Published May 28, 2024

NEJM Evid 2024; 3 (6)

DOI: 10.1056/EVIDoa2300335

ORIGINAL ARTICLE

Vasodilators for Acute Heart Failure — A

Systematic Review with Meta-Analysis
Jasmin D. Lukoschewitz, M.D.,1 Kristina C. Miger, M.D.,2 Anne Sophie O. Olesen, M.D.,2 Nora O. E. Caidi, M.B.,1
Caroline K. Jørgensen,3,4 Olav W. Nielsen, M.D., Ph.D., D.M.Sc.,2,5 Christian Hassager, M.D., Ph.D., D.M.Sc.,2,6
Jens D. Hove, M.D., Ph.D., D.M.Sc.,1,5 Ekim Seven, M.D., Ph.D.,1 Jacob E. Møller, M.D., Ph.D.,6,7,8
Janus Christian Jakobsen, M.D., Ph.D.,3,4 and Johannes Grand, M.D., Ph.D.1

Abstract
BACKGROUND Acute heart failure is a public health concern. This study systematically
reviewed randomized clinical trials (RCTs) to evaluate vasodilators in acute heart failure.

METHODS The search was conducted across the databases of Medline, Embase, Latin
American and the Caribbean Literature on Health Sciences, Web of Science, and the
Cochrane Central Register of Controlled Trials. Inclusion criteria consisted of RCTs that
compared vasodilators versus standard care, placebo, or cointerventions. The primary
outcome was all-cause mortality; secondary outcomes were serious adverse events
(SAEs), tracheal intubation, and length of hospital stay. Risk of bias was assessed in
all trials.

RESULTS The study included 46 RCTs that enrolled 28,374 patients with acute heart
failure. Vasodilators did not reduce the risk of all-cause mortality (risk ratio, 0.95; 95%
confidence interval [CI], 0.87 to 1.04; I2=9.51%; P=0.26). No evidence of a difference
was seen in the risk of SAEs (risk ratio, 1.01; 95% CI, 0.97 to 1.05; I2=0.94%) or length
of hospital stay (mean difference, –0.10; 95% CI, –0.28 to 0.08; I2=69.84%). Vasodilator
use was associated with a lower risk of tracheal intubation (risk ratio, 0.54; 95% CI, 0.30
to 0.99; I2=51.96%) compared with no receipt of vasodilators.

CONCLUSIONS In this systematic review with meta-analysis of patients with acute heart
failure, vasodilators did not reduce all-cause mortality.

The author affiliations are listed

at the end of the article.

Dr Lukoschewitz can be contacted

Introduction at Jasmin.dam.lukoschewitz@

A
cute heart failure represents a significant global health concern, with increasing regionh.dk or at Department of
Cardiology, Amager and Hvidovre
incidence rates and substantial morbidity, mortality, and health care costs.1-6 Hospital, Kettegård Alle 30, 2650
Acute heart failure may manifest in acute decompensation of chronic heart Hvidovre, Copenhagen, Denmark.

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failure or as a new-onset heart failure, with symptoms
including dyspnea, fatigue, orthopnea, and peripheral
edema.7 As a medical emergency, acute heart failure
necessitates rapid evaluation, diagnosis, and management.
Although several well-established therapies for reducing
mortality and morbidity for chronic heart failure exist, few
medical interventions have been shown to improve out-
comes in acute heart failure. Consequently, patients admit-
ted due to acute heart failure reportedly have persistently
high 1-year mortality rates of approximately 24%.1-4 The
European Society of Cardiology (ESC) 2021 guidelines
for heart failure recommend intravenous loop diuretics
(Class I) and intravenous vasodilators (Class IIb), which
may be considered when systolic blood pressure is higher
than 110 mm Hg in cases of pulmonary edema or conges-
tion.7 However, the evidence for vasodilators is conflicting.
More than two decades ago, Cotter et al.8 reported that
vasodilation (isosorbide dinitrate) was superior to loop
diuretics in treating acute heart failure with pulmonary
edema. However, the 2019 GALACTIC (Goal-directed
Afterload Reduction in Acute Congestive Cardiac Decom-
pensation Study) individual randomized trial9 and the
cluster-randomized ELISABETH (Early and Comprehensive
Care Bundle in Elderly for Acute Heart Failure: a Stepped
Wedge Cluster Randomized Trial) trial10 found no signifi-
cant benefit of vasodilators. Consequently, vasodilation was
downgraded from Class IIA to Class IIb in the 2021 ESC
guidelines for heart failure.7,10
A systematic review evaluating all vasodilator drugs that
uses rigorous methodologies, including adhering to estab-
lished guidelines such as the Preferred Reporting Items
for Systematic Reviews and Meta-Analysis (PRISMA), trial
sequential analysis (TSA), and the Cochrane Collaboration
risk of bias tool, is warranted.11-13 The aim, therefore, of
the current systematic review was to assess the evidence
available regarding the efficacy and safety of vasodilators
for patients with acute heart failure, as well as investigate
potential variations in treatment effect among distinct
patient subgroups.
Methods
This systematic review and meta-analysis was conducted
in accordance with PRISMA guidelines.12 The study pro-
tocol,14 detailing the methodology, was published before
the literature search and registered with PROSPERO
(CRD42022306879). The PRISMA checklist is presented
in Table S2 of the Supplementary Appendix.
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SEARCH STRATEGY AND SELECTION CRITERIA
A systematic search was conducted of the Medline, Embase,
Latin American and the Caribbean Literature on Health
Sciences, Web of Science, and the Cochrane Central Regis-
ter of Controlled Trials databases; there were no restrictions
on publication year, type, or language. A specialized search
coordinator conducted the literature search on June 12,
2023, based on the PICO (Population, Intervention, Control,
and Outcome) format. A detailed search strategy is provided
in the Methods section of the Supplementary Appendix.
Trials were included if they met the following criteria: the
trial was a randomized controlled trial; participants were
adults with acute heart failure (as defined by trialists),
regardless of age, sex, or comorbidities; the treatment
involved vasodilator drugs intended for potential benefit
in patients with acute heart failure; and interventions
were compared against placebo, no intervention, or another
active treatment.
Trials using inodilators as intervention (e.g., levosimendan,
dobutamine, milrinone) and trials that included patients
with cardiogenic shock were excluded.
Two reviewers (J.D.L., J.G.) independently screened all
titles and abstracts using predefined criteria and system-
atic review software (Covidence systematic review soft-
ware, Veritas Health Innovation; available at https://
www.covidence.org/). Full-text reports of potentially rele-
vant publications were reviewed by at least two reviewers.
Disagreements regarding eligibility were resolved through
discussion, and study authors were contacted as needed
by email.
OUTCOMES AND SUBGROUP ANALYSIS
The predefined primary outcome was all-cause mortality.
Secondary and exploratory outcomes included serious
adverse events (SAEs), tracheal intubation, length of hos-
pital stay, and blood pressure reduction. Quality of life,
days alive outside the hospital, N-terminal pro–brain natri-
uretic peptide levels, ejection fraction, dyspnea, time to
stabilization, and renal replacement therapy were initially
planned as secondary and exploratory outcomes but were
excluded because of insufficient data. We adhered to the
International Conference for Harmonisation of Technical
Requirements for Pharmaceuticals for Human Use criteria
for SAEs (i.e., any untoward medical occurrence that
resulted in death, was life-threatening, required hospitaliza-
tion or prolonging of existing hospitalization, and resulted
in persistent or significant disability or jeopardized the
2
participant).15 The study relied on the results reported at
the longest follow-up for outcomes. Meta-analyses of pri-
mary and secondary outcomes were performed with sub-
group analysis based on the type of vasodilator and acute
heart failure phenotype, including acute decompensated
heart failure, pulmonary edema, or a mixed population of
acute heart failure.
DATA COLLECTION AND RISK OF BIAS
Two authors (J.D.L., J.G.) independently extracted data
using standardized forms (provided in the Supplementary
Appendix). Further details on data collection are provided
in the study protocol, available with the full text of this
article at evidence.nejm.org. The assessment of risk of
bias in each trial was performed by two independent
investigators (J.D.L., K.C.M., or A.S.O.O.). To resolve any
discrepancies, online meetings were organized for discus-
sion. Authors were contacted for any additional data not
sufficiently reported in the publication. The bias risk
assessment conducted in this study used the Cochrane
Risk of Bias tool, version 2 (RoB 2), as recommended in
the Cochrane Handbook of Systematic Reviews of Interven-
tions.16 A trial was classified as overall “high risk of bias”
if at least one of the bias domains was classified as
“unclear” or “high risk” of bias.
DATA ANALYSIS AND TSA
The statistical software Stata version 17 (StataCorp) was
used for all meta-analysis. For dichotomous outcomes,
risk ratios with 95% confidence intervals (CIs) were calcu-
lated. For continuous outcomes, the mean differences
with 95% CIs were calculated. Both fixed-effects and
random-effects meta-analyses were conducted to evaluate
the primary and secondary outcomes, with a P value of 0.05
as the threshold for statistical significance of the primary out-
come. No multiplicity adjustments for the secondary and
exploratory end points were defined. Therefore, only point
estimates and 95% CIs are provided. The CIs have not been
adjusted for multiple comparisons and should not be used to
infer definitive treatment effects. Before analysis, it was
planned that the most conservative result would be reported
primarily, and the less conservative results would be consid-
ered a sensitivity analysis.17 To ensure consistency in report-
ing, we opted during the peer review process to primarily
report the random-effects meta-analysis results, with the
fixed-effects results included in the supplementary materials.
To control the risks of type I and II errors and to estimate
the required information size, TSA was used on the
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primary and secondary outcomes. A detailed description
of TSA is provided in the TSA manual.13 TSA software ver-
sion 0.9.5.10 Beta from The Copenhagen Trial Unit was
used for analyses.18 Possible heterogeneity was investi-
gated by calculating inconsistency (I2) and by performing
subgroup analyses.
Results
The initial database search identified 26,809 publications.
After review, 126 publications were deemed potentially
relevant. After further examination, 80 publications were
excluded, resulting in the inclusion of 46 randomized clin-
ical trials (RCTs) that enrolled 28,374 patients. A visual
representation of the study selection process is provided in
the PRISMA flow diagram (Fig. 1). The included RCTs inves-
tigated several vasodilators; nesiritide was studied in 14
trials,19-32 serelaxin in 7 trials,33-38 nitrates in 6 trials,8-10,39-42
and tezosentan in 5 trials.43-47 The remaining trials exam-
ined other forms of vasodilators such as enalaprilat,48,49
clevidipine,50 ularitide,51-53 urapidil,54,55 enoximone,56
nicorandil,57,58 TRV027 (an angiotensin receptor blocker),59
cimlanod,60 and a recombinant human atrial natriuretic
peptide.61
Most of the trials compared the respective vasodilator
against placebo or usual care, whereas nine trials used
other pharmacologic agents as comparators (two trials
used furosemide,8,39 four trials used nitroglycerin,20,49,54,55
two used dobutamine,25,29 and one used captopril and
prazosin).41 All patients were hospitalized, and three dif-
ferent phenotypes of acute heart failure were investigated.
Nine trials focused on pulmonary edema,8,39-41,44,48-50,56
24 trials focused on acute decompensated heart
failure,19-29,31,32,34,45,47,51,52,55,57-61 and 14 focused on mixed
acute heart failure phenotypes.9,10,30,33,35-38,42,43,46,53,54
Table 1 presents the trial characteristics. The trials included
in this analysis had a mean participant age range of
46 years41 to 87 years.10,30 The proportion of male partici-
pants varied from 30%37 to 91%.30 In addition, the preva-
lence of preexisting heart failure among patients ranged
from 14%37 to 100%.32,46-48,51,54 Detailed baseline charac-
teristics of the included trials are presented in Table S1.
ALL-CAUSE MORTALITY
Data on all-cause mortality were reported in 40 trials,
comprising 14,392 (52%) participants in the intervention
3
 Vasodilators in Acute Heart Failure
26,809 Studies from databases/registers
Identif ication
26,809 Citation searching
25,963 Studies screened
126 Studies sought for retrieval
Screening
126 Studies assessed for eligibility
Included
46 Studies included in review
Figure 1. Study Selection Process.
Preferred Reporting Items for Systematic Reviews and Meta-Analysis flow diagram.
group and 13,325 (48%) participants in the control group.
Among these participants, 1453 individuals (10%) in the
intervention group and 1455 individuals (10%) in the con-
trol group died. The remaining six trials23,27,28,49,55,57 did
not provide information on mortality; the trialists were
contacted via email but did not respond.
Meta-analysis of all-cause mortality showed no evidence
of a difference when comparing vasodilators with control
in acute heart failure (risk ratio, 0.95; 95% CI, 0.87 to
1.04; I2=9.51%; P=0.26) (Fig. 2 and Fig. S1). TSA confirmed
no difference in all-cause mortality between patients who
received vasodilators compared with those who received
control or placebo and indicated that there was enough
information to reject that vasodilator therapy reduces all-
cause mortality (Fig. 3). We found no indication of interac-
tion when comparing trials with different vasodilator
agents (Figs. S2 and S3). TSA for the vasodilator nesiritide
showed that there was enough information to reject that
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846 References removed
846 Duplicates
25,837 Studies excluded
0 Studies not retrieved
80 Studies excluded
5 Substudy
28 Duplicate
9 Not available
3 Wrong outcomes
1 Wrong comparator
16 Wrong intervention
13 Wrong study design
5 Wrong patient population
this vasodilator reduces all-cause mortality. TSA of the
vasodilator serelaxin showed that there was enough infor-
mation to confirm that serelaxin had a potential beneficial
effect on all-cause mortality. However, TSA for nitrates,
tezosentan, ularitide, and renin–angiotensin–aldosterone
inhibitors showed that there was not enough information
to reject or confirm that these vasodilators reduce all-cause
mortality (Figs. S4 to S9).
Among the 24 trials that focused on the application of
vasodilator therapy in acute decompensated heart failure,
information regarding all-cause mortality was available in
20 trials. Meta-analysis of these 20 trials showed no evi-
dence of a difference in the overall mortality rate (risk
ratio, 0.95; 95% CI, 0.86 to 1.05; I2=0%). Meta-analysis
of the eight trials that encompassed patients with pulmo-
nary edema showed no evidence of a difference in vasodi-
lator therapy on all-cause mortality among this phenotype
(risk ratio, 0.87; 95% CI, 0.41 to 1.88; I2=0%). In the case
4
 Table 1. Trial Characteristics.*

No. Time to Max Follow-

Randomized Intervention Up for Total No.
Author Year Trial Design Type of AHF Vasodilator Control to Treatment (h) Mortality of Deaths
56
Flammang et al. 1990 Open-label, parallel group RCT Pulmonary edema Enoximone SOC therapy 44 48 hours 3

NEJM EVIDENCE
Annane et al.48 1996 Double-blinded, placebo-controlled RCT Pulmonary edema Enalaprilat Placebo 20 12–24 8 hours 3
8
Cotter et al. 1998 Open-label, active-control group RCT Pulmonary edema Isosorbide dinitrate Furosemide 110 12 hours 4
Beltrame et al.39 1998 Open-label, active-control group RCT Pulmonary edema Nitroglycerin Furosemide 69 24 hours 3
Adigun et al.41 1998 Single-blinded, active-control group RCT Pulmonary edema Hydralazine- Captopril- 17 24 hours 1
isosorbide dinitrate prazosin
Hirschl et al.49 1999 Open-label, active-control group RCT Pulmonary edema Enalaprilat Nitroglycerin 46 24 hours
Mills et al.32 1999 Double-blinded, placebo-controlled RCT Decompensated Nesiritide Placebo 55 15 days 2
Sharon et al.40 2000 Open-label, active-control group RCT Pulmonary edema Isosorbide dinitrate BiPAP and 40 24 hours 2
conventional
treatment
Colucci et al., 2000 Double-blinded, placebo-controlled, dose- Decompensated Nesiritide Placebo 84 6
efficacy trial21† ranging RCT
Colucci et al., 2000 Open-label, parallel-group, dose-ranging RCT Decompensated Nesiritide SOC therapy 202 21 days 12
comparative
trial21†
Silver et al.29 2002 Open-label, active-control group RCT Decompensated Nesiritide dobutamine 158 180 days 42
VMAC19 2002 Double-blinded, placebo-controlled RCT Decompensated Nesiritide Placebo 346 180 days 79
Burger et al.25 2002 Open-label, active-control group, Decompensated Nesiritide Dobutamine 255 14 days 4
dose-ranging RCT
O’Connor et al.45 2003 Double-blinded, placebo-controlled RCT Decompensated Tezosentan Placebo 192 30 days 6
Kaluski et al.44 2003 Double-blinded, placebo-controlled RCT Pulmonary edema Tezosentan Placebo 84 30 days 7
Torre-Amione 2003 Double-blinded, placebo-controlled RCT Decompensated Tezosentan Placebo 195 180 days 36

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et al.47
Cotter et al.46 2004 Double-blinded, placebo-controlled RCT Mixed Tezosentan Placebo 53 30 days 1

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Peacock et al.27 2005 Double-blinded, placebo-controlled RCT Decompensated Nesiritide Placebo 250

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Mitrovic et al.51 2005 Double-blinded, placebo-controlled RCT Decompensated Urodilatin Placebo 12 20 days 0
52
Mitrovic et al. 2006 Double-blinded, placebo-controlled RCT Decompensated Ularitide Placebo 108 30 days 5
McMurray et al.43 2007 Double-blinded, placebo-controlled RCT Mixed Tezosentan Placebo 1466 11 180 days 205
Witteles et al.24 2007 Double-blinded, placebo-controlled RCT Decompensated Nesiritide Placebo 75 30 days 6

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Owan et al.23 2008 Open-label, parallel-group RCT Decompensated Nesiritide SOC therapy 75 5
Miller et al.26 2008 Double-blinded, placebo-controlled RCT Decompensated Nesiritide Placebo 101 90 days 1
Sakr et al.28 2008 Open-label, parallel group RCT Decompensated Nesiritide SOC therapy 34
Teerlink et al.37 2009 Double-blinded, placebo-controlled, Mixed Serelaxin Placebo 234 8 180 days 14
dose-ranging, RCT
Chow et al.20 2011 Open-label, active-control group RCT Decompensated Nesiritide Nitroglycerin 89 14 180 days 14
O’Connor et al.22 2011 Double-blinded, placebo-controlled RCT Decompensated Nesiritide Placebo 7141 16 30 days 267

5
(continued)
 Table 1. (cont.)

No. Time to Max Follow-

Randomized Intervention Up for Total No.
Author Year Trial Design Type of AHF Vasodilator Control to Treatment (h) Mortality of Deaths
30
Fu et al. 2012 RCT, placebo controlled Mixed Nesiritide SOC therapy 140 60 days 23

NEJM EVIDENCE
Chen et al.31 2013 Double-blinded, placebo-controlled RCT Decompensated Nesiritide Placebo 238 11 180 days 48
Teerlink et al.35 2013 Double-blinded, placebo-controlled RCT Mixed Serelaxin Placebo 1161 8 180 days 105
Ponikowski et al.33 2014 Double-blinded, placebo-controlled RCT Mixed Serelaxin Placebo 71 28 30 days 4
50
Peacock et al. 2014 Open-label, parallel-group RCT Pulmonary edema Clevidipine SOC therapy 104 3 30 days 5
Sato et al.38 2015 Double-blinded, placebo-controlled RCT Mixed Serelaxin Placebo 31 60 days 0†
Yang et al.55 2016 Open-label, active-control group RCT Decompensated Urapidil Nitroglycerin 120 180 days
Wang et al.61 2016 Double-blinded, placebo-controlled RCT Decompensated Recombinant Placebo 477 30 days 14
human atrial
natriuretic peptide
Harada et al.58 2017 RCT, placebo controlled Decompensated Nicorandil Placebo 123 1 60 days 6
Packer et al.53 2017 Double-blinded, placebo-controlled RCT Mixed Ularitide Placebo 2157 6 180 days 841
Pang et al.59 2017 Double-blinded, placebo controlled RCT Decompensated TRV027 Placebo 309 6 180 days 41
(angiotensin
receptor blocker)
Yang et al.54 2017 Open-label, active-control group RCT Mixed Urapidil Nitroglycerin 180 30 days 3
Sato et al.42‡ 2018 Double-blinded, placebo-controlled RCT Mixed Serelaxin Placebo 870 9 180 days 74
Metra et al.34 2019 Double-blinded, placebo-controlled RCT Decompensated Serelaxin Placebo 6600 7 180 days 755
Maggioni et al.36 2019 Open-label, blinded-endpoint, parallel-group Mixed Serelaxin SOC therapy 2666 8 30 days 95
RCT
Kozhuharov et al.9 2019 Open-label, blinded end point, parallel group Mixed Vasodilators§ SOC therapy 788 180 days 116
RCT

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Freund et al.10 2020 Open-label, parallel group, cluster RCT Mixed Nitrates¶ SOC therapy 503 6 30 days 45
Felker et al.60 2021 Double-blinded, placebo-controlled RCT Decompensated Cimlanod Placebo 97 12 180 days 10
Zhang et al.57 2022 RCT Decompensated Nicorandil SOC therapy 184 90 days

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* AHF denotes acute heart failure; BiPAP, bilevel positive airway pressure; RCT, randomized clinical trial; SOC, standard of care; and VMAC, Vasodilatation in the Management of Acute CHF.
† One publication encompassing two distinct trials.
‡ This was the RELAX-AHF-ASIA (Efficacy, Safety and Tolerability of Serelaxin When Added to Standard Therapy in AHF) study. The article was not published, and the study was terminated early.
Results were published on ClinicalTrials.gov.
§ Early intensive and sustained vasodilation combining individualized doses of sublingual and transdermal nitrates, low-dose oral hydralazine for 48 hours, and rapid up-titration of angiotensin-

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converting enzyme inhibitors, angiotensin receptor blockers, or sacubitril and valsartan.
¶ The intervention in this trial was the implementation of a guideline-recommended care bundle for the early management of acute heart failure in the emergency department, which included
specific treatment protocols such as the administration of diuretics and intravenous nitrates, as well as the identification and management of precipitating factors.

6
 All-Cause Mortality
Vasodilation Control Risk Ratio Weight
Trial Yes No Yes No with 95% CI (%)
Flammang, 1990 1 21 2 20 0.50 (0.05–5.12) 0.14
Annane, 1996 1 10 2 7 0.41 (0.04–3.82) 0.15
Cotter, 1998 1 55 3 51 0.32 (0.03–3.00) 0.15
Adigun, 1998 1 7 0 9 3.33 (0.15–71.90) 0.08
Beltrame, 1998 1 36 2 30 0.43 (0.04–4.55) 0.13
Mills, 1999 1 25 1 28 1.12 (0.07–16.95) 0.10
Colucci, 2000 (efficacy trial) 3 39 3 39 1.00 (0.21–4.67) 0.31
Colucci, 2000 (comparative trial) 6 94 6 96 1.02 (0.34–3.06) 0.61
Sharon, 2000 0 20 2 18 0.20 (0.01–3.92) 0.08
Silver, 2002 24 76 18 40 0.77 (0.46–1.30) 2.57
Burger, 2002 2 82 2 84 1.02 (0.15–7.10) 0.20
VMAC, 2002 51 153 28 114 1.27 (0.84–1.91) 3.96
O’Conner, 2003 3 94 3 92 0.98 (0.20–4.73) 0.30
Torre-Amione, 2003 20 79 16 78 1.19 (0.66–2.15) 2.00
Kaluski, 2003 5 37 2 40 2.50 (0.51–12.17) 0.30
Cotter, 2004 1 26 0 25 2.79 (0.12–65.38) 0.08
Mitrovic, 2005 0 6 0 6 1.00 (0.02–43.70) 0.05
Mitrovic, 2006 0 55 5 48 0.09 (0.00–1.55) 0.09
Witteles, 2007 4 35 2 34 1.85 (0.36–9.48) 0.28
McMurray, 2007 104 626 101 617 1.01 (0.79–1.31) 8.64
Miller, 2008 0 53 1 47 0.30 (0.01–7.25) 0.07
Teerlink, 2009 (PRE-RELAX-AHF) 5 45 9 53 0.69 (0.25–1.93) 0.69
O’Connor, 2011 126 3438 141 3436 0.90 (0.71–1.14) 9.62
Chow, 2011 7 38 7 37 0.98 (0.37–2.56) 0.79
Fu, 2012 12 58 11 59 1.09 (0.52–2.30) 1.29
Chen, 2013 23 96 25 94 0.92 (0.55–1.53) 2.69
Teerlink, 2013 41 540 64 516 0.64 (0.44–0.93) 4.60
Ponikowski, 2014 2 32 2 35 1.09 (0.16–7.30) 0.21
Peacock, 2014 3 48 2 51 1.56 (0.27–8.95) 0.24
Sato (RELAX-AHF-JAPAN), 2015 0 15 0 15 1.00 (0.02–47.38) 0.05
Wang, 2016 11 347 3 115 1.21 (0.34–4.26) 0.47
Harada, 2017 2 47 4 48 0.53 (0.10–2.77) 0.27
Pang, 2017 17 108 24 159 1.04 (0.58–1.85) 2.10
Packer, 2017 443 645 398 671 1.09 (0.98–1.22) 22.36
Yang, 2017 0 89 3 88 0.15 (0.01–2.79) 0.09
Sato (RELAX-AHF-ASIA), 2018 33 404 41 392 0.80 (0.51–1.24) 3.49
Metra, 2019 367 2931 388 2914 0.95 (0.83–1.08) 18.57
Maggioni, 2019 57 1714 38 857 0.76 (0.51–1.13) 4.06
Kozhuharov et al. (GALACTIC), 2019 55 327 61 338 0.94 (0.67–1.32) 5.53
Freund et al. (ELISABETH), 2020 16 183 29 270 0.83 (0.46–1.49) 2.07
Felker, 2021 4 45 6 42 0.65 (0.20–2.17) 0.51

Overall 0.95 (0.87–1.04)

Heterogeneity: W2=0.01, I2=9.51%, H2=1.11
Test of Ti=Tj: Q(40)=28.70
Test of T=0: z=−1.13, P=0.26
1/128 1/8 2 32
Favors Vasodilation Favors Control
Random-effects REML model
Sorted by: YearPublished

Figure 2. Random-Effects Meta-Analysis and Forest Plot of All-Cause Mortality.

Meta-analysis comparing vasodilators and control for all-cause mortality. The meta-analysis showed no evidence of a difference (risk
ratio, 0.95; 95% confidence interval, 0.87 to 1.04; I2=9.51%; P=0.26). CI denotes confidence interval; RELAX-AHF-ASIA/JAPAN, Efficacy,
Safety and Tolerability of Serelaxin When Added to Standard Therapy in AHF; REML, restricted maximum likelihood; and VMAC,
Vasodilatation in the Management of Acute CHF.

of mixed phenotypes of acute heart failure, 13 trials pro- 95% CI, 0.90 to 1.07; I2=17.40%). Visual inspection of the
vided mortality information. Meta-analysis of these 13 forest plot and test of interaction did not seem to show
trials revealed no evidence of a difference in vasodilators a difference when comparing the effect of vasodilator therapy
versus control on the mortality rate (risk ratio, 0.98; on the different acute heart failure phenotypes (Figs. S10 and

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 5% Symmetric O’Brien-Fleming is a two-sided graph
Cumulative
z Score Monitoring boundaries
5% symmetric O’Brien-Fleming = 11,254
8

7
Favours Vasodilators

5
4
3 Conventional
boundaries (P=0.05) Futility boundaries (inner wedge area)
2
1
z Curve

–1
–2
Favours Control

–3
–4
–5

–6

–7

–8
(1998)Adigun

(2000)Sharon

(2011)Fu

(2013)Chen

(2020)Freund
(2003)Kaluski

(2013)Ponikowski

(2019)Maggioni
(1999)Mills

(2007)Witteles

(2017)Harada

(2019)Metra
(2018)Sato
(1996)Annane

(1998)Beltrame

(2000)Colucci, Comparative

(2003)Torre-Amione
(2002)VMAC
(1990)Flammang

5% symmetric O’Brien-Fleming

(2016)Wang

(2017)Pang
(2017)Yang

(2019)Kozhuharov
(2006)Mitrovic
(2000)Colucci, Efficacy

(2007)McMurray

(2009)Teerlink

(2013)Teerlink
(2014)Peacock
(2011)Chow
(1988)Cotter

(2002)Burger
(2002)Silver

(2003)O’Connor

(2004)Cotter

(2008)Miller

(2011)O’connor

(2017)Packer

(2021)Felker
Figure 3. Trial Sequential Analysis for All-Cause Mortality.
Trial sequential analysis graph of vasodilators versus control on the outcome of all-cause mortality using random-effects meta-analysis.
The x axis shows participant numbers for each trial, and the y axis represents the z score. Positive z scores favor vasodilators, whereas
negative z scores favor the control group. The blue z curve represents the cumulative z score as each randomized clinical trial is
included. The red boundaries represent the conventional threshold (P=0.05). The green boundaries represent monitoring, and the green
boundaries within the conventional boundaries (the green triangle) represent futility boundaries (inner wedge area). No significant
difference in all-cause mortality exists between the two groups. The z curve falls within the futility boundaries (inner wedge area),
indicating that further studies are unlikely to alter the no-effect results. The vertical green line represents the required information size
(11,254 participants).

S11). TSA for acute decompensated heart failure and mixed
phenotypes of acute heart failure showed that there was
enough information to reject that vasodilator therapy
reduces all-cause mortality. TSA for the patient population
with pulmonary edema could not be conducted because of
inadequate power (too few patients) (Figs. S12 to 14).
SECONDARY OUTCOMES
The 22 trials that provided data on SAEs8,19-22,24,26,28,31,
33-38,43,45,46,50,52,59,61
revealed no difference (risk ratio, 1.01;
95% CI, 0.97 to 1.05; I2=0.94%) between patients adminis-
tered vasodilators and those given control or placebo treat-
ments (Figs. S15 and S16). TSA found that there was enough
information to reject that vasodilator therapy reduces the risk
of SAEs (Fig. S17). A test for interaction did not seem to show
evidence of a difference when comparing trials with different
vasodilator agents (Figs. S18 and S19) and trials with differ-
ent phenotypes of acute heart failure (Figs. S20 and S21).
Vasodilator use was associated with a reduced need
for tracheal intubation in the meta-analysis of nine

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trials8,24,28,34,37,40,42,44,50 that provided sufficient data
(risk ratio, 0.54; 95% CI, 0.30 to 0.99; I2=51.96%) (Fig. 4
and Fig. S22). However, TSA revealed that there was not
enough information to confirm that vasodilators reduce the
risk of tracheal intubation (Fig. S23). Trials using different
vasodilator agents were associated with different effects on
intubation (Figs. S24 and S25). Notably, among the sub-
groups, the use of nitric oxide donors was associated with a
reduced need for intubation (risk ratio, 0.29; 95% CI, 0.16
to 0.52; I2=0%) (Fig. S24). Furthermore, when exploring
the various phenotypes of acute heart failure, meta-analysis
and subgroup analysis suggested differences among the
three groups in the fixed-effects meta-analysis. However,
these differences were not evident in the random-effects
analysis (Figs. S26 and S27).
Length of hospital stay did not exhibit variation between
vasodilation and control (mean difference, –0.10; 95% CI,
–0.28 to 0.08; I2=69.84%) (Figs. S28 and S29). However,
trials with different vasodilators were associated with
varying effects on length of hospital stay (Figs. S30
and 31).
REDUCTION OF BLOOD PRESSURE BY
VASODILATORS
Meta-analysis incorporating all RCTs that provided data on
systolic blood pressure showed an association between lower
systolic blood pressure and treatment with vasodilators
(mean difference, –6.26 mm Hg; 95% CI, –8.06 to –4.46;
I2=90.51%) (Figs. S32 and S33). Trials using different vaso-
dilators were associated with different effects of blood
pressure lowering (Figs. S34 and S35). Among the three
phenotypes of acute heart failure, an association between
blood pressure lowering and vasodilators was observed in
the fixed-effects meta-analysis, but this difference was not
evident in the random-effects analysis (Figs. S36 and S37).
There was no evidence of a correlation between systolic
blood pressure at baseline and rates of mortality or intuba-
tion (Figs. S40 and S41).
TIME FROM ADMISSION TO INTERVENTION
Eighteen trials provided information on time from admis-
sion to intervention. Time to intervention exhibited substan-
tial heterogeneity across these trials; times ranged from
1 hour in the trial conducted by Harada et al.58 to 28 hours
in the trial conducted by Ponikowski et al.33 (Fig. S38).
There was no link between the time to intervention and the
incidence of mortality (Fig. S42).
RISK OF BIAS
Our bias evaluation of the individual trials is presented in
Figure 5. Overall, our assessment was that only 7 of the 40
included trials had a low potential risk of bias in all
domains, whereas 5 trials displayed some concerns, and
the remaining 28 trials was evaluated as having a high risk
of bias. Notably, five of the seven trials that were assessed
as potential low risk of bias in all domains were the most
recent trials.9,10,34,36,53 Trials that were evaluated as

Tracheal Intubations
Vasodilation Control Risk Ratio Weight
Trial Yes No Yes No with 95% CI (%)
Cotter, 1998 7 49 21 33 0.32 (0.15–0.69) 20.53
Sharon, 2000 4 16 16 4 0.25 (0.10–0.62) 18.20
Kaluski, 2003 4 38 1 41 4.00 (0.47–34.31) 6.21
Witteles, 2007 0 39 1 35 0.31 (0.01–7.34) 3.20
Sakr, 2008 3 14 5 12 0.60 (0.17–2.12) 13.04
Teerlink, 2009 (PRE-RELAX-AHF) 0 50 0 62 1.24 (0.02–61.18) 2.19
Peacock, 2014 0 51 1 52 0.35 (0.01–8.31) 3.19
Sato (RELAX-AHF-ASIA), 2018 0 432 2 424 0.20 (0.01–4.10) 3.46
Metra, 2019 170 3128 182 3120 0.94 (0.76–1.15) 29.97

Overall 0.54 (0.30–0.99)

Heterogeneity: W2=0.30, I2=51.96%, H2=2.08
Test of Ti=Tj: Q(8)=17.80
Test of T=0: z=−1.99
1/64 1/8 1 8
Favors Vasodilation Favors Control
Random-effects REML model
Sorted by: YearPublished

Figure 4. Random-Effects Meta-Analysis and Forest Plot of Tracheal Intubation.

Meta-analysis comparing vasodilators and control for the risk of tracheal intubation including all trials providing information on tracheal
intubation (risk ratio, 0.54; 95% CI, 0.30 to 0.99; I2=51.96%). REML indicates restricted maximum likelihood.

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 Trial D1 D2 D3 D4 D5 Overall
Teerlink, 2013 + + + + – – + Low risk
Cotter, 1998 – ! + – ! – ! Some concerns
VMAC, 2002 + – – – – High risk
! !
Teerlink, 2009 + + + ! – –
D1 Randomisation process
Metra, 2019 + + + + + +
D2 Deviations from the intended interventions
Maggioni, 2019 + + + + + +
D3 Missing outcome data
Ponikowski, 2013 + + + – + – D4 Measurement of the outcome
Chow, 2011 ! ! + – ! – D5 Selection of the reported result
Colucci (Efficacy trial), 2000 + + – ! ! –
Colucci (Comparative trial), 2000 + ! – ! ! –
O’connor, 2011 + + + + + +
Witteles, 2007 + + + ! – –
Beltrame, 1998 ! ! – – ! –
Burger, 2002 ! ! – ! ! –
Miller, 2007 + + + – ! –
Annane, 1996 ! ! + – ! –
Peacock, 2014 ! ! + ! ! !
McMurray, 2007 ! + + ! ! !
Packer, 2017 + + + + + +
Flammang, 1990 ! – – – ! –
Pang, 2007 + + + + + +
Kozhuharov, 2019 + + + + + +
Freund, 2020 + + + + + +
Silver, 2002 ! ! + – ! –
Felker, 2021 ! + + – + –
Wang, 2016 + + + ! ! !
Fu, 2011 ! ! – – ! –
Yang, 2017 ! ! + ! ! !
Mitrovic, 2006 + + + – ! –
Torre-Amione, 2003 + + + – ! –
Sharon, 2000 ! ! – – ! –
Harada, 2017 ! ! + – ! –
Chen, 2013 + + + ! + !
Sato, 2015 + + + – + –
Kaluski, 2003 ! + + – ! –
Mills, 1999 ! + + – ! –
O’Connor, 2003 ! + + – + –
Cotter, 2004 ! + – ! ! –
Adigun, 1998 ! ! + – ! –
Hirschl, 1999 ! ! – ! ! –

Figure 5. Risk of Bias in Individual Studies.

Risk of bias summary for included randomized controlled trials for the outcome all-cause mortality. Risk of bias assessment using the
Cochrane Collaboration risk of bias tool, version 2, in trials reporting mortality rates. Green indicates low risk; yellow indicates some
concerns; and red indicates high risk. Seven of the 40 included studies had a low potential risk of bias in all domains, whereas 5 trials
displayed some concerns and 28 trials were evaluated as having a high risk of bias. D1 denotes bias arising from the randomization
process; D2, bias due to deviations from the intended intervention; D3, bias resulting from missing outcome data; D4, bias in
measurement of outcome; and D5, bias in selection of reported results.

having a high risk or with some concerns often lacked the

detailed information necessary for proper evaluation of
the domains. Furthermore, trials that did not publish a
prior study protocol turned out to display a high risk of
bias due to limited information about the domains. The
low probability of publication bias was shown through a
funnel plot (Fig. S39).
Discussion
Vasodilators have been a central part of acute heart failure
treatment for decades. The current systematic review of
these interventions with meta-analysis adhered to the
PRISMA guidelines, used TSA, and included only RCTs.

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We performed a meta-analysis of all published trials of all
different vasodilators and found no evidence of a differ-
ence in the risk of all-cause mortality. Regarding second-
ary end points, the meta-analysis revealed an association
between vasodilator use and reduced intubation rates. No
such association was observed regarding risk of SAEs and
length of hospital stay.
In a systematic review, Farag et al.62 investigated the use
of intravenous nitrates in acute heart failure and found no
beneficial effect on mortality. Similarly, Alexander et al.63
reported that intravenous nitrates, when used in the treat-
ment of acute heart failure in emergency departments and
similar settings, improved short-term symptoms and seemed
safe to administer, but they had no effect on mortality.
Wakai et al.64 uniquely employed the Cochrane Collabora-
tion risk of bias tool65 and found no significant difference
between nitrate vasodilator therapy and alternative inter-
ventions in treating acute heart failure. These reviews all
concluded that there was a lack of data to draw any firm
conclusions regarding the use of vasodilators in acute heart
failure, as the evidence was based on a few low-quality
studies.
The GALACTIC trial9 and the cluster-randomized ELISA-
BETH trial10 have disputed the efficacy of vasodilators in
the treatment of acute heart failure, leading to a down-
grading of vasodilation from Class IIA to Class IIb in the
2021 ESC guidelines.7,10 However, the GALACTIC trial
did not include patients presenting to the emergency
department and had a prolonged time from admission to
randomization (>5 hours). This systematic review high-
lights potential vasodilator trial shortcomings, particularly
delayed randomization, and treatment initiation. We iden-
tified a wide timespan from patient admission to interven-
tion (1 to 28 hours) in the included trials, which may lead
to an underestimation of the potential effect of vasodila-
tors. Because vasodilators are often administered during
emergency treatment at hospital admission, trials enroll-
ing patients several hours later may risk only including
patients who have been stabilized, which is not reflective
of typical clinical practice and may restrict the applicabil-
ity of the results. To avoid bias due to stabilization of
patients before the intervention, future research should
prioritize early intervention that aligns with real-life clini-
cal practice.
We found that vasodilators were associated with reduced
intubation rates. Subgroup analysis revealed a difference
in intubation between patients treated with vasodilators
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and those not treated with vasodilators and that differ-
ences were predominantly driven by trials using nitric
oxide donors. These findings primarily stem from two
trials, those by Cotter et al.8 and Sharon et al.,40 in which
isosorbide dinitrate was used as the vasodilator agent.
However, the trials were conducted with small sample
sizes and were deemed to carry a high risk of bias, which
may limit the generalizability and reliability of the findings.
Consequently, a larger RCT investigating vasodilators and
more interestingly nitric oxide donors is warranted.
Quality of life, planned as a secondary outcome, was
excluded because of insufficient data. However, its impor-
tance in evaluating patient perspective is emphasized.
Vasodilators, believed to offer short-term symptomatic
relief in the acute phase, may reduce symptoms such as
dyspnea at home, an effect not measurable through mor-
tality outcomes. It is more challenging to envisage an
improvement in quality of life after a longer period (e.g.,
180 days postintervention). Although there may be an
impact on pulmonary pressure, this is a speculative consid-
eration. This highlights the need for future research on
quality of life outcomes in acute heart failure treatment.
The meta-analysis noted an association with reduced sys-
tolic blood pressure across the included trials, which is
consistent with the anticipated pharmacologic effects of
vasodilators. Current guidelines for acute heart failure
management advise a cautious reduction in blood pres-
sure,66 but limited evidence supports these strategies.
Vasodilators have varying hemodynamic effects, but all
effectively reduce blood pressure.67 Intravenous vasodila-
tors induce potent vasodilation within minutes of adminis-
tration, leading to potential symptom relief and reduced
congestion.68-72 As a result, vasodilators have been consid-
ered effective for patients with acute heart failure, in
which increased cardiac filling pressure and systemic
blood pressures are markedly elevated.3,7 Timing and type
of vasodilator for various patient populations and acute
heart failure phenotypes should be explored in future
studies.
The assessment of risk of bias for the outcome all-cause
mortality found that only 7 of 40 trials had a potential for
low risk of bias. These trials had mortality as a primary or
secondary outcome, and, as such, the authors provided a
comprehensive description of the methodologies used to
investigate the outcome. In contrast, the remaining trials
were evaluated as having a high risk of bias because
of inadequate information and often missing a study
11
protocol. This finding underscores the significance of well-
designed trials with clearly defined outcomes and method-
ologies to mitigate the risk of bias and improve the validity
of the results.
This systematic review was conducted in strict adherence
to established methodologies, including PRISMA guide-
lines, TSA, comprehensive database searches, and the use
of the Cochrane Collaboration’s tool for assessing the risk
of bias in each trial. Although our conclusions regarding
all-cause mortality are consistent with previous reviews,
the included trials presented notable limitations that chal-
lenge the clarity of our conclusions. These limitations
encompassed a variety of comparators, the presence of a
high risk of bias in certain trials, and the issue of small
sample sizes in others, which could potentially skew
results. Moreover, the range of vasodilators analyzed was
broad, including some that are rarely used in clinical prac-
tice, adding to the complexity of our analysis. Heterogeneity
was further compounded by the studies’ varying inclusion
criteria, specifically the different phenotypic characteriza-
tions of acute heart failure, which contributed to the vari-
ability of our results. All vasodilator drugs across various
phenotypes were included in the primary outcome analysis
due to the similar physiological mode of action of vasodila-
tors. This was supported by individual analysis of each
drug class, and, overall, the different analyses supported
each other with similar findings. Another significant lim-
itation that we encountered was the inconsistency in
follow-up periods across the trials. Such discrepancies,
although not affecting the randomized controlled effects,
pose a considerable challenge to the comparability of the
trials, potentially affecting the synthesis of long-term
outcomes.
In response to these challenges, we conducted extensive
subgroup analyses in an effort to normalize these discrep-
ancies within the collective group of vasodilator drugs.
Despite the analytical adjustments made to accommodate
the varying methodologies and patient groups within the
included studies, our evidence from these analyses sup-
ports the conclusion that vasodilators do not significantly
affect the primary outcome. The use of vasodilators in the
management of acute heart failure therefore presents a
nuanced picture. Although our evidence does not support
a reduction in all-cause mortality with vasodilator therapy,
we did find a potential effect on the rates of tracheal intu-
bation. Vasodilators may thus play a role in improving
respiratory outcomes in patients with acute heart failure.
Further research is necessary to establish this and any
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other clinical benefits, determine the optimal timing and
type of vasodilator for different patient populations and
acute heart failure phenotypes, and address the limitations
observed in previous trials.
Conclusions
In patients with acute heart failure, vasodilators did not
reduce all-cause mortality.
Disclosures
Author disclosures and other supplementary materials are available at
evidence.nejm.org.
The literature search was conducted by Sarah Klingenberg, M.Sc., who specia-
lizes in search strategies. No writing assistance has been received except from
within the author group. The study did not receive funding; however, some of
the authors’ research salary during the work was supported by the following
not-for-profit funds: Danish Cardiovascular Academy, funded by Novo Nor-
disk Foundation grant numbers NNF20SA0067242 and NNF17SA0031406,
and the Danish Heart Foundation.
Author Affiliations
1
Department of Cardiology, Hvidovre Hospital, Copenhagen University
Hospital, Copenhagen
2
Department of Cardiology, Bispebjerg and Frederiksberg Hospital,
Copenhagen University Hospital, Copenhagen
3
Copenhagen Trial Unit, Centre for Clinical Intervention Research,
Copenhagen University Hospital, Rigshospitalet, Copenhagen
4
Department of Regional Health Research, Faculty of Health Sciences,
University of Southern Denmark, Odense, Denmark
5
Department of Clinical Medicine, University of Copenhagen, Copenhagen
6
Department of Cardiology, The Heart Center, Copenhagen University
Hospital Rigshospitalet, Copenhagen
7
Department of Clinical Medicine, University of Southern Denmark,
Odense, Denmark
8
Department of Cardiology, University of Southern Denmark, Odense,
Denmark
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