Eline M. Rodenburg

Electrolyte disorders in community subjects: Prevalence and risk factors

BACKGROUND Electrolyte disorders have been studied mainly in hospitalized patients, whereas data in the general population are limited. The aim of this study was to determine the prevalence and risk factors of common electrolyte disorders in older subjects recruited from the general population. METHODS A total of 5179 subjects aged 55 years or more were included from the population-based Rotterdam Study. We focused on hyponatremia, hypernatremia, hypokalemia, hyperkalemia, and hypomagnesemia. Multivariable logistic regression was used to study potential associations with renal function, comorbidity, and medication. The adjusted mortality also was determined for each electrolyte disorder. RESULTS A total of 776 subjects (15.0%) had at least 1 electrolyte disorder, with hyponatremia (7.7%) and hypernatremia (3.4%) being most common. Diabetes mellitus was identified as an independent risk factor for hyponatremia and hypomagnesemia, whereas hypertension was associated with hypokalemia. Diuretics were independently associated with several electrolyte disorders: thiazide diuretics (hyponatremia, hypokalemia, hypomagnesemia), loop diuretics (hypernatremia, hypokalemia), and potassium-sparing diuretics (hyponatremia). The use of benzodiazepines also was associated with hyponatremia. Hyponatremic subjects who used both thiazides and benzodiazepines had a 3 mmol/L lower serum sodium concentration than subjects using 1 or none of these drugs (P < .001). Hyponatremia and hypomagnesemia were independently associated with an increased mortality risk. CONCLUSIONS Electrolyte disorders are common among older community subjects and mainly associated with diabetes mellitus and diuretics. Subjects who used both thiazides and benzodiazepines had a more severe degree of hyponatremia. Because even mild electrolyte disorders were associated with mortality, monitoring of electrolytes and discontinuation of offending drugs may improve outcomes.

Sex-related differences in hospital admissions attributed to adverse drug reactions in the Netherlands

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT Women are more at risk for developing adverse drug reactions (ADRs) due to differences in pharmacokinetics, pharmacodynamics and drug use. ADRs regularly lead to hospital admissions. WHAT THIS STUDY ADDS There are differences between the sexes in hospital admissions attributed to ADRs. The risk of being hospitalized with an ADR varies between the sexes in the type of reaction and the causative drug. AIM Adverse drug reactions (ADRs) are a major burden in health care, regularly leading to hospital admission, morbidity or death. Women tend to have a higher risk of adverse drug reactions with a 1.5 to 1.7-fold greater risk than men. Our primary aim was to study differences in ADR-related hospitalizations between the sexes. METHODS We conducted a nationwide study of all ADR-related hospitalizations in the period between 2000 and 2005 in the Netherlands, which were selected from all 9,287,162 hospital admissions in this period. ADR-drug group combinations with at least 50 admissions in one of the sexes were selected. Relative risks and confidence intervals were calculated with respect to total admissions and total prescriptions with men as reference. RESULTS In total, 0.41% of the 4,236,368 admissions in men (95% CI 0.40, 0.42%) and 0.47% of the 5,050,794 admissions in women (95% CI 0.46, 0.48%) were attributed to an ADR by medical specialists (57% of all ADR-related admissions were in women). Differences between the sexes in risk for ADR-related hospitalization were found for antineoplastic and immunosuppressive drugs, antirheumatics, anticoagulants and salicylates, cardiovascular and neurological drugs, steroids and antibiotics. In certain drug categories, risks for hospitalization changed after taking into account total drug prescriptions. CONCLUSION In all different drug classes, significant differences exist between the sexes in ADR-related hospital admissions. Cardiovascular drugs account for the most pronounced differences between men and women. More research is needed to explain the clear sex differences in ADR-related hospital admissions.

Adverse drug reaction-related hospitalizations in persons aged 55 years and over: a population-based study in the Netherlands.

AbstractBackground: Elderly individuals appear to be particularly at risk of developing adverse drug reactions (ADRs) because of higher rates of polypharmacy, age-related pharmacokinetic changes, pharmacodynamic variations and substantial co-morbidity levels. Thus, the increasing contribution of elderly individuals to the total population means ADR-related hospitalizations are expected to become more frequent. However, a recent study conducted in the Netherlands found that ADR-related hospitalizations had stabilized during the years 1997–2007. Nonetheless, this study did not take into account the number of medicines used. Objectives: Therefore, the objectives of this study were to describe the association between age and sex, and the risk of an adverse drug reaction (ADR)-related hospitalization in persons aged 55 years and over in the Netherlands and to correlate these ADR-related hospitalizations with the number of dispensed medicines over the same period. Methods: Data on hospital admissions were obtained from the Dutch nationwide registry of hospital discharges. Data from Statistics Netherlands were used to obtain population demographics. Data on dispensed medicinal products were obtained from the Dutch Foundation for Pharmaceutical Statistics. Analyses were performed by calculating relative risks (RRs). Results: Those aged ≥75 years were at a more than 4-fold increased risk of being hospitalized in comparison with those aged 55–64 years (RR 4.15; 95% CI 4.12, 4.18). In addition, female sex was associated with an increased risk of an ADR-related hospitalization (RR 1.05; 95% CI 1.03, 1.08) in comparison with males. When taking into account the number of dispensings, elderly ≥75 years of age were at an increased risk of being hospitalized for an ADR due to anticoagulants (RR 2.20; 95% CI 2.12, 2.28), antidiabetic agents (RR 3.53; 95% CI 3.39, 3.66), salicylates (RR 1.70; 95% 1.54, 1.86) and antirheumatics (RR 2.19; 95% CI 2.06, 2.33). Conclusion: In our study, we showed that elderly aged ≥75 years were at increased risk of an ADR-related hospitalization. Given that the number of elderly and very old will continue to grow, it is of pivotal importance to further endorse drug safety in this vulnerable patient group.

Adverse drug reaction-related hospitalizations in persons aged 55 years and over

AbstractBackground: Elderly individuals appear to be particularly at risk of developing adverse drug reactions (ADRs) because of higher rates of polypharmacy, age-related pharmacokinetic changes, pharmacodynamic variations and substantial co-morbidity levels. Thus, the increasing contribution of elderly individuals to the total population means ADR-related hospitalizations are expected to become more frequent. However, a recent study conducted in the Netherlands found that ADR-related hospitalizations had stabilized during the years 1997–2007. Nonetheless, this study did not take into account the number of medicines used. Objectives: Therefore, the objectives of this study were to describe the association between age and sex, and the risk of an adverse drug reaction (ADR)-related hospitalization in persons aged 55 years and over in the Netherlands and to correlate these ADR-related hospitalizations with the number of dispensed medicines over the same period. Methods: Data on hospital admissions were obtained from the Dutch nationwide registry of hospital discharges. Data from Statistics Netherlands were used to obtain population demographics. Data on dispensed medicinal products were obtained from the Dutch Foundation for Pharmaceutical Statistics. Analyses were performed by calculating relative risks (RRs). Results: Those aged ≥75 years were at a more than 4-fold increased risk of being hospitalized in comparison with those aged 55–64 years (RR 4.15; 95% CI 4.12, 4.18). In addition, female sex was associated with an increased risk of an ADR-related hospitalization (RR 1.05; 95% CI 1.03, 1.08) in comparison with males. When taking into account the number of dispensings, elderly ≥75 years of age were at an increased risk of being hospitalized for an ADR due to anticoagulants (RR 2.20; 95% CI 2.12, 2.28), antidiabetic agents (RR 3.53; 95% CI 3.39, 3.66), salicylates (RR 1.70; 95% 1.54, 1.86) and antirheumatics (RR 2.19; 95% CI 2.06, 2.33). Conclusion: In our study, we showed that elderly aged ≥75 years were at increased risk of an ADR-related hospitalization. Given that the number of elderly and very old will continue to grow, it is of pivotal importance to further endorse drug safety in this vulnerable patient group.

Risk of Hyponatremia with Diuretics: Chlorthalidone versus Hydrochlorothiazide

BACKGROUND Chlorthalidone and hydrochlorothiazide are often considered as interchangeable. However, greater (nighttime) blood pressure reduction, and alleged pleiotropic effects have renewed the interest in chlorthalidone. A recent study showed an increased risk of adverse events with chlorthalidone, including hyponatremia. METHODS To investigate differences in risk of hyponatremia between chlorthalidone and hydrochlorothiazide, adjusted for daily dose, we conducted a population-based case-control study within the Dutch IPCI (Integrated Primary Care Information) database. The study population included all subjects ≥18 years without diabetes mellitus, heart failure, liver failure, and malignancy, who were registered in the IPCI database from 1996 to 2011. Cases were subjects with a serum sodium <130 millimoles per liter or hospitalization due to hyponatremia. Controls were matched on practice, age within 5 years, sex, and date of onset. RESULTS A total of 1033 cases of hyponatremia were identified. Hyponatremia was more common with chlorthalidone than with hydrochlorothiazide at equal dose per day: adjusted odds ratio was 2.09 (95% confidence interval [CI], 1.13-3.88) for 12.5 milligrams per day and 1.72 (95% CI, 1.15-2.57) for 25 milligrams per day. Risks were not significantly increased with chlorthalidone compared with twice the dose per day of hydrochlorothiazide. CONCLUSIONS This is the first study that shows an increased risk of hyponatremia with chlorthalidone relative to hydrochlorothiazide at equal milligram-to-milligram dose per day. The need for a lower dose of chlorthalidone than hydrochlorothiazide to achieve similar blood pressure reduction likely compensates for the increased risk of hyponatremia at equal dose.

High-ceiling diuretics are associated with an increased risk of basal cell carcinoma in a population-based follow-up study

INTRODUCTION In Caucasians, basal cell carcinoma (BCC) is among the most frequently diagnosed cancers and its incidence is increasing. Known risk factors for the development of BCC are age, sun exposure, and certain skin characteristics. Despite photosensitizing abilities of diuretic agents, little is known about a possible association with BCC. METHODS Data were obtained from the Rotterdam Study; a large prospective population-based follow-up study with coverage of prescription-only drugs from pharmacies. The diagnoses of BCC were obtained through general practitioners, and by linkage with a registry of histo- and cytopathology. Cumulative use of diuretics at the date of diagnosis was categorized into quartiles for users of high-ceiling diuretics, potassium sparing agents and thiazides. The association between these drugs and BCC was assessed by Cox proportional hazard modeling with adjustment for age, gender and potential confounders. Effect modification was tested with interaction terms. RESULTS Use of high-ceiling diuretics in the highest quartile (>3.7 years cumulative exposure) was associated with an increased hazard of BCC of 62% compared to no use (HR 1.6; 95% CI 1.1-2.4). Patients who used high-ceiling diuretics and had a high tendency of getting sunburned had a higher risk of diagnosis than non-users who do not easily get sunburned. Neither the use of potassium sparing agents, nor the use of thiazides was associated with BCC. CONCLUSION In our study, cumulative use of high-ceiling diuretics was associated with an increased risk of diagnosis of BCC. This effect is stronger in patients who easily get sunburned.

Isotretinoin use and compliance with the Dutch Pregnancy Prevention Programme: a retrospective cohort study in females of reproductive age using pharmacy dispensing data.

AbstractBackground: Isotretinoin is very effective in the treatment of severe acne. However, because of the teratogenic properties of this agent an isotretinoin Pregnancy Prevention Programme (PPP) was implemented in the Netherlands to guarantee that treatment is contraindicated in women of reproductive age unless at least one effective method of contraception is used. Furthermore, the PPP stipulates that isotretinoin treatment should be managed by physicians or specialists experienced in treatment with this drug and that only monthly prescriptions are issued. Objective: To assess compliance with the Dutch isotretinoin PPP in women of reproductive age during the study period of 1 January 2005 to 31 December 2008. Methods: Detailed information on dispensed medication and co-medication was available from the Dutch Foundation of Pharmaceutical Statistics. Four types of outcome were studied: concomitant dispensing of hormonal contraceptive with isotretinoin; the proportion of specialist prescribing of isotretinoin; prescribing of conventional acne therapy prior to isotretinoin initiation; and isotretinoin dispensing exceeding the maximum amount. The use of contraceptives in women aged between 15 and 45 years was defined as concomitant if the period of systemic contraceptive use overlapped the period of isotretinoin dispensing for at least 10 days, or if any dispensing of an intrauterine or intravaginal contraceptive was recorded since the year 2000. Dispensings were separated into those prescribed by either specialists or general practitioners (GPs). The use of antibacterials, anti-androgens or topical agents against acne was checked 4 months prior to an isotretinoin dispensing, and a possible excess of the maximum amount of isotretinoin was defined as prescriptions of more than 100 defined daily doses. Results: During the study period, data were available for 442 Dutch pharmacies encompassing 4881 women of reproductive age using isotretinoin at least once during study period. Among women of reproductive age, the use of isotretinoin increased during the study period. The proportion of isotretinoin initiation with concomitant oral hormonal or intrauterine contraceptives was low (59.3% [95% CI 57.6, 61.0]). Initiation of isotretinoin by a specialist increased the chance for concomitant contraception by 26% (95% CI 6.0, 49.0); in 78.2% (95% CI 76.8, 79.6) of women, isotretinoin was initiated by a specialist. Conventional acne therapy up to 16 months prior to isotretinoin initiation was found in 70% of the women (70.3% [95% CI 66.0, 74.6]). In 1.4% (95% CI 1.0, 1.8) of cases of treatment initiation, the amount of isotretinoin dispensed on one prescription seemed too high. Conclusion: Attention should be paid to improving the implementation of the isotretinoin PPP. Despite clear guidelines and warnings in the product information, our study strongly suggests that concomitant use of isotretinoin and contraceptives is too low. Even though we will have missed non-pharmacological forms of contraception, these results raise doubts about the safe use of isotretinoin in women of reproductive age in the Netherlands. Furthermore, isotretinoin does not seem to be used in cases of severe acne only. Reserving isotretinoin prescribing to specialists may improve adherence to the PPP.

History of tuberculosis as an independent prognostic factor for lung cancer survival

INTRODUCTION It is well known that pulmonary tuberculosis is associated with an increased risk of lung cancer. We investigated whether a history of pulmonary tuberculosis is an independent risk factor for lung cancer survival in Caucasian patients. METHODS The data of the prospective population-based cohort of The Rotterdam Study were used. During a mean follow-up time of 18 years, there were 214 incident cases of pathology-proven lung cancer in a source population of 7983 study participants. History of tuberculosis was assessed at baseline by interviewers using standardized questionnaires. Associations of lung cancer survival with the occurrence of pulmonary tuberculosis were assessed using Coxs proportional hazard regression analysis adjusted for age, gender, pack-years, educational level and tumor stage. RESULTS A history of tuberculosis was reported in 13 of the 214 subjects with lung cancer. The survival of patients with lung cancer was significantly shorter in subjects with a history of pulmonary tuberculosis (HR=2.36, CI95%: 1.1-4.9), than in subjects without a history of pulmonary tuberculosis with a mean difference of 311 days. CONCLUSION The presence of a history of pulmonary tuberculosis may be an important prognostic factor in the survival of lung cancer.

Thiazides and the risk of hypokalemia in the general population.

Objectives: Hypokalemia is a frequent adverse reaction to thiazide diuretics, but is often asymptomatic. However, even asymptomatic hypokalemia may contribute to chronic disabilities and mortality. The aim of this study was to assess the risk of thiazide-induced hypokalemia in men and women in the general population. Methods: Within the Rotterdam study, which is a population-based cohort study, the association between thiazide exposure and hypokalemia (serum potassium level <3.5 mmol/l; moderate to severe ⩽3.0 mmol/l) was studied using Cox proportional-hazard regression analysis over a 10-year period, with thiazide use as a time-varying exposure. Results: During follow-up, 507 cases of hypokalemia occurred in 13 328 patients. Thiazide use was associated with an 11 times higher risk of hypokalemia than no use [relative risk (RR) 11.18, 95% confidence interval (CI) 8.95, 13.96] after adjustment for sex, age, and use of a renin–angiotensin system (RAS) inhibitor or separate potassium-sparing diuretic. In users of a thiazide in combination with triamterene, the risk was still six times higher (RR 5.93, 95% CI 4.65, 7.55) than in nonusers. The risk of thiazide-induced hypokalemia was significantly higher in men than in women and changed significantly with age and dosage. The risk of moderate to severe hypokalemia was almost five times higher in thiazide users (RR 4.80, 95% CI 2.61, 8.84) than in nonusers. Conclusion: The risk of thiazide-induced hypokalemia is high, and more than twice as high in men as in women. Hypokalemia risk is influenced by age and dosage, and is still increased if used in combination with triamterene.

Genetic variance in CYP2C8 and increased risk of myocardial infarction.

Background Epoxyeicosatrienoic acids (EETs) are important mediators in vasodilatation, acting as endothelium-derived hyperpolarizing factors. CYP2C enzymes catalyze the metabolism of arachidonic acid to EETs. Genetic variation within the genes encoding for these enzymes may result in differences in vascular response, among others in myocardial tissue, and may therefore increase the risk of myocardial infarction (MI). CYP2C8 and CYP2C9 are encoded by the genes of the same name. CYP2C9 polymorphisms have been associated with an increased risk of MI. As CYP2C8 is genetically linked to CYP2C9 and on account of its role in EET production, we hypothesized that CYP2C8 polymorphisms are associated with the risk of MI. Methods This study was embedded within the Rotterdam study, a prospective population-based cohort study. The study population included all participants with successful genotyping and without prevalent MI (n=5199). Twenty-five tagging single nucleotide polymorphisms within and around the gene-coding areas of CYP2C8 and CYP2C9 were tested for an association with incident MI using survival analysis techniques with multivariable adjustment for potential confounders. Results During follow-up, 290 persons developed an incident MI. One tag-SNP in the CYP2C8 gene was associated with incident MI after Bonferroni correction, rs1058932C>T (variant genotype hazard ratio 1.54; 95% CI: 1.22–1.95). There was a significant gene–sex interaction with a relative excess risk of 1.40 (95% CI: 0.33–2.47) for men. Conclusion SNP rs1058932C>T within the CYP2C8 gene is associated with an increased risk of MI, which is, possibly because of a vascular effect of sex steroids, highest in males.