Drug interactions in hospital prescriptions in Denmark: Prevalence and associations with adverse outcomes

Importance While the beneficial effects of medications are numerous, drug-drug interactions may lead to adverse drug reactions that are preventable causes of morbidity and mortality. Objective To quantify the prevalence of potential drug-drug interactions in drug prescriptions at Danish hospitals, estimate the risk of adverse outcomes associated with discouraged drug combinations, and highlight the patient types (defined by the primary diagnosis of the admission) that appear to be more affected. Design Cross-sectional (descriptive part) and cohort study (adverse outcomes part). Setting Hospital electronic health records from two Danish regions (approx. 2.5 million people) from January 2008 through June 2016. Participants Inpatients receiving two or more medications during their admission. Exposure Concomitant prescriptions of potentially interacting drugs as per the Danish Drug Interaction Database. Main outcome and measure Descriptive part: prevalence of potential drug-drug interactions in general and discouraged drug pairs in particular during admissions. Adverse outcomes part: post-discharge all-cause mortality rate, readmission rate and length-of-stay. Results Among 2,886,227 hospital admissions (945,475 patients; median age 62 years [IQR: 41-74]; 54% female; median number of drugs 7 [IQR: 4-11]), patients in 1,836,170 admissions were exposed to at least one potential drug-drug interaction (659,525 patients; median age 65 years [IQR: 49-77]; 54% female; median number of drugs 9 [IQR: 6-13]), and in 27,605 admissions to a discouraged drug pair (18,192 patients; median age 68 years [IQR: 58-77]; female 46%; median number of drugs 16 [IQR: 11-22]). Meropenem-valproic acid (HR: 1.5, 95% CI: 1.1–1.9), domperidone-fluconazole (HR: 2.5, 95% CI: 2.1–3.1), imipramine-terbinafine (HR: 3.8, 95% CI: 1.2–12), agomelatine-ciprofloxacin (HR: 2.6, 95% CI: 1.3–5.5), clarithromycin-quetiapine (HR: 1.7, 95% CI: 1.1–2.7), and piroxicam-warfarin (HR: 3.4, 95% CI: 1–11.4) were associated with elevated mortality. Confidence interval bounds of pairs associated with readmission were close to 1; length-of-stay results were inconclusive. Conclusions and Relevance Well-described potential drug-drug interactions are still missed and alerts at point of prescription may reduce the risk of harming patients; prescribing clinicians should be alert when using strong inhibitor/inducer drugs (i.e. clarithromycin, valproic acid, terbinafine) and prevalent anticoagulants (i.e. warfarin and NSAIDs) due to their great potential for dangerous interactions. The most prominent CYP isoenzyme involved in mortality and readmission rates was 3A4.