REVIEWS OF THERAPEUTICS

A Systematic Review and Meta-Analysis of Metolazone

Compared to Chlorothiazide for Treatment of Acute
Decompensated Heart Failure
Taylor D. Steuber1,2* Kristin M. Janzen,3,4 and Meredith L. Howard5
1
Department of Pharmacy Practice, Auburn University Harrison School of Pharmacy, Huntsville, Alabama;
2
Department of Pharmacy, Huntsville Hospital, Huntsville, Alabama; 3Division of Pharmacy Practice, The
University of Texas at Austin College of Pharmacy, Austin, Texas; 4Department of Pharmacy, Dell Seton Medical
Center at the University of Texas, Austin, Texas; 5Department of Pharmacotherapy, University of North Texas
System College of Pharmacy, Fort Worth, Texas,

Treatment of volume overload in the setting of acute decompensated heart failure (ADHF) is typically
achieved through the use of loop diuretics. While they are highly effective, some patients may develop
loop diuretic resistance. One strategy to overcome this scenario includes sequential nephron blockade
with a thiazide-type diuretic; however, it is unknown which thiazide-type diuretic used in this setting
is most effective. A systematic review and meta-analysis were performed to compare the efficacy and
safety of chlorothiazide with metolazone as add-on therapy in the setting of loop diuretic resistance
for the treatment of ADHF. Literature searches were conducted through PubMed, Google Scholar, and
Science Direct from inception through February 2020 using the following search terms alone or in
combination: metolazone, chlorothiazide, acute decompensated heart failure, loop diuretic, and urine
output. All English-language prospective and retrospective trials and abstracts comparing metolazone
to chlorothiazide for the treatment of ADHF were evaluated. Studies were included if they analyzed
urine output for at least 24 hours in patients with ADHF. Meta-analysis was conducted to evaluate
pooled effect size by using a random-effect model. Primary outcomes included net and total urine out-
put. Secondary outcomes included commonly reported safety outcomes. Four studies comparing the
use of metolazone to chlorothiazide as an adjunct to loop diuretics to treat ADHF were included in
the evaluation. Metolazone was as effective as chlorothiazide to augment loop diuretic therapy in
ADHF in most studies with no pooled difference in net or total urine output. However, there were
notable differences in baseline loop diuretic dosing, ejection fraction, renal function, race, and end-
point timing across studies. Adverse effects were commonly observed and included electrolyte abnor-
malities, change in renal function, and hypotension but were comparable between groups. Metolazone
is as effective as chlorothiazide as add-on to loop diuretics in treating ADHF without an increase in
safety concerns.
KEY WORDS metolazone, chlorothiazide, thiazide, diuretic resistance, sequential nephron blockade,
heart failure, diuretic.
(Pharmacotherapy 2020;40(9):924–935) doi: 10.1002/phar.2440

Conflict of interest: The authors have declared no conflicts of interest for this article.
*Address for correspondence: Taylor D. Steuber, Department of Pharmacy Practice, Auburn University Harrison School of
Pharmacy, 301 Governors Drive SW, Suite 357, Huntsville, AL 35801; e-mail: tds0038@auburn.edu.
Ó 2020 Pharmacotherapy Publications, Inc.
 METOLAZONE VERSUS CHLOROTHIAZIDE Steuber et al
Management of volume overload in the setting
of acute decompensated heart failure or other
acute illnesses is generally best achieved with
loop diuretics given their ability to produce sig-
nificant diuresis. Consequently, loop diuretics
such as bumetanide, furosemide, and torsemide
are recommended as first-line treatment of vol-
ume overload, especially in patients with heart
failure of any type, both in the maintenance and
acute settings.1 Loop diuretics exert their potent
diuretic effects through inhibition of the
sodium-potassium-chloride co-transporter in the
ascending loop of Henle, excreting both water
and excess sodium.2
While loop diuretics are highly efficacious,
some patients may experience reduced diuresis,
or loop diuretic resistance, posing a challeng-
ing clinical scenario, especially in the acute
setting when timely diuresis is necessary.
There are no set criteria that define loop
diuretic resistance, but it is generally recog-
nized as the inability to reach urine output
goals despite significant doses of loop diuret-
ics. Loop diuretic resistance is reported in var-
ious clinical settings, but is most often
reported in the setting of heart failure.3 A
variety of mechanisms can be responsible for
loop diuretic resistance, often related to
actions in the nephron. One resistance mecha-
nism includes increased sodium retention after
loop diuretic doses have worn off which over-
comes the diuretic effects. Another mechanism
involves decreased efficacy of the diuretic with
repeated dosing due to loop of Henle hyper-
function. Distal tubule hypertrophy leading to
rebound sodium retention may also play a
role. Finally, low glomerular filtration rates or
decreased kidney blood flow may also be
linked to diuretic resistance.2, 3
Various strategies aimed at overcoming loop
diuretic resistance exist, and success often
depends on the cause of resistance. Increasing
the loop diuretic dose or dosing frequency,
switching to continuous infusion dosing, or
sodium restriction are examples of initial
approaches.2 In patients unresponsive to these
methods, additional strategies may be necessary,
such as combination diuretic therapy to achieve
sequential nephron blockade. Sequential
nephron blockade with the addition of a thi-
azide-type diuretic to a loop diuretic works by
blocking distal tubule sodium reabsorption.
Doing this may help overcome the additional
sodium retention mechanisms that may
925
commonly lead to loop diuretic resistance.
Aligning with this proposed mechanism, the
2013 American Heart Association Guideline for
the Management of Heart Failure recommends
sequential nephron blockade to overcome loop
diuretic resistance.1
Although the combination of thiazide-type
diuretics with loop diuretics is recommended to
overcome loop diuretic resistance, numerous
options exist. Two commonly used thiazide-type
diuretics for this indication are chlorothiazide, a
benzothiadiazine or thiazide diuretic adminis-
tered intravenously and orally but often used
intravenously, and metolazone, a thiazide-like
diuretic administered orally. Thiazide-type
diuretics, as a class, can lead to electrolyte
abnormalities, including hyponatremia, hypoka-
lemia, and hypomagnesemia. When combined
with loop diuretics, these effects may be more
pronounced. Additionally, the choice between
chlorothiazide and metolazone depends on phar-
macokinetic and pharmacodynamic factors.
Intravenous (IV) chlorothiazide has the benefit
of a faster onset of action of 15 minutes com-
pared with one hour for oral metolazone.4, 5
Conversely, oral metolazone is more potent and
has a longer duration of effect, potentially up to
24 hours, which may assist in providing diuresis
past any loop diuretic dosing intervals. In con-
trast, the effects of chlorothiazide last up to
12 hours. Along with these differences, metola-
zone is less costly and offers a less invasive
route of administration.
Patient-specific factors may also come into
play regarding the choice of thiazide-type diure-
tic. Specifically, in patients with acute decom-
pensated heart failure (ADHF), gut edema may
lead to erratic absorption of oral diuretics. Meto-
lazone may have much slower absorption in
ADHF patients with edema, with peak effects
potentially taking longer than the typical one
hour onset.5–7 Patients with ADHF may also
have concomitant chronic kidney disease, or
alternatively, acute kidney injury secondary to
kidney hypoperfusion or cardiorenal syndrome.
Chlorothiazide may not achieve adequate con-
centrations at the site of action in the setting of
renal dysfunction (e.g. creatinine clearance
(CrCl) < 10 or < 30 ml/min without a loop
diuretic), potentially causing it to be less effec-
tive.4, 8 Alternatively, metolazone does not
appear to be impacted by renal dysfunction and
is labeled for edema accompanying renal disease,
including renal dysfunction.5
926 PHARMACOTHERAPY Volume 40, Number 9, 2020
Despite a general recommendation for thi-
azide-type diuretic use, numerous differences
exist between these options. As such, the ques-
tion remains as to which agent has the most
favorable efficacy and safety profile in combina-
tion with loop diuretics. The purpose of this
review is to analyze the efficacy and safety of
chlorothiazide compared to metolazone as
diuretics in the setting of loop diuretic resistance
for the treatment of ADHF.
Methods
An English language systematic literature
review was performed through a PubMed, Goo-
gle Scholar, and Science Direct search from
inception through February 2020 using the fol-
lowing terms alone or in various combinations:
metolazone, chlorothiazide, acute decompensated
heart failure, loop diuretic, and urine output. Boo-
lean search strings were used in the following
manner: (metolazone AND chlorothiazide) AND
(acute decompensated heart failure OR ADHF)
with all parameters. Search parameters were lim-
ited to prospective and retrospective clinical tri-
als, reviews, and abstracts conducted in humans.
Reference lists in relevant articles were reviewed
for additional studies. A reference librarian
assisted in conducting the literature search.
Studies eligible for inclusion in this review were
prospective and retrospective clinical trials in
adult (18 yrs or older) patients with ADHF com-
paring oral metolazone to parenteral chloroth-
iazide to augment loop diuretic therapy that
reported change in total urine output (UOP) or
net UOP for at least 24 hours. They were
included if the study population consisted exclu-
sively of patients with ADHF or if the publica-
tion reported outcomes in a subgroup of the
ADHF population. Differences in adverse effects
or clinical outcomes were desired, but not
required. Studies that included patients with
both heart failure with preserved ejection frac-
tion (HFpEF) and heart failure with reduced
ejection fraction (HFrEF) were included. Studies
that did not report comparative effectiveness of
the two therapies, did not include exclusively
patients with ADHF, or did not report markers
of efficacy (e.g. UOP) were excluded. If there
was a question about whether a study should be
included, all authors discussed to assess eligibil-
ity for inclusion. Outcomes abstracted included
baseline demographics, change in UOP, change
in weight, incidence of adverse effects, and clini-
cal outcomes. Relevant data were extracted and
compiled into a table by one author and were
subsequently confirmed by another. Discrepan-
cies were settled through discussion.
Risk of bias for each study was independently
assessed by two investigators using the GRACE
checklist (Good ReseArch for Comparative
Effectiveness, Version 5.0), which evaluates the
quality of data and methods in observational
studies.9 Eleven questions involving study data
and methods were answered as Yes, No, or Not
Reported. Discrepancies were resolved through
discussion.
Data were analyzed using Review Manager,
Version 5.3 software (RevMan; The Cochrane
Collaboration, Oxford, United Kingdom).
Heterogeneity was assessed using the I2 statistic.
A random-effects model was used to analyze the
effects of metolazone on total and net UOP com-
pared to chlorothiazide using standard mean dif-
ference (SMD). Key safety outcomes were
assessed using odds ratios (ORs). A sensitivity
analysis was performed by excluding individual
trials to examine the impact on the overall
results. Standard deviations were estimated using
the provided median, interquartile range, and
sample size. Corresponding authors were con-
tacted if certain efficacy data were not reported
in a study. Forest plots also indicated the results
of the meta-analysis. A p-value of < 0.05 was
considered statistically significant.
Results
After abstract and publication review, four
studies fulfilled inclusion criteria. Details regard-
ing study inclusion are shown in Figure 1. Data
evaluating the efficacy and safety of oral metola-
zone compared to parenteral chlorothiazide are
primarily limited to single center, retrospective
cohort studies conducted between 2015 and
2019, with only one prospective, randomized
trial.10–13 Table 1 summarizes study design,
duration, treatment arms, baseline characteris-
tics, and efficacy/safety outcomes of individual
studies. Table 2 summarizes the results of the
GRACE checklist. Pooled analysis revealed no
difference in net urine output (SMD = 0.04;
95% CI, 0.25 to 0.18; p=0.75) or total urine
output (SMD = 0.09; 95% CI, 0.30 to 0.11;
p=0.36) when comparing chlorothiazide to
metolazone (Figure 2A,B). There was also no
difference in rates of study-defined hypokalemia
(OR 0.85; 95% CI, 0.51–1.41; p=0.73) or wors-
ening of renal function (OR 1.18; 95% CI, 0.58–
2.39; p=0.36) when comparing metolazone
 METOLAZONE VERSUS CHLOROTHIAZIDE Steuber et al
Articles identified by MEDLINE/Scopus/Google
Scholar search (n=38)
Abstracts reviewed
(n=38)
Publications reviewed
(n=11)
Studies included in review
(n=4)
Figure 1. Studies meeting inclusion criteria for review.
against chlorothiazide, though only three studies
reported data on each of these endpoints (Fig-
ure 2C,D). Pooled results for hypotension were
not compared as only two studies reported data
on this outcome. Further detail about results
and characteristics from individual studies fol-
low.
The first study comparing these agents was
conducted in 2015. The investigators compared
chlorothiazide and metolazone in 55 adult
patients hospitalized with a diagnosis of ADHF
with significant renal dysfunction, defined as a
CrCl of 15–50 ml/minute.10 Patients received
initial treatment with IV furosemide for at least
24 hours, followed by at least 72 hours of expo-
sure to one of the study drugs. Most patients in
this study were African American males, and
69% had heart failure with reduced ejection frac-
tion (HFrEF). The average left ventricular ejec-
tion fraction (LVEF) was 33%, and patients had
an average CrCl of 27 ml/minute. Prior to
admission, 36% of patients were treated with
either a thiazide (33%) or thiazide-type (3%)
diuretic. Patients were similarly matched, with
927
Additional articles identified through references
(n=0)
Articles excluded:
Reviews (n=23)
Case series (n=2)
Scientific meeting abstract (n=2)
Additional studies excluded:
Did not compare two treatments (n=4)
Study design rationale publications (n=2)
Not exclusive heart failure population (n=1)
the exception of slightly higher home doses of
loop diuretics in the metolazone group, with
average furosemide equivalents in the metola-
zone group at 90 mg versus 70 mg in chloroth-
iazide group (p<0.01). Patients in the
metolazone group received a median dose of
2.5 mg daily during the study period, whereas
patients in the chlorothiazide group received
median doses increasing in 250-mg increments
each day (day 1: 500 mg; day 2: 750 mg, day 3:
1,000 mg). The median total dose of furosemide
was significantly higher in the chlorothiazide
group compared to the metolazone group during
the treatment period (1015 mg vs 500 mg,
respectively; p<0.001). The primary efficacy
endpoint was net urine output (UOP) at
72 hours, which showed no significant differ-
ence. There were also no differences in the sec-
ondary endpoints, including attainment of 3 L
or more total net UOP at 72 hours (p=0.17) and
total UOP (p=0.47). Length of stay in the meto-
lazone group was significantly shorter than in
the chlorothiazide group (7 vs 16 days, p=0.03)
despite similar rates of inotrope use between the
 928
Table 1. Summary of Clinical Trials Evaluating Oral Metolazone versus Intravenous Chlorothiazide
Study Change in Urine
Year/Study Study Design Duration Study Groups Baseline Characteristics Output Clinical Outcomes Adverse Effects
201510 Retrospective 72 hrs • Metolazone (n=33) • Age: 69 yrs Net UOP at 72 hrs Hospital LOS • Hypokalemia
cohort • Race: 85% AA a not defined,
• MTD: 7.5 mg • Weight: 71.5 kg • 4828 mlNet • 7 days reported as
• MDD: 2.5 mg UOP of 3 L “nearly half”
• SCr: 2.2 mg/dl
• MTD Furose-a • Inpatient furosemide • Two with
mide: 500 mg dose: 100 mg IV
• 73%Total UOP worsening
• Baseline UOP: • 9442 ml renal function
1600 ml/day
• HFrEF: 70%
• HFpEF: 30%
• Chlorothiazide • Age: 70.5 yrs Net UOP at 72 hrs Hospital LOS • Hypokalemia
(n=22) • Race: 73% AA a not defined,
• Weight: 69.6 kg • 3779 mlNet • 16 days reported as
• MTD: 2500 mg UOP of 3 L “nearly half”
• SCr: 2.2 mg/dl
• MDD: 500 mg • Inpatient Furosemide • 55%Total UOP • Three with
(D1) – 1000 mg Dose: 150 mg IV worsening
(D3) • 7500 ml renal function
MTD Furose- • Baseline UOP:
• 817.5 ml/day
mide: 1015 mga
• HFrEF:68%
• HFpEF: 32%
201611 Retrospective 24 hrs • Metolazone (n=89) • Age: 57.6 yrs Increase in Net UOP Hospital LOS • Hypokalemia:
cohort, non- • Race: 50.6% AA b 60.7%a
inferiority • ATD: 5.8 mg • Weight: 104.5 kg • 1319.6 ml Net • 16 days30- • Severe hypo-
trial • ATD Furose-a UOP at 24 hrs day readmis- kalemia:
mide: 272.3 mg • SCr: 1.9 mg/dl sion
• Inpatient furosemide • 2030.2 mlTotal 24.7%
dose: 268.4 mg IVa UOP • 18%In-hospi-
• Baseline net UOP: tal mortality
710.6 ml • 3945.7 ml
• HFrEF: 59.6% • 13.5%
PHARMACOTHERAPY Volume 40, Number 9, 2020

• HFpEF: 40.4%
• Chlorothiazide • Age: 60.3 yrs Increase in Net UOP Hospital LOS • Hypokalemia:
(n=88) • Race: 50% AA 75%a
• Weight: 98.5 kg • 1397.6 mlNet • 16 days30- • Severe hypo-
• ATD: 491 mg UOP at 24 hrs day readmis- kalemia:
• SCr: 1.8 mg/dl sion
• ATD Furose-a • Inpatient Furosemide 30.7%
mide: 316.7 mg a • 2274.6 mlTotal
Dose: 318.9 mg IV UOP

(continued)
Table 1. (continued)

Study Change in Urine

Year/Study Study Design Duration Study Groups Baseline Characteristics Output Clinical Outcomes Adverse Effects
• Baseline net UOP: • 3625.2 ml • 19.3%In-hos-
877 ml pital mortal-
• HFrEF: 62.5% ity
• HFpEF: 37.5%
• 5.7%
12
2019 Retrospective 24 hrs • Metolazone (n=60) • Age: 63 yrs Increase in UOP at Hospital LOS • Hypokalemia:
cohort • Race: 56.6% Caucasian 24 hrs 15%
• ATD: ≥ 5 mg • SCr: 1.61 mg/dl • 13 daysICU • Hypona-
• ATD Furose- • 1458 mlTotal LOS tremia: 31.7%
mide: ≥ 80 mg • Inpatient furosemide UOP
dose: ≥80 mg IV • 2 days • Hypochlore-
• Baseline UOP: 1675 ml • 3400 mlNet mia: 28.3%
• Baseline net UOP: UOP at 24 hrs • Hypotension:
552 ml 16.7%
• HFrEF: 100% • 2191.5 ml
• HFpEF: 0%
• Chlorothiazide • Age: 64 yrs Increase in UOP at Hospital LOS • Hypokalemia:
(n=108) • Race: 68.5% Caucasian 24 hrs 15.7%
• SCr: 1.49 mg/dl • 16 daysICU • Hypona-
• ATD: ≥ 500 mg • 1820 mlTotal LOS tremia: 20.4%
• ATD Furose- • Inpatient furosemide UOP
dose: ≥ 80 mg IV • 4 days • Hypochlore-
mide: ≥ 80 mg mia: 24.1%
• Baseline UOP: • 3552 mlNet
1692.5 ml UOP at 24 hrs • Hypotension:
• Baseline net UOP: 24.1%
350 ml • 1870.5 ml
• HFrEF: 100%
• HFpEF: 0%
201913d Prospective, 48 hrs • Metolazone (n=20)d • Age: 61 yrs Weight loss at 48 hrs 30-day • Hypokalemia:
randomized, • Race: 65% Caucasian c readmission 15%
double-blind, • ATD: 5 mg twice • SCr: 2.0 mg/dl • 4.6 kg Total • Hypona- a
double daily UOP at 48 hrs tremia: 10%
METOLAZONE VERSUS CHLOROTHIAZIDE Steuber et al

• Inpatient Furosemide • 25%

dummy • ATD Furose- Dose: 680 mg IV c
mide: 700 mg • 7.78 L • Hypotension:
• Baseline UOP: 10%
1170 ml/12 hrs • SCr
• HFrEF: 60% increase > 1 -
• HFpEF: 40% mg/dl: 5%
• Chlorothiazide • Age: 67 yrs Weight loss at 48 hrs 30-day • Hypokalemia:
d
(n=20) • Race: 60% Caucasian readmission 10%

(continued)
929
 930 PHARMACOTHERAPY Volume 40, Number 9, 2020

groups. There were no significant differences in

AA = African American; ADHF = acute decompensated heart failure; ATD = Average Total Dose (for study duration); HFpEF = heart failure with preserved ejection fraction; HFrEF = heart
increase > 1 -
• Hypotension:
• Hypona- a
tremia: 45%

mg/dl: 15%
safety outcomes, though hypokalemia occurred
Adverse Effects

with reduced ejection fraction; ICU = intensive care unit; LOS = length of stay; MDD = Median Daily Dose; MTD = Median Total Dose (for study duration); UOP = urine output.
in approximately half of patients in both groups.
No differences in efficacy endpoints emerged

• SCr
0%
when the authors examined subgroups with
CrCl 15–30 or 15–40 ml/minute, though they
noted a trend favoring metolazone in the latter.
The authors concluded that sequential nephron
Clinical Outcomes

blockade with either metolazone or chloroth-

iazide appears to be efficacious and safe in
ADHF with renal dysfunction. This retrospective
35%

review laid the groundwork for future studies in

this setting.10
•

In 2016, researchers11 conducted a retrospec-

tive, non-inferiority study comparing metolazone
and chlorothiazide in 177 patients admitted with
UOP at 48 hrs
5.8 kgcTotal
Change in Urine

ADHF and loop diuretic resistance, defined as

160 mg/day or more of furosemide equivalents.
• 8.77 Lc

Patients must have received at least one dose of

Output

study drug, and the loop diuretic dose could not

be increased by > 25% during the 24-hour per-
•

iod following the dose of thiazide-type diuretic.

Approximately half the patients were African
American and male, and 60% had HFrEF.
Inpatient furosemide
Baseline Characteristics

Patients in the study had an average LVEF of

dose: 611 mg IV

1372 ml/12 hrs

36%. Of note, 18% of patients were reported to

SCr: 2.1 mg/dl

Baseline UOP:

HFpEF: 20%
HFrEF: 80%

be on a thiazide-type diuretic prior to admission,

although details were not provided. Other base-
line characteristics were evenly matched with a
few notable exceptions. Patients in the chloroth-
iazide group had more advanced heart failure
•
•
•
•
•

based on New York Heart Association class and

Also included another arm (tolvaptan, n=20) but did not include based on review.

NT-proBNP concentrations. Additionally, 48% of

Statistically significant compared between groups for non-inferiority (p<0.05).

patients in the chlorothiazide group were receiv-

ATD: 500 mg

ATD Furose-

ing inotropes as compared to 32% with metola-

mide: 712 mg

zone (p=0.04). Of note, patients in the

twice daily
Study Groups

chlorothiazide group were receiving significantly

higher doses of IV furosemide before and during
Statistically significant compared between groups (p<0.05).

the study period, including higher rates of con-

•
•

tinuous infusion loop diuretics during the study

significant compared to baseline (p<0.05).

period (69% vs 37%, p<0.001). The primary effi-

cacy endpoint was non-inferiority of metolazone
Duration

for increase in net UOP, which met the thresh-

Study

old for non-inferiority (p=0.026). Controlling

for inotrope administration, metolazone still met
criteria for non-inferiority (p=0.013). There
were no significant differences in any secondary
Study Design

endpoints, including total UOP at 24 hours, net

Table 1. (continued)

UOP at 24 hours, body weight, length of stay,

hospital readmission, or in-hospital mortality.
For safety endpoints, patients in the chloroth-
iazide group experienced significantly more
Year/Study

Statistically

hypokalemia (defined as serum potas-

sium < 4 mEq/L) than the metolazone group,
failure

although this could be attributed to higher doses

d
b
a

c
 METOLAZONE VERSUS CHLOROTHIAZIDE Steuber et al 931
Table 2. GRACE Checklist Evaluation of Studies Included in Analysis9
Study D1 D2 D3 D4 D5 D6 M1 M2 M3 M4 M5
201510 Y Y Y Y Y Y N Y N Y NR
201611 Y Y Y Y Y Y Y Y Y Y Ya
201912 Y Y Y Y Y N Y Y N Y NR
201913 Y Y Y Y Y Y Y Y Y Y NR
Y
a
– criterion met; N – criterion not met; N/A – criterion not applicable; NR – criterion not reported.
Study results did not substantially change based on sensitivity analysis.

Figure 2. Pooled results of studies comparing metolazone to chlorothiazide for (A) Net urine output, (B) Total urine output,
(C) Hypokalemia, and (D) Worsening renal function. [Color figure can be viewed at wileyonlinelibrary.com]

of loop diuretics. Rates of severe hypokalemia
and other electrolyte abnormalities were not sig-
nificantly different. The authors concluded that
oral metolazone was non-inferior to IV chloroth-
iazide for enhancing net UOP in patients with
ADHF and loop diuretic resistance with similar
safety profiles, supporting the findings.10, 11
While the two prior studies included a mix of
HFpEF and HFrEF patients with ADHF, in a
recent study, the investigators analyzed 168
932 PHARMACOTHERAPY Volume 40, Number 9, 2020
patients admitted with ADHF but limited the
cohort to patients with HFrEF (LVEF 40% or
less).12 This is the only study to date that exam-
ined patients with HFrEF exclusively. All
patients received IV loop diuretic at least
24 hours prior to receiving at least one dose of
metolazone or chlorothiazide at doses of at least
5 or 500 mg, respectively. Patients were mostly
Caucasian and male, and all patients were trea-
ted with 80 mg or more of furosemide or equiv-
alent per day prior to the intervention period.
Only one patient reported taking a thiazide-type
diuretic prior to admission. The average LVEF
was 22%, and the average CrCl was 45 ml/min-
ute. A substantial proportion of patients were on
inotropes (46%), vasopressors (30%), and con-
tinuous infusion loop diuretics (55%). Com-
pared to metolazone, there were significantly
more patients with continuous infusion loop
diuretics (62% vs 47.1%), mechanical ventilation
(13.9% vs 3.3%), and expiration during hospital-
ization (19.4% vs 1.7%) in the chlorothiazide
arm. Most patients received two doses of the thi-
azide-type diuretic. In the primary efficacy out-
come of change in 24-hour UOP, there were no
significant differences between the groups. Simi-
larly, secondary endpoints of 24-hour UOP, total
UOP, net 24-hour UOP, and net total UOP
showed no difference. Safety endpoints were
similar between the two groups, with hypona-
tremia, hypokalemia, and hypotension being the
most common adverse effects. A subgroup analy-
sis examining patients on vasopressors found no
differences in efficacy measures of UOP or safety
measures of hypokalemia and hypochloremia.
The authors concluded that metolazone and
chlorothiazide increase UOP to a similar degree
when utilized as an adjunct to loop diuretics in
patients with ADHF and HFrEF.12
In the most recent study, researchers analyzed
60 patients admitted with ADHF and treated with
either PO metolazone, IV chlorothiazide, or PO
tolvaptan.13 To date, this is the only prospective,
randomized trial of its nature. Patients were ran-
domized in a 1:1:1 fashion and were treated with
PO metolazone 5 mg twice daily, IV chloroth-
iazide 500 mg twice daily, or PO tolvaptan 30 mg
once daily in double-dummy fashion. To be
included in the trial, patients were required to
have loop diuretic resistance and confirmed
hypervolemia. Loop diuretic resistance was
defined as total UOP less than 2 L in last 12 hours
despite IV furosemide equivalent to 240 mg or
more. Hypervolemia was defined as either (i) pul-
monary capillary wedge pressure (PCWP) greater
than 19 mm Hg plus either peripheral edema,
rales on auscultation, or ascites or, (ii) in the
absence of PWCP, at least two positive findings
from peripheral edema ascites, jugular venous
pressure greater than 10 mm Hg, or pulmonary
edema on chest radiography. Patients were
excluded if they had an estimated glomerular fil-
tration rate (eGFR) less than 15 ml/minute/1.73
m2 or required renal replacement therapy or
ultrafiltration. Additionally, patients with
hypotension, hypokalemia, hyper- or hypona-
tremia, advanced liver disease, severe malnutri-
tion, pregnancy, or current breastfeeding were
excluded. All patients were started on a continu-
ous infusion loop diuretic, with bolus and mainte-
nance rates determined by furosemide equivalent
doses. Patients were mostly Caucasian, male,
obese, and had HFrEF (77%). The mean dose of
IV furosemide equivalents was 614 mg adminis-
tered in the 24 hours prior to enrollment. The
mean LVEF was 30%, and eGFR was 41 ml/min-
ute/1.73 m2. Ten percent of patients reported tak-
ing a thiazide diuretic as a home medication.
There was no difference between groups in the
primary efficacy outcome of change in standing
weight at 48 hours. While there were many sec-
ondary endpoints, key findings included no dif-
ference in total UOP at 24 or 48 hours and no
difference in 30-day readmission rate. Fractional
excretion of sodium (FENa) was significantly
greater at 24 hours in patients receiving chloroth-
iazide as compared to metolazone, but this effect
diminished at 48 hours. Similarly, total UOP was
numerically greater in chlorothiazide at 24 hours,
but this did not reach statistical significance.
Patients treated with chlorothiazide were less
likely to be considered poor responders, defined
as a 48 hour weight loss below the 25th percentile
for the total population (2.2 kg). However, this
finding was only significant when compared to
pooled metolazone-tolvaptan and not the individ-
ual arms (5% vs 30%; p=0.043). Hyponatremia
was more common in chlorothiazide than metola-
zone (45% vs 10%; p=0.031), but other electrolyte
abnormalities were common and similar across
groups. The authors concluded that weight loss
and UOP were significant with the addition of
either chlorothiazide or metolazone, with no dif-
ference detected at either 24 or 48 hours.13
Discussion
Treatment of ADHF in patients with loop
diuretic resistance poses a challenging clinical
scenario. Increasing loop diuretic dose or
 METOLAZONE VERSUS CHLOROTHIAZIDE Steuber et al
frequency, switching to continuous infusion loop
diuretics, or sodium restriction may be accept-
able approaches.2 Although high-dose loop
diuretic therapy may be the preferred method,
situations exist in which additional intervention
may be necessary, including sequential nephron
blockade by adding a thiazide-type diuretic.14
The choice of agent has historically been focused
on oral metolazone and IV chlorothiazide.
Despite the advantages of metolazone being
orally available, significantly less expensive, and
possessing some appealing pharmacokinetic
characteristics, providers may prefer chloroth-
iazide due to faster onset of diuresis and per-
ceived superior efficacy of IV therapy. Until
recently, there was a lack of head-to-head com-
parisons to support the use of one agent over
the other; however, studies published in the last
5 years have sought to end this debate.10–13 All
studies demonstrated increased net UOP with
both agents and found either no difference or
non-inferiority of oral metolazone compared to
IV chlorothiazide.10–13 Combined, these data
have demonstrated that both agents augment
diuresis to a similar degree in ADHF patients
with high-dose loop diuretic resistance with
comparable safety profiles.
Despite the promising results observed in
these studies, it is important to note limitations
and key differences. Currently, most studies
were small, retrospective analyses with the lar-
gest trial to date including 177 patients.11 The
small sample sizes may introduce the possibility
of a type II error in some of the studies. How-
ever, studies11, 13 included power calculations,
and both were met. These studies found metola-
zone to be either non-inferior or no different
than chlorothiazide when evaluating change in
UOP and other efficacy measures.11, 13 Addition-
ally, pooling and analyzing the combined results
further minimizes this possibility. Several studies
had significant variations in baseline loop diuret-
ics, with chlorothiazide groups having higher IV
furosemide equivalents in studies10–12 and more
continuous infusion loop diuretics in the Bohn
study. Though metolazone was shown to have
similar efficacy despite less aggressive loop
diuretic use than in the chlorothiazide groups of
these studies, it may be perceived that patients
in the chlorothiazide groups had a greater
degree of loop diuretic resistance. Furthermore,
while APACHE II scores did not differ in the
Bohn trial, patients in the chlorothiazide group
had five times more patients requiring mechani-
cal ventilation (p=0.033) and ten times more
933
deaths prior to discharge (p=0.001).12 Finally,
most studies utilized the primary endpoint of
volume removed (e.g. UOP) as a surrogate mar-
ker for ADHF clinical outcomes. Adequately
powered studies with larger sample sizes might
be warranted to detect differences in clinical
endpoints such as hospital or ICU length of stay,
30-day readmission, or mortality. In addition,
the retrospective nature and design of most of
these studies introduces the potential for numer-
ous biases. Selection bias may have occurred
given that patients in the chlorothiazide arms
may have been perceived as having a higher dis-
ease severity overall. This is highlighted by some
of the differences observed in the patient charac-
teristics described above, potentially limiting the
generalizability of the results. Additionally,
information bias might exist as all trials relied
on the accurate charting of UOP. However, both
groups would be equally at risk for these errors
in all studies. Despite this, the evaluation by the
GRACE checklist in conjunction with pooled
results of these retrospective analyses and subse-
quent prospective, randomized trial, support
individual findings.13
Another important limitation when comparing
these trials as a whole is the difference in base-
line demographics in the study populations.
Each group of investigators applied strict inclu-
sion and exclusion criteria in order to answer a
specific clinical question. For example, three
studies included varying percentages of HFrEF
and HFpEF patients, while a study included only
HFrEF patients. In these studies, there was also
no consensus on the definition of loop diuretic
resistance. As such, the doses of furosemide
equivalents required for inclusion varied from
no minimum dose to greater than 240 mg in the
24 hours prior to thiazide-type diuretic initia-
tion. Due to these differences in inclusion crite-
ria, doses ranged from averages of 100–680 mg/
day of IV furosemide equivalents during the
study period. Rates of background thiazide-type
diuretic use were different across studies as well,
and most studies did not include which specific
agent patients were taking at home. There were
also differences in baseline renal function that
existed among the studies. Inherent differences
in patient population at a specific sites were
observed, as some studies were conducted in a
primarily African American population and
others in a primarily Caucasian population.
There was slight variation in the endpoints
assessed, as a study examined UOP at 72 hours
while others looked at UOP at 24 or 48 hours.
934 PHARMACOTHERAPY Volume 40, Number 9, 2020
Additionally, another study examined weight
loss as the primary endpoint. Despite these dif-
ferences, these studies consistently demonstrated
a similar effect of metolazone compared to
chlorothiazide at augmenting UOP in patients
with loop diuretic resistance. These results were
reproduced despite studies being conducted at a
single site in varying populations and baseline
characteristics, which would improve external
validity of these findings. Currently, there is an
additional ongoing randomized clinical trial
comparing IV chlorothiazide to oral metolazone
to further gain insight into this issue and better
inform practice.15
Regardless of the agent utilized to achieve
sequential nephron blockade in patients with
ADHF, it is important to recognize the safety
implications of both agents. All studies demon-
strated high rates of hypokalemia, ranging from
15% to 75%, though no difference was observed
between agents in our pooled analysis.10–13 The
studies utilized different definitions of hyper-
kalemia which may have explained this wide
range. For example, a study used a definition of
hypokalemia as potassium less than 4 mEq/L
and severe hypokalemia as less than 3.5 mEq/L,
while another study11, 12 defined hypokalemia
as less than 3.3 mEq/L. Based on study defini-
tion, one study11 found higher rates of any
hypokalemia in the chlorothiazide arm, but no
difference in severe hypokalemia. This finding
could be attributed to the higher doses of loop
diuretics used in the chlorothiazide arm rather
than the study drug itself. Nevertheless, hypoka-
lemia is common with either chlorothiazide or
metolazone, especially with concomitant loop
diuretic therapy, and prevention and treatment
are essential. Worsening of renal function was
also commonly reported. Though definitions
widely varied among studies, pooled analysis
revealed no difference between metolazone and
chlorothiazide. Rates of other electrolyte abnor-
malities, including hyponatremia, hypomagne-
semia, hypochloremia, and hypocalcemia were
disclosed to varying degrees across studies, but
were relatively common when reported. Finally,
hypotension was also common when reported.
These findings remind practitioners of obligation
to diligently monitor for the safety of these
agents.
Given the significant cost difference that
exists, clinicians may consider metolazone first-
line for patients with ADHF and loop diuretic
resistance who are able to take oral or per tube
medications. It may be reasonable to attempt
increasing the loop diuretic dose before adding a
thiazide-type diuretic. In the studies reviewed,
patients were receiving at least 80 mg of IV fur-
osemide equivalents prior to receiving the study
drug. Although the recommended starting dose
of metolazone is 2.5 mg, it may be reasonable to
initiate at least 5 mg in patients with ADHF,
which is the minimum average dose utilized in
all the studies.10–13 If an undesired response to
metolazone is observed, chlorothiazide could be
considered, though another study found no
improvement in diuresis in patients with ADHF
determined to be refractory to the combination
of loop diuretics and metolazone and treated
with 500 mg of IV chlorothiazide.16 Alternative
strategies that could be considered based on the
classification of ADHF include vasodilators, ino-
tropes, ultrafiltration, tolvaptan, or alternative
diuretics.1, 14 With all of these strategies, a
team-based approach and expert consultation
with diligent monitoring should be employed.
Overcoming diuretic resistance in patients with
ADHF should viewed holistically and close mon-
itoring not only of urine output, but other fac-
tors such as weight, peripheral edema, relief of
dyspnea, and other factors should be taken into
account.
Conclusion
Based upon limited available evidence, metola-
zone appears to be as effective as chlorothiazide
at augmenting UOP in patients with ADHF and
loop diuretic resistance with similar rates of
adverse effects.
Acknowledgements
The authors would like to acknowledge Alan
Backer, MA, MLIS, for his assistance with conducting
the literature search for this systematic review
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