Targeting the Beta-2-Adrenergic Receptor and the Risk of Developing Alzheimer's Disease:A Retrospective Inception Cohort Study

BACKGROUND: Animal studies suggested that β2-Adrenergic receptors (β2AR) may be a potential target for the treatment of Alzheimer's disease (AD). OBJECTIVE: This retrospective inception cohort study aimed to assess the association between antagonists and agonists of the β2AR and the risk of starting treatment for AD in older adults. METHODS: A retrospective inception cohort study was conducted among older adults who initiated either non-selective βAR antagonists or selective β2AR agonists using the University Groningen IADB.nl prescription database (study period 1994-2019). For each exposed cohort, two reference cohorts (A and B) were matched on age at index date. The main outcome was defined as at least two prescriptions for cholinesterase inhibitors (rivastigmine, galantamine, and donepezil) and/or memantine. Cox proportional hazard regression models were used to estimate hazard ratios (HR). RESULTS: The risk of developing AD was elevated among patients exposed to non-selective βAR antagonists (A: aHR 3.303, 95% CI 1.230-8.869, B: aHR 1.569, 95% CI 0.560-4.394) and reduced among patients exposed to selective β2AR agonists (A: aHR 0.049, 95% CI 0.003-0.795, B: aHR 0.834, 95% CI 0.075-9.273) compared to reference patients. CONCLUSION: These findings suggest that exposure to non-selective βAR antagonists is associated with an increased risk for developing AD whereas there may be a decreased risk for developing AD after exposure to selective β2AR agonists

Association between statins and infections among patients with diabetes:a cohort and prescription sequence symmetry analysis

PURPOSE: A previous meta-analysis of randomized trials did not confirm findings from observational studies that suggested that statins reduce the risk of infection. However, animal experiments indicate that statins may be more effective in reducing the risk and/or the severity of infection among patients with diabetes. Hence, we evaluated the effect of statins on antibiotic prescriptions (a proxy for infections) among patients with drug-treated type 2 diabetes using two confounding-reducing observational designs. METHODS: We conducted a prescription sequence symmetry analysis and a cohort study using the IADB.nl pharmacy prescription database. For the prescription sequence symmetry analysis, a sequence ratio was calculated. The matched cohort study, comparing the time to first antibiotic prescription between periods that statins are initiated and non-use periods, was analyzed using stratified Cox regression. RESULTS: Prescription sequence symmetry analysis of 4684 patients with drug-treated type 2 diabetes resulted in an adjusted sequence ratio of 0.86 (95% confidence interval [CI]: 0.81 to 0.91). Corresponding figures for the cohort analysis comparing 9852 statin-initiation with 4928 non-use periods showed similar results (adjusted hazard ratio: 0.88, 95%CI: 0.83 to 0.95). CONCLUSIONS: These findings suggest that statins are associated with a reduced risk of infections among patients with drug-treated type 2 diabetes. © 2016 The Authors. Pharmacoepidemiology and Drug Safety Published by John Wiley & Sons Ltd. © 2016 The Authors. Pharmacoepidemiology and Drug Safety Published by John Wiley & Sons Ltd

The burden and management of cytochrome P450 2D6 (CYP2D6)-mediated drug–drug interaction (DDI):Co-medication of metoprolol and paroxetine or fluoxetine in the elderly

Purpose: Metoprolol and paroxetine/fluoxetine are inevitably co-prescribed because cardiovascular disorders and depression often coexist in the elderly. This leads to CYP2D6-mediated drug-drug interactions (DDI). Because systematic evaluations are lacking, we assessed the burden of metoprolol-paroxetine/fluoxetine interaction in the elderly and how these interactions are managed in Dutch community pharmacies. Method: Dispensing data were collected from the University of Groningen pharmacy database (IADB.nl, 1999-2014) for elderly patients (60years) starting beta-blockers and/or antidepressants. Based on the two main DDI alert systems (G-Standard and Pharmabase), incidences were divided between signalled (metoprolol-fluoxetine/paroxetine) and not-signalled (metoprolol-alternative antidepressants and alternative beta-blockers-paroxetine/fluoxetine) combinations. Incident users were defined as patients starting at least one signalled or a non-signalled combination. G-Standard signalled throughout the study period, whereas Pharmabase stopped after 2005. Results: A total of 1763 patients had 2039 metoprolol-paroxetine/fluoxetine co-prescriptions, despite DDI alert systems, and about 57.3% were signalled. The number of metoprolol-alternative antidepressant combinations (incidences=3150) was higher than alternative beta-blocker-paroxetine/fluoxetine combinations (incidences=1872). Metoprolol users are more likely to be co-medicated with an alternative antidepressant (incidences=2320) than paroxetine/fluoxetine users (incidences=1232) are. The number of paroxetine/fluoxetine users co-prescribed with alternative beta-blockers was comparable to those co-medicated with metoprolol (about 50%). Less than 5% of patients received a substitute therapy after using metoprolol-paroxetine/fluoxetine. Most of the metoprolol users (90%) received a low dose (mean DDD=0.47) regardless whether they were prescribed paroxetine/fluoxetine. Conclusion: Despite the signalling software, metoprolol-paroxetine/fluoxetine combinations are still observed in the elderly population. The clinical impact of these interactions needs further investigation

Long-term comparative effectiveness of antihypertensive monotherapies in primary prevention of cardiovascular events:A population-based retrospective inception cohort study in the Netherlands

OBJECTIVE: To determine the long-term effectiveness of antihypertensive monotherapies in primary prevention of cardiovascular events.DESIGN: Retrospective inception cohort study covering a 25-year study period.SETTING: University Groningen IADB.nl pharmacy prescription database with data from 1996 to 2020.PARTICIPANTS: Patients aged 18 years or older, free of any cardiovascular disease (CVD) drug therapies prior to initiation of a preventive antihypertensive monotherapy (ACE inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), beta-blockers (BBs), calcium channel blockers (CCBs) and thiazides).OUTCOME MEASURES: Primary outcome was the time to first prescription of acute cardiac drug therapy (CDT) measured by valid drug proxies to identify a first major CVD event in patients without a history of CVD.RESULTS: Among 33 427 initiators, 5205 (15.6%) patients experienced an acute CDT. The average follow-up time was 7.9±5.5 years. The 25-year incidence rate per 1000 person-years were 25.3, 22.4, 18.2, 24.4 and 22.0 for ACEI, ARB, BB, CCB and thiazide starters, respectively. Inverse probability of treatment-weighted Cox regression showed that thiazide starters had lower hazards than the reference BB starters (HR: 0.88, 95% CI: 0.81 to 0.95). Among patients on diabetes drugs, risks were lower (HR: 0.49, 95% CI: 0.28 to 0.85). CCB starters had higher hazards than reference BB (HR: 1.21, 95% CI: 1.07 to 1.36). The overall estimated number needed to treat for thiazides compared with BBs to prevent one acute CDT in 25 years was 26, and four among patients on diabetes drugs.CONCLUSIONS: After adjustments for confounders, patients starting on monotherapy with thiazides had a lower incidence of CDT compared with those starting on BBs, notably among patients on diabetes drugs. Conversely, patients who began CCB monotherapy had a higher incidence of CDT compared with those starting on BBs. Other monotherapies had comparable incidence of cardiovascular disease compared with BBs.</p

Inclusion of the birth cohort dimension improved description and explanation of trends in statin use

Objective: Including the birth cohort dimension improves trend studies of mortality and health. We investigated the effect of including the birth cohort dimension in trend studies of prescription drug use by studying prevalence of statin use among adults. Study Design and Setting: Data from a drug prescription database in the Netherlands (IADB.nl) were used to obtain the number of users of statin per 1,000 population (prevalence) in the age range 18-85 years from 1994 to 2008. We applied descriptive graphs and standard age-period-cohort (APC) models. Results: From 1994 to 2008, the prevalence increased from similar to 10 to similar to 90 users per 1,000 population, with the peak in prevalence shifting from age 63 to 78 years. The APC model shows patterns that were masked in the age-period (AP) model. The prevalence rate ratio increased from the 1911 birth cohort to the 1930 birth cohort and then declined. Similar for both sexes, adding nonlinear period effects contributed similar to 4.4% to reductions in deviance, whereas adding nonlinear birth cohort effects contributed similar to 12.9%. Conclusion: Adding the birth cohort dimension to AP analysis is valuable for academic and professional practice as trends can be more accurately described and explained and it can help improve projections of future trends. (c) 2012 Elsevier Inc. All rights reserved

Association between adherence to statin therapy and low-density lipoprotein cholesterol (LDL-c) response in first-time users of standard-dose and low-dose statins:The PharmLines initiative

Objective: To investigate whether statin adherence (defined as proportion days covered, PDC) is associated with LDL-c response in statin initiators on standard and low starting doses of statins, and to detect a possible interaction with sex. Methods: An inception cohort study was conducted using the PharmLines Initiative, a linkage between the Lifelines Cohort Study and the University of Groningen's IADB.nl (prescription database). First-time statin users were followed from baseline to follow-up measurement. We matched participants (1:1) between the standard-dose and the low-dose group of statin users on the duration of follow-up. Multiple linear regression analysis was used to model the association. Results: In univariate analysis, PDC was significantly associated with LDL-c response similarly (slope = -0.021), in both the standard-dose group (N = 115, p < .001) and the low-dose group (N = 115, p = .003). In the standard-dose group, the same level of PDC appeared to be significantly associated with a greater LDL-c level reduction in women (slope = -0.027, N = 48, p < .001) than in men (slope = -0.017, N = 67, p < .001). Meanwhile, in the low-dose group, the reduction of LDL-c level from baseline seemed to be greater in men (slope = -0.023, N = 56, p < .001) than in women (slope = -0.020, N = 59, p < .001) for the same level of PDC. In multiple regression analysis, the significant association between PDC and LDL-c with a similar pattern to the univariate result was maintained only in the standard-dose group. Conclusions: Adherence is significantly associated with LDL-c response to statins at follow-up. Sex appears to significantly modify this association. At a similar adherence level, women seem to experience a better LDL-c response to standard-dose statins compared to men in a real-world setting

Antibiotic use in children and the use of medicines by parents

Objective Antibiotic drugs are frequently used for viral infections in children. It is probable that health beliefs and parental concern have great influence on the use of drugs in children. This study, performed in The Netherlands, investigates whether the use of antibiotics in children is associated with the use of medicines by parents. Patients and methods In this observational cohort study, the authors selected 6731 children from the prescription database IADB.nl who did not receive antibiotics until their fifth birthday and 1479 children who received at least one antibiotic prescription every year. The authors then selected parents for each group of children (5790 mothers and 4250 fathers for the children who did not receive antibiotics and 1234 mothers and 1032 fathers for the children who regularly received antibiotics). The authors compared the use of antibiotics and other medicines between the two groups of parents. Results Parents of children who received antibiotics recurrently were found to use more antibiotics themselves compared with parents of children who did not receive antibiotics. Moreover, this group also showed a higher percentage of chronic medication use: (11.3 vs 6.2% (mothers) and 13.1% vs 9.5% (fathers)). Mothers more often use antacids, non-steroidal anti-inflammatory drugs (NSAIDs), analgesics, anxiolytics, hypnotics, antidepressants, drugs for treatment of asthma and antihistamines. Fathers use more antacids, cardiovascular drugs, NSAIDs and asthma drugs. Conclusions The parents of children who receive antibiotic drugs regularly use more medicines compared with the parents of children who use no antibiotic drugs. Parents' medicine use may influence that of children and is a factor physicians and pharmacists should take into account

Antidepressant use during pregnancy and the risk of developing gestational hypertension:A retrospective cohort study

Background: Prior studies reported that exposure to antidepressants during pregnancy may be associated with gestational hypertension. The aim of this study is to assess the association between the use of antidepressants during pregnancy and the risk of developing gestational hypertension. Methods: A retrospective cohort study using the prescription database IADB.nl was conducted among nulliparous women with singleton pregnancies between 1994 and 2015 in the Netherlands. Logistic regression analysis was used to estimate odds ratios (OR), adjusted OR (aOR) and their corresponding 95% confidence intervals (95% CI). Gestational hypertension as main outcome measure was defined as at least one dispensed record of an antihypertensive drug (methyldopa, nifedipine, labetalol, ketanserin, nicardipine) after 20 weeks of gestation until 14 days after delivery. Sub- analyses were conducted for class of antidepressant, duration and amount of use of antidepressant (= 30 Defined Daily Doses or DDDs), and maternal age. Sensitivity analyses to assess uncertainties were conducted. Results: Twenty-eight thousand twenty women were included, of which 539 (1.92%) used antidepressants. The risk of gestational hypertension was doubled for women using antidepressant (aOR 2.00 95% CI 1.28-3.13). Significant associations were also found for the subgroup selective serotonin reuptake inhibitors (SSRIs) (aOR 2.07 95% CI 1.25-3.44), >= 30 DDDs (aOR 2.50 95% CI 1.55-3.99) and maternal age of 30-34 years (aOR 2.59 95% CI 1.35-4.98). Varying the theoretical gestational age showed comparable results. Conclusion: Prolonged use of antidepressants during the first 20 weeks of gestation appeared to be associated with an increased risk of developing gestational hypertension. When balancing the benefits and risks of using these drugs during pregnancy, this should be taken into account

Switching pattern and dose adjustment of antidepressants before and during pregnancy

The purpose of the study is to examine the switching pattern and dose adjustment of antidepressants (ADs) prescribed to women from six months before to six months during pregnancy in the Netherlands. The recorded dispenses or refills were collected from the University of Groningen IADB.nl pregnancy subset for all singleton pregnancies in which the mother received ≥ 1 prescription of an AD dispensed before pregnancy and was present in the database at least six months after conception. The rates of continuation, discontinuation, and switching between 2001 and 2020 were assessed for the ADs studied. The mean number of Defined Daily Doses (DDDs) of the most frequently continued ADs used was calculated both before and during pregnancy, and a paired t-test was used to test for significant changes. The continuation rates for AD users, especially for SSRI and SNRI continued users, increased over time from 27% and 19% (2001-2005) to 65% and 65% (2016-2020). The switching rate between ADs remained consistently low from the start of the study (2001-2005) at 2.0% to the end of the study (2016-2020) at 2.3%. Most women who switched between antidepressants during pregnancy received a different SSRI monotherapy (85%), followed by an SNRI (6%), a TCA (4%), and an "other AD" (4%). In most cases observed, the dose adjustment for the mean DDDs during pregnancy compared to the mean DDDs before pregnancy only changed little (less than 10%). Continued use of SSRIs among singleton pregnancies doubled over the study period. The low rate of AD switching and little changes in the DDD adjustment for most AD continuers indicate that pregnant women prefer to continue their prepregnancy medication rather than switch it. Most observed findings cohere with the Dutch national guidelines for antidepressant use during pregnancy.</p

Use of antibiotics in rural and urban regions in the Netherlands:an observational drug utilization study

Background: Large livestock farms might increase the infection risk for the nearby human population because of an increased risk for disease outbreaks and because antibiotic-resistant bacteria are more likely to be present. We hypothesized that populations residing in rural areas have more contact with cattle compared with populations in urban areas, and will use more antibiotics or more frequently require a new course of antibiotics. Methods: Using data from the prescription database IADB.nl, we compared antibiotic use by patients living in rural areas to the use by patients living in urban areas. We also followed cohorts of antibiotic users and determined the patients who required a second antibiotic within 14 days after beginning the first antibiotic. Results: The yearly prevalence of antibiotic use was greater in rural areas compared with urban areas (2009: 23.6% versus 20.2% (p <0.001), especially in the younger age groups. More adult patients residing in rural areas required a second course of antibiotic treatment within 14 days after starting the first treatment. Conclusion: Individuals use more antibiotics, and adults more frequently require a second antibiotic prescription within 14 days, in rural areas compared with urban areas. Although the differences were small and the risks for the general rural population were not high, this difference should be investigated further