Pharmacological Optimization in Prevention in Heart Failure: A Sex-gap?

Prior treatment

• Mechanical ventilation (not including CPAP/BIPAP) in the 24 hours prior to Screening.
• Myocardial infarction, unstable angina or cardiac surgery within 3 months, or cardiac resynchronization therapy (CRT) device implantation within 3 months, or percutaneous transluminal coronary intervention (PTCI), within 1 month prior to Screening or during the index event.
• Index Event (admission for Acute Heart Failure) triggered primarily by a correctable aetiology such as significant arrhythmia (e.g., sustained ventricular tachycardia, or atrial fibrillation/flutter with sustained ventricular response \>130 beats per minute, or bradycardia with sustained ventricular arrhythmia \<45 beats per minute), infection, severe anaemia, acute coronary syndrome, pulmonary embolism, exacerbation of Chronic Obstructive Pulmonary Disease (COPD), planned admission for device implantation or severe non-adherence leading to very significant fluid accumulation prior to admission and brisk diuresis after admission. Troponin elevations without other evidence of an acute coronary syndrome are not an exclusion.
• Sustained ventricular arrhythmia with syncopal episodes within the 3 months prior to screening that is untreated.
• Stroke or Transient Ischemic Attack (TIA) within the 3 months prior to Screening.
• Prior (defined as less than 30 days from screening) or current enrollment in a CHF trial or participation in an investigational drug or device study within the 30 days prior to screening or 5 half-lives of the study drug, whichever is longer.
• Discharge for the AHF hospitalization anticipated to be \>14 days from admission, or to a long-term care facility. Randomization must occur within 12 days following admission and at 1-2 days prior to anticipated discharge.

Other illness

• Significant pulmonary disease contributing substantially to the patients' dyspnoea such as FEV1 \<1 liter or need for chronic systemic or nonsystemic steroid therapy, or any kind of primary right heart failure such as primary pulmonary hypertension or recurrent pulmonary embolism.
• Uncorrected thyroid disease, active myocarditis, or known amyloid or hypertrophic obstructive cardiomyopathy.
• History of heart transplant or on a transplant list or using or planned to be implanted with a ventricular assist device.
• Primary liver disease considered to be life threatening.
• Psychiatric or neurological disorder, cirrhosis, or active malignancy leading to a life expectancy \< 6 months.
• Inability to comply with all study requirements, due to major co-morbidities, social or financial issues or a history of noncompliance with medical regimens, that might compromise the patient's ability to understand and/or comply with the protocol instructions or follow-up procedures.
• Hypersensitivity to the active substance or to any of the excipients as indicated in Summary of Product Characteristics of Investigational Medicinal Product (IMPs).
• Severe heart failure (NYHA class IV).

Lab values

• Active infection at any time during the AHF hospitalization prior to Randomization based on abnormal temperature and elevated WBC or need for intravenous antibiotics.
• Renal disease or eGFR \< 30 mL/min/1.73m2 (as estimated by the simplified MDRD formula) at Screening or history of dialysis.

Age

• Age \< 18 or \> 85 years.

Other

• Male patients
• Presence at Screening of any hemodynamically significant valvular stenosis or regurgitation, except mitral or tricuspid regurgitation secondary to left ventricular dilatation, or the presence of any hemodynamically significant obstructive lesion
• Pregnant or nursing (lactating) women.
• Angioedema.

• Female patients \>18 \<85 years.
• Hospital admission within the 72 hours prior to Screening for acute heart failure with dyspnea at rest and pulmonary congestion on chest X-ray, and other signs and/or symptoms of heart failure such as edema and/or positive rales on auscultation.
• All measures within 24 hours prior to Randomization of systolic blood pressure ≥ 100 mmHg, and of heart rate ≥ 60 bpm.
• All measures within 24 hours prior to Randomization of serum potassium ≤ 5.0 mEq/L (mmol/L).
• Biomarker criteria for persistent congestion:
  • 5.1. At Screening, NT-proBNP \>1,800 pg/mL (2,350 pg/mL in case of atrial fibrillation) 5.2. At the time of Randomization (1-2 days prior to discharge), NT-proBNP \>1,000 pg/mL (1,300 pg/mL in case of Atrial Fibrillation) to ensure the persistence of congestion and the acuity of the index episode).
• At 1 week prior to admission, at Screening, and at Visit 2 6.1. If EF\<50% (ie HFrEF or HFmrEF) either \<½ the optimal dose of ACEi/ARB/ARNi and MRA and BB or no SGLT2i (see Table) must have been prescribed 6.2. If EF\>50% (ie HFpEF): \<½ the optimal dose of MRA (see Table) or no SGLT2i.
• Written informed consent to participate in the study.