Metolazone and Furosemide Combination in
Cardiorenal Syndrome: Short-Term Safety and Efficacy Among Admitted Patients in a Tertiary Hospital
Bataclan RP1* and Alonso RS2
1Department of Medicine, University of the East Ramon Magsaysay Medical Center, Philippines
2Section of Nephrology, Dept. of Medicine, UP-Philippine General Hospital, Philippines
Submission: December 28, 2018;Published: January 22, 2019
*Corresponding author: Rommel P Bataclan, Department of Medicine, University of the East Ramon Magsaysay Medical Center, Aurora Blvd, Brgy, Dona Imelda, Quezon City, Philippines.
How to cite this article: Bataclan RPa, Alonso RSa. Metolazone and Furosemide Combination in Cardiorenal Syndrome: Short-Term Safety and Efficacy Among Admitted Patients in a Tertiary Hospital. JOJ uro & nephron. 2019; 6(3): 555686. DOI: 10.19080/JOJUN.2018.06.555686
Background: Diuretics are considered one of the essential drugs in the management, wherein Furosemide is usually given. But in some cases, it can be ineffective due to diuretic resistance. Metolazone is a thiazide-like diuretic, can be combined with loop diuretics to control volume overload. Since the drug is just newly introduced in our country, this study examines the immediate effect of Metolazone-Furosemide combination and possible adverse reactions in patients with Cardiorenal Syndrome.
Methods: This is an observational study of adult patients admitted at the UP-Philippine General Hospital diagnosed with Cardiorenal Syndrome. All the subjects involved were initially given Furosemide IV either bolus or drip (maximum 200mg/d) and Metolazone 5mg single dose. The primary outcome measure is the comparison of net hourly output rate, while secondary outcome measures include comparison of serum sodium, potassium, creatinine (baseline and 24 hours after administration), need for dialysis and adverse events.
Results: Forty-six patients were included in the study, most of which have Type 2 Cardiorenal Syndrome (47.8%, n=22). Overall, there was improvement of the net output hourly rate, without significant change in serum sodium, potassium and creatinine. However, 9 patients (19.6%) had episodes of hypotension, 6 patients (13%) still eventually needed hemodialysis and 6 patients had hypokalemia. Three patients (6.5%) died during hospital stay while the rest were discharged improved.
Conclusion: A combination of Metolazone and Furosemide is a feasible, safe management of patients with Cardiorenal Syndrome.
At present, there is already progress in understanding the
complex interplay between the cardiovascular and renal system.
Although there are still gaps to be answered, it is acknowledged
that presence of kidney disease is a risk factor for development
of cardiovascular diseases [1,2]. It is also known that
cardiovascular disease is the leading cause of death in patients
with End Stage Renal Disease . Vice-versa, in the presence
of cardiovascular disease, whether acute or long-standing, can
also predispose individuals to kidney disease as a short or longterm
complication . Due to the bidirectional nature of heartkidney
interaction and the vast interrelated derangements that
can happen, the term “Cardiorenal Syndrome” was coined. The
National Heart, Lung and Blood Institute (NHLBI) defined it as
a condition in which therapy to relieve congestive symptoms
of heart failure is limited by further decline in renal function
. In 2008, Acute Dialysis Quality Initiative (ADQI) consensus
group proposed a classification of Cardiorenal Syndrome into
categories whose labels reflect the most likely primary and
secondary pathology and time frame (Table 1) .
Depending on the type of Cardiorenal Syndrome and setting,
incidence ranges from 5 to 50% and found to be an independent
risk factor of mortality [7,8]. Cardiac (heart failure) and/or
renal dysfunction (manifested by oliguria and azotemia) is the
endpoint of this syndrome. This usually leads to fluid retention
and subsequently volume overload, which is one of the main
reasons for further worsening of both systems, and potentially
fatal [3,9]. If present, managing volume overload is one of the
immediate goals in order to relieve symptoms and prevent
further complications [10,11]. Diuresis has become an integral
part in the management of volume overload associated with
Cardiorenal Syndrome. Of particular use is intravenous loop
diuretics, which is easily available and has long history of clinical
experience. Theoretically, increasing urine output will help
relieve congestion, facilitating prompt relief of symptoms .
Also, diuretics is said to flush out debris to limit acute tubular
obstruction and decrease tubular cell metabolic demand,
consequently preventing Acute Tubular Necrosis (ATN).
However, clinical studies have proven otherwise. There has been
note of increased mortality in observational studies, presumably
due to electrolyte imbalance, leading to dysrhythmias and
sudden cardiac death . In addition, analysis of the data
from the Evaluation Study of Congestive Heart Failure and
Pulmonary Artery Catheterization Effectiveness (ESCAPE) study
demonstrated a nearly linear relationship between loop diuretic
dose and mortality over 6 months of follow-up in patients
hospitalized with advanced heart failure .
There are several mechanisms that can possibly explain
the limited efficacy of loop diuretics alone. Heart failure, which
is a feature in cases of Cardiorenal Syndrome, shifts the dose
response curve of diuretics, downward and right, hence the
need of higher dose. Also, progressively diminishing response
to diuretics called “braking phenomenon” is frequent. This is
related to activation of the Renin-Angiotensin-Aldosterone Axis
and Sympathetic Nervous System, reducing renal blood flow
and increasing sodium reabsorption in the proximal tubule
. Distal tubule hypertrophy, tubular hyperfunction and
concomitant reduced glomerular filtration rate are additional
pathophysiological changes among these patients, and these
may lead to Diuretic Resistance. Patients with heart failure with
diuretic resistance also have poor outcomes, which may be a
function of their more severe underlying disease process .
Besides optimization of loop diuretic dosing (i.e. increase
frequency; continuous drip) and investigating other causes
(i.e. Excessive Sodium Intake, Nephrotoxic Drugs), sequential
nephron blockade is another option to overcome diuretic
resistance. In majority of situations, a thiazide-type diuretic is
given in addition to loop diuretic. Its additive effect is related to
increased delivery of Na+ to the more distal thiazide-sensitive
segments of the kidney and changes in distal tubular cell
structure and/or function .
One of the thiazide-type diuretics used is Metolazone, which
structurally differs from this drug class with the methyl group
in C-2 and o-tolyl group in C-3. It is the only drug in its class
which acts on both the cortical thick ascending limb at the Loop
of Henle (proximal tubule) and the distal convoluted tubule.
This makes sodium excretion more effective and further inhibits
sodium reabsorption . It is also said that Metolazone causes
electrolyte abnormalities less frequently, hence it does not
commonly cause hyperlipidemia and hyperglycemia found in
other thiazide diuretics . In studies, Metolazone was found
to increase urine output in various fluid overload states such
as Ascites/Liver Cirrhosis [19,20], Nephrotic Syndrome [19,21]
and Chronic Kidney Disease . There are numerous studies
also in patients with Congestive Heart Failure, with varying
results [14, 19, 21, 23].
The drug was just introduced in our country about eight
years ago. There were no previous local studies with regards to
the drug and since the above-mentioned studies are mostly from
the last century, no known studies on Heart Failure using the
Cardiorenal Syndrome classification. Hence, the aim of the study
was to describe the initial experience of combination therapy
of Furosemide and Metolazone in patients with Cardiorenal
Syndrome, in terms of efficacy, safety and outcome.
This is a retrospective observational study in a single tertiary
university hospital. All adult patients (>18 years old) admitted
at the UP-Philippine General Hospital from October 2011 to
September 2012, diagnosed with Cardiorenal Syndrome, as
defined by the Acute Dialysis Quality Initiative Consensus Group.
Patients were included regardless of etiology, severity & type of
cardiac dysfunction. Patients were excluded if:
a) They are diagnosed case of End Stage Renal Disease,
with history of renal replacement therapy (dialysis, kidney
b) Patient or relatives opted not to have aggressive
management or medical treatment (i.e. Advanced Directives;
Do Not Resuscitate)
c) Serum creatinine, other labs were not available prior to
giving of the intervention.
Baseline demographics, cardiac diagnosis, co-morbidities,
other medical problems and initial medications/ interventions
were collected. Initial (on admission or prior to administration
of Metolazone) serum creatinine, sodium, potassium and urine
output were also noted. All of the subjects involved were initially
given Furosemide IV either bolus or drip (maximum 200mg/d).
Metolazone 5mg single dose was subsequently added in all
subjects, duration varies based on clinical assessment. Urine
output was noted for the first 24 hours after Metolazone was
given, as well as repeat serum creatinine, sodium and potassium.
Clinical course was also noted up to the final disposition of all
The primary outcome measure is the comparison of hourly
output rate (before versus after giving of Metolazone), while
secondary outcome measures include comparison of serum
sodium, potassium, creatinine, symptomatic relief within 24
hours, need for dialysis and adverse events such as hypotension,
hypokalemia and death. Descriptive statistics were made, with
computation of frequency percentage or mean + standard
deviation if applicable. For comparison of the laboratories,
analysis of variance (ANOVA) computed at 95% Confidence
Interval, with p-value of less than 0.05 deemed to be statistically
significant. Data were analyzed using the STATA 9.1 software
(STATA corp., Texas, USA).
Forty-six patients were included in the study, most of which
have Type 2 Cardiorenal Syndrome (47.8%, n=22). Table 2
shows the clinical characteristics of included subjects. Majority
of subjects were males, with Hypertension, Diabetes. More
frequently, subjects had Acute Kidney Injury with severity index
Almost all of the patients were started with continuous
Furosemide drip (dose range 10-20mg/hr), while the rest were
given intermittent intravenous Furosemide (dose range 40-
80mg every 4-6 hours). Half of the patients were administered
with Metolazone within 2 hours after Furosemide was started,
a third of them meanwhile were given Metolazone prior to start
of Furosemide, and rest started 2-6 hours after. Concomitant
medications given to these patients is described in (Table 3).
Overall, there was an improvement of the net output hourly
rate, without significant change in serum sodium, potassium
and creatinine Table 4. 78.2% of the patients (36 of 46 patients)
experienced symptomatic relief within 24 hours, based on
the review of charts. However, nine (9) patients (19.6%) had
episodes of hypotension, six (6) patients (13%) still eventually
needed hemodialysis and same number of patients had
hypokalemia. Although majority of patients were diabetics,
no significant hyperglycemia occurred on all patients. Three
patients (6.5%) died during hospital stay while the rest were
discharged improved .
This study showed improvement of diuresis among
patients with Cardiorenal Syndrome when given a diuretic
combination of Furosemide and Metolazone. It resulted in
symptomatic improvement in almost four-fifths of patients,
without causing significant electrolyte abnormalities and high percentage of mortalities. Significant diuresis and good safety
profile with Metolazone-Furosemide were also noted in other
studies. The randomized trial done by Channer comparing
Metolazone against Bendrofluazide (another Thiazide diuretic)
also showed significant diuresis in more than 90% of patients,
without significant changes in serum sodium, potassium urea
& creatinine . In a study by Desai and colleagues, adding
Metolazone 5mg showed an average weight loss of 4.78kg
in 6 days, with significant increase in urine volume and urine
sodium. This was achieved without significant increase of urine
potassium excretion, creatinine, blood sugar and lipid profile
and creatinine. There was some increase in serum sodium,
but majority still has normal values . Meanwhile, in a
retrospective cohort study by Ng and colleagues showed that
Furosemide-Metolazone regimen showed significant increase
in urine output compared to Continuous Furosemide Infusion.
Incidence of worsening renal function was not different between
regimens; however, blood urea nitrogen (BUN) tended to
increase more and incidence of hyponatremia was higher with
Furosemide-Metolazone combination . In an early study
of African patients by Gunstone and colleagues showed that
Metolazone combined with Furosemide showed success in 47%
of patients with Congestive Heart Failure, defined as weight loss
of 0.5kg/day for at least 4 days .
Weight loss was initially considered as an outcome. However,
since this parameter was not monitored routinely in CHF
patients in our institution (and inability to monitor in some
patients in the ICU due to instrument limitations), we did not
include this as a surrogate marker. The medication was still in its
initial phase of approval from the Food and Drug Administration
(Compassionate Use) at the time the study was collated, hence
the retrospective nature, which encompass the usual limitations.
There are ongoing randomized controlled trials for this
diuretic combination and hope to further shed light on its efficacy
and long-term safety. In conclusion, Metolazone and Furosemide
combination is a feasible, safe management of patients with