Impact of ivabradine on the cardiac function of chronic heart failure reduced ejection fraction: Meta‐analysis of randomized controlled trials

Abstract 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.

chronic heart failure, ejection fraction, ivabradine, LV remodeling, re-hospitalization 1 | BACKGROUND Elevated heart rate (HR) is an independent risk factor for left ventricular remodeling, poor cardiovascular outcomes, as well as higher allcause mortality in patients with cardiovascular disease. 1,2 Framingham study has shown an increment in all-cause mortality by 14% at every 10 beats per minute increase in HR, along with 2-fold increased risk of incident heart failure (HF). 3 The involved mechanisms are possibly related to increased myocardial oxygen demand, accelerate atherosclerosis event, decrease myocardial blood supply, and shortens diastolic time. [4][5][6] In patients with HF, previous studies have also show resting HF around 60-70 beats per minute is an important therapeutic goal. [7][8][9][10] Beta-blocker is essential for the treatment of HF patients due to their efficiency on cardiac remodeling, reduction of hospital readmission, and cardiovascular death. [11][12][13] Although beta-blocker is regarded as the first-line agent for HF patients, several contraindications, complications, and side effects, such as hypotension, worsening cardiac function, asthma, acute exacerbation of chronic obstructive pulmonary disease may limit its use in clinical practice. [14][15][16] Ivabradine is the new promising pure bradycardic agent without affecting cardiac conductivity. Ivabradine is selectively acted to lower the HR through specific inhibition of the I f channel in the sinus node, thus resulting in a reduction of HR by prolonging diastolic depolarization of a pacemaker action potential. 17 Ivabradine was officially approved by US FDA for the treatment of HF in 2015 with indications of heart failure reduced ejection fraction (HFrEF) and sinus rhythm ≥70 beats per minute on a maximal dosage of beta-blocker or when beta-blocker is contraindicated. 18 To date, there are only two large studies conducted the use of Ivabradine in HF patients including BEAUTIFUL study 19 and SHIFT study 20 ; however, both studies had different inclusion criteria and the findings were inconsistent. 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.

| METHODS
This study was conducted per standard article publication in Medical Journals, as this article has been made in coherence with Preferred Reporting Items for Meta-Analysis PRISMA Checklist. 25

| Search strategy
We systematically searched PubMed, Medline, Clinical Trials.gov, and The Cochrane Central Register of Controlled Trials for RCTs with search terms Ivabradine (MeSH terms), chronic heart failure and betablocker without any specific time restriction (Figure 1).

| Inclusion/exclusion criteria
RCTs with the following inclusion criteria are included 1 : RCT on Ivabradine and published in English 2 ; chronic HFrEF 3 ; Effect and safety of added Ivabradine (2.5-7.5 mg bid) compared to control group with standard optimal medical treatment, including beta-blockers, angiotensinconverting enzyme inhibitors, angiotensin receptor blockers, diuretics, and aldosterone antagonist 4 ; Echocardiographic assessment 5 ; Exercise tolerance and quality of life (supplement Table 1).
The exclusion criteria were as following: (1) Non-human studies; (2) Articles in a language other than English; (3) No follow up data; (4) Other types of HF; (5) No comparison between intervention and control groups (Table 1).

| Safety
Adverse events include cardiovascular mortality, rehospitalization for worsening HF, asymptomatic bradycardia, and visual disturbances were recorded in Ivabradine and placebo groups.

| Data analysis
Data analysis was done by using RevMan 5.4, dichotomous data are reported by using Mantel-Haenszel statistical method, fixed/ random effects analysis model, risk ratio effect measure with 95% CIs, while Continuous variables are evaluated using mean differences (MD) with 95% CIs. Effect model was used in data analysis depends on the degree of heterogeneity and P-value, a fixedeffect model was used if I 2 < 50% and P-value >.10, while random effect model preferred in high heterogeneity I 2 > 50% and low P-value <.10. If heterogeneity was detected, subgroup analyses to explore the source of heterogeneity will be conducted. Meanwhile, a sensitivity analysis to evaluate robustness of the outcomes was done by removing the study with high risk or unclear risk of selection bias.

| Assessment risk of bias and quality of studies
The Cochrane risk of bias domains were used to analyze the bias rat- where the disagreement about inclusion data will be settled by a third investigator (Gang Liu) through a discussion and consensus.

| RESULTS
In total, six RCTs and one subgroup analysis with 7074 participants (3523 in the placebo group, 3551 in the Ivabradine group) were enrolled in this meta-analysis. The main outcomes of this study were the effect of Ivabradine therapeutic on HR, LVEF, exercise capacity, QoL, and left ventricular remodeling. The high heterogeneity presented might be attributed to a distinct measurement index, insufficient number of studies on preferred outcomes, and different baseline characteristics of represented studies, such as sample size, age, gender, and follow-up time.

| Effect of ivabradine on main outcomes
Six RCTs included in our study showed that Ivabradine added to the standard HF treatment was associated with a better optimization for resting HR reduction in chronic HFrEF patients (MD = −9.57; 95% CI -11.15, −8.00) compared to the placebo group. 20   Exercise capacity between optimal HF treatment compared to added Ivabradine treatment was measured by total exercise duration. 21

| Adverse events
The therapeutic safety evaluation index of Ivabradine was analyzed by using risk ratio, and fixed/random effect model.  (Figure 4).

| Investigation of heterogeneity
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, In the present study, high heterogeneity also existed in the other outcomes, such as in the left ventricular remodeling indexes, exercise capacity, and QoL. As for the LV remodeling parameters, after conducting a sensitivity analysis, low heterogeneity was displayed on LVEDV and LVESV. Meanwhile, owing to an insufficient number of studies, subgroup analyses for exercise capacity and QoL was unable to be conducted.

| DISCUSSION
The present meta-analysis demonstrated apart from several adverse events mentioned, added Ivabradine treatment was not only safe, but also effective for HR reduction, improvement of cardiac function, and better exercise tolerance in patients with chronic HFrEF. To the best of our knowledge, this meta-analysis is among the few meta-analyses to discuss the effect of Ivabradine in chronic HFrEF patients.
In terms of the efficiency of Ivabradine, the present meta-analysis complies with SHIFT 20 study and Pei, et al 29

| LIMITATIONS
There are several unavoidable limitations in this study. First, although we included six RCTs and one subgroup analysis associated with Ivabradine efficiency and safety in patients with chronic HFrEF, however, the high heterogeneity and the numbers of patients included to each study contributed to the statistical analysis and conclusion.