Conditions: Congestive Heart Failure
Keywords: congestive heart failure diuretics combination
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 8
Healthy volunteers: no

Brief summary:
Objective: To establish which combination of diuretics is the most effective in promoting diuresis in congestive heart failure patients. Secondary Objectives: To determine the duration of action of furosemide as monotherapy and in combination hydrochlorothiazide with metolazone. To determine the effect of diuretic combination therapy on neurohormonal activation. Background: Diuretic resistance occurs when a potent diuretic drug, such as furosemide, is given in therapeutic doses and fails to reduce extracellular fluid volume to the desired level in an edematous patient. Studies have shown that metolazone and hydrochlorothiazide have demonstrated a synergistic response when used in combination with furosemide in congestive heart failure patients. The current guidelines for treating diuretic resistance in congestive heart failure patients recommend the metolazone-furosemide combination. However, there is no evidence to conclude that this combination is superior to hydrochlorothiazide-furosemide in increasing diuresis. Methods: Study to compare the efficacy of hydrochlorothiazide with metolazone in combination with stable doses of furosemide in 13 patients with congestive heart failure. The primary endpoint will be change in urinary output. Secondary endpoints will be changes in weight, neurohormones (angiotensin II, catecholamines, brain natriuretic peptide, aldosterone), and electrocardiographic parameters of ventricular instability. Study procedures will be performed at the UNM General Clinical Research Center. Patients will be hospitalized for 2 separate 4-day admissions, separated by a 1-week washout period. At each admission each patient will receive furosemide in combination with either metolazone or hydrochlorothiazide (metolazone for one admission and hydrochlorothiazide for the other). Following administration of combination therapy, blood and urine samples will be collected throughout the day to chart the onset and magnitude of effect of each treatment regimen. Various hemodynamic, renal, endocrine, and neurohormonal parameters will be assesed as will the effect of each combination treatment on ventricular instability using 12-lead electrocardiography. Data will be analyzed using ANOVA to compare changes from baseline and the Student t-test to analyze intertreatment differences.

All statistical analysis will be performed using SAS v6.12.d

Detailed description:

Arms:
arm 1: A randomized, double-blind, crossover study designed to compare the efficacy of hydrochlorothiazide in combination with stable doses of furosemide in congestive heart failure patients. arm 2: A randomized, double-blind, crossover study designed to compare the efficacy of metolazone in combination with stable doses of furosemide in congestive heart failure patients.

Interventions: intervention 1: Treatment of Furosemide + Hydrochlorothiazide intervention 2: Treatment of Furosemide + Metolazone
Intervention descriptions: intervention 1: A randomized, double-blind, crossover study designed to compare the efficacy of hydrochlorothiazide in combination with stable doses of furosemide in congestive heart failure patients. intervention 2: A randomized, double-blind, crossover study designed to compare the efficacy of metolazone in combination with stable doses of furosemide in congestive heart failure patients.

Protocol document:
ICF_001.pdf: 
 
 
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OFFICIAL USE ONLY 
Approved:  06/09/09 
 
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The University of New Mexico Human Research Review Committee 
UNIVERSITY OF NEW MEXICO HEALTH SCIENCES CENTER 
CONSENT TO PARTICIPATE IN RESEARCH 
 
A COMPARISON OF HYDROCHLOROTHIAZIDE AND METOLAZONE IN COMBINATION 
WITH FUROSEMIDE IN CONGESTIVE HEART FAILURE PATIENTS 
 
 
PURPOSE AND BACKGROUND 
 
Joe R. Anderson, Pharm.D., who is the Principal Investigator and Co-Investigators James J. 
Nawarskas, Pharm.D., and associates from the College of Pharmacy, and Robert Taylor, M.D., 
from the College of Medicine are conducting a research study to compare the effectiveness of 
hydrochlorothiazide or metolazone in combination with furosemide.  Patients with heart failure 
suffer from swelling because of too much fluid in the body.  Furosemide, hydrochlorothiazide, 
and metolazone are all water pills used to treat the swelling.  For most patients, taking 
furosemide alone is successful.  However, sometimes patients need to add another water pill.  
Doctors usually add either metolazone or hydrochlorothiazide.  It is not clear which water pill is 
better when added to furosemide.  The purpose of this study is to determine which water pill 
when added to furosemide is the best at reducing excess fluid in the body.  You are being asked 
to participate in this study because you have heart failure and are taking furosemide.  
Approximately 26 patients from the University Hospital will participate in this study. 
 
PROCEDURES 
 
If you volunteer to participate in this study, the following things will happen: 
 
While participating in this study you will have two hospital stays.  Starting three (3) days before 
each hospital stay, you must agree to eat only foods given to you by the University of New 
Mexico (UNM) General Clinical Research Center (GCRC).  The foods contain a specific amount 
of sodium (salt).  Salt intake must be controlled during the study since sodium influences water 
retention. 
 
You will then be admitted to the UNM GCRC for a period of five (5) days on two separate 
occasions (one week apart). 
 
You will be asked about what types of medications you are taking.  You will continue taking your 
regular medications throughout this study.  On the first day of admission you will continue taking 
your regular medications.   
 
You will then be assigned by chance (like flipping a coin) to receive your first study treatment.  
There are two treatments (hydrochlorothiazide and metolazone) in this study and you will be 
taking both treatments. 
 
For days two, three, and four of each admission you will be given either hydrochlorothiazide or 
metolazone one hour before taking your first dose of furosemide.  After four days, the study 
treatment will be discontinued and you will be discharged to home on all of your regular 


 
 
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medications.  You will then be scheduled to return to the hospital at least one week later.  For 
the first 24-hours on your second visit you will continue taking your regular medications. For 
days two, three, and four you will be given hydrochlorothiazide or metolazone, whichever you 
did not receive the first time.  The two drugs will look the same and neither you nor the 
investigators will know which you are taking. 
 
If you are taking potassium or magnesium supplements, the investigators may need to increase 
the dose of these supplements during the study treatment period.  If you are not taking 
potassium or magnesium supplements, the investigators may need to provide you with 
supplements during the study treatment period. 
 
At each hospitalization, the following will occur: you will have a physical examination, your 
medical chart will be reviewed, blood and urine will be collected for laboratory tests, and an 
electrocardiogram will be done to determine the electrical activity of your heart.  A catheter (a 
small tube used for drawing blood) will be inserted into a vein in your forearm to obtain blood for 
laboratory tests and will be removed at the end of the hospitalization.  In addition, your blood 
pressure and weight will be monitored.  On days one and two, your blood pressure will be 
measured every hour for the first six hours, then every 2 hours for the next 6 hours, and then 
every 4 hours for the remainder of the 24 hours for each day.  On days one and two, your 
weight will be measured initially and then at 2 hours, 6 hours, 12 hours, and 24 hours. 
 
You will need to have your blood drawn for laboratory analysis of blood chemistry and kidney 
function (sodium, potassium, creatinine, etc) as well as for neurohormones.  Neurohormones 
are substances normally produced by your body.  Previous studies have shown that these 
substances are elevated in heart failure patients. During this study, a blood sample of 
approximately two tablespoonfuls of blood will be drawn from your arm four times each day on 
days one and four.  Approximately one teaspoonful of blood will be drawn four times on day two 
and two times on day three.  Some blood samples will be sent to an out of state laboratory for 
analysis, however, your name and medical record number will be removed from the sample and 
labeled instead with a unique code number before being sent.  The reason for analyzing your 
blood chemistry and neurohormones is to determine a baseline for our study and to monitor any 
changes that may occur during the study.  You will be allowed to walk around following each 
blood draw, but must relax quietly, lying in bed, for at least 30 minutes prior to each blood draw 
on days one and four and prior to the first blood draw on day three. 
 
Your urine will be collected each of the four days.  The reason for collecting your urine is to 
measure the amount of fluid leaving your body and to determine your kidney function.   
 
You will have an electrocardiogram done four (4) times on each day of each hospital stay.  The 
reason for analyzing your electrocardiogram is to determine if either of the study treatments 
affects the electrical activity of your heart. 
 
You will be placed on a low salt diet (< 3,000 mg per day) and can drink up to 12 glasses of fluid 
each 24-hour period while you are in the hospital.   
 


 
 
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Approximately 35 tablespoons (2 and ¼ cups) of blood will be drawn throughout the study (1 
cup for each hospital visit).  This amount is slightly less than the amount provided for a standard 
blood donation.   
 
Participation in the study will take a total of about 228 hours over a period of 21 days (10 total 
days in the hospital).  All study procedures will be done at the UNM GCRC. 
 
You cannot participate in this study if you are pregnant or breastfeeding.  If you are a woman of 
childbearing age, a pregnancy test (1 teaspoon blood or 1 Tablespoon urine) will be done prior 
to participation in this study.  You must agree to use an effective form of birth control throughout 
the study period. 
 
Table 1: Description of study procedures 
Procedure 
 
Day 0 
 
Day 1 
 
Day 2 
 
Day 3 
Day 4 
 
Admit to 
hospital 
 
 
 
 
Study Medication 
 
 
X 
X 
X 
Physical Examination 
X 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
Blood pressure 
X 
X 
X 
X 
X 
Blood Samples 
 
X  
X 
X 
X 
24 Hour Urine 
Collection 
 
 
X 
 
X 
 
X 
 
X 
Electrocardiogram 
 
X 
X 
X 
X 
 
 
RISKS AND DISCOMFORTS 
 
While receiving hydrochlorothiazide, a possible side effect is low potassium levels.  This effect 
occurs in less than 10% of persons receiving the drug in previous human studies.  Other side 
effects that are possible include low blood pressure, dizziness, sensitivity to the sun, allergic 
reactions, cardiac arrhythmias, and high blood sugar.  These effects have occurred in less than 
1% of persons receiving the drug in previous human studies.   
 
While receiving metolazone, the side effects that are possible include dizziness, headache, low 
potassium levels, and muscle cramps.  These effects have occurred in less than 10% of 
persons receiving the drug in previous human studies.  Other side effects include low blood 
pressure, drowsiness, sensitivity to the sun, rash, nausea and vomiting, allergic reactions, 
cardiac arrhythmias, and high blood sugar.  These effects have occurred in less than 1% of 
persons receiving the drug in previous human studies. 
 
Frequent risks associated with blood drawing include temporary pain and discomfort at the site 
of the needlestick, and occasional bruising, sweating, or lightheadedness, and in rare cases, 
faintness or infection. 
 


 
 
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You may experience some discomfort or bruising from the inflation of the blood pressure cuff 
when taking a blood pressure measurement. 
 
Your participation in this research study involves the following risks: emotional distress, stress, 
inconvenience, loss of privacy.  Your information will be handled as confidentially as possible.  
 
BENEFITS 
 
Although you may or may not benefit directly from this research, your participation may lead to 
information that could help other people suffering from heart failure. 
 
Based on experience with previous human studies, researchers believe that the combination of 
two water pills in some cases is the best way to reduce swelling.  However, because each 
person responds differently to therapy, this cannot be guaranteed.  Upon completion of the 
study, if it is determined that your symptoms are better with the combination of water pills, your 
primary care provider will be notified and you will be given the opportunity to continue treatment 
with the combination of water pills.  
 
ALTERNATIVES TO PARTICIPATION: 
 
Your alternative to participating in this study is simply deciding not to participate.  Your doctor 
can prescribe other treatments and other combinations of therapy used in this study if your 
doctor thinks they are needed. 
 
CONFIDENTIALITY 
 
Participation in research will involve a loss of privacy, but information about you will be handled 
as confidentially as possible.  Representatives from the University of New Mexico Health 
Science Center Human Research Review Committee that oversees human subject research will 
be permitted access to your records.  Also, your participation in the study and information in 
your study records may be shown to your doctors and nurses, and may be disclosed as 
otherwise provided by law.  However, your name will not be used in any published reports about 
this study. 
 
COSTS OF STUDY 
 
You will not be charged for any of the study treatments or procedures.  The costs of 
hydrochlorothiazide, metolazone, the physical exam, blood tests, electrocardiogram, and 
hospital stay will be covered by the study. 
 
EMERGENCY TREATMENT AND COMPENSATION FOR INJURY: 
 
If you are injured as a result of this study, the University of New Mexico Health Sciences Center 
(UNMHSC) will provide you with emergency treatment at usual charge.  No commitment is 
made by the UNMHSC to provide free medical care or money for injuries to participants in this 
study.  If you have any questions about these issues, or believe that you have been treated 


 
 
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The University of New Mexico Human Research Review Committee 
carelessly in this study, please contact the the University of New Mexico Health Sciences 
Center (UNMHSC) Human Research Review Committee (HRRC) University of New Mexico, 
Albuquerque, New Mexico, 87131, at (505) 272-1129. 
 
PAYMENT FOR PARTICIPATION: 
 
In return for your time and effort for participating in this study, you will receive $550.00.  If you 
do not complete the study, you will be paid for the parts of the study you complete.  You should 
receive payment within 6 weeks of your completion of the study.  If you do not receive payment 
by this time, please contact Dr. Anderson at (505) 272-3664. 
 
NEW FINDINGS  
 
You will be notified of any significant new findings that become available during the course of 
the study, such as changes in the risks or benefits resulting from participation in the research 
that might change your mind about participating. 
 
WITHDRAWAL 
 
Your participation in this study is strictly voluntary.  You have the right to choose to not 
participate or to withdraw your participation at any point in this study without prejudice to your 
future health care or other services to which you are otherwise entitled. 
 
QUESTIONS 
 
You have the right to ask questions concerning this study at any time, and you are urged to do 
so.  If you have any questions about the research study, please contact Dr. Anderson at 
telephone number (505) 272-3664 from 8 AM-5 PM Monday-Friday.  At any other time and on 
weekends, please call the UNM Hospital operator at 272-2111 and ask for the cardiologist on 
call.  If you have any question regarding your legal rights or injuries, please contact the 
University of New Mexico Health Sciences Center (UNMHSC) Human Research Review 
Committee (HRRC) University of New Mexico, Albuquerque, New Mexico, 87131, at (505) 272-
1129. 


 
 
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The University of New Mexico Human Research Review Committee 
C ONSENT 
You will be given a copy of this consent form to keep.  By signing this consent form, you are not 
waiving any of your legal rights, claims, or remedies.  If you have questions about your legal 
rights as a research subject, please contact  the University of New Mexico Health Sciences 
Center (UNMHSC) Human Research Review Committee (HRRC) University of New Mexico,  
lbuquerque, New Mexico, 87131, at (505) 272-1129.  
A 
A copy of this consent form will be kept in your permanent medical record. 
 
  
I have read (or someone has read to me) the information in this consent form.  I have had an 
opportunity to ask questions and all of my questions have been answered to my satisfaction.  By 
signing this consent form, I willingly agree to participate in the study.” 
 
 
________________________________________ 
Name of Subject (type or print) 
 
_________________________________________     _______________ 
Signature of Subject                                                       Date 
 
________________________________________ 
Name of Witness (type or print) 
 
________________________________________         ______________ 
Signature of Witness 
Date 
 
I have explained the research to the subject or his/her legal representative, and answered all of 
his/her questions.  I believe that he/she understands the information described in this consent 
form and freely consents to participate. 
 
 
________________________________________________ 
Name of Investigator/Research Team Member (type or print)  
 
________________________________________         ______________ 
Signature of Investigator/Research Team Member         Date 

Prot_000.pdf: 
COVER PAGE: 
PROTOCOL_NCT0069051_05.25.2007 


Project Title: 
A comparison of hydrochlorothiazide and metolazone 
in combination with furosemide in congestive heart 
failure patients. 
 
Principal Investigator: 
Joe R. Anderson, Pharm.D. 
Assistant Professor of Pharmacy 
University of New Mexico 
College of Pharmacy 
2502 Marble NE 
Albuquerque, NM 87131-5691 
(505) 272-3664 
janderson@salud.unm.edu 
 
Co-Investigators: 
James J. Nawarskas, Pharm.D. 
Associate Professor of Pharmacy 
University of New Mexico 
College of Pharmacy 
2502 Marble NE 
Albuquerque, NM 87131-5691 
(505) 272-0584 
nawarska@unm.edu 
 
Robert Taylor, M.D. 
Assistant Professor of Internal Medicine 
University of New Mexico 
School of Medicine 
2211 Lomas NE 
Albuquerque, NM 87131 
(505) 272-6020 
rtaylor@salud.unm.edu 
 
Sarah Rivera, Pharm.D. candidate 
University of New Mexico 
College of Pharmacy 
2502 Marble NE 
Albuquerque, NM 87131-5691 
(505) 272-3664 
srivera@salud.unm.edu 
 
HRRC Protocol #:  
02-276 
 
 


 
2
 
A. 
SPECIFIC AIMS – HYPOTHESIS: 
 
Null-Hypothesis: 
 
This research will test the following null-hypothesis: 
 
The diuretic combination of furosemide-metolazone is equivalent to furosemide-
hydrochlorothiazide in promoting diuresis for patients with congestive heart 
failure. 
 
Objective: 
To establish if there is a difference between furosemide-metolazone versus 
furosemide-hydrochlorothiazide in promoting diuresis in patients with congestive 
heart failure. 
Secondary Objectives: 
To determine the duration of action of furosemide as monotherapy and in 
combination with either hydrochlorothiazide or metolazone. 
To determine the effect of diuretic combination therapy on neurohormonal 
activation. 
To determine the relative influence of metolazone and hydrochlorothiazide on 
parameters predicting ventricular arrhythmias. 
 
B. 
BACKGROUND AND SIGNIFICANCE: 
Diuretics serve as a primary pharmacological treatment of congestive heart 
failure with acute or chronic fluid overload.  Loop diuretics, such as furosemide, 
are the most effective agents in producing diuresis.  These agents act to inhibit 
the sodium/chloride cotransport in the ascending limb of the loop of Henle, where 
25% of the filtered load of sodium is reabsorbed. 1,2,3,4,5  Thiazide diuretics, such 
as hydrochlorothiazide, act at the distal convoluted tubule to inhibit sodium and 
chloride reabsorption.  These diuretics are comparatively less potent versus the 
loop diuretics for the reason that only 5%-10% of the filtered load of sodium is 
reabsorbed in the distal convoluted tubule.1,2,3,5  Metolazone, a quinazoline 
diuretic, has similar pharmacologic characteristics as the thiazides.  It acts 
primarily to inhibit sodium reabsorption at the distal convoluted tubule and to a 
lesser extent at the proximal convoluted tubule. 1,2,3,5,6  
Diuretic resistance occurs when a potent diuretic drug, such as furosemide, is 
given in therapeutic doses and fails to reduce extracellular fluid volume to the 
desired level in an edematous patient.2,3,5,6  Diuretic resistance can simply occur 
as a result of excessive salt intake, patient noncompliance, or drug-induced 


 
3
resistance.  Other forms of resistance include acute adaptation, postdiuretic 
retention, and chronic adaptation.  
Acute adaptation limits the utility of single diuretic therapy by increasing the 
ability of the kidneys to reabsorb sodium chloride (NaCl).  When a loop diuretic is 
administered, it acts on the thick ascending limb of the loop of Henle where it 
blocks the sodium reabsorbing capacity.  Consequently, more sodium is 
delivered to the distal parts of the nephron.  Since the NaCl transport system in 
the distal convoluted tubule is unsaturated and load dependent, this increased 
NaCl delivery leads to increased NaCl reabsorption. 2,3,4,5,7  This mechanism of 
acute adaptation can be prevented by the addition of a diuretic that acts on the 
distal convoluted tubule such as metolazone or hydrochlorothiazide, to block this 
increased reabsorption. 
Postdiuretic retention is an adaptive response in which there is a decrease in 
response to a diuretic after the first dose has been administered. As a result of 
the short half-lives of loop diuretics, for example furosemide has a half-life of 0.5-
1.1 hours, the plasma drug concentration usually falls below therapeutic 
concentrations before the next dose of the diuretic is administered.8  During this 
time the nephron undergoes rebound sodium retention and reabsorbs large 
amounts of sodium, which may nullify the prior natriuresis.  Since this rebound 
sodium retention is thought to be mediated by increased sodium reabsorption in 
the distal convoluted tubule, it may be prevented by the administration of an 
additional diuretic, which inhibits transport in this segment.2,3,4,5,9  The added 
drug should preferably have a half-life greater than the loop diuretic. 3  Two 
possible choices are hydrochlorothiazide and metolazone which both have longer 
half-lives, 5.6-14.8 hours and 6-20 hours respectively, and act to inhibit sodium 
reabsorption in the distal convoluted tubule.8  
With chronic administration of a loop diuretic, the constant increase in the 
concentration of solute that escapes from the loop of Henle floods the more distal 
regions of the nephron.  These cells undergo structural and functional adaptive 
processes such as increasing the number of membrane Na+-K+-ATPase pumps. 
The increase in Na+-K+-ATPase pumps leads to an increased transport capacity 
of the distal nephron.  This adaptation is activated by the necessity for increased 
cellular reabsorption, which leads to a decrease in overall diuresis and seems to 
be an important cause of diuretic resistance.   Diuretics such as metolazone and 
hydrochlorothiazide that block the distal regions in the nephron would act to block 
this adaptation and increase diuresis. 2,3,4,5,6,7 
Studies have shown that metolazone and hydrochlorothiazide have 
demonstrated a synergistic response when used in combination with furosemide 
in congestive heart failure patients.  A study conducted by Grosskopf and 
colleagues demonstrated that the combination of furosemide and metolazone 
induced greater natriuresis, urinary output, and weight loss compared with those 
produced by furosemide or metolazone alone.10  The study included ten severe 
congestive heart failure patients, six females and four males, with a mean age of 
67 years. On the first day, the patients received an I.V. dose of 120 mg of 


 
4
furosemide. The mean 24-hour urine volume was 1810 ± 397.4 mL and the mean 
body weight was found to be 53.4 ± 9.3 kg. After the addition of 5 mg of oral 
metolazone, the 24-hour urine volume was found to be 2470 ± 608.8 mL and the 
mean body weight was 51.2 ± 9.0 kg (P < 0.05).  
In addition, a study performed by Dormans and Gerlag showed that the addition 
of hydrochlorothiazide with furosemide had a synergistic effect and resulted in 
decreased body weight, increased urine volume, and increased fractional sodium 
excretion.7  This study included twenty patients with severe congestive heart 
failure, six females and fourteen males, with a mean age of 70.8 years and a 
proven diuretic resistance to furosemide (daily dose greater than 250mg).  These 
patients were given hydrochlorothiazide (25-100 mg orally) in combination with 
furosemide.  This combination led to a mean reduction in body weight of 6.7 ± 
3.3 kg per patient. Mean daily urine volume increased from 1899 ± 958 ml to 
3065 ± 925 ml (P< 0.001) and fractional sodium excretion increased from 3.5 ± 
3.2% to 11.5 ± 9.0% (P<0.001). 
Restricting dietary sodium intake and administering a single diuretic drug will lead 
to clinical improvement in the majority of congestive heart failure patients.  
However, some patients with congestive heart failure even when given therapy 
with high-dose furosemide still have edema.  A major problem results when 
furosemide and a restricted diet fail to reduce the extracellular volume to the 
desired level.  The extreme fluid retention that results, if left untreated, may result 
in hospitalization.  Loop diuretics have similar pharmacologic characteristics; 
therefore, administering another loop diuretic is not a valid option.2,8  As a result, 
diuretics with different mechanisms of action should be utilized.1,7  Studies show 
that the combination of metolazone-furosemide act synergistically to induce 
greater urinary output and weight loss.10,11,12,13  In addition, the combination of 
hydrochlorothiazide-furosemide also act synergistically to induce increased 
diuresis.7  The current guidelines for treating diuretic resistance in congestive 
heart failure patients recommend the metolazone-furosemide combination.14  
However, there is no evidence to conclude that this combination is superior to 
hydrochlorothiazide-furosemide in increasing diuresis. 
Sudden death is predominantly caused by ventricular arrhythmias (tachycardia or 
fibrillation). The interplay of a cardiac substrate for ventricular instability such as 
infarction or dysfunction with dilation and autonomic and electrolyte factors is 
central to the triggering of these arrhythmias.  The electrolyte and fluid shifts 
produced during diuresis may place patients with the substrate for ventricular 
arrhythmias at further risk due to the loss of potassium and magnesium.  
Monitoring of the patient’s rhythm by telemetry can aid in evaluating patients 
undergoing diuresis.  Evaluation of electrocardiographic parameters on the 
surface electrocardiogram including QRS and QT dispersion can predict the risk 
of ventricular instability in a patient undergoing physiologic changes such as 
diuresis.15,16   
Activation of the neurohormonal system in response to heart failure serves as an 
initial adaptive mechanism but over time becomes maladaptive impairing the 


 
5
function of the heart, vasculature, and kidneys.  Sympathetic activation has been 
demonstrated to be arrhythmogenic.17  Increases in angiotensin II are deleterious 
in heart failure due to vasoconstriction, promotion of proximal renal tubule 
sodium reabsorption, and stimulates the release of additional neurohormones 
such as endothelin, aldosterone, vasopressin, and cytokines.  In addition, 
angiotensin II and high concentrations of aldosterone augment sympathetic 
activation.18,19  By reducing volume, diuretics reflexively increase the 
concentrations of renin, and thus angiotensin II and aldosterone.20,21  The 
natriuretic peptides, atrial and brain natriuretic peptide (ANP and BNP), act in 
opposition to the renin-angiotensin-aldosterone system.22  These peptides act to 
dilate renal blood vessels, decrease renin and aldosterone secretion, and 
decrease sodium reabsorption in the collecting duct.  ANP and BNP are 
respectively synthesized in the atria and ventricle of the heart.  BNP, also known 
as B-type natriuretic peptide, concentrations are normally much lower than ANP 
concentrations.  However in CHF patients plasma BNP levels increase 
progressively more than ANP values and have been used to provide diagnostic 
and prognostic information.22-24  Therefore, the current study will measure 
concentrations of these neurohormones and determine the effects of combination 
diuretic therapy on these parameters. 
The purpose of this study is to compare the diuretic efficacy of the combination of 
furosemide-metolazone with furosemide-hydrochlorothiazide in patients with 
congestive heart failure. The primary objective is to establish which combination 
is the most effective in promoting diuresis in congestive heart failure patients.  
The effects of both regimens on electrocardiographic parameters of ventricular 
instability and neurohormonal parameters will also be assessed as secondary 
objectives. 
C. 
PRELIMINARY STUDIES: 
To the best of our knowledge, there have been no studies comparing the efficacy 
of the two diuretic combinations. 
D. 
RESEARCH DESIGN AND METHODS: 
Study Design: 
This will be a randomized, double-blind, crossover study designed to compare 
the efficacy of hydrochlorothiazide and metolazone in combination with stable 
doses of furosemide in congestive heart failure patients. 
The specific dose of hydrochlorothiazide will be determined by the individual’s 
creatinine clearance. A creatinine clearance of 30-50 mL/min will indicate a dose 
of 50 mg per day. A creatinine clearance of > 50 mL/min will indicate a dose of 
25 mg per day.5 If metolazone is added to their regimen, the specific dose will be 
determined using the equivalence ratio of 5 mg metolazone to 50 mg 
hydrochlorothiazide.8 


 
6
Twenty-six subjects will be studied.  They will be recruited from the University of 
New Mexico Congestive Heart Failure Clinic. 
Inclusion criteria: 
▪ Age >18 years 
▪ Diagnosis of chronic congestive heart failure with an ejection fraction ≤45% 
▪ Currently on a stable regimen of furosemide consisting of a daily dose of 80 
mg for at least two weeks. 
▪ Patients receiving ACE-inhibitors and/or beta-blockers must be taking these 
medications for at least two weeks in stable doses.  
Exclusion criteria: 
▪ Renal dysfunction (serum creatinine >2 mg/dl or creatinine clearance of <30 
ml/min as calculated by the Cockroft and Gault equation)25 
▪ Hepatic dysfunction (AST and ALT >3 times the upper limit of the normal) 
▪ Hypokalemia (<4.0 mg/dl) 
▪ Concomitant treatment with any diuretic other than furosemide (with the 
exception of spironolactone). 
▪ Gout 
▪ Lupus erythematosus 
Study procedures: 
Study procedures will be performed at the University of New Mexico General 
Clinical Research Center. 
After obtaining written informed consent, patients will be randomly assigned to 
one of two groups.  Both groups will be admitted to the hospital for a period of 
four days (five nights) on two separate occasions.  Daily sodium intake will be 
restricted to less than three grams per day, and fluid intake to less than three 
liters per day.  For the first twenty-four hours of each admission, both groups will 
continue their regular medication regimen to establish a baseline for the 
measured variables.  For the remaining three days, the patients will have either 
hydrochlorothiazide or metolazone added to their daily regimen of furosemide.  
Blinding and randomization will be maintained by the UNMH research pharmacist 
(Nancy Morgan, R.Ph.).  The dose of the additional drug will be administered one 
hour prior to the dose of furosemide to ensure adequate absorption.  After the 
initial four-day hospitalization, the patients will undergo a washout period of one 
week where they will be sent home and continue on their regular medication 
regimen.  When the patients return for the next four-day period they will be 
treated with the alternate drug.  Patients will be asked to maintain a consistent 


 
7
dietary intake (sodium, potassium, etc.) and drug therapy throughout the study, 
i.e. potassium supplements and drugs that promote sodium retention (NSAIDS, 
etc.).  Starting 3 days prior to each admission, the patients will be required to eat 
only the food provided by the UNM General Clinical Research Center.  The foods 
provided will be consistent with the dietary sodium and fluid limitations. 
Study Variables: 
Hemodynamic measures:  During each admission, the patients’ blood pressure 
and pulse will be measured every hour for the first six hours, every two hours for 
the next six hours, and then every four hours for the remainder of the twenty-four 
hours on days one and two.  On days three and four, the patients’ blood pressure 
and pulse will be taken every six hours.  Weight will be measured at baseline, 
two hours, six hours, twelve hours, and twenty-four hours on days one and two.  
On days three and four weight be will be taken once daily in the morning. 
Renal, electrolyte, and endocrine parameters: Twenty-four hour urine will be 
collected daily.  Urinary output will be quantified at 2 hours, 6 hours, 12 hours, 
and 24 hours on days one, two, and four and at 24 hours on day 3.  In addition 
we will measure the following urinary variables: potassium, sodium, creatinine, 
aldosterone, and protein.  On days one, two, and four, blood samples will be 
taken at baseline, 2 hours, 6 hours, 12 hours and 24 hours after the dose of 
diuretic(s) to determine changes in serum sodium, potassium, chloride, 
bicarbonate, uric acid, creatinine, magnesium, blood urea nitrogen.  In addition 
blood samples will be taken on the same days and times to determine changes 
in: catecholamines, angiotensin II, plasma renin, aldosterone, and brain 
natriuretic peptide.  On day three blood will be obtained 6 hours post diuretics to 
monitor serum electrolytes as a safety precaution.  
Measures of ventricular instability: A standard 12-lead electrocardiogram (ECG) 
will be performed at the following times: time 0, 2 hours, 6 hours, and 12 hours 
post-dose.  The QT and QRS intervals will be measured on all ECG’s. QRS 
dispersion and QT dispersion will be calculated on all ECG’s and defined as the 
maximum difference in the QRS and QT intervals. 
 
Statistical Analysis: 
The main analysis will be repeated measures ANOVA with day (comparison to 
baseline) and added drug (due to crossover) as repeated factors. Post-hoc 
testing will be done using paired t-tests.   
The sample size was calculated based on the primary outcome variable, the 
mean difference in 24-hour urinary output in milliliters (mL).  For simple and 
robust power analysis, the paired t-test that compares 24-hour urinary output on 
day 3 with each added drug was used.  We determined a mean difference in 
change from baseline in 24-hour urinary output of 300 ml between the 
furosemide-metolazone and furosemide-hydrochlorothiazide regimens to be 


 
8
clinically significant.  Previous studies with furosemide and hydrochlorothiazide 
and furosemide and metolazone demonstrated mean 24-hour urinary outputs ± 
s.d. of 1899 ± 958 ml and 1810 ± 397 ml at baseline with furosemide 
monotherapy and 3065 ± 925 ml and 2470 ± 608 ml with combination therapy, 
respectively.7,10  Using these data and assuming moderate correlations within 
subject due to the baseline-controlled crossover design is 0.7, a sample size of 
20 patients is adequate to detect the 300 ml difference with 80% power at a 5% 
level of significance.  This is reasonable since comparison of the two referenced 
studies found a difference in the change from baseline of 506 ml.7,10  Accounting 
for a 25% dropout rate, 26 subjects will be enrolled in the study. 
All statistical analysis will be performed using SAS v6.12. 
Potential assumptions and limitations: 
A major limitation to the study is that patients included in the study are clinically 
stable and therefore the results may not be generalizable to decompensated 
CHF patients.  For the purposes of our study we are assuming that the patients 
will remain on the same drug therapy, as well as sodium and fluid intake 
throughout the study, so as not to introduce any additional variables.  We are 
also assuming that the dose of metolazone given to the patients is equivalent to 
the dose of hydrochlorothiazide.  The fact that there is no way of determining an 
exact equivalent dosage limits our study.  Another limitation is the fact that our 
patients will only be receiving the additional drug and being monitored for 4 days.  
The study drugs may not have enough time to reach maximal effect.  Therefore 
in practice, where the drug may be given over a greater period of time, diuresis 
and adverse effects may be more pronounced. 
 
E.  
HUMAN SUBJECTS: 
 
1. 
Gender and minority inclusion: 
 
This study will enroll 26 patients with the diagnosis of congestive heart failure 
over 18 years of age.  This project will involve subjects of race and gender 
commensurate with the general population of Albuquerque, NM and the 
population seen in the University Hospital Congestive Heart Failure Clinic.  The 
population of Albuquerque, NM is approximately 40% Hispanic and 50% female 
and our subject enrollment should reflect this.   
 
 
African 
American 
Hispanic Asian 
American 
Indian 
Caucasian 
Other 
Total 
Female 1 
6 
0 
0 
6 
0 
13 
Male 
1 
6 
0 
1 
5 
0 
13 


 
9
Total 
2 
12 
0 
1 
11 
0 
26 
 
2. 
Sources of research material: 
 
Each subject will have about 13 tablespoonfuls of blood taken over the duration 
of the study.  This will amount to about 400 mL of blood withdrawn from each 
subject for the entire study.  All blood samples will be used solely for research 
purposes.  Each subject will have their urine collected for the entire 8-day 
admission period. 
 
3. 
Plans for recruitment: 
 
Recruitment of subjects will involve personal contact in the University Hospital 
Congestive Heart Failure Clinic and from the UNMH Adult Cardiology Inpatient 
service.  Informed consent will be obtained from each subject prior to the 
initiation of study procedures by study personnel.  The consent form to be used 
in this study is attached to this proposal as Appendix A.  
 
4. 
Potential risks: 
 
Subjects involved with this study may experience hypokalemia, dizziness, 
headache, and muscle cramps.  These side effects occur in less than 10% of 
patients.8  Other potential side effects include hyperglycemia, sun sensitivity, 
hypotension, nausea and vomiting which have been reported to occur in less 
than 1% of patients.8  There is also a slight risk associated with the blood draws, 
including possible infections at injection sites, and pain upon needle insertion.  
The subjects due to the diuresis and possible potassium and magnesium 
depletion may be at higher risk for ventricular arrhythmias. 
 
5. 
Procedures for protecting against/minimizing risks: 
 
The 3-day treatment regimen selected should minimize any adverse effects 
associated with this study.  In addition, serum electrolytes will be monitored 
frequently and potassium and magnesium supplementation will be provided if 
necessary.  If symptomatic hypotension develops, the next dose of study drug 
will be withheld.  The risks involved with blood draws will be minimized by having 
all blood samples drawn by experienced GCRC nursing personnel.  The subjects 
will be monitored for potential ventricular arrhythmias during the study by 
performing standard 12-lead electrocardiogram (ECG) at the following times: 
time 0, 2 hours, 6 hours, and 12 hours post-dose. This is probably an advantage 
over the usual outpatient management of these subjects, which would have no 
monitoring of their heart rhythm. 
 
6. 
Clinical benefit to subjects: 
 


 
10
Although subjects are unlikely to benefit directly from this research, their 
participation may lead to information that could help direct the therapy of 
individuals with congestive heart failure requiring combination diuretic therapy.  
The risk:benefit ratio of this study is fairly low. 
 
F. 
JUSTIFICATION FOR UTILIZATION OF GCRC: 
 
The use of GCRC resources is important for the success of this study.  This is an 
investigator-initiated clinical project operating on very limited outside resources.  
Patients are not acutely ill, and cannot therefore be housed elsewhere in the 
hospital. The expertise of the GCRC nursing staff is needed to perform blood 
draws, collect urine, obtain electrocardiographic data, and vital signs all of which 
are integral for the success of the study. 
 
G. 
REFERENCES: 
1. 
Gehr, T, Sica, DA. Diuretics in congestive heart failure. Cardiology Clinics. 
February 1989; 7:87-96.  
2. 
Sica, DA , Gehr, TWB. Principles of combination diuretic therapy in 
congestive heart failure. CHF. 1997: 29-383.  
3. 
Ellison, DH. Diuretic combinations in the treatment in edema: Rationale 
and recommendations. Drug Therapy 1994; : 23-33.  
4. 
Ellison, DH. The physiologic basis of diuretic synergism: Its role in treating 
diuretic resistance. Ann Intern Med 1991; 114:886-94.   
5. 
Brater, DC. Diuretic therapy. NEJM 1998; 339: 387-395.   
6. 
Cody, R, Kubo, SH, Pickworth, KK. Diuretic treatment for the sodium 
retention of congestive heart failure. Arch Intern Med 1994; 154:1905-
1914.  
7. 
Dormans, TPJ, Gerlag, PGG. Combination of high-dose furosemide and 
hydrochlorothiazide in the treatment of refractory congestive heart failure. 
Eur Heart J. 1996; 17:1867-74.  
8. 
Thiazides and Related Diuretics. In: Drug Facts and Comparisons 1999 
53rd ed. St. Louis (MO): Facts and Comparisons; 1999. p. 135a-136c.  
9. 
Ferguson, JA, Sunbald KJ, Becker, PK, Gorski, JC, Rudy, DW, Brater, 
DC. Role of duration of diuretic effect in preventing sodium retention. Clin 
Pharmacol Ther. 1997;62:203-208.  
10. 
Grosskopf, I, Rabinoute, M, Rosenfeld JB. Combination of furosemide and 
metolazone in the treatment of severe congestive heart failure. Israel 
Journal of Medicine Sciences. 1986; 22: 787-790.  


 
11
11. 
Channer, KS, McLean, KA, Lawson-Matthew, P, Richardson, M. 
Combination diuretic treatment in severe heart failure: a randomized 
controlled trial. Br Heart J 1994; 71:146-150.  
12. 
Davis, LJ, Shimomura, SK, Hart, LL. Metolazone-Furosemide synergism. 
Drug Intelligence and Clinical Pharmacology 1980; 14:842-843.  
13. 
Gunstone, RF, Wing, AJ, Shani, HGP, Njemo, D, Sabuka, EMW. Clinical 
experience with metolazone in fifty-two African patients: synergy with 
frusemide. Postgrad Med J 1971;47:789-793.   
14. 
Consensus recommendations for the management of chronic heart failure. 
Am J Cardiol 1999; 83(2A):1A-30A.  
15. 
Anastasiou-Nana, MI, Nanas, JN, Karagounis, LA, et al.  Relation of 
dispersion of QRS and QT in patients with advanced congestive heart 
failure to cardiac and sudden death mortality. Am J Cardiol.2000; 
85(10);1212-17. 
16. 
Oikarinen L, Nieminen MS, Viitasalo M, et al.  Relation of QT interval and 
QT dispersion to echocardiographic left ventricular hypertrophy and 
geometric pattern in hypertensive patients. The LIFE study.  J. 
Hypertension.  2001; 19(10);1883-91. 
17. 
Meredith IT, Broughton A, Jennings Gl, Esler MD. Evidence of a selective 
increase cardiac sympathetic activity in patients with sustained ventricular 
arrhythmias. N Engl J Med 1991;325:618-24. 
18. 
Arora RB, Somari P. Ectopic arrhythmia provoking action of aldosterone. 
Life Sci 1962;5:215-8. 
19. 
Mombouli JV, Vanhoutte PM. Endothelial dysfunction: from physiology to 
therapy. J Mol Cell Cardiol 1999;31:61-74. 
20. 
Broqvist M, Dahlstrom U, Karlberg BE, et al. Neuroendocrine response in 
acute heart failure and the influence of treatment. Eur Heart J 
1989;10:1075-83. 
21. 
Francis GS, Benedict C, Johnstone DE, et al. Comparison of 
neuroendocrine activation in patients with left ventricular dysfunction with 
and without congestive heart failure: a substudy of the Studies of Left 
Ventricular Dysfunction (SOLVD). Circulation 1990;82:1724-29. 
22. 
Levin ER,  Gardner DG, Samson WK. Natriuretic peptides. N Engl J Med 
1998;339:321-8. 
23. 
Maeda K, Tsutamoto T, Wada A. et al. Plasma brain natriuretic peptide as 
a biochemical marker of high left ventricular end-diastolic pressure in 
patients with symptomatic left ventricular dysfunction. Am Heart J 
1998;135:825-32. 


 
12
24. 
Clerico A, Lervasi G, Del Chicca MG, et al. Circulating levels of cardiac 
natriuretic peptides (ANP and BNP) measured by highly sensitive and 
specific immunoradiometric assays in normal subjects and in patients with 
different degrees of heart failure. J Endocrinol Invest 1998;21:170-9. 
25. 
Cockcroft, DW, Gault MH. Prediction of creatinine clearance from serum 
creatinine. Nephron. 1976; 16:31-41. 
H. 
SUPPORT: 
This project is currently receiving support from the University of New Mexico 
Health Sciences Center Research Allocation Committee Award.  $7,150.00 . 
I. 
GCRC NEEDS: 
Please see attachments I-V. 
J. 
INFORMED CONSENT: 
Please see attached consent form which is currently under review by the Human 
Research Review Committee of the University of New Mexico (Appendix A). 
K. 
BIOGRAPHICAL SKETCHES: 
Please see Appendix B. 
L. 
SUMMARY-ABSTRACT: 
Objective:  To establish which combination of diuretics is the most effective in 
promoting diuresis in congestive heart failure patients.  Secondary Objectives:  
To determine the duration of action of furosemide as monotherapy and in 
combination with either hydrochlorothiazide or metolazone.  To determine the 
effect 
of 
diuretic 
combination 
therapy 
on 
neurohormonal 
activation.  
Background:  Diuretic resistance occurs when a potent diuretic drug, such as 
furosemide, is given in therapeutic doses and fails to reduce extracellular fluid 
volume to the desired level in an edematous patient.  Studies have shown that 
metolazone and hydrochlorothiazide have demonstrated a synergistic response 
when used in combination with furosemide in congestive heart failure patients.  
The current guidelines for treating diuretic resistance in congestive heart failure 
patients recommend the metolazone-furosemide combination.  However, there is 
no evidence to conclude that this combination is superior to hydrochlorothiazide-
furosemide in increasing diuresis.  Methods:  Randomized, double-blind, 
crossover study to compare the efficacy of hydrochlorothiazide and metolazone 
in combination with stable doses of furosemide in 26 patients with congestive 
heart failure.  The primary endpoint will be change in urinary output.  Secondary 
endpoints will be changes in weight, neurohormones (angiotensin II, 
catecholamines, brain natriuretic peptide, aldosterone), and electrocardiographic 
parameters of ventricular instability.  Study procedures will be performed at the 
UNM General Clinical Research Center.  Patients will be hospitalized for 2 
separate 4-day admissions, separated by a 1-week washout period.  At each 


 
13
admission each patient will receive furosemide in combination with either 
metolazone or hydrochlorothiazide (metolazone for one admission and 
hydrochlorothiazide for the other).  Following administration of combination 
therapy, blood and urine samples will be collected throughout the day to chart the 
onset and magnitude of effect of each treatment regimen.  Various 
hemodynamic, renal, endocrine, and neurohormonal parameters will be assesed 
as will the effect of each combination treatment on ventricular instability using 12-
lead electrocardiography.  Data will be analyzed using ANOVA to compare 
changes from baseline and the Student t-test to analyze intertreatment 
differences. All statistical analysis will be performed using SAS v6.12.   
 
Consent form 
HRRC letter of submission