The effect of ivabradine therapy on dilated cardiomyopathy patients with congestive heart failure: a systematic review and meta-analysis

Background Ivabradine improves cardiac function in patients with heart failure, but its effect on dilated cardiomyopathy (DCM) remains unclear. We performed a systematic review and meta-analysis to study the efficacy and potential mechanisms of ivabradine's effect on cardiac function and prognosis in patients with DCM. Methods We searched PubMed, Cochrane Library, Embase, Web of Science, and four registers through September 28, 2022. All controlled trials of ivabradine for the treatment of DCM with congestive heart failure were included. Articles were limited to English, with the full text and necessary data available. We performed random- or fixed effects meta-analyses for all included outcome measures and compared the effect sizes for outcomes in patients treated with and without ivabradine. The quality of the studies was assessed using the Cochrane risk-of-bias tool for randomized trials (RoB2.0). Findings Five trials with 357 participants were included. The pooled risk ratio was 0.48 [95% confidence interval (CI) (0.18, 1.25)] for all-cause mortality and 0.38 [95% CI (0.12, 1.23)] for cardiac mortality. The pooled mean difference was −15.95 [95% CI (−19.97, −11.92)] for resting heart rate, 3.96 [95% CI (0.99, 6.93)] for systolic blood pressure, 2.93 [95% CI (2.09, 3.77)] for left ventricular ejection fraction, −5.90 [95% CI (−9.36, −2.44)] for left ventricular end-systolic diameter, −3.41 [95% CI (−5.24, −1.58)] for left ventricular end-diastolic diameter, −0.81 [95% CI (−1.00, −0.62)] for left ventricular end-systolic volume, −0.67 [95% CI (−0.86, −0.48)] for left ventricular end-diastolic volume, −11.01 [95% CI (−19.66, −2.35)] for Minnesota Living with Heart Failure score, and −0.52 [95% CI (−0.73, −0.31)] for New York Heart Association class. Interpretation Ivabradine reduces heart rate and ventricular volume, and improves cardiac function in patients with DCM, but showed no significant effect on the prognosis of patients.

statistically significant results are more likely to be published compared to studies with nonsignificant results (i.e., negative result studies).In recent years, some revelations have shown that the concealment of "negative" results from industry-sponsored research is quite common.
2. When only a small number of preliminary studies are available early on, completed systematic reviews tend to overestimate the effect size, particularly when "negative result" studies are published with a delay.
3. Early positive studies with small sample sizes, especially small-scale trials, are worthy of skepticism.
4. Systematic review authors should pay particular attention to publication bias, especially when the included primary studies have small sample sizes, and particularly when small-scale studies are funded by industry.(1) Equivalence line: 1 or 0 (2) Clinically significant benefit or harm: RR value of 0.75 or 1.25 2. The total number of events or cases does not exceed OIS (the total sample size including all studies, <300 for categorical variables, and <400 for continuous variables).
Meet one of the The result of the pooled analysis is negative.
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes.The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.

Very low quality:
We are very uncertain about the estimate.
1 Downgraded one level due to study limitations, as most of the information comes from studies with moderate risk of bias, and one study reported high risk of bias for RHR, LVEF, LVEDD, and SBP.
2 Downgraded one level due to imprecision, as the sample size included in the study was small.
3 Downgraded one level due to inconsistency, as I 2 is between 50% and 75%, and the direction of the results is inconsistent.
4 Downgraded one level due to imprecision, as the confidence interval is wide.
5 Upgraded one level due to large effect, as the RR is lower than 0.5.Supplementary Table S3.PRISMA 2020 Main Checklist

4
Data items 10a List and define all outcomes for which data were sought.Specify whether all results that were compatible with each outcome domain in each study were sought (e.g. for all measures, time points, analyses), and if not, the methods used to decide which results to collect.

10b
List and define all other variables for which data were sought (e.g.participant and intervention characteristics, funding sources).Describe any assumptions made about any missing or unclear information. 4 Study risk of bias assessment 11 Specify the methods used to assess risk of bias in the included studies, including details of the tool(s) used, how many reviewers assessed each study and whether they worked independently, and if applicable, details of automation tools used in the process.

4
Effect measures 12 Specify for each outcome the effect measure(s) (e.g.risk ratio, mean difference) used in the synthesis or presentation of results.

4-5
Synthesis methods 13a Describe the processes used to decide which studies were eligible for each synthesis (e.g.tabulating the study intervention characteristics and comparing against the planned groups for each synthesis (item 5)).

4
13b Describe any methods required to prepare the data for presentation or synthesis, such as handling of missing summary statistics, or data conversions.

Study selection
16a Describe the results of the search and selection process, from the number of records identified in the search to the number of studies included in the review, ideally using a flow diagram.
6, Figure 1 16b Cite studies that might appear to meet the inclusion criteria, but which were excluded, and explain why they were excluded.
6, Figure 1 Study characteristics 17 Cite each included study and present its characteristics.6, Table 1 Risk of bias in studies 18 Present assessments of risk of bias for each included study.6, Figure 2 Results of individual studies 19 For all outcomes, present, for each study: (a) summary statistics for each group (where appropriate) and (b) an effect estimate and its precision (e.g.confidence/credible interval), ideally using structured tables or plots.7-8, Table 2 20d Present results of all sensitivity analyses conducted to assess the robustness of the synthesized results.
7, Figure 4 Reporting biases 21 Present assessments of risk of bias due to missing results (arising from reporting biases) for each synthesis assessed.
7-8, Figure 6, Supplementary Figure 1 Certainty of evidence 22 Present assessments of certainty (or confidence) in the body of evidence for each outcome assessed.

5.
Classic methods for examining the type of test results (e.g., funnel plots) may indicate publication bias but require careful interpretation.the confidence intervals do not cross over, does the study meet the OIS criteria?Alternatively, is the event rate very low with a large sample size (at least 2000, possibly 4000 cases)?If it fails to meet either of these criteria, the evidence quality level may be downgraded due to imprecision.1.The 95% confidence interval (CI) crosses the line (MD only considers the equivalence line).

513c
Describe any methods used to tabulate or visually display results of individual studies and syntheses.methods used to synthesize results and provide a rationale for the choice(s).If meta-analysis was performed, describe the model(s), method(s) to identify the presence and extent of statistical heterogeneity, and software package(s) used.513eDescribe any methods used to explore possible causes of heterogeneity among study results (e.g.subgroup analysis, meta-regression)used to assess risk of bias due to missing results in a synthesis (arising from reporting biases).5Certaintyassessment15 Describe any methods used to assess certainty (or confidence) in the body of evidence for an outcome.
of all statistical syntheses conducted.If meta-analysis was done, present for each the summary estimate and its precision (e.g.confidence/credible interval) and measures of statistical heterogeneity.If comparing groups, describe the direction of the effect.7-9, Figure3,7-920c Present results of all investigations of possible causes of heterogeneity among study results.
sources (e.g.databases, registers) used to identify studies and the date when each was last searched.YesRiskof bias 5 Specify the methods used to assess risk of bias in the included studies.Yes main outcomes, preferably indicating the number of included studies and participants for each.If meta-analysis was done, report the summary estimate and confidence/credible interval.If comparing groups, indicate the direction of the effect (i.esummary of the limitations of the evidence included in the review (e.g.study risk of bias, inconsistency and imprecision).Yes Interpretation 10 Provide a general interpretation of the results and important implications.Yes OTHER Funding 11 Specify the primary source of funding for the review.No Registration 12 Provide the register name and registration number.No Supplementary TableS2.Summary of findings for all included outcome measures Ivabradine compared to Control for improving prognosis and cardiac function of patients with dilated cardiomyopathy Patient or population: patients were diagnosed with DCM with congestive heart failure trials, where allocation is based on factors like the day of the week, birth date, or chart number).2.Lack of blinding: Patients, caregivers, outcome assessors, adjudicators, or data analysts are aware of the group to which the patients are assigned (or the current drug treatment they are receiving in a outcome measurement is the use of surrogate or substitute endpoints to replace the clinically relevant patientimportant outcomes of interest.4.Indirect comparison (network metaanalysis).downgradingAbbreviation:RCT = randomized controlled trial; OIS = optimal information size; MD = mean difference; RR = risk ratio.
Discuss implications of the results for practice, policy, and future research.Report which of the following are publicly available and where they can be found: