Diuretic Effect of Metolazone Pre-dosing Versus Concurrent Dosing With Furosemide: a Pilot Study
Phase: PHASE4
Conditions: Fluid Overload, Heart Failure Acute
Sponsor: University of Maryland, Baltimore

Diuretic Effect of Metolazone Pre-dosing Versus Concurrent Dosing with Furosemide: A Pilot 
Study 
(NCT03746002) 
 
Study Protocol and Statistical Analysis Plan 
 
August 14, 2018 
 
Research Team: 
Mallory Mouradjian, PharmD; Stormi Gale, PharmD; Gautam Ramani, MD; Brent Reed, PharmD 
 
 
 

Diuretic Effect of Metolazone Pre-dosing Versus Concurrent Dosing with Furosemide: A Pilot 
Study (NCT03746002) 
 
Study Protocol and Statistical Analysis Plan 
 
 
Research Team 
Mallory Mouradjian, PharmD; Stormi Gale, PharmD; Gautam Ramani, MD; Brent Reed, PharmD  
 
Keywords: Heart failure, decompensated heart failure, diuresis, diuretics, furosemide, 
metolazone  
 
Introduction and Supporting Literature:  
Acute decompensated heart failure (ADHF) is the primary diagnosis for greater than 1 million 
hospitalizations per year.1 Intravenous (IV) loop diuretics prescribed at doses higher than a 
patient’s home regimen are the treatment of choice for patients presenting with volume 
overload in ADHF.2 Diuretic resistance, defined as failure of diuretics to relieve congestion, is a 
complex process that occurs via pathophysiologic retention of sodium and decreased renal 
response to diuretic therapy and further complicates hospitalizations for ADHF. There are 
multiple mechanisms through which diuretic resistance can occur, including the “braking” 
phenomenon where decreased diuresis occurs with repeated doses of loop diuretics, the post-
diuretic effect in which sodium reabsorption at the loop of Henle increases once the loop 
diuretic has worn off, and nephron remodeling including hypertrophy of the distal convoluted 
tubule that leads to increased sodium reabsorption.3,4 Neuberg et al. found diuretic resistance, 
indicated by greater total daily doses of furosemide, to be associated with increased mortality.5 
 
Sequential nephron blockade, or combination diuretic therapy, with a loop and thiazide-type 
diuretic is a frequently used strategy to overcome diuretic resistance caused by hypertrophy of 
the distal convoluted tubule.4 In healthy patients, approximately 25% of sodium is reabsorbed 
proximally at the ascending loop of Henle and 5% of sodium is reabsorbed at the distal 
convoluted tubule. With increasing doses of loop diuretics, a compensatory increase in sodium 
reabsorption occurs via the sodium chloride cotransporter at the distal convoluted tubule.4 
Adding a thiazide-type diuretic, such as metolazone limits this distal reabsorption and therefore 
restores effectiveness of diuretic therapy. Most studies examining combination diuretic therapy 
in AHDF are retrospective and evaluate a limited number of patients (1 to 45 patients).6-13 
Overall, combination diuretic therapy has been found to be safe and efficacious in increasing 
urine output and decreasing weight. The most common side effect noted in these studies is 
hypokalemia. Of the available thiazide diuretics, one has not been found to be more effective 
than another; however, metolazone is often used due to its potency and long duration of action 
(up to 20 hours).14 
 
Based on this observed synergy, combination therapy with furosemide and metolazone is 
routinely prescribed in patients presenting with ADHF without adequate diuresis from loop 
diuretics alone. It has been recommended to administer the thiazide-type diuretic one hour 

prior to the loop diuretic to allow the thiazide-type diuretic to achieve peak diuretic effect.15 
This practice of pre-administration likely comes from pharmacokinetic and pharmacodynamic 
data that found the peak diuretic effect of metolazone to be delayed approximately 80 minutes 
after administration.16 However, this pharmacokinetic study was performed in two healthy 
volunteers that were administered metolazone alone. The administration time of metolazone in 
relation to furosemide dosing has not been studied and is not commented on in the 
observational and randomized controlled trials looking at combination diuretic therapy. Given 
the long duration of effect of metolazone, it is unlikely that the delay in peak diuresis would be 
of clinical importance in terms of desired synergistic effect. Furthermore, the practice of 
staggering administration times complicates the regimen and puts a burden on nursing staff, 
especially in units with greater patient to nurse ratios or patients with contact precautions.  
 
Therefore, the practice of administering metolazone 60 minutes prior to loop diuretic therapy 
increases the complexity for nursing staff and patients without proven clinical benefit. Despite 
this information, the practice remains common in clinical settings. The purpose of this study is 
to examine whether administering metolazone 60 minutes prior to furosemide increases urine 
output compared with administering metolazone and furosemide concomitantly.  
 
Methods:  
 
Study Design:  
This will be a prospective, randomized, open-label, active control trial at the University of 
Maryland Medical Center (UMMC). The objective of this study is to examine whether 
administering metolazone 60 minutes prior to IV furosemide bolus increases urine output 
compared with administering metolazone and IV furosemide bolus concurrently. The study has 
been approved by the institutional review board at UMMC, and written informed consent will 
be obtained for all patients.  
 
Study Participants:  
Adults aged 18 to 89 years are eligible for enrollment if they present within the previous 48 
hours with ADHF to the advanced heart failure service at UMMC. ADHF will be defined on the 
basis of the presence of at least one symptom (dyspnea, orthopnea, cough, or edema) and one 
sign (rales, peripheral edema, ascites, jugular venous distention, or pulmonary vascular 
congestion on chest radiography) of heart failure. Additional eligibility criteria are receipt of an 
oral loop diuretic prior to admission and plan to administer furosemide 120 – 200 mg IV bolus 
twice daily over the next 24 hours with additional diuresis deemed necessary. Patients are to be 
excluded if they have cirrhosis, an estimated glomerular filtration rate (GFR) less than 10 
mL/min/1.73m2, need for concurrent renal replacement therapy, or if they were prescribed 
metolazone prior to admission. Non-English speaking patients and patients that could not 
provide consent and do not have a legally authorized representative to provide consent will 
also be excluded.  
 
Randomization and Treatment Assignments:  

Patients will be randomized in a 1:1 ratio to a pre-dosing strategy (metolazone 5 mg orally 
dosed 60 minutes prior to furosemide 120 – 200 mg IV bolus) or a concurrent dosing strategy 
(metolazone 5 mg dosed simultaneously with furosemide 120 – 200 mg IV bolus). All treatment 
during the 24-hour study period will be open-label at the discretion of the treating physician. 
Patients enrolled in the study can receive additional IV boluses up to every 6 hours during the 
24-hour study period. If per the treating physician, patients required additional doses of 
metolazone, switch to furosemide IV continuous infusion, titration of IV inotrope or IV 
vasodilator, or renal replacement during the 24-hour study period, the appropriate therapy will 
be ordered and the patient will be excluded from the study at that time. Patients will be 
followed until discharge.  
 
Endpoints:  
The primary endpoint will be total urine output (mL) 24 hours post-metolazone dose. The total 
urine output will be collected and entered into EPIC electronic medical record by nursing staff 
and the value will be collected by study investigator during chart review. Additional pre-
specified secondary endpoints that will be assessed 24 hours post-metolazone dose include: 
net fluid balance (mL), change in weight (kg), change in SCr (mg/dL), proportion of patients with 
acute kidney injury (AKI) (defined as an increase in SCr by > 0.3 mg/dL or > 50% from baseline), 
hypokalemia (K <4.0 mEq/L), hypomagnesemia (Mg <2.0 mEq/L), and hyponatremia (Na 125 - 
135 mEq/L 24).  
 
Statistical Analysis:  
We calculated that 126 patients would have to be enrolled in order to achieve 80% power to 
detect an effect size of 500 mL. Given that this was a pilot study, our target patient enrollment 
will be 30 patients as this was felt to be a feasible number of patients to enroll during the study 
period. Descriptive statistics will be used to characterize data. When target enrollment is 
reached, the primary endpoint will be analyzed using student t-test. For other variables and 
outcomes, data will be analyzed using student t-test or chi-square/Fisher’s exact test as 
appropriate.  
 
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