Acute Heart Failure, Heart Failure
Conditions
Brief summary
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.
Interventions
DRUGDapagliflozin
Dapagliflozin
DRUGPlacebo
Matched placebo
Sponsors
The TIMI Study Group
AstraZeneca
Worldwide Clinical Trials
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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) 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: 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) 5. 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
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Participants With the Composite Outcome of Cardiovascular Death or Worsening Heart Failure | 2 months | Composite of cardiovascular death or worsening heart failure event (defined as worsening heart failure during index admission, rehospitalization for worsening heart failure, or urgent heart failure visit) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Participants With the Composite Outcome of Cardiovascular Death, Rehospitalization for Heart Failure, Urgent Heart Failure Visit | 2 months | — |
| Participants With the Composite Outcome of Cardiovascular Death or Rehospitalization for Heart Failure | 2 months | — |
| Participants With Rehospitalization for Heart Failure or Urgent Heart Failure Visit | 2 months | — |
| Number of Participants With All-cause Death | 2 months | — |
| Hierarchical Composite of Time to Cardiovascular Death, Worsening Heart Failure Events, Time to First Worsening Heart Failure Event, and Change From Baseline in KCCQ-12 Total Symptom Score (% Wins) | 2 months | Hierarchical Composite Endpoint combines time to all-cause mortality, number of heart failure events, time to first worsening HF events, KCCQ-12 total symptom score in a hierarchical fashion. The method compares every participant with every other participant within strata, assigning a +1 to the "better" participant and a -1 to the "worse" participant and 0 if they are "tied". 'Win' represents a participant doing better based on hierarchical comparison. The reported unit is the total number of "wins" for each treatment group from performing such a hierarchical comparison across stratification factors in the study. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORDavid D Berg, MD, MPH
TIMI Study Group, Brigham and Women's Hospital
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 69 years |
| eGFR <60 ml/min/1.73m^2 | 551 Participants |
| Estimated GFR | 62.5 ml/min/1.73m^2 |
| Heart Failure chronicity Newly diagnosed heart failure | 518 Participants |
| Heart Failure chronicity Worsening chronic heart failure | 665 Participants |
| Heart rate | 77 bpm |
| History of atrial fibrillation | 542 Participants |
| History of hypertension | 943 Participants |
| KCCQ-12 total symptom score at randomization | 33.3 points |
| Left ventricular ejection fraction | 30 % of blood ejected from the heart |
| LVEF ≤40% | 852 Participants |
| Medication use at randomization ACE inhibitor or ARB | 539 Participants |
| Medication use at randomization ARNI | 648 Participants |
| Medication use at randomization Beta-blocker | 1981 Participants |
| Medication use at randomization Digoxin | 64 Participants |
| Medication use at randomization Loop diuretic | 998 Participants |
| Medication use at randomization Mineralocorticoid receptor antagonist | 602 Participants |
| Medication use at randomization Renin-angiotensin system inhibitor | 823 Participants |
| Natriuretic peptides (qualifying) BNP | 1092 pg/ml |
| Natriuretic peptides (qualifying) NT-proBNP | 5016 pg/ml |
| NYHA class 30 days prior to admission NYHA class I | 31 Participants |
| NYHA class 30 days prior to admission NYHA class II | 221 Participants |
| NYHA class 30 days prior to admission NYHA class III | 350 Participants |
| NYHA class 30 days prior to admission NYHA class IV | 56 Participants |
| Principal cause of heart failure Ischemic | 296 Participants |
| Principal cause of heart failure Non-ischemic | 727 Participants |
| Principal cause of heart failure Unknown | 168 Participants |
| Prior heart failure hospitalization | 742 Participants |
| Prior myocardial infarction | 222 Participants |
| Race/Ethnicity, Customized Asian | 26 Participants |
| Race/Ethnicity, Customized Black or African American | 224 Participants |
| Race/Ethnicity, Customized Other | 14 Participants |
| Race/Ethnicity, Customized White | 927 Participants |
| Region Europe | 314 Participants |
| Region North America | 869 Participants |
| Serum potassium | 4.0 mmol/L |
| Sex: Female, Male Female | 403 Participants |
| Sex: Female, Male Male | 771 Participants |
| Systolic blood pressure | 119 mmHg |
| Type 2 diabetes mellitus | 415 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 36 / 1,218 | 53 / 1,183 |
| other Total, other adverse events | 58 / 1,210 | 56 / 1,179 |
| serious Total, serious adverse events | 24 / 1,210 | 21 / 1,179 |
Outcome results
None listed