Renal Outcomes of Sacubitril/Valsartan Compared with Valsartan Under Triple Whammy Exposure in Heart Failure Patients: A Retrospective Observational Study

• Triple Whammy exposure was associated with early increases in serum creatinine in patients with heart failure. • Sacubitril/valsartan was associated with smaller relative increases in serum creatinine compared with valsartan. • Higher loop-diuretic–equivalent dose was independently associated with acute kidney injury. • Sacubitril/valsartan use was not independently associated with acute kidney injury in Firth logistic regression analysis. • These findings highlight the importance of diuretic intensity in renal vulnerability under Triple Whammy exposure. Background: The concurrent use of renin–angiotensin–aldosterone system (RAAS) inhibitors, diuretics, and nonsteroidal anti-inflammatory drugs (NSAIDs), known as the “Triple Whammy (TW),” increases the risk of acute kidney injury (AKI). Sacubitril/valsartan has demonstrated favorable renal effects in heart failure populations; however, its impact under Triple Whammy exposure remains unclear. Methods: This single-center retrospective observational study included patients with heart failure receiving valsartan or sacubitril/valsartan in combination with diuretics who were newly prescribed an NSAID between May 2013 and July 2024. Changes in serum creatinine (SCr) within 30 days after NSAID initiation were compared between groups. Multivariable linear regression was performed to identify determinants of relative SCr change. Factors associated with AKI, defined as an increase in SCr ≥0.3 mg/dL, were evaluated using multivariable logistic regression with Firth’s penalized likelihood method to address sparse event counts. Results: A total of 168 patients were included (valsartan, n=71; sacubitril/valsartan, n=97). The sacubitril/valsartan group had a higher diuretic burden at baseline. Despite this, relative increases in SCr were significantly smaller compared with the valsartan group. In multivariable linear regression analysis, higher loop-diuretic–equivalent dose was independently associated with greater SCr elevation, whereas sacubitril/valsartan use was associated with smaller relative SCr increases. In Firth logistic regression analysis, higher loop-diuretic dose was independently associated with AKI, while sacubitril/valsartan use was not significantly associated with AKI. Conclusions: Under Triple Whammy exposure, sacubitril/valsartan was associated with smaller early increases in SCr compared with valsartan, while diuretic intensity emerged as a consistent determinant of renal deterioration. Although causality cannot be established, these findings highlight the importance of volume management and support further prospective investigation.