Journal of the American College of Cardiology
13, 2013
2013 by the American College of Cardiology Foundation
Published by Elsevier Inc.
EDITORIAL COMMENT
Increasing Diuresis in
Congestive Heart Failure
Ready for Prime Time?*
Wilfried Mullens, MD, PHD,yz
Frederik H. Verbrugge, MDyx
Genk and Diepenbeek, Belgium
Despite major advances in pharmacological therapy and
cardiac devices, heart failure patients continue to be fre-
quently hospitalized because of signs and symptoms of
congestion (1). Too often, randomized clinical trials have
failed to produce clinically meaningful benets in this
context. The ASCEND-HF (Acute Study of Clinical
Effectiveness of Nesiritide in Decompensated Heart
Failure) tested the hypothesis that addition of nesiritide to
standard treatment would improve dyspnea relief and
outcomes in a general study group of patients hospitalized
with acute decompensated heart failure (ADHF). Treatment
See page 1177
with nesiritide, a recombinant B-type natriuretic peptide
(BNP) with vasodilator properties, improved dyspnea relief
compared to placebo, but the pre-specied level for signi-
cance was not met and there was no benet on all-cause
mortality or heart failure admissions after 30 days (2).
Despite these disappointing results, such a large randomized
clinical trial still offers ample opportunity for subanalysis,
which may provide further insights into the pathophysiology
(and treatment) of ADHF. The analysis on the effect of
nesiritide on urinary output, published by Gottlieb et al. (3) in
this issue of the Journal, is therefore of great interest to us all.
The authors demonstrate that nesiritide had no net effect on
diuresis in a study group of very sick heart failure patients
(median NT-proBNP approximately 4,500 pg/ml) with
concomitant, moderately impaired renal function. They
*Editorials published in the Journal of the American College of Cardiology reect the
views of the authors and do not necessarily represent the views of JACC or the
American College of Cardiology.
From the yDepartment of Cardiology, Ziekenhuis Oost-Limburg, Genk, Belgium;
zBiomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt
University, Diepenbeek, Belgium; and the xDoctoral School for Medicine and Life
Sciences, Hasselt University, Diepenbeek, Belgium. Both authors are researchers for
the Limburg Clinical Research Program (LCRP) UHasselt-ZOL-Jessa, supported by
the foundation Limburg Sterk Merk (LSM), Hasselt University, Ziekenhuis Oost-
Limburg and Jessa Hospital. John Teerlink, MD, served as Guest Editor for this
paper.
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further conclude that the dose of loop diuretics, degree of
congestion, blood pressure, and crude degree of neurohu-
moral stimulation assessed by blood urea nitrogen (BUN) all
inuence the amount of diuresis. Although it seems appealing
to conclude that nesiritide is just not working in ADHF,
a critical reection on the reasons for yet another failed trial
may be helpful to advance the eld.
A major problem in all ADHF studies is that no single
treatment target has proven to be clinically relevant as
surrogate marker for outcome. Obviously, early dyspnea
relief is the rst treatment goal in many patients, and in the
ASCEND-HF it was associated with a lower incidence of
the combined endpoint of all-cause mortality or heart failure
readmission (4). However, assessment of dyspnea is highly
subjective and may be inuenced by age, comorbidity, and
variability around the timing of measurement. Although
improving dyspnea is one of the principal immediate goals,
successful inpatient therapy for ADHF involves a more
comprehensive care plan. Treatment to relieve symptoms
should be applied in a way that limits side effects and
reduces the risk of cardiac and renal injury. Also, precipi-
tating factors must be identied and maintenance therapy
must be optimized during hospitalization. In addition,
instruments to quantify dyspnea have not been satisfactorily
validated and, even in placebo arms of randomized clinical
trials, dyspnea improves markedly, indicating that the
current mainstay treatment is already very effective in this
respect. On the other hand, the use of hard outcome
parameters, such as mortality or hospital readmissions after
an episode of acute heart failureda strategy that has been so
successful in studies on acute coronary syndromesdis
problematic because heart failure is not one specic disease,
but rather a complex clinical syndrome with a clinical
outcome strongly inuenced by patient-specic factors,
including a wide array of comorbidities (5).
As congestion, more than low cardiac output, is the main
treatment target, and importantly the most frequent reason
of readmissions for ADHF, measuring decongestion prob-
ably should be a good manner to evaluate treatment strate-
gies in ADHF (6,7). However, although it is relatively easy
for experienced practicing clinicians to acknowledge overt
signs and symptoms of congestion, estimating effective
decongestion is more difcult. Moreover, goals for thorough
decongestion, by clinical examination, neurohumoral and
hemodynamic response, or assessment of renal function, are
not well dened. Indeed, subclinical congestion is very
prevalent in patients with AHDF (8). Additionally,
a strategy of routinely performed hemodynamic evaluations
with therapy guided by the pulmonary artery catheter has
failed to improve outcomes (9). Alternatively, measuring
total amount of diuresis may be a very straightforward way to
assess decongestion, which should be easily applicable in
clinical practice. This is where the study by Gottlieb et al.
comes in (3). In a subgroup of 5,864 patients from the
original ASCEND-HF, the authors report that loop diuretic
dose was the strongest predictor of urinary output, with
 JACC Vol. 62, No. 13, 2013
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other independent predictors, including male sex, greater
body mass index, higher diastolic blood pressure, elevated
jugular venous pressure, recent weight gain, and lower BUN.
It is remarkable that all those predictors, except for male sex,
can be linked to more absolute baseline congestion, and in
that sense absolute urine output may not be a right marker to
assess, as it may not necessarily reect more complete
decongestion. From a pathophysiological and clinical
perspective, it would make sense that patients who were more
congested at baseline did receive a higher dose of diuretics (as
the physicians were left free to decide on the dose of loops in
the ASCEND-HF) and eventually achieved a higher urinary
output. However, what remains an open question is the
amount of diuresis that is needed in an individual patient to
achieve adequate decongestion. As the correlation between
dyspnea relief and urinary output was conrmed to be very
poor (Spearmans r 0.123), symptoms seem of little value
in this respect. As other predictors suffer from high interin-
dividual variability (i.e., body weight or blood pressure) or are
difcult to assess in every single patient (i.e., jugular venous
pressure), BUN may be the most helpful and only readily
available in guiding therapy. Indeed, Testani et al. (10) have
reported an improved survival in patients with low-baseline
BUN who were treated with high-dose loop diuretics, as
opposed to a reduced survival with the same treatment in
patients with high-baseline BUN (10). However, the
assumption that increases in total body salt and water always
underlie systemic congestion has been disputed lately, as
changes in volume distribution (resulting in similarly
increased lling pressures) may occur due to altered capaci-
tance of the splanchnic venous vessels (11). Applying
decongestive therapies in such patients may lead to intra-
vascular volume depletion aggravating neurohumoral stimu-
lation and worsening renal function.
As is often the case, the study by Gottlieb et al. (3) offers
more questions than answers. It would be interesting to
know whether patients who achieved a higher urinary output
during the acute treatment phase remained free from
congestion in the long term. In fact, predictors of persistent
decongestion are the ones for which we are looking. Also,
Gottlieb et al. (3) did not provide any insight if more ex-
tensive diuresis leads to improved outcome (i.e., a reduction
in AHDF hospitalizations). In addition, as total body water
is largely dependent of renal sodium homeostasis, natriuresis
may be even better at reecting effective decongestion
compared to urinary output. What constitutes an adequate
dose of diuretics remains to be dened, as classical tools like
weight gain have failed to dene treatment response. For
example, when patients in the study by Gottlieb et al. (3)
were stratied to urine output below and above the median
value (2,250 ml during rst 24 h), only 59% versus 71%,
respectively, did experience any weight gain at the moment
of hospital admission, yet they all received diuretic therapy,
which led to a signicant amount of diuresis, even in a lot of
patients without weight gain. Finally, as the treatment of
ADHF usually comprises the delicate balance between
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Mullens and Verbrugge 1185
Increasing Diuresis in Congestive Heart Failure
treating harmful systemic congestion and avoiding intra-
vascular underlling with detrimental neurohumoral up-
regulation, an individually tailored approach with better
phenotyping of heart failure patients is urgently needed.
Whether nesiritide may play a role in such an individually
tailored approach is unsure. Certainly, the nding that
nesiritide failed to increase urinary output in all different
subgroups assessed is disappointing. Yet, as nesiritide leads
to intrarenal vasodilation and, as a recombinant natriuretic
peptide it is anticipated to increase natriuresis, it may still
benet the select study group with cardiorenal syndrome and
persistent congestion. This hypothesis is currently tested in
the ROSE (Renal Optimization Strategies Evaluation in
Acute Heart Failure) study (NCT01132846). Importantly in
this respect, serelaxin or recombinant human relaxin-
2danother renal vasodilator that increases renal blood ow
during pregnancy in womendhas been demonstrated to
provide decongestion in ADHF without adverse renal
outcome. Serelaxin was associated with a statistically signi-
cant lower 180-days mortality in the RELAX-AHF (Relaxin
in Acute Heart Failure) trial (12). In addition, it was dem-
onstrated only recently in the Journal that targeting sodium
avidity with recombinant natriuretic peptides early on in
heart failure, before emerging clinical congestion and neuro-
humoral up-regulation occur, may be an appealing treatment
strategy (13).
How will the results presented by Gottlieb et al. (3)
inuence clinical practice? Certainly, it is reassuring that
loop diuretic dose was the most important predictor of
diuresis in the ASCEND-HF. Therefore, the study un-
derscores that (loop) diuretics remain a good therapy to
treat congestion in ADHF patients. This suggests that
when patients are congested, adequate diuresis can and
should be achieved with diuretics. The success with titrated
combination therapy of diuretics in the conservative
treatment arm of CARRESS (Cardio-Renal Rescue Study)
even suggests that this may hold true in many patients who
are assumed to be refractory to diuretic therapy (14). It still
remains difcult to assess whether adequate decongestion
has been achieved in an individual patient, nevertheless, the
amount of diuresis (and possibly natriuresis even more) is
ready for prime time, as outcome parameters in randomized
clinical trials of patients who are admitted with ADHF and
overt congestion.
Reprint requests and correspondence: Dr. Wilfried Mullens,
Department of Cardiology, Ziekenhuis Oost-Limburg, Schiepse
Bos 6, 3600 Genk, Belgium. E-mail: wilfried.mullens@zol.be.
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Key Words: acute heart failure - decongestion - diuresis - natriuresis -
nesiritide.