Clinical trial NCT01921829
Conditions: Cardiac Failure Renal Failure Kidney Failure
Keywords: Cardiorenal failure Cardiorenal syndrome Diuretic resistance Volume overload Edema Health-related quality of life Outcomes Treatment protocol
Sponsor: Kelly V. Liang, MD
Start date: 2013-11-01; Completion date: 2015-11-01
Enrollment: 19 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
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.

Detailed 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.

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.

Arms: arm 1: Participants randomized to the Usual Care group (control arm) will receive escalating diuretics and medical therapy per HF guidelines published by the American College of Cardiology (ACC)/American Heart Association (AHA) and Heart Failure Society of America (HFSA), dosed in variable fashion at the discretion of the treating cardiologist. arm 2: Participants randomized to the Protocolized Diuretic Strategy group will receive escalating diuretics according to an algorithm targeting a goal diuresis of urine output (UO) 3-5 L/day with diuretics intensified in a stepped fashion using both loop diuretics given by intravenous (IV) bolus followed by IV continuous infusion (furosemide or alternative loop diuretic at equivalent dose), with or without concomitant thiazide diuretic (oral (PO) metolazone or IV chlorothiazide). If UO is \< 3 L/day, diuretic regimen will be increased. If UO is 3-5 L/day, diuretic regimen will be continued at current doses. If UO is \> 5 L/day, diuretic regimen will be reduced.
Interventions: intervention 1: Protocolized Diuretic Strategy
Intervention descriptions: intervention 1: The Protocolized Diuretic Strategy will administer diuretics according to an algorithm based on based on the "stepped pharmacologic care arm" used by the CARRESS-HF trial investigators. This algorithm targets a relatively aggressive goal diuresis of urine output (UO) 3-5 L/day with diuretics intensified in a stepped fashion using both loop diuretics given by intravenous (IV) bolus followed by IV continuous infusion (furosemide or alternative loop diuretic at equivalent dose), with or without concomitant thiazide diuretic (oral (PO) metolazone or IV chlorothiazide).

Protocol documents: