Dapagliflozin and Effect on Cardiovascular Events in Acute Heart Failure -Thrombolysis in Myocardial Infarction 68 (DAPA ACT HF-TIMI 68)

Inclusion Criteria

1. Age ≥18 years (male or female)

2. Currently hospitalized for AHF defined as meeting all the following criteria:

3. Presentation with worsening symptoms of heart failure (e.g., worsening dyspnea or dyspnea at rest, progressive fatigue, rapid weight gain, worsening edema/abdominal distention/anasarca)

4. Objective signs or diagnostic testing consistent with volume overload (e.g., jugular venous distension, pulmonary basilar crackles, S3 gallop, ascites, hepatomegaly, peripheral edema, radiological evidence of pulmonary congestion, noninvasive or invasive hemodynamic evidence of elevated filling pressures)

5. Intensification of AHF therapy during admission defined as at least one of the following:

i. Augmentation of oral diuretic therapy [e.g., ≥2x outpatient regimen dose, addition of a second diuretic agent, or new initiation of diuretic therapy in a previously naïve patient] ii. Initiation of intravenous diuretic therapy iii. Initiation of intravenous vasoactive agent (e.g., inotrope or vasodilator)

3. Left ventricular ejection fraction (LVEF) measured within the past 12 months (including during the current hospitalization)

4. Elevated NT-proBNP or BNP during current hospitalization:

5. For patients with LVEF ≤40%: NT-proBNP ≥1600 pg/mL or BNP ≥400 pg/mL (NT-proBNP ≥2400 pg/mL or BNP ≥600 pg/mL if patient in atrial fibrillation or atrial flutter)

6. For patients with LVEF >40%: NT-proBNP ≥1200 pg/mL or BNP ≥300 pg/mL (NT-proBNP ≥1800 pg/mL or BNP ≥450 pg/mL if patient in atrial fibrillation or atrial flutter)

7. Eligible patients will be randomized no earlier than 24 hours and up to 14 days after presentation while still hospitalized once they have been stabilized, as defined by:

8. No increase (i.e., intensification) in the dose of intravenous diuretics during the 12 hours prior to randomization

9. No use of intravenous vasodilators or inotropes during the 24 hours prior to randomization

Exclusion Criteria

1. Symptomatic hypotension in the past 24 hours

2. Concurrent use of two or more intravenous inotropic agents during the index hospitalization

3. eGFR <25 ml/min/1.73 m2 as measured by the CKD-EPI equation at screening or rapidly progressive renal disease

4. Current use of an SGLT2 inhibitor

5. Prior intolerance of SGLT2 inhibitors

6. Type 1 diabetes mellitus or history of diabetic ketoacidosis

7. (Only applies to patients with T2DM who are on insulin and/or a sulfonylurea) History of recurrent major hypoglycemia (i.e., resulting in severe impairment in consciousness or behavior, or requiring emergency external assistance)

8. Implantation of a cardiac resynchronization therapy (CRT) device or valve repair or replacement within 30 days prior to randomization or intent to do so during the trial

9. ST-segment elevation myocardial infarction or coronary revascularization (percutaneous coronary intervention or coronary artery bypass grafting) within 30 days prior to randomization or intent to undergo coronary revascularization during the trial

10. Untreated sustained ventricular arrhythmias or Mobitz type II or third-degree heart block (i.e., without an ICD or pacemaker, respectively)

11. History of heart transplantation or current transplant listing; mechanical circulatory support use (either durable or temporary) during the index hospitalization

12. History of heart failure due to restrictive or infiltrative cardiomyopathy, active myocarditis, constrictive pericarditis, hypertrophic (obstructive) cardiomyopathy, uncorrected primary valvular disease, complex congenital heart disease, or heart failure felt to be due to a transient process (e.g., stress [takotsubo] cardiomyopathy, tachycardia-induced cardiomyopathy) expected to resolve within 2 months.

13. History of end-stage liver disease

14. Women of child-bearing potential (unless using adequate contraception) or currently breastfeeding

15. Current participation in a clinical trial with an unlicensed drug or device

16. Study staff or their family members

17. Any condition that, in the opinion of the investigator, would make trial participation not in the best interest of the subject, or would compromise compliance with the trial protocol (e.g., active severe infection, active malignancy)