Risk of cardiovascular events after an exacerbation of chronic obstructive pulmonary disease: results from the EXACOS-CV cohort study using the PHARMO Data Network in the Netherlands.

BACKGROUND: People living with chronic obstructive pulmonary disease (COPD) have an increased risk of experiencing cardiovascular (CV) events, particularly after an exacerbation. Such CV burden is not yet known for incident COPD patients. We examined the risk of severe CV events in incident COPD patients in periods following either moderate and/or severe exacerbations. METHODS: Persons aged ≥ 40 years with an incident COPD diagnosis from the PHARMO Data Network were included. Exposed time periods included 1-7, 8-14, 15-30, 31-180 and 181-365 days following an exacerbation. Moderate exacerbations were defined as those managed in outpatient settings; severe exacerbations as those requiring hospitalisation. The outcome was a composite of time to first severe CV event (acute coronary syndrome, heart failure decompensation, cerebral ischaemia, or arrhythmia) or death. Hazard ratios (HR) were estimated for association between each exposed period and outcome. RESULTS: 8020 patients with newly diagnosed COPD were identified. 2234 patients (28%) had ≥ 1 exacerbation, 631 patients (8%) had a non-fatal CV event, and 461 patients (5%) died during a median follow-up of 36 months. The risk of experiencing the composite outcome was increased following a moderate/severe exacerbation as compared to time periods of stable disease [range of HR: from 15.3 (95% confidence interval 11.8-20.0) in days 1-7 to 1.3 (1.0-1.8) in days 181-365]. After a moderate exacerbation, the risk was increased over the first 180 days [HR 2.5 (1.3-4.8) in days 1-7 to 1.6 (1.3-2.1) in days 31-180]. After a severe exacerbation, the risk increased substantially and remained higher over the year following the exacerbation [HR 48.6 (36.9-64.0) in days 1-7 down to 1.6 (1.0-2.6) in days 181-365]. Increase in risk concerned all categories of severe CV events. CONCLUSIONS: Among incident COPD patients, we observed a substantial risk increase of severe CV events or all-cause death following either a moderate or severe exacerbation of COPD. Increase in risk was highest in the initial period following an exacerbation. These findings highlight the significant cardiopulmonary burden among people living with COPD even with a new diagnosis.

Clinical effectiveness of liraglutide vs basal insulin in a real-world setting: Evidence of improved glycaemic and weight control in obese people with type 2 diabetes.

AIMS: To compare real-world antidiabetic treatment outcomes over 12 months in obese people with type 2 diabetes mellitus (T2DM) who previously received oral antidiabetic therapy and then initiated a first injectable therapy with liraglutide or basal insulin. PATIENTS AND METHODS: This was a retrospective, propensity score-matched, longitudinal cohort study using real-world data (January 2010 to December 2015) from the Dutch PHARMO Database Network. Adult obese (body mass index [BMI] ≥35 kg/m2 ) patients with T2DM with ≥2 dispensing dates for liraglutide or basal insulin supported oral therapy (BOT) were selected. The primary endpoint was the change in glycated haemoglobin (HbA1c) from baseline during 12 months of follow-up. The secondary endpoints were the changes in weight, BMI and cardiovascular risk factors from baseline. Clinical data were analysed using descriptive statistics and compared using mixed models for repeated measures. RESULTS: Obese patients with T2DM (N = 1157) in each treatment group were matched (liraglutide cohort, n = 544; BOT cohort, n = 613). From 3 months onwards, glycaemic control improved in both cohorts but improved significantly more with liraglutide than with BOT (12 months: -12.2 mmol/mol vs -8.8 mmol/mol; P = .0053). In addition, weight and BMI were significantly lower for treatments with liraglutide vs BOT (12 months: -6.0 kg vs -1.6 kg and - 2.1 kg/m2 vs -0.5 kg/m2 , respectively; P < .0001 for both). No significant differences were seen in changes in cardiovascular risk factors. CONCLUSIONS: The results of this real-world study in matched obese patients with T2DM showed that liraglutide was more effective than BOT for HbA1c control and weight/BMI reductions. Patients were more likely to maintain glycaemic control over time after initiating liraglutide than after initiating BOT.

No Evidence for an Association Between Renal Function and Serious Bleeding Events in Patients Treated With Coumarins: A Population-Based Study.

BACKGROUND: Although anticoagulation therapy is closely monitored in the Netherlands, coumarin-induced serious bleeding events are still observed. Current literature suggests that renal impairment may contribute to this. OBJECTIVE: To explore the association between renal function and bleeding events during coumarin treatment. METHODS: A nested case-control study was conducted using data from the PHARMO Database Network. Patients hospitalized for a bleeding event during coumarin treatment were selected as cases and matched on sex, birth year, and geographic region to up to 2 controls using coumarins without hospitalization for bleeding. All values of estimated glomerular filtration rates (eGFRs) were selected in the year before index date (case hospitalization date) and compared between cases and controls using logistic regression analyses. RESULTS: In total, 2224 cases were matched to 4398 controls (61% male; mean ± SD age 75 ± 11 and 78 ± 11 years among cases and controls, respectively). Availability of eGFR values was higher among cases compared with controls (mean ± SD eGFR values 4.5 ± 7.1 vs 3.2 ± 5.5), reflected in the significantly shorter time since last eGFR value (at index date, mean ± SD = 2.7 ± 3.0 vs 3.8 ± 3.1 months; odds ratio [OR] = 0.91, 95%CI = 0.89-0.92). No statistically significant difference was found for the mean eGFR value in the year before index date (mean ± SD 65.7 ± 22.8 vs 64.6 ± 20.9 mL/min/1.73 m2; OR per 10 units [95%CI] = 0.99 [0.96-1.02]). CONCLUSIONS: No association between renal function and serious bleeding events during coumarin treatment was observed.

Thrombotic risk minimization for Diane-35 and generics.

BACKGROUND: This study aimed to evaluate the effect of risk minimization measures on cyproterone acetate/ethinylestradiol (CPA/EE) use in the Netherlands. Potential indications of use and concomitant pharmacy dispensing of other hormonal contraceptives (HC) were assessed among new users in 2011, 2012, and 2014. METHODS: In this retrospective drug utilization study, new CPA/EE users were identified by pharmacy dispensings in the PHARMO Database Network in 2011, 2012, and 2014. Recent dispensing of drugs to treat acne and concomitant dispensing of other HC were also assessed. General practitioner records were linked to identify diagnoses of acne, other hyperandrogenic conditions, menstrual problems, or consultations for contraceptive management in the preceding year. RESULTS: The number of new CPA/EE users identified per year was 7876 in 2011 and 7562 in 2012 (3.7 new users per 1000 women in both years) and 1401 in 2014 (0.7 per 1000 women). The proportions of users with acne diagnosis or treatment were 55% in 2011, 52% in 2012, and 47% in 2014. Concomitant use of other HC was observed for 3% of new CPA/EE users in 2011, and 2% in 2012 and 2014 (median duration 78 days). Another 25% were potential concomitant users (median duration 60 days). CONCLUSION: This descriptive analysis showed similar proportions of CPA/EE users examined with acne or other hyperandrogenic conditions, or with recent acne treatment, or concomitant dispensing of other HC in the Netherlands before and after the referral procedure. The key observation was a strong overall reduction of CPA/EE use in the Netherlands.

Post authorization safety study comparing quetiapine to risperidone and olanzapine.

OBJECTIVES: To compare rates of specific adverse outcomes between patients starting quetiapine, olanzapine, or risperidone use in the Netherlands. METHODS: Observational study using the PHARMO Database Network, including patients starting quetiapine (4658), olanzapine (5856), or risperidone (7229) in 2000-2009, comparing rates of all-cause mortality, failed suicide attempts, extrapyrimidal symptoms (EPS), diabetes mellitus (DM), hypothyroidism, and acute myocardial infarction (AMI). KEY FINDINGS: Median follow-up until discontinuation/end of follow-up was 0.6 years. Prescribed doses were generally lower than the approved defined daily doses, especially for quetiapine. Quetiapine was significantly associated with lower EPS rates (HR 0.18; 95% CI 0.13-0.24), but higher failed suicide attempt rates (HR 2.07; 95% CI 1.35-3.16) compared to risperidone. Quetiapine was significantly associated with lower EPS rates (HR 0.59; 95% CI 0.42-0.84) and DM rates (HR 0.66; 95% CI 0.44-0.97) compared to olanzapine. Rates for all-cause mortality, hypothyroidism, and stroke were similar between groups. AMI events were too infrequent to draw conclusions. CONCLUSIONS: Quetiapine was associated with lower EPS, but higher failed suicide attempt rates compared to risperidone. Quetiapine was associated with lower EPS and DM rates compared to olanzapine. The results should be interpreted with caution because of possible channelling and residual confounding. Copyright © 2016 John Wiley & Sons, Ltd.

Rates of prostate surgery and acute urinary retention for benign prostatic hyperplasia in men treated with dutasteride or finasteride.

BACKGROUND: Previous studies have suggested a greater benefit for various outcomes in men diagnosed with benign prostatic hyperplasia (BPH) who are treated with dutasteride than for men treated with finasteride. This study investigates whether the rates of BPH-related prostate surgery and acute urinary retention (AUR) differ between dutasteride and finasteride users in the Netherlands. METHODS: From the PHARMO Database Network, men aged ≥50 years with a dispensing of dutasteride or finasteride with or without concomitant alpha-blocker treatment between March 1, 2003 and December 31, 2011 were selected. The incidence of BPH-related prostate surgery and AUR was determined during dutasteride or finasteride treatment and stratified by type of initial BPH-treatment (5-ARI monotherapy or combination with alpha-blocker) and prescriber (general practitioner (GP) or urologist). Comparison of the incidence of BPH-related prostate surgery and AUR between the treatment groups was done by Cox proportional hazard regression. RESULTS: 11,822 dutasteride users and 5,781 finasteride users were identified. Most users started treatment in combination with an alpha-blocker. Overall, dutasteride users had a lower risk of BPH-related prostate surgery was lower among dutasteride users than finasteride users (HR: 0.75; 95 % CI: 0.56-0.99). This lower risk among dutasteride users was also seen when stratifying by monotherapy or combination therapy (HR: 0.73; 95 % CI: 0.54-0.98 for monotherapy and HR: 0.85; 95 % CI: 0.74-0.97 for combination therapy). However, the association was only present among men treated by urologists. For AUR the rates were low and no statistical significant difference was observed between dutasteride and finasteride users. CONCLUSIONS: The risk of undergoing BPH-related prostate surgery was lower among men using dutasteride compared to men using finasteride. The association was observed for monotherapy as well as combination therapy, however, only among men who received their prescription from a urologist.

Use of oral contraceptives in three European countries: a population-based multi-database study.

OBJECTIVES: The aim of the study was to assess the prevalence of oral contraceptive (OC) use, user characteristics and prescribing patterns by accessing health care databases of three European countries. METHODS: A retrospective study was performed from 2009 to 2010 in three general practice (GP) databases from the Netherlands, UK and Italy and in one database of linked pharmacy and hospitalisation data in the Netherlands. The presence of selected chronic conditions and diagnoses of diseases associated with OC use were assessed, as were switches, discontinuations and types of OC used during the study period. RESULTS: Among 2.16 million women aged 15 to 49 years, 16.0% were using an OC on 1 January 2010. The prevalence ranged from 19.7% in a Dutch database to 2.6% in the Italian database. During 2009 and 2010, mainly second-generation progestogens were prescribed in the Netherlands (79.4% and 78.3% of users), both second- (57.9%) and third-generation progestogens (43.6%) were prescribed in the UK, and mainly third-generation progestogens in Italy (61.8%). Most switches were to third- or fourth-generation pills. The prevalence of chronic diseases tended to be higher among OC users, and the proportions of women with a history of disease associated with OC use tended to be lower than among non-users. CONCLUSIONS: Second-generation OCs were most frequently prescribed in the Netherlands. In the UK, and even more so in Italy, many women used third- or fourth-generation OCs. Preparation switches were mainly to third- or fourth-generation OCs. Among OC users, a somewhat higher prevalence of chronic diseases was observed; however, information bias cannot be ruled out.

Infants born before 32 weeks of gestation or with respiratory disease are most likely to receive palivizumab in the Netherlands.

AIM: Palivizumab is reported to be effective in reducing respiratory syncytial virus hospitalisation. Its licensed uses include infants younger than six months of age, born before 35 weeks of gestation or under two years old with congenital heart disease or bronchopulmonary dysplasia. We redressed lack of research in the Netherlands by studying whether infants who met the licensed indications received the drug. METHODS: Data were obtained from the PHARMO Database Network and The Netherlands Perinatal Registry for all linked infants born between 1 April 1999 and 31 March 2007. Determinants for receiving palivizumab were examined using logistic regression analyses. RESULTS: Only 15% of the 3321 infants who met the licensed indications received palivizumab and the strongest predictor was being born before 32 weeks of gestation, with an odds ratio of 49.1 (95% confidence interval 31.5-76.4). However, 50% of infants born before 32 weeks did not receive palivizumab and the subanalyses showed that the probability increased for infants born in later years, those who had respiratory distress syndrome and those hospitalised during the respiratory syncytial virus season. CONCLUSION: Only 15% of eligible infants in the Netherlands received palivizumab and they were mostly born before 32 weeks, in line with Dutch guidelines.

Burden of Exacerbations in Patients with Moderate to Very Severe COPD in the Netherlands: A Real-life Study.

OBJECTIVE: The objective of this study was to compare rates of different types of acute exacerbations of COPD (AECOPDs) and healthcare utilization among patients with different severities of COPD. METHODS: Data for this study was obtained from the PHARMO Database Network, which includes drug dispensing records from pharmacies, hospitalization records and information from general practitioners. Patients with moderate to very severe COPD (GOLD II-III-IV) and a moderate or severe AECOPD between 2000 and 2010 were included in the study. Moderate and severe AECOPDs were defined by drug use and hospitalizations respectively. Study patients were followed from the first AECOPD to end of registration in PHARMO, death or end of study period, whichever occurred first. During follow-up, all recurrent AECOPDs were characterized and healthcare utilization was assessed. RESULTS: Of 886 patients in the study, 52% had GOLD-II, 34% GOLD-III and 14% had GOLD-IV. The overall AECOPD recurrence rate per person year (PY) increased from 0.63 for patients with GOLD-II to 1.09 for patients with GOLD-III and 1.33 for patients with GOLD-IV. The rate of severe AECOPD was 0.06, 0.14 and 0.17 per PY, respectively. CONCLUSION: AECOPD recurrence rates and healthcare utilization are significantly higher among patients with more severe COPD.

First year of life medication use and hospital admission rates: premature compared with term infants.

OBJECTIVE: To compare hospitalization and medication use during the first year of life in preterm-born and term-born infants. STUDY DESIGN: Data for this retrospective cohort study were obtained from the linked PHARMO-Netherlands Perinatal Registry cohort. From this linked birth cohort, preterm infants (<37 weeks) born between 2004 and 2007 were randomly matched to 4 full-term infants. During follow-up, hospitalization and medication use were assessed. Cox proportional hazard regression models were used to estimate and compare the relative risk (RR) of hospitalization and medication use in preterm and full-term infants. Population-attributable risk percentages were calculated to estimate the proportion of hospitalizations and medication use attributable to preterm birth. RESULTS: Among the 71,607 singletons born between 2004-2007, 4277 (6%) were born preterm. Of these, 90% were hospitalized at birth, compared with 55% of full-term infants. Preterm infants were twice as likely to be rehospitalized (RR, 2.0; 95% CI, 1.9-2.2), specifically for respiratory-related diseases. Prematurity accounted for 6% of the respiratory disease readmissions. The most frequently used outpatient drugs in the second half year of life were antibacterials for systemic use and drugs for obstructive airway diseases. Preterm infants were 50% more likely to receive a respiratory medication (RR, 1.5; 95% CI, 1.4-1.7). CONCLUSION: In the first year of life, preterm born infants are up to 2 times more likely than full-term infants to be hospitalized or use medication, especially related to respiratory disease.

Pulmonary embolism, myocardial infarction, and ischemic stroke in lung cancer patients: results from a longitudinal study.

PURPOSE: In this cohort study, the rates of pulmonary embolism (PE), myocardial infarction (MI), and ischemic stroke (IS) before and after lung cancer (LC) diagnosis were compared to cancer-free controls. METHODS: Patients with LC during 2000-2007 were selected from PALGA, the Dutch Pathology Registry, and linked to the PHARMO medical record linkage system, including drug use and hospitalizations of 3 million inhabitants in the Netherlands. Included LC patients were matched 1:10 by age and gender to cancer-free controls. Hospitalizations for PE, MI, and IS were assessed in the 12 months before and after LC diagnosis. RESULTS: LC patients (N = 3,717) were six times more likely than cancer-free controls to have had a PE in the 12 months before diagnosis. After LC diagnosis, patients experienced an extremely increased risk of PE in the first 6 months (hazard ratio [HR] 16.8; 95 % confidence interval [CI] 7.6-36.8) compared with controls), which decreased to a five times increased risk (HR 5.1; 95 % CI 2.7-9.4) thereafter. However, there were less than two events per 100 person years during both time periods. LC patients receiving chemotherapy were eight times more likely to develop PE, whereas surgery increased the risk on PE three times. For MI and IS, no significant difference was observed compared with cancer-free controls before or after LC diagnosis. CONCLUSIONS: LC patients have a higher risk of developing PE compared with cancer-free controls, although the frequency of PE hospitalizations was low. Surgery and chemotherapy were associated with an increased risk of PE.

Completeness and Representativeness of the PHARMO General Practitioner (GP) Data: A Comparison with National Statistics.

Purpose: When using incomplete or non-representative real-world data (RWD), bias is more likely to occur. The aim of the current study was to assess the completeness and representativeness of the PHARMO GP data for the Dutch population. Patients and Methods: A cross-sectional study was performed. The PHARMO GP data comprise data from electronic health records registered by GPs. Data on the Dutch population were obtained from Statistics Netherlands (CBS), which offers publicly available data on several themes. The standardized difference (std.diff) was used to compare proportions between the PHARMO GP population and the Dutch population. An absolute std.diff >0.2 was considered a difference. Results: On January 1st, 2018, 3,466,321 persons were included in the PHARMO GP data (mean age: 41.6 years, 49.7% males). The sex and age distribution was similar to the Dutch population. The PHARMO GP data captured less not urbanized areas compared to the Dutch population (not urbanized areas: 9.4% vs 17.1% [std.diff: -0.23]). Regarding medication use, only the pharmacological subgroups "viral vaccines" and "hormonal contraceptives for systemic use" differed (std.diff >0.2); use in the GP data was more complete than in the Statistics Netherlands (CBS) data. No differences were observed regarding diagnoses. Conclusion: The PHARMO GP data are representative of the Dutch population with regard to the demographic characteristics and diagnoses in primary care. Medication data in the PHARMO GP data are more complete than national statistics, and differences are related to reimbursement. Use of the data and interpretation of results based on these sources should be done with experts on the data sources, the Dutch healthcare system and (pharmaco)epidemiology.

Occurrence of Comorbidities before and after Soft Tissue Sarcoma Diagnosis.

Background. Data is limited on the burden of common comorbidities, such as cardiovascular disease (CVD), respiratory disease and diabetes, or comorbidities related to cancer and its treatment, such as anemia and depression, in patients with soft tissue sarcoma (STS). Patients and Methods. From the Dutch Pathology Registry linked to the PHARMO database (including data on drug use and hospitalizations), 533 patients with STS were selected during 2000-2007 and matched 1 : 10 to cancer-free controls. The occurrences of comorbidities were assessed in the 12 months before and after STS diagnosis. Results. STS patients were 2-4 times more likely to have comorbidities at diagnosis compared with cancer-free controls. The incidence of CVD, anemia, and depression after STS diagnosis differed significantly from cancer-free controls and decreased during followup from 40-124 per 1,000 person-years (py) during the first six months to 11-38 per 1,000 py more than 12 months after diagnosis. The incidence of respiratory disease and diabetes among STS patients remained stable during followup (5-21 per 1,000 py) and did not differ significantly from cancer-free controls. Conclusions. STS patients were more likely to have comorbidities before cancer diagnosis and to develop CVD, anemia, and depression after diagnosis compared to cancer-free controls.

Venous thromboembolism prophylaxis after total knee or hip replacement: treatment pattern and outcomes.

PURPOSE: To determine the thromboprophylactic treatment pattern and occurrence of venous thromboembolism (VTE), major bleeding, and wound infections in patients undergoing total knee replacement (TKR) or total hip replacement (THR). METHODS: From the PHARMO database, all patients ≥ 18 years hospitalized for TKR or THR between January 2003 and September 2008 were selected. Patients with pharmacy data up to 3 months after hospitalization were included in the study cohort. Duration and type of thromboprophylaxis were assessed. VTE, major bleeding, and wound infections were identified by hospitalizations. Regarding VTE, timing of event in relation to thromboprophylaxis was determined. RESULTS: The study population included 2930 patients with TKR, 5332 patients with THR without hip fracture, and 289 patients with THR and hip fracture. Mean duration of thromboprophylaxis was about 30 (± 20) days for all procedures, with low-molecular-weight heparin being the most frequently used drug. During 3 months of follow-up, 1% to 2% of patients were hospitalized for an event. The most observed event was wound infection (58%), followed by major bleeding (29%), and VTE (13%). For wound infection and major bleeding, median time after surgery was about 19 days. Median time between surgery and VTE was 24 days for TKR and 60 days for THR. Eighteen of 23 VTE occurred during thromboprophylaxis. CONCLUSIONS: Although patients are often treated for fewer days than recommended, thromboprophylaxis after TKR and THR in the Netherlands is adequate. Only 5 of 23 VTE hospitalizations occurred off-treatment and might have been prevented. Furthermore, fewer than 1% of patients were hospitalized for bleeding.

Existing Data Sources for Clinical Epidemiology: The PHARMO Database Network.

The PHARMO Database Network provides a unique opportunity to gain insight in the complete patient journey and healthcare in the Netherlands. The PHARMO Database Network is a population-based network of electronic healthcare databases and combines anonymous data from different primary and secondary healthcare settings in the Netherlands. Healthcare settings include general practitioners, out-patient and in-patient pharmacies, hospitals and clinical laboratories. Furthermore, databases are linked with external registries such as the Cancer Registry, Pathology Registry and Perinatal Registry. The different data sources are linked on a patient level through probabilistic linkage based on validated algorithms. The longitudinal and ongoing nature of the PHARMO Database Network system enables to follow up more than 10 million residents of the Netherlands for an average of 12 years. Data collection period, catchment area and overlap between data sources differ. Access to the PHARMO Database Network is, by governance regulations of the data collection, restricted to researchers of the PHARMO Institute and academic affiliates. Each data request is checked against privacy and company policies, and requires approval of the privacy and governance board. The terms and conditions and a data application form are available on the PHARMO website (www.pharmo.com).

Reduction in use of cyproterone/ethinylestradiol (Diane-35 and generics) after risk minimization measures in the Netherlands, UK and Italy.

OBJECTIVES: To study the effect of risk minimization measures taken in 2013 for cyproterone acetate/ethinylestradiol (CPA/EE) on initiation, concomitant use of other hormonal contraceptives (HC) and potential indications. STUDY DESIGN: This retrospective study included data on CPA/EE use in 2011-2017 from the Netherlands, UK, and Italy. RESULTS: The initiation rate of CPA/EE decreased by 44%-91% between 2011 and 2017. Proportions with concomitant use of other HC (<3%) and approved indications did not change over time. CONCLUSION: Apart from a strong reduction in CPA/EE use following risk minimization measures, no major changes were observed regarding concomitant use of other HC or potential reasons for use.

Evaluating the Effectiveness of an Additional Risk Minimization Measure to Reduce the Risk of Prescribing Mirabegron to Patients with Severe Uncontrolled Hypertension in Four European Countries.

BACKGROUND: Mirabegron, indicated for the treatment of overactive bladder, is contraindicated in patients with severe uncontrolled hypertension (systolic blood pressure ≥180 mm Hg and/or diastolic blood pressure ≥110 mm Hg). In September 2015, a Direct Healthcare Professional Communication (DHPC) letter was disseminated as an additional risk minimisation measure. PURPOSE: To assess the effectiveness of the DHPC in reducing the proportions of patients with severe or non-severe uncontrolled hypertension at mirabegron initiation. METHODS: An observational multi-database cohort study was undertaken using routinely collected healthcare data (December 2012-December 2016) from the PHARMO Database Network (Netherlands), SIDIAP database (Spain), CPRD (United Kingdom, UK) and national healthcare registers and electronic medical records from Finland. DHPC effectiveness was evaluated using interrupted time series analyses comparing trends and changes in monthly proportions of severe or non-severe uncontrolled hypertensive mirabegron initiations relative to the timing of the DHPC dissemination. RESULTS: The study population comprised 52,078 patients. Prior to DHPC dissemination, across the four databases, 0.3-1.3% had severe uncontrolled hypertension. Estimated absolute changes (EAC) in proportions of severe uncontrolled hypertension post-DHPC indicated a tendency towards a lower proportion in the Netherlands (EAC -0.36%, p=0.053), unchanged proportions in Spain and the UK and a higher proportion in Finland (EAC +0.73%, p=0.016). For non-severe uncontrolled hypertension (13-16% pre-DHPC), post-DHPC proportions tended to be lower in the Netherlands (EAC -2.02%, p=0.038) and Spain (EAC -1.04%, p=0.071), and unchanged in the UK and Finland. CONCLUSION: Severe uncontrolled hypertension prior to mirabegron initiation was uncommon in these four European countries even before DHPC dissemination. This suggests that other risk minimisation communications (prior to the DHPC dissemination) had worked adequately with respect to minimising mirabegron use among patients with severe uncontrolled hypertension. No strong and consistent evidence of further risk minimisation after the DHPC dissemination was observed in this study.

Topical corticosteroids and the risk of diabetes mellitus: a nested case-control study in the Netherlands.

BACKGROUND: The relationship between topical corticosteroid use, potency, treatment duration, concomitant exposure to systemic corticosteroids, and risk of diabetes has been incompletely studied. OBJECTIVE: To investigate an association between intense, longstanding topical corticosteroid use and diabetes mellitus. METHODS: Data for this nested case-control study were obtained from the PHARMO Record Linkage System, including linked drug dispensing and hospital records of >2.5 million individuals in defined areas of the Netherlands. Users of topical corticosteroids during 1992-2004, without diabetes, with >or=2 topical corticosteroid dispensings and >or=4 years of follow-up were selected. Diabetes onset was defined as first occurrence (index date) of an antidiabetic drug dispensing or hospitalization for diabetes. Cases were matched 1:4 by age and sex to controls, with >or=2 topical corticosteroid dispensings and similar follow-up duration. Use of topical corticosteroids and systemic corticosteroids and/or inhaled corticosteroids as co-medication was classified as current, recent and past/never (4 years ago, respectively). Multivariate regression analyses were adjusted for co-medication and co-morbidity. RESULTS: Among 192,893 incident topical corticosteroid users, 2,212 developed diabetes and could be matched to 8,582 controls. Current topical corticosteroid use was associated with an (unadjusted) 1.24-fold increased risk of diabetes (unadjusted OR 1.24; 95% CI 1.11, 1.40). The odds ratio increased to 1.32 with >180 days of topical corticosteroid use (95% CI 1.14, 1.54) and to 1.44 with a cumulative topical corticosteroid load (combined potency and amount) of 731-1460 mg (95% CI 1.21, 1.72). Among past/never users of systemic corticosteroids and/or inhaled corticosteroids, current use of topical corticosteroids remained associated with a 1.27-fold increased diabetes risk (unadjusted OR 1.27; 95% CI 1.10, 1.47) compared with past users of topical corticosteroids. CONCLUSION: An increased risk of new-onset diabetes may be an important consideration in the treatment of patients with topical corticosteroids, especially when intense skin treatment is needed. Future studies are needed to endorse these findings in other populations.

Haemoglobin A1c goal attainment in relation to dose in patients with diabetes mellitus taking metformin: a nested, case-control study.

BACKGROUND AND OBJECTIVE: Conclusions from clinical trials suggest possible therapeutic advantages for once-daily agents over twice-daily agents in the treatment of type 2 diabetes mellitus. This study set out to investigate the relationship between metformin dosing frequency and glycosylated haemoglobin (HbA1c)-goal attainment in daily practice. METHODS: This was a nested case-control study. Data were obtained from the PHARMO Record Linkage System, which includes linked drug-dispensing and clinical-laboratory records for approximately three million individuals in defined areas of the Netherlands. The study cohort included new users of oral antihyperglycaemic drugs between 1999 and 2005 with a baseline HbA1c> or =7% and at least one further HbA1c measurement within 18 months after the index date. Cases attained HbA1c goal (<7%) within 18 months; controls did not attain this HbA1c goal. Compliant cases and controls taking metformin monotherapy were included in the analyses. Dosing frequency was dichotomized into once daily and twice daily or more frequently. In the multivariate analysis we considered oral antihyperglycaemic dose, baseline HbA1c, first prescriber and number of HbA1c measurements. RESULTS: The study cohort included 3107 new oral antihyperglycaemic drug users. The analyses included 753 cases and 477 controls taking metformin. Dosing twice daily or more was associated with a 71% higher probability of attaining goal (odds ratio 1.71 [95% CI 1.31, 2.24]) compared with once-daily dosing, after adjustment for baseline HbA1c, first prescriber, sex and age. We could not distinguish between the effect of dose and dosing frequency as these were closely related. Statistical testing in the analyses stratified by dose was prohibited by small numbers. CONCLUSION: About 40% of compliant metformin users did not achieve their HbA1c goal within 18 months because of dosing problems. However, the strong correlation between total daily dose and dosing frequency did not permit identification of which of these dosing issues was the most important contributor to not achieving HbA1c goal.

Observational cohort study: safety outcomes in children using proton pump inhibitors or histamine-2 receptor antagonists.

OBJECTIVE: Acid suppression with histamine-2 receptor antagonists (H2RAs) or proton pump inhibitors (PPIs) is recommended for children with persistent gastroesophageal reflux disease symptoms. In this retrospective, observational postauthorization study, we aimed to assess and compare safety outcomes in pediatric first-time users of esomeprazole, other PPIs or H2RAs. METHODS: Data on children (aged 0-18 years) first dispensed esomeprazole, other PPIs or H2RAs between September 2008 and August 2011 was obtained from the Dutch PHARMO Database Network. Hospitalizations for seven predefined safety outcomes were evaluated (maximum follow-up: 18 months). Rate ratios were calculated using Poisson regression adjusted for baseline imbalances. Discharge letters were reviewed for event occurrence confirmation. RESULTS: Of 23,470 included children, 2820 (median age: 3 years) were prescribed esomeprazole, 13,818 (median age: 15 years) other PPIs and 6832 (median age: 5 years) H2RAs. In total, 504 (2%) children were hospitalized for 762 predefined events: gastroenteritis (246); convulsion/seizure (200); pneumonia (154); failure to thrive (119); acute interstitial nephritis (19); thrombocytopenia (23); and angioneurotic edema (1). Significant differences between cohorts were observed only for failure to thrive, with adjusted rate ratios (95% confidence interval) for esomeprazole of 6.1 (2.4-15.7) vs. other PPIs and 6.1 (2.9-12.8) vs. H2RAs among current users. Occurrence was confirmed for 74% of assessable events. Confirmation rates were highest for pneumonia (81%) and lowest for failure to thrive (40%). CONCLUSIONS: Hospitalization rates for predefined outcomes were low and mostly similar in pediatric first-time users of PPIs and of H2RAs. TRIAL REGISTRATION: NCT01338363.