Quick assessment of drug-related admissions over time (QUADRAT study).

PURPOSE: To develop a computerized prescreening procedure for the identification of possible/probably Hospital Admissions potential Related to Medications (HARMs). METHOD: Pairs of drugs and reasons for hospitalization (generated automatically from the PHARMO record linkage database by using two data mining techniques) were assessed manually to determine whether they represented pharmacologically plausible adverse drug events (PP-ADEs). Two crude samples of these PP-ADEs (from 2005 and 2008) were examined manually to establish causality and preventability on the basis of hospital discharge letters plus medication dispensing data. The results were used to calculate the positive predictive value (PPV) of the crude causality PP-ADEs, the net percentage of possible/probably HARMs, and their potential preventability. RESULTS: Data mining by Gamma Poisson Shrinkage and trend analysis produced 1330 and 2941 significant drug-event pairs, respectively. After manual assessment, 307 different PP-ADEs remained. The annual prevalence of these PP-ADEs was stable at approximately 8% throughout 2000-2009. Manual assessment of two samples of crude PP-ADEs showed that their causality PPV was 53.7% (95%CI: 52.7%-54.7%) in 2005 and 47.9% (95%CI: 46.9%-49.0%) in 2008. The net contribution of possible/probably HARMs to all acute admissions was 4.6% (95%CI: 4.5%-4.8%) in 2005 and 3.9% (95%CI: 3.8%-4.0%) in 2008. The potential preventability of all possible/probably HARMs in the two samples was 19.3% (95%CI: 18.5-20.1). CONCLUSION: Automated pre-selection of PP-ADEs is an efficient way to monitor crude trends. Further validation and manual assessment of the automatically selected hospitalizations is necessary to get a more detailed and precise picture.

Thiazide-associated hyponatremia: a population-based study.

BACKGROUND: Hyponatremia is one of the most common adverse reactions to thiazide diuretics. In the present study, we analyzed differences in thiazide-associated hyponatremia between men and women and between different categories of age, body mass index (BMI), daily thiazide dose, and estimated glomerular filtration rate. STUDY DESIGN: Population-based cohort study. SETTING & PARTICIPANTS: 13,325 individuals 45 years and older living in a suburb of Rotterdam, as part of the Rotterdam Study. PREDICTOR: Exposure to thiazide diuretics. OUTCOMES: The association between thiazide exposure and hyponatremia (defined as sodium level ≤135 mmol/L; mild hyponatremia, 130-≤135 mmol/L; moderate, >125-<130 mmol/L; and severe, ≤125 mmol/L) was studied in a period covering more than 10 years using Cox proportional hazard regression analyses. RESULTS: 718 participants used thiazides at baseline, and 2,738 participants started on thiazide therapy during follow-up. 522 participants developed hyponatremia, of whom 32.4% were exposed to thiazide diuretics at the time of hyponatremia. Thiazide exposure was associated with an almost 5 times higher risk of hyponatremia than no exposure (HR, 4.95; 95% CI, 4.12-5.96). The risk of mild hyponatremia was more than 4.5 times higher in thiazide-exposed individuals; risks of moderate and severe hyponatremia were both 8 times higher in individuals exposed to thiazides. Age and BMI (but not sex [P = 0.8] or estimated glomerular filtration rate [P = 0.2]) significantly modified this risk of thiazide-associated hyponatremia (P < 0.05). LIMITATIONS: Some cases of severe hyponatremia may have been missed if patients were admitted to the hospital without assessment of serum sodium in the general practitioner's laboratory. Nonproportionality of hazards in the first period was explained as possible "depletion of susceptibles" in this closed cohort. CONCLUSIONS: Thiazide use is associated with a substantially increased risk of hyponatremia. Age and BMI significantly influenced the thiazide-associated risk of hyponatremia.

Sex differences in cardiovascular drug-induced adverse reactions causing hospital admissions.

AIMS: Cardiovascular disease in women is often underestimated. The effects of cardiovascular drugs differ between the sexes because of pharmacokinetic and pharmacodynamic differences. Adverse drug reactions (ADRs) within these drug classes may have serious consequences, leading to hospital admission. We aimed to study differences between men and women in hospital admissions for ADRs due to cardiovascular drugs. METHODS: We conducted a nationwide study of all hospital admissions between 2000 and 2005 with data from the Dutch National Medical Register. Relative risks were calculated of hospital admissions due to ADRs to the different cardiovascular drug groups for women compared with men. By an ecological design, risks were adjusted for the total number of Dutch inhabitants and the total number of prescriptions. RESULTS: In total, 14 207 of the hospital admissions (34% of all ADR-related admissions) were attributed to cardiovascular drugs [7690 in women (54%; 95% confidence interval 53-55%)]. 'Anticoagulants and salicylates' (n= 8988), 'high- and low-ceiling diuretics' (n= 2242) and 'cardiotonic glycosides' (n= 932) were responsible for the majority of the ADR-related hospital admissions. The most pronounced sex differences were seen in users of low-ceiling diuretics (relative risk 4.02; 95% confidence interval 3.12-5.19), cardiotonic glycosides (relative risk 2.38; 95% confidence interval 2.06-2.74), high-ceiling diuretics (relative risk 2.10; 95% confidence interval 1.91-2.32) and coronary vasodilators (relative risk 0.77; 95% confidence interval 0.65-0.91). CONCLUSIONS: Clear sex differences exist in ADRs requiring hospital admission for different cardiovascular drug groups. Sex differences should be taken into account in the prescription and evaluation of drugs.

Invited commentary: sex-steroid hormones and QT-interval duration.

In this issue of the Journal, Zhang et al. (Am J Epidemiol. 2011;174(4):403-411) make a substantial contribution to research in the area of hormonal influences on cardiac repolarization by demonstrating an inverse association between testosterone levels and the Bazett's adjusted QT interval (QTc) and RR-adjusted QT interval in men but not in postmenopausal women. They suggest that testosterone levels might explain the difference in QTc-interval duration between men and women and could contribute to population variability in QTc-interval duration among men. In this commentary, the gender difference and the role of testosterone in human cardiac repolarization are addressed. In addition, the gender differences in the congenital long-QT syndrome, drug-induced ventricular arrhythmias, and sudden cardiac death are discussed.

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.

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.

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.

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.

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.

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

BACKGROUND: 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.

CYP1A2 and coffee intake and the modifying effect of sex, age, and smoking.

BACKGROUND: The enzyme CYP1A2 (cytochrome 1A2) is involved in the metabolism of certain drugs and caffeine, and its activity can be influenced by factors such as sex, age, and smoking. The single nucleotide polymorphism (SNP) rs762551A>C, which has also been studied for its modifying effect on cardiovascular disease, has been reported to alter enzyme activity. OBJECTIVE: The objective was to study the effect of CYP1A2, sex, age, and smoking on coffee intake. DESIGN: Within the Rotterdam Study, a population-based cohort, all coffee drinkers for whom genome-wide association data were available were selected. Because SNP rs762551 was not on the Illumina 550 platform, SNP rs2472299 was used as a proxy, with the A allele of rs762551 linked to the G allele of rs2472299. Linear regression analyses were used to determine the effect and interaction of rs2472299, sex, age, and smoking on coffee intake. Adjusted geometric means of coffee intake were calculated per genotype for the different smoking and sex strata by using multivariable general linear models. A combined analysis, with the use of a "risk score," was performed to determine the contribution of each separate factor. RESULTS: rs2472299G>A, female sex, and nonsmoking were significantly inversely related to coffee intake. Coffee intake was lowest in nonsmoking women homozygous for rs2472299G>A (3.49 cups/d; ∼436 mL). All factors contributed almost linearly to the intake of coffee, with the highest coffee intake in smoking men without the A allele (5.32 cups/d; ∼665 mL). CONCLUSION: rs2472299G>A, linked to rs762551A>C, sex, age, and smoking significantly contribute to coffee intake.

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 Cox's 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.

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.