The combined use of RAAS inhibitors and diuretics is a cornerstone of pharmacologic therapy for heart failure. In routine clinical practice, however, NSAIDs are frequently prescribed, often by other specialties. As a result, all three drug classes are sometimes administered concurrently, leading to the so-called “triple whammy.” This combination is associated with an increased risk of renal hemodynamic compromise. Mechanistically, TW represents the convergence of efferent arteriolar dilation caused by RAAS inhibitors, reductions in circulating plasma volume due to diuretics, and afferent arteriolar constriction induced by NSAIDs. Acting together, these effects substantially reduce intraglomerular pressure and the glomerular filtration rate (GFR), thereby predisposing patients to prerenal AKI and other forms of renal dysfunction.1–3

Epidemiologic data highlight the clinical relevance of this interaction. Lapi et al. reported that triple therapy increased the 30-day risk of AKI by 1.82-fold (95% CI, 1.35–2.46) compared with dual therapy consisting of a RAAS inhibitor plus a diuretic.4 In addition, a large population-based study from the United Kingdom showed that 8.8% of adults aged 65 years or older received at least one annual NSAID prescription while concurrently using renin–angiotensin system inhibitors and diuretics.5 These findings underscore the need for clinicians and patients to remain aware of the substantial renal hazards associated with NSAID exposure under these conditions. The 2018 Japanese chronic kidney disease (CKD) guidelines similarly recommend avoiding this triple therapy, particularly in older adults and patients with CKD stage G3b or more advanced disease.6 TW-related renal injury has therefore become an increasingly recognized clinical problem, especially among vulnerable populations such as older adults and individuals with heart failure, dehydration, or multiple comorbidities.1,7

Sacubitril/valsartan, an angiotensin receptor–neprilysin inhibitor (ARNI), has recently been introduced into clinical practice and has demonstrated not only superior outcome benefits in heart failure compared with conventional RAAS inhibitors, but also potential renal safety advantages and renoprotective effects.8,9 Meta-analyses involving heart failure patients with CKD have reported that sacubitril/valsartan may attenuate increases in serum creatinine, slow declines in eGFR, and reduce the progression to end-stage renal disease (ESRD).10–12 Real-world studies also suggest that ARNI therapy may maintain or even improve GFR following initiation.13

Despite these accumulating data, a critical knowledge gap remains. No previous studies have examined whether ARNI therapy confers renal benefit specifically under the high-risk pharmacologic conditions of TW, in which NSAIDs are added to RAAS inhibitors (or ARNI) and diuretics. Consequently, it is unclear whether substituting ARNI for a conventional ARB might reduce or prevent renal impairment induced by TW.

To address this gap, the present study compared renal function trajectories and AKI incidence over 30 days following initiation of NSAID therapy in the setting of concomitant RAAS inhibitor and diuretic use between patients treated with conventional ARB therapy (valsartan) and those treated with ARNI (sacubitril/valsartan). Our objective was to compare renal function changes and AKI incidence following TW exposure between patients receiving valsartan and those receiving sacubitril/valsartan, and to evaluate whether ARNI therapy is associated with differential renal effects under these high-risk conditions.

This study investigated the renal effects of sacubitril/valsartan compared with valsartan in patients exposed to the high-risk combination of RAAS inhibition, diuretics, and NSAIDs, which is commonly known as the TW. This represents a novel and clinically relevant perspective because prior research has largely compared RAAS inhibitors in isolation,17 with limited evaluation of real-world prescribing patterns that frequently involve NSAIDs and multiple diuretics. In this retrospective observational study of patients receiving RAAS inhibitors and diuretics who initiated NSAID therapy, sacubitril/valsartan use was associated with smaller relative increases in serum creatinine compared with valsartan. In contrast, higher loop-equivalent diuretic dose was independently associated with greater renal function deterioration. These findings suggest that under triple-drug exposure, diuretic intensity may be a primary determinant of acute renal vulnerability, while the type of RAAS inhibition may modulate early creatinine dynamics.

Prior clinical evidence supports a favorable renal profile of sacubitril/valsartan.13,18,19 However, its renal effects under triple-drug exposure involving NSAIDs, RAAS inhibition, and diuretics remain unclear. Therefore, the present study addresses an important gap in the literature. Although prior randomized trials and meta-analyses have demonstrated a favorable renal profile of sacubitril/valsartan compared with conventional RAAS inhibitors in heart failure populations, these studies did not specifically evaluate patients concurrently exposed to NSAIDs and substantial diuretic burden.10 Given that temporary NSAID use is common in clinical practice, particularly among patients with cardiovascular comorbidities, our analysis provides real-world insight into renal responses under this clinically relevant pharmacologic stress.

Notably, patients receiving sacubitril/valsartan had higher baseline BNP levels and were treated with a greater number of concomitant diuretics, suggesting more advanced heart failure severity. Despite this potentially higher-risk profile, relative increases in serum creatinine were attenuated in this group. Although residual confounding and confounding by indication cannot be excluded, these observations suggest that differences in baseline risk alone are unlikely to fully explain the observed renal findings.

In multivariable analyses, higher loop-equivalent diuretic dose was independently associated with AKI defined by a ≥0.3mg/dL increase in serum creatinine. Sacubitril/valsartan use, however, was not independently associated with overt AKI. The dissociation between smaller relative creatinine changes and unchanged AKI incidence suggests that sacubitril/valsartan may attenuate early or mild renal functional fluctuations without substantially altering the risk of clinically defined AKI. This distinction highlights the importance of evaluating continuous renal function changes in addition to dichotomous AKI endpoints, particularly in studies with limited event numbers. Consistent with these findings, subgroup analyses within the sacubitril/valsartan group demonstrated that loop-equivalent diuretic dose was significantly higher among patients who developed AKI compared with those who did not. This concordance between subgroup comparisons and multivariable Firth logistic regression further supports the central role of diuretic intensity as a key determinant of renal vulnerability under triple-drug exposure.

Several mechanisms may account for these findings. Neprilysin inhibition augments natriuretic peptide activity, promoting vasodilation and natriuresis, which may help preserve renal perfusion in the setting of NSAID-induced afferent arteriolar constriction and diuretic-related effective volume depletion. Improved systemic hemodynamics in heart failure may further contribute to renal perfusion stability. However, these mechanistic interpretations remain speculative and require confirmation in prospective physiological studies.

From a clinical perspective, our results emphasize careful diuretic management when NSAIDs are initiated in patients receiving RAAS inhibition. While our data do not support definitive renoprotective claims for sacubitril/valsartan in this context, they generate the hypothesis that RAAS inhibitor selection may influence early renal responses under pharmacologic stress.

Several limitations should be considered. First, this was a retrospective observational study, and residual confounding cannot be excluded. Second, NSAID exposure was defined based on prescription data; actual adherence and precise dosing could not be verified, potentially resulting in exposure misclassification and limiting assessment of dose–response relationships. Third, AKI was defined solely based on changes in serum creatinine because reliable urine output data were unavailable, which may have led to misclassification of events. Fourth, markers of heart failure severity such as BNP and LVEF were not uniformly available at the time of NSAID initiation, and due to their incomplete availability and the risk of overfitting given the limited number of events, these variables were not included in the multivariable models. Finally, loxoprofen was the predominant NSAID in this cohort, reflecting regional prescribing patterns in Japan; therefore, generalizability to other populations with different NSAID utilization patterns may be limited. Larger prospective studies with greater event numbers and standardized assessment of heart failure severity and NSAID exposure are warranted to confirm these findings.

In patients exposed to concurrent RAAS inhibition, diuretics, and NSAIDs, sacubitril/valsartan was associated with smaller early increases in serum creatinine compared with valsartan, whereas diuretic intensity emerged as a consistent determinant of renal deterioration. These findings underscore the central role of volume management under triple-drug exposure. Although causality cannot be established, the results support prospective studies to clarify differential renal hemodynamic responses among RAAS inhibitors.

YN conceived and designed the study and drafted the manuscript; MN collected the data and performed the statistical analysis; YK contributed to the study design and provided clinical interpretation of the data; TK critically revised the manuscript for important intellectual content and gave final approval of the version to be published.

This study was conducted in accordance with the Declaration of Helsinki and was approved by the Institutional Review Board of The Jikei University School of Medicine (Approval No. 36-022 [12121]).

The requirement for written informed consent was waived because of the retrospective study design, and an opt-out consent process was applied.

The authors used ChatGPT (OpenAI) for language editing and polishing of the manuscript. The authors reviewed and revised the content and take full responsibility for the integrity of the work.

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

The authors declare no conflicts of interest.

The data that support the findings of this study are available from the corresponding author upon reasonable request.