Clinical trial NCT01921829: Protocolized Diuretic Strategy in Cardiorenal Failure
Official title: Effect of Protocolized Diuretic Strategy on Clinical Outcomes and Health-related Quality of Life in Cardiorenal Failure: A Randomized Trial
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE4
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
Lead sponsor: University of Pittsburgh
Sponsor class: OTHER
First posted: 2013-08-13
Enrollment: 19
Sex: MALE
Minimum age (years): 21
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Change in Body Weight (kg) From Randomization to Day 4 or Date of Discharge (Whichever Comes First)
timeFrame: 4 days (96 hours)
Secondary outcomes:
measure: Length of Hospitalization
timeFrame: 1 month
measure: Number of Rehospitalizations for Heart Failure (HF)
timeFrame: Up to 3 months (assessed at 1 month and 3 months)
measure: Number of Total Rehospitalizations
timeFrame: Up to 3 months (assessed at 1 month and 3 months)
measure: All-cause Mortality
timeFrame: Up to 3 months (assessed at 1 month and 3 months)
measure: Difference From Baseline to 1 Month in Change in Right Internal Jugular Vein (RIJV) Cross-sectional Area (CSA) Pre- and Post-Valsalva
timeFrame: Up to 1 month (measured at baseline and 1 mo)
measure: Fluid Balance
timeFrame: Daily while in hospital
measure: Acute Kidney Injury
timeFrame: Daily while in hospital, 1 mo & 3 mos
measure: Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Score Change at 1 Month
timeFrame: Baseline to 1 month
measure: Kansas City Cardiomyopathy Questionnaire (KCCQ) Overall Score Change at 1 Month
timeFrame: Baseline to 1 month
measure: SF-36 Mental Component Score (MCS) Change at 1 Month
timeFrame: Baseline to 1 month
measure: SF-36 Physical Component Score (PCS) Change at 1 Month
timeFrame: Baseline to 1 month
measure: PHQ-9 Depression Index Change at 1 Month
timeFrame: Baseline to 1 month
measure: PSQI Total Score Change at 1 Month
timeFrame: Baseline to 1 month
measure: Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Score Change at 3 Months
timeFrame: Baseline to 3 months
measure: Kansas City Cardiomyopathy Questionnaire (KCCQ) Overall Score Change at 3 Months
timeFrame: Baseline to 3 months
measure: SF-36 Mental Component Score (MCS) Change at 3 Months
timeFrame: Baseline to 3 months
measure: SF-36 Physical Component Score (PCS) Change at 3 Months
timeFrame: Baseline to 3 months
measure: PHQ-9 Depression Index Change at 3 Months
timeFrame: Baseline to 3 months
measure: PSQI Total Score Change at 3 Months
timeFrame: Baseline to 3 months
Other outcomes:
measure: Adverse Events
timeFrame: Daily while in hospital , 1 mo, & 3 mos
Locations:
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center
state: Pennsylvania
Study officials:
affiliation: University of Pittsburgh
name: Kelly V Liang, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.