Efficacy of ARNIs on hard renal outcomes in heart failure with and without chronic kidney disease: when endpoint definition matters-an updated meta-analysis.

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 analysed 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 (risk ratio [RR] 0.68, 95% confidence interval [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 favourable 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.