The Prevalent New‐User Design to Study Drug–Drug Interactions: The Example of Sulfonylureas and Warfarin Interaction on the Risk of Severe Hypoglycemia

• Published in: Pharmacoepidemiology and drug safety 2024-10, Vol.33 (10), p.e70014-n/a
• Main Authors: Wang, Wanqi, Cui, Ying, Yu, Oriana Hoi Yun, Suissa, Samy, Douros, Antonios
• Format: Article
• Language: English
• Subjects: Aged; Aged, 80 and over; Anticoagulants; Anticoagulants - administration & dosage; Anticoagulants - adverse effects; cohort; Databases, Factual; Drug development; Drug interaction; Drug Interactions; drug–drug interaction; Female; Humans; Hypoglycemia; Hypoglycemia - chemically induced; Hypoglycemia - epidemiology; Hypoglycemic Agents - administration & dosage; Hypoglycemic Agents - adverse effects; Male; Middle Aged; Pharmacoepidemiology - methods; prevalent new‐user; Propensity Score; Proportional Hazards Models; Research Design; Sensitivity analysis; Statistical analysis; Sulfonylurea; Sulfonylurea Compounds - adverse effects; United Kingdom - epidemiology; Warfarin; Warfarin - administration & dosage; Warfarin - adverse effects
• ISSN: 1053-8569; 1099-1557; 1099-1557
• DOI: 10.1002/pds.70014

ABSTRACT Purpose The optimal design for pharmacoepidemiologic drug–drug interactions (DDIs) studies is unclear. Using the association between concomitant use of sulfonylureas and warfarin and the risk of severe hypoglycemia as a case study, a DDI with little or no clinical impact, we tested whether the prevalent new‐user design can be applied in the area. Methods Among all patients initiating sulfonylureas in the UK's Clinical Practice Research Datalink (1998–2020), we identified those adding‐on warfarin while on a sulfonylurea. For each co‐exposed patient, we defined a prescription‐based exposure set including other sulfonylurea users not adding‐on warfarin (comparators). Within each exposure set, we matched each co‐exposed patient to five comparators on time‐conditional propensity scores (TCPS) and followed them using an as‐treated approach. Cox proportional hazards models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) of severe hypoglycemia associated with concomitant use of sulfonylureas and warfarin compared to use of sulfonylureas alone. Sensitivity analyses addressed the impact of different potential sources of bias. Results The study cohort included 17 890 patients co‐exposed to sulfonylureas and warfarin and 88 749 matched comparators. After TCPS matching, patient characteristics were well‐balanced between groups. Compared to use of sulfonylureas alone, concomitant use of sulfonylureas and warfarin was not associated with the risk of severe hypoglycemia (HR, 1.04; 95% CI, 0.92–1.17). Sensitivity analyses were consistent with the primary analysis (HRs ranging from 1.01 to 1.15, all not statistically significant). Conclusions Our study suggests that the prevalent new‐user design could be used for the assessment of clinical effects of DDIs.