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Comparative Study
. 2025 Jan;34(1):e70092.
doi: 10.1002/pds.70092.

The European Drug-Drug Interaction (EuroDDI) Study Protocol: A Cross-Country Comparison of Drug-Drug Interaction Prevalence in the Older Community-Dwelling Population

John E Hughes  1 , Enrica Menditto  2 , Sara Mucherino  2 , Valentina Orlando  2 , Aida Moreno-Juste  3   4   5 , Antonio Gimeno-Miguel  3   4 , Beatriz Poblador-Plou  3   4 , Mercedes Aza-Pascual-Salcedo  3   4 , Francisca González-Rubio  3   4   6 , Ignatios Ioakeim-Skoufa  3   4   6   7   8 , Kathleen Bennett  1 , Caitriona Cahir  1
Affiliations
Comparative Study

The European Drug-Drug Interaction (EuroDDI) Study Protocol: A Cross-Country Comparison of Drug-Drug Interaction Prevalence in the Older Community-Dwelling Population

John E Hughes et al. Pharmacoepidemiol Drug Saf. 2025 Jan.

Abstract

Background: Drug-drug interactions (DDIs), highly prevalent amongst the elderly, can lead to avoidable medication-related harm. Cardiovascular and central nervous system (CNS) drugs are commonly implicated. To date, there is no consensus on how to measure DDIs, making comparisons across countries challenging.

Objective: To (i) establish a common data model (CDM) to measure DDI prevalence in the older (aged ≥ 70 years) community-dwelling population of three European countries and (ii) compare and describe cardiovascular and CNS DDI prevalence rates across these countries.

Methods: This cross-country study will apply a harmonised method of DDI identification and analysis using the WHO ATC classification system and national pharmacy claims data from three European countries (Ireland, Italy, Spain). Patients aged ≥ 70 years dispensed ≥ 2 medications during 2016 will be identified from each country's national database. 'Severe' cardiovascular and CNS DDIs (i.e., may result in a life-threatening event/permanent detrimental effect) will be identified using the British National Formulary and Stockley's Drug Interactions. Two separate lists of 'severe' DDIs, per medications reimbursed, will be applied to each database: (i) DDIs relevant to each individual country and (ii) DDIs relevant to all three countries. DDIs will be defined as co-dispensed (same day) and concomitantly (±7 days) dispensed.

Results: Descriptive statistics, including DDI prevalence and 95% confidence intervals, will be reported for each country. Prevalence will be pooled and compared across countries using random effects models and meta-regression, where feasible.

Conclusion: The EuroDDI study will develop a harmonised method to measure and compare DDI prevalence across health-related databases in Europe.

Keywords: adverse drug reactions; cardiovascular; common data model; drug interactions; elderly; medication safety; nervous system; pharmacoepidemiology; polypharmacy; protocol.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

FIGURE 1
FIGURE 1
Six‐Step process used to implement the harmonised EuroDDI methodology. CDM, common data model; DDI, drug–drug interaction.
FIGURE 2
FIGURE 2
Identification of ‘Severe’ DDIs using BNF 77 and Stockley's Drug Interactions. Red DDIs: A life‐threatening or contraindicated combination; Orange DDIs: Dosage adjustment or close monitoring is needed; Blue DDIs: Give guidance about possible adverse effects and/or consider some monitoring; Green DDIs: No interactions or no interaction of clinical significance. BNF, British National Formulary; DDI drug–drug interaction.
FIGURE 3
FIGURE 3
Drug dispensing patterns. Co‐dispensed (dispensed on the same day; for example amiodarone + warfarin [both dispensed on Day 1]); concomitantly dispensed (dispensed ± 7 days of date of claim; for example warfarin [day 7] + clarithromycin [day 14]).
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