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

Effect on Clinical Status, Structural and Functional Cardiac Parameters and Myocardial Fibrosis of Triple Combination Therapy With a Sodium-glucose Cotransporter 2 Inhibitor, Angiotensin Receptor/Neprilysin Inhibitor and Mineralocorticoid Receptor Antagonist in Patients With 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

Study Overview

• Status: Recruiting
• Conditions: Myocardial Fibrosis; HFpEF; LVDD
• Intervention / Treatment: Drug: [SGLTi + previously taken RAAS blocker]; Drug: [ARNI + SGLTi + AMR]

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 50
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Artem G Ovchinnikov, MD, PhD, DSc; Phone Number: +74954146612; Email: artcardio@mail.ru

Study Locations

• Russia
  • Moscow, Russia
    • Recruiting
    • National Medical Research Center for Cardiology, Ministry of Health of Russian Federation
    • Contact: Artem G Ovchinnikov,, MD, PhD, DSc; Phone Number: +74954146612; Email: artcardio@mail.ru

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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%

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: [ARNI + SGLTi + AMR]; Patients will receive combination therapy with ARNI, gliflozin and AMR	Drug: [ARNI + SGLTi + AMR]; Empagliflozin 10mg tablet, Valsartan+Sacubitril 100-200-400 mg tablet, Finerenone 20-40 mg tablet
Active Comparator: [SGLTi + previously taken RAAS blocker]; Patients will receive combination therapy with gliflozin and previously taken RAAS blocker	Drug: [SGLTi + previously taken RAAS blocker]; Empagliflozin 10mg tablet, previously taken RAAS inhibitor

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in myocardial extracellular volume (MRI)	Difference in myocardial extracellular volume assessed by MRI data between 52 weeks after baseline and at baseline	52 weeks
Change in 6-minute walking distance (6MWD)	Difference in distance walked during 6-minute walking test (6MWT) between 52 weeks after baseline and at baseline	52 weeks
Change in N-terminal pro b-type natriuretic peptide (NT-proBNP)	Difference in NT-proBNP plasma levels between 52 weeks after baseline and at baseline	52 weeks
Change in average E/e' ratio and tricuspid regurgitation velocity	Difference in E/e' ratio and tricuspid regurgitation velocity assessed by echocardiography both at rest and at peak exercise during diastolic stress test (DST) between 52 weeks after baseline and at baseline	52 weeks
Change in left atrial volume index (LAVi)	Difference in LAVi assessed by echocardiography between 52 weeks after baseline and at baseline	52 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in left ventricular mass index (LVMi)	Difference in LVMi assessed by MRI between 52 weeks after baseline and at baseline	52 weeks
Change in biomarkers of inflammation and fibrosis	Difference in plasma levels of inflammatory and fibrosis biomarkers (hsCRP, GDF-15, PICP, galectin-3, MCP-1) between 52 weeks after baseline and at baseline	52 weeks
Change in Minnesota Living with Heart Failure Questionnaire (MLHFQ) score	Difference in Minnesota Living with Heart Failure Questionnaire (MLHFQ, potential scoring range between 0 and 105; higher scores mean a worse outcome) score between 52 weeks after baseline and at baseline	52 weeks
Change in Kansas City Cardiomyopathy Questionnaire (KCCQ) score	Difference in Kansas City Cardiomyopathy Questionnaire (KCCQ; a range of possible subscale scores is from 0 to 100, with 100 representing the least burden of symptoms. The total KCCQ score represents the mean of the three subscale scores) score between 52 weeks after baseline and at baseline	52 weeks
Change in cardiac hemodynamic reserves - LV contractile	Difference in cardiac hemodynamic reserves (LV contractile) during DST between 52 weeks after baseline and at baseline	52 weeks
Change in cardiac hemodynamic reserves - LV diastolic	Difference in cardiac hemodynamic reserves (LV diastolic) during DST between 52 weeks after baseline and at baseline	52 weeks
Change in cardiac hemodynamic reserves - LA reservoir	Difference in cardiac hemodynamic reserves (LA reservoir) during DST between 52 weeks after baseline and at baseline	52 weeks
Change in cardiac hemodynamic reserves - cardiac chronotropic	Difference in cardiac hemodynamic reserves (cardiac chronotropic) during DST between 52 weeks after baseline and at baseline	52 weeks
Change in cardiac hemodynamic reserves - RV contractile	Difference in cardiac hemodynamic reserves (RV contractile) during DST between 52 weeks after baseline and at baseline	52 weeks

Collaborators and Investigators

• Sponsor: National Medical Research Center for Cardiology, Ministry of Health of Russian Federation
• Collaborators: Lomonosov Moscow State University Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): March 18, 2025
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): December 31, 2027

Study Registration Dates

• First Submitted: October 21, 2024
• First Submitted That Met QC Criteria: October 21, 2024
• First Posted (Actual): October 23, 2024

Study Record Updates

• Last Update Posted (Actual): April 24, 2026
• Last Update Submitted That Met QC Criteria: April 21, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: diastolic dysfunction; HF; HFpEF; left ventricular hypertrophy; myocardial fibrosis; LV filling pressures; cardiac reserves
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Pathological Conditions, Anatomical; Heart Diseases; Cardiomegaly; Hypertrophy; Pathological Conditions, Signs and Symptoms; Hypertrophy, Left Ventricular
• Other Study ID Numbers: 124020200111-6

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No