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

Study Overview
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Brief Summary
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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.

Official Title
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A Multicenter, Randomized, Double-Blind, Parallel Group, Placebo-Controlled Trial to Evaluate the Effect of In-Hospital Initiation of Dapagliflozin on Clinical Outcomes in Patients Who Have Been Stabilized During Hospitalization for Acute Heart Failure DAPAgliflozin and Effect on Cardiovascular Events in ACuTe Heart Failure -Thrombolysis in Myocardial Infarction 68 (DAPA ACT HF-TIMI 68)

Conditions
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Acute Heart Failure, Heart Failure

Intervention / Treatment
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* Drug: Dapagliflozin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Age ≥18 years (male or female) Currently hospitalized for AHF defined as meeting all the following criteria: 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) 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) 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). Left ventricular ejection fraction (LVEF) measured within the past 12 months (including during the current hospitalization) Elevated NT-proBNP or BNP during current hospitalization: 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) 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) 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: No increase (i.e., intensification) in the dose of intravenous diuretics during the 12 hours prior to randomization 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 Symptomatic hypotension in the past 24 hours Concurrent use of two or more intravenous inotropic agents during the index hospitalization eGFR <25 ml/min/1.73 m2 as measured by the CKD-EPI equation at screening or rapidly progressive renal disease Current use of an SGLT2 inhibitor Prior intolerance of SGLT2 inhibitors Type 1 diabetes mellitus or history of diabetic ketoacidosis (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) 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 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 Untreated sustained ventricular arrhythmias or Mobitz type II or third-degree heart block (i.e., without an ICD or pacemaker, respectively) History of heart transplantation or current transplant listing; mechanical circulatory support use (either durable or temporary) during the index hospitalization 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. History of end-stage liver disease Women of child-bearing potential (unless using adequate contraception) or currently breastfeeding Current participation in a clinical trial with an unlicensed drug or device Study staff or their family members 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)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dapagliflozin<br>Dapagliflozin 10 mg administered orally once daily for 2 months | Drug: Dapagliflozin<br>* Dapagliflozin<br>|
| Placebo Comparator: Placebo<br>Matching placebo administered orally once daily for 2 months | Drug: Placebo<br>* Matched placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cardiovascular (CV) death or worsening heart failure | Time to first occurrence of CV death or worsening heart failure | 2 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite CV death, rehospitalization for heart failure, urgent heart failure visit | Time to first occurrence of composite of CV death, rehospitalization for heart failure, or urgent heart failure visit | 2 months | 
| Composite CV death, rehospitalization for heart failure | Time to first occurrence of composite of CV death or rehospitalization for heart failure | 2 months | 
| Rehospitalization for heart failure, urgent heart failure visit | Time to first occurrence of rehospitalization for heart failure or urgent heart failure visit | 2 months | 
| Readmission | Readmission within 30 days of hospital discharge | 2 months | 
| CV death | Time to CV death | 2 months | 
| Death | Time to death | 2 months |