Thrombolysis in Myocardial Infarction 68 (DAPA ACT HF-TIMI 68)

This is an international, multicenter, parallel-group, randomized, double-blind, placebo-controlled trial in patients who have been stabilized during hospitalization for acute heart failure, evaluating the effect of in-hospital initiation of dapagliflozin versus placebo on the clinical outcome of cardiovascular death or worsening heart failure.

Inclusion Criteria

1. Age ≥18 years (male or female)

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

   1. 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)

   2. 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)

   3. 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) The majority of enrolled patients should have an established history of heart failure (defined as present for ≥2 months and for which the patient is on treatment). Trial leadership will monitor this proportion and may cap enrollment of patients without an established history of heart failure (i.e., patients presenting with de novo heart failure).

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

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

   1. 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)

   2. 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)

3. 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:

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

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

Patients across the spectrum of LVEF are eligible for participation in the trial. Trial

leadership will monitor the proportion of patients with various LVEFs and may cap

enrollment of certain subgroups to ensure a broad population.

In addition, patients with and without type 2 diabetes are eligible for participation in

the trial. Trial leadership will monitor the proportion of patients with and without type 2

diabetes and may cap enrollment of one subgroup to ensure adequate representation of the

other.

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