[Show abstract][Hide abstract] ABSTRACT: Background:
Low serum magnesium has been implicated in cardiovascular mortality, but results are conflicting and the pathway is unclear. We studied the association of serum magnesium with coronary heart disease (CHD) mortality and sudden cardiac death (SCD) within the prospective population-based Rotterdam Study, with adjudicated end points and long-term follow-up.
Methods and results:
Nine-thousand eight-hundred and twenty participants (mean age 65.1 years, 56.8% female) were included with a median follow-up of 8.7 years. We used multivariable Cox proportional hazard models and found that a 0.1 mmol/L increase in serum magnesium level was associated with a lower risk for CHD mortality (hazard ratio: 0.82, 95% CI 0.70-0.96). Furthermore, we divided serum magnesium in quartiles, with the second and third quartile combined as reference group (0.81-0.88 mmol/L). Low serum magnesium (≤0.80 mmol/L) was associated with an increased risk of CHD mortality (N=431, hazard ratio: 1.36, 95% CI 1.09-1.69) and SCD (N=217, hazard ratio: 1.54, 95% CI 1.12-2.11). Low serum magnesium was associated with accelerated subclinical atherosclerosis (expressed as increased carotid intima-media thickness: +0.013 mm, 95% CI 0.005-0.020) and increased QT-interval, mainly through an effect on heart rate (RR-interval: -7.1 ms, 95% CI -13.5 to -0.8). Additional adjustments for carotid intima-media thickness and heart rate did not change the associations with CHD mortality and SCD.
Low serum magnesium is associated with an increased risk of CHD mortality and SCD. Although low magnesium was associated with both carotid intima-media thickness and heart rate, this did not explain the relationship between serum magnesium and CHD mortality or SCD. Future studies should focus on why magnesium associates with CHD mortality and SCD and whether intervention reduces these risks.
Full-text · Article · Jan 2016 · Journal of the American Heart Association
[Show abstract][Hide abstract] ABSTRACT: We review the cardiac safety of the drugs available at present for the maintenance treatment of chronic obstructive pulmonary disease (COPD) in stable disease, focusing on inhaled long-acting muscarinic antagonists (LAMA) and long-acting β2 agonists (LABA), used either as a monotherapy or as a fixed-dose combination. We report the difficulties of, and pitfalls in, the investigation of the safety of drug treatments in COPD, which is hampered by the so-called COPD trial paradox: on the one hand, COPD is defined as a systemic disease and is frequently associated with comorbidities (especially cardiovascular comorbidities), which have an important effect on the prognosis of individual patients; on the other hand, patients with COPD and cardiovascular or other coexisting illnesses are often excluded from participation in randomised controlled clinical trials. In these trials, inhaled long-acting bronchodilators, both LAMA or LABA, or both, seem to be safe when used in the appropriate dose in adherent patients with COPD without uncontrolled cardiovascular disease or other notable comorbidities. However, the cardiac safety of LAMA and LABA is less evident when used inappropriately (eg, overdosing) or in patients with COPD and substantial cardiovascular disease, prolonged QTc interval, or polypharmacy. Potential warnings about rare cardiac events caused by COPD treatment from meta-analyses and observational studies need to be confirmed in high quality large randomised controlled trials. Finally, we briefly cover the cardiac safety issues of chronic oral drug treatments for COPD, encompassing theophylline, phosphodiesterase inhibitors, and macrolides.
No preview · Article · Jan 2016 · The Lancet Respiratory Medicine
[Show abstract][Hide abstract] ABSTRACT: Background Suboptimal use of antibiotics may lead to antimicrobial resistance. The aim of this study was to develop and assess two new quality indicators (QIs) of optimal community-based prescribing applied to childhood community antibiotic (AB) prescribing in three European countries.
Methods A cohort study was conducted using electronic primary care medical records of 2,195,312 children up to 14 (Italy, Pedianet database, 2001–2010) or 18 years of age (UK, THIN database, 1995–2010; the Netherlands, IPCI database, 1996–2010) contributing for a total of 12,079,620 person-years (PYs). Prevalence rates of antibiotic prescribing were defined as the number of children with at least one antibiotic prescription per year and were expressed as the number of users per 100 PYs (%). Quality of prescribing was determined using four QIs: the drug utilisation 90% method, the ratio between users of broad and narrow spectrum penicillins, cephalosporins and macrolides (B/N ratio) and two new QMs: (i) the overall proportion of amoxicillin users (amoxicillin index, AI); (ii) the ratio between users of amoxicillin and those of broad spectrum antibiotics (the A/B ratio).
Results The overall annual prevalence of antibiotic prescriptions was 18% in the Netherlands, 36.2% in the UK and 52% in Italy. Prevalence was highest in the youngest children. Almost half of all prescriptions included amoxicillin with or without clavulanic acid. Cephalosporins were frequently prescribed in Italy. The AI provided trends for the utilization of a relatively narrow spectrum option targeting acute respiratory infections, and was highest in the Netherlands and in the UK (50–60%) and lower in Italy (30%), with a slight decrease over time in the UK and Italy. The overall B/N ratio varied between countries from 0.3 to 74.7, whereas the overall A/B ratio varied less from 0.5 in Italy to 6 in the UK, indicating a substantial proportion of narrower-spectrum prescribing in the UK.
Conclusions The prevalence of antibiotic prescribing varied highly with age and country. A combination of total antibiotic prevalence and quality of prescribing based on amoxicillin use provide a clear picture of community childhood antibiotic prescribing. These measures could be used to evaluate the impact of programs aiming at reduction of AB use and appropriate antibiotic prescribing.
No preview · Article · Jan 2016 · Archives of Disease in Childhood
[Show abstract][Hide abstract] ABSTRACT: Background:
Tricyclic 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.
In 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.
We 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.
TCAs 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.
Full-text · Article · Dec 2015 · Psychological Medicine
[Show abstract][Hide abstract] ABSTRACT: Background and purpose:
Serotonin-specific antidepressants may increase the risk of adverse bleeding events. In a previous cross-sectional study, we did not observe an association between antidepressant use and presence of subclinical cerebral bleedings. In this study, we investigated longitudinally whether antidepressant use is associated with an increased risk of new subclinical cerebral microbleeds.
In total, 2559 participants aged ≥45 years of the population-based Rotterdam Study, all without microbleeds at baseline, underwent baseline and repeat brain magnetic resonance imaging between 2005 and 2013 (mean time interval, 3.9 years; SD, 0.5) to determine the incidence of microbleeds. Antidepressant use (yes versus no) was assessed between baseline and follow-up scan. In additional analyses, antidepressants were classified as low, intermediate, or high affinity for the serotonin transporter, and alternatively as selective serotonin reuptake inhibitors or non-selective serotonin reuptake inhibitors. We used multivariable logistic regression models to investigate the association of antidepressants with incident microbleeds.
Antidepressant use was associated with a higher cerebral microbleed incidence (odds ratio, 2.22; 95% confidence interval, 1.31-3.76) than nonuse. When stratified by affinity for the serotonin transporter, intermediate serotonin affinity antidepressant use was associated with an increased risk of developing microbleeds (odds ratio, 3.07; 95% confidence interval, 1.53-6.17). Finally, selective serotonin reuptake inhibitor and non-selective serotonin reuptake inhibitor use were both associated with increased microbleed incidence.
Antidepressant use was associated with an increased risk of developing microbleeds. Our results may support findings from previous clinical studies about increased intracranial and extracranial bleeding risk in antidepressant users.
[Show abstract][Hide abstract] ABSTRACT: International travel is considered to be an important risk factor for acquisition of multidrug-resistant Enterobacteriaceae (MRE). The aim of this systematic review was to determine the effect of international travel on the risk of post-travel faecal carriage of MRE. Secondary outcomes were risk factors for acquisition of MRE. A systematic search for relevant literature in seven international databases was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Articles needed to report on (i) foreign travel, (ii) screening of asymptomatic participants, (iii) antimicrobial susceptibility data and (iv) faecal Enterobacteriaceae carriage. Two researchers independently screened the abstracts, assessed the full article texts for eligibility and selected or rejected them for inclusion in the systematic review. In case of disagreement, a third researcher decided on inclusion. Eleven studies were identified. In all studies, a high prevalence (> 20%) of carriage of MRE after international travel was found. The highest prevalence was observed in travellers returning from southern Asia. Foreign travel was associated with an increased risk of carriage of MRE. Further research is needed to assess if this leads to an increase in the number of infections with MRE. Systematic review registration number: PROSPERO CRD42015024973.
Full-text · Article · Dec 2015 · Eurosurveillance: bulletin europeen sur les maladies transmissibles = European communicable disease bulletin
[Show abstract][Hide abstract] ABSTRACT: Purpose:
Antidepressants, specifically selective serotonin reuptake-inhibiting antidepressants (SSRIs), decrease platelet activation and aggregation in in vitro experiments and could therefore decrease the risk of myocardial infarction (MI). However, prior studies addressing this hypothesis showed contradictory results. Our purpose was to investigate the association between the use of any antidepressant drug and incident MI among middle-aged and older adults.
We embedded a case-control study in the prospective Rotterdam Study (1991-2011). Controls were matched to MI cases based on sex and age at the same calendar date, and confounding factors were taken into account as time-varying covariates. The relative risk of MI during current and past use of an antidepressant was analyzed with conditional logistic regression with never use of antidepressant drugs as the reference category.
A total of 744 out of a cohort of 9499 study participants developed MI during follow-up. After statistical adjustment for traditional cardiovascular risk factors and depression, current use of any antidepressant was associated with a lower risk of MI (odds ratio (OR), 0.71; 95 % confidence interval (CI), 0.51-0.98) compared with never use of any antidepressant. SSRI use showed the lowest relative risk (OR, 0.65; 95 % CI, 0.41-1.02), albeit marginally not statistically significant. Past use of any of the antidepressant classes was not associated with a lower risk of MI.
Current use of antidepressants was associated with a lower risk of MI. Of the different classes, the use of SSRIs showed the lowest risk of MI, and therefore confirming the research hypothesis.
Full-text · Article · Nov 2015 · European Journal of Clinical Pharmacology
[Show abstract][Hide abstract] ABSTRACT: Objective:
The ATP-binding cassette B1 (ABCB1) gene encodes P-glycoprotein, a transport protein, which plays an important role in the bioavailability of digoxin. We aimed to investigate the interaction between variants within the ABCB1 gene and digoxin on the risk of sudden cardiac death (SCD).
Within the Rotterdam Study, a population-based cohort study in persons 45 years of age and older, we used Cox regression to analyse the association between three polymorphisms that have been associated with digoxin bioavailability, extracted from 1000-Genomes imputed ABCB1 genotypes and the risk of SCD, stratified by digoxin use.
In a total study population of 10 932 persons, 419 SCDs occurred during a median follow-up of 9.8 years. In non-users of digoxin, the risk of SCD was not different across genotypes. In digoxin users, homozygous T allele carriers of C1236T (HR 1.90; 95% CI 1.09 to 3.30; allele frequency 0.43), G2677T (HR 1.89; 95% CI 1.10 to 3.24; allele frequency 0.44) and C3435T (HR 1.72; 95% CI 1.03 to 2.87; allele frequency 0.53) had a significantly increased risk of SCD in a recessive model. Interaction between the ABCB1 polymorphisms and digoxin use was significant for C1236T and G2677T in the age-adjusted and sex-adjusted model.
In this study, we showed that in digoxin users variant alleles at each of the three loci in the ABCB1 gene were associated with an increased risk of SCD compared with digoxin users with none or one T allele. If replicated, the findings imply that the ABCB1 genotype modifies the risk of cardiac digoxin toxicity.
No preview · Article · Nov 2015 · Heart (British Cardiac Society)
[Show abstract][Hide abstract] ABSTRACT: Background:
Data are scarce for the lifetime risk of developing impaired glucose metabolism, including prediabetes, as are data for the risk of eventual progression from prediabetes to diabetes and for initiation of insulin treatment in previously untreated patients with diabetes. We aimed to calculate the lifetime risk of the full range of glucose impairments, from normoglycaemia to prediabetes, type 2 diabetes, and eventual insulin use.
In this prospective population-based cohort analysis, we used data from the population-based Rotterdam Study. We identified diagnostic events by use of general practitioners' records, hospital discharge letters, pharmacy dispensing data, and serum fasting glucose measurements taken at the study centre (Rotterdam, Netherlands) visits. Normoglycaemia, prediabetes, and diabetes were defined on the basis of WHO criteria for fasting glucose (normoglycaemia: ≤6·0 mmol/L; prediabetes: >6·0 mmol/L and <7·0 mmol/L; and diabetes ≥7·0 mmol/L or use of glucose-lowering drug). We calculated lifetime risk using a modified version of survival analysis adjusted for the competing risk of death. We also estimated the lifetime risk of progression from prediabetes to overt diabetes and from diabetes free of insulin treatment to insulin use. Additionally, we calculated years lived with healthy glucose metabolism.
We used data from 10 050 participants from the Rotterdam Study. During a follow-up of up to 14·7 years (between April 1, 1997, and Jan 1, 2012), 1148 participants developed prediabetes, 828 developed diabetes, and 237 started insulin treatment. At age 45 years, the remaining lifetime risk was 48·7% (95% CI 46·2-51·3) for prediabetes, 31·3% (29·3-33·3) for diabetes, and 9·1% (7·8-10·3) for insulin use. In individuals aged 45 years, the lifetime risk to progress from prediabetes to diabetes was 74·0% (95% CI 67·6-80·5), and 49·1% (38·2-60·0) of the individuals with overt diabetes at this age started insulin treatment. The lifetime risks attenuated with advancing age, but increased with increasing BMI and waist circumference. On average, individuals with severe obesity lived 10 fewer years without glucose impairment compared with normal-weight individuals.
Impaired glucose metabolism is a substantial burden on population health, and our findings emphasise the need for more effective prevention strategies, which should be implemented as soon in a person's life as possible. The substantial lifetime risk of prediabetes and diabetes in lean individuals also supports risk factor control in non-obese individuals.
Erasmus MC and Erasmus University Rotterdam; Netherlands Organisation for Scientific Research; Netherlands Organisation for Health Research and Development; Research Institute for Diseases in the Elderly; Netherlands Genomics Initiative; Netherlands Ministry of Education, Culture and Science; Netherlands Ministry of Health, Welfare and Sports; European Commission; and Municipality of Rotterdam.
Full-text · Article · Nov 2015 · The Lancet Diabetes & Endocrinology
[Show abstract][Hide abstract] ABSTRACT: Hypertension is a major risk factor for a spectrum of cardiovascular diseases (CVD), including myocardial infarction, sudden death, and stroke. In the US, over 65 million people have high blood pressure and a large proportion of these individuals are prescribed antihypertensive medications. Although large long-term clinical trials conducted in the last several decades have identified a number of effective antihypertensive treatments that reduce the risk of future clinical complications, responses to therapy and protection from cardiovascular events vary among individuals.
[Show abstract][Hide abstract] ABSTRACT: Rationale:
Worldwide, chronic obstructive pulmonary disease (COPD) and stroke are leading causes of death. Increasing evidence suggests an association between both diseases, either caused by an increased atherosclerosis risk in patients with COPD, or as a consequence of shared risk factors between stroke and COPD.
To examine the associations between COPD and subtypes of stroke in the general population and to explore the role of cardiovascular risk factors and exacerbations on these associations.
Within the prospective population-based Rotterdam Study, we followed 13115 participants without history of stroke for occurrence of stroke. Follow-up started in 1990-2008 and ended in 2012. COPD was related to stroke using a time-dependent Cox proportional hazard model.
Measurements and main results:
COPD was diagnosed in 1566 participants. During 126347 person-years, 1250 participants suffered a stroke, of which 701 were ischemic and 107 hemorrhagic. Adjusted for age, age2, and sex, COPD was significantly associated with all stroke (HR 1.20; 95%CI 1.00-1.43), ischemic stroke (HR 1.27; 1.02-1.59), and hemorrhagic stroke (HR 1.70; 1.01-2.84). Adjusting for cardiovascular risk factors gave similar effect sizes. In contrast, additional adjusting for smoking attenuated the effect sizes: HR 1.09 (0.91-1.31) for all stroke, HR 1.13 (0.91-1.42) for ischemic stroke, and HR 1.53 (0.91-2.59) for hemorrhagic stroke. Following an acute severe exacerbation subjects with COPD had a 6.66-fold (2.42-18.20) increased risk of stroke.
Our cohort study demonstrated a higher risk of both ischemic and hemorrhagic stroke in subjects with COPD, and revealed the importance of smoking as a shared risk factor.
No preview · Article · Sep 2015 · American Journal of Respiratory and Critical Care Medicine
[Show abstract][Hide abstract] ABSTRACT: Importance
Atrial fibrillation (AF) has been suggested as a risk factor for dementia since it may lead to chronic cerebral hypoperfusion and stroke. However, longitudinal studies assessing the association between AF and dementia have shown inconsistent results.Objective
To determine the effect of AF on the risk of developing dementia during 20 years of follow-up.Design, Setting, and Participants
The association of prevalent and incident AF with incident dementia was assessed from July 6, 1989, to February 4, 2010, in 6514 dementia-free participants in the prospective population-based Rotterdam Study. Data analysis was conducted from September 18, 2014, to April 17, 2015. Cox proportional hazards regression models adjusting for age, sex, and cardiovascular risk factors; censored for stroke; and stratified by median age were used. In addition, we investigated whether the association between incident AF and dementia varied according to the duration of exposure, categorized in 6-year time bands.Exposures
Prevalent and incident AF.Main Outcomes and Measures
Incident dementia, determined according to the Diagnostic and Statistical Manual of Mental Disorders (Third Edition Revised) and the National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer’s Disease and Related Disorders Association criteria.Results
At baseline, 318 of 6514 participants (4.9%) had prevalent AF, and during 81 483 person-years of follow-up, 994 participants (15.3%) developed incident dementia. With findings presented as adjusted hazard ratio (95% CI), prevalent AF was related to an increased risk of dementia (1.33; 1.02-1.73). Among 6196 participants without prevalent AF during 79 003 person-years of follow-up, 723 participants (11.7%) developed incident AF and 932 individuals (15.0%) developed incident dementia. Incident AF was associated with an increased risk of dementia in younger participants (<67 years: 1.81; 1.11-2.94 vs ≥67 years: 1.12; 0.85-1.46; P = .02 for interaction). The risk of dementia was strongly associated with duration of exposure to AF in the younger participants (in the highest stratum: 3.30; 1.16-9.38; P = .003 for trend) but not in the elder participants (0.25; 0.04-1.86; P = .94 for trend).Conclusions and Relevance
Atrial fibrillation is associated with an increased risk of dementia, independent of clinical stroke. This association was strongest for younger participants with the longest duration of AF. Future studies should investigate whether optimal treatment of AF can prevent or postpone dementia.
[Show abstract][Hide abstract] ABSTRACT: The Rotterdam Study is a prospective cohort study ongoing since 1990 in the city of Rotterdam in The Netherlands. The study targets cardiovascular, endocrine, hepatic, neurological, ophthalmic, psychiatric, dermatological, otolaryngological, locomotor, and respiratory diseases. As of 2008, 14,926 subjects aged 45 years or over comprise the Rotterdam Study cohort. The findings of the Rotterdam Study have been presented in over 1200 research articles and reports (see www.erasmus-epidemiology.nl/rotterdamstudy ). This article gives the rationale of the study and its design. It also presents a summary of the major findings and an update of the objectives and methods.
Full-text · Article · Sep 2015 · European Journal of Epidemiology
[Show abstract][Hide abstract] ABSTRACT: Background:
Despite frailty being an important geriatric syndrome, its prevalence and associated mortality risk in older patients with chronic obstructive pulmonary disease (COPD) are unknown.
We examined the relationship between COPD confirmed by spirometry, COPD severity, and frailty defined by the Fried criteria within 2,142 participants (aged 74.7±5.6 years) of the Rotterdam Study, a prospective population-based cohort study.
The frailty prevalence was significantly higher (p < .001) in participants with COPD (10.2%, 95% CI: 7.6%-13.5%) compared with participants without COPD (3.4%, 95% CI: 2.6%-4.4%). Adjusted for age, sex, smoking, corticosteroids, and other confounders, participants with COPD had a more than twofold increased prevalence of frailty (odds ratio 2.2, 95% CI: 1.34-3.54, p = .002). The prevalence was highest when severe airflow limitation, dyspnea, and frequent exacerbations were present. Participants with mild airflow limitation were more frequently prefrail. COPD elderly who were frail had significant worse survival.
This population-based cohort study in elderly demonstrates that COPD is associated with frailty even after adjusting for shared risk factors. Our findings suggest that frailty-in addition to COPD severity and comorbidities-identifies those COPD participants at high risk of mortality.
No preview · Article · Sep 2015 · The Journals of Gerontology Series A Biological Sciences and Medical Sciences
[Show abstract][Hide abstract] ABSTRACT: Osteoporosis is a progressive bone disease characterized by decreased bone mass resulting in increased fracture risk. The objective of this investigation was to test whether a recently developed disease systems analysis model for osteoporosis could describe disease progression in a placebo-treated population from the Early Postmenopausal Intervention Cohort (EPIC) study. First, we qualified the model using a subset from the placebo arm of the EPIC study of 222 women who had similar demographic characteristics as the 149 women from the placebo arm of the original population. Second, we applied the model to all 470 women. Bone mineral density (BMD) dynamics were changed to an indirect response model to describe lumbar spine and total hip BMD in this second population. This updated disease systems analysis placebo model describes the dynamics of all biomarkers in the corresponding datasets to a very good approximation; a good description of an individual placebo response will be valuable for evaluating treatments for osteoporosis.
Full-text · Article · Aug 2015 · CPT: Pharmacometrics and Systems Pharmacology