Randomized Controlled Trial of urinE chemiStry Guided aCute heArt faiLure treATmEnt (ESCALATE) (ESCALATE)

A Randomized Trial of Protocolized Diuretic Therapy Compared to Standard Care in Emergency Department Patients With Acute Heart Failure

This is a randomized trial of protocolized diuretic therapy guided by urinary sodium compared to structured usual care in ED patients with AHF. Participants will be recruited following an initial standard evaluation in the ED and randomized in a 1:1 fashion to structured usual care or protocolized diuretic therapy guided by urinary sodium.

Study Overview

• Status: Recruiting
• Conditions: Heart Failure; Acute Heart Failure
• Intervention / Treatment: Drug: Protocolized diuretic therapy

Detailed Description

A standardized protocol driven treatment pathway for hospitalized patients started in the first few hours of ED evaluation and utilizing objective measures of diuretic response is needed. The investigators believe this would maximize diuretic efficiency, facilitate quicker resolution of congestion, avoid WHF and prolonged LOS, and reduce AHF readmissions. Propr data suggests low urine sodium predicts length of stay and outcomes after initial diuretic dosing in the outpatient and inpatient setting. Further, use of our pathway using spot urine sodium to titrate subsequent loop diuretic doses and maximize response in inpatients with AHF has shown compelling improvements in congestion and weight loss. However, a randomized trial is necessary to determine if initiating this protocol ,started in the ED, will improve AHF outcomes relative to structured usual care. Specifically, the investigators hypothesize use of spot urine sodium guided diuretic therapy will result in significant improvement in days of benefit over the 14 days after randomization. Days of benefit combines patient symptoms captured by global clinical status with clinical state quantifying the need for hospitalization and IV diuresis.

• Study Type: Interventional
• Enrollment (Estimated): 474
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Sean P. Collins, MD; Phone Number: 615-936-0253; Email: sean.collins@vumc.org
• Study Contact Backup: Name: Karen F. Miller, RN; Phone Number: 615-936-4790

Study Locations

• United States
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Recruiting
      • Vanderbilt University Medical Center
      • Contact: Karen F. Miller, RN; Phone Number: 615-936-4790
      • Contact: Sean P Collins, MD; Phone Number: 615-936-0253; Email: sean.collins@vumc.org
    • Nashville, Tennessee, United States, 37232
      • Recruiting
      • VA Tennessee Valley Health Service
      • Contact: Sean P. Collins, MD; Phone Number: 615-936-0253; Email: sean.collins@vumc.org
      • Contact: Karen F. Miller, RN; Phone Number: 615-936-4790

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 17 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age > 18
• Emergency Department diagnosis of Acute Heart Failure (AHF)

• Any one of the following:

  i. Chest radiograph or lung ultrasound consistent with AHF ii. Jugular venous distension iii. Pulmonary rales on auscultation iv. Lower extremity edema v. S3 gallop

• > 10 pounds of volume overload physician estimate or historical dry weight
• IV diuretic ordered or planned to be during first 24 hours of ED or inpatient stay

Exclusion Criteria:

• End Stage Renal Disease (ESRD) requiring dialysis
• Need for immediate intubation
• Acute Coronary Syndrome - presentation consistent with myocardial ischemia AND new ST-Segment elevation/depression
• Temperature > 100.5ºF
• End Stage Heart Failure: transplant list or ventricular assist device
• Concurrent use of ototoxic medications including intravenous aminoglycosides and cisplatin
• Systolic Blood Pressure < 90 mmHg at time of consent
• LV outflow obstruction, severe uncorrected stenotic valvular disease or severe restrictive cardiomyopathy
• Greater than 2 doses of IV diuretic administered at the time of screening from the time of the hospital presentation leading to this admission (outside hospital time is included)
• Severe, uncorrected serum electrolyte abnormalities at the time of consent (serum potassium <3.0 mEq/L, magnesium <1.0 mEq/L or sodium <125 or >150 mEq/l)
• Lack of informed consent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Protocolized spot urine sodium guided diuretic therapy; Patients will have a spot urine sodium and urine creatinine obtained. The urine and creatinine results will be input into the diuretic calculator and the diuretic dose will be chosen based on daily goals for urine output and net negative fluid balance. Performed 3 times per day, diuretic dosing will be individualized based on the proportion of 24-hour diuresis achieved since the prior IV diuretic dose. Every 24 hours new goals for urine output and net negative fluid balance are established based on the study and treatment team's assessment of residual congestion until protocol completion.	Drug: Protocolized diuretic therapy; The urine sodium, urine creatinine and serum creatinine results will be input into the diuretic calculator and the diuretic dose will be chosen based on daily goals for urine output and net negative fluid balance.
No Intervention: Guideline-based care; Patients will be placed on guideline-based diuretic dosing consistent with usual practice. The initial dose will be two times their home dose and will be subsequently adjusted by the treating team based on renal function and symptom severity. The treating team can increase or decrease the frequency and dose of diuretic based on urine output and clinical assessment. Patients in this arm also have urine collected 3 times per day by the bedside nurse to mirror the intervention arm.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical Status Score	Daily composite of the clinical state and global clinical status (GCS), expressed as an integer ranging in value from 0 (deceased) to 15 (outpatient; best possible GCS).	From the time of randomization through day 14

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Congestion	Daily orthodema score	from the time of randomization until protocol transition to oral diuretics, approximately 14 days
CV Death and AHF Readmission	Cardiovascular death and Acute Heart Failure Readmission	within 30 days of hospital discharge
Global clinical status (GCS)	measured daily using a continuous scale of 1-100	from the time of randomization through day 14
Change in natriuretic peptides	Blood measurement	from the time of randomization until protocol transition to oral diuretics, approximately 14 days
Net fluid loss	difference between fluid input and urine output in ml	from the time of randomization until protocol transition to oral diuretics, approximately 14 days
Total urine output	cumulative urine output in ml	from the time of randomization until protocol transition to oral diuretics, approximately 14 days
Weight Loss	cumulative weight loss in pounds	from the time of randomization until protocol transition to oral diuretics, approximately 14 days
Home days	Those days not in the hospital, rehab or a skilled nursing facility	within 30 days from randomization
Shift in audiometry	Significant change in hearing threshold (dB) across frequencies from 250-8000 Hz	from the time of randomization until protocol transition to oral diuretics, approximately 14 days
Cumulative natriuresis	cumulative sodium excretion estimated using the NRPE (based on spot urine creatinine and sodium)	from the time of randomization until protocol transition to oral diuretics, approximately 14 days
Average daily natriuresis	mean daily sodium excretion estimated using the NRPE (based on spot urine creatinine and sodium)	from the time of randomization until protocol transition to oral diuretics, approximately 14 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dyspnea score	measured daily using a continuous scale from 1-100	from the time of randomization until protocol transition to oral diuretics, approximately 14 days
Change in Kidney injury biomarkers	changes in the urinary tubular injury markers including KIM-1 and NGAL	from the time of randomization until protocol transition to oral diuretics, approximately 14 days
Length of stay	number of days in the hospital	from the time of hospital admission to discharge, approximately 7 days
180-day all cause death	all-cause death	within 180 days of hospital discharge
Hypotension	Incidence of symptomatic (lightheaded, chest pain) hypotension (SBP < 80 mmHg confirmed on 2 successive measurements at least 30 minutes apart)	from the time of randomization through 7 days off diuretic protocol, or discharge
Acute Kidney Injury Differences in Epithelial sodium channel (ENaC) levels	AKI (defined as a need for renal replacement therapy or KDIGO stage 2 or greater from a serum creatinine at randomization)	from the time of randomization through 7 days off diuretic protocol, or discharge
CV death or Myocardial Infarction (MI) during hospitalization	CV death or MI as adjudicated by a clinical events committee	from the time of randomization through 7 days off diuretic protocol, or discharge
Ototoxicity or tinnitus	Clinically significant ototoxicity or tinnitus as determined by the study team	from the time of randomization through 7 days off diuretic protocol, or discharge

Collaborators and Investigators

• Sponsor: Vanderbilt University Medical Center
• Investigators: Principal Investigator: Sean P. Collins, MD, Vanderbilt University Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2022
• Primary Completion (Estimated): September 30, 2026
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: July 19, 2020
• First Submitted That Met QC Criteria: July 19, 2020
• First Posted (Actual): July 22, 2020

Study Record Updates

• Last Update Posted (Actual): September 15, 2023
• Last Update Submitted That Met QC Criteria: September 14, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: Emergency Department; Diuretic Therapy
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure; Physiological Effects of Drugs; Natriuretic Agents; Diuretics
• Other Study ID Numbers: 190690

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

The Publication Committee will authorize access to study data. Investigators must submit a proposal requesting approval to access our trial data. Our trial will participate in the NHLBI Central Repository for study data and specimens.

All data access will follow guidelines described in the NHLBI Limited Access Data Policy.

IPD Sharing Access Criteria

The Publication Committee will authorize access to study data. Investigators must submit a proposal requesting approval to access our trial data. Our trial will participate in the NHLBI Central Repository for study data and specimens.

All data access will follow guidelines described in the NHLBI Limited Access Data Policy

• IPD Sharing Supporting Information Type: CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No