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

• Status: Recruiting
• Trial end date: 2023-05-31
• Target enrollment: 0
• Participant gender: All

Summary

This is an international, multicenter, parallel-group, randomized, double-blind, placebo-controlled trial in patients with heart failure with reduced ejection fraction (left ventricular ejection fraction [LVEF] ≤40%) 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.

• Phase: Phase 4
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: The TIMI Study Group
• Collaborators: AstraZeneca; Worldwide Clinical Trials
• Treatments: 2-(3-(4-ethoxybenzyl)-4-chlorophenyl)-6-hydroxymethyltetrahydro-2H-pyran-3,4,5-triol; Dapagliflozin

Criteria

Inclusion Criteria:

1. Age ≥18 years (male or female)

2. Currently hospitalized for acute heart failure (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 heart failure 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 with reduced ejection fraction (HFrEF) (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 HFrEF (i.e., patients presenting with de novo HFrEF).

3. Most recent LVEF ≤40% within the past 12 months (including current hospitalization)

4. Elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) (≥1600 pg/mL) or B-type natriuretic peptide (BNP) (≥400 pg/mL) during current hospitalization (NT-proBNP ≥2400 pg/mL or BNP ≥600 pg/mL if patient in atrial fibrillation) (NB: for patients treated with angiotensin receptor neprilysin inhibitor (ARNI) in the 4 weeks prior to randomization, only NT-proBNP values should be used)

5. Eligible patients will be randomized no earlier than 24 hours and up to seven 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 24 hours prior to randomization

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

Patients with and without type 2 diabetes are eligible for participation in the trial. The 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. Use of two or more inotropic agents during the index hospitalization

3. Estimated glomerular filtration rate (eGFR) <30 ml/min/1.73 m2 as measured by the Chronic kidney disease epidemiology collaboration equation (CKD-EPI) equation at screening or rapidly progressive renal disease

4. Use of an Sodium-glucose cotransporter-2 (SGLT2) inhibitor within the last 30 days

5. Prior intolerance of SGLT2 inhibitors

6. Type 1 diabetes mellitus or history of diabetic ketoacidosis

7. In patients with diabetes on insulin or a sulfonylurea, a 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 3 months 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 3 months 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 implantable cardioverter defibrillator [ICD] or pacemaker, respectively)

11. History of heart transplantation, current transplant listing, or history of mechanical circulatory support (either durable or temporary)

12. History of heart failure due to restrictive or infiltrative cardiomyopathy, active myocarditis, constrictive pericarditis, hypertrophic (obstructive) cardiomyopathy, uncorrected primary valvular disease, or complex congenital heart disease

13. History of cirrhosis with evidence of portal hypertension

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 center employees 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)