Opinion
EDITORIAL
Vasodilator Therapy in Acute Heart Failure
Gregory Curfman, MD
Acute decompensated heart failure is a common clinical syn-
drome characterized by sudden onset of dyspnea due to ac-
cumulation of fluid within the pulmonary interstitial and al-
veolar spaces, referred to as cardiogenic pulmonary edema.
In most cases, acute heart fail-
ure results from abrupt in-
Related article page 2292
creases in cardiac filling pres-
sures due to fluid overload in conjunction with left ventricular
dysfunction, but it may sometimes be caused by elevated left
ventricular afterload due to hypertension in the absence of
frank volume overload.
Hospitalization for acute heart failure is associated with
high rates of rehospitalization and mortality. In a recent study,
death or all-cause readmission was reported in 26% of 744 pa-
tients within 30 days of discharge and in 38% within 60 days
of discharge.1 The high mortality and readmission rates may
result in part from organ damage that occurs during the pe-
riod of severe pulmonary congestion, including injury to the
myocardium and kidneys.2
Acute decompensated heart failure with severe pulmo-
nary congestion but normal blood pressure requires urgent
treatment, which should be initiated with intravenous loop
diuretics.3 Diuretic therapy should generally be continued even
in the face of worsening renal function. In contrast, acute heart
failure due to hypertension results from fluid redistribution
as a consequence of vasoconstriction, increased cardiac work,
and left ventricular dysfunction.4 In hypertensive acute heart
failure, vasodilator therapy is the treatment of choice to rap-
idly reduce ventricular afterload.4 However, the role of vaso-
dilator therapy in normotensive patients with pulmonary con-
gestion due to volume overload is less certain. Vasodilator
agents typically have been used as adjunctive therapy when
congestion persists despite diuretic therapy, ie, a clinical tra-
jectory of “initial improvement, then stalled.”5
During the past several years, 4 clinical trials that exam-
ined vasodilator therapy in acute heart failure have been re-
ported, all of which call into question the efficacy of vasodi-
lators in patients with acute heart failure in the absence of
hypertension.6-9 In the ASCEND-HF trial,6 nesiritide, a recom-
binant B-type natriuretic peptide (BNP) with vasodilator prop-
erties, was studied in 7141 patients with acute heart failure.
There was no difference in dyspnea at 6 or 24 hours between
the nesiritide and placebo groups, nor were there differences
in rates of hospitalization or death at 30 days. Nesiritide did,
however, produce more hypotension, leading to the authors’
conclusion that nesiritide cannot be recommended for rou-
tine treatment of acute heart failure.
In the TRUE-AHF trial,7 2157 patients with acute heart
failure were randomized to receive treatment with ularitide,
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a synthetic analogue of the endogenous vasodilator urodila-
tin, or placebo. Compared with placebo, ularitide had no sig-
nificant effect on either a short-term, hierarchical composite end
point that evaluated the initial 48-hour clinical course or a long-
term end point, death due to cardiovascular causes at 15 months.
In the RELAX-AHF-2 trial,8 the effects of serelaxin vs pla-
cebo were compared in 6545 patients with acute heart fail-
ure. Serelaxin is a recombinant form of human relaxin 2, an
endogenous vasodilator involved in physiologic adaptations
during pregnancy. In this randomized, double-blind trial, sere-
laxin, compared with placebo, was found to have no effect on
worsening heart failure at 5 days or death due to cardiovascu-
lar causes at 180 days.
In this issue of JAMA, Kozhuharov and colleagues report
the results of the GALACTIC clinical trial.9 In this trial, 788
patients with acute heart failure and a median blood pressure
of 130/75 mm Hg were randomized to receive intensive, mul-
timodal, up-titrated vasodilator therapy with sublingual and
transdermal nitrates; oral hydralazine; and angiotensin-
converting enzyme inhibitors, angiotensin receptor blockers,
or sacubitril-valsartan (later in the trial) vs standard care. This
intervention represents the most intensive treatment of the
recent trials. The primary end point of a composite of all-
cause mortality or rehospitalization for acute heart failure at
180 days was not significantly different between the 2 ran-
domized groups (30.6% [117 patients] in the intensive vasodi-
lation group vs 27.8% [111 patients] in the usual care group).
Among the 2 components of the primary end point, rehospi-
talization for acute heart failure occurred in 20% of the vaso-
dilator group and 18% of the usual care group, while death
due to all causes occurred in 14% and 15%, respectively. Also,
there was no significant difference between the 2 groups in
the short-term end point of dyspnea at 2 or 6 days. The
authors concluded that in patients with acute heart failure
after initial stabilization, relative to standard care consisting
principally of intravenous loop diuretics, the role of acute
vasodilation seems to be smaller than previously thought. It
should be noted, however, that relatively few patients in this
trial received sacubitril-valsartan. In the PIONEER-HF trial,
the administration of sacubitril-valsartan, compared with
enalapril, to patients hospitalized with acute heart failure
resulted in greater reduction in N-terminal pro-BNP at weeks
4 and 8.10 Levels of this biomarker correlate with subsequent
cardiovascular events.
Collectively, the results of these 4 clinical trials suggest
that in the absence of hypertension, use of early intensive va-
sodilator therapy in acute heart failure due to fluid overload
may not provide clinically significant benefit compared with
standard therapy with loop diuretics to reverse congestion.
jama.com
 Editorial Opinion

The trials failed to demonstrate benefit in either short-term,
symptomatic end points or longer-term outcomes, including car-
diovascular mortality. In patients with pulmonary congestion
who are normotensive, emphasis should be placed on ad-
equate diuresis, with vasodilators reserved for patients whose
clinical improvement has stalled. In lieu of intensive vasodila-
tor therapy early in the hospitalization, it may be more impor-
tant to ensure that after adequate diuresis, patients with acute
heart failure receive a maintenance regimen at discharge that
includes sacubitril-valsartan,10 dapagliflozin,11 or both.11

ARTICLE INFORMATION
Author Affiliation: Deputy Editor, JAMA, Chicago,
Illinois.
Corresponding Author: Gregory Curfman, MD,
JAMA, 330 N Wabash Ave, 41st Floor, Chicago, IL
60611 (gregory.curfman@jamanetwork.org).
Conflict of Interest Disclosures: None reported.
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