Levosimendan for the treatment of acute severe heart failure: a meta-analysis of randomised controlled trials.
ABSTRACT The objective of this study was to critically review the literature to evaluate whether levosimendan compared to standard therapy, in patients with acute severe heart failure, is associated with improved clinical outcomes.
Medline, EMBASE, and the Cochrane central register of clinical trials were searched. We also searched clinical trials registries, bibliographies of included studies and review articles and contacted the manufacturers of levosimendan to identify unpublished studies. Randomised clinical trials comparing levosimendan to standard therapy or placebo, in adult patients with acute severe heart failure, reporting at least one outcome of interest were included. Data were extracted regarding the characteristics, methodological quality and clinical outcomes, and combined using a fixed-effect meta-analysis.
We identified 19 RCTs enrolling 3650 patients, only two studies fulfilled all of the validity criteria. There was a non-significant reduction in mortality with levosimendan compared with placebo (OR 0.83, 95%CI, 0.62-1.10, p=0.20). Levosimendan was associated with reduced mortality compared to dobutamine (OR 0.75, 95%CI, 0.61-0.92, p=0.005). Levosimendan was associated with improvements in haemodynamic parameters when compared to either placebo or dobutamine.
Levosimendan improved haemodynamic parameters when compared with placebo, without showing evidence of survival benefit. Levosimendan improved both haemodynamics and survival when compared with dobutamine.
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ABSTRACT: Inotropes are widely used in hospitalized systolic heart failure (HF) patients, especially those with low systolic blood pressure (SBP) or cardiac index. Also inotropes are considered harmful in nonischemic HF.Journal of cardiac failure. 05/2014;
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ABSTRACT: Organ dysfunction consequent to infection ('severe sepsis') is the leading cause of admission to an intensive care unit (ICU). In both animal models and early clinical studies the calcium channel sensitizer levosimendan has been demonstrated to have potentially beneficial effects on organ function. The aims of the Levosimendan for the Prevention of Acute oRgan Dysfunction in Sepsis (LeoPARDS) trial are to identify whether a 24-hour infusion of levosimendan will improve organ dysfunction in adults who have septic shock and to establish the safety profile of levosimendan in this group of patients.Trials. 06/2014; 15(1):199.
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ABSTRACT: Background The intravenous inodilator levosimendan was developed for the treatment of patients with acutely decompensated heart failure. In the last decade scientific and clinical interest has arisen for its repetitive or intermittent use in patients with advanced chronic, but not necessarily acutely decompensated, heart failure. Recent studies have suggested long-lasting favourable effects of levosimendan when administered repetitively, in terms of haemodynamic parameters, neurohormonal and inflammatory markers, and clinical outcomes. The existing data, however, requires further exploration to allow for definitive conclusions on the safety and clinical efficacy of repetitive use of levosimendan. Methods and results A panel of 30 experts from 15 countries convened to review and discuss the existing data, and agreed on the patient groups that can be considered to potentially benefit from intermittent treatment with levosimendan. The panel gave recommendations regarding patient dosing and monitoring, derived from the available evidence and from clinical experience. Conclusions The current data suggest that in selected patients and support out-of-hospital care, intermittent/repetitive levosimendan can be used in advanced heart failure to maintain patient stability. Further studies are needed to focus on morbidity and mortality outcomes, dosing intervals, and patient monitoring. Recommendations for the design of further clinical studies are made.International Journal of Cardiology. 06/2014; 174(2):360–367.
Levosimendan for the treatment of acute severe heart failure: A
meta-analysis of randomised controlled trials
Anthony Delaneya,b,⁎, Celia Bradforda,b, John McCaffreya,
Sean M. Bagshawc,d, Richard Leea,b
aIntensive Care Unit, Royal North Shore Hospital, St. Leonards, NSW, Australia
bNorthern Clinical School, University of Sydney, St. Leonards, NSW, Australia
cDivision of Critical Care Medicine, University of Alberta Hospital, Edmonton, AB, Canada
dFaculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
Received 30 October 2007; received in revised form 27 June 2008; accepted 10 August 2008
Available online 24 September 2008
Background: The objective of this study was to critically review the literature to evaluate whether levosimendan compared to standard therapy,
in patients with acute severe heart failure, is associated with improved clinical outcomes.
Methods: Medline, EMBASE, and the Cochrane central register of clinical trials were searched. We also searched clinical trials registries,
of interest were included. Data were extracted regarding the characteristics, methodological quality and clinical outcomes, and combined using a
compared to dobutamine (OR 0.75, 95%CI, 0.61–0.92, p=0.005). Levosimendan was associated with improvements in haemodynamic
parameters when compared to either placebo or dobutamine.
Conclusions: Levosimendan improved haemodynamic parameters when compared with placebo, without showing evidence of survival
benefit. Levosimendan improved both haemodynamics and survival when compared with dobutamine.
Crown Copyright © 2008 Published by Elsevier Ireland Ltd. All rights reserved.
Keywords: Heart failure; Drugs; Meta-analysis; Levosimendan; Inotropic agents
Recent international studies have highlighted the scope
and impact of acute heart failure [1,2]. Heart failure is one of
the most important causes of morbidity and mortality in the
developed countries , with the numbers of patients hos-
pitalised for acute heart failure increasing due to ageing
populations andimprovements inthetreatmentsofischaemic
heart disease and chronic heart failure [4,5]. Patients with
acute severe heart failure have an estimated one-year morta-
lity of 30–50% . Acute heart failure accounts for 2–3% of
annually in the United States alone . Clearly the manage-
ment of acute severe heart failure is an important issue with
considerable health resource implications.
After correcting the precipitant and treating the under-
lying cause of the acute deteriorations in cardiac function,
current management largely focuses on the use of diuretics
and vasodilators , combined with non-invasive positive
International Journal of Cardiology 138 (2010) 281–289
⁎Corresponding author. Intensive Care Unit, Royal North Shore Hospital,
Pacific Highway, St. Leonards, NSW, 2065, Australia. Tel.: +61 2 9926
8656; fax: +61 2 9439 8418.
E-mail address: email@example.com (A. Delaney).
0167-5273/$ - see front matter. Crown Copyright © 2008 Published by Elsevier Ireland Ltd. All rights reserved.
pressure ventilation for those with acute pulmonary oedema
. When heart failure is severe and, not responding to first
line treatments, positive inotropic agents such as dobutamine
or milrinone may be indicated . However, there is little
high quality evidence for the efficacy of these agents to
improve long-term cardiac performance or survival .
troponin C, stabilizing the bound Ca2+, prolonging the inter-
action between of actin and myosin, and thus enhancing
cardiac contractility . Preclinical studies demonstrated the
efficacy of levosimendan in enhancing myocardial function
with improvements in a number of measured haemodynamic
variables and neurohumoral marker [10–14]. Levosimendan
also exerts a significant vasodilatory action that may have an
important clinical effect [15,16].
Early clinical trials suggested that levosimendan may be a
useful adjunct in the treatment of acute heart failure [17,18].
These studies, however, were not designed or powered to
detect reductions in clinically relevant and patient-centred
outcomes such as mortality. Yet, on the basis of these trials,
levosimendan has been recommended for the treatment of
patients with symptomatic low cardiac output heart failure
.More recently, a number of largerclinical trials have now
been completed. Accordingly, the principal objective of this
study was to critically review the literature to evaluate whe-
ther levosimendan compared to standard therapy, in patients
with acute severe heart failure, is associated with improved
clinical outcomes, in particular survival.
The primary search for randomised clinical trials (RCTs)
was conducted using the Medline (via the PubMED interface)
and EMBASE databases, as well as the Cochrane Central
Registry of Clinical Trials (using the OVID interface). Search
terms used were levosimendan or calcium sensit⁎. This search
was combined with sensitive filters to identify RCTs in the
Medline database  and the EMBASE database . The
search was limited to human subjects, with no language res-
triction placed on the search. Two authors (AD and CB)
independently conducted the search. The search was finalised
on 18th June, 2007. We also searched the metaRegister of
Controlled Trials (http://www.controlled-trials.com/mrct/), in-
cluding the Medical Editors Trial Amnesty and other archived
registriesusingthe searchterm“levosimendan”. We contacted
identified), and reviewed the bibliographies of included RCTs
and review articles, to identify otherwise unrecognised or
unpublished RCTs .
2.2. Study selection
Two authors (AD and CB) reviewed all abstracts to
identify potentially eligible RCTs. If the abstract described a
study that could potentially meet the inclusion criteria, then
that study was considered for further review. Where possible,
full text articles were retrieved and reviewed, by the same
authors, to determine if they met the eligibility criteria. Dis-
author (RL) if needed. Reports of RCTs of levosimendan
compared to any other agent, for acute heart failure in adult
humans, and that reported at least one of the outcomes of
included mortality, changes in haemodynamic parameters (i.e.
ejection fraction (EF), cardiac index (CI), pulmonary capillary
2.3. Validity assessment and data abstraction
All included articles were assessed for validity by two au-
thors (AD CB), independently, with disputes resolved by dis-
knowing the upcoming treatment assignments ), blinding
(defined as attempts to keep trial participants, investigators or
assessors unaware of the assigned treatment ) and the per-
formance of an intention to treat analysis. When it was unclear
whether a criterion had been met it was adjudicated as absent
Data were abstracted onto specific data collection forms by
two authors (AD and CB) and entered into a spreadsheet where
it was checked for accuracy (JM). Data collected included:
patient baseline characteristics, study definition of acute heart
failure, details of delivery of levosimendan, specific of com-
parator therapy and haemodynamic and clinical outcomes (i.e.
mortality for each group for the longest period of follow-up).
validity of the study, or outcome data were missing, attempts to
contact the authors, by email and in writing were made.
Fig. 1. Study flow diagram.
282 A. Delaney et al. / International Journal of Cardiology 138 (2010) 281–289
Summary of the characteristics of randomised clinical trials of levosimendan in patients with acute severe heart failure.
Study YearPopulationN Definition of
% Male Levo bolus
Levosimendan v placebo
2000 Heart failure of ischaemic origin 151
2002 AMI with evidence of LVF on
CXR and need for inotropes
2003 Hospitalised for acute
decompensated heart failure
2004 NYHA III/IV
2004 Hospitalised with EFb35%
2005 NYHA III/IV hospitalised
2005 AMI with LV dysfunction
LVF on CXR
3 to 36
6 to 24
0.05 to 0.6
0.1 to 0.4
REVIVE I 100 NANRNR12 0.1 to 0.124NA2490
De Luca 
18 and CIb2.5
0.1 to 0.4
0.1 to 0.4
REVIVE II 
Adamopolous  2006 NYHA III/IVadmitted with
2006 Hospitalised for Heart failure
2006 NYHA III/IVadmitted to CCU
0.1 to 0.2
decompensated heart failure
Levosimendan v dobutamine
Follath  1999 Low output heart failure or
2000 Heart failure of ischaemic
2002 Admitted to hospital with
low output heart failure
2004 Hospitalised with EFb35%
2005 NYHA IV hospitalized
19CIb2.5 58.8 78.912 0.2 to 0.624 8 to 16 µg/kg/min 2414
Nieminen  EFb40% 63 87.8 3 to 36 0.05 to 0.6246 µg/kg/min249
5986.7240.1 to 0.2 245 to 10 24180
Adamopolous  2006 NYHA III/IVadmitted with
5 to 10
5 to 10
decompensated heart failure
2006 Hospitalised for heart failure
2006 Low cardiac output after
heart surgery with
2005 Septic shock with EFb45%
41CIb2.2, PCWPN15 69.1
0.1 to 0.2
5 to 40
Levosimendan v milrinone
Al-Shawaf 2006 Type II diabetics with
EFb35% post CABG
2007 Elective cardiac surgery
30CIb2.259.293.3 120.1 to 0.22450 µg/kg then
De Hert 30LVEFb30%6866.700.119 +/− 424Hospital LOS
Levosimendan v PGE1
Moertl 2005 Admitted with decompensated
73NYHA III or IV,
55.380.8 120.1242.5 – 10 ng/kg24 7
Heart Association classification, CI = cardiac index, LV = left ventricular, PCWP = pulmonary capillary wedge pressure, CABG = coronary artery bypass graft surgery, ICU = intensive care unit, LOS = length of stay.
A. Delaney et al. / International Journal of Cardiology 138 (2010) 281–289
2.4. Data synthesis
Agreement on RCT inclusion was assessed using the
kappa statistic. Heterogeneity was assessed using the chi-
square statistic and quantified using the I2statistic, with an
I2of N50% taken as representing at least moderate hetero-
geneity . The potential for bias was assessed by the
inspection of funnel plots and the use of Eggers statistic .
Studies that compared levosimendan to dobutamine were
combined separately from studies that compared levosimen-
dan to placebo. As there were three studies that had three
groups (i.e. levosimendan, dobutamine and placebo), we cal-
culated a pooled estimate of the effect of dobutamine com-
pared to placebo. Data were extracted from the primary
studies to allow calculation of the odds ratio (OR) for each
study. The primary analyses were performed using a fixed-
effect model  to produce a pooled OR . Sensitivity
analyses were conducted using the random effects model of
Der Simonian and Laird. The effect of trial quality on out-
come was examined by pooling studies adjudicated to have
adequate allocation concealment, blinding and an intention to
treat analysis separately, to examine for between group hete-
rogeneity. Changes in haemodynamic parameters and BNP
were pooled using weighted mean differences . All ana-
lyses were performed using STATA 8.2 (Statcorp, College
Station, Tx). The authors had full access to the data and take
responsibility for its integrity. All authors have read and agree
to the manuscript as written.
3.1. Study characteristics
There were 393 reports identified by the search, 41 full
text articles were retrieved for in depth review. In total, 19
studies enrolling 3650 participants fulfilled all eligibility
criteria. Fig. 1 shows the flow of studies and the reasons for
exclusion. Of the trials included, 16 [12–14,17,18,31–41]
Summary of the validity assessments of randomised clinical trials of
levosimendan in patients with acute severe heart failure.
REVIVE I 
REVIVE II 
Fig. 2. The effect of levosimendan compared to placebo on mortality.
284A. Delaney et al. / International Journal of Cardiology 138 (2010) 281–289
were available as full reports and 3 [42–44] in abstract form
only. Agreement on study inclusion was reached in 39 of 41
cases (kappa=0.90). The trial characteristics are shown in
Table 1. The validity assessments are shown in Table 2. Only
two studies fulfilled all of the validity criteria.
3.2. Levosimendan v placebo
There were six studies [12,17,40,42–44] including at total
of 1578 participants that compared the effect of levosimendan
to placebo and reported mortality. There was no evidence of
significant heterogeneity (χ2p=0.24, I2=25.7%). Neither
inspection of the funnel plot (Appendix) nor Egger's bias
statistic (bias=−0.41, p=0.07) revealed evidence of bias. The
fixed-effect pooled estimate of the OR for mortality was 0.83
(95%CI 0.62 to 1.10, p=0.20), suggesting that levosimendan
was no better than placebo for reducing mortality in acute
cardiac failure (Fig. 2). This result was consistent when the
studies were pooled using a random effects model, the pooled
OR=0.80 (95%CI 0.54 to 1.17, p=0.24).
Fig. 3. The effect of levosimendan compared to dobutamine on mortality.
Fig. 4. The effect of dobutamine compared to placebo on mortality.
285A. Delaney et al. / International Journal of Cardiology 138 (2010) 281–289
3.3. Levosimendan v dobutamine
There were eight studies [12,18,31,33,37,39,40,43] inclu-
ding a total of 1979 participants that compared levosimendan
to dobutamine and reported mortality. There was no evi-
dence of significant bias on visual inspection of the funnel
plot (Appendix) or by examination of Egger's bias statistic
(bias=−1.16, p=0.17). There was evidence of some hetero-
showed levosimendan was associated with a significant reduc-
tion in mortality compared with dobutamine (OR 0.75, 95%CI
0.61 to 0.92, p=0.005) (Fig. 3). This finding was similar when
data was pooled using a random effects model (OR 0.58, 95%
CI, 0.37 to 0.91, p=0.02).
3.4. Dobutamine v placebo
There were three studies [12,40,43] that randomised
301 participants to dobutamine or placebo and reported
mortality. There was no evidence of significant bias
(Egger's statistic, bias=0.34, p=0.73), funnel plot asym-
metry or statistical heterogeneity (χ2p=0.72, I2=0%). The
pooled estimate of the OR for mortality for dobutamine
compared to placebo was 1.82 (95%CI 1.06 to 3.12,
p=0.03), indicating a significant increase in mortality for
dobutamine compared to placebo in patients with acute
severe acute heart failure (Fig. 4). This finding was similar
when pooled using a random effects model (OR 1.81, 95%CI
1.06 to 3.11, p=0.03).
3.5. Levosimendan compared to other agents
The OR for mortality for levosimendan compared to mil-
rinone was 0.33 (95%CI 0.05 to 2.1, p=0.24) indicating no
statistical evidence of an effect of levosimendan compared to
milrinone on mortality.
One study compared levosimendan to PGE1in patients
admitted to hospital with acute decompensated heart failure
. Mortality was not reported in this study.
3.6. The effect of study quality on estimates of efficacy
by pooling studies adjudicated to be higher quality separately.
The results of this assessment are shown in Table 3. When
levosimendan was compared to dobutamine, there was an
exaggerated estimate of efficacy in studies without adequate
The effect of study quality indicators on odds of mortality for levosimendan compared with control for patients with acute heart failure.
Control groupQuality indicator Number of studies Estimate of OR95%CI Test for between subgroup heterogeneity
Placebo Allocation concealmentYes
Intention to treat analysisp=0.64
Dobutamine Allocation concealmentp=0.005
Intention to treat analysisp=0.006
OR = odds ratio, CI = confidence interval.
Summary of the haemodynamic effects of levosimendan compared to control.
Control groupHaemodynamic parameterNumber of studies WMD95%CIp value
Placebo EF (%)
Cardiac index (l/min/m2)
PAOP (mm Hg)
Cardiac index (l/min/m2)
PAOP (mm Hg)
Cardiac index (l/min/m2)
PAOP (mm Hg
PAOP (mm Hg)
0.3 to 6.0
−0.1 to 0.4
−6.3 to −1.3
−617 to −42
−1.4 to 7.4
0.24 to 0.43
−3.3 to −2.5
−1000 to −180
−0.48 to 0.68
−4.5 to 0.5
−3.4 to 1.4
−611 to 191
WMD = weighted mean difference, CI= confidence interval, EF = ejection fraction, PAOP = pulmonary artery occlusion pressure, BNP = B-type natureitic peptide.
286A. Delaney et al. / International Journal of Cardiology 138 (2010) 281–289
allocation concealment, and those that did not perform an
intention to treat analysis.
3.7. Effects of levosimendan on haemodynamic parameters
The effect of levosimendan on the various measured
haemodynamic parameters and BNP are shown in Table 4.
Levosimendan was associated with improvements in all the
haemodynamic parameters evaluated, however, broad infer-
ences are limited due to a small number of RCTs reporting
data for each parameter.
We performed a systematic review and meta-analysis of
RCTs evaluating the effect of levosimendan compared with
standard therapies or placebo on survival and haemody-
namics parameters in patients presenting with acute severe
heart failure. We found levosimendan, when compared to
placebo, was associated with a non-significant reduction in
the odds for mortality, and was associated with significant
improvements in several haemodynamic parameters along
with a reduction in serum BNP. More interestingly, we found
that levosimendan was superior to dobutamine, and asso-
ciated with improved haemodynamics, lower serum BNP,
and a significant survival benefit. Our data suggest that this
finding may, in part, be due to a higher mortality associated
with the use of dobutamine, rather than only a reduction in
mortality associated with levosimendan. This finding is sup-
ported by evidence of increased mortality with use of dobu-
tamine when compared to only placebo.
We believe our study has a number of notable strengths.
First, we have applied the recommended methods for the
performance of systematic reviews . The use of duplicate
searches reduces the likelihood that significant studies were
missed, and the thorough methods for applying the inclusion
criteria, extracting and verifying the data, avoids errors and
biases. Second, our study is the most comprehensive and up-
our study has benefited from the recent completion of a
number of larger RCTs.
As with all meta-analyses, there are also potential weak-
nesses. The methodological quality of the studies included in
this analysis was less than optimal, with only two studies
meeting all of the validity criteria. Some of these deficiencies
may relate to the reporting of the studies rather than the
conduct of the studies . Certainly, as some of the larger
more recent studies are yet to appear in peer reviewed jour-
nals, these deficiencies may be corrected. Not all trials re-
ported all haemodynamic parameters or measured BNP,
so these estimates are based on relatively small numbers of
measurements and should be interpreted with caution. Simi-
larly, the pooled estimate for effect of dobutamine compared
to placebo was also based on few trials and, as an explora-
tory analysis should be considered more hypothesis
generating rather than definitive. Finally, there is a huge
variation in follow-up time, varying between 2 and 180 days.
Clearly this limits the strengths of the conclusions in this
With these limitations in mind, we believe our findings
are important and relevant for clinicians. While the estimate
of the OR for mortality favoured levosimendan over placebo,
this result did not reach statistical significance. This may
suggest that the use of levosimendan in a general population
of patients with acute severe heart failure does not offer a
mortality benefit. However, even the pooled analysis could
have been insufficiently powered to detect a clinically rele-
vant reduction in mortality in a general population of patients
with acute heart failure. The other potential role for levo-
simendan in patients with acute heart failure may be in
targeted populations. Non randomised studies have provided
cautious support for the use of levosimendan in patients with
acute severe heart failure that is expected to recover with
time; for example those with peripartum cardiomyopathy
, early graft failure following heart transplantation 
and those with left ventricular failure following cardiac
surgery . There is also some evidence to support the use
of levosimendan in patients with right heart failure .
improvements seen with levosimendan. It is also possible that
levosimendan may have a role in subgroups of patients with
acute heart failure, such as those already taking beta-blockers
issues with the data available in this review, and so further
studies are warranted.
The overall benefit seen with the use of levosimendan
compared to dobutamine also warrants closer scrutiny. The
overall estimate of treatment effect may be exaggerated by
the inclusion of lower quality RCTs. This observation is
supported by the evidence from the sensitivity analysis that
shows a greater treatment effect in studies without allocation
concealment and those that did not perform an intention to
treat analysis. It is also plausible that the dosing regime of
dobutamine used was less than optimal. As dobutamine is a
drug with a short half-life, it is generally titrated to clinical
effect , and is used for as long as clinically indicated.
Levosimendan has metabolites that exert a clinical effect for
up to a week . In most RCTs, dobutamine was only given
for 24 h, and therefore equipotent doses of dobutamine and
levosimendan were not compared. Interestingly, in the
SURVIVE study , where dobutamine was given accor-
ding to clinical need, no mortality benefit was found. The
other possibility is that the difference in mortality was due
not to a decrease in mortality with levosimendan, but rather
an increase in mortality with the use of dobutamine.
While the finding of an increase in mortality with dobu-
tamine should be viewed as preliminary, it is in keeping
with other evidence for adverse effects of dobutamine in
patients with heart failure , and with evidence that β-
blocking agents are associated with a beneficial effect in
patients with more chronic heart failure . The results of
this review would certainly give rise to concerns about the
287A. Delaney et al. / International Journal of Cardiology 138 (2010) 281–289
continued use of dobutamine outside the confines of a well-
The fact that the findings of this meta-analysis are at odds
with those of the most recent large clinical trials also gives
rise to some concerns. It is recognised that the results of
meta-analyses are often discordant with those of large cli-
nical trials . In these cases, it is prudent to examine the
individual studies to resolve these discrepancies. The pub-
lication of studies such as CASINO, REVIVE I and II in peer
reviewed journals, as well as other ongoing studies, will shed
further light on the role of levosimendan in the treatment of
patients with acute severe heart failure.
There are still some important questions that require fur-
ther investigation. The role of levosimendan in targeted po-
pulations, such as those waiting for cardiac transplantation,
those with acute heart failure following cardiac surgery, and
other potentially reversible causes of cardiac failure are still
needed. In addition, the role of dobutamine in the manage-
ment of acute heart failure requires further investigation.
In summary, this systematic review of 19 randomised
clinical trials found that there was no evidence of survival
benefit when levosimendan was compared to placebo. On the
other hand, levosimendan was associated with an improve-
ment in both haemodynamics and survival when compared
with dobutamine. This difference may have been due to either
an increase in mortality with the use of dobutamine or a
reduction in mortality with use of levosimendan. We believe
additional high quality studies of adjunctive inotropic therapy,
in particular to further delineate the role of dobutamine, for
patients with acute heart failure are clearly needed.
The authors would like to thank Dr Doreen Rabi for her
insightful comments on the manuscript. The authors of this
manuscript have certified that they comply with the
Principles of Ethical Publishing in the International Journal
of Cardiology .
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