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

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.

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