Abstract
We present a framework for detecting possible adverse drug reactions (ADRs) using the Utah Medicaid administrative data. We examined four classes of ADRs associated with treatment of dementia by acetylcholinesterase inhibitors (AChEIs): known reactions (gastrointestinal, psychological disturbances), potential reactions (respiratory disturbance), novel reactions (hepatic, hematological disturbances), and death. Our cohort design linked drug utilization data to medical claims from Utah Medicaid recipients. We restricted the analysis to 50 years-old and older beneficiaries diagnosed with dementia-related diseases. We compared patients treated with AChEI to patients untreated with anti-dementia medication therapy. We attempted to remove confounding by establishing propensity-score-matched cohorts for each outcome investigated; we then evaluated the effects of drug treatment by conditional multivariable Cox-proportional-hazard regression. Acute and transient effects were evaluated by a crossover design using conditional logistic regression. Propensity-matched analysis of expected reactions revealed that AChEI treatment was associated with gastrointestinal episodes (Hazard Ratio [HR]: 2.02; 95%CI: 1.28-3.2), but not psychological episodes, respiratory disturbance, or death. Among the unexpected reactions, the risk of hematological episodes was higher (HR: 2.32; 95%CI: 1.47-3.6) in patients exposed to AChEI. AChEI exposure was not associated with an increase in hepatic episodes. We also noted a trend, identified in the case-crossover design, toward increase odds of experiencing acute hematological events during AChEI exposure (Odds Ratio: 3.0; 95% CI: 0.97 - 9.3). We observed an expected association between AChEIs treatment and gastrointestinal disturbances and detected a signal of possible hematological ADR after treatment with AChEIs in this pilot study. Using this analytic framework may raise awareness of potential ADEs and generate hypotheses for future investigations. Early findings, or signal detection, are considered hypothesis generating since confirmatory studies must be designed to determine if the signal represents a true drug safety problem.
Highlights
Despite its limitations, the Food and Drug Administration’s (FDA) Adverse Drug Event Reporting System (FAERS) has successfully identified rare and unexpected adverse events[1,2,3]
We present a framework for directed discovery of possible adverse drug reactions (ADRs) using population-based administrative data sources, an approach intended to complement the FDA’s adverse reporting system
We examined the associations between drug use and possible ADRs resulting from treatment of dementia with acetylcholinesterase inhibitors (AChEIs), namely, donepezil hydrochloride, rivastigmine tartrate, and galantamine hydrobromide
Summary
The Food and Drug Administration’s (FDA) Adverse Drug Event Reporting System (FAERS) has successfully identified rare and unexpected adverse events[1,2,3]. Administrative data sources have been used to estimate the extent of the problem or confirm safety signals identified from AERS4,5. Fewer studies have demonstrated the potential of administrative data for first-line adverse drug reaction (ADR) surveillance[6]. In this pilot study, we present a framework for directed discovery of possible ADRs using population-based administrative data sources, an approach intended to complement the FDA’s adverse reporting system. We measured associations for four classes of ADEs—established reactions (gastrointestinal and psychological disturbance), potential reactions based on drug pharmacology (respiratory disturbance), novel unexpected reactions (hepatic and hematological disturbance), and death. Hepatic and hematologic syndromes were evaluated because they are two examples of potentially fatal reactions that have been found in postmarketing surveillance of drug-induced disease[7]
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