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

Neuropsychiatric safety of varenicline in the general and COPD population with and without psychiatric disorders:a retrospective cohort study in a real-world setting

OBJECTIVES: To evaluate the real-world association between varenicline and neuropsychiatric adverse events (NPAEs) in general and chronic obstructive pulmonary disease (COPD) population with and without psychiatric disorders compared with nicotine replacement therapy (NRT) to strengthen the knowledge of varenicline safety. DESIGN: A retrospective cohort study. SETTING: Prescription database IADB.nl, the Netherlands. PARTICIPANTS: New users of varenicline or NRT among general (≥18 years) and COPD (≥40 years) population. Psychiatric subcohort was defined as people prescribed psychotropic medications (≥2) within 6 months before the index date. OUTCOME MEASURES: The incidence of NPAEs including depression, anxiety and insomnia, defined by new or naive prescriptions of related medications in IADB.nl within 24 weeks after the first treatment initiation of varenicline or NRT. RESULTS: For the general population in non-psychiatric cohort, the incidence of total NPAEs in varenicline (4480) and NRT (1970) groups was 10.5% and 12.6%, respectively (adjusted OR (aOR) 0.85, 95% CI 0.72 to 1.00). For the general population in psychiatric cohort, the incidence of total NPAEs was much higher, 75.3% and 78.5% for varenicline (1427) and NRT (1200) groups, respectively (aOR 0.82, 95% CI 0.68 to 0.99). For the COPD population (1598), there were no differences in the incidence of NPAEs between comparison groups in both the psychiatric cohort (aOR 0.97, 95% CI 0.66 to 1.44) and non-psychiatric cohort (aOR 0.81, 95% CI 0.54 to 1.20). Results from subgroup or sensitivity analyses also did not reveal increased risks of NPAEs but showed decreased risk of some subgroup NPAEs associated with varenicline. CONCLUSIONS: In contrast to the concerns of a possible increased risk of NPAEs among varenicline users, we found a relative decreased risk of total NPAEs in varenicline users of the general population in psychiatric or non-psychiatric cohorts compared with NRT and no difference for NPAEs between varenicline and NRT users in smaller population with COPD

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

Influence of age on real-life effects of doxycycline for acute exacerbations among COPD outpatients:A population-based cohort study

INTRODUCTION: Although bacteria contribute significantly to acute exacerbations of chronic obstructive pulmonary disease (AECOPD), the added value of antibiotics remains controversial, especially in outpatient settings. Age may affect antibiotic effectiveness, but real-world evidence is lacking. We aimed to assess the influence of age on the effectiveness of doxycycline for AECOPD. METHODS: A retrospective cohort study among outpatients with the first recorded AECOPD treated with oral corticosteroids was conducted using a large pharmacy dispensing database. The primary outcome was treatment failure within 15-31 days after treatment start. Secondary outcome was time to second exacerbation. All analyses were stratified by age groups. RESULTS: We identified 6300 outpatients with the first AECOPD. 2261 (36%) received doxycycline and 4039 (64%) did not receive any antibiotic (reference group). Overall, there was no difference in treatment failure (adjusted OR: 0.97, 95% CI: 0.84 to 1.12) between two groups. Similarly, no difference in treatment failure was observed in younger groups. However, in patients with advanced age (≥75 years), treatment failure was significantly reduced by doxycycline compared with reference (16% vs 20%, adjusted OR: 0.77, 95% CI: 0.62 to 0.97). Overall, median time to second exacerbation was 169 days (95% CI: 158 to 182 days) in doxycycline group compared with 180 days (95% CI: 169 to 191 days) in reference group (adjusted HR: 1.06, 95% CI: 0.99 to 1.12). Although in older patients there was a trend within 3 months towards longer time of next exacerbation by doxycycline, it did not achieve statistical significance. CONCLUSIONS: Our findings showed short-term treatment benefit of doxycycline added to oral corticosteroids for chronic obstructive pulmonary disease patients with advanced age. This value remains unclear for persons aged under 75 years in current primary care. Long-term preventive benefits of doxycycline for the next exacerbation were not observed, irrespective of age

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

Identification of Dutch children diagnosed with atopic diseases using prescription data:a validation study

The aim of this study is to validate medication proxies for the identification of children diagnosed with atopic disorders that can be applied in various types of epidemiological research. Records of 7439 children, aged between 0 and 10 years, in the period 2001 until 2010, were retrieved from the Registration Network Groningen database, a general practitioners database in the north-eastern part of the Netherlands. The sensitivity and positive predictive value (PPV) of 22 medication proxies for the identification of children diagnosed with atopic disorders (asthma, atopic dermatitis, and allergic rhinitis) were computed using the registered diagnoses as gold standards. In addition, different capture periods (1 year, half year, and length of study period) for the detection of prescriptions were tested for all the medication proxies. The highest PPV (0.84, 95 % CI 0.81-0.87) in combination with a sufficient sensitivity value (0.54, 95 % CI 0.50-0.57) for the identification of children diagnosed with asthma was yielded for the medication proxy, a parts per thousand yen2 prescriptions for anti-asthma medication within 1 year, including 1 inhaled steroid. PPV and sensitivity were even higher in the age group 6-10 years. The proxies designed for the identification of children diagnosed with atopic dermatitis and allergic rhinitis yielded only high PPVs (a parts per thousand yen0.75) in combination with low sensitivity values (a parts per thousand currency sign0.22). Altering the capture period for the detection of prescriptions to half a year or the length of the study period only affected sensitivity values. Children diagnosed with asthma can be identified reliably with a range of medication proxies. The use of prescription data for the identification of children diagnosed with atopic dermatitis and allergic rhinitis is questionable

Direct costs of hypertensive patients admitted to hospital in Vietnam:a bottom-up micro-costing analysis

Background: There is an economic burden associated with hypertension both worldwide and in Vietnam. In Vietnam, patients with uncontrolled high blood pressure are hospitalized for further diagnosis and initiation of treatment. Because there is no evidence on costs of inpatient care for hypertensive patients available yet to inform policy makers, health insurance and hospitals, this study aims to quantify direct costs of inpatient care for these patients in Vietnam. Methods: A retrospective study was conducted in a hospital in Vietnam. Direct costs were analyzed from the health-care provider's perspective. Hospital-based costing was performed using both bottom-up and micro-costing methods. Patients with sole essential or primary hypertension (ICD-code I10) and those comorbid with sphingolipid metabolism or other lipid storage disorders (ICD-code E75) were selected. Costs were quantified based on financial and other records of the hospital. Total cost per patient resulted from an aggregation of laboratory test costs, drug costs, inpatient-days' costs and other remaining costs, including appropriate allocation of overheads. Both mean and medians, as well as interquartile ranges (IQRs) were calculated. In addition to a base-case analysis, specific scenarios were analyzed. Results: 230 patients were included in the study (147 cases with I10 code only and 83 cases with I10 combined with E75). Median length of hospital stay was 6 days. Median total direct costs per patient were US$65 (IQR: 37 -95). Total costs per patient were higher in the combined hypertensive and lipid population than in the sole hypertensive population at US$78 and US$53, respectively. In all scenarios, hospital inpatient days' costs were identified as the major cost driver in the total costs. Conclusions: Costs of hospitalization of hypertensive patients is relatively high compared to annual medication treatment at a community health station for hypertension as well as to the total health expenditure per capita in Vietnam. Given that untreated/undetected hypertension likely leads to more expensive treatments of complications, these findings may justify investments by the Vietnamese health-care sector to control high blood pressure in order to save downstream health care budgets

Persistence of Antipsychotic Use After Clozapine Discontinuation:A Real-World Study Across Antipsychotics

Although clozapine treatment is often discontinued due to limited efficacy or low tolerability, there is a lack of guidelines and evidence on treatment options after discontinuation of clozapine in patients with schizophrenia. Persistence has proven to be an adequate indicator for treatment effectiveness in patients with schizophrenia. The aim of this study was, therefore, to compare persistence of antipsychotic use between antipsychotic treatment options in patients after stopping clozapine treatment. Registry data from a prescription database representative of the Dutch population (1996-2017) was collected to investigate persistence in patients with schizophrenia who had been using clozapine for >= 90 days. Persistence with antipsychotics after clozapine discontinuation was analyzed using Cox-proportional hazard regression models. Our study population consisted of 321 participants, of whom 138 re-initiated clozapine and 183 started some other antipsychotic in the year after clozapine discontinuation (N = 518 antipsychotic use periods, N = 9,178 months). Second-generation antipsychotics (SGAs) as a group were associated with better persistence compared to first-generation antipsychotics (adjusted hazard ratio (aHR), 0.73; 95% confidence interval (CI) 0.57-0.93; P = 0.011). Compared with other antipsychotics, the following oral monotherapy antipsychotics were associated with significantly better persistence: restarting clozapine (aHR 0.48; 95% CI 0.32-0.71; P <0.001) and switching to risperidone (aHR 0.52; 95% CI 0.32-0.84; P = 0.008) or olanzapine (aHR 0.55; 95% CI 0.35-0.87; P = 0.010). Sensitivity analyses confirmed the results. In conclusion, oral SGAs are associated with better persistence than alternative antipsychotic treatment options in patients discontinuing clozapine for undefined reasons. Especially clozapine (except in those with previous serious adverse reactions to clozapine), olanzapine and risperidone should be considered as oral monotherapy for these patients

Trends in polypharmacy and dispensed drugs among adults in the Netherlands as compared to the United States

BACKGROUND AND PURPOSE: Polypharmacy is becoming increasingly common owing to the ageing population, which can pose problems for patients and society. We investigated the trends in polypharmacy and underlying drug groups among adults in the Netherlands from 1999 to 2014 stratified by age, and compared these with findings from the United States (US). METHODS: We conducted a repeated cross-sectional study using the Dutch IADB.nl prescription database. All patients aged 20 years and older in the period 1999 to 2014 were included. Polypharmacy was defined as the dispensing of five or more chronic drugs at the pharmacological subgroup level. Chi-square tests were applied to calculate the p-value for trends. Changes in prevalences were compared between the Netherlands and the US. RESULTS: The prevalence of polypharmacy increased from 3.1% to 8.0% (p-value for trend <0.001) over 15 years, and increased in all age groups. The highest rates were observed in patients aged ≥65 years, but the relative increase over time was higher in the younger age groups. Overall, large increases were observed for angiotensin-II inhibitors, statins and proton-pump inhibitors. The relative increase in polypharmacy was larger in the Netherlands than in the US (ratio of polypharmacy prevalence 2.4 versus 1.8). The Netherlands showed larger relative increases for angiotensin-II inhibitors, statins, proton-pump inhibitors, biguanides and smaller relative increases for antidepressants, benzodiazepines and insulins. CONCLUSIONS: Polypharmacy more than doubled from 1999 to 2014, and this increase was not limited to the elderly. The relative increase was larger in the Netherlands compared to the US, which was partly due to larger increases in several guideline-recommended preventive drugs