Medication-related problems (MRPs) are considered a public health priority and pose a major challenge to patient safety, particularly in patients with multiple chronic diseases.1 Numerous studies show that MRPs are highly preventable and are associated with multimorbidity, polypharmacy, inappropriate prescribing, duplication, and interactions.2,3 Published data indicate that approximately 10% of emergency department (ED) visits are associated with preventable MRPs,4 a figure similar to that recorded in other settings.5

In 2017, the World Health Organisation launched its third Global Patient Safety Challenge, with the goal of reducing severe avoidable medication-related harm by 50% over 5 years. The strategy for improvement actions addresses 3 priority areas: inappropriate polypharmacy, transitions of care, and high-risk medicines.6 Within this framework, hospital pharmacy services play a key role in reducing medication errors and ensuring greater safety in the administration of medicines.

High-risk medicines carry a significant risk of causing severe or fatal harm in the event of an error. Lists adapted to different healthcare settings have been established to prioritise interventions according to the care setting. The high-risk medicines for chronic patients (MARC) list was developed in Spain specifically for such patients.7

Although research on MRPs leading to ED visits has advanced, sex differences in this area remain largely unexplored. Women have a greater risk of adverse effects and often receive higher doses, whereas men are more likely to underuse necessary medications.8 These disparities can have more serious clinical consequences when high-risk medications are involved. Furthermore, many high-risk medications have a narrow therapeutic margin or specific contraindications. In the case of renal clearance disorders, biological differences between sexes increase the incidence and severity of MRPs.9 A sex-based analysis and characterisation of the types of MRP leading to ED visits involving MARC-list medications are essential to guide preventive strategies in chronic patients, as identifying differences between women and men would enable the development of safer and more equitable medication use strategies.

The objective of this study was to characterise the problems associated with high-risk medications leading to ED visits in a high-complexity tertiary hospital in Catalonia (Spain), and to analyse sex differences in relation to the type of MRPs and medications involved.

The sample comprised 1611 adult patients (926 women and 685 men), who attended the ED with an MRP as their primary or secondary diagnosis. Table 1 shows the baseline sociodemographic and clinical characteristics by sex.

Of the total patients, 1028 (64%) had an MRP associated with a MARC medication: 580 women (63% of all women in the sample) and 448 men (65% of all men in the sample). Women had a higher frequency of MRPs associated with loop diuretics than men (136 [70%] vs 57 [30%], p  =  .000), antipsychotics (30 [65%] vs 16 [35%], p  =  .039), opioids (37 [73%] vs 11 [27%], p  =  .000), and digoxin (22 [81%] vs 5 [19%], p  =  .02). The age-stratified analysis showed that men under 75 years had a higher frequency of MRPs associated with insulin (11 women [30%] vs 26 men [70%], p = 0.014) and oral hypoglycaemic agents (5 women [24%] vs 16 men [76%], p = 0.016). Table 2 shows the overall distribution of MRPs by sex and drug type, and the supplementary material details the age-stratified analysis.

The comorbidity level analysis showed that the proportion of women who experienced MRPs was significantly higher in the moderate- and high-risk groups (AMG 3 and 4) than in the lower-risk groups (AMG 1 and 2). In these higher-risk categories, a statistically significant association was found between female sex and a higher frequency of MRPs associated with loop diuretics (AMG 3: 31 women [72%] vs 12 men [28%], p = 0.004; AMG 4: 91 women [71%] vs 38 men [29%], p < 0.001), digoxin (AMG 4: 19 women [79%] vs 5 men [21%], p = 0.004), and opioids (AMG 4: 24 women [80%] vs 6 men [20%], p = 0.001). Non-significant trends were observed in the AMG 3 group for digoxin (2 women [100%] vs 0 men, p = 0.5) and opioids (6 women [86%] vs 1 man (14%), p = 0.125). Fig. 1 shows the distribution of MRPs by drug type in AMG 3 and AMG 4. The supplementary material shows the distribution of MRPs by drug type and sex in all AMGs.

Figure 1.

Distribution of MRPs by drug type and sex in moderate- (AMG 3) and high-comorbidity (AMG 4) risk groups.

NSAIDs, non-steroidal anti-inflammatory drugs; AMG, adjusted morbidity group; Non-MARC, drug not included in the MARC list; MRP, medication-related problem.

Analysis of the association between MRPs and MARC medications by sex showed that the probability of experiencing a safety problem increased 5-fold for both men and women when a quantitative safety problem occurred and the drug was included in the MARC list (men: odds ratio [OR] = 4.9; 95% confidence interval [95% CI]: 3.21–7.34; women: OR = 5.3; 95% CI: 3.60–7.77). In addition, the probability of experiencing a non-quantitative safety issue increased 2.5-fold for both men and women when an ADR involving a MARC medication occurred (men: OR = 2.5; 95% CI: 1.85–3.35; women: OR = 2.7; 95% CI: 2.12–3.52).

Analysis of the relationship between the reason for consultation, the drug type associated with the MRP, and sex showed that women were more likely to experience unintentional drug poisoning, although this difference was not statistically significant (OR = 2.5; 95% CI: 0.79–8.36, p  =  .119). Men were 1.41 times more likely to experience problems associated with nonadherence when a MARC medication was involved, although this difference was not statistically significant (OR: 0.711, 95% CI: 0.473–1070, p = 0.102). All cases of hypokalaemia occurred in the MARC medication group. The proportion of hyponatraemia increased 20-fold in men (OR = 20.0; 95% CI: 2.68–149.0) and 7-fold in women (OR = 7.1; 95% CI: 3.54–14.29) when a MARC medication was involved. Table 3 shows the relationship between MARC medications and sex according to the type of MRP and the reason for consultation.

The results show that high-risk medicines are involved in a high proportion of MRPs, leading to ED visits. This finding is in line with those of previous studies, suggesting that a high proportion of preventable adverse drug events are caused by these drugs.19 The value of this study lies in being, to the best of our knowledge, the first to provide a sex-based analysis of MRPs associated with MARC medications leading to ED visits. These MRPs include not only ADRs but also negative outcomes related to therapeutic effectiveness and treatment necessity.

Medication-related problems associated with loop diuretics, digoxin, opioids, and antipsychotics showed significant sex differences, with women being more frequently affected across all age groups. These results support the development of specific recommendations tailored to different healthcare settings and a sex-based approach to safe medication management.7

Notably, the study shows that dosing-related MRPs were observed more frequently in women and that, when a high-risk medication was involved, the clinical consequences significantly differed between women and men. Furthermore, unintentional drug poisoning was observed more frequently in women; however, this difference was not statistically significant. Although pharmacokinetic differences influencing women's drug metabolism and pharmacologic response are well documented,20 sex-adjusted dosing is often underutilised when aiming to reduce the risk of MRPs, particularly for high-risk medications.21,22 This study confirms previous evidence that women experience ADRs more frequently than men.23

Additionally, the results show that both male and female patients who used a MARC medication at doses higher than recommended were 5 times more likely to have an MRP. These findings provide a new perspective by highlighting that the inappropriate use of MARC medications increases the risk of MRPs in both men and women.

Nonadherence to therapy remains a key factor contributing to ED visits for MRPs. Three out of 5 patients in the sample were women who were nonadherent to therapy. However, analysis of the relationship between medication type and sex showed that men had a 1.4-fold higher risk of ED visits due to non-adherence, although this difference was not statistically significant. This finding may be related to sex differences in the management of chronic diseases, including type 2 diabetes. Men tend to rely mainly on support from their partner for health-related matters, whereas women tend to be more actively engaged in managing their own health or to draw on broader social networks, which may promote better adherence to therapy.24

This study has several limitations. Firstly, the integrated medical record system of Catalonia does not collect variables related to sex roles, such as domestic and family responsibilities, or potential sex biases in clinical care. Similarly, no data were collected on educational and income levels, which have been identified as common risk factors for MRPs associated with poor therapeutic adherence. Secondly, no data were collected on the frequency of use of health services, although we believe that this may have had little influence on the results, even though men consult health services less often and tend to seek help later than women.25 Thirdly, the methodology used, which included patients only during a limited period of the day and within working hours, did not comply with the guidelines required for conducting a prevalence analysis. Fourthly, information bias may have been introduced because the medication code database does not include over-the-counter medicines, patients who attended the emergency department after consuming medicines in a suicide attempt, or those in the terminal phase with an estimated life expectancy of less than 30 days, according to the emergency physician's judgement. The limited number of cases included for some of the MARC medications prevented a specific multivariate analysis to confirm sex differences for each drug, highlighting an important issue to address in future studies. Finally, we did not conduct an epidemiological analysis to assess the relationship between the MRPs observed in the ED and those expected based on the use of the same drugs in the general Catalan population.

In conclusion, this study highlights the need for the structured integration of the sex-based perspective into prescribing and pharmacotherapeutic follow-up protocols, staff training programmes, and educational materials for patients. This approach is of particular relevance to patients with multimorbidity and polypharmacy, who are more likely to experience adverse events with high-risk medications. Future research should investigate the factors contributing to the discrepancies observed between women and men to improve understanding of sex disparities in medication safety.

This study identifies sex-based differences in problems associated with high-risk medicines treated in emergency departments and provides evidence of the need to incorporate a sex-based perspective into patient safety.

The findings support the development of safe medication strategies that integrate a sex-based approach in clinical and hospital practice, particularly for high-risk medicines.

All authors have fulfilled all the responsibilities established by the International Committee of Journal Editors. In the event of publication, the authors exclusively assign the rights of reproduction, distribution, translation, and public communication of this work, by any means or medium, to Farmacia Hospitalaria and, by extension, to the Spanish Society of Hospital Pharmacy (SEFH).

This work was developed in the context of the Doctoral Programme in Pharmacology at the Autonomous University of Barcelona.

None declared.

None declared. The authors took full responsibility for the published content.