Triple-drug therapy (ARNI + SGLT2 inhibitor + MRA) for 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

This study will test whether giving an ARNI together with an SGLT2 inhibitor and an MRA helps people with advanced HFpEF stay healthier over 52 weeks compared with individualized medical therapy.

Quick facts

• Phase: PHASE2
• Study type: Interventional
• Enrollment: 50 (estimated)
• Ages: 40 Years to 80 Years
• Sex: All
• Sponsor: National Medical Research Center for Cardiology, Ministry of Health of Russian Federation (other gov)
• Drugs / interventions: chemotherapy
• Locations: 1 site (Moscow)
• Trial ID: NCT06655480 on ClinicalTrials.gov

What this trial studies

This is a randomized, open-label, multicenter Phase 2 trial that will assign patients with symptomatic HFpEF and evidence of diastolic dysfunction to either a triple-drug combination (ARNI + SGLT2 inhibitor + MRA) or individualized therapy (SGLT2 inhibitor plus a RAS blocker) for 52 weeks. Participants must have preserved LVEF (>50%) and elevated NT-proBNP and will undergo clinical, hemodynamic, echocardiographic, and biomarker assessments during follow-up. The investigators hypothesize that the triple combination will produce faster and stronger clinical and hemodynamic improvements largely by reducing inflammation and myocardial fibrosis. Safety and tolerability will be monitored, and comparisons will focus on symptoms, hospitalizations, functional measures, and biomarkers of cardiac stress and fibrosis.

Who should consider this trial

Good fit: Ideal candidates are adults with symptomatic HFpEF (LVEF >50%), elevated NT-proBNP and echocardiographic evidence of diastolic dysfunction who can consent and attend the study visits.

Not a fit: Patients with evidence of myocardial ischemia, significant main coronary artery disease, uncontrolled atrial fibrillation (resting HR >110 bpm), or recent continuous treatment with ARNI, SGLT2 inhibitors, or MRAs are excluded and unlikely to benefit from this protocol.

Why it matters

Potential benefit: If successful, the combination could reduce symptoms and hospitalizations and may slow or reverse myocardial fibrosis and inflammation in patients with HFpEF.

How similar studies have performed: Large randomized trials have shown benefits of SGLT2 inhibitors and MRAs and some ARNI benefits for HFpEF-related outcomes, but no randomized study has tested all three drug classes together.

Eligibility criteria

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%

Where this trial is running

Moscow

• National Medical Research Center for Cardiology, Ministry of Health of Russian Federation — Moscow, Russia (RECRUITING)

Study contacts

• Study coordinator: Artem G Ovchinnikov, MD, PhD, DSc

Conditions: HFpEF, LVDD, Myocardial Fibrosis, HF, left ventricular hypertrophy, diastolic dysfunction, cardiac reserves, LV filling pressures