Clinical Practice

Dilemmas in the Dosing of Heart Failure Drugs: Titrating Diuretics

in Chronic Heart Failure
David Pham and Justin L Grodin

Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA

Abstract
Despite advances in medical therapy over the past few decades, the incidence of heart failure hospitalisation continues to rise. Diuretics
are the most common therapy used to treat heart failure as they relieve congestion. However, there is a lack of guidance on how to best
use these medications. Guidelines support the use of diuretics at the lowest clinically effective dose but do not specify a diuretic strategy
beyond that. Here we review the diuretics available for treatment, potential mechanisms of diuretic resistance and ways to address this
in the ambulatory setting, and review tools that have been developed to help guide diuretic use in the treatment of chronic heart failure.

Keywords
Loop diuretic, furosemide, torsemide, bumetanide, diuretic resistance, heart failure.

Disclosure: The authors have no conflicts of interest to declare.

Received: 30 July 2017 Accepted: 12 September 2017 Citation: Cardiac Failure Review 2017;3(2):108–12. DOI: 10.15420/cfr.2017:10:1
Correspondence: Justin L. Grodin, MD, MPH, 5323 Harry Hines Blvd, Dallas, TX 75390-9047, USA. E: justin.grodin@utsouthwestern.edu

Introduction
Advances in heart failure medical therapy over the past few decades
have improved the prognosis of patients with this condition. Despite
this, heart failure remains a significant burden to the medical system
as the incidence of heart failure hospitalisation continues to rise.1
Diuretics have been a mainstay of therapy in heart failure to relieve
congestion and improve symptoms. Despite the widespread use of
diuretics, there is a lack of guidance on how to best titrate these
medications in chronic use. Guidelines support the use of diuretics
at the lowest clinically effective dose, but do not specify a diuretic
strategy beyond that.2 Here we review the diuretics available for use in
heart failure, potential mechanisms of diuretic resistance and ways to
address this in the ambulatory setting, and review tools that have been
developed with the goal to help guide diuretic use to treat patients with
chronic heart failure.
Loop Diuretics
Loop diuretics remain the diuretic of choice for treating patients with
heart failure.3 Furosemide, torsemide and bumetanide are the agents
widely available for clinical use, with furosemide the predominant agent
of the three. All three loop diuretics are available in oral formulation
and are first absorbed in the gastrointestinal track. Once absorbed,
the majority of the diuretic becomes protein bound in the vascular
space, which in turn requires the drug to be transported into the
nephron by organic anion transporters.4 Loop diuretics then travel to
the ascending loop of Henle and inhibit the Na+/2Cl/K+ cotransporter to
block reabsorption of sodium and chloride, resulting in natriuresis. Loop
diuretics also induce renal prostaglandin synthesis, which results in renal
and peripheral vascular smooth muscle relaxation and venodilation.5
The dose–response curve is sigmoidal, demonstrating that the drug
concentration must reach a diuretic threshold to have an effect, and
further diuresis above this threshold is achieved by increased frequency
of administration rather than increased drug concentration.5
There are key pharmacokinetic differences between the loop diuretics
(Table 1). Torsemide and bumetanide have an oral bioavailability
of 80–100 %, while furosemide has a wide variant bioavailability of
10–100 %.6 Ingestion of food also has an effect on pharmacokinetics
as it can decrease the maximum concentration of loop diuretics
by one-half and increase the time to peak serum concentration by
30–60 min.7–9 The effect of food intake on the impairment of diuretic
absorption is greater with furosemide and bumetanide, whereas
torsemide’s bioavailability is relatively unchanged by food intake. The
overall rate of absorption is also negatively affected when the patient is
congested.10,11 In patients with chronic renal insufficiency, furosemide
has been shown to have a variable dose response compared with
a more consistent dose effect with bumetadine due to altered
metabolism of furosemide in patients with kidney disease.12 With the
oral formulations, furosemide has a half-life of 2 h, bumetanide has
a half-life of 1 h, and torsemide has the longest half-life at 3.5 h.13
Furosemide is the most common loop diuretic prescribed but has a
bioavailability that can be quite variable between similar patients as
well as within the same patient during different disease states. This
may be due to pharmacological factors inherent to furosemide and
genetic differences between individuals as well.14,15
Despite the variable bioavailability, furosemide is commonly the
first loop diuretic prescribed to patients with heart failure. However,
there are few adequately powered or designed studies assessing the
comparative effectiveness of these loop diuretics. The Torsemide in
Chronic Heart Failure study is the largest study to date comparing
furosemide to torsemide.16 The study found that after an average
follow up period of 9 months in 1,377 patients, those in the torsemide
group had a risk reduction in overall mortality, reduction in cardiac
mortality and improvement in functional status. Unfortunately, the
study was a non-randomised prospective cohort as it was a post-
market surveillance of safety, with surprisingly low use of beta-

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blockers and angiotensin converting enzyme inhibitors.16 Torsemide in
Chronic Heart Failure was also an open label study, so the comparison
between torsemide and furosemide was not without bias. Other
smaller studies support the benefits of torsemide over furosemide,
suggesting less heart failure-related hospital days but no differences
in hospitalisations due to heart failure.17,18 Some of these plausible
benefits might result from torsemide’s aldosterone antagonistic
properties.19,20 Practically speaking, the use of torsemide is reserved
in patients that have demonstrated some degree of diuretic resistance
to furosemide. However, doubts remain regarding its impact on clinical
outcomes. Bumatenide, on the other hand, is even less well studied
and its impact on clinical outcomes in comparison to furosemide is
still unclear.21
Loop Diuretic Resistance
A diminished response to loop diuretics, or diuretic resistance,
can lead to an adverse clinical course and prolong hospital stays.
Diuretic resistance occurs frequently, with data from the Prospective
Randomized Amlodipine Survival Evaluation study reporting that
up to 25 % of participants displayed diuretic resistance, defined as
absolute diuretic dose above the population median dose.3 This is a
common clinical scenario that requires an increase in diuretic dose
for decongestion. Another metric of diuretic resistance is diuretic
efficiency, which is the net fluid loss per mg of diuretic. It may be
a more precise measurement of diuretic resistance then absolute
diuretic dose and low diuretic efficiency has a stronger association
with mortality than does absolute diuretic dose.22
Although loop diuretics have not demonstrated a mortality benefit in
heart failure, evidence of diuretic resistance carries a poor prognosis
with a higher predicted mortality and increased risk of readmissions
for heart failure.22–25 Mechanisms to explain diuretic resistance are
multifactorial. In a congested state, aspects of gut wall oedema,
decreased splanchnic blood flow and decreased intestinal motility
due to an increased sympathetic state all lead to a delayed time to
maximum peak and decreased peak concentration of the drug.10 In
patients with renal insufficiency, other organic acids such as blood urea
nitrogen can compete with loop diuretics for transport by the organic
anion transporters, with less drug therefore reaching the site of action.
This decrease in drug concentration results in a failure to reach the
diuretic threshold concentration needed for the drug to be effective.
Further changes in sodium handling in response to loop diuretics
also contribute to diuretic resistance. During periods of decreased
drug levels between diuretic doses there is a rebound in sodium
reabsorption that has been termed a ‘post-diuretic effect’. 26
A ‘braking phenomenon’ has also been described after chronic
diuretic use due to renal adaptation. Hypertrophy of cells in the distal
convoluted tubules, away from the site of action of loop diuretics,
leads to increased efficiency of sodium reabsorption and decreases
the effect of loop diuretics.25 And lastly, other drugs can contribute
to diuretic resistance. Non-steroidal anti-inflammatory drugs are
common over-the-counter medications that clinicians should ask
their patients about as patients commonly view them as benign due
to their availability but they can contribute to diuretic resistance as
well as increased risk of hospitalisations.27
Diuretic resistance and decreased response to loop diuretics is,
unfortunately, not uncommon in clinical practice. Guidelines do
not dictate which loop diuretic to use, only to use the lowest dose
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Table 1: Properties of Loop Diuretics
Furosemide Torsemide Bumetanide
Relative intravenous 40 20 1
potency (mg)
Oral : intravenous 1:2 1:1 1:1
dosing
Bioavailability (%) 10–100 80–100 80–100
Drug half-life (h) 1.5–2.0 3–4 1.0–1.5
Duration of effect (h) 6–8 6–16 4–6
Reproduced from Felker & Mentz,6 with permission from Elsevier.
possible to achieve the desired effect.2 As diuretic resistance
becomes increasingly suspected due to a decreasing response to a
stable dose of loop diuretic, the diuretic dose can be increased in an
effort to achieve comparably efficacious natriuresis. Another option
at this time can also be to change from one loop diuretic to another
with the hope that better pharmacokinetics between the loop
diuretics can achieve the desired effect. Changing from furosemide
to torsemide is common due to more consistent bioavailability
of torsemide and the longer half-life of torsemide can potentially
counter the ‘post-diuretic’ effect seen with furosemide.
Ambulatory Intravenous Loop Diuretics
Another growing practice used to counter resistance to increasing oral
doses of loop diuretic is to administer intravenous loop diuretics in the
ambulatory setting. This strategy has been utilised by several centres to
help reduce hospitalisations, specifically targeting those patients that
would only require one or two doses of intravenous diuretic to achieve
euvolemia. Preliminary reported experiences so far have demonstrated
this as a safe and effective way to decongest hemodynamically stable
patients and potentially reduce hospitalisations for heart failure and
overall healthcare costs.28–30 These outpatient heart failure units may
therefore be useful to address those stable patients who appear to
have diuretic resistance not surmountable by oral doses and just
need some decongestion in order to respond to oral doses again.
Furthermore, these centers also present another opportunity to involve
a multidisciplinary care team as these patients are being monitored for
a few hours while being given intravenous diuretics.
Thiazide Diuretics
When higher doses of a loop diuretic or changing loop diuretics are
not achieving adequate decongestion, adding non-loop diuretics
is an additional strategy – commonly referred to as ‘sequential
nephron blockade’. Thiazide diuretics and metolazone are frequently
utilised with loop diuretics to achieve this sequential blockage
as thiazide diuretics inhibit the Na+Cl– cotransporter in the distal
convoluted tubule. This can counter sodium reabsorption that
occurs with the increased sodium load being delivered to the distal
convoluted tubule after loop diuretic administration, as well as counter
the increased sodium transport capacity or ‘braking phenomenon’
that occurs with chronic loop diuretic use. Although the use of loop
and thiazide diuretics is common clinical practice, the majority of the
data on this combination diuretic use is limited to small observational
trials or case studies.31 Despite this, the evidence in these studies
supports the use of combination diuretic therapy in those on high dose
loop diuretics demonstrating diuretic resistance.31 Common diuretics
used to augment loop diuretics are metolazone, hydrochlorothiazide,
chlorothiazide and bendroflumethiazide. Metolazone is commonly used
for combination therapy, but no study thus far has demonstrated one
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thiazide-type drug as being superior to another in augmenting diuresis
and this appears to be a class effect.31,32 This strategy does have risks,
as a more robust diuresis with combination diuretic therapy can lead to
electrolyte abnormalities including hypokalemia and, less commonly,
hyponatremia and hypochloremia. The increase in decongestion can
also worsen renal function if hypovolemia develops. Due to this,
frequent monitoring of electrolytes and renal function is paramount
when this strategy is used. When starting combination therapy in the
outpatient setting, starting with a low dose of metolazone such as
2.5 mg (or equivalent dosing of another thiazide-type diuretic) two
to three times a week and close monitoring to assess response and
monitor for adverse events is warranted.31 Similar to loop diuretics, the
concentration of thiazide diuretics must be adequate enough to cross
a threshold for effectiveness. After the initial dose of thiazide diuretic,
if there is not an augmentation in diuretic response, a higher dose
of thiazide diuretic is then warranted. Although it is common clinical
practice to administer the thiazide-type diuretic at least 30 min prior
to the loop diuretic, evidence is lacking with regard to this practice as
most studies administered the diuretics simultaneously.31
Mineralocorticoid Receptor Antagonists
Mineralocorticoid receptor antagonists (MRA), such as spironolactone
and eplerenone, are common medications used in chronic heart
failure to reduce adverse clinical outcomes.33–35 However, the doses
commonly used and studied in these landmark trials have minimal
diuretic effect, with their prognostic benefits likely resulting from
their neurohormonal antagonism. In contrast, small studies have
suggested that using doses in the range of 100–200 mg spironolactone
daily may increase diuretic efficacy in those thought to have diuretic
resistance and improve symptoms of congestion.36–38 The Aldosterone
Targeted NeuroHormonal Combined with Natriuresis Therapy – Heart
Failure study evaluated spironolactone 100 mg versus placebo in
hospitalised patients with acute decompensated heart failure and did
not find differences in their primary end point between NT pro B-type
natriuretic peptide levels or their secondary outcome of dyspnea
relief, clinical congestion, net urine output or weight loss between
standard of care and high-dose spironolactone.39 Of note, there was
no difference in the safety outcomes of incidence of hyperkalemia or
change from baseline estimated glomerular filtration rates between
the placebo and high-dose spironolactone groups at 96 h. Although
this study demonstrated that high doses of spironolactone were
reasonably well tolerated, the use of high-dose MRAs for treating
diuretic resistance remains unclear. Although uncommon, the
evolution of hyperkalemia remains a strong consideration with MRA
use. Estimations suggest that the incidence rates in heart failure
patients using MRAs range from 5 to 15 %.40–42
Vasopressin Antagonists
Vasopressin antagonists have also been considered for use in those
with diuretic resistance. This class of drug blocks the effects of
vasopressin on the aquaporin V2 receptor at the cortical collecting
duct, leading to an increase in free water excretion or ‘aquaresis’.
In the Efficacy of Vasopressin Antagonism Heart Failure: Outcome
Study with Tolvaptan, the investigators evaluated the addition of
tolvaptan 30 mg daily to intravenous loop diuretics in hospitalised
patients for heart failure. There was an increase in weight reduction
and lower discharge weight in the tolvaptan group, but no evidence
of long-term benefit in morbidity or mortality.43 When tolvaptan was
started in addition to chronic loop diuretic therapy in ambulatory
patients with heart failure, a dose-dependent weight loss was
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CFR_Grodin_FINAL.indd 110
observed early on, but this failed to translate into any long-term
improvement in congestion with continued therapy.44,45 As a result
of these disappointing findings in combination with two recent null
clinical trials attempting to elucidate the use of tolvaptan as part of
an additional strategy for the management of acute decompensated
heart failure, the role of tolvaptan for the routine management of
congestion remains in question.46,47
Strategies to Guide Diuretic Titration
Heart failure is the leading cause of hospitalisation in the US and
Europe; from 2001 to 2009, more than 1 million patients were
hospitalised with heart failure as the primary diagnosis, comprising
1–2 % of all hospitalisations.48 This, in addition to the high rate of
readmission after heart failure hospitalisation, presents a significant
burden to the healthcare system. Optimising diuretic therapy in heart
failure patients is a challenging task. Not surprisingly, there has been
an increase in research to investigate complementary tools to help
clinicians monitor and adjust diuretics, as well as other therapies to
avoid congestion and prevent subsequent hospitalisations. Here we
review several recent advances, such as ambulatory hemodynamic
monitoring both invasive and non-invasive, and the emergence of
subcutaneous furosemide as a potential option for patients in the future.
Many patients with heart failure have implantable cardioverter
devices in place, and these devices allow for the collection of
additional clinical data such as heart rate variability, patient activity and
arrhythmias. These devices are also capable of calculating intrathoracic
impedance, which is a characteristic of the electrical current that
can pass from the device case to the right ventricular electrode.49
As pulmonary congestion increases, the device senses a drop in
electrical impedance. Not surprisingly, there is an inverse correlation
between the intrathoracic impedance with both pulmonary capillary
wedge pressure and net fluid loss during an acute hospitalisation.49
This information, in addition to other parameters measured from the
device, may identify patients at risk for heart failure events, heart
failure hospitalisations or 30-day rehospitalisations after discharge.
However, whether thoracic impedance might guide diuretic titration
and or impact doses in other heart failure therapies still has no clear
impact on rehospitalisations or clinical outcomes.50–53
Direct pulmonary artery pressure device monitors have had promising
results in the management of heart failure. The CardioMEMSTM device
by St Jude Medical (Atlanta, GA, USA) is placed in the pulmonary artery
during a right heart catheterisation and allows for measurement of
pulmonary artery pressures. The CardioMEMSTM Heart Sensor Allows
Monitoring of Pressure to Improve Outcomes in NYHA class III Heart
Failure Patients (CHAMPION) study evaluated this device. In that
study, clinicians had access to the treatment group’s pulmonary
artery pressure results but not the pressure results of the control
group.54 Patients in the treatment group had a 28 % relative risk
reduction in the primary end point of heart failure hospitalisations at
6 months, and over the entire study period of 15 months there was
a 37 % relative risk reduction in heart failure hospitalisation in the
treatment group.54 One caveat when interpreting these results is that
the treatment group had additional clinical contact and support due
to having a device implanted, which may have a had a confounding
effect on clinical outcome.55 Post-marketing efficacy studies are
ongoing, testing whether the benefits in the CardioMEMSTM device
translate into improvement in real-world patient care.56 For example,
a recent retrospective cohort study observed a reduction in heart
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 Dilemmas in the Dosing of HFrEF Drugs: Titrating Diuretics in Chronic Heart Failure
failure hospitalisations in the 6 months after CardioMEMS implantation
compared with the 6 months prior to implantation, supporting the
results of the CHAMPION trial on the use of the device in addition to
standard of care.57 At this point, however, the therapeutic role of the
CardioMEMS device continues to evolve.
In contrast to invasive implantable monitors, non-invasive systems
have been developed to assess pulmonary congestion and avoid
acute decompensations. An electromagnetic energy-based technology
(Remote Dielectric Sensing, ReDSTM) non-invasively measures the
dielectric properties of tissues using low-power electromagnetic
signals. This is performed non-invasively as patients wear a vest for a
few minutes in which this measurement is recorded to give an indication
of the fluid content in the lungs, a method that has been validated in
prior studies using chest computed tomography as a comparator.58 A
recent small study using 50 patients shows that in patients recently
discharged for decompensated heart failure, outpatient therapy guided
by the ReDSTM device results appears to decrease the rate of heart
failure rehospitalisation.59 A larger multicentre trial is ongoing to further
confirm these preliminary findings.60 Non-invasive lung impedance
monitoring is also being investigated as a surrogate to monitor for
pulmonary edema. A recent moderate-sized randomised control trial
performed at two centres demonstrated that patients who had their
heart failure therapies guided by lung impedance measurements at
outpatient visits over 1 year had a reduction in hospitalisations for
heart failure.61 If proven effective in improving clinical outcomes, these
devices can potentially serve as another tool available for clinicians
to monitor patients in the ambulatory setting and provide additional
objective data to assist in titrating diuretics. However, non-invasive
assessments, whether through measurement of electrical impedance,
lung impedance or dielectric properties, with routine care have yet
been shown to improve hard clinical outcomes in patients with heart
failure. Nevertheless, these methods do provide additional insight that
may guide chronic decongestion strategies.
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Although furosemide has been used for decades, utilisation of a
novel administration route by subcutaneous injection may be a viable
alternative for patients with congestive heart failure. One early case
series evaluated subcutaneous furosemide to a placebo injection of
normal saline, with the group receiving subcutaneous furosemide
demonstrating a higher amount of urine voided and higher urine sodium
concentration.62 The subcutaneous furosemide group demonstrated a
30-min onset of diuresis and a duration of increased diuresis of be 3–4 h.
Currently, this is an off-label use, with the limited published data
available being from small case studies and uses in palliative care.63–65
The sc2WearTM Infusor, developed by scParmaceuticalsTM (Burlington,
MA, USA), is a small pump that attaches to the body via an adhesive
and delivers subcutaneous injections of medications. It is currently
being investigated for the administration of subcutaneous furosemide
in patients admitted for acute decompensated heart failure.66 The
study will compare the strategy of early discharge with subcutaneous
furosemide compared with usual care in a group of patients that
have been stabilised but need further decongestion with intravenous
diuretics. As a result, subcutaneous furosemide may be another option
in the ambulatory setting for patients that become less responsive to
escalating oral diuretic doses.
Conclusion
Diuretics play a pivotal role in the management of heart failure to
decrease congestion and symptoms. This is made difficult by the
development of diuretic resistance, which is sometimes insurmountable
with the common practices of increased doses of diuretics or a change
in the loop diuretic. Combination therapy is frequently employed, with
thiazide-type diuretics being the most commonly used. Despite diuretics
being used for decades in the treatment of heart failure, guidance on
the best management strategy of heart failure is still lacking. Continued
investigations into diuretics and fluid-management strategies will
benefit our knowledge base on the use of these medications and
hopefully improve clinical outcomes for our patients with heart failure. n
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9343(98)00111-9 efficiency: a metric of diuretic responsiveness with
Voelker JR, Cartwright-Brown D, Anderson S, et al. prognostic importance in acute decompensated heart
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Vargo DL, Kramer WG, Black PK, et al. Bioavailability, in acute heart failure: clinical characteristics and prognostic
pharmacokinetics, and pharmacodynamics of torsemide significance. Eur Heart J 2014;35:1284-93. DOI: 10.1093/
and furosemide in patients with congestive heart failure. eurheartj/ehu065; PMID: 24585267
Clin Pharmacol Ther 1995;57:601–9. DOI: 10.1016/0009- 24. Aronson D, Burger AJ. Diuretic response: clinical and
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Muller K, Gamba G, Jaquet F, Hess B. Torasemide vs 27. Huerta C, Varas-Lorenzo C, Castellsague J, Garcia Rodriguez LA.
furosemide in primary care patients with chronic heart Non-steroidal anti-inflammatory drugs and risk of first
failure NYHA II to IV – efficacy and quality of life. Eur J Heart Fail hospital admission for heart failure in the general population.
2003;5:793–801. DOI: 10.1016/S1388-9842(03)00150-8 Heart 2006;92:1610–5. DOI: 10.1136/hrt.2005.082388; PMID:
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randomized trial of torsemide compared with furosemide 28. Buckley LF, Carter DM, Matta L, et al. Intravenous diuretic
therapy for patients with heart failure. Am J Med 2001;111:513– therapy for the management of heart failure and volume
20. DOI: 10.1016/S0002-9343(01)00903-2 overload in a multidisciplinary outpatient unit. JACC Heart Fail
Yamato M, Sasaki T, Honda K, et al. Effects of torasemide on 2016;4:1–8. DOI: 10.1016/j.jchf.2015.06.017; PMID: 26656139
left ventricular function and neurohumoral factors in patients 29. Ryder M, Murphy NF, McCaffrey D, et al. Outpatient
with chronic heart failure. Circ J 2003;67:384-90. DOI: 10.1253/ intravenous diuretic therapy: potential for marked reduction
circj.67.384; PMID: 12736474 in hospitalisations for acute decompensated heart failure.
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transcardiac extraction of aldosterone in patients with PMID: 18308632
congestive heart failure. J Am Coll Cardiol 2004;44:2252–3. 30. Makadia S, Simmons T, Augustine S, et al. The diuresis clinic:
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