Acute Heart Failure
Conditions
Brief summary
The purpose of this study is to determine the benefits and safety of intravenous administration of low dose nesiritide or low dose dopamine in patients with congestive heart failure and kidney dysfunction. There is a substudy in a subset of subjects that is being used to determine whether the Provocative Dyspnea Severity Score (pDSS) is a more sensitive index of variability in clinical status than the dyspnea VAS assessed without standardization of conditions at assessments.
Detailed description
Acute heart failure (AHF) is the most common cause of hospital admission in patients over age 65, accounting for 1,000,000 admissions, over 6 million hospital days, and $12 billion in costs annually. The prognosis of patients admitted with AHF is dismal, with a 20-30% readmission rate and a 20-30% mortality rate within six months after admission. Recent studies have established the prognostic importance of renal function in patients with heart failure. In patients who are hospitalized with decompensated congestive heart failure, worsening renal function is also associated with worse outcome, Various studies have estimated that 25-30% of patients hospitalized for decompensated CHF have worsening of renal function leading to prolonged hospitalization, increased morbidity and mortality. Although there are no FDA approved renal adjuvant therapies for AHF, several novel adjuvant therapies for use in AHF are being investigated in randomized clinical trials. Additionally, there are currently available strategies, with the potential for improving renal function in AHF such as low dose dopamine and low dose nesiritide. However, these strategies have not been investigated. Participation in this study will last 6 months. All potential participants will undergo initial screening, which wil include a medical history, physical exam, blood draws, measurements of fluid intake and output, and questionnaires. The same evaluations and procedures will be repeated at various points during the study. Eligible participants will be randomly assigned to receive low dose nesiritide or placebo with optimal diuretic dosing or low dose dopamine or placebo with optimal diuretic dosing. Follow-up assessments will occur at Baseline, 24 hours, 48 hours, 72 hours, day 7 or discharge, day 60 and 6 months. Follow-up assessments will include medical history, physical exam, blood draws, measurements of fluid intake and output, questionnaires and questions about medications and changes in health. The RED ROSE substudy involves a subset of ROSE patients in looking at the dyspnea assessment. The dyspnea visual analog scale (dyspnea VAS) has been suggested to be superior to other ordinal (Likert) scales in assessment of dyspnea in acute heart failure syndromes (AHFS)1. However, there is no standardization of conditions (oxygen supplementation, position, activity) at the time of VAS assessment and thus, it may not optimally reflect the variability in dyspnea severity in AHFS patients. This insensitivity to variability at baseline and subsequent assessment may limit the ability to reflect variation in response over time and with alternate treatment strategies. A standardized and sequentially provocative assessment of dyspnea (provocative dyspnea severity score, pDSS) may better reflect variation in dyspnea severity and variation in response over time and with alternate treatment strategies. Substudy subjects will be asked to complete a provocative dyspnea assessment at baseline, 24, 48 and 72 hours. The subjects will be asked to complete a 6 minute walk assessment at the 72 hour visit.
Interventions
OTHERPlacebo
Participants will be randomized to receive Low dose Dopamine or placebo plus optimal diuretic or Low dose Nesiritide or placebo plus optimal diuretic.
DRUGNesiritide
Active Comparator: Low Dose Nesiritide Participants randomized to the low dose nesiritide arm will receive nesiritide of 0.005 ug/kg/min or placebo during the first 72 hours in the trial.
DRUGDopamine
Participants randomized to the low dose dopamine arm will receive dopamine of 2ug/kg/min or placebo during the first 72 hours in the trial.
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Duke University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* A diagnosis of heart failure as defined by the presence of at least 1 symptom (dyspnea, orthopnea, or edema) AND 1 sign (rales on auscultation, peripheral edema, ascites, pulmonary vascular congestion on chest radiography) * Prior clinical diagnosis of heart failure Must be identified within 24 hours of hospital admission (24 hour clock begins when the admission orders are placed) * Estimated GFR of \> 15 but \< 60 mL/min/1.73m2 determined by the MDRD equation * Male or female patient ≥18 years old * Willingness to provide informed consent * Ability to have a PICC or central line placed (if needed) within 12 hours of randomization and study drug infusion started * Anticipated hospitalization of at least 72 hours
Exclusion criteria
* Received IV vasoactive treatment or ultra-filtration therapy for heart failure since initial presentation * Anticipated need for IV vasoactive treatment or ultra-filtration for heart failure during this hospitalization * Systolic BP \<90 mmHg * Hemoglobin (Hgb) \< 9 g/dl * Renal replacement therapy * History of renal artery stenosis \> 50% * Hemodynamically significant arrhythmias including ventricular tachycardia or defibrillator shock within 4 weeks * Acute coronary syndrome within 4 weeks as defined by electrocardiographic (ECG) ST-segment depression or prominent T-wave inversion and/or positive biomarkers of necrosis (e.g., troponin) in the absence of ST-segment elevation and in an appropriate clinical setting (chest discomfort or anginal equivalent) * Active myocarditis * Hypertrophic obstructive cardiomyopathy * Greater than moderate stenotic valvular disease * Restrictive or constrictive cardiomyopathy * Complex congenital heart disease * Constrictive pericarditis * Non-cardiac pulmonary edema * Clinical evidence of digoxin toxicity * Need for mechanical hemodynamic support * Sepsis * Terminal illness (other than HF) with expected survival of less than 1 year * Previous adverse reaction to the study drugs * Use of IV iodinated radiocontrast material in last 72 hours or planned during hospitalization * Enrollment or planned enrollment in another randomized clinical trial during this hospitalization * Inability to comply with planned study procedures * Pregnancy or nursing mothers
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Cystatin C | Randomization to 72 hours | The primary Safety endpoint is change in serum cystatin C from randomization to 72 hours. |
| Change in Dyspnea Assessment (RED-ROSE Substudy) | Baseline to 72 hours | To determine whether the pDSS is a more sensitive index of variability in dyspnea status than the dyspnea VAS assessed without standardization of conditions at assessment as assessed by change in Dyspnea VAS. Dyspnea VAS range -100 to + 100 Larger number is better |
| Decongestive Changes- RED-ROSE | Baseline to 72 hours | To determine whether changes in pDSS or dyspnea VAS are related to the response to decongestive therapy as evidenced by fluid volume loss Fluid volume loss is defined as cumulative urinary output minus fluid intake during the first 72 hours post randomization. |
| Cumulative Urinary Volume | Randomization to 72 hours | The primary efficacy endpoint is cumulative urinary volume (UV; +/- indwelling urinary catheter) at 72 hours |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Serum Creatinine | randomization to 72 hours | — |
| Change in Heart Failure Status | randomization to 72 hours | Persistent or worsening heart failure defined as need for rescue therapy. |
| Change in Treatment Response | randomization to 72 hours | Treatment failure including any of the following: * development of cardio-renal syndrome * worsening/persistent heart failure * significant hypotension requiring discontinuation of study drug * significant tachycardia requiring discontinuation of study drug death |
| Dyspnea Visual Analog Scale Area Under the Curve | randomization to 72 hours | Range 0 to 7200 Higher is better |
| Change in Blood Urea Nitrogen (BUN)/ Serum Cystatin C Ratio | Randomization to 72 hours | BUN measured in mg/dL Cystatin C measured in mg/L No units were used in calculated the ratio |
| Development of Cardio-renal Syndrome | Randomization to 72 hours | — |
| Global Visual Analog Scale Area Under the Curve | Randomization to 72 hours | Range 0 to 7200 Higher is better/improved |
| Cumulative Urinary Sodium Excretion | Randomization to 72 hours | — |
| Change in Weight | randomization to 72 hours | Change in weight from randomization to 72 hours. Secondary Endpoint |
| Worst Reported Symptom Changes-RED-ROSE | Change from Baseline to 72 hours | To determine whether changes in worst reported symptom (WRS) (dyspnea, body swelling or fatigue) VAS (WRS-VAS) are related to the response to decongestive therapy as assessed by change in WRS VAS. WRS range -100 to + 100 Higher number is better (improved) |
| Change in Clinical Stability- RED-ROSE | Baseline to 60 days | Change in clinical stability as assessed by 60 day death, re-hospitalization or unscheduled outpatient visit |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Low Dose Dopamine Drug: Dopamine
Participants will be randomized to receive low dose dopamine or placebo during first 72 hours of participation in the study
Dopamine: Participants randomized to the low dose dopamine arm will receive dopamine of 2ug/kg/min or placebo during the first 72 hours in the trial. | 122 |
| Placebo Drug: Placebo Participants will receive placebo in place of low dose dopamine or low dose nesiritide depending on randomization.
Placebo: Participants will be randomized to receive Low dose Dopamine or placebo plus optimal diuretic or Low dose Nesiritide or placebo plus optimal diuretic. | 119 |
| Low Dose Nesiritide Drug: Nesiritide Participants could be randomized to receive low dose nesiritide or placebo during the first 72 hours in the trial.
Participants randomized to the low dose nesiritide arm will receive nesiritide of 0.005 ug/kg/min or placebo during the first 72 hours in the trial. | 119 |
| Total | 360 |
Baseline characteristics
| Characteristic | Total | Low Dose Nesiritide | Placebo | Low Dose Dopamine |
|---|---|---|---|---|
| Age, Continuous | 69.6 years STANDARD_DEVIATION 12.3 | 68.3 years STANDARD_DEVIATION 13 | 69.3 years STANDARD_DEVIATION 12.6 | 71.0 years STANDARD_DEVIATION 11.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 14 Participants | 3 Participants | 5 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 344 Participants | 116 Participants | 112 Participants | 116 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 0 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 7 Participants | 3 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 1 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 74 Participants | 24 Participants | 23 Participants | 27 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 0 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) White | 272 Participants | 91 Participants | 91 Participants | 90 Participants |
| Sex: Female, Male Female | 96 Participants | 28 Participants | 30 Participants | 38 Participants |
| Sex: Female, Male Male | 264 Participants | 91 Participants | 89 Participants | 84 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 122 | 0 / 119 | 0 / 119 |
| serious Total, serious adverse events | 30 / 122 | 24 / 119 | 21 / 119 |
Outcome results
Primary
Change in Cystatin C
The primary Safety endpoint is change in serum cystatin C from randomization to 72 hours.
Time frame: Randomization to 72 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low Dose Dopamine | Change in Cystatin C | .12 mg/L | Standard Deviation 0.32 |
| Placebo | Change in Cystatin C | .11 mg/L | Standard Deviation 0.27 |
| Low Dose Nesiritide | Change in Cystatin C | .07 mg/L | Standard Deviation 0.34 |
Primary
Change in Dyspnea Assessment (RED-ROSE Substudy)
To determine whether the pDSS is a more sensitive index of variability in dyspnea status than the dyspnea VAS assessed without standardization of conditions at assessment as assessed by change in Dyspnea VAS. Dyspnea VAS range -100 to + 100 Larger number is better
Time frame: Baseline to 72 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low Dose Dopamine | Change in Dyspnea Assessment (RED-ROSE Substudy) | 16.1 units on a scale | Standard Deviation 30.7 |
| Placebo | Change in Dyspnea Assessment (RED-ROSE Substudy) | 16.2 units on a scale | Standard Deviation 22.3 |
| Low Dose Nesiritide | Change in Dyspnea Assessment (RED-ROSE Substudy) | 16.8 units on a scale | Standard Deviation 24.2 |
Primary
Cumulative Urinary Volume
The primary efficacy endpoint is cumulative urinary volume (UV; +/- indwelling urinary catheter) at 72 hours
Time frame: Randomization to 72 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low Dose Dopamine | Cumulative Urinary Volume | 8524 mL | Standard Deviation 3418 |
| Placebo | Cumulative Urinary Volume | 8296 mL | Standard Deviation 2973 |
| Low Dose Nesiritide | Cumulative Urinary Volume | 8574 mL | Standard Deviation 3115 |
Primary
Decongestive Changes- RED-ROSE
To determine whether changes in pDSS or dyspnea VAS are related to the response to decongestive therapy as evidenced by fluid volume loss Fluid volume loss is defined as cumulative urinary output minus fluid intake during the first 72 hours post randomization.
Time frame: Baseline to 72 hours
Population: RED-ROSE is a substudy of the overall ROSE study. Only consented and enrolled RED-ROSE subjects participated.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low Dose Dopamine | Decongestive Changes- RED-ROSE | 4526.0 mL | Standard Deviation 3191.9 |
| Placebo | Decongestive Changes- RED-ROSE | 4659.9 mL | Standard Deviation 2862.5 |
| Low Dose Nesiritide | Decongestive Changes- RED-ROSE | 5177.2 mL | Standard Deviation 2830.5 |
Secondary
Change in Blood Urea Nitrogen (BUN)/ Serum Cystatin C Ratio
BUN measured in mg/dL Cystatin C measured in mg/L No units were used in calculated the ratio
Time frame: Randomization to 72 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low Dose Dopamine | Change in Blood Urea Nitrogen (BUN)/ Serum Cystatin C Ratio | -2.34 ratio | Standard Deviation 25.33 |
| Placebo | Change in Blood Urea Nitrogen (BUN)/ Serum Cystatin C Ratio | 0.23 ratio | Standard Deviation 5.16 |
| Low Dose Nesiritide | Change in Blood Urea Nitrogen (BUN)/ Serum Cystatin C Ratio | 0.74 ratio | Standard Deviation 7.6 |
Secondary
Change in Clinical Stability- RED-ROSE
Change in clinical stability as assessed by 60 day death, re-hospitalization or unscheduled outpatient visit
Time frame: Baseline to 60 days
Population: RED-ROSE was a substudy of the main ROSE trial. Only subjects consented and enrolled in RED-ROSE were included in this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Low Dose Dopamine | Change in Clinical Stability- RED-ROSE | 30 participants |
| Placebo | Change in Clinical Stability- RED-ROSE | 34 participants |
| Low Dose Nesiritide | Change in Clinical Stability- RED-ROSE | 27 participants |
Secondary
Change in Heart Failure Status
Persistent or worsening heart failure defined as need for rescue therapy.
Time frame: randomization to 72 hours
Population: Based upon data completeness, sample size for this endpoint does not match the overall ROSE population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Low Dose Dopamine | Change in Heart Failure Status | 11 participants |
| Placebo | Change in Heart Failure Status | 5 participants |
| Low Dose Nesiritide | Change in Heart Failure Status | 6 participants |
Secondary
Change in Serum Creatinine
Time frame: randomization to 72 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low Dose Dopamine | Change in Serum Creatinine | 0.00 mg/dL | Standard Deviation 0.44 |
| Placebo | Change in Serum Creatinine | 0.02 mg/dL | Standard Deviation 0.33 |
| Low Dose Nesiritide | Change in Serum Creatinine | 0.02 mg/dL | Standard Deviation 0.42 |
Secondary
Change in Treatment Response
Treatment failure including any of the following: * development of cardio-renal syndrome * worsening/persistent heart failure * significant hypotension requiring discontinuation of study drug * significant tachycardia requiring discontinuation of study drug death
Time frame: randomization to 72 hours
Population: Based upon data completeness, sample size for this endpoint does not match the overall ROSE population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Low Dose Dopamine | Change in Treatment Response | 35 participants |
| Placebo | Change in Treatment Response | 32 participants |
| Low Dose Nesiritide | Change in Treatment Response | 48 participants |
Secondary
Change in Weight
Change in weight from randomization to 72 hours. Secondary Endpoint
Time frame: randomization to 72 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low Dose Dopamine | Change in Weight | -7.40 lbs | Standard Deviation 7.94 |
| Placebo | Change in Weight | -7.73 lbs | Standard Deviation 7.04 |
| Low Dose Nesiritide | Change in Weight | -7.15 lbs | Standard Deviation 7.8 |
Secondary
Cumulative Urinary Sodium Excretion
Time frame: Randomization to 72 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low Dose Dopamine | Cumulative Urinary Sodium Excretion | 527.0 mmol | Standard Deviation 299 |
| Placebo | Cumulative Urinary Sodium Excretion | 539.8 mmol | Standard Deviation 302.7 |
| Low Dose Nesiritide | Cumulative Urinary Sodium Excretion | 515.2 mmol | Standard Deviation 261.4 |
Secondary
Development of Cardio-renal Syndrome
Time frame: Randomization to 72 hours
Population: Based upon data completeness, sample size for this endpoint does not match the overall ROSE population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Low Dose Dopamine | Development of Cardio-renal Syndrome | 23 participants |
| Placebo | Development of Cardio-renal Syndrome | 24 participants |
| Low Dose Nesiritide | Development of Cardio-renal Syndrome | 28 participants |
Secondary
Dyspnea Visual Analog Scale Area Under the Curve
Range 0 to 7200 Higher is better
Time frame: randomization to 72 hours
Population: Based upon data completeness, sample size for this endpoint does not match the overall ROSE population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low Dose Dopamine | Dyspnea Visual Analog Scale Area Under the Curve | 4935.8 units on a scale * hours | Standard Deviation 1472.1 |
| Placebo | Dyspnea Visual Analog Scale Area Under the Curve | 4997.6 units on a scale * hours | Standard Deviation 1479.9 |
| Low Dose Nesiritide | Dyspnea Visual Analog Scale Area Under the Curve | 4831.4 units on a scale * hours | Standard Deviation 1294.1 |
Secondary
Global Visual Analog Scale Area Under the Curve
Range 0 to 7200 Higher is better/improved
Time frame: Randomization to 72 hours
Population: Based upon data completeness, sample size for this endpoint does not match the overall ROSE population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low Dose Dopamine | Global Visual Analog Scale Area Under the Curve | 4553.4 units on a scale * hours | Standard Deviation 1324.9 |
| Placebo | Global Visual Analog Scale Area Under the Curve | 4703.6 units on a scale * hours | Standard Deviation 1403.4 |
| Low Dose Nesiritide | Global Visual Analog Scale Area Under the Curve | 4498.3 units on a scale * hours | Standard Deviation 1301.5 |
Secondary
Worst Reported Symptom Changes-RED-ROSE
To determine whether changes in worst reported symptom (WRS) (dyspnea, body swelling or fatigue) VAS (WRS-VAS) are related to the response to decongestive therapy as assessed by change in WRS VAS. WRS range -100 to + 100 Higher number is better (improved)
Time frame: Change from Baseline to 72 hours
Population: RED-ROSE was a substudy of the main ROSE study. Only subjects consented and enrolled in RED-ROSE were included in this analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low Dose Dopamine | Worst Reported Symptom Changes-RED-ROSE | 20.9 units on a scale | Standard Deviation 29.6 |
| Placebo | Worst Reported Symptom Changes-RED-ROSE | 19.6 units on a scale | Standard Deviation 22.7 |
| Low Dose Nesiritide | Worst Reported Symptom Changes-RED-ROSE | 25.6 units on a scale | Standard Deviation 25.6 |