Protocolized Diuretic Strategy in Cardiorenal Failure

Heart failure (HF) accounts for over 1 million hospital admissions annually in the United
States and is a leading cause of disability and healthcare costs. Cardiorenal syndrome and
worsening renal function are independent risk factors for morbidity and mortality in HF.
Effective fluid removal, manifested by a decrease in body weight, is one of the most
important goals of treatment in cardiorenal syndrome. Current medical therapeutic options,
including sodium and fluid restriction, diuretics, blockade of the
renin-angiotensin-aldosterone system, inotropes, and nesiritide, are suboptimal in patients
with advanced cardiorenal syndrome. When medical therapies fail, ultrafiltration (UF) may be
used for mechanical fluid removal using dialysis or UF machines. UF can effectively remove
fluid in HF patients, but its precise role in the therapy of cardiorenal syndrome is still
unclear. A multicenter randomized controlled trial (CARRESS-HF) suggested that UF was not
superior to a stepped pharmacologic diuretic regimen, with a similar amount of weight loss
with the two approaches and a higher rate of adverse events in the UF group. Therefore, a
protocolized diuretic strategy is needed that is superior to current clinical care in the
management of cardiorenal syndrome.

Current HF guidelines do not provide any standard protocol for diuretic dosing. The
variation in usual clinical care may explain the long hospital stays and worsening renal
function common in these patients. One retrospective observational study compared a diuretic
dosing protocol to usual diuretic therapy for patients admitted with acute decompensated HF.
Protocol diuretic use was associated with greater weight loss and significantly lower risk
of 30-day readmission. However, due to its retrospective design, the baseline
characteristics of the two groups differed in many pertinent covariates, and its
generalizability is limited.

The proposed study aims to determine if a protocolized diuretic treatment strategy, as
opposed to usual clinical care, results in improved clinical decongestion, clinical
outcomes, and health-related quality of life (HRQOL), while preserving renal function in
hospitalized patients with cardiorenal syndrome. It is a prospective randomized single-blind
trial with equal allocation (1:1) and random block randomization of 150 participants
hospitalized at University of Pittsburgh Medical Center (UPMC) for cardiorenal syndrome
recruited over 3 years (approximately 50 participants/year). Participants with cardiorenal
syndrome will be randomized to a Protocolized Diuretic Strategy (based on the stepped
pharmacologic algorithm used in the CARRESS-HF trial) vs. Usual Care. Participants will be
followed daily in the hospital during the treatment period, as well as at 1-month and
3-month follow-up visits in the outpatient HF clinic.

Primary Research Question:

1. In hospitalized patients with cardiorenal syndrome, does a protocolized diuretic
treatment strategy, as opposed to usual clinical care, result in improved clinical
decongestion based on change in body weight at day 4 or hospital discharge (whichever comes
first)? Primary Hypothesis. In hospitalized patients with cardiorenal syndrome, protocolized
diuretic therapy will result in greater reduction in body weight and improved clinical
decongestion compared to usual care.

Secondary Research Questions:

1. Do clinical outcomes, including length of hospitalization, number of rehospitalizations
for HF, and mortality, improve after protocolized diuretic therapy compared to usual
care over 3 months? Hypothesis 1. Protocolized diuretic therapy will be associated with
reduced length of hospital stay, decreased rehospitalization rates, and decreased
mortality, compared to usual care.

2. Do other measures of volume status improve after protocolized diuretic therapy compared
to usual care during hospitalization and over 3 months? Hypothesis 2. Protocolized
diuretic therapy will be associated with greater decongestion based on increased venous
compliance of the internal jugular vein (via Doppler ultrasound), negative fluid
balance, and clinical decongestion, compared to usual care.

3. Do HRQOL outcomes improve after protocolized diuretic therapy compared to usual care
over 3 months? Hypothesis 3. HRQOL indices in physical well-being, mental well-being,
and sleep quality domains will improve after protocolized diuretic therapy compared to
usual care.

4. Do renal outcomes (safety endpoints), including renal function changes and need for UF
or renal replacement therapy, differ between protocolized diuretic therapy and usual
care during hospitalization and over 3 months? Hypothesis 4. Protocolized diuretic
therapy will be superior to usual care in terms of worsening renal function and need
for UF or renal replacement therapy.

Subgroup Research Questions:

1. Do outcomes differ between the Protocolized Diuretic Strategy vs. Usual care stratified
by type of heart failure (e.g., systolic dysfunction (EF <40%) vs. diastolic dysfunction (EF
≥40%); ischemic vs. other; none-mild vs. moderate-severe mitral regurgitation (MR) or
tricuspid regurgitation (TR))? Hypothesis 1. No difference will be seen between treatment
and control groups based on type of heart failure.

This trial is of utmost interest to cardiologists and nephrologists, who struggle to find
the optimal diuretic and medical management strategy to effectively remove excess fluid yet
preserve renal function. It is highly relevant to many clinicians and the community at
large, as HF and cardiorenal syndrome are a leading cause of hospitalizations and healthcare
costs. If a protocolized diuretic strategy can be found that optimally removes fluid in an
efficient and safe manner, it could potentially be disseminated to community physicians
and/or incorporated into public policy or HF treatment guidelines in order to improve
quality of care and reduce healthcare costs in this population with high morbidity and
mortality.

Inclusion Criteria:

- Age ≥21 years

- History of heart failure (HF), with either left ventricular (LV) dysfunction (EF<40%)
or at least stage I diastolic or right ventricular (RV) dysfunction based on
echocardiogram (ECHO) within the last year or diagnosis of HF by International
Classification of Diseases (ICD-9)

- Evidence of renal dysfunction based on one of the following:

- Estimated glomerular filtration rate (GFR) 15-59 mL/min/1.73 m2 based on the
Modification of Diet in Renal Disease (MDRD) equation using serum creatinine
(Cr) obtained within 6 months of admission

- Elevated Cr above upper limits of normal

- An increase in serum Cr of ≥0.3 mg/dL or ≥50% from baseline on admission or
during diuretic therapy, with no alternative cause for worsening renal function,
while demonstrating signs and symptoms of persistent volume overload occurring
within 7 days before admission or during hospitalization

- Evidence of volume overload by clinical and/or radiographic features, with at least 2
of the following: 1) peripheral edema ≥2+; 2) jugular venous distension ≥7 cm; 3)
radiographic pulmonary edema or pleural effusion; 4) enlarged liver or ascites; 5)
pulmonary rales, paroxysmal nocturnal dyspnea, or orthopnea; 6) elevated brain
natriuretic peptide (BNP) level; 7) documentation of elevated right heart filling
pressures by pulmonary artery catheter or right heart catheterization

Exclusion Criteria:

- Use of inotropes (at time of screening)

- Acute indications for hemodialysis (HD) (e.g., severe hyperkalemia, metabolic
acidosis, uremic signs or symptoms, pericardial friction rub)

- Specific forms of HF by chart diagnoses:

1. Congenital heart disease

2. Primary valvular heart disease due to severe valvular stenosis or acute severe
valvular regurgitation or valvular disease requiring immediate surgical repair

3. Infiltrative cardiomyopathies

4. Pulmonary hypertension (PH) as defined by World Health Organization (WHO) group
I and WHO group IV - Prior use of ultrafiltration (UF) or HD in the 3 months
preceding hospitalization

- End-stage renal disease (ESRD) requiring chronic dialysis or estimated GFR <15
mL/min/1.73 m2 by MDRD equation (i.e., pre-existing ESRD)

- Prior cardiac or kidney transplantation

- Intravascular volume depletion based on clinical assessment

- Cardiogenic shock and/or systolic blood pressure (SBP) <90 mmHg

- Unstable coronary disease or acute coronary syndrome within 1 month of admission

- Alternative explanation for worsening renal function (e.g., obstructive nephropathy,
contrast-induced nephropathy, acute tubular necrosis, intrinsic renal diseases)

- Life expectancy < 3 months due to other chronic health conditions (e.g., end-stage
liver disease, pulmonary disease, malignancy, etc.)

- Psychiatric disorder requiring admission to a psychiatric hospital during HF
admission

- Previous enrollment in this trial or other diuretic or UF trial in the prior 3 months

- Expected geographic unavailability for 3 months following hospital admission

- Pregnancy

- Inability to provide informed consent

- Physician's assessment that use of the protocol could be unsafe or lead to adverse
consequences for the patient