ABSTRACT
Introduction
The efficacy and safety of Ivabradine for patients with acute heart failure (AHF) is controversial, and there are few clinical trials addressing this topic.
Methods
We performed this meta‐analysis to evaluate efficacy and safety of Ivabradine treatment for patients with acute heart failure. We obtained data for controlled trials using the PubMed, Cochrane Library, EMBASE, and Clinical Trials.gov databases. The efficacy endpoints included change in heart rate, brain natriuretic peptide (BNP) levels, N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) levels, ejection fraction (EF) values, and a 6‐min walk distance. The safety endpoints included mortality, cardiogenic mortality, incidents of hospital readmission, bradycardia, and atrial fibrillation. Ten randomized controlled trials (RCTs) met our criteria, and data from 656 patients were included for the study.
Results
Ivabradine treatment significantly decreased heart rate and BNP and NT‐proBNP levels compared with those seen in the control group. EF values were significantly increased upon ivabradine treatment. No significant differences were observed in the endpoints of the 6‐min walk distance, all‐cause mortality, cardiogenic mortality, incidents of hospital readmission, bradycardia, and atrial fibrillation data between ivabradine treated and control groups.
Conclusions
Ivabradine can reduce heart rate and BNP and NT‐pro BNP levels and elevate EF values and 6‐min walk distance data significantly in acute heart failure patients. It also exhibits a stable safety profile, with similar risks of all‐cause mortality, cardiogenic mortality, incidents of readmission, and major adverse cardiovascular effects compared with those of the control group.
Keywords: acute heart failure, Ivabradine, meta‐analysis, safety, systematic reviews
Ivabradine can reduce the heart rate and BNP and NT‐pro BNP levels and elevate EF and 6‐min walk distance significantly in acute heart failure patients. It also has a stable safety profile, with similar risks of all‐cause mortality, cardiogenic mortality, the incidence of readmission, and major adverse cardiovascular compared with the control group.
Introduction
Of all deaths worldwide, 30% are attributable to cardiovascular disease (“Global, regional, and national age‐sex specific all‐cause and cause‐specific mortality for 240 causes of death, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013,” 2015). Heart failure (HF) is the final stage of cardiovascular disease, and it is of two types: acute heart failure (AHF) and chronic heart failure (CHF). Acute heart failure develops from primary or chronic heart failure acute decompensation, and the symptoms of heart failure in patients develop rapidly and deteriorate. This can easily lead to acute pulmonary edema, systemic circulation congestion, malignant arrhythmia, and even sudden death (Bozkurt et al. 2021). Elevated heart rate (HR) is an independent risk factor for left ventricular remodeling, poor cardiovascular outcomes, as well as higher all‐cause mortality in patients with cardiovascular disease (Fox et al. 2007; Kannel et al. 1987). Ivabradine is a novel bradycardic agent that acts without affecting cardiac conductivity. Ivabradine selectively acts to reduce the HR through specific inhibition of the If channel in the sinus node, thus resulting in the reduction of the HR by prolonging diastolic depolarization of the pacemaker action potential (DiFrancesco and Camm 2004). Ivabradine has been used to treat chronic heart failure; however, early use of ivabradine to treat acute heart failure has not been included in the treatment guidelines. Further, the number of trials and evaluation of patients with acute heart failure is limited. Few clinical trials including ivabradine treatment for acute heart failure have been performed in recent years and the scale of trials is small. And these trials have contradictory endpoints. This RCT meta‐analysis was conducted to investigate the efficacy and safety of ivabradine for patients with acute heart failure.
1. Materials and Methods
The Preferred Reporting Items for Systematic Reviews and Meta‐analyses (PRISMA) (Walther et al. 2011) guidelines were followed in order to conduct a high‐quality meta‐analysis.
1.1. Data Sources and Searches
RCT data were obtained from the Cochrane Library, Excerpta Medica dataBASE (EMBASE), PubMed, and Clinical Trials.gov databases. Search time was set from January 1990 through February 2023 using keywords such as “ivabradine”; “acute heart failure”; and a sensitive filter was set for RCTs. Also, references in the selected trials were reviewed to find additional trials.
1.2. Study Selection
Literature reviews were independently performed and screened by two investigators (JH and XY); a third investigator performed literature reviews in case of disagreements. Studies which met the following criteria were included: (1) randomized controlled trial conducted in humans; (2) acute heart failure patients treated with ivabradine; (3) control group treated with placebo or generally treated for acute heart failure; and (4) the study reported outcomes of interest including the change in heart rate, BNP and NT‐proBNP levels, EF, 6 min walk distance, and adverse events including all‐cause mortality, cardiogenic mortality, and incidents of hospital readmission, bradycardia, and atrial fibrillation. If duplicate results from the same trial and similar outcomes were reported, the most recent and comprehensive outcomes were included. Reviews, meta‐analyses, editorials, observational studies which lacked control groups, or results of which could not be assessed were excluded.
1.3. Data Extraction and Quality Assessment
Clinical data were independently extracted by two different authors using a standardized extraction form. The following information was extracted from the investigations including trial names; NCT numbers; year of publication, baseline characteristics of the participants, total number of studies and control groups, mean age, percentage of female participants, body‐mass index (BMI) data, and basic disease information. Outcomes of the following endpoints were extracted: change in heart rate, BNP and NT‐proBNP levels, EF values, 6‐min walk distance data, and rate of adverse events, including all‐cause mortality, cardiogenic mortality, and incidents of hospital readmission, bradycardia, and atrial fibrillation. Additionally, information blinding, random sequence generation, allocation concealment, indications of incomplete outcome results, indications of selective reporting, and other biases were also collected to evaluate the quality of the investigations included.
1.4. Statistical Analysis
Data were analyzed according to the intention‐to‐treat principle. Risk ratio (RR) and a 95% confidence interval (CI) were used to describe differences between dichotomous outcomes, and standard mean differences (SMDs) including 95% CI values were used to describe differences between continuous outcomes. Heterogeneity was assessed using Cochran's Q test and the I 2 statistic; p < 0.10 for Cochran's Q test results and I 2 > 50 were considered to be indicative of significant heterogeneity when the random effect model was used for pooled analyses. Begg's Test was used to assess the publication bias. Data analyses were performed using the Review Manager (RevMan) software (version 5.4; The Cochrane Collaboration, Copenhagen, Denmark). The Begg's Test used to evaluate symmetry of the funnel plot was performed using the STATA software (version 11.1; Stata Corp LP, College Station, TX, USA). Also, sensitivity analysis was conducted by excluding each study using the STATA software.
2. Results
2.1. Search Results
A total of 739 relevant publications were identified using the above search strategy; 86 full studies were reviewed and 10 studies (Barillà et al. 2016; Cavusoglu et al. 2015; Chuanrong 2019; Haiyan et al. 2020; Hidalgo et al. 2016; Huaiyu, Yanqiu, and Xiaoling 2017; Lofrano‐Alves et al. 2016; Mentz et al. 2020; Mert et al. 2017; Othman et al. 2019; Rong et al. 2021) met the inclusion criteria as shown in Figure 1. Baseline characteristics of the studies included are shown in Table S1. Data of 656 participants were included in this meta‐analysis (329 for ivabradine treatment and 327 for Control). Quality assessment details are provided in Table S2 and Figures S1 and S2.
FIGURE 1.
Flow chart showing progress of data selection. From: Moher et al. (2009).
2.2. Clinical Results
Changes in heart rate, BNP and NT‐proBNP levels, EF values, and 6‐min walk distance data were considered as the primary efficacy endpoints. Rates of adverse events including all‐cause mortality, cardiogenic mortality, incidents of hospital readmission, bradycardia, and atrial fibrillation were served as secondary endpoints.
2.3. Changes in Heart Rate
Eight RCTs involving 448 patients reported changes in heart rate where 226 patients were treated with ivabradine and 222 patients were considered as controls. Heart rate was significantly reduced upon ivabradine treatment (SMD = −0.73; 95% CI = −0.93, −0.54; p = 0.0004; I 2 = 73%) as shown in Figure 2.
FIGURE 2.
Forest plot showing changes in heart rate.
2.4. Changes in BNP Levels
Three RCTs involving 142 patients reported changes in BNP levels where 71 patients were treated with ivabradine and 71 patients were considered as controls. BNP levels reduced upon ivabradine treatment (SMD = −0.43; 95% CI = −0.76, −0.09; p = 0.15; I 2 = 48%) as shown in Figure 3.
FIGURE 3.
Forest plot showing changes in BNP levels.
2.5. Changes of NT‐proBNP
Five RCTs involving 351 patients reported changes in NT‐proBNP levels where 186 patients were administered ivabradine and 165 patients were assigned to the control group. NT‐proBNP levels reduced upon ivabradine treatment (SMD = −0.23; 95% CI = −0.45, −0.02; p = 0.005; I 2 = 73%) as shown in Figure 4.
FIGURE 4.
Forest plot showing changes in NT‐proBNP levels.
2.6. Changes in EF
Seven RCTs involving 448 patients reported changes in EF values where 232 patients were administered ivabradine and 216 patients were assigned to the control group. EF values were significantly increased upon ivabradine administration (SMD = 0.38; 95% CI = 0.19, 0.57; p < 0.0001; I 2 = 81%) as shown in Figure 5.
FIGURE 5.
Forest plot showing changes in EF.
2.7. Changes in the 6‐Min Walk Distance
Four RCTs involving 206 patients reported changes in the 6‐min walk distance data where 103 patients were treated with ivabradine and 103 patients were assigned to the control group. Changes in data of the 6‐min walk distance did not exhibit statistically significant differences (SMD = 0.26; 95% CI = −0.01, 0.60; p = 0.18; I 2 = 38%) as shown in Figure 6.
FIGURE 6.
Forest plot showing changes in 6‐min walk distance results.
2.8. Adverse Event Rates
No significant differences were observed between ivabradine treatment and control groups in the endpoints of all‐cause mortality (SMD = 1.02; 95% CI = 0.98, 1.06; p = 61; I 2 = 0%, Figure S3), cardiogenic mortality (SMD = 1.00; 95% CI = 0.98, 1.02; p = 1.00; I 2 = 0%, Figure S4), incidents of hospital readmission (SMD = 0.98; 95% CI = 0.91, 1.06; p = 0.97; I 2 = 0%, Figure S5), incidents of bradycardia (SMD = 0.99; 95% CI = 0.95, 1.03; p = 0.96; I 2 = 0%, Figure S6), and incidents of atrial fibrillation (SMD = 1.00; 95% CI = 0.96, 1.04; p = 0.94; I 2 = 0%, Figure S7).
2.9. Publishing Bias and Sensitivity Analysis
The Begg's regression outcome of the primary clinical endpoints was found to be p = 0.076, which demonstrated no publishing bias in our study. As illustrated in Figure 7, similar results were obtained after excluding each study which demonstrates that our meta‐analysis results are stable.
FIGURE 7.
Sensitivity analysis.
3. Discussion
This meta‐analysis included 656 acute heart failure patients randomized into the ivabradine or control groups based on data collected from 10 RCTs. From the results of this meta‐analysis, we showed that compared with the control group, ivabradine treatment significantly decreased heart rate and BNP and NT‐proBNP levels. EF values were significantly increased upon ivabradine treatment. No significant differences were observed between ivabradine and control groups in the endpoints of 6‐min walk distance, all‐cause mortality, cardiogenic mortality, incidents of hospital readmission, bradycardia, and atrial fibrillation.
I f currents are an inward sodium ion current activated upon hyperpolarization. Ivabradine is the first novel specific inhibitor of I f currents in the sinoatrial node that can specifically bind to hyperpolarization‐activated cyclic nucleotide–gated (HCN) channels inside sinoatrial node cells to inhibit I f currents and affect automatic depolarization of action potential stage 4, thereby reducing heart rate. Compared to β‐blockers, ivabradine exhibits the beneficial pure negative chronotropic effect and has no effect on myocardial contraction and blood pressure; for example, early combined use of ivabradine can control patient heart rate faster and, in an enhanced manner, relieve symptoms of heart failure and improve patient prognosis (Bryan Richard et al. 2021; Lixin et al. 2019). In 2016 an early therapy with Ivabradine in patients with congestive acute heart failure (ETHIC‐AHF) study showed that the heart rate of patients treated with ivabradine was significantly reduced within 28 days, and 4 months after discharge, the ejection fraction and BNP levels were improved, whereas the all‐cause mortality, readmission incidents, and serious adverse reactions were not different from those seen in the control group (Hidalgo et al. 2016). The RCT conducted by Khaled et al. in 2019 suggested that heart rate, NYHA grade improvement, and 6‐min walking distance results between the two groups did not exhibit statistically significant differences (Othman et al. 2019).
Compared with a recently published meta‐analysis (Bryan Richard et al. 2021; Lixin et al. 2019), this study focused on ivabradine treatment against acute heart failure instead of all types of heart failure. Also, we conducted Begg's regression and sensitivity analysis to demonstrate that this study is stable and credible. This study includes all clinical data available and results that met the inclusion criteria. The clinical trials included in this study exhibited significant quality with respect to procedures. Our study had some limitations: first, our analysis was restricted because of the limited sample sizes and limited number of clinical trials included. Second, few studies reported long‐term outcomes upon ivabradine treatment for acute heart failure. Due to various limitations, a substantial number of RCTs involving ivabradine treatment for acute heart failure are necessary to further examine its efficacy and safety profile in clinical practice.
4. Conclusion
Ivabradine treatment can reduce heart rate and BNP and NT‐pro BNP levels and elevate EF and 6‐min walk distance results significantly in acute heart failure patients. It also has a stable safety profile and bears similar risks with respect to all‐cause mortality, cardiogenic mortality, incidents of readmission, and major adverse cardiovascular effects compared with those seen in the control group.
Author Contributions
Jing Han and Xia Yin contributed to the study conception and design. All authors collected the data and performed the data analysis. All authors contributed to the interpretation of the data and the completion of figures and tables. All authors contributed to the drafting of the article and final approval of the submitted version.
Ethics Statement
The authors have nothing to report.
Conflicts of Interest
The authors declare no conflicts of interest.
Supporting information
Figure S1. Risk of bias graph.
Figure S2. Risk of bias summary.
Figure S3. Forest plot for all‐cause mortality.
Figure S4. Forest plot for cardiogenic mortality.
Figure S5. Forest plot for hospital readmission.
Figure S6. Forest plot for bradycardia.
Figure S7. Forest plot for atrial fibrillation.
Table S1. Baseline characteristics of studies included.
Table S2. Quality assessment.
Acknowledgments
The authors have nothing to report.
Funding: The authors received no specific funding for this work.
Data Availability Statement
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Figure S1. Risk of bias graph.
Figure S2. Risk of bias summary.
Figure S3. Forest plot for all‐cause mortality.
Figure S4. Forest plot for cardiogenic mortality.
Figure S5. Forest plot for hospital readmission.
Figure S6. Forest plot for bradycardia.
Figure S7. Forest plot for atrial fibrillation.
Table S1. Baseline characteristics of studies included.
Table S2. Quality assessment.
Data Availability Statement
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.