Background Adverse drug events, including adverse drug reactions (ADRs), are responsible for approximately 5% of unplanned hospital admissions: a major health concern. Women are 1.5–1.7 times more likely to develop ADRs. The main objective was to identify sex differences in the types and number of ADRs leading to hospital admission. Methods ADR-related hospital admissions between 2005 and 2017 were identified from the PHARMO Database Network using hospital discharge diagnoses. Patients aged ≥ 16 years with a drug possibly responsible for the ADR and dispensed within 3 months before admission were included. Age-adjusted odds ratios (OR) with 95% CIs for drug-ADR combinations for women versus men were calculated. Results A total of 18,469 ADR-related hospital admissions involving women (0.35% of all women admitted) and 14,678 admissions involving men (0.35% of all men admitted) were included. Most substantial differences were seen in ADRs due to anticoagulants and diuretics. Anticoagulants showed a lower risk of admission with persistent haematuria (ORadj 0.31; 95%CI 0.21, 0.45) haemoptysis (ORadj 0.47, 95%CI 0.30,0.74) and subdural haemorrhage (ORadj 0.61; 95%CI 0.42,0.88) in women than in men and a higher risk of rectal bleeding in women (ORadj 1.48; 95%CI 1.04,2.11). Also, there was a higher risk of admission in women using thiazide diuretics causing hypokalaemia (ORadj 3.03; 95%CI 1.58, 5.79) and hyponatraemia (ORadj 3.33, 95%CI 2.31, 4.81) than in men. Conclusions There are sex-related differences in the risk of hospital admission in specific drug-ADR combinations. The most substantial differences were due to anticoagulants and diuretics.

Background: Metoprolol, a beta-blocker, is used to reduce the heart rate. Although it has been demonstrated that the metoprolol plasma concentration is higher in women than in men, the same dose is recommended. In this study, we investigated whether the metoprolol concentration was associated with a stronger heart-rate reduction and bradycardia in women than in men. Methods: This study is part of the Rotterdam Study (RS), a population-based prospective cohort study. Blood samples from a random subset of 2000 participants were used to assess metoprolol plasma levels. An analysis of heart rate (beats per minute, bpm) and bradycardia (<60 bpm) was performed in metoprolol users with an ECG at the day of blood collection to study sex-specific differences in heart rate and the risk of bradycardia. Results: In total, 40 women and 39 men were included. There was a statistically significant association between metoprolol concentration and heart rate in women (p-value: 0.014) but not in men (p-value: 0.639). Furthermore, women in the highest concentration group had a more than 15-times-higher risk of bradycardia than women in the lowest concentration group (OR = 15.6; 95% CI = 1.1, 217.3); however, this was not seen in men (OR = 1.3; 95% CI = 0.1, 12.4). After adjustment for age, BMI, time between blood sample and ECG, hypertension, myocardial infarction, heart failure, atrial fibrillation, digoxin use, and calcium channel blocker use, the association between concentration and bradycardia in women remained statistically significant. Conclusions: Women, but not men, had a statistically significantly lower heart rate at higher metoprolol plasma concentration and a statistically significantly increased risk of bradycardia.

Purpose: Current guidelines have no sex-specific dosage advice for metoprolol. To evaluate whether women and men are prescribed the same dose a cohort analysis was performed in the population-based Rotterdam Study (RS). Results were replicated in the Integrated Primary Care Information (IPCI) database of automated general practice data. Methods:The mean daily starting doses of metoprolol in both sexes were compared with independent-samples t-tests and a linear regression analysis was used to adjust in the RS for co-variables, notably, cardiovascular comorbidity, migraine, age, SBP, DBP, BMI, socioeconomic status, use of other antihypertensive drugs, smoking, and alcohol. In the IPCI-database, adjustment was for age only. Results:The mean daily starting dose was statistically significantly lower in women than in men in both the RS and IPCI database, with a mean difference of 4.8 mg (95% CI −7.8, −1.8) and 4.6 mg (95%CI −5.3,-4.0), respectively. Statistical significance remained after adjustment in both databases.Conclusions: Women received lower starting doses of metoprolol than men in two independent data collections despite non-sex specific cardiovascular guideline recommendations. This example of real-life pharmacotherapy can lead to a form of confounding by contraindication in pharmacoepidemiology.