Loes E. Visser

Background Older adults constitute more than 50% of newly diagnosed cancer cases and polypharmacy is highly prevalent in this population. The Anticholinergic Burden (ACB) score quantifies the cumulative anticholinergic effects of all medications. Few studies link high ACB to adverse health outcomes in this population, and its effect on treatment outcomes remains largely unknown. Objective This study investigates the association between the ACB-score and treatment-related toxicity (grade ≥ 3), functional decline, and emergency room (ER) visits or hospitalization in older adults with cancer receiving chemotherapy and/or targeted therapy. Method Data from the Triage of Elderly Needing Treatment study were used and patients aged ≥ 70 years were included before start of chemotherapy and/or targeted therapy. Medication use was used to calculate the ACB score; ACB ≥ 3 was defined as high. The primary outcome was the association between ACB score and grade ≥ 3 toxicity. Associations were analyzed using univariable and multivariable logistic regression. Results 434 patients were included with a median age of 75.4 years; 56% were male and 15% had a high ACB-score. Grade ≥ 3 toxicity occurred more frequently in the high ACB group (OR 2.04, p = 0.013). In the multivariable model, ACB score and frailty were associated with grade ≥ 3 toxicity (OR 1.99, p = 0.022 and OR 1.79, p = 0.007). Conclusions High ACB is associated with poorer outcomes in older adults with cancer in addition to the known risk for toxicity of frailty.

The liver is crucial for metabolizing the anticancer drug palbociclib, but limited information is available on the impact of hepatic impairment on its toxicity and efficacy, with no real‐world data available. This study aims to evaluate how hepatic impairment affects hematological toxicity and progression‐free survival (PFS) of palbociclib in advanced hormone receptor‐positive/human epidermal growth factor receptor 2‐negative breast cancer, using the National Cancer Institute scoring system, in a large real‐world dataset. This multicenter retrospective observational study included female patients treated with palbociclib between August 2017 and February 2024. Regression analysis was used to compare the risk of developing grade 3/4 hematological toxicity and PFS between patients with normal and mild impaired liver function. In total, 478 female patients were included. Patients with mild hepatic impairment (n = 205) did not have an increased risk of developing grade 3/4 neutropenia compared with patients with normal hepatic function (n = 273) (hazard ratio (HR) = 1.11; 95% CI 0.83–1.47). In addition, the PFS was not significantly different between both groups (HR = 1.15; 95% CI 0.93–1.42). In real‐world settings, patients with mild hepatic impairment do not have a higher risk of developing palbociclib‐induced neutropenia or disease progression than patients with normal hepatic function. These findings can guide clinicians when treating breast cancer patients with mild hepatic impairment.

Background: Hyponatremia is a common electrolyte disturbance and known adverse drug reaction of diuretics. Women tend to be more susceptible for diuretic associated hyponatremia. The aim of this study was to find more evidence whether women have a higher risk of diuretic associated hyponatremia than men measured at hospital admission for specific diuretic groups and whether there is a sex difference in risk of severity of hyponatremia.Methods: All patients using a diuretic and admitted for any reason to Tergooi MC and Haga Teaching hospital in the Netherlands between the 1st of January 2017 and the 31st of December 2021, with recorded sodium levels at admission were included in this study. Cases were defined as patients with a sodium level <135 mmol/L, while control patients had a sodium level ≥135 mmol/L at admission. Logistic regression analysis was used to calculate odds ratios (OR) with 95% CIs for women versus men and adjusted for potential confounding covariables (age, body mass index, potassium serum level, systolic and diastolic blood pressure, estimated glomerular filtration rate, number of diuretics, comedications and comorbidities). Stratified analyses were conducted for specific diuretic groups (thiazides, loop diuretics and aldosterone antagonists), and adjusted for dose. Furthermore, stratified analyses were performed by severity of hyponatremia (severe: <125 mmol/L), mild: 125–134 mmol/L).Results: A total of 2,506 patients (50.0% women) were included, of which 516 had hyponatremia at admission (20.6%, 56.2% women). Women had a statistically significantly higher risk for hyponatremia at admission than men (OR 1.37; 95% CI 1.12–1.66) and after adjustment for potential risk factors (ORadj 1.55; 95% CI 1.22–1.98). Stratified analyses showed increased odds ratios for thiazides (ORadj 1.35; 95% CI 1.00–1.83) and loop diuretics (ORadj 1.62; 95% CI 1.19–2.19) among women. Use of aldosterone antagonists was also increased but not statistically significant (ORadj 1.15; 95% CI 0.73–1.81). Women had a statistically higher risk to develop mild and severe hyponatremia than men (ORadj 1.36; 95% CI 1.10–1.68 and ORadj 1.96; 95%CI 1.04–3.68, respectively).Conclusion: Women have a higher risk of a hospital admission associated with hyponatremia while using diuretics than men. Further research is necessary to provide sex-specific recommendations.

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 (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.

Introduction Hypokalemia is a potentially life-threatening adverse event of flucloxacillin with unknown incidence. The risk of flucloxacillin-induced hypokalemia has recently been suggested to be increased among females compared to males. The aim of this study is to describe the incidence and to determine the influence of sex and other risk factors on flucloxacillin-induced hypokalemia. Methods A retrospective single-centre cohort study was performed. Patients treated with intravenous flucloxacillin for >24 hours between January 2017 and October 2020, a baseline potassium level of ≥3.5 mmol/L and potassium measurement during treatment were included. The primary endpoint was incidence of hypokalemia defined as the percentage of patients with a potassium measurement 8 g/24 hours. No sex differences were found for lower daily doses. Other risk factors for hypokalemia were older age, concomitant antibiotic use, lower bodyweight, lower baseline plasma potassium concentration and longer treatment duration. Conclusion Hypokalemia is a frequent complication in patients treated with intravenous flucloxacillin. Females receiving >8 g intravenous flucloxacillin per day are more prone to develop hypokalemia compared to males.

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.

We aimed to investigate the association between antidepressants and serum lipid levels in a population-based study in older adults. We included participants from the prospective Rotterdam Study with data on lipid levels (total, low-density lipoprotein (LDL) and high-density lipoprotein cholesterol, and triglycerides). We classified antidepressants based on binding affinity to the serotonin transporter (low/intermediate- and high-affinity antidepressants). We compared lipid levels in users of these groups of antidepressants with lipid levels in non-users. Furthermore, we studied effect modification by the 102C>T polymorphism (HTR2A gene), which is associated with antidepressant drug response and metabolic outcomes. Compared with non-users (N = 6438), LDL cholesterol level was higher (2.9 versus 3.1 mmol/L, respectively; p = 0.05) in users of high-affinity antidepressants (N = 89). Similar levels of the other lipids were observed between the groups for the other lipids. The mean difference in serum LDL cholesterol level between non-users and users of high-affinity antidepressants was largest in participants with the CC genotype compared with the other genotypes (notably 0.47 mmol/L), indicative of effect modification (p-value for interaction = 0.03). Antidepressants with a high serotonin reuptake transporter affinity were associated with higher LDL cholesterol levels, which were modified by a common genetic variation in the HTR2A gene.