Acute Decompensated Heart Failure
Conditions
Keywords
Metolazone, Heart Failure
Brief summary
The primary objective of the study is to determine efficacy of metolazone as synergistic therapy with Lasix in patients with acute decompensated heart failure. This will be a single center double blinded randomized placebo- controlled pilot study of the addition of 5 mg of metolazone per day for 2 days compared to placebo in patients admitted with acute decompensated heart failure.
Detailed description
Heart failure is a major source of morbidity, mortality and growing public health cost. In US, the number of congestive heart failure patients is more than 4 million with more than 550,000 new annually reported cases. The annual cost of heart failure management exceeds 35 billion dollars per year.The heart failure readmissions and average length of hospital stay cost approximately $11,000 per patient. Loop diuretics are used alone in the majority of cases to promote diuresis. An association of increased creatinine and increased risk of renal dysfunction, the cardiorenal syndrome, in the face of high dose loop diuretics has raised questions regarding the safety and toxicity of high dose loop diuretics. While the dose of diuretics is ubiquitous, little data exists to guide their use and many clinicians are uncertain as to when and how to initiate and limit therapy. Prospective randomized data on large number of decompensated heart failure patients receiving metolazone in addition to standard therapy is scarce and needs further definitive evaluation in terms of clinical outcomes and safety. In many cases, a stepped approach with oral loop diuretics advancing to intravenous and finally combination high dose diuretics is employed. Primary endpoint: Total urinary output and negative fluid balance in millilitres (ml) at 48 hours following first dose of intravenous diuretic. Secondary endpoints: 1. Change in weight from admission to day 2. 2. Degree of improvement in dyspnea at 6,12, 24,36, and 48 hours assessed with Modified Borg Scale (1-10) 3. All cause mortality at 30 days. This is a single center study of at least 200 patients who are admitted to Aultman Hospital with clinical decompensated congestive heart failure ( NYHA III-IV). It is a double blinded randomized placebo- controlled pilot study of the addition of 5 mg of metolazone per day for 2 days compared to placebo in patients admitted with acute decompensated heart failure. We will compare a strategy of early institution of metolazone with standard of care in patients admitted with decompensated heart failure and volume overload. All patients will receive standard heart failure therapy, including but not restricted to diuretics, digoxin, angiotensin converting enzyme inhibitors or angiotensin II receptor blockers, beta blockers, aldosterone antagonists, hydralazine, and/or nitrates, at the discretion of the treating physician. After informed consent is obtained, patients will be randomized 1:1 to the treatment arm or placebo arm. Two additional doses of metolazone within 6 and 24 hours of administration of standard intravenous diuretics will be given to the treatment arm. Patients and physicians will be blinded to the administered drug (metolazone vs placebo).Drug will be distributed by pharmacy when a patient is consented and enrolled in the trial. Specific guidance/recommendations regarding diuretic therapy will be provided (documented in detail below) but will be at the discretion of the treating physician. We will collect data on demographics, co-morbidities, clinical presentations and outcomes with metolazone administration with patient follow up at one week (+3) and 30 (±7) days post discharge.
Interventions
DRUGExperimental: Placebo
All patients will receive standard heart failure therapy, including but not restricted to diuretics, digoxin, angiotensin converting enzyme inhibitors or angiotensin II receptor blockers, beta blockers, aldosterone antagonists, hydralazine, and/or nitrates, at the discretion of the treating physician. After informed consent is obtained, patients will be randomized 1:1 to the treatment arm or placebo arm. The first placebo dose is given within six hours of admininstration of first dose of intravenous diuretic. The second placebo dose is given at 24-hours after the first dose.
DRUGExperimental: Metolazone
All patients will receive standard heart failure therapy, including but not restricted to diuretics, digoxin, angiotensin converting enzyme inhibitors or angiotensin II receptor blockers, beta blockers, aldosterone antagonists, hydralazine, and/or nitrates, at the discretion of the treating physician. After informed consent is obtained, patients will be randomized 1:1 to the treatment arm or placebo arm. The first dose of metolazone is given within six hours of admininstration of first dose of intravenous diuretic The second dose of metolazone is given 24-hours after the first dose.
Sponsors
Aultman Health Foundation
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age 18 years or older * Current hospitalization for chronic congestive heart failure with admission up to 48 hours prior to inclusion. * Chronic heart failure will be defined as requiring treatment for a minimum of 30 days prior to current admission, NYHA Class III or IV at the time of hospitalization, and left ventricular ejection fraction less than 40% within one year or evidence of heart failure with preserved ejection fraction and evidence of diastolic dysfunction on echocardiogram. * Admitted with clinical decompensated heart failure based on history, physical exam, and parameters indicating extracellular volume expansion such as including JVP ≥ 8 cm of water and 1+ or greater peripheral edema * Is able to be dosed with study medication within six (6) hours of first dose of IV diuretics
Exclusion criteria
* Baseline severe hypotension (Mean arterial pressure \< 55 mm Hg) * Creatinine clearance less than 20 ml/min or creatinine greater than 2.5 mg/dl. * Serum sodium less than 128 meq/L. * Serum Potassium \< 3.0 meq/L. * Known adverse reaction to metolazone * Inability to take oral medications * Severe Aortic Stenosis (AVA \< 0.8cm2) * History of Hypertrophic obstructive cardiomyopathy * Metastatic Carcinoma per history * Severe COPD, FEV \< 1L * Severe dyspnea requiring prolonged CPAP,BIPAP or intubation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Total Urinary Output at 48 Hours | 48 hours | Total urinary output in milliliters (ml) at 48 hours. Measurement timing began with administration of first dose of investigational product, ended 48 hours later. |
| Fluid Balance at 48 Hours | 48 hours | Difference in value between input and output in milliliters (ml) at 48 hours. Measurement timing began with administration of first dose of investigational product, ended 48 hours later. Fluid balance = Fluid in minus Fluid out. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Degree of Improvement in Dyspnea at 6, 12, 24, 36 and 48 Hours. | 6, 12, 24, 36 and 48 hours. | Dyspnea assessed at 6, 12, 24, 36 and 48 hours with Modified Borg Scale (1-10). Range is from 1 (very slight) to 10 (maximal) dyspnea. |
| Total Dose Diuretics First 48 Hours | 48 hours | Total dosage loop diuretic in first 48 hours using conversion tool to calculate intravenous Lasix equivalence |
| All Cause Mortality at 30 Days | 30 Days | All Cause Mortality at 30 Days |
| Number of Participants With Inotrope Administration During First 48 Hours | 48 hours | Number of Participants with Inotrope administration during first 48 hours following study enrollment. |
| Change in Weight First 48 Hours | 48 hours | Change in weight from the date/time of study enrollment (baseline) and 48 hours. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Length of Hospital Stay | Inpatient Hospitalization | Length of hospital stay in days |
| All Cause Readmission Within 30 Days | 30 Days | All Cause Readmission Within 30 Days |
| Heart Failure Readmission Within 30 Days | 30 Days | Heart Failure Readmission Within 30 Days |
| Number of Participants With Potassium Electrolyte Abnormality Requiring Replacement | 48 Hours | Severe electrolyte abnormalities requiring aggressive replacement defined as potassium levels less than 3.0 meq/L during the study. |
| Number of Participants With Magnesium Electrolyte Abnormality Requiring Replacement | 48 Hours | Number of Participants with severe electrolyte abnormalities requiring aggressive replacement defined as magnesium levels less than 1.5 meq/L during the study. |
Countries
United States
Participant flow
Recruitment details
147 participants from one local institution (inpatient hospital) were enrolled between October 2015 and November 2017
Pre-assignment details
Participants who signed consent but after further evaluation did not to meet inclusion or met one or more exclusion criteria were not included in the analysis. There were four screen failures following consent.
Participants by arm
| Arm | Count |
|---|---|
| Experimental: Placebo This group will receive all standard heart failure therapy and placebo pill.
Experimental: Placebo: All patients will receive standard heart failure therapy, including but not restricted to diuretics, digoxin, angiotensin converting enzyme inhibitors or angiotensin II receptor blockers, beta blockers, aldosterone antagonists, hydralazine, and/or nitrates, at the discretion of the treating physician. After informed consent is obtained, patients will be randomized 1:1 to the treatment arm or placebo arm. The first placebo dose is given within six hours of admininstration of first dose of intravenous diuretic. The second placebo dose is given at 24-hours after the first dose. | 66 |
| Experimental: Metolazone This group will receive all standard heart failure therapy with addition of metolazone.
Experimental: Metolazone: All patients will receive standard heart failure therapy, including but not restricted to diuretics, digoxin, angiotensin converting enzyme inhibitors or angiotensin II receptor blockers, beta blockers, aldosterone antagonists, hydralazine, and/or nitrates, at the discretion of the treating physician. After informed consent is obtained, patients will be randomized 1:1 to the treatment arm or placebo arm. The first dose of metolazone is given within six hours of admininstration of first dose of intravenous diuretic The second dose of metolazone is given 24-hours after the first dose. | 66 |
| Total | 132 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 1 |
| Overall Study | Discharged prior to 2nd dose | 2 | 5 |
| Overall Study | Drug shortage prevented 2nd dose | 0 | 1 |
Baseline characteristics
| Characteristic | Total | Experimental: Placebo | Experimental: Metolazone |
|---|---|---|---|
| Age, Continuous | 72.77 years STANDARD_DEVIATION 13.1 | 73.67 years STANDARD_DEVIATION 13.5 | 71.86 years STANDARD_DEVIATION 12.8 |
| N-Terminal proBNP Value Upon Admission | 10545.12 pg/mL STANDARD_DEVIATION 12024.2 | 10905.6 pg/mL STANDARD_DEVIATION 12749.9 | 10184.7 pg/mL STANDARD_DEVIATION 11340.1 |
| NYHA Class at Enrollment Class 3 | 53 participants | 28 participants | 25 participants |
| NYHA Class at Enrollment Class 4 | 79 participants | 38 participants | 41 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 3 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 127 Participants | 63 Participants | 64 Participants |
| Region of Enrollment United States | 132 participants | 66 participants | 66 participants |
| Sex: Female, Male Female | 55 Participants | 26 Participants | 29 Participants |
| Sex: Female, Male Male | 77 Participants | 40 Participants | 37 Participants |
| Time Difference Qualifying Diuretic and Study Drug Initiation | 132.5 minutes STANDARD_DEVIATION 114.3 | 147.7 minutes STANDARD_DEVIATION 147.7 | 121.3 minutes STANDARD_DEVIATION 112.9 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 70 | 4 / 72 |
| other Total, other adverse events | 13 / 70 | 15 / 72 |
| serious Total, serious adverse events | 0 / 70 | 0 / 72 |
Outcome results
Primary
Fluid Balance at 48 Hours
Difference in value between input and output in milliliters (ml) at 48 hours. Measurement timing began with administration of first dose of investigational product, ended 48 hours later. Fluid balance = Fluid in minus Fluid out.
Time frame: 48 hours
Population: All participants who received both doses of the investigational product and completed the 48 hour assessments were included in the efficacy analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Experimental: Placebo | Fluid Balance at 48 Hours | -4260.762 Mililiters | Standard Deviation 2705.871 |
| Experimental: Metolazone | Fluid Balance at 48 Hours | -6510.091 Mililiters | Standard Deviation 4121.3808 |
p-value: <0.000195% CI: [-3454.4999, -1044.1589]t-test, 2 sided
Primary
Total Urinary Output at 48 Hours
Total urinary output in milliliters (ml) at 48 hours. Measurement timing began with administration of first dose of investigational product, ended 48 hours later.
Time frame: 48 hours
Population: All participants who received both doses of the investigational product and completed the 48 hour assessments were included in the efficacy analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Experimental: Placebo | Total Urinary Output at 48 Hours | 6893.777 Milliliters | Standard Deviation 3122.6532 |
| Experimental: Metolazone | Total Urinary Output at 48 Hours | 9333.288 Milliliters | Standard Deviation 4188.5731 |
p-value: <0.000195% CI: [1160.8485, 3718.1734]t-test, 2 sided
Secondary
All Cause Mortality at 30 Days
All Cause Mortality at 30 Days
Time frame: 30 Days
Population: All participants who received both doses of the investigational product and completed the 48 hour assessments were included in the efficacy analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Experimental: Placebo | All Cause Mortality at 30 Days | 1 Participants |
| Experimental: Metolazone | All Cause Mortality at 30 Days | 4 Participants |
p-value: 0.171Chi-squared
Secondary
Change in Weight First 48 Hours
Change in weight from the date/time of study enrollment (baseline) and 48 hours.
Time frame: 48 hours
Population: All participants who received both doses of the investigational product and completed the 48 hour assessments were included in the efficacy analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Experimental: Placebo | Change in Weight First 48 Hours | -3.23227 killograms | Standard Deviation 2.538462 |
| Experimental: Metolazone | Change in Weight First 48 Hours | -5.93939 killograms | Standard Deviation 4.033661 |
p-value: <0.000195% CI: [-3.8637732, -1.54651]t-test, 2 sided
Secondary
Degree of Improvement in Dyspnea at 6, 12, 24, 36 and 48 Hours.
Dyspnea assessed at 6, 12, 24, 36 and 48 hours with Modified Borg Scale (1-10). Range is from 1 (very slight) to 10 (maximal) dyspnea.
Time frame: 6, 12, 24, 36 and 48 hours.
Population: All participants who received both doses of the investigational product and completed the 48 hour assessments were included in the efficacy analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Experimental: Placebo | Degree of Improvement in Dyspnea at 6, 12, 24, 36 and 48 Hours. | Baseline | 9 score on a scale | Standard Deviation 0 |
| Experimental: Placebo | Degree of Improvement in Dyspnea at 6, 12, 24, 36 and 48 Hours. | 6 hours | 6.21 score on a scale | Standard Deviation 1.524 |
| Experimental: Placebo | Degree of Improvement in Dyspnea at 6, 12, 24, 36 and 48 Hours. | 12 hours | 4.88 score on a scale | Standard Deviation 1.564 |
| Experimental: Placebo | Degree of Improvement in Dyspnea at 6, 12, 24, 36 and 48 Hours. | 24 hours | 3.77 score on a scale | Standard Deviation 1.662 |
| Experimental: Placebo | Degree of Improvement in Dyspnea at 6, 12, 24, 36 and 48 Hours. | 36 hours | 2.924 score on a scale | Standard Deviation 1.6249 |
| Experimental: Placebo | Degree of Improvement in Dyspnea at 6, 12, 24, 36 and 48 Hours. | 48 hours | 2.295 score on a scale | Standard Deviation 1.664 |
| Experimental: Metolazone | Degree of Improvement in Dyspnea at 6, 12, 24, 36 and 48 Hours. | 36 hours | 2.123 score on a scale | Standard Deviation 1.5663 |
| Experimental: Metolazone | Degree of Improvement in Dyspnea at 6, 12, 24, 36 and 48 Hours. | Baseline | 9 score on a scale | Standard Deviation 0 |
| Experimental: Metolazone | Degree of Improvement in Dyspnea at 6, 12, 24, 36 and 48 Hours. | 24 hours | 2.95 score on a scale | Standard Deviation 1.643 |
| Experimental: Metolazone | Degree of Improvement in Dyspnea at 6, 12, 24, 36 and 48 Hours. | 6 hours | 5.49 score on a scale | Standard Deviation 1.532 |
| Experimental: Metolazone | Degree of Improvement in Dyspnea at 6, 12, 24, 36 and 48 Hours. | 48 hours | 1.600 score on a scale | Standard Deviation 1.5441 |
| Experimental: Metolazone | Degree of Improvement in Dyspnea at 6, 12, 24, 36 and 48 Hours. | 12 hours | 3.98 score on a scale | Standard Deviation 1.441 |
p-value: 0.01495% CI: [-1.2506, -0.1403]t-test, 2 sided
Secondary
Number of Participants With Inotrope Administration During First 48 Hours
Number of Participants with Inotrope administration during first 48 hours following study enrollment.
Time frame: 48 hours
Population: All participants who received both doses of the investigational product and completed the 48 hour assessments were included in the efficacy analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Experimental: Placebo | Number of Participants With Inotrope Administration During First 48 Hours | 9 Participants |
| Experimental: Metolazone | Number of Participants With Inotrope Administration During First 48 Hours | 4 Participants |
p-value: 0.144Chi-squared
Secondary
Total Dose Diuretics First 48 Hours
Total dosage loop diuretic in first 48 hours using conversion tool to calculate intravenous Lasix equivalence
Time frame: 48 hours
Population: All participants who received both doses of the investigational product and completed the 48 hour assessments were included in the efficacy analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Experimental: Placebo | Total Dose Diuretics First 48 Hours | 346.470 Milligrams | Standard Deviation 381.948 |
| Experimental: Metolazone | Total Dose Diuretics First 48 Hours | 350.160 Milligrams | Standard Deviation 444.864 |
p-value: 0.95995% CI: [-1395694, 147.1545]t-test, 2 sided
Other Pre-specified
All Cause Readmission Within 30 Days
All Cause Readmission Within 30 Days
Time frame: 30 Days
Population: All participants who received both doses of the investigational product and completed the 48 hour assessments were included in the efficacy analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Experimental: Placebo | All Cause Readmission Within 30 Days | 10 Participants |
| Experimental: Metolazone | All Cause Readmission Within 30 Days | 9 Participants |
p-value: 0.804Chi-squared
Other Pre-specified
Heart Failure Readmission Within 30 Days
Heart Failure Readmission Within 30 Days
Time frame: 30 Days
Population: All participants who received both doses of the investigational product and completed the 48 hour assessments were included in the efficacy analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Experimental: Placebo | Heart Failure Readmission Within 30 Days | 2 Participants |
| Experimental: Metolazone | Heart Failure Readmission Within 30 Days | 4 Participants |
p-value: 0.403Chi-squared
Other Pre-specified
Length of Hospital Stay
Length of hospital stay in days
Time frame: Inpatient Hospitalization
Population: All participants who received both doses of the investigational product and completed the 48 hour assessments were included in the efficacy analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Experimental: Placebo | Length of Hospital Stay | 5.33 days | Standard Deviation 4.695 |
| Experimental: Metolazone | Length of Hospital Stay | 5.44 days | Standard Deviation 3.672 |
p-value: 0.88595% CI: [-1.346, 1.558]t-test, 2 sided
Other Pre-specified
Number of Participants With Magnesium Electrolyte Abnormality Requiring Replacement
Number of Participants with severe electrolyte abnormalities requiring aggressive replacement defined as magnesium levels less than 1.5 meq/L during the study.
Time frame: 48 Hours
Population: All participants who received both doses of the investigational product and completed the 48 hour assessments were included in the efficacy analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Experimental: Placebo | Number of Participants With Magnesium Electrolyte Abnormality Requiring Replacement | 2 Participants |
| Experimental: Metolazone | Number of Participants With Magnesium Electrolyte Abnormality Requiring Replacement | 1 Participants |
p-value: 0.559Chi-squared
Other Pre-specified
Number of Participants With Potassium Electrolyte Abnormality Requiring Replacement
Severe electrolyte abnormalities requiring aggressive replacement defined as potassium levels less than 3.0 meq/L during the study.
Time frame: 48 Hours
Population: All participants who received both doses of the investigational product and completed the 48 hour assessments were included in the efficacy analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Experimental: Placebo | Number of Participants With Potassium Electrolyte Abnormality Requiring Replacement | 0 Participants |
| Experimental: Metolazone | Number of Participants With Potassium Electrolyte Abnormality Requiring Replacement | 3 Participants |
p-value: 0.08Chi-squared