Time until onset of acute kidney injury by combination therapy with “Triple Whammy” drugs obtained from Japanese Adverse Drug Event Report database

Abstract

Acute kidney injury (AKI) associated with “Triple Whammy” drug therapy consisting of renin-angiotensin system inhibitors, diuretics, and nonsteroidal anti-inflammatory drugs (NSAIDs) has been reported. There have been no reports investigating “Triple Whammy” 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 “Triple Whammy” drug therapy. We analyzed AKI cases registered in the Japanese Adverse Drug Event Report database. The data were analyzed using the Kaplan–Meier 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–Meier 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.

Hospitalisations Related to the Combination of ACE Inhibitors and/or Angiotensin Receptor Blockers with Diuretics and NSAIDs: A Post Hoc Analysis on the Risks Associated with Triple Whammy

“…Nevertheless, only 9 out of 80 patients reported AKI (11%). This result agrees with a recently published Japanese study on spontaneous reports of adverse reactions, highlighting that only about 5% of the patients accessing the ED for triple whammy-related AEs had renal manifestations [9,22]. Noteworthy, in all patients with renal manifestations, drug-drug interactions contributed to the event.…”

Preoperative prescriptions and polypharmacy in elective total hip and knee arthroplasty from 2010 to 2017, a descriptive cohort study

“…20 Thus, a recent Japanese study found an adjusted odds ratio of 2.4 for AKI in patients taking this combination. 31 That the prescription of a triple whammy may pose a challenge in THA and TKA patients was demonstrated in a previous Danish national study investigating postoperative drug-drug interactions and finding that >8% received a postoperative triple whammy. 19 We found that 4.3% of our study population was prescribed a preoperative triple whammy, suggesting that about half of patients with a prescribed postoperative triple whammy may merely have continued their regular treatments.…”

“…The combination of ANG‐II/ACE‐inhibitor, NSAID and a diuretic, also known as a triple whammy may be especially problematic as it has been demonstrated to increase the risk of renal failure, especially in the elderly 20 . Thus, a recent Japanese study found an adjusted odds ratio of 2.4 for AKI in patients taking this combination 31 . That the prescription of a triple whammy may pose a challenge in THA and TKA patients was demonstrated in a previous Danish national study investigating postoperative drug–drug interactions and finding that >8% received a postoperative triple whammy 19 .…”

Detection of potential drug-drug interactions for risk of acute kidney injury: a population-based case-control study using interpretable machine-learning models

“…AKI tends to occur within 7 days from the initiation of a culprit drug, and sub-acute kidney injury occurs within 4 weeks ( Mehta et al, 2015 ). In fact, it has been reported that several nephrotoxic drugs are more likely to induce acute kidney injury within 7 days, and most cases of acute kidney injury occur within 30 days from the initiation of the drug ( Khalili et al, 2013 ; Miano et al, 2018 ; Ide et al, 2019 ; Kunitsu et al, 2022 ; Wu et al, 2022 ). Hence, if a drug class was newly started within 1–7 days before the event date, the drug class was regarded as “use.” If a drug class was newly started on the event date, the drug class was regarded as “non-use,” to prevent reverse causality bias.…”