DAPAgliflozine to Attenuate Cardiac RemOdeling afTEr aCuTe myOcardial Infarction

Overview

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.

Interventions

• Drug Dapagliflozin propanediol (FORXIGA™/FARXIGA™1)
  Dapagliflozin (10 mg per day; per os) on top of standard of care as recommended in current guidelines\* for 6 months (experimental group) \*All patients will receive optimal medical therapy (including antithrombotic, beta-blockers, statins, angiotensin converting enzyme inhibitors or angiotensin receptor blocker or sacubitril/valsartan, diuretics, antagonists of the mineralocorticoid receptor) according to their clinical condition as recommended.
• Drug Placebo comparator
  Placebo daily on top of standard of care as recommended in current guidelines\* for 6 months (control group) \*All patients will receive optimal medical therapy (including antithrombotic, beta-blockers, statins, angiotensin converting enzyme inhibitors or angiotensin receptor blocker or sacubitril/valsartan, diuretics, antagonists of the mineralocorticoid receptor) according to their clinical condition as recommended.

Primary outcome measures

• Change in left ventricular ejection fraction (LVEF) from baseline to Month 6 (±1 month) by TTE [Time frame: 6 months (+4 weeks) from randomization]
• Change in left atrium volume (LAV) from baseline to Month 6 (±1 month) by TTE [Time frame: 6 months (+4 weeks) from randomization]

Secondary outcome measures (12)

• Change in left ventricular end-systolic volume (LVESV) [Time frame: 6 months (+4 weeks) from randomization]
• Change in left ventricular end-diastolic volume (LVEDV) [Time frame: 6 months (+4 weeks) from randomization]
• Change in LV global longitudinal strain (LS) [Time frame: 6 months (+4 weeks) from randomization]
• Change in left atrial strain (LAS) [Time frame: 6 months (+4 weeks) from randomization]
• Duration of hospital stay (index hospitalization) [Time frame: 6 months (+4 weeks) from randomization]
• All-cause mortality at 6-months [Time frame: 6 months (+4 weeks) from randomization]
• Cardiovascular death or worsening HF at 6-months [Time frame: 6 months (+4 weeks) from randomization]
• Number of re-admission due to HF at 6-months [Time frame: 6 months (±1 month) from randomization]
• 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 [Time frame: 6 months (+4 weeks) from randomization]
• Change from baseline to Month 6 (+4 weeks) in plasma levels of NT-pro BNP and HBA1C [Time frame: 6 months (+4 weeks) from randomization]
• Change in body weight from baseline to Month 6 (+4 weeks) [Time frame: 6 months (+4 weeks) from randomization]
• Adverse events [Time frame: 6 months (+4 weeks) from randomization]

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

France · 1 center

• Department of Cardiology AP-HP Hôpital européen Georges - Pompidou — Paris

Identifiers

NCT: NCT05764057 · APHP211054 · 2022-001901-28 · AOM20806

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗