A major mechanism by which these agents are thought to provide benefit is by reducing myocardial oxygen demand by lowering heart rate through antagonism of sympathetic receptors in myocardial pacemaking tissue. This mechanism is supported by studies demonstrating strong associations between increasing resting heart rate HR and cardiovascular outcomes in patients with ischemic cardiomyopathy. The novel sinus node modifying agent ivabradine lowers heart rate by inhibiting the "funny current" If channel which is critical in determining the automaticity rate of pacemaking cells in the sinoatrial node. Given this very targeted mechanism of action, ivabradine may allow for further HR lowering despite maximally-tolerated doses of beta blocker therapy. Given that the benefits of ivabradine were somewhat attenuated in the subgroup of patients on at least half-dose beta blocker therapy, this raises the question of whether ivabradine truly benefits patients already on target dose beta blocker therapy.
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Abstract Background Although there are established drugs for treatment of cardiovascular diseases, due to adverse effects these drugs may not be clinically applicable to all patients. Recent trends have seen the emergence of drugs which act on funny current channels to induce selective heart rate reduction. Ivabradine is one such drug developed for coronary artery disease and heart failure. There is inconsistent evidence about the effect of this selective inhibitor in reduction of cardiovascular related mortality and morbidity.
Such an inconsistency warrants the need for a meta-analysis to consider the effectiveness and efficacy of Ivabradine in the treatment of coronary artery disease and heart failure. Each eligible study was assessed for risk of bias by using the Cochrane Risk of Bias Assessment tool.
The outcomes assessed in this study included: all cause mortality, cardiovascular-related mortality, hospitalization for new or worsening heart failure, and adverse events. Subgroup analysis and publication bias were assessed. We used Mantel-Haenszel method for random-effects.
Analysis was done using RevMan5. Result Three trials with a total of 36, participants met the meta-analysis criteria. Pooled analysis showed that ivabradine is not effective in reducing cardiovascular deaths OR: 1. However, the drug was found to significantly increase adverse events: phosphenes OR Subgroup analysis by duration of follow up on cardiovascular outcomes found that there is no difference in effect of ivabradine depending on the duration of follow up.
There was no publication bias in reporting of included studies. Conclusion This meta-analysis suggests that ivabradine is not effective in reducing cardiovascular-related morbidity and mortality unless used for specific conditions. On the contrary, the use of this drug was strongly associated with the onset of untoward and new adverse events.
This finding strongly supports previous findings and further informs the rational and evidence-informed clinical use of ivabradine. Electronic supplementary material The online version of this article doi Keywords: Ivabradine, Randomized trials, Meta-analysis, Funny current, Coronary artery disease Background Globally, cardiovascular diseases CVD , generally, and coronary artery disease CAD is the leading cause of death in developed contexts and is emerging as a leading cause in developing countries [ 1 ].
To reduce the burden of CVD morbidities and mortality, a range of preventive and therapeutic interventions exist. Previous studies suggest that the major established risk factors for CVD include smoking, hypertension, obesity, diet, and harmful use of alcohol, amongs to thers [ 3 , 4 ]. In addition to these major established risk factors, a recent follow-up epidemiologic study showed that resting heart rate is a predictor of CVD morbidity and mortality [ 5 ].
Increased heart rate independent of other cardiovascular diseases or risk factors has been associated with atherosclerosis, heart failure, coronary artery disease, hypertension, and stroke [ 6 — 9 ]. A number of preventive therapies have been developed to prevent the onset and complications of CAD [ 10 — 12 ].
Different classes of medications, such as beta-blockers, calcium channel blockers, and nitrates, reduce the heart rate, thereby reducing mortality risk attributable to higher heart rates [ 10 — 12 ].
Although these classes of drugs have clinical uses in many CVD, they lack of selectivity and specificity for the reduction of heart rate and are frequently associated with adverse effects [ 10 — 13 ]. With the recognition that pacemaker current is the modulating attribute, one of the first medications designed, tested, and implemented to inhibit the If channel of the sino-atrial node [ 13 ] was Ivabradine.
Previous randomized trials on ivabradine showed that atrial fibrillation [ 14 , 15 , 18 ], excessive bradycardia [ 14 , 15 , 18 , 19 ] and phosphenes [ 14 , 15 , 18 , 20 ] were the most frequently reported side effects in the trials.
A recent pooled analysis on the effect of ivabradaine in patients with stable angina with or without left ventricular dysfunction showed that unselective use of ivabradine is not supported by the evidence and has been associated with new-onset atrial fibrillation, bradycardia, and drug-related nuisance adverse events [ 18 ].
Based on these findings, it is imperative to summarize and synthesize the extant evidence on this medication in relation to use or non-use for stable angina. Therefore, this meta-analysis was undertaken to synthesize and analyze relevant randomized control trials conducted between and for the overall effect of ivabradine on stable CAD in relation to cardiovascular-related morbidity and mortality. Further, included studies required measured cardiovascular end points, minimum follow up of one year, and occurred within the timeframe of the period of through January In order to address risk of bias in accordance with Cochrane Collaboration recommendations, studies with participants that had myocardial infarction or unstable angina before starting treatment and which do not have a clear measure of the outcome of interest were excluded.
Types of outcome and interventions The outcomes analyzed were all-cause mortality, cardiovascular related deaths, cardiovascular related hospitalizations, hospitalization for worsening or new onset heart-failure, and coronary revascularization in patients with stable CAD and clinical heart failure. Adverse event outcomes included: trial fibrillation, symptomatic bradycardia, phosphene, cardiac disorders, as well as any other documented serious adverse events or infections.
We searched for studies in the reference lists of a meta-analysis study, controlled trials, and review articles from the established review period. Efforts were made to identify, include, and acquire grey literature i. Data extraction, measure of effect and analysis Data was extracted by two independent reviewers using a data extraction template.
Where disagreement exists reviewers discussed about the issues to reach consensus. Individual patients were the units of analysis. Missing data was considered by intent to treat analysis using imputation assuming missing data happened at random and would have similar outcomes to the available data. The effect of ivabradine on cardiovascular outcomes by stratifying based on duration of follow up of patients was investigated using random and fixed effects meta-regression analyses.
Analysis was done using Rev. Man 5. Assessment of risk of bias in included studies The risk of bias in this study was assessed using the risk of bias assessment tool for randomized control trials [ 22 ]. The Cochrane risk of bias domains was used to identify the risk of bias in individual studies [ 22 ].
The domains were: random sequence generation selection bias , allocation concealment selection bias , blinding of participants and personnel performance bias , blinding of outcome assessors detection bias , incomplete outcome data attrition bias , selective outcome reporting reporting bias , academic bias and source of funding bias.
Each included study was assessed for each domains, with ratings of low, uncertain, or high risk in accordance with the criteria as published in PROSPERO [ 23 ]. Ethical clearance Ethical clearance was not necessary for this study.
Results Study selection and characteristics of the included studies In this analysis a total of 11, records were assessed for eligibility and of these 10, records were excluded because they were duplicates and after titles were examined. After further screening, three 3 trials met the requirements for inclusion in the current meta-analysis. The major reasons for exclusion were: not double blind, non-human sample, and non-placebo controlled randomized studies.
Abstract Background Although there are established drugs for treatment of cardiovascular diseases, due to adverse effects these drugs may not be clinically applicable to all patients. Recent trends have seen the emergence of drugs which act on funny current channels to induce selective heart rate reduction. Ivabradine is one such drug developed for coronary artery disease and heart failure. There is inconsistent evidence about the effect of this selective inhibitor in reduction of cardiovascular related mortality and morbidity. Such an inconsistency warrants the need for a meta-analysis to consider the effectiveness and efficacy of Ivabradine in the treatment of coronary artery disease and heart failure. Each eligible study was assessed for risk of bias by using the Cochrane Risk of Bias Assessment tool. The outcomes assessed in this study included: all cause mortality, cardiovascular-related mortality, hospitalization for new or worsening heart failure, and adverse events.
Kimi Between December,and December,we screened 12 patients at centres in 33 countries. Provide sufficient details of any financial or non-financial competing interests to enable users to assess whether your comments might lead a reasonable person to question your impartiality. You must be a registered member of The Cardiology Advisor to post a comment. The use of certain tools provided by this website is subject to additional Terms and Conditions.