Clinical trial NCT04393493
Conditions: Cardiorenal Syndrome
Sponsor: Hospital Civil de Guadalajara
Start date: 2017-07-01; Completion date: 2020-04-01
Enrollment: 80 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
In double-blind clinical trial, determine renal recovery with two different furosemide strategies in patients with type 1 cardiorenal syndrome.

Detailed description:
In a patient with type 1 cardiorenal syndrome, we tried to compare two Furosemide strategies: both with a morning bolus, and randomized in two groups:

Group A: Furosemide 80 mg every 24 hrs (morning) intravenously every 24 hrs for 4 consecutive days, additionally:

* Day 1 furosemide 100mg / day infused with 100cc of Hartmann solution
* Day 2 Furosemide 200mg / day infused with 100cc of Hartmann solution
* Day 3 Furosemide 300mg / day infused with 100cc of Hartmann solution
* Day 4 Furosemide 400mg / day infused with 100cc of Hartmann solution

Group B: Furosemide 80 mg every 24 hrs (morning) intravenously every 24 hrs for 4 consecutive days, additionally:

* Day 1 furosemide 100mg / day infused with 100cc of Hartmann solution + Chlortalidone 50mg VO every 24 hours + Spironolactone 50mg VO every 24 hrs.
* Day 2 furosemide 100mg / day infused with 100cc of Hartmann solution + Chlortalidone 50mg VO every 24 hours + Spironolactone 50mg VO every 24 hrs.
* Day 3 furosemide 100mg / day infused with 100cc of Hartmann solution + Chlortalidone 50mg VO every 24 hours + Spironolactone 50mg VO every 24 hrs.
* Day 4 furosemide 100mg / day infused with 100cc of Hartmann solution + Chlortalidone 50mg VO every 24 hours + Spironolactone 50mg VO every 24 hrs.

ution + Chlortalidone 50mg VO every 24 hours + Spironolactone 25mg VO every 24 hrs.

With the primary objective of improving renal function measured by serum creatinine, as secondary objectives the efficacy in vascular decongestion and electrolyte alterations.

Arms: arm 1: Furosemide 80 mg every 24 hrs (morning) intravenously every 24 hrs for 4 consecutive days, additionally:

* Day 1 furosemide 100mg / day infused with 100cc of Hartmann solution
* Day 2 Furosemide 200mg / day infused with 100cc of Hartmann solution
* Day 3 Furosemide 300mg / day infused with 100cc of Hartmann solution
* Day 4 Furosemide 400mg / day infused with 100cc of Hartmann solution arm 2: Furosemide 80 mg every 24 hrs (morning) intravenously every 24 hrs for 4 consecutive days, additionally:

* Day 1 furosemide 100mg / day infused with 100cc of Hartmann solution + Chlortalidone 50mg VO every 24 hours + Spironolactone 50mg VO every 24 hrs.
* Day 2 furosemide 100mg / day infused with 100cc of Hartmann solution + Chlortalidone 50mg VO every 24 hours + Spironolactone 50mg VO every 24 hrs.
* Day 3 furosemide 100mg / day infused with 100cc of Hartmann solution + Chlortalidone 50mg VO every 24 hours + Spironolactone 50mg VO every 24 hrs.
* Day 3 furosemide 100mg / day infused with 100cc of Hartmann solution + Chlortalidone 50mg VO every 24 hours + Spironolactone 50mg VO every 24 hrs.
Interventions: intervention 1: Furosemide intravenous solution intervention 2: Chlortalidone intervention 3: Spironolactone
Intervention descriptions: intervention 1: Administrated as an 80 mg intravenous bolus every 24 hours in both arms and then as a continuous infusion dosed according to the experimental arm. intervention 2: One 50 mg pill administrated every 24 hours in group B intervention 3: One 50 mg pill administrated every 24 hours in group B

Protocol documents:
Prot_000.pdf: 
07/17/2020 
The Effect in Renal Function and Vascular Decongestion in Type 1 Cardiorenal Syndrome Treated with 
Two Strategies of Diuretics, a Randomized Clinical Trial  
NCT04393493 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


07/17/2020 
Study protocol 
Study participants 
This was a prospective single-center double-blind randomized clinical trial that screened all 
consecutive patients admitted for acute decompensation (ADHF) and acute kidney injury (AKI), 
who met the criteria of cardiorenal type 1 syndrome (CRS-1) and were evaluated by the 
Nephrology service at the Hospital Civil de Guadalajara Fray Antonio Alcalde, a large referral 
hospital that attends patients without health care insurance and low socioeconomic resources in 
Jalisco, México. Patients were enrolled from July 2017 to February 2020.  
The research was conducted in accordance with the World Medical Association Declaration of 
Helsinki. The study was approved by the Institutional Review Board (HCG/CEI-0550/17), and all 
patients provided written informed consent. No funding was received to conduct this study. The 
trial was registered in ClinicalTrials.gov with number NCT04393493. 
 
Definitions 
Cardiorenal type 1 syndrome (CRS-1) was defined according to the 2008 classification system 
by Ronco et al; to meet the criteria of CRS-1, AKI was defined as an increase in serum 
creatinine (sCr) according to KDIGO and acute heart failure decompensation (AHFD) was 
defined clinically. Both criteria need to be present at the moment of the initial evaluation. 
Chronic kidney disease (CKD) was defined according to the KDIGO guideline. The estimated 
glomerular filtration rate (eGFR) in ml/min/1.73 m2 was calculated according to the Chronic 
Kidney Disease Epidemiology Collaboration (CKD-EPI). Baseline eGFR was considered 
according to the last sCr (previous 3 months). Renal function recovery was defined as sCr 
return to baseline value at any point during the trial (complete recovery). 
All comorbidities and clinical data were prospectively collected by direct contact with the patient 
during the first evaluation. Additional data were collected from medical records and the hospital 
electronic database. 
The primary endpoint was to assess renal function recovery (sCr return to baseline value) 
after 96 hours, and the secondary endpoints were a combination of variables related to 
vascular decongestion during the treatment and follow up, namely, the change in urinary output, 
sCr, sCr worsening, in-hospital mortality, mortality during follow up, dyspnea improvement, 


07/17/2020 
dyspnea improvement before day 3, time until dyspnea improved, renal replacement therapy, 
change in electrolytes and acid-base status. As exploratory endpoints, we evaluated changes in 
copeptine levels, BNP, BNP reduction and intervention stop because of clinical improvement. 
Prespecified adverse events were reported. 
 
Randomization and treatments assignments 
Patients who met the inclusion criteria were randomly assigned in a 1:1 ratio to the 
administration of stepped furosemide or combined diuretics. Randomization was carried out by 
the use of sequentially numbered cases prepared before starting the study by a computerized 
sequence. A double-blind, double-dummy design was used. All patients received a bolus of 
furosemide 80 mg every day, a hyposodic diet (<2.4 gr sodium/day), and strict fluid control was 
prescribed.  
The Stepped Furosemide (SF) group received a continuous daily infusion of furosemide 100 
mg diluted in 100 ml of Hartmann solution during the first day, with daily incremental doses to 
200 mg, 300 mg and 400 mg during the second, third and fourth day, respectively. 
The Combined Diuretics (CD) group was given a combination of diuretics trying to block 
different tubular segments, similar to the CARRESS-HF trial, including 4 consecutive days of 
oral chlortalidone 50 mg, spironolactone 50 mg and continuous infusion of furosemide 100 mg 
diluted in 100 ml of Hartmann for 24 hours. In both groups, the assigned treatment strategy was 
continued until the signs and symptoms of congestion went away or until the end of the trial (96 
hours). Inotropes, vasopressors, continuous positive airway pressure ventilation or management 
of any other comorbid condition were modified at the discretion of the attending physicians, who 
maintained constant communication with nephrology staff. 
 

SAP_001.pdf: 
07/17/2020 
The Effect in Renal Function and Vascular Decongestion in Type 1 Cardiorenal Syndrome Treated with 
Two Strategies of Diuretics, a Randomized Clinical Trial  
NCT04393493 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


07/17/2020 
Statistical analysis 
Based on the Shapiro-Wilk test, continuous variables are reported as the means (standard 
deviation [SD]) if they were normally distributed, or medians (interquartile range [IQR]) if they 
were not normally distributed. These variables were compared between groups with Mann-
Whitney or t-tests as appropriate. Categorical variables are expressed as proportions and were 
compared by x2 tests or Fisher’s exact test. For all tests, p values were two-sided, and a 
value <0.05 was considered statistically significant. MedCalc Statistical Software (Ostend, 
Belgium. Ver 19.1.3) was used for statistical analysis and graphics.