Efficacy and Safety of Dapagliflozin in Acute Heart Failure

NCT04298229 | Completed Phase 3 Results DMC FDA Drug

• 1 other identifier: 200017
• Study Type: interventional
• Target: 240
• Locations: 1 country
• Sites: 6

Brief Summary

This is a randomized trial of the addition of dapagliflozin to patients with or without type 2 diabetes hospitalized with acute decompensated heart failure (ADHF). Participants will be recruited following an initial standard evaluation in the ED and randomized within 24 hours of presentation for ADHF in a 1:1 fashion to protocolized diuretic therapy or dapagliflozin + protocolized diuretic therapy.

Conditions

Heart Failure; Diabetes Mellitus, Type 2

Outcome Measures

Primary Outcomes (1)

• Cumulative Change in Weight (Kilograms) Per 40mg of IV Furosemide Equivalents, Adjusted for Baseline Weight

  cumulative change in weight (kilograms) per 40mg of IV furosemide equivalents from enrollment to day 5 or discharge (if earlier) between protocolized diuretic therapy and dapagliflozin plus protocolized diuretic therapy guided by urine output

  Baseline to Day 5 or discharge if earlier

Secondary Outcomes (2)

• Number of Participants With Inpatient Worsening Heart Failure

  Baseline to hospital discharge, an average of 5 days

• Hospital Readmission

  Day 30

Study Arms (2)

Protocolized diuretic therapy

ACTIVE COMPARATOR

The patients with diabetes will receive standard of care point of care blood glucose monitoring 4 times daily (before meals and at bedtime) and sliding scale insulin. The initial loop diuretic regimen after enrollment: Loop diuretic naïve: If the patient does not take a scheduled loop diuretic as an outpatient, the initial IV loop diuretic dose will be 40mg of furosemide equivalents every 12 hours. Chronic, oral loop diuretic therapy: If the patient takes a scheduled loop diuretic regimen as an outpatient prior to hospital admission, the initial IV loop diuretic daily dose will be 2 times the total daily home regimen dose. Diuretic therapy will be titrated to goal urine output using a standardized diuretic protocol.

Other: Protocolized Diuretic Therapy

Protocolized diuretic therapy plus SGLT2 inhibitor therapy

EXPERIMENTAL

The patients with diabetes will receive standard of care point of care blood glucose monitoring 4 times daily (before meals and at bedtime) and sliding scale insulin. The initial loop diuretic regimen after enrollment: Loop diuretic naïve: If the patient does not take a scheduled loop diuretic as an outpatient, the initial IV loop diuretic dose will be 40mg of furosemide equivalents every 12 hours. Chronic, oral loop diuretic therapy: If the patient takes a scheduled loop diuretic regimen as an outpatient prior to hospital admission, the initial IV loop diuretic daily dose will be 2 times the total daily home regimen dose. Diuretic therapy will be titrated to goal urine output using a standardized diuretic protocol. The patient will receive SGLT2 inhibitor therapy with dapagliflozin 10 mg orally once daily until 5 days or hospital discharge.

Drug: Dapagliflozin 10 MG; Other: Protocolized Diuretic Therapy

Interventions

Dapagliflozin 10 MG DRUG

SGLT2 inhibitors being investigated for its diuretic and natriuretic effects on top of protocolized diuretic therapy.

Also known as: sodium-glucose cotransporter-2(SGLT2) inhibitors

Protocolized diuretic therapy plus SGLT2 inhibitor therapy

Protocolized Diuretic Therapy OTHER

Structured usual care arm with protocolized diuretic therapy based on urine output.

Protocolized diuretic therapy; Protocolized diuretic therapy plus SGLT2 inhibitor therapy

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age of 18 years or older
• Randomized within 24 of presentation during a hospital admission for hypervolemic decompensated heart failure defined as:
• pulmonary artery catheterization with a pulmonary capillary wedge pressure greater than 19mmHg plus a systemic physical exam finding of hypervolemia (peripheral edema, ascites, or pulmonary edema on auscultation)
• in the absence of pulmonary artery catheterization data 2 of the following signs or symptoms: peripheral edema, ascites, jugular venous pressure \> 10mmHg, orthopnea, paroxysmal nocturnal dyspnea, 5-pound weight gain, or signs of congestion on chest x-ray or lung ultrasound
• Planned use of IV loop diuretic therapy during current hospitalization
• eGFR of 25 ml/min/1.73m2 by the MDRD equation or greater

You may not qualify if:

• Type 1 diabetes
• Serum glucose \< 80mg/dl at enrollment
• Systolic blood pressure \< 90mmHg at enrollment
• Requirement of intravenous inotropic therapy or anticipated need during the study
• History of hypersensitivity to any SGLT2 inhibitors
• Women who are pregnant or breastfeeding
• Severe anemia (Hemoglobin \< 7.5g/dl)
• Severe uncorrected aortic or mitral stenosis
• Inability to perform standing weights or measure urine output accurately
• History of diabetic ketoacidosis
• Scheduled combination nephron blockade with loop and thiazide therapy as an outpatient for more than 7 days prior to admission (excluding HCTZ \< 50mg for blood pressure)
• Diffuse anasarca with 4+ edema and projected hypervolemia exceeding 40-pounds
• Severe hepatic impairment (Child-Pugh class C)
• Clinical picture consistent with acute myocardial infarction including troponin rise and fall or ischemic changes on electrocardiogram
• Site investigator determines the subject is not a good candidate to participate in the study at this tine

Sponsors & Collaborators

• Vanderbilt University Medical Center: lead
• AstraZeneca: collaborator

Study Sites (6)

University of Mississippi Medical Center

Jackson, Mississippi, 39216, United States

Location

University of North Carolina

Chapel Hill, North Carolina, 27514, United States

Location

INTEGRIS

Oklahoma City, Oklahoma, 73112, United States

Location

TriStar Centennial Medical Center

Nashville, Tennessee, 37203, United States

Location

Saint Thomas West Hospital

Nashville, Tennessee, 37205, United States

Location

Vanderbilt University Medical Center

Nashville, Tennessee, 37232, United States

Location

Related Publications (28)

• Adams KF Jr, Fonarow GC, Emerman CL, LeJemtel TH, Costanzo MR, Abraham WT, Berkowitz RL, Galvao M, Horton DP; ADHERE Scientific Advisory Committee and Investigators. Characteristics and outcomes of patients hospitalized for heart failure in the United States: rationale, design, and preliminary observations from the first 100,000 cases in the Acute Decompensated Heart Failure National Registry (ADHERE). Am Heart J. 2005 Feb;149(2):209-16. doi: 10.1016/j.ahj.2004.08.005.

  PMID: 15846257 BACKGROUND

• Chioncel O, Mebazaa A, Maggioni AP, Harjola VP, Rosano G, Laroche C, Piepoli MF, Crespo-Leiro MG, Lainscak M, Ponikowski P, Filippatos G, Ruschitzka F, Seferovic P, Coats AJS, Lund LH; ESC-EORP-HFA Heart Failure Long-Term Registry Investigators. Acute heart failure congestion and perfusion status - impact of the clinical classification on in-hospital and long-term outcomes; insights from the ESC-EORP-HFA Heart Failure Long-Term Registry. Eur J Heart Fail. 2019 Nov;21(11):1338-1352. doi: 10.1002/ejhf.1492. Epub 2019 May 24.

  PMID: 31127678 BACKGROUND

• Damman K, Testani JM. The kidney in heart failure: an update. Eur Heart J. 2015 Jun 14;36(23):1437-44. doi: 10.1093/eurheartj/ehv010. Epub 2015 Apr 2.

  PMID: 25838436 BACKGROUND

• Echouffo-Tcheugui JB, Xu H, DeVore AD, Schulte PJ, Butler J, Yancy CW, Bhatt DL, Hernandez AF, Heidenreich PA, Fonarow GC. Temporal trends and factors associated with diabetes mellitus among patients hospitalized with heart failure: Findings from Get With The Guidelines-Heart Failure registry. Am Heart J. 2016 Dec;182:9-20. doi: 10.1016/j.ahj.2016.07.025. Epub 2016 Aug 27.

  PMID: 27914505 BACKGROUND

• Mebazaa A, Gayat E, Lassus J, Meas T, Mueller C, Maggioni A, Peacock F, Spinar J, Harjola VP, van Kimmenade R, Pathak A, Mueller T, Tavazzi L, Disomma S, Metra M, Pascual-Figal D, Laribi S, Logeart D, Nouira S, Sato N, Parenica J, Deye N, Boukef R, Collet C, Van den Berghe G, Cohen-Solal A, Januzzi JL Jr; GREAT Network. Association between elevated blood glucose and outcome in acute heart failure: results from an international observational cohort. J Am Coll Cardiol. 2013 Feb 26;61(8):820-9. doi: 10.1016/j.jacc.2012.11.054. Epub 2013 Jan 16.

  PMID: 23333145 BACKGROUND

• Kosiborod M, Inzucchi SE, Spertus JA, Wang Y, Masoudi FA, Havranek EP, Krumholz HM. Elevated admission glucose and mortality in elderly patients hospitalized with heart failure. Circulation. 2009 Apr 14;119(14):1899-907. doi: 10.1161/CIRCULATIONAHA.108.821843. Epub 2009 Mar 30.

  PMID: 19332465 BACKGROUND

• Cox ZL, Lai P, Lewis CM, Lindenfeld J. Change in admission blood glucose from chronic glycemic status in acute heart failure hospitalization and 30-day outcomes: A retrospective analysis. Int J Cardiol. 2020 Jan 15;299:180-185. doi: 10.1016/j.ijcard.2019.07.069. Epub 2019 Jul 23.

  PMID: 31395364 BACKGROUND

• Packer M, O'Connor C, McMurray JJV, Wittes J, Abraham WT, Anker SD, Dickstein K, Filippatos G, Holcomb R, Krum H, Maggioni AP, Mebazaa A, Peacock WF, Petrie MC, Ponikowski P, Ruschitzka F, van Veldhuisen DJ, Kowarski LS, Schactman M, Holzmeister J; TRUE-AHF Investigators. Effect of Ularitide on Cardiovascular Mortality in Acute Heart Failure. N Engl J Med. 2017 May 18;376(20):1956-1964. doi: 10.1056/NEJMoa1601895. Epub 2017 Apr 12.

  PMID: 28402745 BACKGROUND

• O'Connor CM, Starling RC, Hernandez AF, Armstrong PW, Dickstein K, Hasselblad V, Heizer GM, Komajda M, Massie BM, McMurray JJ, Nieminen MS, Reist CJ, Rouleau JL, Swedberg K, Adams KF Jr, Anker SD, Atar D, Battler A, Botero R, Bohidar NR, Butler J, Clausell N, Corbalan R, Costanzo MR, Dahlstrom U, Deckelbaum LI, Diaz R, Dunlap ME, Ezekowitz JA, Feldman D, Felker GM, Fonarow GC, Gennevois D, Gottlieb SS, Hill JA, Hollander JE, Howlett JG, Hudson MP, Kociol RD, Krum H, Laucevicius A, Levy WC, Mendez GF, Metra M, Mittal S, Oh BH, Pereira NL, Ponikowski P, Tang WH, Tanomsup S, Teerlink JR, Triposkiadis F, Troughton RW, Voors AA, Whellan DJ, Zannad F, Califf RM. Effect of nesiritide in patients with acute decompensated heart failure. N Engl J Med. 2011 Jul 7;365(1):32-43. doi: 10.1056/NEJMoa1100171.

  PMID: 21732835 BACKGROUND

• Cox ZL, Lenihan DJ. Loop diuretic resistance in heart failure: resistance etiology-based strategies to restoring diuretic efficacy. J Card Fail. 2014 Aug;20(8):611-22. doi: 10.1016/j.cardfail.2014.05.007. Epub 2014 May 28.

  PMID: 24879974 BACKGROUND

• Heerspink HJ, Perkins BA, Fitchett DH, Husain M, Cherney DZ. Sodium Glucose Cotransporter 2 Inhibitors in the Treatment of Diabetes Mellitus: Cardiovascular and Kidney Effects, Potential Mechanisms, and Clinical Applications. Circulation. 2016 Sep 6;134(10):752-72. doi: 10.1161/CIRCULATIONAHA.116.021887. Epub 2016 Jul 28.

  PMID: 27470878 BACKGROUND

• Heise T, Seewaldt-Becker E, Macha S, Hantel S, Pinnetti S, Seman L, Woerle HJ. Safety, tolerability, pharmacokinetics and pharmacodynamics following 4 weeks' treatment with empagliflozin once daily in patients with type 2 diabetes. Diabetes Obes Metab. 2013 Jul;15(7):613-21. doi: 10.1111/dom.12073. Epub 2013 Feb 17.

  PMID: 23356556 BACKGROUND

• Testani JM, Brisco MA, Turner JM, Spatz ES, Bellumkonda L, Parikh CR, Tang WH. Loop diuretic efficiency: a metric of diuretic responsiveness with prognostic importance in acute decompensated heart failure. Circ Heart Fail. 2014 Mar 1;7(2):261-70. doi: 10.1161/CIRCHEARTFAILURE.113.000895. Epub 2013 Dec 30.

  PMID: 24379278 BACKGROUND

• Palazzuoli A, Testani JM, Ruocco G, Pellegrini M, Ronco C, Nuti R. Different diuretic dose and response in acute decompensated heart failure: Clinical characteristics and prognostic significance. Int J Cardiol. 2016 Dec 1;224:213-219. doi: 10.1016/j.ijcard.2016.09.005. Epub 2016 Sep 10.

  PMID: 27657476 BACKGROUND

• Lala A, McNulty SE, Mentz RJ, Dunlay SM, Vader JM, AbouEzzeddine OF, DeVore AD, Khazanie P, Redfield MM, Goldsmith SR, Bart BA, Anstrom KJ, Felker GM, Hernandez AF, Stevenson LW. Relief and Recurrence of Congestion During and After Hospitalization for Acute Heart Failure: Insights From Diuretic Optimization Strategy Evaluation in Acute Decompensated Heart Failure (DOSE-AHF) and Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARESS-HF). Circ Heart Fail. 2015 Jul;8(4):741-8. doi: 10.1161/CIRCHEARTFAILURE.114.001957. Epub 2015 Jun 3.

  PMID: 26041600 BACKGROUND

• Kronmal RA. Spurious Correlation and the Fallacy of the Ratio Standard Revisited. J Roy Stat Soc a Sta. 1993;156:379-392.

  BACKGROUND

• Walker SH, Duncan DB. Estimation of the probability of an event as a function of several independent variables. Biometrika. 1967 Jun;54(1):167-79. No abstract available.

  PMID: 6049533 BACKGROUND

• Harrell FE. Regression Modeling Strategies: With Applications to Linear Models, Logistic and Ordinal Regression, and Survival Analysis, 2nd Edition. Springer Ser Stat. 2015.

  BACKGROUND

• Teerlink JR, Cotter G, Davison BA, Felker GM, Filippatos G, Greenberg BH, Ponikowski P, Unemori E, Voors AA, Adams KF Jr, Dorobantu MI, Grinfeld LR, Jondeau G, Marmor A, Masip J, Pang PS, Werdan K, Teichman SL, Trapani A, Bush CA, Saini R, Schumacher C, Severin TM, Metra M; RELAXin in Acute Heart Failure (RELAX-AHF) Investigators. Serelaxin, recombinant human relaxin-2, for treatment of acute heart failure (RELAX-AHF): a randomised, placebo-controlled trial. Lancet. 2013 Jan 5;381(9860):29-39. doi: 10.1016/S0140-6736(12)61855-8. Epub 2012 Nov 7.

  PMID: 23141816 BACKGROUND

• Konstam MA, Gheorghiade M, Burnett JC Jr, Grinfeld L, Maggioni AP, Swedberg K, Udelson JE, Zannad F, Cook T, Ouyang J, Zimmer C, Orlandi C; Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) Investigators. Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST Outcome Trial. JAMA. 2007 Mar 28;297(12):1319-31. doi: 10.1001/jama.297.12.1319. Epub 2007 Mar 25.

  PMID: 17384437 BACKGROUND

• Felker GM, Mentz RJ, Cole RT, Adams KF, Egnaczyk GF, Fiuzat M, Patel CB, Echols M, Khouri MG, Tauras JM, Gupta D, Monds P, Roberts R, O'Connor CM. Efficacy and Safety of Tolvaptan in Patients Hospitalized With Acute Heart Failure. J Am Coll Cardiol. 2017 Mar 21;69(11):1399-1406. doi: 10.1016/j.jacc.2016.09.004. Epub 2016 Sep 18.

  PMID: 27654854 BACKGROUND

• Konstam MA, Kiernan M, Chandler A, Dhingra R, Mody FV, Eisen H, Haught WH, Wagoner L, Gupta D, Patten R, Gordon P, Korr K, Fileccia R, Pressler SJ, Gregory D, Wedge P, Dowling D, Romeling M, Konstam JM, Massaro JM, Udelson JE; SECRET of CHF Investigators, Coordinators, and Committee Members. Short-Term Effects of Tolvaptan in Patients With Acute Heart Failure and Volume Overload. J Am Coll Cardiol. 2017 Mar 21;69(11):1409-1419. doi: 10.1016/j.jacc.2016.12.035.

  PMID: 28302292 BACKGROUND

• Chen HH, Anstrom KJ, Givertz MM, Stevenson LW, Semigran MJ, Goldsmith SR, Bart BA, Bull DA, Stehlik J, LeWinter MM, Konstam MA, Huggins GS, Rouleau JL, O'Meara E, Tang WH, Starling RC, Butler J, Deswal A, Felker GM, O'Connor CM, Bonita RE, Margulies KB, Cappola TP, Ofili EO, Mann DL, Davila-Roman VG, McNulty SE, Borlaug BA, Velazquez EJ, Lee KL, Shah MR, Hernandez AF, Braunwald E, Redfield MM; NHLBI Heart Failure Clinical Research Network. Low-dose dopamine or low-dose nesiritide in acute heart failure with renal dysfunction: the ROSE acute heart failure randomized trial. JAMA. 2013 Dec 18;310(23):2533-43. doi: 10.1001/jama.2013.282190.

  PMID: 24247300 BACKGROUND

• Voors AA, Davison BA, Teerlink JR, Felker GM, Cotter G, Filippatos G, Greenberg BH, Pang PS, Levin B, Hua TA, Severin T, Ponikowski P, Metra M; RELAX-AHF Investigators. Diuretic response in patients with acute decompensated heart failure: characteristics and clinical outcome--an analysis from RELAX-AHF. Eur J Heart Fail. 2014 Nov;16(11):1230-40. doi: 10.1002/ejhf.170. Epub 2014 Oct 7.

  PMID: 25287144 BACKGROUND

• ter Maaten JM, Dunning AM, Valente MA, Damman K, Ezekowitz JA, Califf RM, Starling RC, van der Meer P, O'Connor CM, Schulte PJ, Testani JM, Hernandez AF, Tang WH, Voors AA. Diuretic response in acute heart failure-an analysis from ASCEND-HF. Am Heart J. 2015 Aug;170(2):313-21. doi: 10.1016/j.ahj.2015.05.003. Epub 2015 May 9.

  PMID: 26299229 BACKGROUND

• Valente MA, Voors AA, Damman K, Van Veldhuisen DJ, Massie BM, O'Connor CM, Metra M, Ponikowski P, Teerlink JR, Cotter G, Davison B, Cleland JG, Givertz MM, Bloomfield DM, Fiuzat M, Dittrich HC, Hillege HL. Diuretic response in acute heart failure: clinical characteristics and prognostic significance. Eur Heart J. 2014 May 14;35(19):1284-93. doi: 10.1093/eurheartj/ehu065. Epub 2014 Feb 28.

  PMID: 24585267 BACKGROUND

• Ter Maaten JM, Valente MA, Damman K, Cleland JG, Givertz MM, Metra M, O'Connor CM, Teerlink JR, Ponikowski P, Bloomfield DM, Cotter G, Davison B, Subacius H, van Veldhuisen DJ, van der Meer P, Hillege HL, Gheorghiade M, Voors AA. Combining Diuretic Response and Hemoconcentration to Predict Rehospitalization After Admission for Acute Heart Failure. Circ Heart Fail. 2016 Jun;9(6):e002845. doi: 10.1161/CIRCHEARTFAILURE.115.002845.

  PMID: 27266853 BACKGROUND

• Cox ZL, Collins SP, Hernandez GA, McRae AT 3rd, Davidson BT, Adams K, Aaron M, Cunningham L, Jenkins CA, Lindsell CJ, Harrell FE Jr, Kampe C, Miller KF, Stubblefield WB, Lindenfeld J. Efficacy and Safety of Dapagliflozin in Patients With Acute Heart Failure. J Am Coll Cardiol. 2024 Apr 9;83(14):1295-1306. doi: 10.1016/j.jacc.2024.02.009.

  PMID: 38569758 DERIVED

MeSH Terms

Conditions

Heart Failure; Diabetes Mellitus, Type 2

Interventions

dapagliflozin

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases; Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Results Point of Contact

• Title: Zachary Cox
• Organization: Vanderbilt University Medical Center

zachary.l.cox@vumc.org

615-966-7107

Study Officials

• JoAnn Lindenfeld, MD

  Vanderbilt University Medical Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Masking Details: The Clinical Event Adjudication Committee will consist of 3 independent clinicians, which will consist of at least one endocrinologist and at least one heart failure specialist. The members of this committee will be independent of the study implementation teams and will be blinded to study arm assignment. This committee will review abstracted clinical data to determine when primary endpoints and major events have occurred. The CEAC will review data for the following study outcomes: * Potential in-hospital worsening heart failure events * 30-day readmission events for heart failure or diabetes-related care * Prolonged hospitalization as a result of the following safety outcomes: hypotension requiring medical intervention or hypoglycemia requiring medical intervention * Inpatient mortality events * Potential ketoacidosis events
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Co-Principal Investigator

Model Details: Participants will be recruited following an initial standard evaluation in the ED and randomized within 24 hours of presentation for ADHF in a 1:1 fashion to protocolized diuretic therapy or dapagliflozin + protocolized diuretic therapy.

Study Record Dates

• First Submitted: March 2, 2020
• First Posted: March 6, 2020
• Study Start: April 1, 2020
• Primary Completion: May 17, 2023
• Study Completion: May 17, 2023
• Last Updated: March 15, 2024
• Results First Posted: March 15, 2024

Record last verified: 2024-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (6)