Protocolized Diuretic Strategy in Cardiorenal Failure

Renal Failure Clinical Trial

— ProDiuS  

Official title:

Effect of Protocolized Diuretic Strategy on Clinical Outcomes and Health-related Quality of Life in Cardiorenal Failure: A Randomized Trial

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01921829
• Other study ID #: PRO13040071
• Status: Terminated
• Phase: Phase 4
• First received: July 23, 2013
• Last updated: December 7, 2015
• Start date: November 2013
• Est. completion date: November 2015

Study information

• Verified date: December 2015
• Source: University of Pittsburgh
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Data and Safety Monitoring Board
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 19
• Est. completion date: November 2015
• Est. primary completion date: November 2015
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 21 Years and older

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Single Blind (Subject), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Cardiac Failure
• Heart Failure
• Kidney Failure
• Renal Failure
• Renal Insufficiency

Intervention

Drug:
• Protocolized Diuretic Strategy
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).

Locations

Country	Name	City	State
United States	University of Pittsburgh Medical Center	Pittsburgh	Pennsylvania

Sponsors (1)

Lead Sponsor	Collaborator
University of Pittsburgh

Country where clinical trial is conducted

United States, 

References & Publications (1)

Bart BA, Goldsmith SR, Lee KL, Givertz MM, O'Connor CM, Bull DA, Redfield MM, Deswal A, Rouleau JL, LeWinter MM, Ofili EO, Stevenson LW, Semigran MJ, Felker GM, Chen HH, Hernandez AF, Anstrom KJ, McNulty SE, Velazquez EJ, Ibarra JC, Mascette AM, Braunwald E; Heart Failure Clinical Research Network. Ultrafiltration in decompensated heart failure with cardiorenal syndrome. N Engl J Med. 2012 Dec 13;367(24):2296-304. doi: 10.1056/NEJMoa1210357. Epub 2012 Nov 6. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Adverse events	Hypokalemia (K <3.0 milliequivalents (mEq)/L), hypotension (systolic BP <90 mmHg), hyponatremia (Na <130 mEq/L), arrhythmias, cramps, and other (recorded as short description).	Daily while in hospital , 1 mo, & 3 mos	Yes
Primary	Change in body weight (kg) from randomization to day 4 or date of discharge (whichever comes first)	The change in body weight (kg) from randomization to day 4 or date of discharge will be determined by the difference between body weight at day 4 after randomization or date of discharge (whichever comes first) and body weight taken at baseline measured in the hospital on standard scales without shoes and wearing a hospital gown, measured before breakfast and post-voiding.	4 days (96 hours)	No
Secondary	Length of hospitalization	Length of hospitalization will be ascertained from admission date to date of discharge.	1 month	No
Secondary	Number of rehospitalizations for heart failure (HF)	Number of rehospitalizations for HF will be ascertained based on chart review of admissions with HF as a coded diagnosis, evidence of clinical volume overload, and treatment with intravenous diuretics.	1 month & 3 months	No
Secondary	All-cause mortality	All-cause mortality will be ascertained based on chart review of vital status (alive/dead) and cause of death.	1 month & 3 months	No
Secondary	Venous compliance of the internal jugular vein	Venous compliance of the right internal jugular vein (RIJV) will be determined noninvasively with Doppler ultrasound.	Baseline, 96 h, 1 mo, & 3 mos	No
Secondary	Fluid balance	Strict intake (oral intake, intravenous medications, fluids, etc.) and output (urine, emesis, stools, drains, etc.) will be documented by the nurses on the HF floors per routine clinical protocol for all patients. Fluid balance will be determined by subtracting the volume of total intake from the volume of total output (in mL) over 24 hours (12 midnight to 12 midnight). Fluid balance and urine output will be ascertained by chart review daily for 5 days during the intervention while the participants are hospitalized (average length of hospitalization anticipated to be approximately 7-10 days).	Daily while in hospital	No
Secondary	Clinical decongestion	Clinical decongestion will be defined based on criteria used in the CARRESS-HF trial, including jugular venous pressure of < 8 cm of water, no more than trace peripheral edema, and the absence of orthopnea. Clinical decongestion will be assessed by the HF physicians caring for the participants daily in the hospital (average length of hospitalization anticipated to be approximately 7-10 days), and ascertained by chart review and/or discussion with the HF physicians.	Daily while in hospital, 1 mo, & 3 mos	No
Secondary	Health-related quality of life (HRQOL)	General HRQOL, Heart failure specific HRQOL, Sleep and fatigue, and Depression questionnaires	Baseline, 1 mo & 3 mos	No
Secondary	Renal Outcomes	Renal function changes will be based on change in serum Cr and change in cystatin C, from time of randomization to each of the following timepoints: daily while in hospital (average length of hospitalization anticipated to be approximately 7-10 days), 1-month, and 3-month follow-ups. Need for UF or renal replacement therapy, defined as need for hemodialysis (HD), peritoneal dialysis (PD), or renal transplant, will be ascertained by chart review. Acute kidney injury will be defined based on the established consensus of a rise in Cr =0.3 mg/dL as a definition for worsening renal function and/or acute kidney injury.	Daily while in hospital, 1 mo & 3 mos	Yes
Secondary	Cardiovascular Mortality	Cardiovascular mortality will be based on deaths due to HF, myocardial infarction (MI), arrhythmias, or valvular disorders.	1 mo & 3 mos	No
Secondary	Urine output	Urine output per 24 h will be ascertained by chart review daily for 5 days during the intervention while the participants are hospitalized (average length of hospitalization anticipated to be approximately 7-10 days).	approximately 7-10 days	No