Letter Regarding the Article ‘Efficacy and Safety of Angiotensin Receptor–Neprilysin Inhibition in Heart Failure Patients with End-Stage Kidney Disease on Maintenance Dialysis: A Systematic Review and Meta-Analysis’

We read with great interest the article by Nguyen et al.1 on the efficacy and safety of angiotensin receptor–neprilysin inhibitors (ARNIs) in heart failure (HF) patients with end-stage kidney disease (ESKD) on maintenance dialysis. This systematic review and meta-analysis provide valuable insights into a population often excluded from landmark trials, addressing a critical gap in evidence-based management of HF in ESKD patients. However, we would like to highlight several considerations that warrant further discussion and exploration. First, while the study demonstrates the potential benefits of ARNI in reversing cardiac remodelling and improving left ventricular function, the heterogeneity in the included studies regarding dialysis modalities (haemodialysis vs. peritoneal dialysis) and HF subtypes (HF with reduced, mildly reduced, and preserved ejection fraction) may limit the generalizability of the findings. For instance, peritoneal dialysis patients often have different haemodynamic profiles and fluid management challenges compared to those on haemodialysis, which could influence the efficacy and safety of ARNI therapy.2 We believe it is necessary for the authors to stratify the results according to dialysis modality in order to provide more targeted recommendations. Second, the pharmacokinetics of sacubitril/valsartan in ESKD patients remain an area of concern. Sacubitril and valsartan are both partially renally excreted, and while the authors reference studies suggesting safety in this population, the potential for drug accumulation and its clinical implications, particularly in peritoneal dialysis patients, requires further investigation. A recent pharmacokinetic study by Judge et al.3 highlighted the need for careful dose adjustments in this subgroup. This underscores the importance of individualized dosing strategies to optimize efficacy while minimizing adverse effects. Third, while the meta-analysis reports favourable safety outcomes, including a low incidence of severe hyperkalaemia and symptomatic hypotension, it is important to note that these adverse events are often underreported in observational studies. Given the high baseline risk of hyperkalaemia and hypotension in ESKD patients, particularly those on renin–angiotensin–aldosterone system inhibitors, robust prospective trials with standardized adverse event reporting are essential to confirm these findings. In conclusion, Nguyen et al. have provided a significant contribution to the understanding of ARNI therapy in a challenging patient population. We advocate for future research to address the pharmacokinetics, dialysis modality-specific outcomes, and long-term safety of ARNIs in ESKD patients.