SGLT-2 Inhibitor and High-Dose Furosemide Plus Small-Volume Hypertonic Saline Solution in Acute HF

Heart Failure With Preserved Ejection Fraction Clinical Trial

— DAPA-TONIC  

Official title:

Enhanced Diuresis and Natriuresis in Acute Decompensated Heart Failure Patients Treated With SGLT-2 Inhibitor and High-Dose Furosemide Plus Small-Volume Hypertonic Saline Solution: A Clinical Trial

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06442280
• Other study ID #: UPalermo7
• Status: Not yet recruiting
• Phase: Phase 4
• Start date: June 2024
• Est. completion date: March 30, 2026

Study information

• Verified date: June 2024
• Source: University of Palermo
• Contact: Antonino Tuttolomondo, Professor
• Phone: +39 091 6552115
• Email: bruno.tuttolomondo[@]unipa.it
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of the current investigation is to demonstrate the efficacy of high-dose furosemide plus small-volume hypertonic saline solution and a Sodium-Glucose cotransporter-2 (SGLT-2) inhibitor among patients admitted for acute exacerbation of heart failure, in determining a significant increase in diuresis and natriuresis. It is also accompanied by a rapid reduction in body weight and a substantial decrease in hospitalization length without compromising renal function.

Description:

All enrolled patients will undergo a comprehensive physical examination post-randomization. This examination will involve a meticulous assessment of congestive heart failure (CHF) indicators, encompassing the measurement of bodyweight (BW) (taken in the morning before breakfast), supine and standing blood pressure (BP [average of 3 readings]), and heart rate (HR). Fasting blood samples will be collected daily throughout the hospital stay to ascertain serum laboratory parameters (creatinine, sodium, potassium, and N-terminal pro b-type natriuretic peptide) until achieving a clinically stabilized condition. Urine output will be measured daily, also to detect creatinine, sodium, potassium urinary levels and glycosuria. Additionally, an electrocardiogram and echocardiogram (to derive EF using the modified Simpson rule with 2 cross-sectional views [4- and 2-chamber apical views], right atrium volume (RA volume, ml/m2), left atrial volume (LA volume ml/m2), inferior vena cava diameter (IVC diameter, cm), interventricular septum thickness at end-diastole (IVSd, cm), right ventricular basal diameter at end-diastole (RVD1 basal, mm), right ventricular mid diameter at end-diastole (RVD2 mid, mm), right ventricular longitudinal diameter at end-diastole (RVD3 long, mm), right ventricular outflow tract at proximal and distal (RVOT prox and distal, mm), fractional area change (FAC, %), E wave dominant (m/s), A wave dominant (m/s), tricuspid valve E/A wave ratio (E/ATrV), tissue Doppler echocardiography (TDE, ms), eak velocity in early diastole of tricuspid annulus (TDI) (m/s), tricuspid valve e'/a' ratio (TDI, m/s), peak systolic velocity tricuspid annulus (Pulsed TDI, m/s) will be conducted prior to hospital discharge.

Patients will be categorized into 4 groups: the first group will undergo 15 minutes intravenous infusion of furosemide combined with hypertonic saline solutions (100 mL) twice daily along with severe water restriction (< 500 mL); the second group will receive intravenous furosemide as a bolus twice daily and severe water restriction (< 500 mL) without hypertonic saline solutions; the third group will undergo 15 minutes intravenous infusion of furosemide combined with hypertonic saline solutions (100 mL) twice daily, severe water restriction (< 500 mL), and SGLT2 inhibitors (Dapagliflozin); the fourth group will receive intravenous furosemide as a bolus without hypertonic saline solutions twice daily, severe water restriction (< 500 mL), and SGLT2 inhibitors (Dapagliflozin). The groups will maintain a normal sodium intake (120 mmol/day). The daily furosemide dosage will be determined based on diuretic requirements, urinary output, BP readings, and the severity of congestion signs and symptoms. The hypertonic saline solutions dosage for each patient (in groups 1 and 3) will be determined following these guidelines: for serum Na values of 125 milliequivalent/L, the hypertonic saline solutions concentration will be 4.6%; for serum Na values between 126 and 135 milliequivalent/L, the hypertonic saline solutions concentration will be 3.5%; and for serum Na values of 135 milliequivalent/L, the hypertonic saline solutions concentration will range between 1.4% and 2.4%. Throughout the study period, patients diagnosed with Heart Failure with Reduced Ejection Fraction (HFrEF) will receive angiotensin converting enzyme inhibitors, sartans, angiotensin receptor-neprilysin inhibitors, beta blockers, and mineralocorticoid inhibitors. The objective is to optimize heart failure therapy in alignment with the most recent European Society of Cardiology guidelines published in August 2023. Daily, there will be meticulous monitoring of body weight (in the morning before breakfast) and 24-hour urinary volume measurements. Serum and urinary laboratory parameters will be assessed daily until achieving a clinically stabilized condition, defined as a shift in New York Heart Association functional class to at least second b and reaching the ideal body weight calculated via the Lorenz formula. Upon attaining this clinically stabilized state, intravenous administration of furosemide and hypertonic saline solutions will cease, transitioning to oral furosemide administration, while maintaining the unchanged optimal therapy post-discharge according to the standard protocol.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 544
• Est. completion date: March 30, 2026
• Est. primary completion date: January 31, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 40 Years to 89 Years

Eligibility

Inclusion Criteria:

• acute heart failure;

• diabetes type 2.

Exclusion Criteria:

• low estimated glomerular filtration rate;

• hypernatremia;

• diabetes type 1;

• non-cardiac causes of dyspnea;

• cardiogenic shock;

• recent occurrence of Acute Coronary Syndrome;

• ketoacidosis;

• hyperosmolar hyperglycemic syndrome.

Related Conditions & MeSH terms

• Diabetes Mellitus, Type 2
• Diabetes Type 2
• Heart Failure
• Heart Failure Acute
• Heart Failure With Preserved Ejection Fraction
• Heart Failure With Reduced Ejection Fraction

Intervention

Drug:
• Dapagliflozin tablet
Dapagliflozin 10 mg 1 tablet once daily
• Hypertonic Saline Solution, 1 Ml
Intravenous infusion of furosemide combined with hypertonic saline solutions (100 mL) twice daily
• Furosemide Injection
Furosemide 20 mg

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
University of Palermo

References & Publications (12)

Arrigo M, Jessup M, Mullens W, Reza N, Shah AM, Sliwa K, Mebazaa A. Acute heart failure. Nat Rev Dis Primers. 2020 Mar 5;6(1):16. doi: 10.1038/s41572-020-0151-7. — View Citation

Clark WF, Sontrop JM, Macnab JJ, Suri RS, Moist L, Salvadori M, Garg AX. Urine volume and change in estimated GFR in a community-based cohort study. Clin J Am Soc Nephrol. 2011 Nov;6(11):2634-41. doi: 10.2215/CJN.01990211. Epub 2011 Sep 1. — View Citation

Heerspink HJL, Stefansson BV, Correa-Rotter R, Chertow GM, Greene T, Hou FF, Mann JFE, McMurray JJV, Lindberg M, Rossing P, Sjostrom CD, Toto RD, Langkilde AM, Wheeler DC; DAPA-CKD Trial Committees and Investigators. Dapagliflozin in Patients with Chronic — View Citation

Liszkowski M, Nohria A. Rubbing salt into wounds: hypertonic saline to assist with volume removal in heart failure. Curr Heart Fail Rep. 2010 Sep;7(3):134-9. doi: 10.1007/s11897-010-0018-4. — View Citation

McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Bohm M, Burri H, Butler J, Celutkiene J, Chioncel O, Cleland JGF, Coats AJS, Crespo-Leiro MG, Farmakis D, Gilard M, Heymans S, Hoes AW, Jaarsma T, Jankowska EA, Lainscak M, Lam CSP, Lyon AR, McMurray — View Citation

Oh SW, Han SY. Loop Diuretics in Clinical Practice. Electrolyte Blood Press. 2015 Jun;13(1):17-21. doi: 10.5049/EBP.2015.13.1.17. Epub 2015 Jun 30. — View Citation

Ostermann M, Bellomo R, Burdmann EA, Doi K, Endre ZH, Goldstein SL, Kane-Gill SL, Liu KD, Prowle JR, Shaw AD, Srisawat N, Cheung M, Jadoul M, Winkelmayer WC, Kellum JA; Conference Participants. Controversies in acute kidney injury: conclusions from a Kidn — View Citation

Parrinello G, Di Pasquale P, Torres D, Cardillo M, Schimmenti C, Lupo U, Iatrino R, Petrantoni R, Montaina C, Giambanco S, Paterna S. Troponin I release after intravenous treatment with high furosemide doses plus hypertonic saline solution in decompensate — View Citation

Parrinello G, Paterna S, Di Pasquale P, Torres D, Mezzero M, Cardillo M, Fasullo S, La Rocca G, Licata G. Changes in estimating echocardiography pulmonary capillary wedge pressure after hypersaline plus furosemide versus furosemide alone in decompensated — View Citation

Paterna S, Di Pasquale P, Parrinello G, Fornaciari E, Di Gaudio F, Fasullo S, Giammanco M, Sarullo FM, Licata G. Changes in brain natriuretic peptide levels and bioelectrical impedance measurements after treatment with high-dose furosemide and hypertonic — View Citation

Solomon SD, Vaduganathan M, Claggett BL, de Boer RA, DeMets D, Hernandez AF, Inzucchi SE, Kosiborod MN, Lam CSP, Martinez F, Shah SJ, Belohlavek J, Chiang CE, Willem Borleffs CJ, Comin-Colet J, Dobreanu D, Drozdz J, Fang JC, Alcocer Gamba MA, Al Habeeb W, — View Citation

Xie Y, Wei Y, Li D, Pu J, Ding H, Zhang X. Mechanisms of SGLT2 Inhibitors in Heart Failure and Their Clinical Value. J Cardiovasc Pharmacol. 2023 Jan 1;81(1):4-14. doi: 10.1097/FJC.0000000000001380. — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Diuresis from the baseline and up to 1 week	Daily urinary volume (mL) are detected by chemiluminescence immunoassay.	an average of 1 week
Primary	Natriuresis from the baseline and up to 1 week	Daily natriuresis (mEq/L) are detected by chemiluminescence immunoassay.	an average of 1 week
Primary	Length of hospital stay	Duration of hospital stay in days.	immediately after the intervention
Secondary	Kidney function during treatment	Daily evaluation of creatinine (mg/dL).	an average of 1 week