ESC Heart Fail. 2026 Jun 5:xvag148. doi: 10.1093/eschf/xvag148. Online ahead of print.
ABSTRACT
BACKGROUND: The renal effects of sacubitril/valsartan (Sac/Val) in heart failure (HF) remain incompletely defined, partly because kidney outcomes in pivotal HF trials have been variably prespecified and heterogeneously defined. We performed an updated systematic review and meta-analysis to assess whether the apparent renal signal of Sac/Val varies according to endpoint definition.
METHODS: This updated systematic review was conducted in accordance with PRISMA 2020. Building on the pre-existing evidence base from prior meta-analyses, we performed an updated search of PubMed and Web of Science. Randomized controlled trials (RCTs) and observational comparative studies in adults with HF comparing Sac/Val with angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or standard care were included if renal outcome data were extractable. Renal outcomes were analyzed using a hierarchical cross-endpoint approach, including sustained ≥50% estimated glomerular filtration rate (eGFR) decline, end-stage kidney disease (ESKD), composite kidney outcomes, and annualized eGFR decline. Random-effects meta-analysis was performed, with Hartung-Knapp and RCT-only sensitivity analyses.
RESULTS: Overall, 13 study-level reports comprising 34,969 patients were included. Sac/Val was associated with a lower risk of sustained 50% eGFR decline (RR 0.68, 95% CI 0.57-0.82) and composite kidney outcome (RR 0.70, 95% CI 0.58-0.84), with the composite endpoint showing the most robust and consistent signal, including in RCT-only analyses. By contrast, the association for ESKD alone was directionally favorable but not statistically significant (RR 0.80, 95% CI 0.64-1.00). Sac/Val was also associated with a slower annualized eGFR decline (MD 0.52 mL/min/1.73 m2/year, 95% CI 0.35-0.69).
CONCLUSIONS: The renal signal associated with Sac/Val in HF appeared at least partly dependent on endpoint definition. Composite kidney outcomes may best capture its potential nephroprotective effect, with sustained 50% eGFR decline showing a consistent pattern, whereas isolated ESKD remains inconclusive. These findings support a potential nephroprotective role of ARNIs but future research are needed.
PMID:42247581 | DOI:10.1093/eschf/xvag148