European Journal of Internal Medicine xxx (xxxx) xxx–xxx

Contents lists available at ScienceDirect

European Journal of Internal Medicine

journal homepage: www.elsevier.com/locate/ejim

Vasodilators in acute heart failure - evidence based on new studies

⁎
André M. Travessa, L. Menezes Falcão
Centro Hospitalar Lisboa Norte, Lisbon, Portugal
Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal

A R T I C L E I N F O A B S T R A C T

Keywords: Acute heart failure (AHF) contributes largely to the worldwide burden of heart failure (HF) and is associated
Acute heart failure with high mortality, poor prognosis and high rehospitalization rate. The pharmacologic therapy of AHF includes
Vasodilators diuretics and vasodilators, which are a keystone when fluid overload and congestion are present. However,
Clinical trials vasodilators are mainly focused on controlling symptoms, and drugs that also improve long-term mortality and
Mortality
morbidity seem to be in high demand. In this review, we summarize the existing evidence on mortality benefits
Outcomes
of IV vasodilators in AHF.
Pharmacologic therapy
There is lack of evidence on the mortality benefits of IV vasodilators in AHF, as well as well-designed and
large-scale trials for some of them. The existing trials on nitrates have conflicting results and are insufficient to
establish definitive conclusions. Other vasodilators, such as enalaprilat, clevidipine, carperitide, and ularitide,
have been evaluated only in a few trials assessing mortality. Levosimendan, nesititide and carperitide are ap-
proved by some regulatory agencies; however, data regarding mortality are also conflicting and large-scale post-
marketing studies would be important. Serelaxin is a recent therapy with a novel mechanism of action and
seemed to be promising; although serelaxin was safe and well tolerated in earlier trials, the results of a larger
phase III trial failed to meet the primary endpoints of reduction in cardiovascular death at day 180 and reduction
of worsening heart failure at day 5.
The absence of definitive mortality benefits and high-quality and large-scale data not allow firm conclusions
to be drawn about the role of IV vasodilators in AHF. Well-designed studies are needed to clarify the role of these
drugs in the long-term outcome of AHF, as well as new therapies entering the clinical investigation.

1. Introduction
Acute heart failure (AHF) is defined as the sudden onset of signs and
symptoms of heart failure (HF) or the worsening of chronic HF mani-
festations, called acutely decompensated HF (ADHF) [1–4]. AHF may
occur without recognized precipitant factors, but frequently one or
more factors, such as infections or non-adherence to therapies, can be
responsible [1].
Patients with AHF require immediate medical assistance and almost
invariably need to be hospitalized [5,6]. In Europe, approximately 5%
of all acute hospital admissions are associated with HF [7]. The median
duration of AHF hospitalization ranges from 4 to 11 days; the in-hos-
pital mortality ranges from 4% to 7% [2–4]. After discharge, the risk of
rehospitalization or death in HF patients is high; the postdischarge
mortality rate up to 3 months ranges from 7% to 11%, and about 25% of
patients are readmitted within 3 months and two thirds within a year
[2,8]. AHF represents a high proportion of HF-related health-care costs
and an increasing major health problem. In fact, HF total cost is
expected to increase from $31 billion in 2012 to $70 billion in the year
2030 in the United States (US) [9]. This equals approximately $244 for
every US adult [10].
Intravenous (IV) loop diuretics are the mainstay in the AHF therapy
[11]. Moreover, an IV vasodilator may also be used to decrease pul-
monary edema, particularly in cases with persistent hypertension or
manifestations despite administration of high doses of diuretics [12].
The ACCF/AHA guidelines suggest to consider the use of IV vaso-
dilators as an adjuvant therapy to diuretics in patients with AHF, with
the aim of relief of dyspnea [13,14]. The 2016 ESC guidelines suggest
that IV vasodilators may be considered for improvement of symptoms
in AHF patients with systolic blood pressure (SBP) above 90 mmHg and
no symptoms of hypotension (Table 1) [1]. The two guidelines do not
discriminate between nitroglycerin, nitroprusside, nesiritide and, in the
ESC guidelines, isosorbide dinitrate (ISDN) [1,13,14]. Most of the data
for these recommendations are provided from studies evaluating ne-
siritide; evidence on nitrates is limited to a few small, single-centre
trials [1,13]. Although no IV vasodilators have been approved in the

⁎
Corresponding author at: Centro Hospitalar Lisboa Norte, Av. Prof. Egas Moniz, 1649-035 Lisboa, Portugal.
E-mail address: luis.falcao@chln.min-saude.pt (L. Menezes Falcão).

https://doi.org/10.1016/j.ejim.2018.02.020
Received 3 September 2017; Received in revised form 4 February 2018; Accepted 21 February 2018
0953-6205/ © 2018 Published by Elsevier B.V. on behalf of European Federation of Internal Medicine.

Please cite this article as: Travessa, A.M., European Journal of Internal Medicine (2018), https://doi.org/10.1016/j.ejim.2018.02.020
A.M. Travessa, L. Menezes Falcão European Journal of Internal Medicine xxx (xxxx) xxx–xxx

Table 1

functional status, and changes in markers of renal

Hospital length of stay, and in-hospital mortality
Clinical indications of IV vasodilators [1,13,14].

Composite of all-cause mortality and cardiac

Change in symptoms of HF, change in SBP,
AHF

ESC guidelines
• IV vasodilators should be considered for symptomatic relief in AHF with
SBP > 90 mmHg (and without symptomatic hypotension);
•

Readmission, and mortality

In patients with hypertensive AHF, IV vasodilators should be considered as initial
therapy to improve symptoms and reduce congestion.

Secondary endpoints
ACCF/AHA guidelines
• If symptomatic hypotension is absent, intravenous nitroglycerin, nitroprusside, or
nesiritide may be considered an adjuvant to diuretic therapy for relief of dyspnea
in patients admitted with ADHF.

transplant
function
Other indications
• Hypertensive emergencies, angina/symptomatic coronary disease, hypertension
following coronary bypass.

ventilation, and development of myocardial

Composite of all-cause mortality and ADHF

All-cause mortality, cardiac transplant, and

ADHD, acutely decompensated heart failure; AHF, acute heart failure, IV, intravenous;

Death in hospital, need for mechanical

All-cause death or re-admission for HF

SBP, systolic blood pressure.

field of AHF since nesiritide in 2001 [15], some compounds have been
evaluated in recent clinical trials.

first readmission for HF

In this paper we review the current role of IV nitrates and other
traditional vasodilators for the treatment of AHF, as well as looking

Primary endpoints
beyond the use of nesiritide and novel compounds under investigation,

Minimum SBP
particularly focusing on mortality outcomes. A systematic search was

readmission

infarction
performed in Pubmed from inception until August 2017 using the
keyword heart failure and one of the following: nitrovasodilators, ni-
troglycerin, isosorbide mononitrate, isosorbide dinitrate, sodium ni-
troprusside (SNP), levosimendan, enalaprilat, clevidipine, serelaxin,

Isosorbide dinitrate (56) vs. furosemide

Hydralazine/isosorbide dinitrate (68)

diuretics only (127) vs. nitrates only
RLX030, cinaciguat, nesiritide, carperitide, ularitide, TRV027, and ni-
Interventions (number of patients)

No diuretics/no nitrates (257) vs.

Sodium nitroprusside (78) vs. no

corandil. The reference lists from identified articles were searched to

Isosorbide dinitrate (25) vs. no

identify any additional studies that may have been missed during the

sodium nitroprusside (97)

isosorbide dinitrate (111)
process, and the ClinicalTrials.gov database was searched using the
above keywords to identify any finished but not yet published trials, as
well as any trials that were still ongoing. We considered articles and

vs. placebo (65)

entrances reporting trials whose results included mortality outcomes,
and critically reviewed all of them.

ADHF, acutely decompensated heart failure; HF, heart failure; IV, intravenous; SBP, systolic blood pressure.
(46)

(54)

2. Nitrovasodilators

As a class, IV nitrovasodilators provide a source of nitric oxide (NO).

Number of

NO binds to soluble guanylate cyclase (GC), and consequently generate

patients

cyclic GMP (cGMP) that leads to vasodilatation [16].

430

110

136

133

175
Summary of most important trials evaluating IV nitrovasodilators in the field of AHF.

There is a large experience in the use of nitrovasodilators in clinical

practice and some small retrospective studies support it [17]. However,
randomized double-blind trial

as shown below, nitrovasodilators have been evaluated in surprisingly

Retrospective cohort study

few large, well-designed trials and high-quality data are lacking. Of the
Observational case series

Observational case series

Prospective, multicentre,
Prospective, randomized

known trials, only a few were head-to-head comparisons of two vaso-

dilators or similar agents, and randomized, controlled trials or even
controlled trial

well-controlled observational studies are lacking, limiting conclusions

Characteristics

of comparative efficacy. The absence of symptomatic, hemodynamic

and long-term benefits and the absence of quality data to support firm
conclusions were the findings of a recent meta-analysis [18]. The most
important trials evaluating the use of IV nitrovasodilators for AHF are
Sodium nitroprusside

summarized in Table 2.
Isosorbide dinitrate

Isosorbide dinitrate

Isosorbide dinitrate
IV nitrovasodilator

Nitroglycerin

2.1. Nitroglycerin

IV nitroglycerin is a nitrovasodilator that was approved by the FDA

for control of manifestations of HF in patients with myocardial infarc-
Cotter et al. (1998)

tion (MI) and also for treatment of angina pectoris refractory to sub-
Aziz et al. (1995)

(2011) [29]

(2008) [33]
BA-HEF (2016)

lingual nitroglycerin and beta-blockers [19]. Some clinical trials eval-

Mullens et al.
Freund et al.

uated the benefit of IV nitroglycerin in the field of AHF [20,21], but

Trial (year)

[22]

[28]

[30]

only one assessed its effect on mortality. In this retrospective study

Table 2

[22], 430 consecutive patients with ADHF were randomized to receive

neither diuretics nor nitroglycerin (group A), diuretics only (group B),

2
A.M. Travessa, L. Menezes Falcão
or both diuretics and nitroglycerin (group C). The primary endpoint
was a composite of all-cause mortality and AHF readmission; it was
observed in 56% of patients in group A, 53% of patients in group B, and
48% of patients in group C (p > 0.05). Readmission at 30 days oc-
curred in 13% of patients in group A, 14% of patients in group B, and
13% of patients in group C (p > 0.05). Survival at 24 months was
higher in group C (87%) than in groups A (79%) and B (82%)
(p = 0.002).
Although some clinical trials showed improved clinical outcomes in
patients with AHF treated with nitroglycerin [23], no well-conducted
randomized, double-blinded trials were or are being performed, as is
apparent in Clinicaltrials.gov (accessed May 30, 2017), and trials on
mortality are lacking.
2.2. Isosorbide mononitrate
Isosorbide mononitrate is infrequently used in the field of AHF. One
trial [24] suggested beneficial hemodynamic and short-term clinical
effects of isosorbide mononitrate in AHF patients, but a large study
evaluating its short- and, in particular, long-term benefits is lacking.
Moreover, the remaining existing trials on isosorbide mononitrate for
AHF are restricted to cases caused by MI [25–27]. No recent trials or
trials on mortality in AHF not due to MI were found.
2.3. Isosorbide dinitrate
ISDN was approved by the FDA for the prevention of angina pectoris
in patients with coronary artery disease. Only a few trials evaluated
ISDN in the field of AHF.
A randomized trial compared high-dose ISDN plus low-dose fur-
osemide (group A, 52 patients) and high-dose furosemide plus low-dose
ISDN (group B, 52 patients) in severe cardiogenic pulmonary edema.
The main endpoints were death, need for mechanical ventilation, and
MI. One patient in group A (1.9%) and three in group B (5.8%) died,
which was not statically significant (p = 0.61) [28].
A single-center retrospective analysis compared ISDN in bolus
(group B, 25 patients) and standard of care (group O, 111 patients) in
elderly patients with AHF. This trial found a higher rate of intensive
care unit (ICU) admission in group B compared with that in group O
(28% [7/25] vs. 11% [12/111]; p = 0.04), but no significant difference
in in-hospital mortality (4% [1/25] in group B vs. 10% [11/111] in
group O; p = 0.3) or median length of stay (14 days in group B vs.
11 days in group O; p = 0.2) [29].
More recently, in the prospective, placebo-controlled, randomized
BA-HEF study [30], 147 patients received 50 mg hydralazine/20 mg
ISDN (n = 68) or matching placebo (n = 65) for 24 weeks followed by
open label ISDN for all patients. Fourteen patients (20.6%) in the hy-
dralazine/ISDN arm died or had a HF readmission by week 24 as
compared with 12 (18.5%) in the placebo arm (p = 0.90); however, by
day 60, 6 (8.8%) and 11 patients (16.9%), respectively, had died or
been hospitalized for HF, which was statistically significant
(p = 0.0268) and represents an early potential benefit. In addition, 9
patients in each treatment group died by week 24 (13.2% in the hy-
dralazine/ISDN group vs. 13.8% in the placebo group), and there was a
trend to benefit on cardiovascular mortality at 24 weeks (5 patients
[7.4%] vs. 9 patients [13.8%], respectively; p = 0.22).
2.4. Sodium nitroprusside
Two trials demonstrated hemodynamic and acute clinical benefits of
SNP in patients with AHF after MI [31,32]. However, no significant
difference was found in all-cause mortality after 1 year in the first trial
(28% [7/25] in the SNP vs. 36% [9/25] in the furosemide group;
p = not significant) [31]. Similarly, the mortality rates at 21 days
(10.4% [42/405] in the placebo group and 11.5% [47/407] in the SNP
group) and at 13 weeks (19.0% [77/405] and 17.0% [69/407],
3
European Journal of Internal Medicine xxx (xxxx) xxx–xxx
respectively) didn't show statistical significance between groups in the
second trial; however, this trial suggested that SNP increased mortality
when started within nine hours of the onset of symptoms (mortality at
13 weeks of 24.2% vs. 12.7%; p = 0.025) but decrease it when begun
later (mortality at 13 weeks of 14.4% vs. 22.3%; p = 0.04) [32].
In the setting of AHF not due to MI, an observational study com-
pared patients treated with SNP (n = 78) to those who did not receive it
(n = 97) [33]. SNP produced greater improvement in hemodynamic
outcomes and had lower rates of all-cause mortality (29% [23/78] in
the SNP group vs. 44% [43/97] in the control group; p = 0.005). Both
early and late all-cause mortality (defined as within or after 30 days
after admission, respectively) were significantly lower in the SNP-
treated patients (both p < 0.01). The two treatment groups did not
differ in cardiac transplant (33% [26/78] in the SNP group vs. 35%
[34/97] in the control group) or HF rehospitalization (60% [47/78] vs.
56% [54/97], respectively) rates.
Given these conflicting results, a large and well-conducted trial
evaluating SNP in the field of AHF, in particular not due to MI, is
lacking. However, as with organic nitrates, SNP became a standard of
care and is off patent, so such a trial is unlikely to be performed. A
randomized, non-blinded trial comparing IV SNP and dobutamine for
AHF is currently ongoing, according to ClinicalTrials.gov (accessed May
30, 2017).
3. Levosimendan
Levosimendan is approved for short-term use in refractory severe
AHF, and when inotropics are considered appropriate. Levosimendan is
not approved for this use in the US, although it is widely used in
Europe.
Short-term administration of levosimendan showed hemodynamic
and symptomatic improvements in patients with AHF [34,35].
Several trials have shown the survival benefits of levosimendan in
the field of AHF. A multicentre, randomized, double-blind study com-
pared IV levosimendan and dobutamine in severe low-output HF pa-
tients [36]. At 31 days, 8 (8%) of 103 patients in the levosimendan
group died compared with 17 (17%) of 100 assigned to dobutamine
(p = 0.049). At 180 days, 27 (26%) patients treated with levosimendan
and 38 (38%) patients treated with dobutamine had died (p = 0.029).
Furthermore, the median number of days alive and out of hospital
during the first 180 days was 157 in the levosimendan group and 133 in
the dobutamine group (p = 0·027).
A randomized, placebo-controlled, double-blind study, included 504
patients and evaluated levosimendan at different doses [37]. Compared
with placebo, mortality was lower with levosimendan at 14 days
(11.7% vs. 19.6%; p = 0.031) and at 180 days (22.6% vs. 31.4%;
p = 0.053).
Other randomized, double-blind study compared also levosimendan
(n = 664) with dobutamine (n = 663) [38]. At 180 days, there were
173 deaths (26%) in the levosimendan group and 185 deaths in the
dobutamine group (28%), which was not significant (p = 0.40). All-
cause mortality at 31 days (79 patients [12%] in the levosimendan
group vs. 91 patients [14%] in the dobutamine group; p = 0.29) and
cardiovascular mortality at 180 days (157 patients [24%] vs. 171 pa-
tients [26%], respectively; p = 0.33) were also not statistically sig-
nificant.
Finally, the REVIVE I and II trials compared levosimendan to pla-
cebo in subjects with ADHF [39]. The REVIVE I trial enrolled 100
subjects (49 assigned to placebo and 51 assigned to levosimendan), and
the REVIVE II trial enrolled 600 patients (301 assigned to placebo and
299 assigned to levosimendan). The number of days alive and out of the
hospital over 14 days (7.3 days in the levosimendan group and 8.9 days
in the placebo group) was not statistically significant between groups in
both trials (p = 0.258). However, in both trials, patients in the levosi-
mendan group were discharged from the hospital earlier than those in
the placebo group. At 90 days, 5 patients (10.2%) in the placebo group
A.M. Travessa, L. Menezes Falcão European Journal of Internal Medicine xxx (xxxx) xxx–xxx

and 4 (7.8%) in the levosimendan group died in the REVIVE I trial, and

Changes in hemodynamic variables; changes in symptoms of HF; proportion of

or diuretics during the infusion of study drug; number of days alive and out of

patient perception of dyspnea, number of days alive and out of hospital, time to
death or worsening HF, NYHA functional classification, and all-cause mortality
patients needing IV rescue therapy with positive inotropic drugs, vasodilators,

All-cause mortality, change in BNP level, number of days alive and out of the

Changes in plasma BNP, changes in the patient global assessment, changes in

35 patients (11.6%) in the placebo group and 45 (15.1%) in the levo-

Risk of death and worsening HF, symptoms of HF, all-cause mortality, and
hospital and not receiving IV drugs during the first month; and time to
simendan group died in the REVIVE II trial (p = 0.21 for the REVIVE II

hospital, change in patient assessed dyspnea, patient assessed global

trial alone and p = 0.29 for the REVIVE I and REVIVE II trials com-
bined).
The most important trials evaluating the use of levosimendan for
AHF are summarized in Table 3.
development of worsening heart failure or death.

4. Enalaprilat

Enalaprilat is the IV formulation of enalapril and belongs to the

assessment, and cardiovascular mortality
group of angiotensin-converting enzyme (ACE) inhibitors. Although
ACE inhibitors are widely studied in the setting of hypertension and
chronic HF, a few studies were performed to evaluate its IV formula-
tions for treatment of AHF. In particular, although some trials docu-
mented beneficial hemodynamic effects [40–42], a well designed study
Secondary endpoints

with a large sample size and studies evaluating mortality and morbidity
outcomes are lacking. No active trials evaluating enalaprilat in AHF are
posted at Clinicaltrials.gov (accessed May 30, 2017). In fact, it seems
unlikely that enalaprilat will be evaluated in the field of AHF in the near
others

future. Given the risk of hypotension, enalaprilat is not indicated for

AHF in general.
Composite that evaluated changes

5. Novel therapies
ischemia of clinical significance
hemodynamic improvement

Hypotension or myocardial
Proportion of patients with

5.1. Clevidipine
All-cause mortality
Primary endpoints

Clevidipine is a third-generation calcium channel blocker that be-

in clinical status

longs to the group of dihydropyridines [43]. A prospective randomized

open-label, active control, safety and efficacy phase IIIa trial enrolled
104 patients presenting with hypertensive AHF and compared clevidi-
pine (n = 51) and standard of care (n = 53) [44]. Clevidipine had non-
significant trends to fewer hospital (90% vs. 98%) and ICU admissions
(23 vs. 27%), shorter median hospital stay (4.0 vs. 5.0 days), fewer 30-
Levosimendan (299) vs. placebo (301)
(0.1–0.4 μg/kg/min) (402) vs. placebo

day all cause readmissions (15 vs. 17%), and longer out-of-hospital
Levosimendan (103) vs. dobutamine

Levosimendan (664) vs. dobutamine

Interventions (number of patients)

times before readmission (11.0 vs. 5.0 days). Thirty-day mortality (3 vs.
Levosimendan at different doses

2 patients) between clevedipine and standard of case was non-sig-

nificant (Table 4).
BNP, brain natriuretic peptide; HF, heart failure; IV, intravenous; NYHA, New York Heart Association.

5.2. Serelaxin

Serelaxin (RLX030) is a recombinant form of the endogenous re-

laxin-2. This protein binds to and upregulates vascular endothelin B
(100)

(102)

(663)

receptor and vascular endothelial growth factor (VEGF), increases the

production of NO, and inhibits the vasoconstrictors angiotensin II and
endothelin (Fig. 1) [45]. In the clinical field, several phase I and II
studies evaluated the safety and pharmacokinetics of serelaxin, as well
Number of
patients
Summary of most important trials evaluating levosimendan for AHF.

as its hemodynamic effects, and others are currently underway [46,47].

1327
203

504

600

Mortality and morbidity outcomes have also been recently assessed

(Table 4). In the phase IIb Pre-RELAX-AHF trial [48], 234 patients with
AHF were double-blind randomized into five groups: one group re-
Randomized, double-blind trial

Randomized, double-blind trial

controlled, double-blind trial

ceived standard treatments plus 48 h of placebo (n = 62), and the other

Randomized, double-blind,

four groups received standard treatments plus relaxin 10 microg/kg

Randomized, placebo-

(n = 40), 30 microg/kg (n = 43), 100 microg/kg (n = 39), or 250

double-dummy trial

microg/kg (n = 50) during 24 h. At day 60, the mean number of days

Characteristics

alive and out of hospital was 4 days (9%) greater in the serelaxin group
than in the placebo group (p = 0.16 for 30 μg/kg group vs. placebo). At
day 60, the incidence of cardiovascular death or hospital readmission
due to HF or renal failure was 17.2% (10 patients) in the placebo group
and 6.1% in all relaxin groups combined (10 patients; p = 0.13 com-
pared to placebo). At day 180, all-cause mortality was 15.8% (8 pa-
LIDO (2002) [36]

RUSSLAN (2002)

SURVIVE (2007)

(2013) [39]
REVIVE I and II

tients) in the placebo group and 7.6% in all serelaxin groups combined
(12 patients; p = 0.17). Three patients died in the relaxin 30 μg/kg
Trial (year)

[37]

[38]

group compared with 8 in the placebo group (p = 0.36). Cardiovascular

Table 3

mortality at day 180 was 14.3% (7 patients) in the placebo group and
3.0% (5 patients) in all combined relaxin groups (p = 0.14). No

4
A.M. Travessa, L. Menezes Falcão European Journal of Internal Medicine xxx (xxxx) xxx–xxx

patients died because of cardiovascular causes in the relaxin 30 μg/kg

Relief of dyspnea, in-hospital worsening HF, renal impairment, length

of initial hospital stay, days alive and out of hospital, death due to
group (p = 0.05 compared with placebo).

cardiovascular causes or readmission for HF or renal failure, and

Days alive and out of the hospital, and cardiovascular death or

In the phase III RELAX-AHF trial [49], 1161 patients with AHF were
randomly assigned to receive serelaxin or placebo. At day 60, there
were no differences in days alive out of hospital (placebo, 47.7 days;
serelaxin, 48.3; p = 0·37) and cardiovascular death or readmission due
to HF or renal failure between the serelaxin and placebo groups (pla-

readmission to hospital for HF or renal failure

cebo, 75 events [27 cardiovascular deaths and 50 readmissions]; ser-
mortality due to cardiovascular causes elaxin, 76 events [9 cardiovascular deaths and 60 readmissions];
p = 0·89). All-cause mortality at day 30 was not significant (19 [3.3%]
in the placebo group vs. 12 [2.1%] in the serelaxin group; p = 0·20).
However, at 180 days, serelaxin reduced cardiovascular death (55
[9.6%] in the placebo group vs. 35 [6.1%] in the serelaxin group;
p = 0·028), and all-cause mortality (65 [11.3%] in the placebo group
Secondary endpoints

Dyspnea reduction

vs. 42 [7.3%] in the serelaxin group; p = 0.02).

The results of RELAX-AHF were hopeful, and larger phase III clinical
trials were initialized. Specifically, the RELAX-AHF2 trial had a planned
enrolment of 6800 patients and the RELAX-AHF-EU trial has a planned
enrolment of 2685 patients, and both had cardiovascular mortality at
180 days as primary endpoint [50,51]. The RELAX-AHF-ASIA study had
Change in patient-reported dyspnea, and

an intended enrolment of 1520 patients; the primary endpoint was a

Median time to, and percent of patients
attaining, a SBP within a pre-specified

composite of treatment success and failure, or no change [52]. How-

moderately or markedly improved

ever, the RELAX-AHF-2 trial did not meet its primary endpoints. There
was no difference in cardiovascular mortality at 180 days and the trend
for a reduction of worsening HF at 5 days was not statistically sig-
patient-reported dyspnea

nificant.
Primary endpoints

target BP range

5.3. Cinaciguat

Cinaciguat is an activator of soluble guanylyl cyclase (sGC) (Fig. 2).

This activation occurs in a NO-independent manner, so the effect occurs
Clevidipine (51) vs. no clevidipine
Interventions (number of patients)

even in nitrate-tolerant patients [53]. A placebo-controlled, phase IIb

Serelaxin (581) vs. placebo (580)
250microg/kg) (172) vs. placebo
Serelaxin at diferente doses (10-

trial enrolled 139 patients with AHF and randomized them to receive
cinaciguat or placebo [54]. Cinaciguat resulted in statistically sig-
nificant hemodynamic benefits compared with placebo. Two patients
(2.1%) in the cinaciguat group and three (5.9%) in the placebo group
died during the initial hospitalization; these deaths were considered
unrelated to the therapy. In addition, ten patients (10.3%) in the ci-
naciguat group and two (3.9%) in the placebo group were re-
(53)

(62)

hospitalized within 30–35 days. This study was stopped prematurely

due to the high incidence of hypotension in the cinaciguat group (71
patients [73.2%] in the cinaciguat group and in 13 patients [25.5%] in
Number of

the placebo group).

patients

The COMPOSE program comprises three randomized, double-blind,

Summary of most important trials assessing clevidipine and serelaxin for AHF.

1161
104

234

placebo-controlled trials that enrolled patients with (COMPOSE 1 and

2) or without (COMPOSE EARLY) invasive hemodynamic monitoring.
controlled, double-blind, trial
controlled, double-blind trial

COMPOSE 1 (n = 12) and COMPOSE EARLY (n = 62) assessed out-

Randomized, open-label,

comes related to hemodynamics and dyspnea, respectively, and ended

Randomized, placebo-

Randomized, placebo-

prematurely because of a high rate of hypotension in the patients re-

active control trial

ceiving cinaciguat, and COMPOSE 2 (n = 4) evaluated hemodynamic

Characteristics

BP, blood pressure; HF, heart failure; IV, intravenous.

effects and ended also prematurely because of concerns about the

duration of the trial [55]. In the COMPOSE 1 trial, one patient receiving
cinaciguat died; the death was considered as a suspected unexpected
serious adverse reaction. In the COMPOSE EARLY trial, one patient in
the cinaciguat group also died, but the death was considered to be
IV vasodilator

unrelated to study drug; two patients in the placebo group (10.5%) and
Clevidipine

Serelaxin

Serelaxin

five in the cinaciguat group (11.6%) were rehospitalized before the

follow-up visit. In addition, the mean length of stay in hospital for the
initial admission was similar in the placebo group (7.3 days) and ci-
naciguat group (7.4 days) in the COMPOSE EARLY trial. These trials are
PRONTO (2014)

(2009) [48]

(2013) [49]
Pre-RELAX-AHF

summarized in Table 5.
RELAX-AHF
Trial (year)

Currently, there are no ongoing trials on cinaciguat according to the

[44]

Clinicaltrials.gov database (accessed May 30, 2017). It seems to be

Table 4

unlikely that further trials will be conducted or will demonstrate ben-

efits for cinaciguat in patients with AHF.

5
A.M. Travessa, L. Menezes Falcão
Fig. 1. Summary of actions of relaxin. Binding of serelaxin to its RXFP1 receptor activates several signaling pathways that lead to vasodilatation and several other effects. In the text
boxes, ↓ indicate decreased and ↑ indicate increased. Ang II, angiotensin II; ANP, atrial natriuretic peptide; ET-1, endothelin-1; NO, nitric oxide; RXFP1, relaxin/insulin like family peptide
receptor 1; TNF-α, tumor necrosis factor-alpha; TNF-β, tumor necrosis factor-beta; VEGF, vascular endothelial growth factor.
Fig. 2. Mechanisms of action of cinaciguat and ularitide. Cinaciguat augments the en-
zymatic activity of sGC resulting in increased generation of cGMP, and beneficial cardi-
ovascular effects through PKG activity. Ularitide selectively targets NPR-A, and thus in-
crease intracellular cGMP.
The final effects are the inhibition of the RAAS and the attenuation of fibrosis, hyper-
trophy, and vasoconstriction. cGMP, Cyclic guanosine monophosphate; GTP, Guanosine-
5′-triphosphate; NPR-A, atrial natriuretic peptide receptor-A; pGC, plasma-membrane-
bound guanylate cyclase; PKG, protein kinase G; RAAS, renin–angiotensin–aldosterone
system; sGC, soluble guanylate cyclase.
6. Natriuretic peptides
6.1. Nesiritide
Nesiritide is a recombinant form of BNP that binds to natriuretic
peptide A receptor (NPR-A) and, like the nitrates, increases cGMP levels
[52,56]. Nesiritide is approved by the FDA for the treatment of AHF
since 2001; it is also approved by some other regulatory agencies.
6
European Journal of Internal Medicine xxx (xxxx) xxx–xxx
However, its effect in reducing mortality and hospital readmission in
AHF was not consensual between small and/or non-randomized un-
controlled trials [57,58].
VMAC, the first large nesiritide study, randomized in a double-blind
manner 489 patients with AHF to receive nesiritide (n = 204), ni-
troglycerin (n = 143), or placebo (n = 142) for 3 h, followed by ne-
siritide (n = 278) or nitroglycerin (n = 216) for 24 h [59]. Nesiritide
improved hemodynamic function and some self-reported symptoms
more effectively than IV nitroglycerin or placebo. Deaths occurred in 1
(0.5%) nitroglycerin and 4 (1.5%) nesiritide patients at day 7; none of
these deaths were considered to be due to the study drugs. There was no
significant difference in mortality at 6 months for nitroglycerin (20.8%)
vs. nesiritide patients (25.1%, p = 0.32). At day 30, readmission for any
cause occurred in 48 (23%) nitroglycerin and 50 (20%) nesiritide pa-
tients (p = 0.36); readmission for ADHF occurred in 27 (13%) ni-
troglycerin and 20 (7%) nesiritide patients.
Following VMAC study, two meta-analyses found that nesiritide had
a significantly higher risk for worsening renal function compared with
other drugs for AHF, and tended to increase all-cause mortality at
30 days [60,61]. Although an increase in mortality with nesiritide at 30
and 180 days was not confirmed by two subsequent meta-analyses
[62,63], a large clinical trial to assess the safety and efficacy of ne-
siritide was lacking. ASCEND-HF was performed to fill up these lacking
data [64]. ASCEND-HF randomized 7141 patients with AHF to receive
IV nesiritide (n = 3496) or placebo (n = 3511). Rehospitalization for
HF or death from any cause at 30 days occurred in 321 patients in the
nesiritide group (9.4%) and in 345 patients in the placebo group
(10.1%) (p = 0.31); death occurred in 126 (3.6%) and 141 (4.0%)
patients and rehospitalization for HF occurred in 210 (6.0%) and 214
(6.1%) patients, respectively. Additionally, the rate of hypotension was
significantly higher in nesiritide group than in placebo group (asymp-
tomatic, 21.4% vs. 12.4%; symptomatic, 7.2% vs. 4.0%; p < 0.001 for
 Table 5
Summary of most important trials assessing cinaciguat for AHF.

Trial (year) Characteristics Number of Interventions (number of patients) Primary endpoints Secondary endpoints
patients

Erdmann et al. (2013) Randomized, placebo- 139 Cinaciguat (90) vs. placebo (49) Change in PCWP Changes in haemodynamic and dyspnea
[54] controlled, double-blind trial
COMPOSE EARLY Randomized, double-blind, 62 Cinaciguat at diferent doses (50- COMPOSE 1 and COMPOSE 2, the primary efficacy endpoint was the Change in dyspnea, overall patient health
(2012) [55] placebo-controlled trial 150 μg/h) (43) vs. placebo (19) change in PCWP COMPOSE 1 and COMPOSE 2, the primary efficacy assessment and physician's assessment
A.M. Travessa, L. Menezes Falcão

endpoint was the change in PCWP COMPOSE 1 and COMPOSE 2, the

primary efficacy endpoint was the change in PCWP Change in dyspnea
COMPOSE 1 (2012) Randomized, double-blind, 12 Cinaciguat at diferent doses (50- Change in PCWP Invasive hemodynamic parameters, EuroQol VAS
[55] placebo-controlled trial 150 μg/h) (9) vs. placebo (3) scores, results of the KCCQ, and physician's
assessment
COMPOSE 2 (2012) Randomized, double-blind, 4 Cinaciguat at diferent doses (10- Change in PCWP Invasive hemodynamic parameters, EuroQol VAS
[55] placebo-controlled trial 25 μg/h) (3) vs. placebo (1) scores, results of the KCCQ, and physician's
assessment

KCCQ, Kansas City Cardiomyopathy Questionnaire; PCWP, pulmonary capillary wedge pressure, VAS, visual analogue scale.

7
Table 6
Summary of most important trials evaluating natriuretic peptides for AHF.

Trial (year) IV vasodilator Characteristics Number of Interventions (number of Primary endpoints Secondary endpoints
patients patients)

VMAC (2002) Nesiritide Randomized, double-blind, 489 Nesiritide (204) vs. Change in PCWP among catheterized patients, Hemodynamic and clinical endpoints
[59] placebo-controlled trial nitroglycerin (143) vs. placebo and patient self-evaluation of dyspnea
(142)
ASCEND-HF Nesiritide Randomized, double-blind, 7007 Nesiritide (3496) vs. placebo Change in dyspnea, and composite of Self-reported overall well-being, composite of persistent or worsening
(2011) [64] placebo-controlled trial (3511) rehospitalization for heart failure or death HF and death from any cause, number of days alive and out of the
hospital, and composite of death from cardiovascular causes and
rehospitalization due to cardiovascular causes
ROSE (2013) [65] Nesiritide Randomized, double-blind, 360 Nesiritide (119) vs. dopamine Cumulative urinary volume, and change in Several decongestion, symptom relief and clinical endpoints
placebo-controlled trial (122) vs. placebo group (119). cystatin-C
PROTECT (2008) Carperitide Randomized, open-labeled, 49 Carperitide (26) vs. no Hemodynamic and clinical endpoints
[67] controlled trial carperitide (23)
SIRIUS IIb (2006) Ularitide Randomized, double-blind, 221 Ularitide (7.5-30 ng/kg/min) Change in PCWP and in dyspnea Hemodynamic and clinical endpoints
[70] placebo-controlled trial (168) vs. placebo (53)
TRUE-AHF Ularitide Randomized, double-blind, 2157 Ularitide (1088) vs. placebo Death from cardiovascular causes, and a Length of stay in the hospital and in the intensive care unit during the
(2017) [71] placebo-controlled trial (1069) hierarchical composite that evaluated the index episode, number of episodes of inhospital HF events, proportion
initial clinical course of patients with an inhospital HF event, rehospitalization for HF, time
until completion of IV treatment for HF, death or rehospitalization for
a cardiovascular cause, and others

HF, heart failure; IV, intravenous; PCWP, pulmonary capillary wedge pressure.
European Journal of Internal Medicine xxx (xxxx) xxx–xxx
A.M. Travessa, L. Menezes Falcão
Table 7
Most important trials assessing TRV120027 and nicorandil for AHF.
Trial (year) IV vasodilator Characteristics Number of
patients
BLAST-AHF TRV120027 Randomized, double- 621
(2017) blind, placebo-controlled
[73] trial
Ishihara et al. Nicorandil Retrospective, 402
(2012) observational study
[74]
AUC, area under the curve; HF, heart failure; IV, intravenous; NTproBNP, N-terminal prohormone of brain natriuretic peptide; VAS, visual analogue scale.
both comparisons) (Table 6) [64].
In a more recent trial, no significant differences were found between
nesiritide (n = 119) and placebo (n = 119) in death at 72 h (0 patients
in both groups), death at day 60 (12 [10%] vs. 11 [9%] patients, re-
spectively), serious adverse events at day 60 (24 [20%] vs. 30 [25%]
patients, respectively; p = 0.41), days alive and free from HF hospita-
lization at day 60 (mean of 46.6 vs. 47.3, respectively; p = 0.68) and
mortality at day 180 (21.1% vs 19.7% of patients, respectively;
p = 0.87) (Table 6) [65].
Some meta-analyses have continued to analyze nesiritide and have
showing that nesiritide does not decrease the mortality of patients with
AHF; however, they suggest that nesiritide increases the rate of cardi-
ovascular events [18]. Despite these findings, the 2016 ESC Guidelines
for the diagnosis and treatment of acute and chronic HF and the 2013
ACCF/AHA Guideline for the Management of HF continue to consider
nesiritide as one of the vasodilators that can be associated with diuretic
therapy to improve fluid overload and congestion [1,13].
6.2. Carperitide
Carperitide has been used for AHF in Japan, where it was approved
in 1995, and is recommended in the current Japanese guidelines.
However, American and European clinical guidelines do not address its
use [1,13]. Moreover, although evidence of carperitide effectiveness in
non-randomized comparisons exists [66], large-scale randomized con-
trolled trials with clinical outcomes are lacking.
An open-label study randomized 49 patients with AHF to receive
low-dose carperitide (n = 26) or standard medication (n = 23). During
18-month follow-up, the combined endpoint of cardiovascular mor-
tality and rehospitalization occurred in 12% (n = 3, 1 cardiac death
and 2 rehospitalizations) of the carperitide group vs. 35% (n = 8, re-
hospitalizations in all) of the control group (p = 0.0359). A statistically
significant difference in mortality was not found between the carperi-
tide and control groups (Table 6) [67]. Carperitide was also evaluated
in a post-marketing surveillance analysis in Japan, but no mortality
outcome was reported [68].
More studies of the effects of carperitide in the management of AHF
are needed. However, no active studies are posted at Clinicaltrials.gov
database (accessed May 30, 2017).
6.3. Ularitide
Ularitide is the synthetic version of a kidney natriuretic peptide.
This peptide, called urodilatin, induces vasodilation, natriuresis, dier-
esis, and other effects (Fig. 2) [69].
In the SIRIUS IIb trial, 221 patients with AHF were randomized in a
double-blind manner to receive ularitide (7.5, 15, or 30 ng/kg/min) or
placebo. At 30 days, 7 (13.2%) patients died in the placebo group and 2
(3.4%), 2 (3.8%), and 1 (1.8%) patients died in the 7.5, 15, and 30 ng/
kg/min ularitide groups, respectively (Table 6) [70]. All placebo pa-
tients and 3 ularitide patients died of HF.
More recently, the phase 3 TRUE-AHF trial randomized 2157
European Journal of Internal Medicine xxx (xxxx) xxx–xxx
Interventions (number Primary endpoints Secondary endpoints
of patients)
TRV120027 (1–25 mg/ Composite of death, HF re-hospitalization, first VAS AUC and change in
h) (438) vs. Placebo assessment time point following worsening HF, core laboratory-
(183) change in dyspnea and length of initial hospital measured NTproBNP
stay
Nicorandil (78) vs. no Death from all causes or rehospitalization for
nicorandil (324) HF
patients with AHF to receive ularitide or matching placebo, also in a
double-blind manner. Death from cardiovascular causes at 15 months
occurred in 236 patients in the ularitide group and 225 patients in the
placebo group (21.7% vs. 21.0%; p = 0.75). The endpoint of all-cause
mortality or hospitalization for a cardiovascular cause at 6 months oc-
curred in 443 (40.7%) and 398 (37.2%) of patients in the ularitide and
placebo groups, respectively (p = 0.10) (Table 6) [71].
7. TRV027
TRV027 is a novel beta-arrestin biased angiotensin II type 1 receptor
(AT1R) ligand [70]. TRV027 have a rapid onset and short duration of
action. This hemodynamic profile should be useful in the field of AHF
[72].
BLAST-AHF was double-blind phase IIb trial that randomized 621
subjects with AHF and compared 1 (n = 128), 5 (n = 182), or 25 mg/h
(n = 125) of TRV027 with placebo (n = 183) [73]. The primary com-
posite endpoint included the following: mortality and HD readmissions
at 30 days, change in dyspnea and worsening HF at 5 days, and length
of hospital stay. At day 30, death occurred in 5 (3.9%), 8 (4.4%), 6
(4.8%) and 7 (3.8%) patients in the TRV027 1.0, 5.0 and 25.0 mg/h,
and placebo groups, respectively. HF rehospitalization at day 30 oc-
curred in 10 (7.8%), 18 (9.9%), 10 (8.0%) and 10 (5.5%) patients,
respectively. The length of initial hospital stay was 8.7, 9.2, 9.7 and 8.8,
respectively. TRV027 did not confer any statistically significant benefit
over placebo at any dose with regards to the primary composite end-
point or any of the individual components. For the 540 patients with
180 day follow-up, estimated rates of all cause mortality did not differ
between placebo and any TRV027 group: 13.1, 11.0, 12.6, and 13.6%
in the placebo, and TRV027 1.0, 5.0, and 25.0 mg/h groups, respec-
tively. Rates of occurrence of adverse events were also similar among
the groups (Table 7).
8. Nicorandil
Nicorandil has two pharmacological mechanisms of action: it acti-
vates the adenosine triphosphate sensitive potassium (KATP) channel
and it produces nitrate-like effects [74].
In an observational study, 402 patients admitted for HF received
nicorandil (n = 70) or only standard therapy (n = 324), and were ret-
rospectively reviewed. At 180 days, mortality or readmission for HF
occurred in 9.0% of patients in the nicorandil group (n = 7) and in
23.3% of patients (n = 75) in the control group (p = 0.0053). Death or
rehospitalization for HF at day 30 was also significantly lower in the
nicorandil group (2.6% vs. 10.8%, p = 0.0238). In addition, event-free
survival was significantly higher in the nicorandil group (p = 0.006)
(Table 7) [75].
Randomized controlled trials are needed to elucidate the role of
nicorandil in AHF and confirm the previous findings.
8
A.M. Travessa, L. Menezes Falcão
9. Conclusions
AHF contributes largely to the burden of HF characterized by fre-
quent hospitalizations and increased mortality. IV nitrovasodilators
have been extensively used in patients with AHF; however, data on
mortality and long-term benefits of the commonly used IV vasodilators
in AHF are limited. During the last years, several vasodilators were
investigated in clinical trials, but they have failed to favorably alter the
course of AHF and to provide a survival benefit. The recent serelaxin
exhibits a novel mechanism of action, was safe and well tolerated in
earlier trials and seemed to be a promising therapy for ADHF, but the
results of the larger phase III RELAX-AHF2 trial failed to meet the
primary endpoints.
There is a need to enroll greater numbers of subjects in large, pro-
spective, and well-designed randomized, controlled studies with stan-
dardized clinical endpoints and methodology assessment. A better un-
derstanding of the pathophysiology of AHF is also needed, and can lead,
in the future, to the development of novel and more effective therapies.
Ultimately, the goal of AHF research should be focused in the devel-
opment of therapies that improve short- and long-term mortality and
reduce rehospitalization.
Conflict of interest
The authors of the article “Vasodilators in Acute Heart Failure –
New Hopes and Mortality Studies” declare there are no conflicts of
interest.
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