Vagal nerve stimulation did not meet the primary endpoint of reduced cardiovascular death or HF hospitalizationTrial shows vagal nerve stimulation for heart failure patients

This randomized controlled trial investigated the impact of vagal nerve stimulation (VNS) on patients diagnosed with heart failure and reduced ejection fraction (HFrEF). The study population included 532 patients meeting specific criteria: NYHA functional class II or III, LVEF ≤35%, and NT-proBNP ≥800 pg/mL. The primary objective was to determine if VNS could reduce the time to cardiovascular death or heart failure (HF) hospitalization compared to a control group.

The intervention involved vagal nerve stimulation, while the comparator was a standard control group. While specific dosing and protocol details were not fully detailed in the summary data, the study focused on assessing autonomic engagement and clinical outcomes in this high-risk population. The trial was terminated by the sponsor for reasons unrelated to futility or efficacy.

Regarding primary outcome results, the study did not meet its primary endpoint of reducing time to cardiovascular death or HF hospitalization. The reported hazard ratio (HR) was 0.84, but the 95% confidence interval (CI) was 0.62-1.12, resulting in a p-value of 0.115. Because this result did not reach statistical significance, the primary efficacy endpoint is considered neutral.

Secondary outcomes included LVEF, 6-minute walk distance, Kansas City Cardiomyopathy Questionnaire scores, and NYHA functional class. The results for LVEF were reported as unchanged. Other secondary measures, including HF hospitalization, Kansas City Cardiomypathy Questionnaire, NYHA functional class, and 6-minute walk distance, were described as favorable but inconclusive. These findings are considered hypothesis-generating due to the underpowered nature of the study design and issues related to multiplicity.

Safety data indicated a high level of procedural safety, with 96.7% freedom from procedure- or device-related serious adverse events. However, specific rates for common adverse events were not reported. The trial's early termination by the sponsor was noted as unrelated to the efficacy or futility of the intervention.

When compared to landmark studies in heart failure management, such as those involving SGLT2 inhibitors or ARNIs, these results do not provide a definitive alternative or addition to current standard-of-care guidelines. While some secondary parameters showed favorable trends, they lack the statistical power to influence immediate clinical guidelines.

Several methodological limitations impacted the strength of the findings, including an underpowered primary endpoint, premature trial termination, and potential for subjective bias. The multiplicity of secondary endpoints further complicates the interpretation of those results. Consequently, the data are currently viewed as hypothesis-generating regarding autonomic engagement in HFrEF.

In clinical practice, these results suggest that while VNS is feasible and appears safe, it does not currently provide a statistically significant reduction in primary mortality or hospitalization for HFrEF patients. The study highlights the need for further research to clarify the role of autonomic modulation. Questions remain regarding the optimal timing for intervention and the specific mechanisms by which VNS might influence secondary symptoms or functional capacity.