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Meta-Analysis
. 2025 Nov;91(11):3031-3041.
doi: 10.1002/bcp.70263. Epub 2025 Aug 28.

Acute kidney injury and morbi-mortality associated with "triple whammy" combination: Systematic review and meta-analysis

Dulce María Calvo  1 , Luis Carlos Saiz  2   3 , Leire Leache  3   4 , Maria Concepción Celaya  3   4 , Marta Gutiérrez-Valencia  2   3
Affiliations
Meta-Analysis

Acute kidney injury and morbi-mortality associated with "triple whammy" combination: Systematic review and meta-analysis

Dulce María Calvo et al. Br J Clin Pharmacol. 2025 Nov.

Abstract

Aims: "Triple whammy" (TW) refers to the concomitant use of diuretics, renin-angiotensin-aldosterone system inhibitors (RAASI) and non-steroidal anti-inflammatory drugs (NSAIDs). The aim of this article is to analyse the association between TW exposure and acute kidney injury (AKI), among other morbi-mortality outcomes.

Methods: We included studies published up to August 2023 in the Cochrane Library, Medline or EMBASE, among others. The risk of AKI within 12 months after TW vs. not exposed to TW was the main outcome.

Results: We included five case-control studies, involving 410 130 participants. The risk of AKI was significantly higher among those exposed to TW vs. not exposed (odds ratio [OR] 2.01, 95% confidence interval [CI] 1.30-3.10; four studies; I2: 90%; low certainty of evidence). Three studies provided data on all-cause mortality, not showing a significantly higher risk with TW exposure (very low certainty of evidence).

Conclusion: The available evidence reveals that TW may lead to a significantly higher risk of AKI and related hospitalizations, with no detrimental effect on mortality.

Keywords: acute kidney injury; drug safety; nephrotoxicity; systematic review.

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Conflict of interest statement

The authors declare that they have no competing interests that might have influenced the work reported in this paper.

Figures

FIGURE 1
FIGURE 1
Flow diagram of the literature search.
FIGURE 2
FIGURE 2
Forest plot for AKI with TW vs. non‐exposure to TW.
FIGURE 3
FIGURE 3
Forest plot for the sensitivity analysis of AKI (A) according to KDIGO'S definition and (B) excluding the study with a high risk of bias.
FIGURE 4
FIGURE 4
Risk of bias assessment for the primary outcome (AKI) using ROBINS‐I tool.
See this image and copyright information in PMC

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