• Low-Gradient aortic stenosis; Heart Failure
• Aortic Stenosis; Low-Flow

Background
Severe aortic stenosis (AS) stands as the most prevalent valvular heart disease in Western countries,
primarily due to the aging population. Low-flow, low-gradient AS (LFLG-AS) is diagnosed
echocardiographically by an aortic valve area (AVA) <1 cm2 or an indexed AVA ≤0.6 cm2/m2, a mean
transaortic gradient <40 mm Hg, a left ventricular ejection fraction (LVEF) < 50%, and a stroke volume
index <36 mL/m2. Managing patients with LFLG-AS solely through medication results in poor outcomes,
emphasizing the need for effective interventions. Transcatheter aortic valve replacement (TAVR) has
emerged as a potential treatment for LFLG-AS patients, offering safety and symptom improvement
comparable to high-gradient cases. Guideline-directed medical therapy (GDMT) for heart failure,
involving beta-blockers, renin-angiotensin system inhibitors, and mineralocorticoid receptor antagonists, is recommended. However, the long-term effects and optimal drug combinations in the context of post-aortic valve disease remain poorly explored. Challenges such as arterial hypotension, chronic kidney disease, hyperkalemia, and bradycardia often limit the use of multiple drugs simultaneously.

Objectives
The objective of this study is to investigate the prognostic implications of triple GDMT in patients with LFLG-AS undergoing TAVR. The research aims to shed light on the effectiveness and safety of
combining these medications in this specific patient population, addressing crucial questions about
dosage and drug selection. This study seeks to fill the existing knowledge gap, providing valuable
insights into the management of LFLG-AS after TAVR.

Methods
This observational study focused on symptomatic patients diagnosed with LFLG-AS who underwent
TAVR at five leading medical centers in Italy. LFLG-AS was defined using established criteria, including specific measurements related to AVA and gradients. Diagnostic uncertainties were resolved using computed tomography assessments. Patients were selected for TAVR after a comprehensive evaluation process involving surgical risk assessment, clinical evaluation, and detailed echocardiographic and computed tomography analyses. Patients' follow-up data, including survival, functional status, medical treatments, and echocardiographic results, were continuously monitored following established guidelines. The primary study outcome was a combination of all-cause mortality and hospitalization due to worsening heart failure over a 5-year period. Therapy was categorized into "GDMT+" if they received triple therapy involving beta-blockers (BB), renin-angiotensin system inhibitors (RASi), and mineralocorticoid receptor antagonists (MRA). "GDMT−" indicated the absence of one or more of these drug classes. To qualify as 'GDMT+', patients had to be on triple therapy for at least one year post-discharge.

Results
Among the approximately 5,000 patients who underwent TAVR at the five medical centers from 2008 to
2023, 438 individuals had detailed medical therapy records and a left ventricular ejection fraction (LVEF) of 40% or below. Out of this group, 126 patients were receiving guideline-directed medical therapy, which comprised beta-blockers, renin-angiotensin system inhibitors, and mineralocorticoid receptor antagonists. Notably, these patients demonstrated significantly higher 5-year survival rates and lower rehospitalization rates in comparison to the 312 patients who were not on GDMT (p<0.00001).
Additionally, the study revealed that GDMT independently predicted a combined outcome of all-cause
mortality and hospitalization due to worsening heart failure. Patients on GDMT had a hazard ratio of 0.57 (95% confidence interval 0.41-0.79; p=0.01) in comparison to those not on GDMT, indicating a
substantial reduction in risk. This positive association between GDMT and improved outcomes remained
consistent across all cases analyzed.

Conclusion
In individuals diagnosed with low-flow, low-gradient aortic stenosis and a left ventricular ejection fraction of 40% or lower, undergoing transcatheter aortic valve replacement, the adoption of guideline-directed medical therapy is associated with a significant 43% reduction in the risk of combined outcomes, including mortality and heart failure-related readmissions, spanning a 5-year duration.