Search

Purpose Antidepressants are well-established fall-risk increasing drugs (FRIDs) and therefore falls should be considered an important adverse drug event (ADE) of antidepressants. However, not all antidepressant users experience fall incidents and factors associated with increased fall risk among antidepressant users are incompletely understood. Our objective was to explore whether antidepressant plasma concentrations are associated with falls in older antidepressant users. Methods For this study, we included antidepressant users of the multicenter B-PROOF study. Fall incidents were recorded prospectively using fall calendars. Antidepressant plasma concentrations were analyzed by Liquid chromatography-mass spectrometry (LC–MS) at baseline and at 2 years follow-up. The associations between the observed antidepressant concentration and fall risk were assessed using Cox proportional hazard and logistic regression models and adjusted for potential confounders. Results In total 93 selective serotonin reuptake inhibitor (SSRI) and 41 antidepressant (TCA) users were identified. There was a significant association between baseline TCA plasma concentration and fall risk within users (HR 2.50, 95% CI 1.07–5.87, crude model). In the adjusted model, there were no significant associations between concentrations of SSRIs and fall risk. Conclusion There might be an association between plasma concentrations of TCAs and the risk of falling in older users. However, these results needs to be interpreted with caution considering the small sample size and accompanying limitation of confinement to crude analyses. Therefore, these novel findings need to replicated in a larger cohort, preferably including adjustment for potential confounders and more frequent measures of plasma concentrations is needed.

Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Senior Scientist Grant from the Dutch Heart Foundation. Aims Due to their dependence on temporality, current atrial fibrillation (AF) classifications are inaccurate and impractical in large cohort studies, resulting in scarce evidence on prognostic differences between AF patterns in the general population. Using our recently developed AF classification, we investigated potential differences in cardiovascular prognosis among participants with various AF patterns and matched non-AF individuals from the general population. Methods 1,111 individuals from the general population were classified as 'single-documented AF episode' (sAF), 198 as 'multiple-documented AF episodes' (mAF), and 52 as 'longstanding persistent AF' (lpAF). Each group was independently matched with non-AF participants through propensity score matching. Participants were followed for the development of coronary heart syndrome (CHD), stroke, heart failure (HF), and cardiovascular mortality. Cox proportional hazards regression analyses were performed to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for each AF pattern. Results Stroke risk was 1.01; 0.82-1.28 (HR; 95% CI) for sAF, 1.36; 0.87-2.11 for mAF, and 1.44; 0.79-3.54 for lpAF, as compared to their matched participants. HF risk was larger in all AF patterns, with the gradient corresponding to AF severity: 3.48; 1.61-7.55 for lpAF, 2.78; 1.94-3.98 for mAF, and 1.71; 1.44-2.03 for sAF. Compared to non-AF participants, cardiovascular mortality risk was larger in the sAF (1.56; 1.37-1.79) and mAF (1.53; 1.11-2.12) categories, but not for lpAF (0.85; 0.40-1.82). Conclusion More severe AF patterns in the general population carried a larger HF risk. We observed a trend regarding a larger stroke risk in more severe AF patterns, albeit statistically not significant. Our new AF classification method may benefit comorbidity and mortality risk stratification associated with AF in a general population.

Aim Antidepressants are well-established fall-risk increasing drugs(FRIDs) and therefore falls should be considered an important adverse drug event(ADE) of antidepressants. However, not all antidepressant users experience fall incidents and factors associated with increased fall risk among antidepressant users are incompletely understood. Our objective was to explore whether antidepressant plasma concentrations are associated with falls in older antidepressant users. Methods For this study, we included antidepressant users of the multicenter B-PROOF study. Fall incidents were recorded prospectively using fall calendars. Antidepressant plasma concentrations were analyzed by Liquid chromatography-mass spectrometry(LC-MS) at baseline and at 2 years follow-up. The associations between the observed antidepressant concentration, or concentration change over time (delta) and fall risk were assessed using Cox proportional hazard and logistic regression models and adjusted for potential confounders. Results In total 93 selective serotonin reuptake inhibitor(SSRI) and 41 antidepressant(TCA) users were identified. There was a significant association between baseline TCA plasma concentration and fall risk within users (HR 2.50, 95% CI 1.07-5.87, crude model). Adjusted there were no significant associations between concentrations of SSRIs and fall risk. Also, for delta concentrations there was no association with fall risk in users. Conclusion There might be an association between plasma concentrations of TCAs and the risk of falling in older users. However, these results needs to be interpreted with caution considering the small sample size and accompanying limitation of confinement to crude analyses. Therefore, replication in a larger cohort, preferably including adjustment for potential confounders and more frequent measures of plasma concentrations is needed.

Background Both elevated and low resting heart rates are associated with atrial fibrillation (AF), suggesting a U-shaped relationship. However, evidence for a U-shaped causal association between genetically-determined resting heart rate and incident AF is limited. We investigated potential directional changes of the causal association between genetically-determined resting heart rate and incident AF. Method and results Seven cohorts of the AFGen consortium contributed data to this meta-analysis. All participants were of European ancestry with known AF status, genotype information, and a heart rate measurement from a baseline electrocardiogram (ECG). Three strata of instrumental variable-free resting heart rate were used to assess possible non-linear associations between genetically-determined resting heart rate and the logarithm of the incident AF hazard rate: 75 beats per minute (bpm). Mendelian randomization analyses using a weighted resting heart rate polygenic risk score were performed for each stratum. We studied 38,981 individuals (mean age 59±10 years, 54% women) with a mean resting heart rate of 67±11 bpm. During a mean follow-up of 13±5 years, 4,779 (12%) individuals developed AF. A U-shaped association between the resting heart rate and the incident AF-hazard ratio was observed. Genetically-determined resting heart rate was inversely associated with incident AF for instrumental variable-free resting heart rates below 65 bpm (hazard ratio for genetically-determined resting heart rate, 0.96; 95% confidence interval, 0.94–0.99; p = 0.01). Genetically-determined resting heart rate was not associated with incident AF in the other two strata. Conclusions For resting heart rates below 65 bpm, our results support an inverse causal association between genetically-determined resting heart rate and incident AF.

Background: The appendix, an organ of immunological and microbiological importance, could be involved in the pathogenesis of cancers, but results are inconclusive. Our objective was to assess the association between appendectomy and the subsequent risk of cancer.Methods: Data were obtained from the Rotterdam Study; a long-term prospective population-based study of individuals aged 55 years and older, of which the first cohort started in 1990 and included 7983 participants. Information on appendectomy was obtained through either medical interview at baseline or linkage with the national automated pathology center (PALGA). Cancer cases were pathology based. End of follow-up was January 1st, 2015. The association between appendectomy and risk of cancer was assessed using Cox proportional hazard models, adjusted for known confounders.Results: Of 7135 included participants, 1373 (19.2%) had undergone an appendectomy and 1632 individuals developed cancer. After adjustment for age, sex, socioeconomic status, BMI, smoking, prevalent diabetes mellitus and alcohol intake, a history of appendectomy was associated with a significantly lower risk of cancer [hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.75-0.98]. Subgroup analyses showed similar results for gastrointestinal cancer (HR 0.75, 95% CI 0.56-0.99), in particular colon cancer (HR 0.65, 95% 0.43-0.97), and cancer of the female reproductive organs (HR 0.35, 95% CI 0.15-0.80).Conclusion: Participants who underwent an appendectomy had a reduced risk of cancer in general after adjustment for potential confounders. Therefore, these results contradict earlier studies suggestive of an increased risk. Further research is necessary to replicate these results and reveal its underlying mechanism.

Introduction: Increasing resistance to beta-lactam antibiotics is an alarming development worldwide. Fecal carriership of TEM, SHV, CTX-M and CMY was studied in a community-dwelling population of middle-aged and elderly individuals.Patients and methods: Feces was obtained from individuals of the Rotterdam Study. Carriership of the TEM, SHV, CTX-M and CMY genes was determined using real-time polymerase chain reaction (qPCR). Possible associations were investigated between carriership of these genes and several risk factors, such as the use of antimicrobial drugs, diabetes mellitus, protein pump inhibitor (PPI) use, travelling, the composition of the gut microbiota, and intake of certain foods.Results: The most prevalent gene was TEM (53.0%), followed by SHV (18.4%), CTX-M (5.4%) and CMY (3.6%). Use of penicillins with extended spectrum was associated with TEM carriership, whereas use of macrolides and lincosamides was associated with TEM and SHV carriership. Interestingly, use of PPIs was associated with a higher prevalence of carriership of TEM, SHV and CMY (TEM: odds ratio [OR] 1.34; 95% confidence interval [CI] 1.05-1.77; SHV: OR 2.17; 95%CI 1.55-2.87; CMY: OR 2.26; 95%CI 1.23-4.11). Furthermore, associations were found between the richness and composition of the gut microbiota and TEM and SHV carriership.Conclusions: The prevalence of carriership of TEM was substantial, but the prevalence of carriership of the extended-spectrum beta-lactamase gene, CTX-M and the AmpC beta-lactamase gene, CMY was relatively low in this community-dwelling, population-based cohort. The composition of the microbiota might play a role in the retention of resistance genes, but future studies are necessary to further elucidate this relationship. (C) 2021 Published by Elsevier Ltd.

Additional file 1.

Additional file 3.

Background Digoxin is one of the oldest cardiovascular medications still used to treat heart failure and atrial fibrillation. Due to its narrow therapeutic window, it is associated with life threatening intoxication and arrhythmias, and with QTc-shortening. Common genetic variation in the nitric oxide synthase-1 adaptor protein (NOS1AP) has been associated with QTc interval prolongation. Purpose We investigated whether the rs10494366 variant of the NOS1AP gene modified the risk of SCD in patients using digoxin. Methods In a prospective population-based cohort study, we included data of the three cohorts, started as of January 1st, 1991 until January 1st 2014. Digoxin current use on the date of cardiac death in cases and the same day of follow-up in the remainder of the cohort was a time-dependent exposure. The main outcome was SCD defined as sudden and unexpected death as a result of cardiac causes, according to international criteria. Identification and adjudication of SCD was performed independently, before the start of this study. We used Cox proportional hazard regression analysis to investigate the associations between NOS1AP rs10494366 variant and incident SCD among digoxin users compared to non-users. Associations were adjusted for age, sex (model 1) in addition to BMI, prevalent diabetes, myocardial infarction, baseline hypertension and smoking status (past, current, never) (model 2). Results We included 14,594 individuals, with a mean age of 65.3 (SD 10.3) years. Almost 59% were female. The cumulative incidence of SCD was 9.5% (609 cases) by the end of follow up. Among them, 98 (16%) individuals were exposed to digoxin at the time of death. In model 1, NOS1AP rs10494366 variant was not associated with SCD in the total study population. However, an interaction term of the gene with the daily dose of digoxin was significantly associated with increased risk of SCD (p-value 0.0001). In model 2, the risk of SCD in current users of digoxin was 4.2 [95% CI 1.3–13.8] for the GG genotype; 2.1 [95% CI 1.1–4.2] for the GT genotype, and 1.5 [95% CI 0.7–3.2] for the TT genotype. Conclusion NOS1AP rs10494366 variant modified the risk of sudden cardiac death in users of digoxin. Our study suggests that individuals with the homozygous minor GG allele have a fourfold increased risk of sudden cardiac death. Funding Acknowledgement Type of funding source: None

Objectives There is an ongoing debate as to what extent antimicrobial resistance (AMR) can be transmitted from animals to humans via the consumption of animal products. Because epidemiological data on the role of diet in AMR in humans are lacking, we investigated this association between diet and AMR for different antimicrobial drugs in Escherichia coli (E. coli) in urinary tract infections (UTIs). Methods Susceptibility of E. coli in urinary cultures and information on diet (with food frequency questionnaires) were obtained from participants of the Rotterdam study, a population-based prospective cohort study. The association between intake of several food groups (meat, seafood, eggs, dairy products, crops) and resistance of E. coli to several antimicrobial drugs (amoxicillin, amoxicillin-clavulanic acid, trimethoprim, sulfamethoxazole-trimethoprim, first-generation cephalosporins, cefotaxime, nitrofurantoin, norfloxacin) was studied. Results Urinary cultures with E. coli were obtained from 612 individuals, of whom 481 (78.6%) were women. Resistance rates varied from 246/611 (40.3%) for amoxicillin and 167/612 (27.3%) for trimethoprim to only 29/612 (4.7%) for nitrofurantoin and 16/462 (3.5%) for cefotaxime. A higher intake of chicken was associated with cefotaxime resistance (OR 2.18; 95% CI 1.05–4.51 per tertile increase); a higher intake of pork was associated with norfloxacin resistance (OR 1.42; 95% CI 1.04–1.95 per quartile increase). In contrast, a higher intake of cheese was associated with lower AMR to amoxicillin (OR 0.84; 95% CI 0.72–0.99 per quartile increase) and amoxicillin-clavulanic acid (OR 0.67; 95% CI 0.53–0.86 per quartile increase). Conclusions These findings support the hypothesis that diet may play a role in the AMR of E. coli in UTIs.

Hypertension (HTN) is a significant risk factor for cardiovascular morbidity and mortality. Metabolic abnormalities, including adverse cholesterol and triglycerides (TG) profiles, are frequent comorbid findings with HTN and contribute to cardiovascular disease. Diuretics, which are used to treat HTN and heart failure, have been associated with worsening of fasting lipid concentrations. Genome-wide meta-analyses with 39,710 European-ancestry (EA) individuals and 9925 African-ancestry (AA) individuals were performed to identify genetic variants that modify the effect of loop or thiazide diuretic use on blood lipid concentrations. Both longitudinal and cross sectional data were used to compute cohort-specific interaction results, which were then combined through meta-analysis in each ancestry. These ancestry-specific results were further combined through trans-ancestry meta-analysis. Analysis of EA data identified two genome-wide significant (p

BackgroundA very high erythrocyte sedimentation rate (ESR) is usually an indication of underlying pathology. Additionally, a moderately elevated ESRmay also be attributable to biological ageing. Whether the ESR is a prognostic factor for mortality, regardless of age, has been scarcely investigated. Therefore, the objective was to analyse the association between elevated ESR levels and the risk of mortality in a prospective cohort of the general population.MethodsWe studied data from the Rotterdam Study (1990-2014). ESR levels were measured at baseline and individuals were followed until death or end of study. Associations between moderately (20-50mmh(-1)) and markedly (>50mmh(-1)) elevated ESR levels and all-cause mortality were assessed using multivariate Cox proportional hazard models.ResultsIn total, 5226 participants were included, and the mean age was 70.3years. During a median follow-up time of 14.9years, 3749 participants died (71.7%). After adjustment, both a moderately elevated ESR and a markedly elevated ESR were associated with a significantly higher risk of overall mortality [hazard ratio (HR) 1.23, 95% confidence interval (CI) 1.12-1.35 and HR 1.89, 95% CI 1.38-2.60, respectively]. Although the ESR becomes higher with age, in a group aged above 75years, without any comorbidities, an ESR>20mmh(-1) remained associated with a significantly increased risk of mortality (HR 1.29, 95%CI 1.01-1.64).ConclusionAn elevated ESR is an independent prognostic factor for mortality. Despite the fact that ESR increases with age, it remains associated with an increased risk of mortality and warrants close follow-up.

Therapeutic response to metformin, a first-line drug for type 2 diabetes (T2D), is highly variable, in part likely due to genetic factors. To date, metformin pharmacogenetic studies have mainly focused on the impact of variants in metformin transporter genes, with inconsistent results. To clarify the significance of these variants in glycemic response to metformin in T2D, we performed a large-scale meta-analysis across the cohorts of the Metformin Genetics Consortium (MetGen). Nine candidate polymorphisms in five transporter genes (organic cation transporter [OCT]1, OCT2, multidrug and toxin extrusion transporter [MATE]1, MATE2-K, and OCTN1) were analyzed in up to 7,968 individuals. None of the variants showed a significant effect on metformin response in the primary analysis, or in the exploratory secondary analyses, when patients were stratified according to possible confounding genotypes or prescribed a daily dose of metformin. Our results suggest that candidate transporter gene variants have little contribution to variability in glycemic response to metformin in T2D.

Background In the Netherlands, like in many other European countries, pancreatic cancer mortality was found to be systematically higher than the incidence. This suggests that there is an underestimation of the reported incidence of pancreatic cancer. Aim We aimed to study the incidence of pancreatic cancer in the Rotterdam area and to compare this with the national level. Methods This study is embedded in the Rotterdam Study (RS), an ongoing population-based prospective cohort study of people aged 45 years and above, enrolled between 1989 till 2006. Details on incident pancreatic cancer cases were available until 2013. Age-specific incidence rates were calculated and compared with data available in the Netherlands Cancer Registry. Results At baseline 14,922 participants were at risk of developing pancreatic cancer. Median follow-up time was 16.4 person years per person. In total, 113 participants developed pancreatic cancer. Rates increased with age with an incidence rate of 109.9 (95% confidence interval [CI]; 85.7–138.8) per 100,000 person years for people older than 75. This is higher than the currently reported 55.9–89.2 per 100,000 person year. Of the 113 cases identified in the RS, only 67.3% was reported as pancreatic cancer in the Netherlands Cancer Registry. Cases that were not registered were significantly older and had significantly poorer survival. Conclusion The incidence of pancreatic cancer, as registered by the Netherlands Cancer Registry, is an underestimation. Patients, not registered by the cancer registry, have a significantly poorer survival. Consequently, we probably overestimate the already poor survival of pancreatic cancer.

BackgroundTricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) may be associated with lower heart rate variability (HRV), a condition associated with increased mortality risk. We aimed to investigate the association between TCAs, SSRIs and HRV in a population-based study.MethodIn the prospective Rotterdam Study cohort, up to five electrocardiograms (ECGs) per participant were recorded (1991–2012). Two HRV variables were studied based on 10-s ECG recordings: standard deviation of normal-to-normal RR intervals (SDNN) and root mean square of successive RR interval differences (RMSSD). We compared the HRV on ECGs recorded during use of antidepressants with the HRV on ECGs recorded during non-use of any antidepressant. Additionally, we analysed the change in HRV on consecutive ECGs. Those who started or stopped using antidepressants before the second ECG were compared with non-users on two ECGs.ResultsWe included 23 647 ECGs from 11 729 participants (59% women, mean age 64.6 years at baseline). Compared to ECGs recorded during non-use of antidepressants (n = 22 971), SDNN and RMSSD were lower in ECGs recorded during use of TCAs (n = 296) and SSRIs (n = 380). Participants who started using TCAs before the second ECG had a decrease in HRV and those who stopped had an increase in HRV compared to consistent non-users (p < 0.001). Starting or stopping SSRIs was not associated with HRV changes.ConclusionTCAs were associated with a lower HRV in all analyses, indicating a real drug effect. For SSRIs the results are mixed, indicating a weaker association, possibly due to other factors.

A systematic review and a meta-analysis were performed to quantify the accumulated information from genetic association studies investigating the impact of the CYP4F2 rs2108622 (p.V433M) polymorphism on coumarin dose requirement. An additional aim was to explore the contribution of the CYP4F2 variant in comparison with, as well as after stratification for, the VKORC1 and CYP2C9 variants. Thirty studies involving 9,470 participants met prespecified inclusion criteria. As compared with CC-homozygotes, T-allele carriers required an 8.3% (95% confidence interval (CI): 5.6�11.1%; P < 0.0001) higher mean daily coumarin dose than CC homozygotes to reach a stable international normalized ratio (INR). There was no evidence of publication bias. Heterogeneity among studies was present (I2 = 43%). Our results show that the CYP4F2 p.V433M polymorphism is associated with interindividual variability in response to coumarin drugs, but with a low effect size that is confirmed to be lower than those contributed by VKORC1 and CYP2C9 polymorphisms. Wiley Online Library

Aims/hypothesis In this study we aimed to replicate the previously reported association between the glycaemic response to metformin and the SNP rs11212617 at a locus that includes the ataxia telangiectasia mutated (ATM) gene in multiple additional populations. Methods Incident users of metformin selected from the Diabetes Care System West-Friesland (DCS, n = 929) and the Rotterdam Study (n = 182) from the Netherlands, and the CARDS Trial (n = 254) from the UK were genotyped for rs11212617 and tested for an association with both HbA1c reduction and treatment success, defined as the ability to reach the treatment target of an HbA1c ≤7 % (53 mmol/mol). Finally, a meta-analysis including data from literature was performed. Results In the DCS cohort, we observed an association between rs11212617 genotype and treatment success on metformin (OR 1.27, 95% CI 1.03, 1.58, p = 0.028); in the smaller Rotterdam Study cohort, a numerically similar but non-significant trend was observed (OR 1.45, 95% CI 0.87, 2.39, p = 0.15); while in the CARDS cohort there was no significant association. In meta-analyses of these three cohorts separately or combined with the previously published cohorts, rs11212617 genotype is associated with metformin treatment success (OR 1.24, 95% CI 1.04, 1.49, p = 0.016 and OR 1.25, 95% CI 1.33, 1.38, p = 7.8 × 10−6, respectively). Conclusions/interpretation A gene variant near ATM is significantly associated with metformin treatment response in type 2 diabetic patients from the Netherlands and the UK. This is the first robustly replicated common susceptibility locus found to be associated with metformin treatment response. Electronic supplementary material The online version of this article (doi:10.1007/s00125-012-2537-x) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Several statins are substrates for the multidrug resistance-associated protein 2 transporter, encoded by the ABCC2 gene. We analyzed in the Rotterdam Study whether the common polymorphisms -24C>T, 1249G>A and 3972C>T in the ABCC2 gene were associated with a dose decrease or switch to another cholesterol-lowering drug in simvastatin and atorvastatin users. These events could indicate an adverse effect or a too strong reduction in cholesterol level. We identified 1014 simvastatin and atorvastatin users during the period 1 January 1991 to 1 January 2010. Associations between genetic variation and the risk of these events were analyzed using Cox proportional hazards modelling. The ABCC2 -24C>T genotype (HR 1.32 95% CI 1.04-1.69) and the H12 haplotype versus the H2 haplotype (HR 1.49; 95% CI 1.06-2.09) were associated with these events in simvastatin users. A similar but not significant association was found in atorvastatin users. To conclude, genetic variation in the ABCC2 gene is associated with these events in simvastatin users.

The organic cation transporter 1, encoded by the SLC22A1 gene, is responsible for the uptake of the anti-hyperglycaemic drug, metformin, in the hepatocyte. We assessed whether a genetic variation in the SLC22A1 gene is associated with the glucose-lowering effect of metformin. Incident metformin users in the Rotterdam Study, whose HbA1c measurements were available, were identified. Associations between 11 tagging single nucleotide polymorphisms in the SLC22A1 gene and change in the HbA1c level were analyzed. A total of 102 incident metformin users were included in this study sample. Except for the rs622342 A > C polymorphism, no significant differences in metformin response were observed. For each minor C allele at rs622342, the reduction in HbA1c levels was 0.28% less (95% CI 0.09-0.47, P = 0.005). After Bonferroni correction, the P-value was 0.050. To conclude, genetic variation at rs622342 in the SLC22A1 gene was associated with the glucose-lowering effect of metformin in patients with diabetes mellitus. The Pharmacogenomics Journal (2009) 9, 242-247; doi: 10.1038/tpj.2009.15; published online 21 April 2009

AIMS The objective of this study was to estimate the risk of acute liver injury associated with individual acid-suppressing drugs and assess the role of dose and duration of treatment. METHODS We used a nested case-control study design within a cohort of over 100,000 users of cimetidine, famotidine, omeprazole and ranitidine. The primary source of information was the General Practitioners Research Database. We identified 108,981 persons aged 20-74 years who received at least one prescription for cimetidine, famotidine, omeprazole, or ranitidine during 1990-93, and we ascertained the first occurrence of clinically acute liver injury referred to a specialist or admitted to a hospital. RESULTS After review of medical records, 33 patients were considered eligible cases of idiopathic acute liver injury with no fatal cases. The type of liver injury was hepatocellular in almost half of the cases, and 80% of all cases presented with jaundice. Twelve cases occurred among current users of cimetidine, five among ranitidine users and one in an omeprazole user. The absolute risk of acute liver injury associated with cimetidine was estimated to be slightly greater than one per 5000 users of cimetidine. The adjusted relative risk (RRs) and 95% CI of developing acute liver injury associated with current use of cimetidine compared to non-use was 5.5 (1.9-15.9), with omeprazole 2.1 (0.2-19.2) and with ranitidine 1.7 (0.5-5.8). In the absence of concomitant use of other hepatotoxic drugs, the RR with cimetidine was 14.4 (2.9-73.7). Among users of cimetidine, the risk was especially high in the first 2 months of starting therapy (RR: 11.3, 3.7-35.1) and at daily doses of 800 mg or greater (RR: 8.8, 3.0-26.0). CONCLUSIONS Cimetidine was the individual anti-ulcer drug with the highest risk of developing symptomatic acute liver disease. Further data are required to confirm this finding. Our study indicates that there is a dose relationship and a short latent period between cimetidine treatment and acute liver injury.

Item does not contain fulltext The objective of this study was to investigate the influence of genotypes associated with reduced activity of vitamin K epoxide reductase complex subunit 1 (VKORC1) and cytochrome P450 2C9 (CYP2C9) on anticoagulation with acenocoumarol during the first 6 weeks of treatment. In 1,525 patients from the Rotterdam Study who were started on anticoagulation therapy with acenocoumarol, the presence of VKORC1 1173C>T and CYP2C9*2 and *3 allele variants was determined. The first international normalized ratio (INR) after initial standard dose, risk of overanticoagulation, and mean dosage at the end of the initiation period were compared between genotypes. The initial standard dosage significantly increased the risk of severe overanticoagulation by 85% for each additional VKORC1 T-allele present. At the end of the initiation period, each VKORC1 T-allele present was shown to decrease the required acenocoumarol dosage by 5.1 mg/week, while each CYP2C9 variant allele present reduced the required dosage by 1.8 mg/week. Our conclusion was that an initial standard dosing regimen with acenocoumarol increases the risk of severe overanticoagulation in patients with variant alleles of the VKORC1 and CYP2C9 genes.

Purpose: Recently, the Blue Mountains Eye Study reported an association between the use of topical timolol and cardiovascular mortality (Lee et al. Ophthalmology 2006). The purpose of the present study was to confirm or falsify this clinically very important finding, using data from the population-based Rotterdam Study. Methods: 6971 participants of the Rotterdam Study, a longitudinal population based study of all residents aged 55 years and older from a district of Rotterdam, The Netherlands, were followed from 1991 onwards. Medication use and morbidity were recorded continuously during follow-up. For the current analysis, baseline use of topical beta-blockers and systemic cardiovascular medication as well as baseline cardiovascular morbidity were used, aiming to follow the design of the Blue Mountains Eye Study as close as possible. Cause of death was registered up to 1-1-2005. Data were analysed using Cox regression; Hazard ratios of topical beta-blocker use were adjusted for age, sex, cardiovascular morbidity and use of systemic cardiovascular medication. Results: Mean age at baseline was 69 years (SD 9 years); 146 participants were using topical beta-blockers at baseline. 2726 participants died during follow-up (all cause mortality 40.1%), 611 (9.0%) had a cardiovascular cause of death. Hazard ratio of topical beta-blocker use was 0.80 (95% confidence interval 0.63-1.02; P=0.07) for all cause mortality and 0.78 (0.46-1.29; P=0.32) for cardiovascular mortality. Conclusions: In our data, the use of topical beta-blockers at baseline was not associated with either all cause mortality or cardiovascular mortality during follow-up.

Objective Failure to correct for lifestyle in routinely collected data may lead to the healthy user or healthy adherer bias, because patients who initiate or adhere to preventive therapy (e.g. statins) may have a healthier lifestyle than patients who do not use or adhere to statins, respectively. We aimed to assess if there is a difference in lifestyle between statin users and non-users and between adherent and nonadherent statin users.

Background and Aims: Nonalcoholic fatty liver disease (NAFLD) is associated with coronary artery calcification and increased prevalence of cardiovascular disease in many cross-sectional studies. However, whether NAFLD per se affect the progression of coronary artery calcification still remains to be elucidated. The aim of this study was to investigate the prospective association between NAFLD and the incidence and progression of coronary artery calcification (CAC) in a longitudinal cohort study. Methods: Among 1732 subjects who underwent serial CAC score evaluation, we evaluated 847 subjects with NAFLD and 885 subjects without NAFLD. Only those without viral hepatitis, significant alcohol consumption and known coronary artery disease were enrolled. NAFLD was diagnosed by ultrasonography in subjects without significant alcohol consumption. CAC score was evaluated by the Agatston method with multi-detector computed tomography. Results: The baseline CAC score was higher in those with NAFLD, and greater number of these subjects showed progression (48.8% vs. 38.4%, p < 0.001 in subjects with vs. without NAFLD). NAFLD was prospectively associated with progression of CAC score (odds ratio [OR] 1.53, 95% confidence interval [CI] 1.26–1.85, p < 0.001). Noticeably, the impact of NAFLD significantly varied with the severity of baseline coronary atherosclerosis. In those without calcification at baseline, NAFLD significantly affected progression of atherosclerosis (adjusted OR 1.54, 95%CI 1.05–2.27, p =0.028), after adjustment for age, hypertension diabetes mellitus, dyslipidemia, smoking, gender and body mass index. Analysis according to the severity of NAFLD showed that NAFLD in its more severe form promotes progression of CAC (adjusted OR 1.77, 95%CI 1.08–2.88, p =0.022). However, in subjects with baseline CAC, NAFLD did not affect progression of CAC (p =0.482). Conclusions: NAFLD plays a role in early stage of coronary atherosclerosis, and it also seems that greater degree of NAFLD affects the progression independent of traditional risk factors. Thus NAFLD does not solely show a simple association, but also plays a role in the development and progression of coronary artery disease.

BACKGROUND: Anaphylactic reactions to cotrimoxazole are often ascribed to the sulphamethoxazole component of this antibacterial drug. OBJECTIVE: To determine whether the trimethoprim component can be the cause of an anaphylactic reaction. METHODS: An analysis was made of reports on anaphylaxis attributed to trimethoprim, as notified to the Drug Safety Unit of the Dutch Inspectorate for Health Care. RESULTS: In the period between September 1981 and November 1995, 13 such reports were received. Nine were classified as probable anaphylaxis. Of these, the causal relationship between exposure to trimethoprim and anaphylaxis was classified as definite in three reports, and as probable in the other six. The remaining four reports were classified as possible anaphylaxis. In one of these, the causal relationship was classified as definite, and in three as probable. CONCLUSION: Although anaphylaxis due to trimethoprim seems to be rare, it may be more common than previously thought. Apparently, anaphylaxis to cotrimoxazole is not always caused by sulphamethoxazole.

The aim of this study was to determine whether use of antiparkinsonian drugs in pharmacy records can be used as a marker for patients with Parkinson's disease (PD).Data were obtained from the Rotterdam Study, a community-based prospective cohort study among people aged 55 years or older who were all screened for PD. For 5510 persons, of whom 74 had PD, pharmacy records were available. Stepwise logistic regression analysis was used to evaluate whether age, sex and use of the antiparkinsonian drugs amantadine, anticholinergics, dopamine agonists, levodopa and selegiline, were predictive variables for PD. For each individual a probability for having PD was calculated. Sensitivity, specificity and positive predictive value (PPV) were calculated at different cut-off values based on calculated probabilities.More than 90% of the users of levodopa, bromocriptine, selegiline, and users of at least two different antiparkinsonian drugs had PD. Age, use of amantadine, anticholinergics, bromocriptine, levodopa, and selegiline were predictive variables for PD. After application of different cut-off values, sensitivity was at most 66.2%, and specificity was at least 99.8%. A PPV of higher than 90% was obtained at higher probabilities.Based on the high PPV of our predictive model, antiparkinsonian drugs can be used as a reliable marker for PD in pharmacy records. Because sensitivity is low, pharmacy records cannot be used to estimate prevalence of PD.

The risk of hemorrhage when using coumarin anticoagulants sharply increases when the International Normalised Ratio (INR) isor =6.0. We performed a prospective cohort study with a nested case-control design among 17,056 outpatients of an anticoagulation clinic to determine the incidence of overanticoagulation and to study the association between overanticoagulation and characteristics of anticoagulant therapy and comorbidity. The incidence rate of an INRor =6.0 was 7.8 per 10,000 treatment days in prevalent users on the starting date and 22.5 per 10,000 treatment days in incident users during the study period. 300 cases with an INRor =6.0 were compared with 302 randomly selected matched controls with an INR within the target zone. Patients on acenocoumarol had an increased risk of an INRor =6.0 compared to patients on phenprocoumon. Regarding comorbidity, impaired liver function, congestive heart failure, diarrhea and fever were risk factors for overanticoagulation. Increased monitoring of INR values if risk factors are present or avoidance of risk factors could prevent excess anticoagulation and potential bleeding complications.

Shortly after their introduction, fluoroquinolones were associated with reports of tendinitis and tendon rupture. During the past years, the number of reports has risen, possibly because of an increased use of fluoroquinolones. In this study, we describe the use of fluoroquinolones in the Dutch community and the possible public health effects of an association between fluoroquinolone use and tendon ruptures.In the PHARMO drug database we identified all prescriptions for fluoroquinolones in the period 1991-1996. The incidence of fluoroquinolone use was expressed as the number of fluoroquinolone episodes per 1000 inhabitants in one year, and extrapolated to the Dutch population after standardisation on age and gender. The annual incidence of non-traumatic tendon ruptures in the period 1991-1996 was calculated with data from the nation-wide hospital registry. The expected number of fluoroquinolone attributable tendon ruptures was calculated on the basis of the use of fluoroquinolones, the number of non-traumatic tendon ruptures and an assumed relative risk of 1.5-10.In 1996, approximately 251,000 patients experienced 318,000 episodes of fluoroquinolone use in the Netherlands. Females used more often fluoroquinolones than males, and the number of episodes increased exponentially with age. In the period 1991 through 1996, the absolute number of fluoroquinolone episodes increased by 160%, from 122,000 to 318,000. The absolute number of hospitalised tendon ruptures increased with 28%, from 768 in 1991 to 984 in 1996. Assuming a relative risk of 1.5 to 10.0, 1 to 15 tendon ruptures could be attributed to fluoroquinolone use in 1996. Only 7% of the observed increase could be attributed to the increased use of fluoroquinolones. If the total increase of hospitalised non-traumatic tendon ruptures would be attributable to the increase in fluoroquinolone use, this would mean that the risk of non traumatic tendon ruptures to fluoroquinolones would be more than 250 times the risk during non-use.In the Netherlands, a large simultaneous increase in non-traumatic tendon ruptures and fluoroquinolone use was observed in the period between 1991 to 1996. Assuming a relative risk of 1.5 to 10.0 for tendon ruptures during fluoroquinolone use, only 0.5 to 7% of the increase in non-traumatic tendon ruptures could be attributed to the increased fluoroquinolone use. The increase in the incidence of non-traumatic hospitalised tendon ruptures in the Netherlands is not likely to be explained solely by the increased use of fluoroquinolones.

Although heart failure is predominantly caused by cardiovascular disorders, several classes of drugs may induce heart failure in patients with pre-existing normal left ventricular function or may precipitate the occurrence of heart failure in patients with left ventricular impairment. These drugs are predominantly those belonging to the categories of cytostatics, anti-arrhythmics, beta-blockers, nonsteroidal anti-inflammatory drugs, calcium channel blockers and anaesthetics. Drug-induced heart failure should be regarded as a potentially preventable cause of heart failure, although sometimes therapeutic alternatives are scarce (e.g. anthracycline-induced cardiomyopathy). Awareness of the possibility of adverse effects on cardiac performance by several classes of drugs, particularly in patients with pre-existing ventricular impairment, may contribute to prevention or timely diagnosis and treatment of drug-induced heart failure.

Fluoroquinolone antibiotics have been associated with tendinitis and tendon rupture. In this paper we report on the followup of 42 spontaneous reports of fluoroquinolone-associated tendon disorders.This study is based on cases of fluoroquinolone-associated tendon disorders reported to the Netherlands Pharmacovigilance Foundation Lareb and the Drug Safety Unit of the Inspectorate for Health Care between January 1, 1988, and January 1, 1998. By means of a mailed questionnaire, we collected information on the site of injury, onset of symptoms, treatment, and course of the tendon disorder as well as information on possible risk factors and concomitant medication.Of 50 mailed questionnaires, 42 (84%) were returned. The data concerned 32 patients (76%) with tendinitis and 10 patients (24%) with a tendon rupture. Sixteen cases (38%) were attributed to ofloxacin, 13 (31%) to ciprofloxacin, 8 (19%) to norfloxacin, and 5 (12%) to pefloxacin. There was a male predominance, and the median age of the patients was 68 years. Most of the reports concerned the Achilles tendon, and 24 patients (57%) had bilateral tendinitis. The latency period between the start of treatment and the appearance of the first symptoms ranged from 1 to 510 days with a median of 6 days. Most patients recovered within 2 months after cessation of therapy, but 26% had not yet recovered at followup.These reports suggest that fluoroquinolone-associated tendon disorders are more common in patients over 60 years of age. Ofloxacin was implicated most frequently relative to the number of filled prescriptions in the Netherlands.

Etretinate has been detected in the blood of women taking acitretine. Because of the proven teratogenic effects of etretinate it was decided to try to trace all users of acitretine in The Netherlands via all drug dispensing outlets (1450 community pharmacies, 95 hospital pharmacies and 636 general practitioners). A request for information on the date of birth, sex, type of prescriber, and the number of capsules dispensed yielded a response rate of 87%. In 61% of all the responding dispensing outlets a prescription for acitretine had been filled. Of these 1153 outlets, 40% had dispensed acitretine to one patient and 52% had dispensed it to 2-5 patients. The 2717 patients comprised 1500 men (55%) and 1217 women, with mean ages of 48 and 53 y, respectively. As against 45% of all the male users, 31% of all the women were in the child-bearing age (15-45 y). The average numbers of dispensed capsules was 167 to users of 10 mg capsules, and 107 to users of the 25 mg capsules. In more than 80% of cases acitretine had been prescribed by dermatologists. Because the large majority of inhabitants in The Netherlands use one community pharmacy, and because most of them have automated records, it is possible to trace a cohort of users quickly and almost completely. Because most large-scale problems with adverse reactions are discovered within the first 2 years of marketing, at a time when exposure and morbidity registries are still collecting information, adhoc formation of a cohort in this way may be a useful resource for postmarketing surveillance.

The benefit of pharmacological treatment of hypertension in the prevention of cardiovascular diseases has been established mainly in subjects younger than 80 years of age. The consequences of undertreatment of hypertension with regard to the occurrence of stroke was studied in the Netherlands. About 33% of the hypertensives younger than 80 years and 55% of the hypertensives older than 80 years were not pharmacologically treated, although they were 'candidates' for pharmacological treatment of hypertension. About 19% (n = 1350) of all strokes that occurred in the Netherlands in 1994 among hypertensives younger than 80 years may be attributable to untreated hypertension. Among hypertensives older than 80 years this percentage was 32% (n = 1345). Although the benefit of pharmacological treatment of hypertension in persons older than 80 years has not been established experimentally, the results suggest that a considerable proportion of the strokes among this group of hypertensives may be prevented.

Voluntary adverse drug reaction (ADR) reporting schemes have operated since the early sixties in many Western countries. It is generally recognized, however, that only a small proportion of ADRs is actually reported. The current survey was conducted to assess attitudes towards reporting of ADRs, and to study which types of ADRs are reported.A questionnaire seeking reasons for nonreporting was sent to a random sample of 10% of medical practitioners in The Netherlands in October 1997. After 6 weeks, a reminder was sent to those who had not responded.One thousand four hundred and forty-two (73%) questionnaires were returned, of which 94% were complete. The percentage of GPs (51%) which had ever reported an ADR to the national reporting centre was significantly higher than the percentage of specialists (35%), who reported more often to the pharmaceutical industry (34% vs 48%). 86% of GPs, 72% of surgical specialists and 81% of medical specialists had ever diagnosed an ADR, which they had not reported. Uncertainty as to whether the reaction was caused by a drug (72%), the ADR being trivial (75%) or too well known (93%) were the most important reasons for not reporting. 18% were not aware of the need to report ADRs, 22% did not know how to report ADRs, 38% did not have enough time, 36% thought that reporting was too bureaucratic and only 26% of Dutch physicians knew which ADRs to report. A serious ADR, an unlabelled ADR, an ADR to a new drug, history of reporting of one or more ADRs, and specialty were all independently associated with reporting of 16 hypothetical ADRs. Surgical and medical specialists tended to report less often than GPs.There is a considerable degree of underreporting, which might partly be explained by lack of knowledge and misconceptions about spontaneous reporting of adverse drug reactions.

Oral vitamin K1 is used for the treatment of excessive anticoagulation. Detailed information on changes in the International Normalized Ratio (INR) in response to vitamin K1 is not available. We therefore measured the INR for the first 7 d following the oral intake of 1-5 mg of vitamin K1 in 24 patients routinely treated with phenprocoumon who had an INRor =6.0 at presentation. On the first 2 d after administration of vitamin K1, the mean INR decreased by 40% and 23% respectively. After day 2, the day-to-day proportional change in the mean INR depended on the dose of vitamin K1 and varied from a decrease of 12% to an increase of 21%. On day 7 the mean INR was higher than on day 2 in three out of five treatment groups. Between day 2 and day 7, in general, 32% of the patients had an INR value within the target zone, 25% had an INR valueor =6.0 and 8% had an INR value2.0. These findings suggest that our routine treatment of overanticoagulation in patients on phenprocoumon should be intensified to improve its efficacy.