Triple Combination Therapy (ARNI, SGLT2i, MRA) in Advanced HFpEF

Patients with advanced heart failure with preserved ejection fraction (HFpEF) will be randomly assigned in open-label multicenter study to receive triple combination therapy with \[angiotensin receptor/neprilysin inhibitor \[ARNI\] + sodium-glucose cotransporter 2 inhibitor \[SGLTi\] + mineralocorticoid receptor antagonist \[MRA\]) or with individualized medical therapy \[SGLTi + renin-angiotensin system inhibitor \[RASi\] \[angiotensin receptor blocker \[ARB\] or angiotensin-converting enzyme inhibitor \[ACE-I\]), and will be treated for 52 weeks

HFpEF has a significant morbidity and mortality, and the therapeutic options for HFpEF are limited. According to the results of clinical HFpEF trials, SGLTis and MRA can improve prognosis (EMPEROR-preserved, DELIVER, FINEARTS-HF trials); and ARNI can reduce the risk of hospitalization due to exacerbation of heart failure (PARAGON-HF trial). There is also clinical and experimental evidence of anti-inflammatory and antifibrotic effects in SGLTi, MRA and ARNI. However, there are currently no randomized clinical trials evaluating the efficacy of the combination therapy with all these drugs in HFpEF. The investigators suppose that triple combination therapy with \[ARNI + SGLTi + AMR\] in HFpEF will have a pronounced, rapid and safe positive clinical and haemodynamic effect primarily through its effect on fibrosis and inflammation in patients with HFpEF.

Inclusion Criteria: 1. Signed and data informed consent; 2. Symptoms and signs of HF; 3. LV ejection fraction \> 50%; 4. NT-proBNP \> 300 pg/mL (for patients with atrial fibrillation NT-proBNP \> 900 pg/mL) 5. LV diastolic dysfunction II-III grade OR LV diastolic dysfunction I grade and at least 2 out of 4: * Е/е' \> 14 * LAVi \> 34 ml/m2 (for those with persistent atrial fibrillation \> 40 ml/m2) * PASP \> 35 mm Hg or TR velocity \> 2.8 m/sec * LV mass index \> 95 g/m2 for women / \> 115 g/m2 for men or LV interventricular septum or posterior wall thickness ≥ 1.1 sm OR Chronic atrial fibrillation and at least 3 out of 4: * Е/е' \> 11 * E-wave velocity \> 100 sm/s * TR velocity \> 2.8 sm/s * DT ≤ 160 ms Exclusion Criteria: 1. Evidence of myocardial ischemia during stress echocardiography; 2. Significant lesions of main coronary arteries; 3. Atrial fibrillation with resting HR \> 110 beats/min; 4. Continuous (\>90 days) treatment with ARNI, SGLTi and/or AMR within 12 months prior to screening. The last administration of these drugs must be at least 30 days prior to randomization. Treatment with these drugs should not be interrupted for the purpose of inclusion in the study. 5. Coronary bypass surgery, stroke or TIA within the last 3 months of screening; 6. Myocardial infarction or myocardial revascularization within the last 3 months of screening; 7. Systolic blood pressure \< 90 mmHg or ≥ 180 mmHg at screening or randomization; 8. Genetic forms of HFpEF (HCM, amyloidosis, Fabry disease, glycogen storage diseases etc.); 9. Peripartum cardiomyopathy, chemotherapy-induced cardiomyopathy, viral myocarditis, isolated right-sided HF without left-sided structural disease, constrictive pericarditis, significant pericardial effusion; 10. Dyspnea due to non-cardiac causes such as pulmonary disease, anemia, severe obesity, primary valvular, or myocardial diseases; 11. Significant lung disease (severe lung disease requiring home oxygen or chronic oral steroid therapy); 12. Primary pulmonary artery hypertension; 13. Significant left sided structural valve disease; 14. Anemia (Hb \< 100 g/L); 15. Obesity (body mass index \> 50 kg/m2); 16. Impaired renal function, defined as estimated glomerular filtration rate (eGFR) \<30 mL/min/1.73 m2 (CKD-EPI); 17. Impaired liver function (serum levels of alanine aminotransferase, aspartate aminotransferase, or alkaline phosphatase above 3 × upper limit of normal); 18. Addison's disease; 19. Known hypersensitivity to medications used the in the study; 20. Non-cardiac conditions that complicate/exclude participation in the study; 21. Diseases associated with isolated LV insufficiency (idiopathic pulmonary hypertension, chronic thromboembolic pulmonary hypertension, etc.); 22. Serum/plasma potassium \>5.0 mmol/L at screening or randomization or a history of hyperkalemia or acute renal failure during AMR treatment for \>7 consecutive days leading to discontinuation of AMR treatment. 23. For patients with diabetes mellitus: * Type 1 diabetes mellitus; * Presence of more than 4 episodes of moderate hypoglycemia within the past month or at least one episode of severe hypoglycemia within the past year; * Glycated hemoglobin level \> 9% or \<6%