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<jats:title>Abstract</jats:title><jats:sec><jats:title>Purpose</jats:title><jats:p>Concomitant use of diuretics, renin–angiotensin–aldosterone system (RAAS) inhibitors, and non‐steroidal anti‐inflammatory drugs (NSAIDs) or metamizole, known as ‘triple whammy’ (TW), has been associated with an increased risk of acute kidney injury (AKI). Nevertheless, there is still uncertainty on its impact in hospitalisation and mortality. The aim of the study was to analyse the association between exposure to TW and the risk of hospitalisation for AKI, all‐cause mortality and the need for renal replacement therapy (RRT).</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>A case–control study nested in a cohort of adults exposed to at least one diuretic or RAAS inhibitor between 2009 and 2018 was carried out within the Pharmacoepidemiological Research Database for Public Health Systems (BIFAP). Patients hospitalised for AKI between 2010 and 2018 (cases) were matched with up to 10 patients of the same age, sex and region of Spain who had not been hospitalised for AKI as of the date of hospitalisation for AKI of the matching case (controls). The association between TW exposure versus non‐exposure to TW and outcome variables was analysed using logistic regression models.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>A total of 480 537 participants (44 756 cases and 435 781 controls) were included (mean age: 79 years). The risk of hospitalisation for AKI was significantly higher amongst those exposed to TW [adjusted odds ratio (aOR) 1.36, 95% confidence interval (95%CI) 1.32–1.40], being higher with current (aOR 1.60, 95%CI 1.52–1.69) and prolonged exposure (aOR 1.65, 95%CI 1.55–1.75). No significant association was found with the need of RRT. Unexpectedly, mortality was lower in those exposed to TW (aOR 0.81, 95%CI 0.71–0.93), which may be influenced by other causes.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>Vigilance should be increased when diuretics, RAAS inhibitors, and NSAIDs or metamizole are used concomitantly, especially in patients at risk such as elderly patients.</jats:p></jats:sec>