Journal of the American College of Cardiology Vol. 62, No.

13, 2013
2013 by the American College of Cardiology Foundation ISSN 0735-1097/$36.00
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further conclude that the dose of loop diuretics, degree of

EDITORIAL COMMENT 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
Increasing Diuresis in to conclude that nesiritide is just not working in ADHF,
a critical reection on the reasons for yet another failed trial
Congestive Heart Failure may be helpful to advance the eld.
A major problem in all ADHF studies is that no single
Ready for Prime Time?* treatment target has proven to be clinically relevant as
surrogate marker for outcome. Obviously, early dyspnea
Wilfried Mullens, MD, PHD,yz relief is the rst treatment goal in many patients, and in the
Frederik H. Verbrugge, MDyx ASCEND-HF it was associated with a lower incidence of
the combined endpoint of all-cause mortality or heart failure
Genk and Diepenbeek, Belgium readmission (4). However, assessment of dyspnea is highly
subjective and may be inuenced by age, comorbidity, and
variability around the timing of measurement. Although
Despite major advances in pharmacological therapy and improving dyspnea is one of the principal immediate goals,
cardiac devices, heart failure patients continue to be fre- successful inpatient therapy for ADHF involves a more
quently hospitalized because of signs and symptoms of comprehensive care plan. Treatment to relieve symptoms
congestion (1). Too often, randomized clinical trials have should be applied in a way that limits side effects and
failed to produce clinically meaningful benets in this reduces the risk of cardiac and renal injury. Also, precipi-
context. The ASCEND-HF (Acute Study of Clinical tating factors must be identied and maintenance therapy
Effectiveness of Nesiritide in Decompensated Heart must be optimized during hospitalization. In addition,
Failure) tested the hypothesis that addition of nesiritide to instruments to quantify dyspnea have not been satisfactorily
standard treatment would improve dyspnea relief and validated and, even in placebo arms of randomized clinical
outcomes in a general study group of patients hospitalized trials, dyspnea improves markedly, indicating that the
with acute decompensated heart failure (ADHF). Treatment 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
See page 1177
an episode of acute heart failureda strategy that has been so
successful in studies on acute coronary syndromesdis
with nesiritide, a recombinant B-type natriuretic peptide problematic because heart failure is not one specic disease,
(BNP) with vasodilator properties, improved dyspnea relief but rather a complex clinical syndrome with a clinical
compared to placebo, but the pre-specied level for signi- outcome strongly inuenced by patient-specic factors,
cance was not met and there was no benet on all-cause including a wide array of comorbidities (5).
mortality or heart failure admissions after 30 days (2). As congestion, more than low cardiac output, is the main
Despite these disappointing results, such a large randomized treatment target, and importantly the most frequent reason
clinical trial still offers ample opportunity for subanalysis, of readmissions for ADHF, measuring decongestion prob-
which may provide further insights into the pathophysiology ably should be a good manner to evaluate treatment strate-
(and treatment) of ADHF. The analysis on the effect of gies in ADHF (6,7). However, although it is relatively easy
nesiritide on urinary output, published by Gottlieb et al. (3) in for experienced practicing clinicians to acknowledge overt
this issue of the Journal, is therefore of great interest to us all. signs and symptoms of congestion, estimating effective
The authors demonstrate that nesiritide had no net effect on decongestion is more difcult. Moreover, goals for thorough
diuresis in a study group of very sick heart failure patients decongestion, by clinical examination, neurohumoral and
(median NT-proBNP approximately 4,500 pg/ml) with hemodynamic response, or assessment of renal function, are
concomitant, moderately impaired renal function. They not well dened. Indeed, subclinical congestion is very
prevalent in patients with AHDF (8). Additionally,
a strategy of routinely performed hemodynamic evaluations
*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 with therapy guided by the pulmonary artery catheter has
American College of Cardiology. failed to improve outcomes (9). Alternatively, measuring
From the yDepartment of Cardiology, Ziekenhuis Oost-Limburg, Genk, Belgium; total amount of diuresis may be a very straightforward way to
zBiomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt
University, Diepenbeek, Belgium; and the xDoctoral School for Medicine and Life assess decongestion, which should be easily applicable in
Sciences, Hasselt University, Diepenbeek, Belgium. Both authors are researchers for clinical practice. This is where the study by Gottlieb et al.
the Limburg Clinical Research Program (LCRP) UHasselt-ZOL-Jessa, supported by comes in (3). In a subgroup of 5,864 patients from the
the foundation Limburg Sterk Merk (LSM), Hasselt University, Ziekenhuis Oost-
Limburg and Jessa Hospital. John Teerlink, MD, served as Guest Editor for this original ASCEND-HF, the authors report that loop diuretic
paper. dose was the strongest predictor of urinary output, with

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 JACC Vol. 62, No. 13, 2013 Mullens and Verbrugge 1185
September 24, 2013:11846 Increasing Diuresis in Congestive Heart Failure

other independent predictors, including male sex, greater treating harmful systemic congestion and avoiding intra-
body mass index, higher diastolic blood pressure, elevated vascular underlling with detrimental neurohumoral up-
jugular venous pressure, recent weight gain, and lower BUN. regulation, an individually tailored approach with better
It is remarkable that all those predictors, except for male sex, phenotyping of heart failure patients is urgently needed.
can be linked to more absolute baseline congestion, and in Whether nesiritide may play a role in such an individually
that sense absolute urine output may not be a right marker to tailored approach is unsure. Certainly, the nding that
assess, as it may not necessarily reect more complete nesiritide failed to increase urinary output in all different
decongestion. From a pathophysiological and clinical subgroups assessed is disappointing. Yet, as nesiritide leads
perspective, it would make sense that patients who were more to intrarenal vasodilation and, as a recombinant natriuretic
congested at baseline did receive a higher dose of diuretics (as peptide it is anticipated to increase natriuresis, it may still
the physicians were left free to decide on the dose of loops in benet the select study group with cardiorenal syndrome and
the ASCEND-HF) and eventually achieved a higher urinary persistent congestion. This hypothesis is currently tested in
output. However, what remains an open question is the the ROSE (Renal Optimization Strategies Evaluation in
amount of diuresis that is needed in an individual patient to Acute Heart Failure) study (NCT01132846). Importantly in
achieve adequate decongestion. As the correlation between this respect, serelaxin or recombinant human relaxin-
dyspnea relief and urinary output was conrmed to be very 2danother renal vasodilator that increases renal blood ow
poor (Spearmans r 0.123), symptoms seem of little value during pregnancy in womendhas been demonstrated to
in this respect. As other predictors suffer from high interin- provide decongestion in ADHF without adverse renal
dividual variability (i.e., body weight or blood pressure) or are outcome. Serelaxin was associated with a statistically signi-
difcult to assess in every single patient (i.e., jugular venous cant lower 180-days mortality in the RELAX-AHF (Relaxin
pressure), BUN may be the most helpful and only readily in Acute Heart Failure) trial (12). In addition, it was dem-
available in guiding therapy. Indeed, Testani et al. (10) have onstrated only recently in the Journal that targeting sodium
reported an improved survival in patients with low-baseline avidity with recombinant natriuretic peptides early on in
BUN who were treated with high-dose loop diuretics, as heart failure, before emerging clinical congestion and neuro-
opposed to a reduced survival with the same treatment in humoral up-regulation occur, may be an appealing treatment
patients with high-baseline BUN (10). However, the strategy (13).
assumption that increases in total body salt and water always How will the results presented by Gottlieb et al. (3)
underlie systemic congestion has been disputed lately, as inuence clinical practice? Certainly, it is reassuring that
changes in volume distribution (resulting in similarly loop diuretic dose was the most important predictor of
increased lling pressures) may occur due to altered capaci- diuresis in the ASCEND-HF. Therefore, the study un-
tance of the splanchnic venous vessels (11). Applying derscores that (loop) diuretics remain a good therapy to
decongestive therapies in such patients may lead to intra- treat congestion in ADHF patients. This suggests that
vascular volume depletion aggravating neurohumoral stimu- when patients are congested, adequate diuresis can and
lation and worsening renal function. should be achieved with diuretics. The success with titrated
As is often the case, the study by Gottlieb et al. (3) offers combination therapy of diuretics in the conservative
more questions than answers. It would be interesting to treatment arm of CARRESS (Cardio-Renal Rescue Study)
know whether patients who achieved a higher urinary output even suggests that this may hold true in many patients who
during the acute treatment phase remained free from are assumed to be refractory to diuretic therapy (14). It still
congestion in the long term. In fact, predictors of persistent remains difcult to assess whether adequate decongestion
decongestion are the ones for which we are looking. Also, has been achieved in an individual patient, nevertheless, the
Gottlieb et al. (3) did not provide any insight if more ex- amount of diuresis (and possibly natriuresis even more) is
tensive diuresis leads to improved outcome (i.e., a reduction ready for prime time, as outcome parameters in randomized
in AHDF hospitalizations). In addition, as total body water clinical trials of patients who are admitted with ADHF and
is largely dependent of renal sodium homeostasis, natriuresis overt congestion.
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 Reprint requests and correspondence: Dr. Wilfried Mullens,
weight gain have failed to dene treatment response. For Department of Cardiology, Ziekenhuis Oost-Limburg, Schiepse
Bos 6, 3600 Genk, Belgium. E-mail: [email protected].
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%,
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Increasing Diuresis in Congestive Heart Failure September 24, 2013:11846

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