change, patient-reported outcomes, β-blocker use/dose, and safety events (symptomatic bradycardia and hypotension). Results Overall, 104 patients (36% women, 64% African American) were randomized, and the study was terminated early because of funding limitations. At 180 days, 21 of 52 (40.4%) of patients randomized to predischarge initiation were treated with ivabradine compared with 6 of 52 (11.5%) randomized to usual care (odds ratio 5.19, 95% CI 1.88-14.33, P = .002). The predischarge initiation group experienced greater reduction in heart rate through 180 days (mean −10.0 beats/min, 95% CI −15.7 to −4.3 vs 0.7 beats/min, 95% CI −5.4 to 6.7, P = .011). Patient-reported outcomes, β-blocker use/dose, and safety events were similar (all P > .05). Conclusions Ivabradine initiation prior to discharge among stabilized HF patients increased ivabradine use at 180 days and lowered heart rates without reducing β-blockers or increasing adverse events. As the trial did not achieve the planned enrollment, additional studies are needed.

Ivabradine is a unique antiarrhythmic drug that was designed to affect chronotropy with no effect on inotropy or lusitropy. It was first approved by the European Medicines Agency in 2005 for stable angina treatment, and then in 2009 the indication was expanded to include uncontrolled angina with heart rates ≥60 beats per minute (bpm) on optimal beta-blocker therapy.1 Based on the SHIFT – HF trial in 2011, it got accepted for use in patients with systolic heart failure with heart rate greater than 70 bpm on maximally tolerated beta-blocker therapy or who have contraindication(s) to beta-blockers.2 It got approved by the Food and Drug Administration (FDA) in 2015 for use in heart failure.1 The FDA did not recommend its use for angina in the United States because the use of ivabradine in coronary disease and angina did not improve outcomes based on the SIGNIFY trial.3 Ivabradine has been on the market for less than a decade in the United States and longer than that in Europe. As its use is expanded worldwide, cases of ivabradine toxidromes are likely to be common. Thus far there are only 3 reported cases of overdoses worldwide4, 5, 6 based on literature search. We report on a 19-year-old woman who was prescribed ivabradine for inappropriate sinus tachycardia and had acute ivabradine toxicity. This case report will add to our repertoire of knowledge on ivabradine toxicity and its pathophysiology in human subjects.

Background Ivabradine, a heart rate-slowing drug used to treat heart failure and (in Europe) angina, had varying impacts upon cardiovascular events in its 3 large outcome trials. Food and Drug Administration (FDA) analyses may explain the reasons for the variability. Methods An FDA reviewer analyzed the raw data from the 3 trials using logistic regressions to assess interactions between ivabradine and other drugs and forest plots to display dose responses. Results Ivabradine in its SHIFT heart failure trial shows a significant interaction with loop diuretics with a beneficial impact upon cardiovascular deaths (odds ratio 0.61; 95% confidence interval, 0.42-0.87, P = .007). This favorable effect is supported by similar interactions in the other 2 trials (BEAUTIFUL, SIGNIFY) and by a dose response for loop diuretics interacting with ivabradine in the SHIFT and BEAUTIFUL trials. The interaction is not related to heart failure severity. Conclusion Ivabradine used concomitantly with a loop diuretic has a beneficial impact upon cardiovascular death.

We studied the effects of heart rate reduction by ivabradine to the ongoing therapy in patients with chronic obstructive pulmonary disease (COPD) and cor pulmonale.100 patients of COPD with cor pulmonale with sinus heart rate ≥ 90 bpm were randomly assigned to either ivabradine 5 mg twice daily (50 patients) or placebo (50 patients) alongwith standard therapy. Assessment was done at baseline and after 6 months which included 6 min walk test (6MWT), dyspnea scoring by modified borg scale, Lung function test by forced expiratory volume in 1 s (FEV1) and pulmonary artery systolic pressure (PASP) by echocardiogram. The drug group showed a significant reduction in heart rate from 95.1 ± 8.2 bpm to 71.1 ± 6.2 bpm (p

Prognostic impact of heart rate reduction therapy using ivabradine, a selective inhibitor of If channel that purely reduces heart rate, in patients with heart failure with reduced ejection fraction and sinus tachycardia has been demonstrated. However, ideal heart rate remains unknown. We experienced an 80-year-old woman with reduced left ventricular ejection fraction who was hospitalized due to congestive heart failure. Following the ivabradine administration that decreased her heart rate from 100 bpm down to around 60 bpm, the “overlap” between E-wave and A-wave in the trans-mitral Doppler echocardiography diminished, accompanied by an improvement in cardiac output. Heart rate optimization targeting to diminish the overlap between E-wave and A-wave might maximize cardiac output and improve the clinical course via facilitated cardiac reverse remodeling. Further studies are warranted to validate the implication of therapeutic strategy to aggressively minimize the echocardiographic “overlap” by heart rate reduction therapy in heart failure patients.

Metoprolol combined with ivabradine have been determined up to nanogram level simultaneously relied on the synchronous fluorescence spectra. First derivative amplitudes of the synchronous spectrofluorimetric spectra are recorded at Δλ = 40 nm using ethanol as diluting solvent. Metoprolol can be measured at 286 nm which is the zero-crossing point of ivabradine, and the later can be measured at 296 nm. The calibration plots were found to be linear over the ranges of concentrations: 100.0-1000.0 ng/mL and 10.0-200.0 ng/mL for metoprolol and ivabradine, respectively. Validation of the procedure was performed using the International Council of Harmonization guidelines. Values of LODs were found to be 28.89, 2.80 ng/mL and LOQs were 87.56, 8.49 ng/mL for metoprolol and ivabradine, respectively. As the two drugs are co-administered safely and effectively to reduce heart rate, angina attacks, the current methodology is utilized for the concurrent analysis of them in their single ingredient pharmaceutical preparations, synthetic mixtures, and biological fluids. The designed method, being cost-effective and simple procedure, is the first method for metoprolol and ivabradine simultaneous analysis. The results agreed statistically with the comparison methods.

Background In the Systolic Heart failure treatment with the If inhibitor Trial (SHIFT) randomised placebo-controlled trial, ivabradine was shown to reduce hospital admissions for worsening heart failure (HF) and deaths due to HF in patients with symptomatic systolic HF and an elevated resting heart rate (HR). This analysis evaluates the cost effectiveness of adding ivabradine to optimal standard HF treatment in patients with a HR ≥ 77 bpm. Methods A Markov model was developed to assess the impact of ivabradine on mean survival and quality of life over a patient’s lifetime (10 years). The hospitalisation and death rates were calculated using patient-level data from SHIFT. The reduction in quality of life due to HF hospitalisations was estimated directly from EQ-5D data collected in SHIFT. Australian costs were applied to the resource use from SHIFT. Results The modelled mean increase in survival with ivabradine was 0.115 years. The mean increase in quality-adjusted survival was 0.108 years. The average cost of ivabradine was A$2,957 and the cost savings associated with a reduction in HF hospitalisations was A$1,344. The cost per quality adjusted life year gained (QALYG) was A$14,905. The conservative approach to the modelled evaluation, as well as results of the sensitivity analysis, demonstrates that ivabradine is likely to be cost-effective in this indication. Conclusions The conservative approach to the modelled evaluation, as well as results of the sensitivity analysis, demonstrates that ivabradine is a cost-effective treatment in the Australian setting for HF patients with a HR ≥ 77 bpm on optimal standard therapy with a cost per QALYG similar or lower than that for other publicly funded treatments.

HFrEF is less common in women than men but with several sex differences in the underlying disease. Women with HFrEF are more likely than men to have hypertension and valvular disease, and less likely to have coronary artery disease. In-hospital mortality is similar and low; however, when hospitalized for acute decompensated heart failure, the 5-year mortality rate is very high for both men and women. Natriuretic peptide serum levels are higher in women with decompensated heart failure than men but yield similar prognostic risk for in-hospital mortality. The CardioMEMS is used to monitor acute decompensated heart failure events and guide therapy, although their utility in women remains unclear based on information from the CHAMPION trial. There remains no sex-specific guideline therapy for HFrEF because women were underrepresented in clinical trials and studies were never designed to prospectively study sex differences. Based on post hoc analyses or retrospective studies, β-blockers, aldosterone antagonists, ARBs, and ivabradine seem beneficial in women with HFrEF. The combination of hydralazine and isosorbide was studied in black women with HFrEF and found to reduce mortality, reduce hospitalizations, and improve quality of life. More studies are needed and should be prospectively designed to study sex differences to better understand the effects of drugs and technology on women with HFrEF.

Ivabradine is most commonly used for the treatment of worsening cardiac failure in patients who cannot tolerate the maximum dose of β-blockers or in whom treatment with β-blockers is contraindicated. While ivabradine is regarded as a highly selective "funny current" (If) inhibitor, the molecular mechanism behind the effect of this drug remains poorly understood. In the present study, we applied ivabradine in the context of osteoarthritis by treating primary human chondrocytes with tumor necrosis factor-α (TNF-α) and measuring degradation of the articular cartilage matrix as well as the expression of various enzymes and pro-inflammatory cytokines. Our results indicate that ivabradine significantly abrogated TNF-α-induced up-regulation of matrix metalloproteinase-3 (MMP-3), MMP-13, a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-4, and ADAMTS-5 at both the gene and protein levels. Notably, ivabradine attenuated TNF-α-induced reduction of type II collagen and aggrecan at both the mRNA and protein levels. Also, we found that ivabradine inhibited the expression and secretion of interleukin-6 (IL-6) and interleukin-1β (IL-1β) as well as the production of reactive oxygen species (ROS). Mechanistically, our results indicate that ivabradine abolished the activation of nuclear factor (NF-κB) by inhibiting nuclear translocation of NF-κB p65. Knockdown of HCN2 enhanced the protective effects of ivabradine against TNF-α- induced degradation of both type II collagen and aggrecan, suggesting that the inhibitory effects of ivabradine in ECM degradation might be mediated by HCN2. Our findings demonstrate that ivabradine may indeed have a potential application in preventing excessive degradation of the articular cartilage matrix, thereby preventing the pathological development and progression of osteoarthritis.

The combination of Ivabradine (IVA) and Metoprolol (MET) was approved by US-FDA for symptomatic treatment of chronic stable angina pectoris. Hence, a potential analytical method that can simultaneously quantify these two drugs is required. In view of this, a novel and fully validated LC-ESI-MS/MS method has been established for the quantification of IVA and MET in rat plasma. Analytes and their deuterated analogues were quantitatively extracted from rat plasma by protein precipitation technique. The analytes were separated using acetonitrile-water consisting 0.1% orthophosphoric acid buffer (30:70 v/v) as a mobile phase with a flow-rate of 1.0 mL/min and 5 min run time on Waters, X-Bridge-C18 (150× 4.6 mm, 3.5 μm) analytical column. The multiple reaction monitoring transitions, m/z 638.14 → 124.22 for IVA, 498.33 → 110.59 for MET; 644.37 → 130.41 for IVA-D6 and 504.46 → 116.28 for MET-D6 were chosen to achieve high selectivity in the analysis. The method exhibited great improvement in sensitivity and good linearity over the concentration range of 0.1-1.5 ng/mL for IVA, 1.0-15.0 ng/mL for MET, with satisfactory precision and accuracy according to USFDA guidelines. Accuracy was within 99.71-100.3% and 99.9-100.31% for IVA and MET. The intra- and inter-day precision ranged between 0.048 and 12.68% and 0.1-2.66% CV for IVA and MET respectively. Further, the results of the pharmacokinetic parameters including C

Introduction By inhibiting the pacemaker current if of the sinoatrial node (SN), ivabradine was first use as an alternative to betablockers in the treatment of heart failure [1] . For a few years, it has been proposed as an adjuvant therapy for postoperative [2] or congenital junctional ectopic tachycardia [3] . But ivabradine can also be effective on atrial and ventricular abnormal automaticity [4] . Case report We report the case of a 9 years old girl who was diagnosed of polymorphic atrial tachycardia at birth. The child was first treated by amiodarone. When amiodarone had to be withdraw because of thyroid dysfunction, multiple antiarrhythmic drugs were tested alone or in association: betablockers, flecainide, digoxine. Despite medication, the child experimented multiple high rate non-sustained tachycardia per day. After an antiarrhythmic washout, ivabradine was started. Fig. 1 is the patient Holter without any treatment showing a very anarchic rhythm, mostly rapid arrhythmia. Fig. 2 is the patient Holter after only 2 takes of ivabradine that shows a marked efficacy of the drug. Discussion Ivabradine inhibits selectively the If current that is responsible of the pacemaker activity of the SN and the AV node. If current can also be responsible of abnormal automaticity of the atrial and ventricular myocardium. In such case, ivabradine is highly effective to control the arrhythmia. Still, ivabradine efficacy is difficult to predict, but regarding its overall safety, it can be tested. In a randomized, double-blind trial of pediatric patient with dilated cardiomyopathy, Bonnet et al. did not report more adverse event with ivabradine than with placebo [5] . The outcome of atrial ectopic arrhythmia in the pediatric population is good: 78% will resolve spontaneously when diagnosed under 3 years old [6] . Ivabradine could be an alternative to catheter ablation in the very young or in pediatric patient with multifocal arrhythmia or organized arrhythmia close to the AV conduction system.

Background: Ivabradine is indicated for heart failure (HF) patients with reduced left ventricular ejection fraction who are in sinus rhythm. However, limited data are available with regards to the use of ivabradine in symptomatic HF patients with reduced EF (HFrEF) and a history of paroxysmal atrial fibrillation (AF). Methods: We conducted a multi-center observational matched cohort study enrolled patient who was diagnosed with symptomatic HFrEF from 2015/01/01 to 2018/12/31 with had a history of paroxysmal AF in Chang Gung Memorial Hospital medical database in Taiwan. After inverse probability of treatment weighting (IPTW), the outcomes of interest during a 12-month observation period were analyzed. The primary outcome was HF hospitalization and cardiovascular death. Results: A total of 2,042 patients were eligible for the study, of whom 887 were prescribed with ivabradine and 1,115 were not. After IPTW, the ivabradine group had a significant lower mean heart rate after 12 months than the non-ivabradine group (P < 0.05). The primary outcome was also significantly higher in the ivabradine group than the non-ivabradine group after 12 months (hazard ratio [HR] = 1.58; 95% confidence interval [CI], 1.26-2.00, P < 0.001). Moreover, the ivabradine group had a significantly higher event rate of HF hospitalization (HR = 1.56; 95% CI, 1.40-1.75, P < 0.001) and HF death (HR = 1.67; 95% CI, 1.14-2.44, P = 0.009) than the non-ivabradine group. Conclusions: Ivabradine treatment was associated with an increased risk of HF hospitalization in symptomatic HFrEF patients with a history of paroxysmal AF, and further prospective studies are warranted. Funding Information: This work was supported by a grant from Chang Gung Memorial Hospital, Taiwan (grant CGRPG6J0041, CMRPG6H0481 and CMRPG6H0482). Declaration of Interests: The authors declare that there is no conflict of interest. Ethics Approval Statement: The Institutional Review Board of Chang Gung Memorial Hospital: (201900915B1).

A simple and sensitive spectrofluorimetric method has been developed for the estimation of Ivabradine HCl in bulk and the tablet dosage form. Ivabradine HCl in methanol produces fluorescence at 325 nm (λem) with excitation at 287 nm (λex). The linearity range was found to be 100–500 ng/ml with a correlation coefficient of 0.999. The limit of detection (LOD) and limit of quantitation (LOQ) for the developed method were found to be 8.38 and 25.39 ng/ml, respectively. The developed method was found to be specific, sensitive, accurate, and precise. It was successfully used for the estimation of Ivabradine HCl in its tablet dosage form. The content of Ivabradine HCl in marketed formulations was found to be 101.25 ± 1.16 % of label claims.

Ivabradine increases the risk of atrial fibrillation (AF). Heart failure (HF) or sinoatrial node (SAN) dysfunction increases the risk of AF, and pulmonary veins (PVs) play a critical role in the pathophysiology of AF. This study investigated the electrophysiologic effects of ivabradine on SANs and PVs in a rabbit model of HF.Conventional microelectrodes were used to simultaneously record the electrical activities and conduction properties of control and HF rabbit SAN-PV preparations before and after perfusion with ivabradine (0.1, 1, or 10 μmol/L), either alone or with isoproterenol (1 μmol/L). HF SANs exhibited a lower beating rate than the control SANs. SAN automaticity exit blocks and SAN-PV conduction blocks were observed in 25% and 50% of samples, respectively, with P.05 for HF SANs (n = 8) but not for control SANs (n = 6). Delayed afterdepolarization (DAD) was observed in 37.5% of HF PVs but not in control PVs. HF PVs exhibited a faster beating rate and more severe fibrosis than control PVs. Ivabradine reduced the SAN beating rates and increased the occurrences of SAN-PV conduction blocks and PV DADs in control and HF preparations. However, ivabradine induced SAN automaticity exit blocks only in HF preparations. Isoproterenol induced PV burst firing and shifting electrical conduction in control and HF preparations. A combination of isoproterenol and ivabradine (10 μmol/L) in HF preparations resulted in the highest incidences of PV burst firing and SAN-PV electrical shifting.HF differentially modulates the effects of ivabradine on the electrical activities of SAN and PVs, which may increase PV arrhythmogenesis and contribute to the risk of AF in HF patients.

Postoperative cardiac ischemic complications are frequent and strongly associated with postoperative mortality. Elevated heart rate before, during and after surgery increases the risk of postoperative myocardial injury, myocardial infarction and mortality. Yet, in absence of strong causal evidence, heart rate is seldom used for risk stratification. While beta-blockers reduce the risk of tachycardia and myocardial infarction, their initiation within 24 h of surgery is harmful. Rather than a "one-size fits all" approach, we propose that safe and efficient administration of beta blockers should take into account both the perioperative risk and the pharmacogenetic profile of each patient. In the future, new drugs designed to modulate heart rate without significant hypotension (e.g. ivabradine) may replace beta-blockers.

Heart failure affects more than 6 million people in the United States each year and the prognosis is poor. The elevated heart rate in heart failure patents is problematic, because it increases myocardial oxygen demand, decreases myocardial perfusion, and has been associated with increased rates of hospitalization and mortality. For these reasons, heart rate reduction has long been a therapeutic target in heart failure. Ivabradine is a selective inhibitor of the sinoatrial pacemaker modulating "f-current" (If) and provides heart rate reduction that can be beneficial in patients with heart failure with reduced ejection fraction.

Background A prophylactic implantable cardioverter defibrillator (ICD) in patients with heart failure and reduced left ventricular ejection fraction (HFrEF) is only indicated when left ventricular ejection fraction (LVEF) reassessment remains ≤35% after 3–6 months on optimal pharmacological therapy. However, LVEF may not improve during this period and the patient may be exposed to an unnecessary risk of sudden cardiac death. This study aimed to determine the incidence and predictors of the absence of left ventricular reverse remodeling (LVRR) after pharmacological treatment optimization in patients with HFrEF to design a risk score of absence of LVRR. Methods Consecutive outpatients with LVEF ≤35% were included in this observational prospective study. Up-titration of angiotensin-converting enzyme (ACE) inhibitors/angiotensin II receptor blockers (ARBs), beta-blockers, mineralocorticoid receptor antagonists (MRAs), and ivabradine was performed in our Heart Failure (HF) Unit. The absence of LVRR was defined as the persistence of an LVEF ≤35% at the 6-month follow-up. Results One hundred and twenty patients were included. At the 6-month follow-up, 64%, 76%, 72%, and 7% of patients were at 100% of the target dose of ACE inhibitors/ARBs, beta-blockers, MRAs, and ivabradine, respectively. LVRR was observed in 48% of the patients. Ischemic cardiomyopathy, prolonged HF duration, and larger left ventricular end-diastolic diameter index (LVEDDI) were independent predictors of the absence of LVRR. The risk score based on these predictors showed a c-statistic value of 0.81. Conclusions Pharmacological treatment optimization is associated with LVRR in approximately half of cases, reducing potential ICD indications in parallel. However, ischemic cardiomyopathy, prolonged HF duration, and larger LVEDDI predict the absence of LVRR and favor ICD implantation without delay. The risk score based on the former predictors may help the clinician with the timing of ICD implantation.

To assess the acute effects of intravenous ivabradine, a selective bradycardic agent, on carotid sinus baroreflex-mediated sympathetic arterial pressure (AP) and heart rate (HR) responses.In anesthetized and vagotomized Wistar-Kyoto rats (n=6), carotid sinus baroreceptor regions were isolated. Changes in splanchnic sympathetic nerve activity (SNA), AP, and HR in response to a step-wise pressure input were examined before and after intravenous ivabradine (2mg/kg). Ivabradine did not affect the response range of SNA (91.8±6.5 vs. 93.5±9.8%) or AP (89.6±10.6 vs. 91.0±9.7mmHg). Ivabradine significantly reduced the minimum HR from 369.4±8.4 to 223.3±13.2 (P0.001) but did not attenuate the HR response range (69.1±7.0 vs. 82.5±9.6beats/min).Ivabradine does not acutely affect baroreflex-mediated sympathetic AP regulation and also spares the magnitude of the sympathetic HR response, despite significant bradycardia. The preserved sympathetic HR response, which could not be afforded by beta-blockers, may contribute to some beneficial clinical effects of ivabradine.

Angina persists for many patients despite modern medical therapy and/or revascularization, and this is referred to as refractory angina. All patients with refractory angina must be treated with aggressive risk factor modification plus optimized medical management. β-Blockers and nitrates are usually first-line agents; however most patients require multiple medications for refractory symptom control. Novel agents, such as ranolazine and ivabradine, as well as non-pharmacologic therapies, such as enhanced external counterpulsation and cardiac rehabilitation, may provide relief or reduction of angina. Other standard treatments such as antiplatelet therapy, lipid reduction therapy, blood pressure control, diabetes control, smoking cessation, and wei1ght control should be part of the management of refractory angina as well.

Background Inappropriate sinus tachycardia (IST) is debilitating despite available treatment. Off-label use of ivabradine for IST prompted this systematic analysis of existing data quality and sample size estimates for adequately powered studies. Objective To determine clinical efficacy of ivabradine in IST from pooled prospective studies. Methods Analysis included ivabradine studies for IST participants without structural heart disease and with follow-up of ≥2 weeks. Heart rate and symptom reduction with ivabradine were estimated based on results of subjective change in symptoms assessed by various data instruments used in each study. Studies were assessed for quality using validated checklists. Sample sizes were calculated based on the magnitude of symptom reduction encountered after treatment with ivabradine. Results Nine studies met criteria, culminating in 145 patients pooled. Most patients were women (≥70%). Studies were small and not adequately powered, and all reported a decrease in maximum or mean resting heart rate or both, with complete or considerable amelioration of symptoms with ivabradine. Most studies had moderate quality with excellent consistency of study quality and narrow limits of agreement between the quality checklists. Sample size estimates for adequately powered studies with various placebo effects and comparisons with β-blockade are reported. Conclusions Ivabradine effectively reduces heart rate and symptoms in IST, but no study was adequately powered to account for the expected placebo effect on symptoms. A multicenter, randomized, placebo-controlled, active, comparative study with a β-blocker is needed for confirmation. This is especially relevant given the ivabradine's potential teratogenic effect, as many IST patients are females of childbearing potential.

Fundamental features of septic shock are vasodilation, increased permeability, hypovolemia, and ventricular dysfunction. Vasodilation owing to increased nitric oxide and prostaglandins is treated with vasopressors (norepinephrine first). Increased permeability relates to several pathways (Slit/Robo4, vascular endothelial growth factor, angiopoietin 1 and 2/Tie2 pathway, sphingosine-1-phosphate, and heparin-binding protein), some of which are targets for therapies. Hypovolemia is common and crystalloid is recommended for fluid resuscitation. Cardiomyocyte-inflammatory interactions decrease contractility and dobutamine is recommended to increase cardiac output. There is benefit in decreasing heart rate in selected patients with esmolol. Ivabradine is a novel agent for heart rate reduction without decreasing contractility.

A Central Composite Rotatable Design (CCRD) was applied to statistically optimized lipospheres (LS) formulated for enhancing the pharmacokinetics of co-administered Ivabradine and Nebivolol as well as improving the patients’ compliance. The lipospheres (LS) were prepared by simple melt emulsification technique and impact of formulation variables (Carnauba wax, Beeswax, and surfactant) on percentage yield (Y1), IVB-release (Y2) and NEB-release (Y3) was statistically investigated. The numerical optimization technique was adopted to select optimized lipospheres (OL) which were then subjected to a comparative in vivo pharmacokinetic analysis against commercially available brands. The physicochemical analysis of LS was performed by FTIR, DSC and x-ray powder diffractometry (XRD). Lipospheres were also analysed for micromeritics, zeta potential, size, and morphology. The spherical, smooth surface, free-flowing LS having zeta potential of −40 to −60 mV and size-range of 10–50 µm were successfully formulated. The physicochemical analysis demonstrated a complete lack of drugs interaction with lipids carriers, and p-XRD showed a transformation of crystalline drugs to amorphous form. The outcomes for Y1 (38–88%), IVB-release (47–96%) and NEB-release (38–88%) followed polynomial quadratic model. The pharmacokinetics analysis of LS showed a significantly decreased Cmax of IVB (39.29 ± 6.39), NEB (56.69 ± 3.73) with an effectively raised Tmax (13.41 h for IVB and 14.53 h for NEB) as compared to IVB (49.67 ± 5.26 ng/mL) and NEB (71.32 ± 4.57 ng/mL) of commercial brands. Moreover, an expressively increased half-life (17hr for IVB, 19 hr for NEB), AUC0-24 (8121 for IVB, 11,368 for NEB) and mean residence time for IVB and NEB indicated the accomplishment of greater bioavailability of drugs released from LS. Conclusively, such an innovative idea of combination loaded LS of IVB, and NEB would convincingly bring an effective management of chronic cardiovascular complications by maintaining the plasma drugs concentration for a prolonged time.

Huntington's disease (HD) is characterized by abnormal involuntary movements together with cognitive impairment and disrupted mood changes. 3-nitropropionic acid (3-NP) is one of the chemo-toxic models used to address the striatal neurotoxicity pattern encountered in HD. This study aims to explain the neuroprotective effect of nano-formulated ivabradine (nano IVA) in enhancing behavioral changes related to 3-NP model and to identify the involvement of ras homolog enriched striatum (Rhes)/mammalian target of rapamycin (m-Tor) mediated autophagy pathway. Rats were divided into 6 groups, the first 3 groups received saline (control), ivabradine (IVA), nano IVA respectively, the fourth received a daily dose of 3-NP (20 mg/kg, s.c) for 2 weeks, the fifth received 3-NP + IVA (1 mg/kg, into the tail vein, every other day for 1 week) and the last group received 3-NP + nano IVA (1 mg/kg, i.v, every other day for 1 week). Interestingly, nano IVA reversed motor disabilities, improved memory function and overcame the psychiatric changes. It boosted expression of autophagy markers combined with down regulation of Rhes, m-Tor and b-cell lymphoma 2 protein levels. Also, it restored the normal level of neurotransmitters and myocardial function related-proteins. Histopathological examination revealed a preserved striatal structure with decreased number of darkly-degenerated neurons. In conclusion, the outcomes of this study provide a well-recognized clue for the promising neuroprotective effect of IVA and the implication of autophagy and Rhes/m-Tor pathways in the 3-NP induced HD and highlight the fact that nano formulations of IVA would be an auspicious approach in HD therapy.

Background Heart failure represents a major global cause of morbidity and mortality. Ivabradine is a selective funny current (If) inhibitor, which acts on sinoatrial node, resulting in a reduction in heart rate [ 1 ]. The Food and Drug Administration (FDA) has approved use of Ivabradine for treatment of stable symptomatic heart failure (HF) due to dilated cardiomyopathy (DCM) in pediatric patients aged 6 months and older, who are in sinus rhythm with an elevated heart rate. Aim of review Ivabradine is a new drug for use in pediatric age group. Key scientific concepts In this review article we examine the mechanism of action of Ivabradine, evaluate the clinical trials underpinning its application in heart failure and we shall also discuss its other uses in other heart conditions in pediatric age group and its current recommendations.

Objectives: We assessed left ventricular (LV) function and central hemodynamic effects in patients with a heart rate (HR) at rest of ≥70 beats per minute (bpm) and chronic coronary syndrome (CCS) after long-term treatment with ivabradine compared to placebo by cardiac magnetic resonance (CMR) imaging. Methods and results: In a randomized, double-blinded, prospective cross-over design, 23 patients (18 male, 5 female) were treated with ivabradine (7.5 mg bid) or placebo for 6 months. CMR imaging was performed at baseline and after 6 and 12 months to determine LV functional parameters.Mean resting HR on treatment with ivabradine was 58 ± 8.2 bpm and 70.2 ± 8.3 bpm during placebo (p

The clinical use of ivabradine has and continues to evolve along channels that are predicated on its mechanism of action. It selectively inhibits the funny current (If) in sinoatrial nodal tissue, resulting in a decrease in the rate of diastolic depolarization and, consequently, the heart rate, a mechanism that is distinct from those of other negative chronotropic agents. Thus, it has been evaluated and is used in select patients with systolic heart failure and chronic stable angina without clinically significant adverse effects. Although not approved for other indications, ivabradine has also shown promise in the management of inappropriate sinus tachycardia. Here, the authors review the mechanism of action of ivabradine and salient studies that have led to its current clinical indications and use.

BACKGROUND Heart rate reduction as a therapeutic target has been investigated in adults with heart failure (HF). Ivabradine has shown promising efficacy, but has not been evaluated in children. Currently, treatment recommendations for chronic pediatric HF are based mainly on chronic HF guidelines for adults. OBJECTIVES The authors explored the dose-response relationship of ivabradine in children with dilated cardiomyopathy and symptomatic chronic HF. The primary endpoint was >= 20% reduction in heart rate from baseline without inducing bradycardia or symptoms. METHODS This was a randomized, double-blind, placebo-controlled, phase II/III study with 12 months of follow-up. Children (n = 116) receiving stable HF therapy were randomized to either ivabradine or placebo. After an initial titration period, the dose was adjusted to attain the primary endpoint. Left ventricular function (echocardiography), clinical status (New York Heart Association functional class or Ross class), N-terminal pro-B-type natriuretic peptide, and quality of life (QOL) were assessed. RESULTS The primary endpoint was reached by 51 of 73 children taking ivabradine (70%) versus 5 of 41 taking placebo (12%) at varying doses (odds ratio: 17.24; p

Glenn N. Levine, MD, FACC, FAHA, Chair Patrick T. O’Gara, MD, FACC, FAHA, Chair-Elect Jonathan L. Halperin, MD, FACC, FAHA, Immediate Past Chair [‡‡][1] Sana M. Al-Khatib, MD, MHS, FACC, FAHA Kim K. Birtcher, PharmD, MS, AACC Biykem Bozkurt, MD, PhD, FACC, FAHA Ralph G. Brindis, MD

Background Ivabradine is indicated to control heart rate in otherwise optimally treated patients with chronic heart failure (CHF) and reduced ejection fraction. However, data on its effectiveness outside clinical trials and longer-term effects are scarce. Methods We performed a prospective cohort study involving 249 German resident cardiologists and analyzed the 1-year effectiveness and safety of ivabradine used in CHF outpatients. Data on symptoms, quality of life, and hospitalizations were collected. Results In total, 767 CHF patients were enrolled to receive ivabradine twice daily, of whom 684 (90%) were still on ivabradine at study end (mean treatment duration 11.2months). The cohort was representative of CHF patients seen in clinical practice in terms of age, risk factor profile, and comorbidities. Concomitant beta-blocker therapy was prescribed in 497 patients (65%). After one year, compared to baseline, heart rate in ivabradine-treated patients was 16bpm lower. This reduction was associated with a significant improvement in NYHA class, and less frequent signs of decompensation (36% to 8%). The proportion of hospitalized patients within 1year decreased from 23% before treatment, to 5% with ivabradine therapy. These improvements in clinical status were accompanied by a reduction in BNP and an increase in LVEF (+5.1% at 1year). Quality of life was significantly improved in all measured dimensions. Adverse drug reactions were noted in 26 patients (3%), and were in line with the known safety profile of ivabradine. Conclusions Ivabradine was effective and well-tolerated in CHF patients seen in clinical practice throughout 1year of treatment.

Heart failure with preserved ejection fraction (HFpEF) is a complex syndrome, characterized by increased diastolic stiffness and a preserved ejection fraction, with no effective treatment options. Here we studied the therapeutic potential of exercise for improving diastolic function in a mouse model with HFpEF-like symptoms, the TtnΔIAjxn mouse model. TtnΔIAjxn mice have increased diastolic stiffness and reduced exercise tolerance, mimicking aspects of HFpEF observed in patients. We investigated the effect of free-wheel running exercise on diastolic function. Mechanical studies on cardiac muscle strips from the LV free wall revealed that both TtnΔIAjxn and wildtype (WT) exercised mice had a reduction in passive stiffness, relative to sedentary controls. In both genotypes, this reduction is due to an increase in the compliance of titin whereas ECM-based stiffness was unaffected. Phosphorylation of titin's PEVK and N2B spring elements were assayed with phospho-site specific antibodies. Exercised mice had decreased PEVK phosphorylation and increased N2B phosphorylation both of which are predicted to contribute to the increased compliance of titin. Since exercise lowers the heart rate we examined whether reduction in heart rate per se can improve passive stiffness by administering the heart-rate-lowering drug ivabradine. Ivabradine lowered heart rate in our study but it did not affect passive tension, in neither WT nor TtnΔIAjxn mice. We conclude that exercise is beneficial for decreasing passive stiffness and that it involves beneficial alterations in titin phosphorylation.

Ivabradine is an inhibitor of mixed NaIn 12 isolated rabbit hearts AF was induced in 7 of 12 hearts (13 episodes) under baseline conditions by a standardized protocol employing atrial burst pacing. Thereafter, a combination of acetylcholine and isoproterenol was employed to enhance AF occurrence. Monophasic action potential recordings showed a decrease of atrial action potential duration (aAPD,-37ms, p0.05) and atrial effective refractory period (aERP;-39ms, p0.05) after infusion of both acetycholine (1μM) and isoproterenol (1μM) as compared with baseline. This led to induction of AF in 11 of 12 hearts (124 episodes). Simultaneous infusion of ivabradine (3μM) led to a significant reduction of AF (6 of 11 hearts, 63 episodes). Ivabradine induced an increase of aAPD (+9ms) and aERP (+30ms, p0.05) leading to a marked increase of atrial post-repolarization refractoriness (aPRR), defined as the difference of aERP and aAPD (+21ms, p0.05). Results were compared to 10 rabbits treated with flecainide. Flecainide treatment also induced a significant increase of aPRR and resulted in induction of AF in 6 of 10 hearts (58 episodes) while 9 of 10 hearts were inducible during sole treatment with acetylcholine and isoproterenol (129 episodes).In the present experimental study, administration of ivabradine reduced inducibility of AF and therefore may represent a supplemental therapeutic option in AF. Of note, its antiarrhythmic efficacy was comparable to the established agent flecainide.

Ivabradine is a heart rate reducing agent that exhibits anti-ischemic effects through the inhibition of funny electrical current in the sinus node resulting in heart rate reduction, thus enabling longer diastolic perfusion time, and reduced myocardial oxygen consumption without detrimental changes in arterial blood pressure, coronary vasomotion, and ventricular contractility. The current guideline-based clinical use of Ivabradine is reserved for patients with stable angina pectoris who cannot tolerate or whose symptoms are inadequately controlled with beta blockers. In patients with chronic heart failure and reduced ejection fraction, Ivabradine has demonstrated beneficial effects in improving clinical outcomes when added to conventional therapy. However, the role of Ivabradine in acute coronary syndromes has not been established. Based on the results from some relevant preclinical studies and a limited amount of clinical data that were reported recently, the role of Ivabradine in acute ischemic events warrants further investigation. The aim of this review is to provide an overview of the available literature on the potential role of Ivabradine in the clinical context of acute coronary syndromes.

Background Heart failure prevalence is rising throughout the world. Despite current multidrug therapy, heart failure is the cause of frequent hospitalizations and high mortality. Objectives To assess the effectiveness and safety of ivabradine in chronic heart failure. Methods We searched the databases: the Cochrane Central Register of Controlled Trials CENTRAL (The Cochrane Library), MEDLINE, EMBASE, CINAHL, Conference Proceedings Citation Index — Science and Science Citation Index Expanded on Web of Science and LILACS. Randomized, placebo-controlled studies comparing ivabradine versus placebo, in patients who have symptomatic heart failure. Two authors independently abstracted the data and assessed the eligibility and methodological quality of each trial. Extracted data were analysed by determining the relative risks for dichotomous data, and difference in means for continuous data, of the treated group compared with controls. Results Eight randomized controlled trials with an overall number of 17,812 participants were included in this review. After 12 months, compared with placebo, ivabradine was not associated with reduction in cardiovascular mortality (RR 0.95, 95% CI 0.88 to 1.02), reduction of all-cause mortality (RR 0.98, 95% CI 0.90 to 1.06) and reduction of hospitalization for heart failure (RR 0.87, 95% CI 0.68 to 1.11). It was not found differences in safety considering cardiac adverse events between ivabradine and placebo (RR 0.96, 95% CI 0.89 to 1.02). Conclusions The available data show that ivabradine did not reduce the risk of death and hospitalization for heart failure compared to placebo. There were no differences in safety considering cardiac adverse events between ivabradine and placebo.