The relationship between childhood leukaemia and childhood asthma: A pharmacoepidemiological study from the Netherlands.

BACKGROUND: It has been suggested that childhood asthma lowers the risk of childhood leukaemia. Studies have found an inverse association between these conditions. However, most studies on this relationship are based on questionnaires and telephone interviews, introducing recall bias. Therefore, we conducted a matched case-control study based on drug prescription data to assess the relationship between both conditions. METHODS: In a large database, covering more than one million individuals, we identified cases of children who had been prescribed 6-mercaptopurine (6-MP). This drug is used in the outpatient maintenance therapy of childhood leukaemia. We matched every child with leukaemia on sex and age (±6 months) to children without leukaemia (controls). The variable of having had asthma was defined as receiving at least two prescriptions for an inhaled corticosteroid within 12 months. RESULTS: We identified 59 children aged 2-18 who had been prescribed 6-MP (cases), and they were matched to 21,918 controls. Of the children with childhood leukaemia, three (5%) had childhood asthma, whereas in the control group 4889 (22%) had childhood asthma (odds ratio [OR] 0.19; 95% confidence interval 0.06-0.60). CONCLUSION: In this study on the relationship between childhood asthma and childhood leukaemia, we found a strong inverse association.

Exposure to psychotropic drugs before and during pregnancy: what has changed over the last two decades?

Trends in prescribing psychotropic drugs before and during pregnancy may have changed over the years, but actual information is lacking. We therefore compared and assessed the exposure and acceptance rates of classes of antipsychotic (+ lithium), anxiolytic, sedative/hypnotic, antidepressant, and psychostimulant before and during pregnancy in the past two decades. All singleton pregnancies with ≥1 prescription of psychotropic drug from six months before pregnancy until child's birthdate were identified in the pregnancy subset of the IADB.nl prescription database. The prescription patterns of psychotropics were distinguished as continuation rate (CR), initiation rate (IR), discontinuation rate (DR), total exposure rate (TER), and acceptance rate. Singleton pregnancies exposed to psychotropic drugs before and during pregnancy increased from 118.4 to 136.5 (per 1000 singleton pregnancies) between decades. Changing trends were observed in decade 2, including a high increase in the TER of antipsychotic class (3.3 to 6.8) and antidepressant class (23.0 to 40.6). A marked increase for individual drugs was seen for sertraline (TER: 0.6 to 6.6 and PAT: 35.3% to 82.5%), citalopram (TER: 2.3 to 10.0 and PAT: 51.1% to 74.6%), and quetiapine (TER: 0.4 to 3.1 and PAT: 57.1% to 66.0%). Although the total exposure rates of five classes of psychotropics in singleton pregnancies increased in decade 2, only antidepressant class had a higher acceptance rate during pregnancy. Certain SSRI antidepressants and atypical antipsychotics were more frequently prescribed in decade 2 than in decade 1, reflecting that treatment options were preferred for safer treatment choices.

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.

Risk of neuropsychiatric adverse events associated with varenicline treatment for smoking cessation among Dutch population: A sequence symmetry analysis.

PURPOSE: Varenicline is an effective treatment for smoking cessation. While clinical trials did not confirm a causal role, case reports suggested a possible link of varenicline with neuropsychiatric adverse drug events (NPAEs). This study aims to investigate the risk of NPAEs associated with varenicline initiation among the general population in a real-world setting. METHODS: We conducted a sequence symmetry analysis (SSA) based on the University of Groningen IADB.nl prescription database. We selected incident users of both varenicline and marker drugs for NPAEs, including depression, anxiety and sleep disorder within different time-intervals. Adjusted sequence ratios (aSR) were calculated for each time-interval. RESULTS: Within 365-days' time-interval 1066 patients were incident users of both varenicline and NPAE marker drugs. In total, 505 patients were prescribed varenicline before NPAE marker drugs and 561 vice versa (crude sequence ratio [cSR] 0.90, 95% CI: 0.80-1.02). After adjustments for trends in prescriptions, overall a null association was found (aSR 1.00, 95% CI: 0.89-1.13). Regarding specific NPAEs, no increased risks were found for depression nor anxiety within any time-interval. A small transient increased risk was found for sleep disorders, particularly in earlier time-intervals 3 and 6 months (aSRs 1.52, 95% CI: 1.10-2.11 and 1.45, 95% CI: 1.15-1.83, respectively). Subgroup and sensitivity analyses showed similar findings. CONCLUSIONS: Varenicline initiation was unlikely to be associated with an increased risk of taking anti-depressants nor anti-anxiety drugs. Yet a small, but statistically significant, transient association with drugs for sleep disorders was noticed, possibly associated with withdrawal symptoms caused by smoking cessation.

Functional vitamin K status and risk of incident chronic kidney disease and microalbuminuria: a prospective general population-based cohort study.

BACKGROUND: Circulating desphospho-uncarboxylated matrix γ-carboxyglutamate (Gla) protein (dp-ucMGP), a marker of vitamin K status, is associated with renal function and may serve as a potentially modifiable risk factor for incident chronic kidney disease (CKD). We aimed to assess the association between circulating dp-ucMGP and incident CKD. METHODS: We included 3969 participants with a mean age of 52.3 ± 11.6 years, of whom 48.0% were male, enrolled in the general population-based Prevention of REnal and Vascular ENd-stage Disease study. Study outcomes were incident CKD, defined as either development of an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 or microalbuminuria. Associations of dp-ucMGP with these outcomes were quantified using Cox proportional hazards models and were adjusted for potential confounders. RESULTS: Median plasma dp-ucMGP was 363 [interquartile range (IQR) 219-532] pmol/L and mean serum creatinine- and serum cystatin C-based eGFR (eGFRSCr-SCys) was 95.4 ± 21.8 mL/min/1.73 m2. During 7.1 years of follow-up, 205 (5.4%) participants developed incident CKD and 303 (8.4%) developed microalbuminuria. For every doubling of plasma dp-ucMGP, hazard ratios for the development of incident CKD and microalbuminuria were 1.85 [95% confidence interval (CI) 1.59-2.16; P < 0.001] and 1.19 (95% CI 1.07-1.32; P = 0.001), respectively. These associations lost significance after adjustment for baseline eGFRSCr-SCys [0.99 (95% CI 0.88-1.12; P = 0.86)] and baseline age [1.03 (95% CI 0.94-1.14; P = 0.50)], respectively. CONCLUSIONS: The associations of plasma dp-ucMGP with incident CKD and microalbuminuria were driven by the respective baseline effects of renal function and age.

A Prescription Trend Analysis of Methylphenidate: Relation to Study Reports on Efficacy.

Use of methylphenidate in children has increased substantially, despite conflicting evidence regarding efficacy. In this study, prescription data were analyzed in relation to the publication of new evidence regarding efficacy. Incidence rates and prescribed doses of methylphenidate increased, with a decline during the last few years. Duration of use is still increasing. In half of the cases, starting dosages are higher than recommended in guidelines. There was little evidence that publication of new evidence directly influenced the use of methylphenidate. Recent and critical study findings should receive more attention to contribute to the development and use of treatment guidelines for ADHD and evidence-based methylphenidate use.

Discontinuation and dose adjustment of metoprolol after metoprolol-paroxetine/fluoxetine co-prescription in Dutch elderly.

PURPOSE: Co-prescription of paroxetine/fluoxetine (a strong CYP2D6 inhibitor) in metoprolol (a CYP2D6 substrate) users is common, but data on the clinical consequences of this drug-drug interaction are limited and inconclusive. Therefore, we assessed the effect of paroxetine/fluoxetine initiation on the existing treatment with metoprolol on the discontinuation and dose adjustment of metoprolol among elderly. METHODS: We performed a cohort study using the University of Groningen IADB.nl prescription database (www.IADB.nl). We selected all elderly (≥60 years) who had ever been prescribed metoprolol and had a first co-prescription of paroxetine/fluoxetine, citalopram (weak CYP2D6 inhibitor), or mirtazapine (negative control) from 1994 to 2015. The exposure group was metoprolol and paroxetine/fluoxetine co-prescription, and the other groups acted as controls. The outcomes were early discontinuation and dose adjustment of metoprolol. Logistic regression was applied to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI). RESULTS: Combinations of metoprolol-paroxetine/fluoxetine, metoprolol-citalopram, and metoprolol-mirtazapine were started in 528, 673, and 625 patients, respectively. Compared with metoprolol-citalopram, metoprolol-paroxetine/fluoxetine was not significantly associated with the early discontinuation and dose adjustment of metoprolol (OR = 1.07, 95% CI:0.77-1.48; OR = 0.87, 95% CI:0.57-1.33, respectively). In comparison with metoprolol-mirtazapine, metoprolol-paroxetine/fluoxetine was associated with a significant 43% relative increase in early discontinuation of metoprolol (OR = 1.43, 95% CI:1.01-2.02) but no difference in the risk of dose adjustment. Stratified analysis by gender showed that women have a significantly high risk of metoprolol early discontinuation (OR = 1.62, 95% CI:1.03-2.53). CONCLUSION: Paroxetine/fluoxetine initiation in metoprolol prescriptions, especially for female older patients, is associated with the risk of early discontinuation of metoprolol.

Economic Consequences and Potentially Preventable Costs Related to Osteoporosis in the Netherlands.

BACKGROUND: Osteoporosis often does not involve symptoms, and so the actual number of patients with osteoporosis is higher than the number of diagnosed individuals. This underdiagnosis results in a treatment gap. OBJECTIVES: To estimate the total health care resource use and costs related to osteoporosis in the Netherlands, explicitly including fractures, and to estimate the proportion of fracture costs that are linked to the treatment gap and might therefore be potentially preventable; to also formulate, on the basis of these findings, strategies to optimize osteoporosis care and treatment and reduce its related costs. METHODS: In this retrospective study, data of the Achmea Health Database representing 4.2 million Dutch inhabitants were used to investigate the economic consequence of osteoporosis in the Netherlands in 2010. Specific cohorts were created to identify osteoporosis-related fractures and their costs. Besides, costs of pharmaceutical treatment regarding osteoporosis were included. Using data from the literature, the treatment gap was estimated. Sensitivity analysis was performed on the base-case results. RESULTS: A total of 108,013 individuals with a history of fractures were included in this study. In this population, 59,193 patients were using anti-osteoporotic medication and 86,776 patients were using preventive supplements. A total number of 3,039 osteoporosis-related fractures occurred. The estimated total costs were €465 million. On the basis of data presented in the literature, the treatment gap in our study population was estimated to vary from 60% to 72%. CONCLUSIONS: The estimated total costs corrected for treatment gap were €1.15 to €1.64 billion. These results indicate room for improvement in the health care policy against osteoporosis.

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 (≥60 years) 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. Copyright © 2017 John Wiley & Sons, Ltd.

Association between medication prescription for atopic diseases and attention-deficit/hyperactivity disorder.

BACKGROUND: Data on the association between atopic diseases and attention-deficit/hyperactivity disorder (ADHD) have been inconclusive. OBJECTIVE: To assess whether children with drug-treated ADHD are more likely to receive treatment for asthma, allergic rhinitis, or eczema before the start of ADHD medication use compared with controls and to examine the effect of parents receiving medication for ADHD and atopic diseases on ADHD medication use in their offspring. METHODS: We conducted a retrospective nested case-control study among children (6-12 years of age) using the Groningen University prescription database. Cases were defined as children with at least 2 prescriptions of methylphenidate within 12 months. For each case, 4 controls were matched on age, sex, and regional area code. Parental prescription data were linked to cases and controls to assess the influence of parents receiving medication for ADHD and atopic diseases on ADHD medication use in their offspring. RESULTS: We identified 4257 cases and 17,028 matched controls. Drug treatment for asthma, allergic rhinitis, and eczema was more common in cases than controls (adjusted odds ratios [aORs], 1.4 [95% confidence interval (CI), 1.3-1.6], 1.4 [95% CI, 1.1-1.8], and 1.3 [95% CI, 1.1-1.5], respectively). Medication for allergic rhinitis and asthma among parents was associated with ADHD treatment in their children (aORs, 1.3 [95% CI, 1.1-1.5] and 1.2 [95% CI, 1.1-1.3], respectively). CONCLUSION: This study provides further evidence to support the hypothesis that atopic diseases are associated with ADHD. The parental-offspring association suggests a possible genetic and/or environmental component.

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.

Poor guideline adherence in the initiation of antidepressant treatment in children and adolescents in the Netherlands: choice of antidepressant and dose.

The Dutch guideline for the treatment of depression in young people recommends initiating antidepressant treatment with fluoxetine, as the evidence for its efficacy is strongest and the risk of suicidality may be lower than with other antidepressants. Furthermore, low starting doses are recommended. We aimed to determine whether antidepressant prescriptions are in accord with guidelines. A cohort of young people aged between 6 and 17 at the time of antidepressant initiation was selected from IABD, a Dutch pharmacy prescription database. The percentage of prescriptions for each antidepressant was determined. Starting and maintenance doses were determined and compared with recommendations for citalopram, fluoxetine, fluvoxamine, and sertraline. During the study period, 2942 patients initiated antidepressant treatment. The proportion of these young people who were prescribed fluoxetine increased from 10.1 % in 1994-2003 to 19.7 % in 2010-2014. However, the most commonly prescribed antidepressants were paroxetine in 1994-2003 and citalopram in 2004-2014. The median starting and maintenance doses were ≤0.5 DDD/day for tricyclic antidepressants and 0.5-1 DDD/day for SSRIs and other antidepressants. Starting doses were guideline-concordant 58 % of the time for children, 31 % for preteens, and 16 % for teens. Sixty percent of teens were prescribed an adult starting dose. In conclusion, guideline adherence was poor. Physicians preferred citalopram over fluoxetine, in contrast to the recommendations. Furthermore, although children were prescribed a low starting dose relatively frequently, teens were often prescribed an adult starting dose. These results suggest that dedicated effort may be necessary to improve guideline adherence.

Drugs associated with teratogenic mechanisms. Part I: dispensing rates among pregnant women in the Netherlands, 1998-2009.

STUDY QUESTION: What are the dispensing rates of drugs suspected to be associated with teratogenic mechanisms among pregnant Dutch women? SUMMARY ANSWER: In a substantial proportion of pregnancies in our study population at least one drug associated with a teratogenic mechanism was dispensed in the first trimester of pregnancy. WHAT IS KNOWN ALREADY: The main teratogenic mechanisms of medical drugs that may affect fetal development in the first trimester of pregnancy have been described previously. However, information on the dispensing rate of such drugs among women at all stages of pregnancy is lacking. STUDY DESIGN, SIZE, DURATION: To determine how often medications suspected to be associated with a teratogenic mechanism are used by pregnant women, we studied 32 016 pregnancies included in the IADB.nl database between 1998 and 2009. PARTICIPANTS/MATERIALS, SETTING, METHODS: We estimated dispensing rates of medical drugs suspected to be associated with teratogenic mechanisms in our study population. The IADB.nl database includes all pharmacy dispensings for an estimated population of 220 000 in 1994-1998 and c.500 000 since 1999. In addition, trends in first trimester dispensing rates over time and patterns of receiving multiple drugs associated with teratogenic mechanisms were evaluated. In addition, we determined the number of pregnancies in which multiple prescription drugs from one or more teratogenic categories were dispensed in the first trimester, and we evaluated the numbers of different medications dispensed that could be grouped within a specific teratogenic mechanism. MAIN RESULTS AND THE ROLE OF CHANCE: In 175 per 1000 pregnancies [95% confidence interval (CI), 171-179] at least one drug associated with a teratogenic mechanism was dispensed in the first trimester. The total dispensing rate was 236 per 1000 pregnancies (95% CI 232-241) in the 3 months before pregnancy and an increasing trend was seen in the second [214 per 1000 (95% CI 209-218)] and third [327 per 1000 (95% CI 322-332)] trimesters. The first trimester dispensing rates increased between 1998 and 2009 for selective serotonin-reuptake inhibitors (P < 0.001) and serotonin receptor agonists/antagonists (P < 0.001). In 71.8% of pregnancies in which drugs associated with teratogenic mechanisms were dispensed in the first trimester, women received drugs related to only one mechanism. Of the pregnancies in which drugs from multiple teratogenic categories were dispensed in the first trimester, 1148 (72.6%) women received drugs from 2 categories, 317 (20.0%) from three categories, 88 (5.6%) from 4 categories, 28 (1.8%) from 5 categories and 1 from 6 categories. Several women received multiple prescription medications grouped within a single teratogenic mechanism in the first trimester, ranging between 13.3% for cyclo-oxygenase inhibitors and 41.8% for serotonin receptor agonists/antagonists. LIMITATIONS, REASONS FOR CAUTION: We used a dispensing database, therefore actual use of the medication prescribed is unknown and non-compliance could have led to overestimation of exposure prevalences. WIDER IMPLICATIONS OF THE FINDINGS: Owing to the uncertainties concerning the safety of medication use during pregnancy, the results of this study stress the need for cautious prescription of medication associated with teratogenic mechanisms to women of reproductive age. This is further supported by our finding that women received multiple prescription medications grouped within a single teratogenic mechanism in the first trimester, which would theoretically increase strongly the risk of birth defects. STUDY FUNDING/COMPETING INTEREST(S): Marleen van Gelder was supported by the Netherlands Organisation for Scientific Research/NWO (grant no. 021.001.008). No competing interests are declared. TRIAL REGISTRATION NUMBER: N/A.

Healthcare databases in Europe for studying medicine use and safety during pregnancy.

PURPOSE: The aim of this study was to describe a number of electronic healthcare databases in Europe in terms of the population covered, the source of the data captured and the availability of data on key variables required for evaluating medicine use and medicine safety during pregnancy. METHODS: A sample of electronic healthcare databases that captured pregnancies and prescription data was selected on the basis of contacts within the EUROCAT network. For each participating database, a database inventory was completed. RESULTS: Eight databases were included, and the total population covered was 25 million. All databases recorded live births, seven captured stillbirths and five had full data available on spontaneous pregnancy losses and induced terminations. In six databases, data were usually available to determine the date of the woman's last menstrual period, whereas in the remainder, algorithms were needed to establish a best estimate for at least some pregnancies. In seven databases, it was possible to use data recorded in the databases to identify pregnancies where the offspring had a congenital anomaly. Information on confounding variables was more commonly available in databases capturing data recorded by primary-care practitioners. All databases captured maternal co-prescribing and a measure of socioeconomic status. CONCLUSION: This study suggests that within Europe, electronic healthcare databases may be valuable sources of data for evaluating medicine use and safety during pregnancy. The suitability of a particular database, however, will depend on the research question, the type of medicine to be evaluated, the prevalence of its use and any adverse outcomes of interest. © 2014 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons, Ltd.

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.

Comparative effectiveness of antihypertensive monotherapies in primary prevention of cardiovascular events-a real-world longitudinal inception cohort study.

Introduction: Antihypertensive drugs are used preventatively to lower the risk of cardiovascular disease events. Comparative effectiveness studies on angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), beta-blockers (BBs), calcium channel blockers (CCBs), and thiazides have yielded inconsistent results and given little consideration to patient adherence. Using a longitudinal cohort and considering time-varying adherence and confounding factors, we aimed to estimate the real-world effectiveness of five major antihypertensive drug monotherapies in the primary prevention of cardiovascular events. Methods: Eligible patients for a retrospective inception cohort study were selected using information obtained from the University of Groningen IADB.nl pharmacy prescription database. Cohort 1 comprised adherent patients with a follow-up time exceeding 1 year, and cohort 2 comprised all patients independent of adherence. The exposures were ACEIs, ARBs, BBs, CCBs, and thiazides. The primary outcome was the time to the first prescription for an acute cardiac drug therapy (CDT) measured using valid drug proxies to identify the first major cardiovascular event. A per-protocol analytical approach was adopted with inverse probability of treatment weighted (IPTW), time-varying Cox regression analysis to obtain the hazard ratios (HRs) and 95% confidence intervals (CIs). Results: In cohort 1 (n = 22,441), 1,294 patients (5.8%) were prescribed an acute CDT with an average follow-up time of 4.2 ± 2.8 years. Following IPTW, the hazard measures of ARBs and thiazides were lower than those of BBs (HRs: 0.79 and 0.80, respectively; 95% CIs: 0.64-0.97 and 0.69-0.94, respectively). Among drug-treated diabetic patients, the hazard measures were even lower, with HR point estimates of 0.43 (CI: 0.19-0.98) for ARBs and 0.32 (CI: 0.13-0.82) for thiazides. In cohort 2 (n = 33,427) and sensitivity analysis, the comparative effectiveness results for thiazides and BBs were similar to those for cohort 1. Conclusion: The findings of this real-world analysis suggest that the incidence of CDT associated with long-term thiazide or ARB monotherapy is lower than the incidence of CDT with BBs, notably among high-risk patients. Incidences of CDT associated with ACEIs and CCBs were comparable relative to those associated with BBs.

Risk factors for drug-treated major adverse cardio-cerebrovascular events in patients on primary preventive statin therapy: A retrospective cohort study.

We aim to identify risk factors of major adverse cardio-cerebrovascular events (MACCE) using a proxy of drug treatment for a MACCE after the start of statin therapy in the primary cardiovascular prevention group, taking drug dose, persistency and adherence into account. We conducted a retrospective inception cohort study using data from the University of Groningen prescription database IADB.nl, covering patients in the Northern part of the Netherlands. We identified adult starters on primary preventive statin therapy as patients without any statin or cardiovascular drug prescription in the two years before the first statin dispensing and used a weighted Cox proportional hazard model to estimate hazard ratios (HR) with their 95 % confidence intervals (95 %CI). Among 39,487 primary preventive statin starters, 23% received drug treatment for a MACCE within a median follow-up period of four years. Increasing age, male gender and presence of diabetes drug treatment were significantly associated with the outcome (HR: 1.03; 95 %CI: 1.02-1.04; HR: 1.27; 95 %CI: 1.12-1.44 and HR: 1.39; 95 %CI: 1.24-1.56, respectively). If patients remained statin therapy persistent, adherence was no longer associated with drug treatment for a MACCE. In 23 % of the statin therapy initiators, incident drug treatment for a MACCE occurred with a median of four years. To reduce event rates in this group, older patients, males and diabetes patients should be closely monitored. Non-adherence in the early stage of treatment should be avoided to prevent non-persistence.

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.

Real-World Dispensing Patterns of Inhalation Medication in Young Adult Asthma: An Inception Cohort Study.

Purpose: The Global Initiative for Asthma (GINA) suggests a step-wise approach for pharmacological treatment of asthma. Valid study of real-world treatment patterns using dispensing databases includes proper measurement of medication adherence. We aim to explore such patterns by applying a time-varying proportion of days covered (tPDC)-based algorithm. Patients and Methods: We designed a retrospective inception cohort study using the University of Groningen IADB.nl community pharmacy dispensing database. Included were 19,184 young adults who initiated asthma medication anywhere between 1994 and 2021, in the Netherlands. Main treatment steps were defined as: 1 - SABA/ICS-formoterol as needed, 2 - low dose ICS, 3 - low dose ICS + LABA or tiotropium, or intermediate dose ICS, 4 - intermediate to high dose ICS + LABA or tiotropium, triple therapy, or high dose ICS, 5 - treatment prescribed by a specialist. Changes in treatment steps were determined using a time-varying proportion of days covered (tPDC)-based algorithm. Individual drug treatment trajectories were visualized over time using a lasagna plot. Results: At initiation, of the 19,184 included individuals, 52%, 7%, 15%, 16%, and 10% started treatment in steps 1 to 5, respectively. The median (IQR) follow-up time was 3 (1-7) years. Median (IQR) number of switches was 1 (0-3). Comparing starting step to last observed step, 37% never switched between treatment steps, 20% of individuals stepped down and 22% stepped up. Conclusion: The low proportion of treatment switches between steps indicates that tailoring of treatment to patients' needs might be suboptimal. The tPDC-based algorithm functions well in translating dispensing data into continuous drug-utilization data, enabling a more granular assessment of treatment patterns among asthma patients.

Association between Incidence of Prescriptions for Alzheimer's Disease and Beta-Adrenoceptor Antagonists: A Prescription Sequence Symmetry Analysis.

BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia, with a growing number of patients worldwide. The association between AD and treatment with drugs targeting the beta-adrenergic receptor is controversial. The aim of this study is to assess the association between the initiation of AD medication and beta-adrenoceptor antagonists (beta-blockers) in adults. MATERIALS AND METHODS: We conducted a prescription sequence symmetry analysis using the University of Groningen IADB.nl prescription database. We determined the order of the first prescription for treating AD and the first prescription for beta-blockers, with the dispensing date of the first prescription for AD defined as the index date. Participants were adults over 45 years old starting any AD medication and beta-blockers within two years. We calculated adjusted sequence ratios with corresponding 95% confidence intervals. RESULTS: We identified 510 users of both AD and beta-blockers, and 145 participants were eligible. The results were compatible with either a significant decrease in the incidence of AD after using beta-blockers (adjusted sequence ratio (aSR) = 0.52; 95% CI: 0.35-0.72) or, conversely, an increase in beta-blockers after AD medication (aSR = 1.96; 95% CI: 1.61-2.30). CONCLUSIONS: There is a relationship between the use of beta-blockers and AD medications. Further research is needed with larger populations to determine whether drug therapy for AD increases the risk of hypertension or whether beta-blockers have potential protective properties against AD development.