Renal Optimization Strategies Evaluation in Acute Heart Failure and Reliable Evaluation of Dyspnea in the Heart Failure Network (ROSE) Study

Study Overview
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Brief Summary
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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
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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.

Official Title
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Renal Optimization Strategies Evaluation in Acute Heart Failure and Reliable Evaluation of Dyspnea in the Heart Failure Network ROSE Study

Conditions
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Acute Heart Failure

Intervention / Treatment
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* Other: Placebo
* Drug: Nesiritide
* Drug: Dopamine


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Low dose Dopamine<br>Drug: Dopamine Participants will be randomized to receive low dose dopamine or placebo during first 72 hours of participation in the study | Drug: Dopamine<br>* 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.<br>|
| Placebo Comparator: Placebo<br>Drug: Placebo Participants will receive placebo in place of low dose dopamine or low dose nesiritide depending on randomization. | Other: Placebo<br>* Participants will be randomized to receive Low dose Dopamine or placebo plus optimal diuretic or Low dose Nesiritide or placebo plus optimal diuretic.<br>|
| Active Comparator: Low Dose Nesiritide<br>Participants could be randomized to receive low dose nesiritide or placebo during the first 72 hours in the trial. | Drug: Nesiritide<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Cystatin C | The primary Safety endpoint is change in serum cystatin C from randomization to 72 hours. | Randomization to 72 hours | 
| 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 | Baseline to 72 hours | 
| 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. | Baseline to 72 hours | 
| Cumulative Urinary Volume | The primary efficacy endpoint is cumulative urinary volume (UV; +/- indwelling urinary catheter) at 72 hours | Randomization to 72 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Weight | Change in weight from randomization to 72 hours. Secondary Endpoint | randomization to 72 hours | 
| 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) | Change from Baseline to 72 hours | 
| Change in Clinical Stability- RED-ROSE | Change in clinical stability as assessed by 60 day death, re-hospitalization or unscheduled outpatient visit | Baseline to 60 days | 
| Change in Serum Creatinine |  | randomization to 72 hours | 
| Dyspnea Visual Analog Scale Area Under the Curve | Range 0 to 7200 Higher is better | randomization to 72 hours | 
| Change in Heart Failure Status | Persistent or worsening heart failure defined as need for rescue therapy. | randomization to 72 hours | 
| 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 | randomization to 72 hours | 
| Cumulative Urinary Sodium Excretion |  | Randomization to 72 hours | 
| 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 | Randomization to 72 hours | 
| Development of Cardio-renal Syndrome |  | Randomization to 72 hours | 
| Global Visual Analog Scale Area Under the Curve | Range 0 to 7200 Higher is better/improved | Randomization to 72 hours |