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Protocolized Diuretic Strategy in Cardiorenal Failure (ProDiuS)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT01921829
Recruitment Status : Terminated (Due to futility due to lower than expected recruitment)
First Posted : August 13, 2013
Results First Posted : July 17, 2017
Last Update Posted : August 21, 2017
Sponsor:
Information provided by (Responsible Party):
Kelly V. Liang, MD, University of Pittsburgh

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.

Condition or disease Intervention/treatment Phase
Cardiac Failure Renal Failure Kidney Failure Drug: Protocolized Diuretic Strategy Phase 4

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 19 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Participant)
Primary Purpose: Treatment
Official Title: Effect of Protocolized Diuretic Strategy on Clinical Outcomes and Health-related Quality of Life in Cardiorenal Failure: A Randomized Trial
Study Start Date : November 2013
Actual Primary Completion Date : November 2015
Actual Study Completion Date : November 2015

Arm Intervention/treatment
No Intervention: Usual Care
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.
Experimental: Protocolized Diuretic Strategy
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.
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).
Other Names:
  • Diuretic Treatment Protocol
  • Stepped Pharmacologic Care




Primary Outcome Measures :
  1. Change in Body Weight (kg) From Randomization to Day 4 or Date of Discharge (Whichever Comes First) [ Time Frame: 4 days (96 hours) ]
    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.


Secondary Outcome Measures :
  1. Length of Hospitalization [ Time Frame: 1 month ]
    Length of hospitalization will be ascertained from admission date to date of discharge.

  2. Number of Rehospitalizations for Heart Failure (HF) [ Time Frame: Up to 3 months (assessed at 1 month and 3 months) ]
    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.

  3. Number of Total Rehospitalizations [ Time Frame: Up to 3 months (assessed at 1 month and 3 months) ]
    Number of rehospitalizations will be ascertained based on chart review of admissions to any hospital after the index hospitalization

  4. All-cause Mortality [ Time Frame: Up to 3 months (assessed at 1 month and 3 months) ]
    All-cause mortality will be ascertained based on chart review of vital status (alive/dead) and cause of death.

  5. Difference From Baseline to 1 Month in Change in Right Internal Jugular Vein (RIJV) Cross-sectional Area (CSA) Pre- and Post-Valsalva [ Time Frame: Up to 1 month (measured at baseline and 1 mo) ]
    The change in cross-sectional area (CSA) of the right internal jugular vein (RIJV) pre- and post-Valsalva is a measurement of venous compliance and was determined noninvasively with Doppler ultrasound. An increase in RIJV CSA >17% during Valsalva effectively rules out elevated right atrial pressure (RAP) and suggests effective volume removal or decongestion. The difference between baseline and 1 month values of change in RIJV CSA are reported.

  6. Fluid Balance [ Time Frame: Daily while in hospital ]
    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 (7 am to 7 am or the preceding 24-h period if no 7 am to 7 am period is available). Fluid balance and urine output will be ascertained by chart review daily during the intervention while the participants are hospitalized.

  7. Acute Kidney Injury [ Time Frame: Daily while in hospital, 1 mo & 3 mos ]
    Acute kidney injury will be defined based a rise in Cr ≥0.3 mg/dL.

  8. Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Score Change at 1 Month [ Time Frame: Baseline to 1 month ]
    The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a well-validated 23-item, self-administered instrument that quantifies physical function, symptoms (frequency, severity and recent change), social function, self-efficacy and knowledge, and quality of life. An overall summary score can be derived from the physical function, symptom (frequency and severity), social function and quality of life domains. For each domain, the validity, reproducibility, responsiveness and interpretability have been independently established. Scores are transformed to a range of 0-100, in which higher scores reflect better health status. A mean difference over time of 5 points on the KCCQ Overall Summary Scale reflects a clinically significant change in heart failure status. A 10 point decline in KCCQ scores has important prognostic significance in terms of survival.

  9. Kansas City Cardiomyopathy Questionnaire (KCCQ) Overall Score Change at 1 Month [ Time Frame: Baseline to 1 month ]
    The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a well-validated 23-item, self-administered instrument that quantifies physical function, symptoms (frequency, severity and recent change), social function, self-efficacy and knowledge, and quality of life. An overall summary score can be derived from the physical function, symptom (frequency and severity), social function and quality of life domains. For each domain, the validity, reproducibility, responsiveness and interpretability have been independently established. Scores are transformed to a range of 0-100, in which higher scores reflect better health status. A mean difference over time of 5 points on the KCCQ Overall Summary Scale reflects a clinically significant change in heart failure status. A 10 point decline in KCCQ scores has important prognostic significance in terms of survival.

  10. SF-36 Mental Component Score (MCS) Change at 1 Month [ Time Frame: Baseline to 1 month ]
    The Medical Outcomes Study (MOS) 36-item Short-Form Health Survey (SF-36) is a well-validated generic HRQOL questionnaire that generates two composite scores: the Physical Component Score (PCS) and Mental Component Score (MCS). The PCS aggregates items from Physical Functioning, Role-Physical, Bodily Pain, General Health, Vitality, and Social Functioning. The MCS aggregates items from Role-Emotional, Mental Health, General Health, Vitality, and Social Functioning. The mean for each summary scale is 50 points with standard deviation of 10 points. The SF-36 consists of eight scaled scores, which are the weighted sums of the questions in their section. Each scale is directly transformed into a 0-100 scale on the assumption that each question carries equal weight. The lower the score the more disability. The higher the score the less disability i.e., a score of zero is equivalent to maximum disability and a score of 100 is equivalent to no disability.

  11. SF-36 Physical Component Score (PCS) Change at 1 Month [ Time Frame: Baseline to 1 month ]
    The Medical Outcomes Study (MOS) 36-item Short-Form Health Survey (SF-36) is a well-validated generic HRQOL questionnaire that generates two composite scores: the Physical Component Score (PCS) and Mental Component Score (MCS). The PCS aggregates items from Physical Functioning, Role-Physical, Bodily Pain, General Health, Vitality, and Social Functioning. The MCS aggregates items from Role-Emotional, Mental Health, General Health, Vitality, and Social Functioning. The mean for each summary scale is 50 points with standard deviation of 10 points. The SF-36 consists of eight scaled scores, which are the weighted sums of the questions in their section. Each scale is directly transformed into a 0-100 scale on the assumption that each question carries equal weight. The lower the score the more disability. The higher the score the less disability i.e., a score of zero is equivalent to maximum disability and a score of 100 is equivalent to no disability.

  12. PHQ-9 Depression Index Change at 1 Month [ Time Frame: Baseline to 1 month ]

    The Patient Health Questionnaire (PHQ-9) Depression Index is a well-established index of depression and has been validated in many patient populations. Its scores range from 0-27 with increasing scores representing increasing depression severity. Score categories represent depression severity and management recommendations:

    0-4 - Minimal or no depression. Monitor; may not require treatment. 5-9 - Mild. Use clinical judgment (symptom duration, functional impairment) to determine necessity of treatment.

    10-14 - Moderate. Use clinical judgment (symptom duration, functional impairment) to determine necessity of treatment.

    15-19 - Moderately severe. Warrants active treatment with psychotherapy, medications, or combination.

    20-27 - Severe. Warrants active treatment with psychotherapy, medications, or combination.


  13. PSQI Total Score Change at 1 Month [ Time Frame: Baseline to 1 month ]
    The Pittsburgh Sleep Quality Index (PSQI) is the most widely used global sleep assessment and has been studied in the renal transplant population. Consisting of 19 items, the PSQI measures several different aspects of sleep, offering seven component scores and one composite score. The component scores consist of subjective sleep quality, sleep latency (i.e., how long it takes to fall asleep), sleep duration, habitual sleep efficiency (i.e., the percentage of time in bed that one is asleep), sleep disturbances, use of sleeping medication, and daytime dysfunction. Each item is weighted on a 0-3 interval scale. The global PSQI score is then calculated by totaling the seven component scores, providing an overall score ranging from 0 to 21, where lower scores denote a healthier sleep quality. Traditionally, the items from the PSQI have been summed to create a total score to measure overall sleep quality.

  14. Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Score Change at 3 Months [ Time Frame: Baseline to 3 months ]
    The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a well-validated 23-item, self-administered instrument that quantifies physical function, symptoms (frequency, severity and recent change), social function, self-efficacy and knowledge, and quality of life. An overall summary score can be derived from the physical function, symptom (frequency and severity), social function and quality of life domains. For each domain, the validity, reproducibility, responsiveness and interpretability have been independently established. Scores are transformed to a range of 0-100, in which higher scores reflect better health status. A mean difference over time of 5 points on the KCCQ Overall Summary Scale reflects a clinically significant change in heart failure status. A 10 point decline in KCCQ scores has important prognostic significance in terms of survival.

  15. Kansas City Cardiomyopathy Questionnaire (KCCQ) Overall Score Change at 3 Months [ Time Frame: Baseline to 3 months ]
    The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a well-validated 23-item, self-administered instrument that quantifies physical function, symptoms (frequency, severity and recent change), social function, self-efficacy and knowledge, and quality of life. An overall summary score can be derived from the physical function, symptom (frequency and severity), social function and quality of life domains. For each domain, the validity, reproducibility, responsiveness and interpretability have been independently established. Scores are transformed to a range of 0-100, in which higher scores reflect better health status. A mean difference over time of 5 points on the KCCQ Overall Summary Scale reflects a clinically significant change in heart failure status. A 10 point decline in KCCQ scores has important prognostic significance in terms of survival.

  16. SF-36 Mental Component Score (MCS) Change at 3 Months [ Time Frame: Baseline to 3 months ]
    The Medical Outcomes Study (MOS) 36-item Short-Form Health Survey (SF-36) is a well-validated generic HRQOL questionnaire that generates two composite scores: the Physical Component Score (PCS) and Mental Component Score (MCS). The PCS aggregates items from Physical Functioning, Role-Physical, Bodily Pain, General Health, Vitality, and Social Functioning. The MCS aggregates items from Role-Emotional, Mental Health, General Health, Vitality, and Social Functioning. The mean for each summary scale is 50 points with standard deviation of 10 points. The SF-36 consists of eight scaled scores, which are the weighted sums of the questions in their section. Each scale is directly transformed into a 0-100 scale on the assumption that each question carries equal weight. The lower the score the more disability. The higher the score the less disability i.e., a score of zero is equivalent to maximum disability and a score of 100 is equivalent to no disability.

  17. SF-36 Physical Component Score (PCS) Change at 3 Months [ Time Frame: Baseline to 3 months ]
    The Medical Outcomes Study (MOS) 36-item Short-Form Health Survey (SF-36) is a well-validated generic HRQOL questionnaire that generates two composite scores: the Physical Component Score (PCS) and Mental Component Score (MCS). The PCS aggregates items from Physical Functioning, Role-Physical, Bodily Pain, General Health, Vitality, and Social Functioning. The MCS aggregates items from Role-Emotional, Mental Health, General Health, Vitality, and Social Functioning. The mean for each summary scale is 50 points with standard deviation of 10 points. The SF-36 consists of eight scaled scores, which are the weighted sums of the questions in their section. Each scale is directly transformed into a 0-100 scale on the assumption that each question carries equal weight. The lower the score the more disability. The higher the score the less disability i.e., a score of zero is equivalent to maximum disability and a score of 100 is equivalent to no disability.

  18. PHQ-9 Depression Index Change at 3 Months [ Time Frame: Baseline to 3 months ]

    The Patient Health Questionnaire (PHQ-9) Depression Index is a well-established index of depression and has been validated in many patient populations. Its scoring ranges from 0-27 with increasing scores representing increasing depression severity. Score categories determine depression severity and recommended management:

    0-4 - Minimal or none. Monitor; may not require treatment. 5-9 - Mild. Use clinical judgment (symptom duration, functional impairment) to determine necessity of treatment.

    10-14 - Moderate. Use clinical judgment (symptom duration, functional impairment) to determine necessity of treatment.

    15-19 - Moderately severe. Warrants active treatment with psychotherapy, medications, or combination.

    20-27 - Severe. Warrants active treatment with psychotherapy, medications, or combination.


  19. PSQI Total Score Change at 3 Months [ Time Frame: Baseline to 3 months ]
    The Pittsburgh Sleep Quality Index (PSQI) is a self-report questionnaire that assesses sleep quality over a 1-month time interval. The measure consists of 19 individual items, creating 7 components that produce one global score, and takes 5-10 minutes to complete. Consisting of 19 items, the PSQI measures several different aspects of sleep, offering seven component scores and one composite score. The component scores consist of subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medication, and daytime dysfunction. Each item is weighted on a 0-3 interval scale. The global PSQI score is then calculated by totaling the seven component scores, providing an overall score ranging from 0 to 21, where lower scores denote a healthier sleep quality. Traditionally, the items from the PSQI have been summed to create a total score to measure overall sleep quality.


Other Outcome Measures:
  1. Adverse Events [ Time Frame: Daily while in hospital , 1 mo, & 3 mos ]
    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).



Information from the National Library of Medicine

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Ages Eligible for Study:   21 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01921829


Locations
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United States, Pennsylvania
University of Pittsburgh Medical Center
Pittsburgh, Pennsylvania, United States, 15213
Sponsors and Collaborators
Kelly V. Liang, MD
Investigators
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Principal Investigator: Kelly V Liang, MD University of Pittsburgh

Publications:
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Responsible Party: Kelly V. Liang, MD, MD, University of Pittsburgh
ClinicalTrials.gov Identifier: NCT01921829     History of Changes
Other Study ID Numbers: PRO13040071
First Posted: August 13, 2013    Key Record Dates
Results First Posted: July 17, 2017
Last Update Posted: August 21, 2017
Last Verified: July 2017

Keywords provided by Kelly V. Liang, MD, University of Pittsburgh:
Cardiorenal failure
Cardiorenal syndrome
Diuretic resistance
Volume overload
Edema
Health-related quality of life
Outcomes
Treatment protocol

Additional relevant MeSH terms:
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Renal Insufficiency
Heart Failure
Kidney Diseases
Urologic Diseases
Heart Diseases
Cardiovascular Diseases
Diuretics
Sodium Potassium Chloride Symporter Inhibitors
Natriuretic Agents
Physiological Effects of Drugs
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action