Y Shi, A Sun, C W Chiang, Y Yang, K M Hunold, J Xu, M Russo, J Caterino, M T Eadon, L Li, J Su, M Donneyong, P Zhang
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We used the conditional logistic regression model to investigate the relationship between the dose of three-drug combination exposure and the risk of ADE. We used Benjamini and Hochberg's procedure to control the false discovery rate (FDR). We explored the relationship between the reduction of drug dose and the risk of ADE.</p><p><strong>Results: </strong>We identified over 500 potential adverse three-drug combinations from approximately two million case-control pairs (all odds ratios ≥ 1.3 and FDR < 0.05). For the signals, compared with a high-dose level of all three drugs, 74% of three-drug combinations had a lower risk by decreasing the dose of one drug without any drug discontinuation (p value < 0.05).</p><p><strong>Conclusions: </strong>Certain three-drug combinations are associated with an increased risk of ADE. Dose of exposure might be used to evaluate the risk of ADE for a majority of adverse three-drug combinations.</p><p><strong>Plain language summary: </strong>Use of three-drug combinations is increasingly prevalent and associated with an increased risk of adverse drug events (ADEs). We identified potential adverse three-drug combinations from real-world data, and revealed the corresponding relationships between doses and risks of ADEs. We find doses might be used to evaluate the risk of ADE for many adverse three-drug combinations. Additionally, we find risk of many adverse three-drug combinations might be decreased by reducing the dose of one drug without any drug discontinuation.</p>","PeriodicalId":19782,"journal":{"name":"Pharmacoepidemiology and Drug Safety","volume":"34 9","pages":"e70199"},"PeriodicalIF":2.4000,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12358767/pdf/","citationCount":"0","resultStr":"{\"title\":\"Potential Drug Dose-Specific Adverse Three-Drug Combinations: A US Insurance Claims Data-Based Study.\",\"authors\":\"Y Shi, A Sun, C W Chiang, Y Yang, K M Hunold, J Xu, M Russo, J Caterino, M T Eadon, L Li, J Su, M Donneyong, P Zhang\",\"doi\":\"10.1002/pds.70199\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Introduction: </strong>Use of three-drug combinations is increasingly prevalent and associated with an increased risk of adverse drug events (ADEs). While real-world data-based pharmacovigilance and pharmacoepidemiology studies have derived knowledge on potential adverse three-drug combinations, the relationship between doses of each drug in three-drug combination exposure and the risk of ADEs remains unclear.</p><p><strong>Methods: </strong>We derived matched case-control datasets from US nationwide health insurance claims data for potential ADEs including acute kidney injury, acute myocardial infarction, gastrointestinal bleeding, hypoglycemia, and opioid-related ADE. We used the conditional logistic regression model to investigate the relationship between the dose of three-drug combination exposure and the risk of ADE. We used Benjamini and Hochberg's procedure to control the false discovery rate (FDR). We explored the relationship between the reduction of drug dose and the risk of ADE.</p><p><strong>Results: </strong>We identified over 500 potential adverse three-drug combinations from approximately two million case-control pairs (all odds ratios ≥ 1.3 and FDR < 0.05). For the signals, compared with a high-dose level of all three drugs, 74% of three-drug combinations had a lower risk by decreasing the dose of one drug without any drug discontinuation (p value < 0.05).</p><p><strong>Conclusions: </strong>Certain three-drug combinations are associated with an increased risk of ADE. Dose of exposure might be used to evaluate the risk of ADE for a majority of adverse three-drug combinations.</p><p><strong>Plain language summary: </strong>Use of three-drug combinations is increasingly prevalent and associated with an increased risk of adverse drug events (ADEs). 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Potential Drug Dose-Specific Adverse Three-Drug Combinations: A US Insurance Claims Data-Based Study.
Introduction: Use of three-drug combinations is increasingly prevalent and associated with an increased risk of adverse drug events (ADEs). While real-world data-based pharmacovigilance and pharmacoepidemiology studies have derived knowledge on potential adverse three-drug combinations, the relationship between doses of each drug in three-drug combination exposure and the risk of ADEs remains unclear.
Methods: We derived matched case-control datasets from US nationwide health insurance claims data for potential ADEs including acute kidney injury, acute myocardial infarction, gastrointestinal bleeding, hypoglycemia, and opioid-related ADE. We used the conditional logistic regression model to investigate the relationship between the dose of three-drug combination exposure and the risk of ADE. We used Benjamini and Hochberg's procedure to control the false discovery rate (FDR). We explored the relationship between the reduction of drug dose and the risk of ADE.
Results: We identified over 500 potential adverse three-drug combinations from approximately two million case-control pairs (all odds ratios ≥ 1.3 and FDR < 0.05). For the signals, compared with a high-dose level of all three drugs, 74% of three-drug combinations had a lower risk by decreasing the dose of one drug without any drug discontinuation (p value < 0.05).
Conclusions: Certain three-drug combinations are associated with an increased risk of ADE. Dose of exposure might be used to evaluate the risk of ADE for a majority of adverse three-drug combinations.
Plain language summary: Use of three-drug combinations is increasingly prevalent and associated with an increased risk of adverse drug events (ADEs). We identified potential adverse three-drug combinations from real-world data, and revealed the corresponding relationships between doses and risks of ADEs. We find doses might be used to evaluate the risk of ADE for many adverse three-drug combinations. Additionally, we find risk of many adverse three-drug combinations might be decreased by reducing the dose of one drug without any drug discontinuation.
期刊介绍：
The aim of Pharmacoepidemiology and Drug Safety is to provide an international forum for the communication and evaluation of data, methods and opinion in the discipline of pharmacoepidemiology. The Journal publishes peer-reviewed reports of original research, invited reviews and a variety of guest editorials and commentaries embracing scientific, medical, statistical, legal and economic aspects of pharmacoepidemiology and post-marketing surveillance of drug safety. Appropriate material in these categories may also be considered for publication as a Brief Report.
Particular areas of interest include:
design, analysis, results, and interpretation of studies looking at the benefit or safety of specific pharmaceuticals, biologics, or medical devices, including studies in pharmacovigilance, postmarketing surveillance, pharmacoeconomics, patient safety, molecular pharmacoepidemiology, or any other study within the broad field of pharmacoepidemiology;
comparative effectiveness research relating to pharmaceuticals, biologics, and medical devices. Comparative effectiveness research is the generation and synthesis of evidence that compares the benefits and harms of alternative methods to prevent, diagnose, treat, and monitor a clinical condition, as these methods are truly used in the real world;
methodologic contributions of relevance to pharmacoepidemiology, whether original contributions, reviews of existing methods, or tutorials for how to apply the methods of pharmacoepidemiology;
assessments of harm versus benefit in drug therapy;
patterns of drug utilization;
relationships between pharmacoepidemiology and the formulation and interpretation of regulatory guidelines;
evaluations of risk management plans and programmes relating to pharmaceuticals, biologics and medical devices.
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