Mengesha et al.

BMC Cardiovascular Disorders (2017) 17:105

DOI 10.1186/s12872-017-0540-3

RESEARCH ARTICLE Open Access

Effect of ivabradine on cardiovascular

outcomes in patients with stable angina:
meta-analysis of randomized clinical trials
Hayelom Gebrekirstos Mengesha1*, Berhe Weldearegawi2, Pammala Petrucka3, Tadese Bekele4,
Mala George Otieno5 and Abraha Hailu6

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.
Methods: Randomized controlled trials with a minimum follow-up period of one year were searched in Pub Med/
Medline, Embase, Cochrane Central Register of Controlled Trials published between 1980 and 2016.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 RevMan5.1.This study was registered in PROSPERO as
[PROSPERO 2016:CRD42016035597].
Result: Three trials with a total of 36,577 participants met the meta-analysis criteria. Pooled analysis showed that
ivabradine is not effective in reducing cardiovascular deaths (OR: 1.02; CI:0.911.15,P = 0.74), all-cause mortality (OR:
1.00; CI:0.911.10,P = 0.98), coronary revascularization (OR: 0.93, CI: 0.771.11, P = 0.41) and hospital admission for
worsening of heart failure (OR: 0.94, CI: 0.711.25, P = 0.69). However, the drug was found to significantly increase
adverse events: phosphenes (OR:7.77, CI: 4.414.6,P < 0.00001), blurred vision (OR:3.07,CI:2.184.32,P < 0.00001),
symptomatic bradycardia (OR: 6.23, CI: 4.29.26, P < 0.00001), and atrial fibrillation (OR: 1.35, CI: 1.191.53, P < 0.
0001). 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.
Keywords: Ivabradine, Randomized trials, Meta-analysis, Funny current, Coronary artery disease

* Correspondence: hayetgeb@gmail.com
1
College of Health Science, Adigrat University, Adigrat, Ethiopia
Full list of author information is available at the end of the article

The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Mengesha et al. BMC Cardiovascular Disorders (2017) 17:105 Page 2 of 9

Background 60 bpm despite -blocker therapy. In 2012, the drug was

Globally, cardiovascular diseases (CVD), generally, and approved, in America, for treatment of chronic heart
coronary artery disease (CAD) is the leading cause of failure (Class II-IV New York Heart Association) follow-
death in developed contexts and is emerging as a leading ing the SHIFT study [15] and, in 2015, heart failure with
cause in developing countries [1]. For populations over a heart rate of 70 bpm [17]. Previous randomized trials
45 years of age in 2020, it is estimated that CAD will be on ivabradine showed that atrial fibrillation [14, 15, 18],
responsible for a total of 11.1 million annual deaths glo- excessive bradycardia [14, 15, 18, 19] and phosphenes
bally [2]. [14, 15, 18, 20] were the most frequently reported side
To reduce the burden of CVD morbidities and mortal- effects in the trials.
ity, a range of preventive and therapeutic interventions A recent pooled analysis on the effect of ivabradaine
exist. Previous studies suggest that the major established in patients with stable angina with or without left ven-
risk factors for CVD include smoking, hypertension, tricular dysfunction showed that unselective use of ivab-
obesity, diet, and harmful use of alcohol, amongs to radine is not supported by the evidence and has been
thers [3, 4]. In addition to these major established risk associated with new-onset atrial fibrillation, bradycardia,
factors, a recent follow-up epidemiologic study showed and drug-related nuisance adverse events [18]. Based on
that resting heart rate is a predictor of CVD morbidity these findings, it is imperative to summarize and
and mortality [5]. Increased heart rate independent of synthesize the extant evidence on this medication in re-
other cardiovascular diseases or risk factors has been lation to use or non-use for stable angina. Therefore, this
associated with atherosclerosis, heart failure, coronary meta-analysis was undertaken to synthesize and analyze
artery disease, hypertension, and stroke [69]. relevant randomized control trials conducted between
A number of preventive therapies have been developed 1980 and 2016 for the overall effect of ivabradine on
to prevent the onset and complications of CAD [1012]. stable CAD in relation to cardiovascular-related morbid-
Different classes of medications, such as beta-blockers, ity and mortality.
calcium channel blockers, and nitrates, reduce the heart
rate, thereby reducing mortality risk attributable to higher Methods
heart rates [1012]. Although these classes of drugs have This study was conducted according to the Recommenda-
clinical uses in many CVD, they lack of selectivity and spe- tions for the Conduct, Reporting, Editing, and Publication
cificity for the reduction of heart rate and are frequently of Scholarly Work in Medical Journals, specifically the
associated with adverse effects [1013]. Preferred Reporting Items for Systematic Reviews and
The limitations of these classes of drugs led to investiga- Meta-analysis PRISMA Checklist (Additional file 1) [21].
tion of the novel site useful for selective or pure reduc-
tion of heart rate called funny current channel(If.)With Inclusion/exclusion criteria
the recognition that pacemaker current is the modulating The study included all accessible randomized double
attribute, one of the first medications designed, tested, and blind, placebo controlled, and non-inferiority studies
implemented to inhibit the If channel of the sino-atrial conducted to determine or compare the effect of ivabra-
node [13] was Ivabradine. Randomized controlled trials dine on stable CAD with heart failure, and without clin-
on Ivabradine, such as the BEAUTIFUL(morBidity-mor- ical heart failure compared with placebo or standard
tality EvAlUaTion of the If inhibitor ivabradine in patients care. Further, included studies required measured car-
with coronary disease and left-ventricULar dysfunction), diovascular end points, minimum follow up of one year,
SHIFT(Systolic Heart failure treatment with the If inhibi- and occurred within the timeframe of the period of 1980
tor ivabradine Trial), and SIGNIFY(Study Assessing the through January 2016. In order to address risk of bias in
MorbidityMortality Benefits of the If Inhibitor Ivabradine accordance with Cochrane Collaboration recommenda-
in Patients with Coronary Artery Disease), considered pa- tions, studies with participants that had myocardial
tients with heart failure and stable CAD [9, 14, 15]. Some infarction or unstable angina before starting treatment
studies found protective effects of ivabradine mainly for and which do not have a clear measure of the outcome
heart rate 70 beats per minute (bpm) [11, 15], whilst a of interest were excluded.
recent study found no additional effects of ivabradine for
CAD patients [14]. Types of outcome and interventions
In light of the evidence, ivabradine was approved in The outcomes analyzed were all-cause mortality, cardio-
Europe for use in patients exhibiting stable CAD accom- vascular related deaths, cardiovascular related hospitali-
panied by normal sinus rhythm with contraindications zations, hospitalization for worsening or new onset
for -blockers [16] and, based on the 2010 findings of heart-failure, and coronary revascularization in patients
the BEAUTIFUL study [9], for patients with uncon- with stable CAD and clinical heart failure. Adverse event
trolled angina symptoms and heart rates in excess of outcomes included: trial fibrillation, symptomatic
Mengesha et al. BMC Cardiovascular Disorders (2017) 17:105 Page 3 of 9

bradycardia, phosphene, cardiac disorders, as well as any outcome data (attrition bias), selective outcome report-
other documented serious adverse events or infections. ing (reporting bias), academic bias and source of funding
bias. Each included study was assessed for each domains,
Search strategy with ratings of low, uncertain, or high risk in accordance
We searchedOvid Medline, Pubmed, Embase, Scopus, with the criteria as published in PROSPERO [23].
Clinical Trials.gov and the Cochrane Central Register of
Controlled Trials for randomized placebo controlled tri- Ethical clearance
als of ivabradine effect using the terms Ivabradine, pro- Ethical clearance was not necessary for this study.
coralan, stable coronary artery disease, stable angina,
ischemic heart disease, randomized controlled trial, Results
and placebo as text words, and corresponding MeSH Study selection and characteristics of the included studies
terms. We searched for studies in the reference lists of a In this analysis a total of 11,042 records were assessed
meta-analysis study, controlled trials, and review articles for eligibility and of these 10,865 records were excluded
from the established review period. Efforts were made to because they were duplicates and after titles were exam-
identify, include, and acquire grey literature (i.e., unpub- ined. Of 177 records 151 were excluded because they
lished studies) via personal contacts and/or emails lead were only abstracts, animal studies, commentaries, and/
by BW and TB. or reviews. After further screening, three (3) trials met
the requirements for inclusion in the current meta-
Data extraction, measure of effect and analysis analysis. The major reasons for exclusion were: not
Data was extracted by two independent reviewers using double blind, non-human sample, and non-placebo con-
a data extraction template. Where disagreement exists trolled randomized studies. Figure 1 provides a graphical
reviewers discussed about the issues to reach consensus. representation of the selection and de-selection process
A Mantel-Haenszel random-effect model was used to at this preliminary stage.
consider the heterogeneity of studies and calculate com- Three eligible randomized clinical trials were screened
bined effect size to provide a more conservative estima- into this analysis, which included a total of 36,577 par-
tion of odds ratio (OR) and 95% confidence interval ticipants (18,297 in the ivabradine group and 18,280 pa-
(CI). When I2 < 50 fixed effect model was used. Individ- tients in the placebo group). Sample representativeness
ual patients were the units of analysis. Missing data was included patients with stable angina with left ventricular
considered by intent to treat analysis using imputation dysfunction in the BEAUTIFUL trial [9], stable CAD
assuming missing data happened at random and would without clinical heart failure in the SIGNIFY trial [14],
have similar outcomes to the available data. and chronic heart failure with systolic ventricular dys-
To assess statistical heterogeneity between summary function (plus a majority with ischemic heart disease-
data at trial level we used the tau statistic (P < 0.10) and originated heart failure) in the SHIFT trial [15]. The me-
the I2statistic (I2 > 50%) was considered low if I2 < 30%, dian follow up period for these studies was less than two
moderate if I2 is between30 75%, and high if I2 > 75% years (i.e., BEAUTIFUL(19 months), SHIFT(22 months),
[21]. Publication and other reporting biases were and SIGNIFY(27.8 months)). The left ventricular ejec-
assessed using funnel plots and Eggers test where neces- tion fraction (LVEF) was less than <40%, <35%, and
sary. The effect of ivabradine on cardiovascular out- 40%, in the BEAUTIFUL, SHIFT, and SIGNIFY studies,
comes by stratifying based on duration of follow up of respectively. In these included trials, the dose range of
patients was investigated using random and fixed effects ivabradine ranged between 5 mg and 7.5 mg twice daily.
meta-regression analyses. The mean pre-treatment resting heart rate across all
Analysis was done using Rev. Man 5.1 and CMA three studies was 70 bpm. The primary composite end
3.0. All tests were two tailed and considered significant point in the three trials was related to cardiovascular
if P < 0.05. death, admission to hospital for new onset or worsening
of heart failure, and admission to hospital for fatal and
Assessment of risk of bias in included studies non-fatal myocardial infarction (refer to Table 1).
The risk of bias in this study was assessed using the risk
of bias assessment tool for randomized control trials Risk of bias assessment of the included studies
[22]. The Cochrane risk of bias domains was used to Based on the Cochrane Collaboration for risk of bias as-
identify the risk of bias in individual studies [22]. The sessment criteria, the three included studies were low
domains were: random sequence generation (selection risk in terms of the six major domains. The interpret-
bias), allocation concealment (selection bias), blinding of ation of low risk for each domain is explained in detail
participants and personnel (performance bias), blinding in our proposal published in PROSPERO [23]. However,
of outcome assessors (detection bias), incomplete assessment for other possible sources of other bias is
Mengesha et al. BMC Cardiovascular Disorders (2017) 17:105 Page 4 of 9

Fig. 1 Study flow diagram for the study inclusion and exclusion process

uncertain due to limited articulation in the respective group. The majority of participants (i.e., 13,905(76.2%))
studies (refer to Table 2). were men. The mean LVEF was 32.4(5.5), 29(5.19), and
Regarding the baseline characteristics of patients the 56.4(8.5) for the BEAUTIFUL, SHIFT, and SIGNIFY tri-
mean (sd) age of patients was 63.5 9 with 63.7 9 in als, respectively. With regard to co-morbidities,
the ivabradine group and 63.4 9.1 in the placebo 7093(38.8%) and 14,319(78.4%) had diabetes mellitus

Table 1 Characteristics of included trials

Trial Method Participants Intervention Outcome Duration(months)
BEAUTIFUL Randomized 10,917(5479 assigned to ivabradine and Ivabradine Cardiovascular death or admission to 19
2008 controlled Trial 5438 assigned to placebo) eligible patients 57.5 mg bid hospital for myocardial infarction or
who had coronary artery disease and a new-onset or worsening heart failure
LVEF of less than 40%
SHIFT 2010 Randomized 6558 patients with symptomatic heart failure Ivabradine Cardiovascular death or hospital 22
controlled Trial and LVEF of 35% or lower, heart rate of 70 7.5 mg bid admission for worsening heart failure
bpm or higher (3268 assigned to ivabradine;
3290 assigned to placebo group)
SIGNIFY 2014 Randomized 19,102 patients(9550 assigned to ivabradine Ivabradine Death from cardiovascular causes or 27.8
controlled trial and 9552 assigned to placebo) who had 7.5 mg bid nonfatal myocardial infarction
both stable coronary artery disease without
clinical heart failure, a heart rate of 70
bpm or more and LVEF of 40%
Bpm beats per minute, LVEF Left ventricular ejection fraction, bid twice a day
Mengesha et al. BMC Cardiovascular Disorders (2017) 17:105 Page 5 of 9

Table 2 Risk of bias table assessment result for the included studies
Study Criteria for risk of bias assessment
Random sequence Allocation Blinding of participants Blinding of outcome Incomplete Selective Other bias
generation concealment & personnel assessment outcome data reporting
BEAUTIFUL 2008 LR LR LR LR LR LR UR
SHIFT 2010 LR LR LR LR LR LR UR
SIGNIFY 2014 LR LR LR LR LR LR UR
LR Low Risk, UR Uncertain risk

and hypertension in the ivabradine group, respectively. Admission to hospital for new onset or worsening
At randomization, 5193(86%) of participants in the ivab- of heart failure: all the three trials had assessed this
radine group and 5201(87%) in the placebo group were endpoint and were therefore included in the analysis.
taking -blockers (refer to Table 3). Ivabradine did not significantly decrease admission to
hospital for new onset or worsening of heart failure
Effect and safety of ivabradine on cardiovascular compared to the placebo (OR: 0.94, CI: 0.711.25,
outcomes P = 0.69).
The effect of ivabradine on cardiovascular outcomes was Coronary revascularization: Two trials with 30,019
analyzed using the random-effects model of Der Simo- patients assessed the effect of ivabradine on coronary re-
nian and Laird considering potential heterogeneity. We vascularization [14, 15]. Pooled analysis of these trials
summarized the effect of ivabradine compared to pla- showed that ivabradine was not effective in reducing the
cebo on cardiovascular outcomes as follows: occurrence/events of coronary revascularization com-
pared to placebo (OR: 0.93, CI: 0.771.11, p = 0.41).
Efficacy of ivabradine on cardiovascular outcomes Overall, ivabradine was not found to decrease the
Cardiovascular deaths: We included three trials with number of events related to cardiovascular morbidity
36,524 patients, which considered cardiovascular deaths and mortality in comparison with placebo group patients
as an outcome variable. On meta-analysis, ivabradine with stable angina and heart failure (Table 4).
did not have a significant effect in reducing cardiovascu-
lar caused deaths/events compared to placebo (OR: 1.02; Safety of ivabradine
CI: 0.911.15, P = 0.74). The details of the analysis and All the trials included had assessed the adverse events of
forest plot are presented in Fig. 2. ivabradine experienced by study participants. These
All-cause mortality: we assessed all-cause mortality as major adverse events are summarized as follows:
a one endpoint and found that the effect of ivabradine in Phosphenes: two trials [14, 15] assessed the adverse ef-
reducing all-cause mortality was not different from the fect of ivabradine on vision. Ivabradine significantly in-
placebo (OR: 1.00; CI: 0.911.10, P = 0.98). creased the incidence of phosphene (OR: 7.77, CI: 4.4

Table 3 Baseline characteristics of participants included in this metaanalysis

Study BEAUTIFUL 2008 SHIFT 2010 SIGNIFY 2014 Study arm
Ivabradine Placebo
Age(mean SD) 65.2(8.5) 60.4(11.3) 65(7.2) 63.7(9) 63.4(9.1)
use of B-blockers
Yes 9487(87) 5820(89) 7939(81) 5193(86) 5201(87)
Male 9047(83) 4970(76) 13,839(72) 13,951(76.4) 13,905(76.2)
Female 1870(17) 1535(24) 5263(28) 4319(23.6) 4349(23.8)
DM status 4036(37) 1979(30) 8230(43) 7093(38.8) 7152(39.20)
Hypertension 7720(71) 4314(66) 16,466(86) 14,319(78.4) 14,181(77.7)
Heart rate(mean SD) 71.5(9.8) 79.8(9.6) 77.1(7) 76(8.7) 76.3(8.93)
Previous stroke 1997(18%) 526(8) 1265(6.6) 627.3(10.9) 633.3(11.2)
LVEF,mean(SD),in % 32.4(5.5) 29(5.19) 56.4(8.5) 39.3(6.4) 39.3(6.4)
2
BMI,kg/m ,mean(SD) 28.5(4.4) 28(5) 28.7(4.6) 28.4(4.7) 28.4(4.7)
BMI Body mass index, SD Standard Deviation, LVEF Left Ventricular Ejection Fraction, DM Diabetes Mellitus, all numbers in bracket except those mentioned
denotes percentage (%)
Mengesha et al. BMC Cardiovascular Disorders (2017) 17:105 Page 6 of 9

Fig. 2 Effect of ivabradine on cardiovascular deaths compared to placebo

14.6, P = <0.00001) and blurred vision (OR: 3.07, CI: Publication bias on the outcome cardiovascular deaths
2.184.32,P = <0.00001) compared to the placebo. The assessment of publication bias on the three out-
Cardiac: Ivabradine significantly increased the inci- comes (cardiovascular, hospital admission for heart fail-
dence of symptomatic bradycardia (OR: 6.23, CI: 4.2 ure and all-cause mortality) showed that there was no
9.26, P = <0.00001) and atrial fibrillation (OR: 1.35, CI: publication bias which could affect the pooled analysis
1.191.53) compared to placebo. of this study. As can be seen in the funnel plot figures,
In addition.two trials [9, 15] generally assessed the ad- all the three trials included to this study had no bias in
verse effects of ivabradine on different systems in which publication. Figures showed that the studies are approxi-
incidence of adverse effect was not significantly different mately symmetrically distributed across the line (see
on cardiac disorders all serious adverse events, infection Figs. 3 and 4).
and infestation compared to placebo (Table 4). Although few number of studies were included to this
analysis, Eggers test to check the publication bias captured
Subgroup analysis by the funnel plot on effect of ivabradine in reducing admis-
A subgroup analysis was undertaken by stratifying the sion to hospital for worsening or new onset of heart failure
trials based on duration of follow up, reflecting a period found that the intercept (B0) was 0.096, 95% confidence
of less than two years [9, 15] and one of 2 years [14]. interval (86.23, 110.13), with t = 1.58, df = 1. The one-
Based on this subgroup analysis we found that effect of tailed p-value is 0.17, and the two-tailed p-value is 0.35. This
ivabradine on cardiovascular deaths (OR: 0.99, CI: 0.84 suggests the absence of significant publication bias.
1.17, P = 0.9) and all-cause mortality (OR: 0.97, CI:
0.841.12, P = 0.69) did not significantly vary depending Discussion
on the duration of follow up by using random effect, This study considered the extant evidentiary base on the
Mantel-Haenszel 95% CI analysis. effects of ivabradine in reducing cardiovascular outcomes

Table 4 Meta-analysis in efficacy and safety of ivabradine in patients with stable coronary angina and heart failure
Ivabradine Placebo Odds ratio P-value I2
in %
Outcome Event/Total, n/N % Event/total % M-H, random
& Fixedb, 95% CI
Cardiovascular death 1247/18270 6.8 1227/18254 6.7 1.02(0.911.15) 0.74 51
All-cause mortality 1560/18270 8.5 1557/18254 8.5 1(0.911.10) 0.98 78
a
Hospital admission 1156/18270 6.3 1280/18254 7 0.94(0.711.25) 0.69 89
Coronary revascularization 717/15029 4.7 750/14990 5 0.93(0.771.11) 0.41 57
Phosphenes 601/12771 4.7 69/12804 5.3 7.77(4.414.6) <0.00001 78
Symptomatic bradycardia 907/12771 7.1 142/12804 1.1 6.23(4.29.26) <0.00001 1 71
Atrial fibrillation 814/12771 6.3 613/12804 4.7 1.35(1.211.51) <0.00001 22
Blurred vision 134/12771 1 44/12804 0.3 3.07(2.184.32) <0.00001 0
Infection& infestation 519/8709 5.9 555/8690 6.3 0.93(0.821.05) 0.26 0
Serious adverse event 2683/8709 31 2792/8690 32 0.97(0.851.11) 0.36 48
Cardiac disorder 2203/8709 2.5 2454/8690 2.8 0.85(0.651.11) 0.24 89
CI Confidence Interval, a shows hospital admission for worsening or new onset of heart failure,bindicates the use of random effect model when I2 50 and fixed
effect if I2 < 50
Mengesha et al. BMC Cardiovascular Disorders (2017) 17:105 Page 7 of 9

Fig. 3 Funnel plot of studies on cardiovascular deaths

in patients with stable angina and heart failure. The re- of the majority of sampled participants exhibiting stable
search hypothesis was that ivabradine may have a signifi- angina and heart failure caused by ischemic heart disease
cant effect in reducing cardiovascular outcomes in and in terms of the outcomes measured). Specifically,
patients with stable angina and heart failure and that such participants in BEAUTIFUL, SHIFT, and SIGNIFY had
effect may vary among subgroups and/or across period of stable angina with left ventriculardysfunction, heart fail-
follow up. Ivabradine pharmacological effectiveness for ure patients (majority with ischemic origin) with ejection
these conditions relates to its selective reduction of heart fraction <35%, and stable angina without clinical heart
rate by acting on the pacemaker sino-atrial nodes so- failure, respectively. As a result, there was similarity in
called funny channel [13] thereby redressing the estab- target population across these studies.
lished risk factor of increased heart rate [59]. Independently, each trial revealed that ivabradine was
A number of large multicenter trials have been con- effective for reducing events in subgroup patients of
ducted; specifically, BEAUTIFUL, SHIFT, and SIGNIFY heart beat 70 bpm in the BEAUTIFUL study and was
studies [9, 14, 15]. Although these trials targeted distinct effective in reducing primary outcome and secondary
patient populations, they exhibited similarities in terms outcomes in the SHIFT study but in the recent trial with

Funnel Plot on effect of ivabradine on admission to hospital for heart failure

0.00

0.05
Standard Error

0.10

0.15

0.20

-2.0 -1.5 -1.0 -0.5 0.0 0.5 1.0 1.5 2.0

MH log odds ratio

Fig. 4 Funnel plot of studies on hospital admission for heart failure

Mengesha et al. BMC Cardiovascular Disorders (2017) 17:105 Page 8 of 9

relatively longer duration follow up but without clinical affirmed that prescribers should be cautious in clinical
heart failure (SIGNIFY) it was found that the addition of use of this drug for unspecified conditions or for off
ivabradine to standard background therapy did not im- label purposes. This meta-analysis suggested that ivabra-
prove outcomes [14]. A recent meta-analysis found that dine is not effective in reducing cardiovascular related
unselective use of ivabradine in patients with CAD is morbidity and mortality in other than specified condi-
not supported by evidence and may be associated with tions and is associated with new onset of adverse events
new onset of adverse effects [18]. In the current study, in non-specified use situations. Therefore, this finding
ivabradine was found not to significantly reduce all effi- strongly supports previous analysis related to the use of
cacy outcomes according to the trials assessed in this ivabradine and emphasizes the imperative for health
study. However, in the SHIFT study, ivabradine was professionals to be aware of these evidences for rational
found effective in reducing primary composite end point use of ivabradine in clinical practice.
and other secondary outcomes such as hospital admis-
sion for worsening of heart failure, but this finding was Additional file
not true in the pooled analysis for ivabradine compared
to placebo participants. Based on this analysis, there is a Additional file 1: PRISMA 2009 Checklist. (DOC 62 kb)
need to be cautious in interpretation of the effectiveness
of ivabradine for patient subgroups with left ventricular Abbreviations
dysfunction and high resting heart rate 70 bpm. BEAUTIFUL: morBidity-mortality EvAlUaTion of the If inhibitor ivabradine in
patients with coronary disease and left-ventricULar dysfunction; BPM: Beats
Further, this meta-analysis showed that ivabradine is per Minute; CAD: Coronary Artery Disease; CMA: Comprehensve
significantly associated with the new onset of adverse MetaAnalysis; CI: Confidence Interval; CVD: Cardiovascular Diseases;
events such as blurred vision, phosphene, atrial fibrilla- PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-analysis
PRISMA Checklist; OR: Odds Ratio; SHIFT: Systolic Heart failure treatment with
tion, and symptomatic bradycardia. Although adverse the If inhibitor ivabradine Trial,; SIGNIFY: Study Assessing the Morbidity
events varied across the trials, the analysis showed most Mortality Benefits of the If Inhibitor Ivabradine in Patients with Coronary
of the adverse events were significantly related to ivabra- Artery Disease

dine compared to placebo. This finding indicates that Acknowledgement

the unspecific use (i.e., off label use) of this drug is not We thank to authors of the studies for SHIFT, BEAUTIFUL and SIGNIFY for
effective and may catalyze untoward, adverse events. creating the chance to conduct this metanalysis.
There were several limitations in this meta-analysis. Funding
Beyond inconsistent diagnostic groups as previously de- We have not received any funding for conducting and publication of this
scribed, some subgroups were too small (i.e., heart manuscript.
rate < 70 bpm versus >70 bpm) and precluded meaning-
Availability of data and materials
ful interpretation of difference. For future we suggest Not applicable.
that a pooled analysis is required to estimate the effect
size of ivabradine among patients with different heart Authors contributions
HG: Conceived the research, writing the draft manuscript and selection of
beats. It was impossible to conduct meta-regression and studies. BS: Participated in writing, search of studies, selection and
assess the effect of important variables like heart rate assessment of the studies. TB: Participated in studies searching, selection
and LVEF which might affect the effect size estimate, be- process and assessment of studies. PP: Mainly contributed in writing and
proof reading. MG: Writing the draft manuscript and participated in studies
cause of few numbers of studies included to this meta- selection process. AH: Contributed in writing and reviewing of the
analysis. manuscript. All authors read and approved the final manuscript.
Subgroup analysis based on duration of follow up, ef-
Competing interests
fect of ivabradine did not significantly vary by duration We declared that we do not have any conflict of interest with any one/
of follow up compared to placebo. This analysis also fills thing.
the gap in the hypothesis is that cardiovascular events
Ethics approval and consent to participate
may vary depending on the duration of follow up.
Not applicable.

Conclusions
Publishers Note
On meta-analysis, we found that ivabradine was not ef- Springer Nature remains neutral with regard to jurisdictional claims in
fective in reducing cardiovascular morbidity and mortal- published maps and institutional affiliations.
ity outcomes but was associated with new onset of
Author details
adverse events. 1
College of Health Science, Adigrat University, Adigrat, Ethiopia. 2College of
In summary, ivabradine is approved by European Med- Health Science, School of Public Health, Mekelle University, Mekelle, Ethiopia.
3
icines Agency [16] and the United States Food and Drug College of Nursing; Adjunct Nelson Mandela African Institute of Science and
Technology, University of Saskatchewan, Saskatoon, Canada. 4College of
Administrations [17] for clinical use in stable CAD and Health Science, Department of Pharmacy, Haramaya University, Harar,
heart failure of specific conditions. This meta-analysis Ethiopia. 5College of Health Science, Department of Medical Biochemistry,
Mengesha et al. BMC Cardiovascular Disorders (2017) 17:105 Page 9 of 9

Mekelle University, Mekelle, Ethiopia. 6College of Health Science, Department

of Internal Medicine, Mekelle University, Mekelle, Ethiopia.

Received: 15 October 2016 Accepted: 22 April 2017

References
1. Gaziano TA, Biton A, Anand S, Abrahams-Gessel MS, Murphy A. Growing
epidemic of coronary heart disease in low- and middle-income countries.
Curr Probl Cardiol. 2010;35(2):72115. doi:10.1016/j.cpcardiol.2009.10.002.
2. Mathers CD, Loncar D. Projections of global mortality and burden of disease
from 2002 to 2030. PLoS Med. 2006;3:e442.
3. World Health Organization. Global status report on noncommunicable
diseases 2010. Geneva: World Health Organization; 2011. p. 162.
4. World Health Organization. Noncommunicable diseases country profiles
2011. Geneva: World Health Organization, 2011.207 p.
5. Reil JC, Custodis F, Swedberg K, et al. Heart rate reduction in cardiovascular
disease and therapy. Clin Res Cardiol. 2011;100:119.
6. Gillman MW, Kannel WB, Belanger A, DAgostino RB. Influence of heart rate
on mortality among persons with hypertension: the Framingham study. Am
Heart J. 1993;125:114854.
7. Kannel WB, Kannel C, Paffenbarger RS Jr, Cupples LA. Heart rate andcardiovascular
mortality: the Framingham study. Am Heart J. 1987;113:148994.
8. Diaz A, Bourassa MG, Guertin MC, Tardif JC. Long-term prognostic value of
rest-ing heart rate in patients with suspected or proven coronary artery
disease. Eur Heart J. 2005;26:96774.
9. Fox K, Ford I, Steg PG, Tendera M, Ferrari R. Ivabradine for patients with
stablecoronary artery disease and left-ventricular systolic dysfunction
(BEAUTIFUL):a randomised, double-blind, placebo-controlled trial. Lancet.
2008;372:80716.
10. Freemantle N, Cleland J, Young P, et al. Beta blockade after myocardial infarction:
systematic review and meta regression analysis. BMJ. 1999;318:17307.
11. Poole-Wilson PA, Lubsen J, Kirwan BA, et al. Effect of long acting nifedipine
on mortality and cardiovascular morbidity in patients with stable angina
requiring treatment (ACTION trial): randomized controlled trial. Lancet. 2004;
364:84957.
12. Parker JD, Parker JO. Nitrate therapy for stable angina pectoris. N Engl J
Med. 1998;338:52031.
13. DiFrancesco D. Funny channels in the control of cardiac rhythm and mode
of action of selective blockers. Pharmacol Res. 2006;53:399406.
14. Fox K, Ford I, Steg PG, Tardif JC, Ferrari R for the SIGNIFY Investigators.
Ivabradine in stable coronary artery disease without clinical heart failure.
N Engl J Med 2014;371:1091-1099.
15. Swedberg K, Komajda M, Bhm M, Borer JS, Ford I, Dubost-Brama A, et al.
Ivabradine and outcomes in chronic heart failure (SHIFT): a randomized
placebo-controlled study. Lancet. 2010;376:87585.
16. European Medicines Agency. EPAR summary for the public. Canary Wharf,
London, UK: European Medicines Agency 2005: 14.
17. U.S. Food and Drug Administration. FDA approves Corlanor to treat heart
failure [Web Page]. Available from: http://www.fda.gov/NewsEvents/
Nwsroom/PressAnnouncements/ucm442978.htm.
18. Cammarano C, Silva M, Comee M, Donovan JL, Malloy MJ. Meta-analysis of
ivabradine in patients with stable coronary artery disease with and without
left ventricular dysfunction. ClinTher. 2016;38(2):38795.
19. Demontis GC, Gargini C, Paoli TG, et al. Selective Hcn1 channels inhibition
by ivabradine in mouse rodphotoreceptors. Invest Ophthalmol Vis Sci. 2009;
50:194855.
20. Thollon C, Vilaine JP. I (f) inhibition in cardiovascular diseases. Adv Pharmacol. Submit your next manuscript to BioMed Central
2010;59:5392.
21. Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for systematic and we will help you at every step:
reviews and meta-analyses: the PRISMA statement. BMJ. 2009;339:b2535.
We accept pre-submission inquiries
22. Higgins JP, Green S. Cochrane handbook for systematic reviews of
interventions. Version 5.1.0 [internet]. Oxford: The Cochrane Collaboration; Our selector tool helps you to find the most relevant journal
2011. Available from: www.cochranehandbook.org. We provide round the clock customer support
23. Mengesha H, Weldearegawi B, Ghezu M, Bekelle T, George M. Effect of
Convenient online submission
ivabradine on coronary artery disease: a systematic review and meta-
analysis of randomized clinical trials. PROSPERO 2016:CRD42016035597 Thorough peer review
Available from http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID= Inclusion in PubMed and all major indexing services
CRD42016035597.
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