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This research study is a randomized clinical trial to evaluate if taking diuretics (medications that increase urine production and help with fluid removal from the body) in a standardized fashion (using a guideline for adjusting doses based on measured urine output) could improve health outcomes in patients with cardiorenal failure or cardiorenal syndrome (combined heart and kidney failure) with edema (too much fluid in their arms, legs, and/or lungs). Under usual care, these patients are treated with diuretics and other medications in increasing doses, but not necessarily to maintain a specific amount of urine output per day. Current heart failure (HF) treatment guidelines do not provide any standard protocol, or guideline, for adjusting diuretic doses. At the point when kidney function worsens to the degree that the kidneys are no longer able to respond to the medications used to remove fluid, either ultrafiltration (UF) or dialysis (also called hemodialysis [HD]) is typically started in order to remove fluid. In both UF and dialysis, excess fluid is removed from the body by using a machine. In dialysis, both waste products and fluid are removed and electrolyte abnormalities are corrected. In UF, only fluid is removed. Both procedures use the same machine. This study will test whether a Protocolized Diuretic Strategy (ProDiuS), a plan for adjusting diuretic doses based on measured urine output, will improve clinical care for cardiorenal syndrome. Such a plan for adjusting diuretic doses is needed to improve symptoms, decrease the length of hospital stays and rehospitalization rates, and improve health-related quality of life (HRQOL) in cardiorenal syndrome patients.
Full description
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.
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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.
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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:
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:
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
Primary purpose
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19 participants in 2 patient groups
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Data sourced from clinicaltrials.gov
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