Clinical trial NCT05764057: DAPAgliflozine to Attenuate Cardiac RemOdeling afTEr aCuTe myOcardial Infarction
Official title: DAPAgliflozine to Attenuate Cardiac RemOdeling afTEr aCuTe myOcardial Infarction
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: AMI
STEMI
NSTEMI
Left Ventricular Dysfunction
Keywords: Acute myocardial infarction
Left ventricular dysfunction
Dapagliflozin
Transthoracic echocardiography
Cardiac remodeling
Cardiovascular Intensive Care Unit (CICU)
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
Collaborators: name: AstraZeneca
First posted: 2023-03-10
Enrollment: 450
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Recent clinical trials have proven the cardiovascular benefits of new medications for patients with heart failure with reduced ejection fraction (HFrEF), especially sodium-glucose co-transporter 2 (SGLT2) inhibitors. There are no existing randomized clinical trials evaluating the efficacy and safety of dapagliflozin (nor any other SGLT2-inhibitor) to limit cardiac remodeling in patients with acute myocardial infarction (AMI) and left ventricular (LV) dysfunction.

Preventing cardiac remodeling, an established predictor of subsequent heart failure (HF) and cardiovascular death, is likely to translate into benefit in reducing clinical events in post-MI patients.

Detailed description: DAPA-PROTECTOR is a prospective multicenter, randomized, double blind, phase III trial.

Patients with confirmed AMI (e.g., STEMI or very high-risk NSTEMI) with LV dysfunction (LVEF≤45%) after completion of percutaneous coronary intervention (PCI) will be assessed for eligibility. Patients will be randomized (in a 1:1 ratio) to receive dapagliflozin (10mg once day) or placebo for 6 months, on top of standard of care as recommended in current guidelines. Treatment will be prescribed as soon as possible after admission The first TTE (TTE-1) will be performed to confirm inclusion criteria (LVEF≤45%). Four visits are scheduled: at baseline and randomization (Visit D0), at discharge from the CICU (Visit 2) at Month 3 ±2 weeks (Visit 3), and at Month 6 (+ 4 weeks) (Visit 4). After randomization, Visit 2 and Visit 3 will be scheduled to check the tolerance of the drug. In addition, a phone call will be done to the patient to make sure he's not taking any Dapagliflozin (or equivalent as Empagliflozin) in addition to experimental treatment. Finally, the last visit (Visit 4) will be scheduled to collect clinical follow-up and to perform a TTE (TTE-2). Efficacy criteria will be assessed from randomization to Month 6 by TTE. All TTE results will be anonymized and centralized at a Corelab with assessment by independent cardiologists unaware of the patient treatment group.

Eligibility criteria: Inclusion Criteria:

* Age ≥18 years;
* STEMI (e.g., ST elevation above the J-point of ≥0.1 millivolt in ≥two contiguous leads or left bundle branch block) or very high-risk NSTEMI (e.g., dynamic ECG changes or ongoing chest pain or acute heart failure or hemodynamic instability independent of ECG changes or life-threatening ventricular arrhythmias) with LV dysfunction (LVEF ≤45%); after completion of PCI or angiography procedure
* eGFR ≥ 25 mL/Min per 1.73m²;
* Systolic blood pressure (SBP) before first dosing \>100 mmHg and/or Diastolic blood pressure (DBP) \>70 mmHg before first dosing;
* Ability to provide written informed consent and willing to participate in the 6-month follow-up period.
* Affiliation to a national health care system (AME are not allowed).

Exclusion Criteria:

* Cardiogenic shock (SBP \<90 mmHg with clinical signs of low output or patients requiring inotropic agents) at randomization;
* Referred to surgery for coronary artery bypass grafting (CABG) or treatment of acute complications (e.g. ventricular septal rupture);
* Any other form of diabetes than diabetes type 2
* History of diabetic ketoacidosis (DKA); Known contra-indication to SGLT-2 inhibitors (hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption);
* \>1 episode of severe hypoglycemia within the last 6 months under treatment with insulin or sulfonylurea;
* Acute symptomatic urinary tract infection (UTI) or genital infection at the time of randomization;
* Concomitant treatment (and/or within the 4 weeks prior to the baseline visit) with any SGLT-2 inhibitor (dapagliflozin, canagliflozin, empagliflozin)
* Echocardiographic examination of insufficient quality to permit adequate analysis of the study end-points.
* Impossibility to evaluate cardiac remodeling using TTE (e.g., pacemaker or defibrillator ...);
* Atrial fibrillation rhythm at randomization;
* Life expectancy \<6 month;
* Known pregnancy at time of randomization;
* Breastfeeding women
* Females of childbearing potential without adequate contraceptive methods (i.e. sterilization, intrauterine device, vasectomized partner; or medical history of hysterectomy)
* Current participation in another interventional trial. Patients under guardianship or curatorship

Primary outcomes:
measure: Change in left ventricular ejection fraction (LVEF) from baseline to Month 6 (±1 month) by TTE
timeFrame: 6 months (+4 weeks) from randomization
measure: Change in left atrium volume (LAV) from baseline to Month 6 (±1 month) by TTE
timeFrame: 6 months (+4 weeks) from randomization
Secondary outcomes:
measure: Change in left ventricular end-systolic volume (LVESV)
timeFrame: 6 months (+4 weeks) from randomization
measure: Change in left ventricular end-diastolic volume (LVEDV)
timeFrame: 6 months (+4 weeks) from randomization
measure: Change in LV global longitudinal strain (LS)
timeFrame: 6 months (+4 weeks) from randomization
measure: Change in left atrial strain (LAS)
timeFrame: 6 months (+4 weeks) from randomization
measure: Duration of hospital stay (index hospitalization)
timeFrame: 6 months (+4 weeks) from randomization
measure: All-cause mortality at 6-months
timeFrame: 6 months (+4 weeks) from randomization
measure: Cardiovascular death or worsening HF at 6-months
timeFrame: 6 months (+4 weeks) from randomization
measure: Number of re-admission due to HF at 6-months
timeFrame: 6 months (±1 month) from randomization
measure: Change from baseline to Month 6 (+4 weeks) in LVESV, LVEDV, LAV, LVEF, LV global LS, LAS and pulmonary congestion (normal lung, mild, moderate or severe ultrasound lung comets [ULCs]) using TTE at month 6
timeFrame: 6 months (+4 weeks) from randomization
measure: Change from baseline to Month 6 (+4 weeks) in plasma levels of NT-pro BNP and HBA1C
timeFrame: 6 months (+4 weeks) from randomization
measure: Change in body weight from baseline to Month 6 (+4 weeks)
timeFrame: 6 months (+4 weeks) from randomization
measure: Adverse events
timeFrame: 6 months (+4 weeks) from randomization
Other outcomes:
Locations:
city: Paris
country: France
facility: Department of Cardiology AP-HP Hôpital européen Georges - Pompidou
Study officials:
affiliation: Assistance Publique - Hôpitaux de Paris
name: Etienne PUYMIRAT, Pr
role: PRINCIPAL_INVESTIGATOR
References: