Potential Drug Dose-Specific Adverse Three-Drug Combinations: A US Insurance Claims Data-Based Study

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.

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.

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).

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.

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.