{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T14:42:32Z","timestamp":1793198552734,"version":"4.5.0"},"reference-count":36,"publisher":"Public Library of Science (PLoS)","issue":"2","license":[{"start":{"date-parts":[[2022,2,9]],"date-time":"2022-02-09T00:00:00Z","timestamp":1644364800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"japan society for the promotion of science","doi-asserted-by":"publisher","award":["21H04191"],"award-info":[{"award-number":["21H04191"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Acute kidney injury (AKI) associated with \u201cTriple Whammy\u201d drug therapy consisting of renin-angiotensin system inhibitors, diuretics, and nonsteroidal anti-inflammatory drugs (NSAIDs) has been reported. There have been no reports investigating \u201cTriple Whammy\u201d drug therapy and the time to AKI onset using adverse drug events report databases. The aim of this study was to determine the relationship between the time to AKI onset and treatment with \u201cTriple Whammy\u201d drug therapy. We analyzed AKI cases registered in the Japanese Adverse Drug Event Report database. The data were analyzed using the Kaplan\u2013Meier approach, generalized Wilcoxon tests, and Weibull distribution. AKI was reported in 18,415 cases, of which 7,466 cases used Triple Whammy drugs. All combinations of Triple Whammy drugs were associated with significantly higher odds ratios for reporting AKI. In Weibull analysis, AKI onset was early for most combination patterns of Triple Whammy drugs. The Kaplan\u2013Meier approach showed that the treatment duration to AKI onset was much shorter in cases using NSAIDs; median onsets, 8 days for triple combination, 7 days for NSAIDs added to renin-angiotensin system inhibitors, 9 days for NSAIDs added to diuretics, 6 days for diuretics added to NSAIDs, and 9 days for NSAIDs alone. AKI associated with Triple Whammy drugs is likely to occur in the early stages of treatment, especially with concomitant NSAIDs. Patients should be monitored for the occurrence of AKI within the first 2 weeks.<\/jats:p>","DOI":"10.1371\/journal.pone.0263682","type":"journal-article","created":{"date-parts":[[2022,2,9]],"date-time":"2022-02-09T18:28:31Z","timestamp":1644431311000},"page":"e0263682","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":19,"title":["Time until onset of acute kidney injury by combination therapy with \u201cTriple Whammy\u201d drugs obtained from Japanese Adverse Drug Event Report database"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0331-6417","authenticated-orcid":true,"given":"Yuki","family":"Kunitsu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8344-2469","authenticated-orcid":true,"given":"Daiki","family":"Hira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aya","family":"Morikochi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomohiro","family":"Ueda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tetsuichiro","family":"Isono","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shin-ya","family":"Morita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomohiro","family":"Terada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,2,9]]},"reference":[{"issue":"4","key":"pone.0263682.ref001","doi-asserted-by":"crossref","first-page":"184","DOI":"10.5694\/j.1326-5377.2000.tb125548.x","article-title":"Diuretics, ACE inhibitors and NSAIDs\u2014the triple whammy","volume":"172","author":"MC Thomas","year":"2000","journal-title":"Med J Aust"},{"issue":"2","key":"pone.0263682.ref002","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1111\/j.0306-5251.2004.2188.x","article-title":"Drug combinations and impaired renal function\u2014the \u2018triple whammy\u2019","volume":"59","author":"KL Katarzyna","year":"2005","journal-title":"Br J Clin Pharmacol"},{"issue":"5","key":"pone.0263682.ref003","doi-asserted-by":"crossref","first-page":"274","DOI":"10.5694\/j.1326-5377.2000.tb125642.x","article-title":"COX-2 inhibitors and renal failure: the triple whammy revisited","volume":"173","author":"IW Boyd","year":"2000","journal-title":"Med J Aust"},{"key":"pone.0263682.ref004","doi-asserted-by":"crossref","first-page":"e8525","DOI":"10.1136\/bmj.e8525","article-title":"Concurrent use of diuretics, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers with non-steroidal anti-inflammatory drugs and risk of acute kidney injury: nested case-control study","volume":"346","author":"F Lapi","year":"2013","journal-title":"BMJ"},{"issue":"2","key":"pone.0263682.ref005","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/j.nefroe.2015.05.010","article-title":"Acute kidney injury secondary to a combination of renin-angiotensin system inhibitors, diuretics and NSAIDS: \"The Triple Whammy\"","volume":"35","author":"RM Garcia Camin","year":"2015","journal-title":"Nefrologia (Engl Ed)"},{"issue":"2","key":"pone.0263682.ref006","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1038\/ki.2015.101","article-title":"Combined use of nonsteroidal anti-inflammatory drugs with diuretics and\/or renin-angiotensin system inhibitors in the community increases the risk of acute kidney injury","volume":"88","author":"T Dreischulte","year":"2015","journal-title":"Kidney Int"},{"issue":"7","key":"pone.0263682.ref007","doi-asserted-by":"crossref","first-page":"1166","DOI":"10.3109\/0886022X.2014.917943","article-title":"More on the \"Triple Whammy\": antihypertensive drugs, non-steroidal anti-inflammatory agents and acute kidney injury\u2014a case\/non-case study in the French pharmacovigilance database","volume":"36","author":"JP Fournier","year":"2014","journal-title":"Ren Fail"},{"key":"pone.0263682.ref008","unstructured":"Pharmaceuticals and Medical Devices Agency. 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