ABSTRACT
Introduction
Left ventricular (LV) hypertrophy and dysfunction secondary to aortic stenosis (AS) are key components of the disease’s underlying pathophysiology. Previous trials suggest that up to 1/3 of patients do not benefit symptomatically after aortic valve replacement (AVR), which could be explained by insufficient LV remodeling. Sodium‒glucose cotransporter-2 (SGLT2) inhibitors are effective in heart failure (HF) and have been shown to improve LV remodeling (change in LV mass).
Methods
The EMPAVR study is an investigator-initiated, randomized, placebo-controlled, and double-blinded trial comparing the effect of empagliflozin to placebo in patients with severe and symptomatic AS undergoing transcatheter aortic valve implantation (TAVI).
The primary outcome for the EMPAVR trial is the difference in LV mass indexed to body surface area (measured by cardiac CT) from pre-AVR to 6 months post-AVR. Patients are randomized in a 1:1 ratio to 180 days of treatment.
Discussion
To the best of our knowledge, the EMPAVR study is the first placebo-controlled trial investigating the effects of SGLT2 inhibition in patients following TAVI because of AS. The EMPAVR study has the potential to pave the way for treatment of the LV in valvular heart disease and may help patients worldwide and expand our understanding of aortic stenosis.
Trial registration
The EMPAVR study was registered in December 2024 ( Clinical Trial Registration number: NCT06171802 ) before enrollment of the first patient. All patients will provide oral and written informed consent. The EMPAVR study is approved by the Regional Committee on Health Research Ethics and the Danish Medicines Agency.
Left ventricular (LV) hypertrophy and dysfunction secondary to aortic stenosis (AS) are key components of the disease’s underlying pathophysiology, including both systolic and diastolic dysfunction. pre and postaortic valve replacement (AVR)-related LV remodeling may be important in improving patient outcomes. Previous randomized clinical trials suggest that approximately 1/3 of the patients with AS experience no symptomatic improvement within 1 year after AVR, regardless of treatment mode (transcatheter aortic valve implantation [TAVI] or surgical aortic valve replacement). The lack of improvement may be explained partially by delayed or impaired LV remodeling. AS is not only a valvular disease; consequently, more focus should be placed on the LV. Currently, patients are selected for valve replacement based on echocardiographic assessment of the valve and the presence of symptoms (dyspnea, angina, fatigue, and edema) , ; however, symptoms are not necessarily a reliable indicator of LV conditioning. Magnetic resonance studies have demonstrated LV scarring in up to 50% of patients with severe AS. , This remodeling process could be an additional therapeutic target AS. In addition, LV remodeling and hypertrophy in AS are established prognostic markers, further underscoring their relevance. Targeting LV hypertrophy and remodeling before AVR may therefore represent a potential therapeutic strategy for improving outcomes.
Sodium–glucose cotransporter-2 (SGLT2) inhibitors are effective in heart failure (HF) and significantly reduce HF hospitalizations. Strong evidence supports their use in HF with reduced ejection fraction (HFrEF), including reductions in mortality. , In the Studies of Empagliflozin and Its Cardiovascular, Renal and Metabolic Effects in Patients With Diabetes Mellitus and Heart Failure (SUGAR-DM-HF) trial and in the Empagliflozin in Heart Failure Patients With Reduced Ejection Fraction (EMPIRE-HF trial), , SGLT2 inhibition improved LV remodeling (LV size). Both randomized trials were performed in patients with nonvalvular HFrEF. SGLT2 inhibitors are also recommended for patients with heart failure with preserved ejection fraction (HFpEF) and may improve LV remodeling. , A significant overlap exists patients with AS and those with HFpEF, as many patients with AS may exhibit a hypertrophic and fibrotic LV. After TAVI, LV recovery may be incomplete; consequently, persistent LV dysfunction may explain the lack of symptomatic relief in a subset of patients. In the recently published DapaTAVI trial, an unblinded randomized study evaluating dapagliflozin in patients undergoing TAVI with a high risk of HF events, dapagliflozin significantly reduced the incidence of death and HF related hospitalization. However, the study was not placebo-controlled and did not include mechanistic outcomes. Thus, robust randomized, placebo-controlled evidence is needed to examine the efficacy of SGLT2 inhibition in patients undergoing TAVI.
The Empagliflozin after Aortic Valve Replacement (EMPAVR) trial is a double-blind, placebo-controlled randomized study designed to assess whether SGLT2 inhibition after TAVI is superior to placebo in reducing LV mass. Secondary outcomes include, among others, changes in symptoms and N-terminal pro‒B-type natriuretic peptide.
We hypothesize that SGLT2 inhibition will substantially reduce LV mass at 6 months post-AVR compared with placebo and improve symptoms for more patients.
Methods
Study design
The EMPAVR trial (NCT06171802) is an investigator-initiated, randomized, placebo-controlled, and double-blinded trial comparing the effect of empagliflozin to placebo in patients with severe and symptomatic AS undergoing TAVI, aiming to include 206 patients.
After TAVI, eligible patients will be randomized in a 1:1 ratio to 180 days/6 months of treatment with either empagliflozin (10 mg) or placebo. Glostrup Pharmacy performed the preliminary draw by labelling the containers containing the capsules with a number randomized through “ www.sealedenvelope.dk ” with varying block sizes (4, 6, and 8 patients). The actual randomization occurred when a container with tablets was given to the patient before discharge. All patients will be analyzed according to the Intention-To-Treat (ITT) principle. The time from the randomization to the start of the allocated treatment will be as short as logistically possible.
The treatment is blinded to both patients and the healthcare staff involved. The investigational medical product is empagliflozin 10 mg or a matching placebo. The identification of each treatment will be kept by Glostrup Pharmacy until the end of the study. Authorized site staff will be provided with sealed opaque envelopes with treatment allocation for emergency unblinding. Unblinding is only done when knowledge of the treatment is essential for the continued treatment of the participant or if needed for safety reporting to regulatory authorities.
Study setting
The EMPAVR trial will be conducted at Rigshospitalet, Copenhagen University Hospital, Denmark. Eligible patients will be identified through the pre-TAVI outpatient clinic, where initial study information will be provided. The final consent from the patient will typically be given 1 to 3 days before the TAVI procedure, and the randomization requires that TAVI is performed and will take place after the procedure and before discharge. Patients will follow the course outlined in Figure 1 .
The course of the EMPAVR study. After the TAVI procedure patients are randomized 1:1 to either active drug (empagliflozin) or placebo. At 1 month, patients are contacted by phone for the first follow-up. At 3 months, patients attend the second follow-up visit, which includes blood sampling, blood pressure measurement, and ECHO. At 6 months after discharge following TAVI, patients attend the final follow-up visit, which includes blood sampling, ECG, blood pressure measurement, ECHO, and cardiac CT. Created in http://www.biorender.com/ . Abbreviations: CT, computed tomography; ECG, electrocardiogram; ECHO, echocardiography; TAVI, transcatheter aortic valve implantation.
Study population/participants
Eligible patients are those with symptomatic severe AS (including dyspnea, angina, fatigue, and edema), defined by peak aortic jet velocity (Vmax) >4 m/s, mean transvalvular gradient >40 mmHg, and aortic valve area ≤1.0 cm², , who are referred for AVR within 3 months. Patients with concomitant coronary artery disease, including prior coronary artery bypass grafting and percutaneous intervention (PCI), will be included. As part of standard care, all patients undergoing TAVI undergo preprocedural evaluation for coronary artery disease, and significant stenosis is assessed at a joint multidisciplinary team conference regarding both TAVI and potential PCI indications, and treated with either PCI or medical therapy. Concomitant valvular heart disease (such as mitral insufficiency, mitral stenosis, or tricuspid regurgitation) does not preclude inclusion if AS is deemed the primary cause of symptoms. Patients with a history of AVR are excluded, as this group was expected to be small and to have a potentially different disease etiology. Participation in other studies is allowed, provided it does not delay or change the allocated treatment in EMPAVR or include SGLT2 inhibitor treatment. The complete inclusion and exclusion criteria are presented in Table 1 . All patients referred to the pre-TAVI outpatient clinic will be screened. The medical history will be reviewed, and an assessment of the inclusion and exclusion criteria will be performed. Patients not eligible for the EMPAVR trial will receive standard-of-care treatment after the AVR procedure, including routine follow-up visits.
Table 1
Inclusion and exclusion criteria for the EMPAVR study
| Inclusion criteria | Exclusion criteria |
|---|---|
|
Severe symptomatic aortic stenosis
AND Transcatheter aortic valve implantation within 3 mo of informed consent (to allow for local changes over time in the waiting period for the procedure) |
• Prior treatment with a sodium-glucose cotransporter-2 (SGLT2) inhibitor
• Left ventricular ejection fraction <45% • eGFR <30mL/min • Hypersensitivity to empagliflozin or the placebo tablet • Type 1 diabetes or other diseases with contraindication for SGLT2 inhibition • Patients who do not understand Danish or English • Women who are pregnant, nursing, or plan to become pregnant during the trial |
eGFR , estimated Glomerular Filtration Rate; SGLT2 , sodium-glucose cotransporter-2.
Schedule of enrollment, intervention, and blinding
The follow-up cardiac computed tomography (CT) scan assessing the primary study outcome will be performed at 6 months post-TAVI, whereas other study outcomes will be assessed at discharge and 3 and 6 months post-TAVI. Blood samples and ECGs will be part of the visits, alongside standardized symptom-scoring tools (KCCQ-12, MLHFQ, and NYHA classification). Follow-up and corresponding visits will be conducted as outlined in Table 2 .
Table 2
Plan for follow-up visits and examinations
| Pre-AVR ⁎ | AVR ⁎ | Discharge ⁎ | 1-mo ‡ | 3-mo ⁎ , § | 6-mo ⁎ , § | |
|---|---|---|---|---|---|---|
| Medical history | X | |||||
| Clinical assessment, vitals, and symptoms | X | X | X | X | ||
| Procedural specification | X | |||||
| Blood samples | X | X | X | X | ||
| ECG | X | X | X | |||
| Transthoracic echocardiography | X | X | X | X | ||
| CT angiogram/ LV mass | X | X | ||||
| Medical compliance assessment | X † | X | X |
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