Sipke T. Visser

The population-based prescription database IADB.nl: its development, usefulness in outcomes research and challenges

Research databases with large numbers of prescriptions in observational settings can provide valuable information in addition to the initial randomized controlled trials. This paper reports on the development of prescription database IADB, formerly known as InterAction Database. IADB contains prescriptions from 54 community pharmacies in The Netherlands and covers a population of 500,000 people. Both the age distribution and the prevalence of drugs used are comparable to a large extent with the Dutch population. The representativeness of the population covered is examined by comparing population composition and drug use with data of the whole Dutch population. Enriching IADB with, among others, clinical parameters by linking to other databases is explored. A strong and unique aspect of IADB is the possibility to track patients over time, even when they receive their medication from different pharmacies. The authors conclude IADB is a useful tool for pharmacoepidemiological and pharmacoeconomic outcomes research.

Association of Cognitive Function with Albuminuria and eGFR in the General Population

BACKGROUND AND OBJECTIVES Recent studies found different associations of cognitive function with albuminuria or estimated GFR (eGFR). Most studies were limited to the elderly or did not take both renal variables into account. Therefore, this study analyzed the association of cognitive function with albuminuria and eGFR in community-dwelling persons aged 35 to 82 years. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This was a cross-sectional study comprising 4095 participants of the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study. Cognitive function, measured with the Ruff Figural Fluency Test (RFFT), was treated as the dependent variable, and albuminuria and eGFR were treated as independent variables. RESULTS The prevalence of albuminuria <10, 10 to 29, and ≥30 mg/24 h was 54%, 31%, and 15%, respectively. Mean eGFR (± SD) was 79 ± 15 ml/min per 1.73 m(2). Because of interaction between albuminuria and age, analyses were performed per age tertile. After multivariate adjustment, albuminuria ≥ 30 mg/24 h, but not eGFR, was associated with lower RFFT score in the youngest tertile (B -5.3; 95% CI, -0.6 to -9.2; P = 0.05), but not in older tertiles. Moreover, subjects in the youngest tertile with increasing albuminuria (5-15 and >15 mg/24 h) before RFFT measurement had lower mean RFFT scores than subjects with stable albuminuria: mean difference -4.9 (P = 0.3) and -6.7 (P = 0.03), respectively. CONCLUSIONS In this community-based cohort, elevated albuminuria was associated with worse cognitive function in young but not in old persons. There was no association of eGFR with cognitive function.

Large increase of the use of psycho-stimulants among youth in the Netherlands between 1996 and 2006.

AIM To describe the use of psycho-stimulants in the Netherlands between 1996 and 2006 in children and adolescents, and in relation to age and sex. METHODS With the pharmacy prescription database the IADB.nl, yearly prevalences of psycho-stimulants per 1000 children were calculated, as was the length of psycho-stimulant use with Kaplan-Meier method in SPSS 12.0. RESULTS Psycho-stimulant use increased in boys (0-19) from 4.5 per thousand in 1996 to 31.1 per thousand in 2006 and for girls from 0.7 to 8.1 per thousand, respectively. The largest increase was among boys aged 10-19 years. There is a trend towards prescribing the sustained release preparation of methylphenidate (Concerta). CONCLUSIONS In the Netherlands a large increase in psycho-stimulants use is observed. However, in the Netherlands the prevalence ratio male/female declined from 6.4 in 1996 to 3.8 in 2006.

Screen-and-treat strategies for albuminuria to prevent cardiovascular and renal disease: Cost-effectiveness of nationwide and targeted interventions based on analysis of cohort data from the Netherlands*

BACKGROUND Albuminuria is a marker for renal and cardiovascular (CV) risk, allowing early diagnosis of subjects with elevated renal and CV risk. OBJECTIVE This study aimed to estimate the cost-effectiveness and budget impact of various population-based screen-and-treat scenarios for elevated albuminuria levels (ie, microalbuminuria) in the Netherlands. METHODS A multistate transition Markov model was developed to simulate the natural course of albuminuria-based disease progression to dialysis and occurrence of CV events. Several population-based strategies directed at screening for elevated albuminuria were evaluated. These strategies depended on urinary albumin concentration (UAC), urinary albumin excretion (UAE), and age. Transition probabilities were derived from the observational community-based Prevention of Renal and Vascular End Stage Disease (PREVEND) cohort study. Health care costs (in year-2008 euros) and life-years gained were calculated over an 8-year period. In the base-case analysis, we analyzed screening for and treatment of microalbuminuria. Screening for microalbuminuria involved prescreening for UAC >or=20 mg/L, followed by a confirmation test for UAE >or=30 mg/d. Other options based on combinations of albuminuria for UAC prescreening (no prescreening, and >or=10, >or=20, >or=100, and >or=200 mg/L) and UAE confirmation test (>or=15, >or=30, and >or=300 mg/d) for treatment were investigated in scenario analyses. Furthermore, these various strategies based on UAC and UAE values were analyzed in different subgroups based on age (all ages, aged >or=50 years, and aged >or=60 years). RESULTS The PREVEND study included 8592 Dutch residents aged 28 to 75 years at the time of initial screening. Among a hypothetical cohort of 1000 subjects identified and treated in the base-case analysis, it was estimated (based on PREVEND follow-up data) that, in the screening/treatment and no-screening scenarios, 76 versus 124 CV events occurred, 16 versus 27 CV deaths, and 3 versus 5 dialysis cases, respectively. The per-person difference in net costs for screening was calculated at euro926 (euro2003 vs euro1077), and prevention of CV deaths was estimated to gain 0.0421 discounted life-year per person. Correspondingly, the cost-effectiveness was estimated at euro22,000 per life-year gained. In the base-case analysis, probabilistic sensitivity analysis indicated that the likelihood of cost-effectiveness of a screen-and-treat strategy was 54%, 90%, and 95% for a maximum acceptable cost-effectiveness threshold of euro20,000, euro50,000, and euro80,000 per life-year gained, respectively. Higher albuminuria thresholds for screening and start of treatment further improved the cost-effectiveness but reduced the overall health gains achieved. Limiting screening to those subjects aged >or=50 and >or=60 years resulted in more favorable cost-effectiveness compared with population-based screening without age restriction. CONCLUSIONS Our analyses suggest the potentially favorable cost-effectiveness of population-based screening for albuminuria in the general Dutch population. The results offer health care decision-makers new tools for considering actual implementation of such screening.

Cost effectiveness of angiotensin receptor blocker monotherapy in patients with hypertension in the Netherlands: a comparative analysis using clinical trial and drug utilization data.

Background and ObjectiveHealth gains and related cost savings achieved by optimizing treatment in hypertensive patients is highly important. The aim of this study was to evaluate the costs and cost effectiveness of treatment with angiotensin II receptor antagonists (angiotensin II receptor blockers [ARBs]) in patients with essential hypertension and to compare within-trial with real-life dosing of ARBs.MethodsCost effectiveness was estimated based on a published clinical trial comparing the BP-lowering effects of olmesartan, losartan, valsartan, and irbesartan. BP lowering after 8 weeks of treatment was entered into the Framingham risk functions to estimate cardiovascular complications after 1 and 5 years, using an international health economics model that was adapted to the Netherlands. Dutch costs (2006 values) and complications derived from the model were discounted at 4% and 1.5%, respectively, and cost effectiveness was expressed in net costs per cardiovascular complication averted. In a drug-utilization study, pharmacy dispensing records were used to evaluate differences between within-trial and daily-practice dosing and related costs for treatment in the Netherlands.ResultsAfter 8 weeks, the trial-based analysis showed that treatment with olmesartan versus losartan, valsartan, and irbesartan resulted in a significantly larger decrease in BP (11.5 vs 8.2, 7.9 and 9.9 mmHg [p<0.05], respectively) and consequently more complications averted. Cost effectiveness for olmesartan, losartan, valsartan, and irbesartan was estimated at €39 100, €77 100, €70 700, and €50 900 per cardiovascular complication averted, respectively. The incremental cost-effectiveness analysis indicated the most favorable cost-effectiveness outcome for olmesartan, with lower costs and less cardiovascular complications for olmesartan compared with the other three ARBs. The drug-utilization analysis showed that the dosing followed within clinical trials was not found in daily practice. On average, losartan, valsartan, and irbesartan were administered at doses above those used in clinical trials, whereas olmesartan was dosed lower than in clinical trials, resulting in relatively lower costs.ConclusionBased on the exact trial data, olmesartan was estimated to be the most favorable option of the four ARBs based on within-trial decreases in BP levels after 8 weeks and in terms of cost-effectiveness for this particular Dutch setting. However, for definite conclusions to be drawn, this hypothesis-generating study requires confirmation from further prospective studies comparing ARBs based on comparable BP control and including hard endpoints.

Baseline albuminuria predicts the efficacy of blood pressure-lowering drugs in preventing cardiovascular events

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT Albuminuria has been proven to be associated with cardiovascular morbidity and mortality. Such an association has been found not only in subjects with diabetes and hypertension, but also in the general population. It could therefore be expected that especially subjects with higher albuminuria levels may benefit from blood pressure-lowering agents to improve their cardiovascular outcome. WHAT THIS STUDY ADDS This study indicates that the efficacy of blood pressure-lowering agents to prevent cardiovascular events is dependent of the level of albuminuria before start of such treatment. The higher baseline albuminuria, the better the relative and absolute risk reduction for cardiovascular events with blood pressure-lowering drugs. The data also suggest a possible better cardiovascular protective effect of renin-angiotensin intervening agents compared with other blood pressure-lowering agents. AIMS Albuminuria has been proven to be associated with cardiovascular (CV) events in specific patient populations, but also in the general population. This study aimed to investigate whether the efficacy of blood pressure-lowering agents in preventing CV events depends on baseline urinary albumin excretion (UAE) and, if so, whether this holds true for blood pressure-lowering agents in general, or is limited to agents that interfere in the renin-angiotensin system. METHODS Data were used from a community-based cohort study and pharmacy dispensing records. Included were subjects with hypertension (systolic blood pressure >or=140 and/or diastolic blood pressure >or=90 mmHg), no cardiovascular disease history, and no previous use of blood pressure-lowering agents. RESULTS During study follow-up (7.1 +/- 1.6 years), 122 CV events were observed in 1185 subjects included. Start of blood pressure-lowering agents vs. non-use was associated with a difference in absolute CV event risk of 0.7%, 6% and 12.6% for all subjects, those with UAE >or= 15 mg day(-1) and >or=30 mg day(-1), respectively. Cox regression analysis showed that the relative risk for CV events after start of blood pressure-lowering agents was significantly dependent (P < 0.05) on baseline UAE; with hazard ratios of 0.87 [95% confidence interval (CI) 0.48, 1.60, P = NS], 0.58 (95% CI 0.36, 0.94, P < 0.05) and 0.37 (95% CI 0.20, 0.68, P < 0.05), for subjects with UAE < 15, >or=15 and >or=30 mg day(-1), respectively. Results adjusted for covariates were essentially similar. The use of angiotensin converting enzyme inhibitor/angiotensin-II receptor blocker (ACEi/ARB) treatment tended to be associated with a more favourable CV prognosis when compared with non-ACEi/ARB treatment (difference P = 0.06). CONCLUSIONS Our results suggest that the efficacy of blood pressure-lowering agents to prevent CV events is dependent on baseline albuminuria. The higher baseline albuminuria, the more absolute as well as relative risk reduction can be achieved. Our data suggest that this may especially be true for ACEi/ARBs. We caution that this is an observational study, and that these conclusions should therefore be regarded as hypothesis generating, rather than hypothesis testing.

Effect of pravastatin and fosinopril on recurrent urinary tract infections

OBJECTIVES Recurrent urinary tract infections (UTIs) are a problem affecting both women and men. Animal experiments and in vitro studies indicate that statins might prevent recurrent UTIs. We assessed the effects of pravastatin on UTI antibiotic prescribing among adults. METHODS A post hoc analysis was conducted with data from PREVEND IT, a trial among participants randomized to receive pravastatin, fosinopril or placebo in a 2 × 2 factorial design over 4 years. Trial data were linked to the pharmacy prescription database IADB.nl. The primary outcome was the number of prescriptions with a nitrofuran derivate, a sulphonamide or trimethoprim as a proxy for UTI antibiotic prescribing. Generalized estimating equations were used to estimate the effect on the number of UTI antibiotic prescriptions. Cox regression was used to determine the effect on first and second (recurrent) UTI antibiotic prescriptions. RESULTS Of the 864 trial participants, 655 were eligible for analysis. During an average follow-up of 3.8 years, 112 (17%) participants received at least one UTI antibiotic prescription. Intention-to-treat analyses showed that pravastatin was associated with a reduced total number of UTI antibiotic prescriptions (relative risk, 0.43; 95% CI, 0.21-0.88) and occurrence of second UTI antibiotic prescriptions [hazard ratio (HR), 0.25; 95% CI, 0.08-0.77]. No significant effect on occurrence of first UTI antibiotic prescriptions was found (HR, 0.83; 95% CI, 0.57-1.20). Fosinopril was associated with an increased occurrence of first UTI antibiotic prescriptions (HR, 1.82; 95% CI, 1.16-2.88). Combination therapy with fosinopril and pravastatin did not significantly influence the number of UTI antibiotic prescriptions. CONCLUSIONS This study suggests that pravastatin can reduce the occurrence of recurrent UTIs. Larger studies among patients with recurrent UTIs are warranted.

Antibiotic usage, dosage and course length in children between 0 and 4 years.

Aim:  Antibiotic drugs are most frequently used by 0‐ to 4‐year‐old children. We performed a cross‐sectional study in the Netherlands using a pharmacy prescription database to investigate the use, dose and course length of antibiotic drugs in 0‐ to 4‐year‐olds.

24 h urinary free cortisol in large-scale epidemiological studies: Short-term and long-term stability and sources of variability

BACKGROUND Function of the hypothalamus-pituitary-adrenal (HPA) axis has been associated with several somatic and psychiatric health problems. The amount of free cortisol excreted in the urine during 24h (24-h UFC) has often been used as a proxy for HPA-axis function. Reference values for 24-h UFC and their stability in the short and long term, as well as sources of variability, are largely lacking. METHODS This study was performed in a general population cohort. Participants collected 24-h UFC on two consecutive days (T1), and repeated this collection approximately 2 years later (T2). Cortisol in urine was measured using LC-MS/MS. Height and weight were measured at the research facilities; glomerular filtration rate was estimated using creatinine clearance. Psychological distress (General Health Questionnaire), smoking, alcohol use and exercise were measured by means of questionnaires. RESULTS 24-h UFC stability on a day-to-day basis was 0.69 (T1, N=1192) and 0.72 (T2, N=963) (both p<0.001). Long-term stability as indicated by correlation between 2-day averages of T1 and T2 was 0.60 (N=972, p<0.001). Multivariable linear regression analysis revealed that 24-h UFC was predicted by urine volume (standardized beta 0.282 (T1, N=1556) and 0.276 (T2, N=1244); both p<0.001) and glomerular filtration rate (standardized beta 0.137 (T1) and 0.179 (T2); both p<0.001), while also sex explained a small part (standardized beta for female sex -0.057 (T1) and -0.080 (T2); both p<0.05). CONCLUSION 24-h UFC is moderately stable both in the short and the long term. The effects of urine volume and glomerular filtration rate on 24-h UFC are much stronger than those of sex.

Prevalence, Cumulative Incidence, Monotherapy and Combination Therapy, and Treatment Duration of Frequently Prescribed Psychoactive Medications in the Netherlands: Retrospective Database Analysis for the Years 2000 to 2005

BACKGROUND Psychoactive drugs have been reported to impair daily activities (eg, driving), but data regarding the use of such drugs in the Netherlands are lacking. OBJECTIVE The aim of this work was to examine the prevalence, cumulative incidence, use of monotherapy and combination therapy, and treatment duration of frequently prescribed psychoactive drug classes in the Netherlands. METHODS Data for the years 2000 through 2005 were derived from IADB.nl, a database with pharmacy dispensing data from a population of ∼500,000 people in the northern region of the Netherlands. The following prescription psychotropic drug classes were considered: antidepressants (as a total group and the 2 subgroups of nonselective monoamine reuptake inhibitors and selective serotonin reuptake inhibitors), antipsychotics, anxiolytics, and hypnotics and sedatives. Patients aged 18 to 89 years who received ≥ 1 prescription for a psychoactive medication of interest were selected, and prevalence and cumulative incidence were calculated per 1000 patients per year. The treatment duration was analyzed by means of Kaplan-Meier survival analysis. Age, sex, and drug class stratifications were performed. RESULTS There was a slight increase in the prevalence of antipsychotics (final median [95% CI] prevalence in 2000 vs 2005: 16.9 [16.5-17.3] vs 18.7 [18.3-19.1]) and antidepressants (60.4 [59.7-61.2] vs 67.1 [66.4-67.9]), with selective serotonin reuptake inhibitors being the most frequently prescribed drugs in these classes (35.2 [34.6-35.7] vs 37.5 [36.9-38.1] in 2000 and 2005, respectively). At the same time, there was a slight decrease in the prevalence of anxiolytics (95.1 [94.2-96.0] vs 83.2 [82.3-84.0]), hypnotics and sedatives (68.1 [67.3-68.9] vs 60.9 [60.1-61.6]), and nonselective monoamine reuptake inhibitors (20.3 [19.8-20.7] vs 19.2 [18.8-19.7]). The data also suggested that women had more prescriptions for the psychoactive medications of interest than did men, although these observations were not assessed for statistical significance. The only increase from 2000 to 2005 in median (95% CI) incidence per 1000 people in prescriptions was for antipsychotics (4.1 [3.9-4.3] vs 4.9 [4.6-5.0]); a decrease was noted in the incidence of antidepressants (18.6 [18.2-19.1] vs 16.2 [15.8-16.6]), nonselective monoamine reuptake inhibitors (7.1 [6.9-7.4] vs 6.8 [6.6-7.1]), selective serotonin reuptake inhibitors (12.0 [11.6-12.3] vs 8.6 [8.3-8.9]), anxiolytics (34.6 [34.1-35.2] vs 30.2 [29.7-30.7]), and hypnotics and sedatives (21.2 [20.8-21.7] vs 18.4 [18.0-18.9]). Combination therapy was most common among those aged 30 to 44 years (6.5%) and those aged 45 to 59 years (6.1%). The longest median (95% CI) treatment duration was noted for antipsychotic use (1781.8 days [1755.2-1808.4]); the shortest was observed for anxiolytic use (617.4 days [608.9-625.9]). CONCLUSIONS From 2000 to 2005 in the Netherlands, the yearly prevalence and cumulative incidence of prescriptions for psychoactive drugs were relatively stable, although there were some changes within specific drug classes. Monotherapy was more prevalent than combination therapy. Antipsychotics had the longest median duration of use; anxiolytics had the shortest duration.