This Will be a Randomized Comparison of the Proteomic Effects of Vicadrostat/Empagliflozin Versus Empagliflozin and Versus Empagliflozin/Spironolactone in Heart Failure Patients With Preserved Ejection Fraction

Prior treatment

• Treatment with an MRA (e.g. spironolactone, eplerenone, finerenone) within 14 days prior to enrollment and no intention to initiate MRA during the study.
• Treatment with amiloride, direct renin inhibitor (e.g. aliskiren), or the combination of ACEi plus ARB.
• Treatment with any other ASi.
• Major contraindication to SGLT2 inhibition, including history of Type 1 diabetes or previous ketoacidosis.
• Myocardial infarction, cerebrovascular accident, transient ischemic attack, stroke, coronary artery bypass graft (CABG) surgery, heart valve surgery or any other major surgery (per investigator judgement) within 90 days prior to enrollment, or scheduled for major elective surgery (e.g. hip replacement, CABG surgery).
• Known cardiomyopathy due to infiltrative diseases (e.g. amyloidosis), accumulation diseases (e.g. haemochromatosis, Fabry disease), muscular dystrophies, hypertrophic obstructive cardiomyopathy, or known pericardial constriction, or cardiomyopathy with potentially reversible cause such as stress or peripartum cardiomyopathy or cardiomyopathy induced by chemotherapy within the 12 months prior to enrollment.

Other illness

• Heart transplant recipient, awaiting heart transplant, or currently implanted left ventricular assist device.
• Acute inflammatory heart disease, such as acute myocarditis, within the 90 days preceding enrollment.
• Known severe valvular heart disease (obstructive or regurgitant), per investigator judgment, or valvular heart disease scheduled for surgical or invasive procedures at enrollment, or anticipated invasive treatment during the study.
• Active or prior cancer of any kind except for non-melanoma skin cancers.
• Psychiatric illness, cognitive impairment, behavioral issues, or social situation that in the opinion of the investigator will compromise the participant's ability to comply with study procedures
• Patient has a known hypersensitivity to any components of the IMPs or any of their excipients that, in the opinion of the investigator, suggests a high risk for a severe hypersensitivity reaction while on treatment.
• Any other condition not specified above that in the opinion of the investigator would confound the interpretation of data from the study
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Lab values

• eGFR \< 20 mL/min/1.73m2 at screening.
• Serum potassium \>5.2 mmol/L at screening.

Other

• Participant is pregnant or lactating or plans to become pregnant during the study or up to 2 weeks after the study.

• Participant is aged ≥18 years.
• Participant provides informed consent to participate in the study in accordance with ICH-GCP and local legislation prior to any study procedures taking place.
• Women of childbearing potential (WOCBP) must agree to use a highly effective method of birth control per ICH M3 (R2) that results in a low failure rate of \<1% per year when used consistently and correctly.
• Participant has chronic HF diagnosed ≥3 months before enrollment, and in New York Heart Association (NYHA) class II-IV.
• Participant has LVEF \>40% in the 12 months prior to enrollment.
• N-terminal pro-B type natriuretic peptide (NT-proBNP) must be:
  • NT-proBNP level (kg/m²) BMI \<27 (kg/m²) BMI ≥27 to \<35 BMI ≥35 Without AF or AFL Non-Black participants ≥300 pg/mL ≥200 pg/mL ≥125 pg/mL Black Participants ≥240 pg/mL ≥160 pg/mL ≥100 pg/mL With AF or AFL Non-Black participants ≥600 pg/mL ≥400 pg/mL ≥250 pg/mL Black Participants ≥480 pg/mL ≥320 pg/mL ≥200 pg/mL Abbreviations: AF: atrial fibrillation; AFL: atrial flutter. Note: Race is self-reported.
• Participants must have ≥1 of the following:
  • Currently treated with diuretic therapy (e.g. loop diuretics or thiazides) and on a stable dose for ≥1 week prior to enrollment.
  • Currently treated with an SGLT2 inhibitor and on a stable dose for at ≥1 week prior to enrollment; those receiving an SGLT2 inhibitor for treatment of diabetes mellitus will be monitored for need of extra glucose lowering treatment by the study investigator in conjunction with the local physician during the washout period per usual care.
  • Documented hospitalization for HF within 6 months prior to enrollment.
  • Elevated cardiac filling pressures (e.g. pulmonary capillary wedge pressure ≥15 mm at rest or ≥25 mm with exercise) within 6 months prior to enrollment.
  • Markedly elevated NT-proBNP
  • In participants without AF/AFL: ≥900 pg/mL
  • In participants with AF/AFL: ≥1800 pg/mL
  • UACR ≥30 mg/g.
  • At least 2 echocardiographic cardiac structural changes from the following:
  • Left ventricular hypertrophy
  • E/e' ≥9
  • Left atrial volume index \>33 mL/m2