Effect of Ivabradine on Left Ventricular Diastolic Function, Exercise Tolerance and Quality of Life in Patients With Heart Failure: A Systemic Review
Effect of Ivabradine on Left Ventricular Diastolic Function, Exercise Tolerance and Quality of Life in Patients With Heart Failure: A Systemic Review and Meta-Analysis of Randomized Controlled Trials
Abstract
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.
Introduction
Heart failure (HF) is a compound clinical syndrome, comprising of a constellation of signs and symptoms portraying a reduction in cardiac output and/or increased in pressures in the heart chambers. Depending on left ventricular ejection fraction (LVEF), HF can be classified into HF with preserved ejection fraction (HFpEF), HF with mid-range ejection fraction (HFmrEF), and HF with reduced ejection fraction (HFrEF). There has been significant improvement in the treatment of cardiac diseases in the past few decades, but HF remains a serious public health issue because of its rising prevalence and poor prognosis. It is well known that elevated heart rate (HR) is an independent risk factor for cardiovascular morbidity and mortality. A high HR increases myocardial demand, decreases myocardial blood supply and oxygen (O2) delivery, shortens the diastolic filling time and increases cardiac filling pressures which consequently lead to a decrease in exercise capacity. In a recent study, an increase in LV diastolic pressure was observed in both patients with HFrEF and HFpEF. Exercise intolerance in the form of dyspnea is one of the main symptoms of HF, and it is of uttermost importance because it is related to poor quality of life (QOL) and increased mortality. Currently there is no drug that has shown to have a significant effect on diastolic dysfunction or improved survival in diastolic HF. Therefore a therapeutic agent targeted at improving diastolic function and resultant increase in exercise tolerance in these patients is needed.
Ivabradine is a HR-lowering drug that selectively blocks the funny (If) channels of the sinoatrial node thereby decreasing the pacemaker current. It is currently recommended in patients with HFrEF in sinus rhythm and a HR of ≥ 70 beats per minute (bpm) at rest despite optimum treatment with other standard therapy. Several studies have reported the effect of ivabradine on HR reduction, but not much is known about its effect on diastolic dysfunction and exercise tolerance. Some experiment studies however have demonstrated improvement of LV diastolic function and reduction in cardiac remodeling by If blockade. Accordingly, the aim of this meta-analysis is to investigate the effect of ivabradine on LV diastolic dysfunction, exercise capacity and QOL.
Materials and Methods
This study was conducted in line with the preferred reporting items for systemic reviews and meta-analysis (Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).
Literature search and selection
Two independent researchers (TRK and SKS) identified studies by searching the electronic databases of PubMed, EMBASE and Cochrane Central Register of Clinical Trials for studies on the effect of ivabradine on LV diastolic dysfunction, exercise tolerance, QOL of patients with HF (HFrEF and HFpEF).
Studies were included in this meta-analysis if they: 1) were randomized controlled trials (RCTs); 2) compared ivabradine treatment with standard medical care or other control group; 3) study population is adult (> 18 years) with HF; 4) reported one or more of the following outcomes: LV diastolic dysfunction, exercise tolerance and QOL. The exclusion criteria were: 1) non-human studies; 2) articles in a language other than English; 3) abstract and posters.
Primary end points were LV diastolic dysfunction, exercise intolerance and QOL. Secondary endpoints considered were readmission for worsening HF and all-cause mortality. Echocardiographic measures of LV diastolic function which are early diastolic mitral inflow to late diastolic flow ratio (E/A) and early diastolic mitral inflow to annular velocity ratio (E/e’) were extracted. The 6-min walk test (6MWT) and peak oxygen uptake during exercise (VO2) were extracted as measurement of exercise tolerance, and Minnesota Living with Heart Failure Questionnaire (MLHFQ) for QOL.
Data extraction and quality assessment
Data were systematically extracted from text, tables and figures from each study independently by two researchers (TRK and SKS), and tallied in an electronic database. These data included study name, author, year of publication, total number of patient studied and setting of the study, intervention, control, mean age, percentage of sex, mean HR, primary endpoints, clinical efficacy outcomes and duration of follow-up. Any disagreement was settled by discussion and consensus.
Statistical analysis
We use STATA version 13 for statistical analysis. We calculate Cohen’s d standardized mean difference (SMD), risk ratio (RR) for categorical events and 95% confidence interval (CI). The I2 statistic was used to describe the percentage variability that is due to heterogeneity. Heterogeneity in the eligible studies was evaluated using χ2 test on the basis of Cochrane’s Q test and at P < 0.10 level of significance. I2 values of 0-25%, 25-50% and > 50% were considered to be low, moderate and high heterogeneity, respectively. When P for the heterogeneity is < 0.1 and I2 ≥ 50%, the inter-study heterogeneity is considered significant. Publication biased was assessed graphically using funnel plot and Egger meta-regression test to detect the potential source of heterogeneity.
Results
The literature search using key words yielded 881 articles. After removing duplicates and screening for relevancy, 75 articles were remained. Of these, 61 articles were excluded because they didn’t meet the inclusion criteria. After a careful and thorough review, one study was excluded because the result was reported in median and not mean ± standard deviation (SD). A total of 13 RCTs met the criteria of inclusion in this study (Fig. 1). Ten studies included patients with HFrEF, and four studies included patients with HFpEF.
Flow diagram for studies included in the meta-analysis.
Characteristics of the included studies on HFpEF are summarized in Table 1, and those on HFrEF in Table 2. A total of 821 patients were enrolled in the 13 included RCTs with duration of follow-up ranging from 7 days to 6 months. There were 125 HFpEF in three studies and 696 HFrEF in 10 studies. The funnel plot of all studies demonstrates that there is low risk of publication bias (Fig. 2). Eggers regression test shows that (coefficient: -4.091; 95% CI: -6.359485, -1.821423; P = 0.007). For the primary end point of interest in the HFpEF group, two studies reported on the effect of ivabradine on change in E/A, three on E/e’ ratio, two on peak VO2, and one on 6MWT. In the HFrEF group, three studies reported on the effect of ivabradine on change in E/A, two on E/e’ ratio, three on peak VO2, three on 6MWT and seven reported on QOL (MLHFQ score). For the secondary endpoints, three studies reported on hospital admission for worsening HF, and five studies over all reported on all-cause mortality.
Table 1
| Author (year) | Number of patients | Setting | Entry LVEF | Control | Mean age (yrs) | Men (%) | Mean HR at baseline (bpm) | Primary endpoint of interest | Follow-up |
|---|---|---|---|---|---|---|---|---|---|
| Kosmala et al, 2013 | 61 | Two centers | ≥ 50% | Placebo | 67 ± 8 | N/A | E/e’, E/A, peak VO2 | 7 days | |
| Cocco et al, 2013 | 42 | Single-center | > 50% | Digoxin | 61.8 ± 4.4 | 48 | 85 ± 5 | E/e’, E/A, 6MWT | 3 months |
| Pal et al, 2015 | 22 | ≥ 50% | Placebo | N/A | N/A | E/e’, peak VO2 | 2 weeks |
LVEF: left ventricular ejection fraction; yrs: years; HR: heart rate; bpm: beats per minute; E/e’: early diastolic mitral inflow to annular velocity ratio; E/A: early diastolic mitral inflow to late diastolic flow ratio; 6MWT: 6-min walk test; VO2: peak oxygen uptake during exercise; N/A: not available.
Table 2
| Author (year) | Number of patients | Setting | Entry LVEF | Control | Mean age (yrs) | Men (%) | Mean HR at baseline (bpm) | Primary endpoint of interest | Follow-up |
|---|---|---|---|---|---|---|---|---|---|
| Abdel-Salam et al, 2015 | 43 | Single-center | < 40% | Placebo | 50.8 ± 14.5 | 53.5 | 85 ± 12 | MLHFQ | 3 months |
| Villacorta et al, 2018 | 19 | < 50% | Pyridostigmine | N/A | Peak VO2, MLHFQ | 6 months | |||
| Mansour et al, 2011 | 53 | Single-center | < 40% | Standard therapy | 49 ± 113 | 60 | N/A | MLHFQ | 3 months |
| Raja et al, 2018 | 125 | Single-center | < 40% | Standard therapy | 47.2 ± 15 | 56.9 | 94.9 ± 10 | 6MWT, MLHFQ | 6 months |
| Sarullo et al, 2010 | 60 | Single-center | < 40% | Placebo | 52.7 ± 5.3 | 75 | Peak VO2 | 3 months | |
| Sisakian et al, 2016 | 54 | Single-center | < 40% | Standard therapy | 81 | N/A | E/A, E/e’ | 3 months | |
| Volterrani et al, 2011 | 121 | Multicenter | HF | Carvedilol | 66.8 ± 9.5 | N/A | 77.5 ± 12.2 | Peak VO2, 6MWT, MLHFQ | 3 months |
| Lofrano-Alves et al, 2016 | 26 | < 40% | Placebo | N/A | N/A | E/e’, E/A | 6 months | ||
| Fasullo et al, 2009 | 155 | Single-center | < 50% | Beta-blocker | E/A | 60 days | |||
| Othman et al, 2019 | Single-center | < 40% | Beta-blockers | 6MWT, MLHFQ | 1 month |
LVEF: left ventricular ejection fraction; yrs: years; HR: heart rate; E/e’: early diastolic mitral inflow to annular velocity ratio; E/A: early diastolic mitral inflow to late diastolic flow ratio; 6MWT: 6-min walk test; VO2: peak oxygen uptake during exercise; MLHFQ: Minnesota Living with Heart Failure Questionnaire; HF: heart failure; N/A: not available.
Funnel plot of relative risk versus standard error.
Effect of ivabradine on diastolic dysfunction
As shown in Figure 3a and b, in the HFpEF subgroup, there was significant reduction in E/A ratio (SMD: -0.53; 95% CI: -0.99, -0.07; P < 0.000; I2 = 94.9%) in the ivabradine group compared to control. E/e’ ratio was significantly increased in the control group (SMD: 0.95; 95% CI: 0.62, 1.27; P < 0.000; I2 = 96.5%).
Forest plot showing the effect of ivabradine on diastolic echocardiographic parameters compared with control in patients with HFpEF and HFrEF; change in E/A, and change in E/e’. E/e’: early diastolic mitral inflow to annular velocity ratio; E/A: early diastolic mitral inflow to late diastolic flow ratio; HFpEF: heart failure with preserved ejection fraction; HFrEF: heart failure with reduced ejection fraction; CI: confidence interval.
For the HFrEF subgroup, there was significant reduction in both E/A ratio (SMD: -0.33; 95% CI: -0.59, -0.06; P < 0.000; I2 = 88.5%) and E/e’ ratio (SMD: -1.01; 95% CI: -1.49, -0.54; P < 0.012; I2 = 84.1%) in the ivabradine group compared to control (Fig. 3c and d).
Effect of ivabradine on exercise tolerance and QOL
For the HFpEF subgroup, peak VO2 was significantly higher with ivabradine therapy than control (SMD: 0.05; 95% CI: -0.35, 0.45; P < 0.00; I2 = 95.1%) (Fig. 4a). For the HFrEF subgroup (Fig. 4b and c), peak VO2 and 6MWT were significantly higher with ivabradine therapy than control (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; I2 = 97.4%, respectively). MLHFQ score decreased significantly in the ivabradine group compared to control (SMD: -0.68; 95% CI: -0.91, -0.45; P < 0.000; I2 = 97.5%) (Fig. 5).
Forest plot showing the effect of ivabradine on exercise tolerance (peak VO2 (mg/kg/min), distance on 6-min walking test (m)) compared with control in patients with HFpEF and HFrEF. VO2: peak oxygen uptake during exercise; HFpEF: heart failure with preserved ejection fraction; HFrEF: heart failure with reduced ejection fraction; CI: confidence interval.
Forest plot showing the effect of ivabradine on QOL (using MLHFQ score) compared with control. HFrEF: heart failure with reduced ejection fraction; CI: confidence interval; MLHFQ: Minnesota Living with Heart Failure Questionnaire; QOL: quality of life.
Effect of ivabradine on worsening HF and all-cause mortality
As shown in Figure 6, there was no significant change in worsening HF and all-cause mortality in response to ivabradine therapy with RR of 1.44; 95% CI: 0.73, 2.16; P < 0.148; I2 = 47.7% and RR of 0.76; 95% CI: 0.19, 1.33; P < 0.907; I2 = 0.0%, respectively.
Forest plot showing the effect of ivabradine on worsening heart failure and all-cause mortality. HFrEF: heart failure with reduced ejection fraction; CI: confidence interval.