Josien Riphagen-Dalhuisen

Predictors of seasonal influenza vaccination among healthcare workers in hospitals: a descriptive meta-analysis

Objective Vaccinating healthcare workers (HCWs) against influenza is one of the most important methods of decreasing influenza transmission among at-risk patients in healthcare facilities. However, despite recommendations, the rate of uptake of influenza vaccine among HCWs remains low. The objective of this meta-analysis was to determine the most important predictors of seasonal influenza vaccine acceptance among HCWs in hospitals. Method A literature search of PubMed and Embase resulted in 4586 hits. Screening of the titles, abstracts and full text identified 13 studies eligible for inclusion in the meta-analysis. Based on the crude data, pooled risk ratios (Mantel-Haenszel risk ratios, mhRR) and their 95% CIs were calculated using Mantel-Haenszel analysis to estimate the associations of predictors with influenza vaccination status. Results and conclusion Knowing that the vaccine is effective (mhRR 2.22; 95% CI 1.93 to 2.54), being willing to prevent influenza transmission (mhRR 2.31; 95% CI 1.97 to 2.70), believing that influenza is highly contagious (RR 2.25; 95% CI 1.66 to 3.05), believing that influenza prevention is important (mhRR 3.63; 95% CI 2.87 to 4.59) and having a family that is usually vaccinated (RR 2.32; 95% CI 1.64 to 3.28) were statistically significantly associated with a twofold higher vaccine uptake. We therefore recommend targeting these predictors when developing new influenza vaccination implementation strategies for hospital HCWs.

Antibiotic therapy for acute Q fever in The Netherlands in 2007 and 2008 and its relation to hospitalization

Data about the effectiveness of different antibiotic regimens for the treatment of acute Q fever from clinical studies is scarce. We analysed the antibiotic treatment regimens of acute Q fever patients in 2007 and 2008 in The Netherlands and assessed whether hospitalization after a minimum of 2 days antibiotic therapy was related to the initial antibiotic therapy. Clinical data on antibiotic treatment and risk factors of acute Q fever patients were obtained from general practitioner medical records and self-reported by patients. For the 438 study patients, doxycycline was the most commonly prescribed initial antibiotic in both study years. After adjustments for confounding factors, doxycycline (200 mg/day), moxifloxacin, as well as other possibly effective antibiotics [including other new fluoroquinolones and doxycycline (100 mg/day)] showed significant lower risks for hospitalization compared to β-lactam antibiotics and azithromycin (reference group), with the lowest risk for doxycycline (200 mg/day) (odds ratio 0·04, 95% confidence interval 0·01-0·22). These data support current guidelines that recommend doxycycline as the first choice antibiotic for treating acute Q fever.

How to develop a program to increase influenza vaccine uptake among workers in health care settings

BackgroundApart from direct protection and reduced productivity loss during epidemics, the main reason to immunize healthcare workers (HCWs) against influenza is to provide indirect protection of frail patients through reduced transmission in healthcare settings. Because the vaccine uptake among HCWs remains far below the health objectives, systematic programs are needed to take full advantage of such vaccination. In an earlier report, we showed a mean 9% increase of vaccine uptake among HCWs in nursing homes that implemented a systematic program compared with control homes, with higher rates in those homes that implemented more program elements. Here, we report in detail the process of the development of the implementation program to enable researchers and practitioners to develop intervention programs tailored to their setting.MethodsWe applied the intervention mapping (IM) method to develop a theory- and evidence-based intervention program to change vaccination behaviour among HCWs in nursing homes.ResultsAfter a comprehensive needs assessment, we were able to specify proximal program objectives and selected methods and strategies for inducing behavioural change. By consensus, we decided on planning of three main program components, i.e., an outreach visit to all nursing homes, plenary information meetings, and the appointment of a program coordinator -- preferably a physician -- in each home. Finally, we planned program adoption, implementation, and evaluation.ConclusionThe IM methodology resulted in a systematic, comprehensive, and transparent procedure of program development. A potentially effective intervention program to change influenza vaccination behaviour among HCWs was developed, and its impact was assessed in a clustered randomised controlled trial.

Hospital-based cluster randomised controlled trial to assess effects of a multi-faceted programme on influenza vaccine coverage among hospital healthcare workers and nosocomial influenza in the Netherlands, 2009 to 2011

Nosocomial influenza is a large burden in hospitals. Despite recommendations from the World Health Organization to vaccinate healthcare workers against influenza, vaccine uptake remains low in most European countries. We performed a pragmatic cluster randomised controlled trial in order to assess the effects of implementing a multi-faceted influenza immunisation programme on vaccine coverage in hospital healthcare workers (HCWs) and on in-patient morbidity. We included hospital HCWs of three intervention and three control University Medical Centers (UMCs), and 3,367 patients. An implementation programme was offered to the intervention UMCs to assess the effects on both vaccine uptake among hospital staff and patient morbidity. In 2009/10, the coverage of seasonal, the first and second dose of pandemic influenza vaccine as well as seasonal vaccine in 2010/11 was higher in intervention UMCs than control UMCs (all p<0.05). At the internal medicine departments of the intervention group with higher vaccine coverage compared to the control group, nosocomial influenza and/or pneumonia was recorded in 3.9% and 9.7% of patients of intervention and control UMCs, respectively (p=0.015). Though potential bias could not be completely ruled out, an increase in vaccine coverage was associated with decreased patient in-hospital morbidity from influenza and/or pneumonia.

Cost-effectiveness of a screening strategy for Q fever among pregnant women in risk areas: a clustered randomized controlled trial

BackgroundIn The Netherlands the largest human Q fever outbreak ever reported in the literature is currently ongoing with more than 2300 notified cases in 2009. Pregnant women are particularly at risk as Q fever during pregnancy may cause maternal and obstetric complications. Since the majority of infected pregnant women are asymptomatic, a screening strategy might be of great value to reduce Q fever related complications. We designed a trial to assess the (cost-)effectiveness of a screening program for Q fever in pregnant women living in risks areas in The Netherlands.Methods/designWe will conduct a clustered randomized controlled trial in which primary care midwife centres in Q fever risk areas are randomized to recruit pregnant women for either the control group or the intervention group. In both groups a blood sample is taken around 20 weeks postmenstrual age. In the intervention group, this sample is immediately analyzed by indirect immunofluorescence assay for detection of IgG and IgM antibodies using a sensitive cut-off level of 1:32. In case of an active Q fever infection, antibiotic treatment is recommended and serological follow up is performed. In the control group, serum is frozen for analysis after delivery. The primary endpoint is a maternal (chronic Q fever or reactivation) or obstetric complication (low birth weight, preterm delivery or fetal death) in Q fever positive women. Secondary aims pertain to the course of infection in pregnant women, diagnostic accuracy of laboratory tests used for screening, histo-pathological abnormalities of the placenta of Q fever positive women, side effects of therapy, and costs. The analysis will be according to the intention-to-screen principle, and cost-effectiveness analysis will be performed by comparing the direct and indirect costs between the intervention and control group.DiscussionWith this study we aim to provide insight into the balance of risks of undetected and detected Q fever during pregnancy.Trial registrationClinicalTrials.gov, protocol record NL30340.042.09.

Planning and process evaluation of a multi-faceted influenza vaccination implementation strategy for health care workers in acute health care settings

BackgroundInfluenza transmitted by health care workers (HCWs) is a potential threat to frail patients in acute health care settings. Therefore, immunizing HCWs against influenza should receive high priority. Despite recommendations of the World Health Organization, vaccine coverage of HCWs remains low in all European countries. This study explores the use of intervention strategies and methods to improve influenza vaccination rates among HCWs in an acute care setting.MethodsThe Intervention Mapping (IM) method was used to systematically develop and implement an intervention strategy aimed at changing influenza vaccination behaviour among HCWs in Dutch University Medical Centres (UMCs). Carried out during the influenza seasons 2009/2010 and 2010/2011, the interventions were then qualitatively and quantitatively evaluated by way of feedback from participating UMCs and the completion of a web-based staff questionnaire in the following spring of each season.ResultsThe IM method resulted in the development of a transparent influenza vaccination intervention implementation strategy. The intervention strategy was offered to six Dutch UMCs in a randomized in a clustered Randomized Controlled Trial (RCT), where three UMCs were chosen for intervention, and three UMCs acted as controls. A further two UMCs elected to have the intervention. The qualitative process evaluation showed that HCWs at four of the five intervention UMCs were responsive to the majority of the 11 relevant behavioural determinants resulting from the needs assessment in their intervention strategy compared with only one of three control UMCs. The quantitative evaluation among a sample of HCWs revealed that of all the developed communication materials, HCWs reported the posters as the most noticeable.ConclusionsOur study demonstrates that it is possible to develop a structured implementation strategy for increasing the rate of influenza vaccination by HCWs in acute health care settings. The evaluation also showed that it is impossible to expose all HCWs to all intervention methods (which would have been the best case scenario). Further study is needed to (1) improve HCW exposure to intervention methods; (2) determine the effect of such interventions on vaccine uptake among HCWs; and (3) assess the impact on clinical outcomes among patients when such interventions are enacted.

Contributing factors to influenza vaccine uptake in general hospitals: an explorative management questionnaire study from the Netherlands

BackgroundThe influenza vaccination rate in hospitals among health care workers in Europe remains low. As there is a lack of research about management factors we assessed factors reported by administrators of general hospitals that are associated with the influenza vaccine uptake among health care workers.MethodsAll 81 general hospitals in the Netherlands were approached to participate in a self-administered questionnaire study. The questionnaire was directed at the hospital administrators. The following factors were addressed: beliefs about the effectiveness of the influenza vaccine, whether the hospital had a written policy on influenza vaccination and how the hospital informed their staff about influenza vaccination. The questionnaire also included questions about mandatory vaccination, whether it was free of charge and how delivered as well as the vaccination campaign costs. The outcome of this one-season survey is the self-reported overall influenza vaccination rate of health care workers.ResultsIn all, 79 of 81 hospitals that were approached were willing to participate and therefore received a questionnaire. Of these, 42 were returned (response rate 52%). Overall influenza vaccination rate among health care workers in our sample was 17.7% (95% confidence interval: 14.6% to 20.8%). Hospitals in which the administrators agreed with positive statements concerning the influenza vaccination had a slightly higher, but non-significant, vaccine uptake. There was a 9% higher vaccine uptake in hospitals that spent more than €1250,- on the vaccination campaign (24.0% versus 15.0%; 95% confidence interval from 0.7% to 17.3%).ConclusionsAgreement with positive statements about management factors with regard to influenza vaccination were not associated with the uptake. More economic investments were related with a higher vaccine uptake; the reasons for this should be explored further.

Effects of a multi-faceted program to increase influenza vaccine coverage among health care workers: A hospital-based cluster randomized controlled trial

Background: The effect of guideline changes on trends of prescription drug use are commonly studied by age and over time period. This masks the birth cohort dimension which affects the age-specific trends in each time period. Objectives: We investigated whether including the birth cohort dimension in time series analysis leads to a more accurate estimation of the effect of a guideline change on the trend of benzodiazepine use. Methods: Outpatient pharmacy data from a drug prescription database in the Netherlands (IADB.nl) were used to obtain the age- (18-85) and sex -specific number of users of benzodiazepine (ATC: N05BA and N05CD) per 1,000 population (prevalence) per quarter year from 1998 to 2008. We studied the prevalence over time by age groups and by birth cohorts. Interrupted time series analyses were performed to the de-seasonalized trend to estimate the effect of the guideline change in 2001. Results: From 1998 to 2008 the overall age-standardized prevalence of benzodiazepine use per 1,000 population declined from ∼55 for males and ∼105 for females to ∼42 for males and ∼78 for females, this decline strengthened in 2001 for both sexes (significant slope change of p <0.05). Similar patterns over time, including slope changes (p <0.05), can be found within the majority of age categories, providing no additional information. Within birth cohorts the prevalence first increased over time but after 2001 this increase stopped or weakened (p <0.05), indicating a reduction in starters or less chronic use of benzodiazepine. Conclusions: Studying trends within birth cohorts can be a useful addition to time series analyses because the same or similar individuals are followed over time, making analysis more intuitive. This is not the case for trends within age-categories, potentially leading to less informed conclusions about guideline effects.Background: Epidemiological research has been criticized as being unreliable. Scientific evidence is strengthened when the study procedures of important findings are transparent, open for review, and easily reproduced by different investigators and in various settings. Studies often have common scientific workflows. The development of generalized execution engines, reusing epidemiological software/script program code for specific clinical questions, can serve as a valuable tool for transparent and reproducible research. Objectives: Learn about standards for transparent, reproducible and reusable research and how it is being applied in pharmacoepidemiolgy. Description: The focus of the symposium will be transparent, reproducible and reusable research. Principles of reproducible research in the context of the Medication History Estimator will be discussed. In addition, an overview of the IMI-PROTECT WP2: Framework for pharmacoepidemiologic studies and the Observational Medical Outcomes Partnership will be given. Outline: 1. Principles of reliability (Helga Gardarsdottir): Introduction to basic principles of transparent reproducible and reusable research. 2. Standardization (Huifang Liang): Standardization of data for drug utilization studies. A discussion of steps involved to convert the raw data into the readily usable data, including how to impute certain fields with examples. 3. Demonstration of the Medication History Estimator (MHE) and a description of the VINCI EpiTools (Brian Sauer). The MHE will be presented to demonstrate concepts of transparency, reproducibility and reuse. 4. The IMI-PROTECT project (Olaf Klungel & Robert Reynolds). Experiences with developing, testing and disseminating methodological standards for the design, conduct and analysis of database studies will be discussed. 5. Lessons from the Observational Medical Outcomes Partnership (Patrick Ryan, PhD). Standardized analytics tools developed by the OMOP community to characterize, visualize, and explore the effects of medical products within a distributed network of observational databases will be presented. 6. Closing summary/discussion. Chairs: Helga Gardarsdottir & Brian Sauer.Background: The Netherlands Pharmacovigilance Centre Lareb received six reports of hearing impairment in association with oral terbinafine use. This study describes these cases and provides support for this association from the Lareb database of spontaneous ADR reporting and from Vigibase, the adverse drug reaction database of the WHO UppsalaMonitoring Centre. Objectives: The objective of the study is to identify whether the observed association between oral terbinafine use and hearing impairment, based on several cases received by Lareb, supports a safety signal. Methods: Cases of hearing impairment in oral terbinafine users are described. In a case/non-case analysis, the strength of the association in Vigibase and the Lareb database was determined by calculating the reporting odds ratios (ROR), adjusted for possible confounding by age, sex and possibly ototoxic concomitant medication. RORs are calculated for deafness, hypoacusis, and the combination of both, defined as hearing impairment. Results: In the Lareb database, six reports concerning individuals aged 31-82 years, who developed hearing impairment after starting oral terbinafine, are present. The use of oral terbinafine is disproportionally associated with hypoacusis in both the Lareb database (adjusted ROR = 3.9, 95% CI: 1.7-9.0), and in Vigibase (adjusted ROR = 1.7, 95% CI: 1.0-2.8). Deafness is not disproportionally present in either of the databases. The pharmacological action of terbinafine is based on the inhibition of squalene epoxidase, an enzyme present in both fungal and human cells. This inhibition might result in decreased cholesterol levels in, among others, the outer hair cells of the cochlea, possibly leading to impaired cochlear function and hearing impairment. Conclusions: To our knowledge, hearing impairment associated with oral terbinafine use has not been described before. A causal relationship between the use of oral terbinafine and hearing impairment is possible, based on statistical analysis of reported cases in different databases and a possible pathophysiological explanation.Background: In observational studies of time-varying exposure and confounders, the use of propensity score (PS) is limited to assigning weights as in marginal structural models (MSMs). Stratification and conditioning on time-varying cofounders which are also intermediates can induce collider-stratification bias and adjust-away the (indirect) effect of exposure. Similar bias could be expected when one conditions on time-dependent PS. Objectives: We explored collider-stratification and confounding bias due to conditioning or stratifying on timedependent PS in a clinical example on the effect of inhaled short and long-acting beta2-agonist use (SABA and LABA, respectively) on coronary heart disease (CHD). Methods: A cohort of patients with an indication for SABA and/or LABA use was extracted from the Netherlands University Medical Center Utrecht General Practitioner Research Network. Information from 1995 to 2005 was used. SABA and LABA use and potential confounders were ascertained on 3 month intervals. Follow-up began the first day of diagnosis of bronchitis, asthma, or COPD and ended at the occurrence of CHD, death, unregistration with the GP, or end of the study, whichever occurred first. HR were estimated using PS stratification as well as covariate adjustment and compared with those of MSMs in both SABA and LABA separately. In MSMs, censoring was accounted for by including inverse probability of censoring weights. Results: The crude HR of CHD was 0.90 [95% CI: 0.63, 1.28] and 1.55 [95% CI: 1.06, 2.62] in SABA and LABA users respectively. When PS stratification, adjustment using PS, and MSMs were used, the HRs were 1.09 [95%CI: 0.74, 1.61], 1.07 [95% CI: 0.72, 1.60], and 0.86 [95% CI: 0.55, 1.34] for SABA, and 1.09 [95%CI: 0.74, 1.62], 1.13 [95%CI: 0.76, 1.67], 0.77 [95% CI: 0.45, 1.33] for LABA, respectively. Conclusions: Results were similar for different PS methods, but systematically higher than those of MSMs. When treatment and confounders vary during follow-up, conditioning or stratification on time-dependent PS may induce substantial collider-stratification or confounding bias. Hence, the use of methods such as MSMs is recommended.Background: Compared to RCTs, observational (nonrandomized) studies often comprise larger sample sizes, which gives adequate power to study interaction. Observational studies, however, are prone to confounding. Objectives: To determine the validity of subgroup and interaction effects (differences between subgroups) for different study designs. Methods: We compared effects of medical interventions based on observational studies, RCTs, and Individual Patient Data Meta-Analysis of RCTs (IPDMAs; reference) on three different clinical topics: (1) mammography screening effects on breast cancer mortality; (2) CABG and all-cause mortality; (3) statins and the incidence of major coronary events. Main, subgroup, and interaction effects were compared. Results: Main and subgroup effects were comparable with respect to the direction of effects for IPDMAs, RCTs, and observational studies. Small differences in the magnitude of subgroup effects in observational studies yielded different interactions compared to IPDMA. In the mammography example the Ratio of Risk Ratios (RRR) (i.e., interaction effect) among observational studies was 1.46 (95% CI 1.09;1.96) compared to an IPDMA effect of 110 (95% CI 0.89;1.37). For the CABG studies the observational RRR was 1.03 (95% CI 0.84;1.26), whereas in the IPDMA this was 1.40 (95% CI 1.08;11.81). Finally, in the statin example the RRR was 1.35 (95% CI 113;1.61) for observational studies, in the IPDMA this was 0.90 (95% CI 0.84;0.97). Conclusions: Main and subgroup effects based on observational data are in line with main and subgroup effects in IPDMAs based on RCTs, yet interactions may differ substantially.Background: Both antidepressants (AD) and benzodiazepines (BZD) have been associated with an increased risk for hip fracture. However, the hazard function is not constant over exposure time and differs for these two medication classes. Hence, the timing of initiation of co-use will determine the overall hazard function. Objectives: The aim of this study was to describe timing of BZD co-medication use among AD users. Methods: The study population included patients from the Netherlands Information Network of General Practice who initiated ADs between 2002 and 2009. AD-treatment episodes were constructed for each patient assuming the start of a new episode when 90 days elapsed between the theoretical end-date of a prior AD prescription (Rx) and the start-date of the next AD Rx. Within the first AD episode, three groups of BZD co-use were defined: “simultaneous” (simultaneous start of AD and BZD, no BZD during 182 days prior to start), “before” and “during” starters. These groups were described according to intensity of BZD use (number of Rxs), mono/polytherapy of AD and duration of AD episode. Results: The study population consisted of 16,617 AD users. The mean age was 50 years (SD = 18) and 63.2% were female. The median duration of the AD episode was 80 days (IQR = 259). Of 28.5% of patients used both AD and BZD. Of these, 57.2% started BZD before the AD, 19.0% were “simultaneous” starters and 23.8% started BZD during their first AD episode. In general, “simultaneous” starters were younger (mean = 45.3 vs. 56.4 years) yet had less intensity of BZD use (mean = 4.3 vs. 7.5 Rxs) compared to “before” starters. “After” starters were slightly older (mean = 48.0 vs. 45.3 years), had more AD polytherapy (20.2% vs. 14.9%) however less intensive BZD use (mean = 3.7 vs. 4.3 Rxs) compared to “simultaneous” starters. Conclusions: Timing of initiating BZD use in AD users is important, as each BZD co-use group is expected to have a different overall hazard function for hip fracture as opposed to when co-medication is defined as constant over time. To calculate accurate hazard function, it is important to take into consideration the timing of initiation of co-medication use in pharmacoepidemiological studies.Background: Pregnancy outcomes in women with preexisting diabetes are known to be worse than in the healthy population: rates of congenital malformations have been reported to be 2 to 10-fold higher. This is due to poor glycaemic control. Objectives: To determine rates of congenital malformations in babies of mothers with type1 (DM1) and type2 (DM2) diabetes and compare with the healthy population. Methods: Patients with pre-existing DM1 or DM2 during pregnancy were identified on the General Practice Research Database using diagnoses, prescribing, use of testing equipment and referral records. Mothers were matched to babies using registration records with the same family number, within 2 months of delivery date. Major congenital malformations were identified in the baby’s record and malformations verified with at least two related medical records; free text entries were checked. Results: Between January 1992 and March 2007 1,057 DM1 patients had 1,329 pregnancies and 365 DM2 patients had 441 pregnancies that resulted in a live birth. Eighty-four major malformations were found in 78 babies of DM1 mothers: 41 were cardiac, 11 were urogenital and eight were limb defects. Twenty-six major malformations were identified in 22 babies of DM2 mothers (seven cardiac defects). Overall, 5.9% of babies of DM1 mothers and 5.0% of babies of DM2 mothers had a malformation compared to 2–3% in the healthy population. The malformation rate for babies of DM2 mothers was comparable with another study (5.8%) but was lower for DM1 (8.2%). The proportion of cardiac malformations in babies of DM1 mothers was three times higher than in the healthy population. Conclusions: Babies whose mothers had DM1 or DM2 during pregnancy had double the rate of malformations. Pregnancy loss due to malformation has not been included but previous work found a greater proportion of terminations for medical reasons (1% in DM1, 1.8% in DM2) compared to healthy pregnancies (0.8%). Limitations include potentially differential recording of malformations between babies of mothers with DM1 and DM2 and the lack of records of glycaemic control. Differences in rates of malformations between treatments including analogue and human insulin will be evaluated next.

Effects of a multi-faceted program to increase influenza vaccine coverage among health care workers

Background: The effect of guideline changes on trends of prescription drug use are commonly studied by age and over time period. This masks the birth cohort dimension which affects the age-specific trends in each time period. Objectives: We investigated whether including the birth cohort dimension in time series analysis leads to a more accurate estimation of the effect of a guideline change on the trend of benzodiazepine use. Methods: Outpatient pharmacy data from a drug prescription database in the Netherlands (IADB.nl) were used to obtain the age- (18-85) and sex -specific number of users of benzodiazepine (ATC: N05BA and N05CD) per 1,000 population (prevalence) per quarter year from 1998 to 2008. We studied the prevalence over time by age groups and by birth cohorts. Interrupted time series analyses were performed to the de-seasonalized trend to estimate the effect of the guideline change in 2001. Results: From 1998 to 2008 the overall age-standardized prevalence of benzodiazepine use per 1,000 population declined from ∼55 for males and ∼105 for females to ∼42 for males and ∼78 for females, this decline strengthened in 2001 for both sexes (significant slope change of p <0.05). Similar patterns over time, including slope changes (p <0.05), can be found within the majority of age categories, providing no additional information. Within birth cohorts the prevalence first increased over time but after 2001 this increase stopped or weakened (p <0.05), indicating a reduction in starters or less chronic use of benzodiazepine. Conclusions: Studying trends within birth cohorts can be a useful addition to time series analyses because the same or similar individuals are followed over time, making analysis more intuitive. This is not the case for trends within age-categories, potentially leading to less informed conclusions about guideline effects.Background: Epidemiological research has been criticized as being unreliable. Scientific evidence is strengthened when the study procedures of important findings are transparent, open for review, and easily reproduced by different investigators and in various settings. Studies often have common scientific workflows. The development of generalized execution engines, reusing epidemiological software/script program code for specific clinical questions, can serve as a valuable tool for transparent and reproducible research. Objectives: Learn about standards for transparent, reproducible and reusable research and how it is being applied in pharmacoepidemiolgy. Description: The focus of the symposium will be transparent, reproducible and reusable research. Principles of reproducible research in the context of the Medication History Estimator will be discussed. In addition, an overview of the IMI-PROTECT WP2: Framework for pharmacoepidemiologic studies and the Observational Medical Outcomes Partnership will be given. Outline: 1. Principles of reliability (Helga Gardarsdottir): Introduction to basic principles of transparent reproducible and reusable research. 2. Standardization (Huifang Liang): Standardization of data for drug utilization studies. A discussion of steps involved to convert the raw data into the readily usable data, including how to impute certain fields with examples. 3. Demonstration of the Medication History Estimator (MHE) and a description of the VINCI EpiTools (Brian Sauer). The MHE will be presented to demonstrate concepts of transparency, reproducibility and reuse. 4. The IMI-PROTECT project (Olaf Klungel & Robert Reynolds). Experiences with developing, testing and disseminating methodological standards for the design, conduct and analysis of database studies will be discussed. 5. Lessons from the Observational Medical Outcomes Partnership (Patrick Ryan, PhD). Standardized analytics tools developed by the OMOP community to characterize, visualize, and explore the effects of medical products within a distributed network of observational databases will be presented. 6. Closing summary/discussion. Chairs: Helga Gardarsdottir & Brian Sauer.Background: The Netherlands Pharmacovigilance Centre Lareb received six reports of hearing impairment in association with oral terbinafine use. This study describes these cases and provides support for this association from the Lareb database of spontaneous ADR reporting and from Vigibase, the adverse drug reaction database of the WHO UppsalaMonitoring Centre. Objectives: The objective of the study is to identify whether the observed association between oral terbinafine use and hearing impairment, based on several cases received by Lareb, supports a safety signal. Methods: Cases of hearing impairment in oral terbinafine users are described. In a case/non-case analysis, the strength of the association in Vigibase and the Lareb database was determined by calculating the reporting odds ratios (ROR), adjusted for possible confounding by age, sex and possibly ototoxic concomitant medication. RORs are calculated for deafness, hypoacusis, and the combination of both, defined as hearing impairment. Results: In the Lareb database, six reports concerning individuals aged 31-82 years, who developed hearing impairment after starting oral terbinafine, are present. The use of oral terbinafine is disproportionally associated with hypoacusis in both the Lareb database (adjusted ROR = 3.9, 95% CI: 1.7-9.0), and in Vigibase (adjusted ROR = 1.7, 95% CI: 1.0-2.8). Deafness is not disproportionally present in either of the databases. The pharmacological action of terbinafine is based on the inhibition of squalene epoxidase, an enzyme present in both fungal and human cells. This inhibition might result in decreased cholesterol levels in, among others, the outer hair cells of the cochlea, possibly leading to impaired cochlear function and hearing impairment. Conclusions: To our knowledge, hearing impairment associated with oral terbinafine use has not been described before. A causal relationship between the use of oral terbinafine and hearing impairment is possible, based on statistical analysis of reported cases in different databases and a possible pathophysiological explanation.Background: In observational studies of time-varying exposure and confounders, the use of propensity score (PS) is limited to assigning weights as in marginal structural models (MSMs). Stratification and conditioning on time-varying cofounders which are also intermediates can induce collider-stratification bias and adjust-away the (indirect) effect of exposure. Similar bias could be expected when one conditions on time-dependent PS. Objectives: We explored collider-stratification and confounding bias due to conditioning or stratifying on timedependent PS in a clinical example on the effect of inhaled short and long-acting beta2-agonist use (SABA and LABA, respectively) on coronary heart disease (CHD). Methods: A cohort of patients with an indication for SABA and/or LABA use was extracted from the Netherlands University Medical Center Utrecht General Practitioner Research Network. Information from 1995 to 2005 was used. SABA and LABA use and potential confounders were ascertained on 3 month intervals. Follow-up began the first day of diagnosis of bronchitis, asthma, or COPD and ended at the occurrence of CHD, death, unregistration with the GP, or end of the study, whichever occurred first. HR were estimated using PS stratification as well as covariate adjustment and compared with those of MSMs in both SABA and LABA separately. In MSMs, censoring was accounted for by including inverse probability of censoring weights. Results: The crude HR of CHD was 0.90 [95% CI: 0.63, 1.28] and 1.55 [95% CI: 1.06, 2.62] in SABA and LABA users respectively. When PS stratification, adjustment using PS, and MSMs were used, the HRs were 1.09 [95%CI: 0.74, 1.61], 1.07 [95% CI: 0.72, 1.60], and 0.86 [95% CI: 0.55, 1.34] for SABA, and 1.09 [95%CI: 0.74, 1.62], 1.13 [95%CI: 0.76, 1.67], 0.77 [95% CI: 0.45, 1.33] for LABA, respectively. Conclusions: Results were similar for different PS methods, but systematically higher than those of MSMs. When treatment and confounders vary during follow-up, conditioning or stratification on time-dependent PS may induce substantial collider-stratification or confounding bias. Hence, the use of methods such as MSMs is recommended.Background: Compared to RCTs, observational (nonrandomized) studies often comprise larger sample sizes, which gives adequate power to study interaction. Observational studies, however, are prone to confounding. Objectives: To determine the validity of subgroup and interaction effects (differences between subgroups) for different study designs. Methods: We compared effects of medical interventions based on observational studies, RCTs, and Individual Patient Data Meta-Analysis of RCTs (IPDMAs; reference) on three different clinical topics: (1) mammography screening effects on breast cancer mortality; (2) CABG and all-cause mortality; (3) statins and the incidence of major coronary events. Main, subgroup, and interaction effects were compared. Results: Main and subgroup effects were comparable with respect to the direction of effects for IPDMAs, RCTs, and observational studies. Small differences in the magnitude of subgroup effects in observational studies yielded different interactions compared to IPDMA. In the mammography example the Ratio of Risk Ratios (RRR) (i.e., interaction effect) among observational studies was 1.46 (95% CI 1.09;1.96) compared to an IPDMA effect of 110 (95% CI 0.89;1.37). For the CABG studies the observational RRR was 1.03 (95% CI 0.84;1.26), whereas in the IPDMA this was 1.40 (95% CI 1.08;11.81). Finally, in the statin example the RRR was 1.35 (95% CI 113;1.61) for observational studies, in the IPDMA this was 0.90 (95% CI 0.84;0.97). Conclusions: Main and subgroup effects based on observational data are in line with main and subgroup effects in IPDMAs based on RCTs, yet interactions may differ substantially.Background: Both antidepressants (AD) and benzodiazepines (BZD) have been associated with an increased risk for hip fracture. However, the hazard function is not constant over exposure time and differs for these two medication classes. Hence, the timing of initiation of co-use will determine the overall hazard function. Objectives: The aim of this study was to describe timing of BZD co-medication use among AD users. Methods: The study population included patients from the Netherlands Information Network of General Practice who initiated ADs between 2002 and 2009. AD-treatment episodes were constructed for each patient assuming the start of a new episode when 90 days elapsed between the theoretical end-date of a prior AD prescription (Rx) and the start-date of the next AD Rx. Within the first AD episode, three groups of BZD co-use were defined: “simultaneous” (simultaneous start of AD and BZD, no BZD during 182 days prior to start), “before” and “during” starters. These groups were described according to intensity of BZD use (number of Rxs), mono/polytherapy of AD and duration of AD episode. Results: The study population consisted of 16,617 AD users. The mean age was 50 years (SD = 18) and 63.2% were female. The median duration of the AD episode was 80 days (IQR = 259). Of 28.5% of patients used both AD and BZD. Of these, 57.2% started BZD before the AD, 19.0% were “simultaneous” starters and 23.8% started BZD during their first AD episode. In general, “simultaneous” starters were younger (mean = 45.3 vs. 56.4 years) yet had less intensity of BZD use (mean = 4.3 vs. 7.5 Rxs) compared to “before” starters. “After” starters were slightly older (mean = 48.0 vs. 45.3 years), had more AD polytherapy (20.2% vs. 14.9%) however less intensive BZD use (mean = 3.7 vs. 4.3 Rxs) compared to “simultaneous” starters. Conclusions: Timing of initiating BZD use in AD users is important, as each BZD co-use group is expected to have a different overall hazard function for hip fracture as opposed to when co-medication is defined as constant over time. To calculate accurate hazard function, it is important to take into consideration the timing of initiation of co-medication use in pharmacoepidemiological studies.Background: Pregnancy outcomes in women with preexisting diabetes are known to be worse than in the healthy population: rates of congenital malformations have been reported to be 2 to 10-fold higher. This is due to poor glycaemic control. Objectives: To determine rates of congenital malformations in babies of mothers with type1 (DM1) and type2 (DM2) diabetes and compare with the healthy population. Methods: Patients with pre-existing DM1 or DM2 during pregnancy were identified on the General Practice Research Database using diagnoses, prescribing, use of testing equipment and referral records. Mothers were matched to babies using registration records with the same family number, within 2 months of delivery date. Major congenital malformations were identified in the baby’s record and malformations verified with at least two related medical records; free text entries were checked. Results: Between January 1992 and March 2007 1,057 DM1 patients had 1,329 pregnancies and 365 DM2 patients had 441 pregnancies that resulted in a live birth. Eighty-four major malformations were found in 78 babies of DM1 mothers: 41 were cardiac, 11 were urogenital and eight were limb defects. Twenty-six major malformations were identified in 22 babies of DM2 mothers (seven cardiac defects). Overall, 5.9% of babies of DM1 mothers and 5.0% of babies of DM2 mothers had a malformation compared to 2–3% in the healthy population. The malformation rate for babies of DM2 mothers was comparable with another study (5.8%) but was lower for DM1 (8.2%). The proportion of cardiac malformations in babies of DM1 mothers was three times higher than in the healthy population. Conclusions: Babies whose mothers had DM1 or DM2 during pregnancy had double the rate of malformations. Pregnancy loss due to malformation has not been included but previous work found a greater proportion of terminations for medical reasons (1% in DM1, 1.8% in DM2) compared to healthy pregnancies (0.8%). Limitations include potentially differential recording of malformations between babies of mothers with DM1 and DM2 and the lack of records of glycaemic control. Differences in rates of malformations between treatments including analogue and human insulin will be evaluated next.

(Cost-)Effectiveness of a Screening Strategy for Q Fever among Pregnant Women in Risk Areas : A Clustered Randomized Controlled Trial

Background: Two case reports of polymyalgia rheumatica (PMR) and one case-report of PMR and temporalis arteritis (AT) suggest that the use of statins may have triggered the development of these inflammatory rheumatic diseases. PMR is closely linked to the disease arteritis temporalis which makes it difficult for physicians to distinguish these two diseases. Data on the association between the use of statins and PMR and/or AT are scarce. Objectives: To assess the association between statin use and the occurrence of PMR/AT. Methods: A case/non-case study based on individual case safety reports (ICSR) listed in the World Health Organisation (WHO) global ICSR database (Vigibase) was conducted. According to WHO adverse reaction terminology, cases were defined as reports of PMR. Each case was matched with five non-cases by age, gender and time of reporting. Non-cases were all other ADR-reports. Use of statins was classified according to the Anatomical Therapeutic Chemical (ATC) classification code system (C10AA, C10BA, C10BX). Potential confounders in the analysis, i.e., use of corticosteroids, immunosuppressive drugs, non-steroidal anti-inflammatory drugs (NSAIDs), antidepressants, anti-epileptics, proton pump inhibitors and cardiovascular drugs were determined. Multivariate logistic regression was used to calculate the reporting odds ratios (RORs) with 95% confidence intervals (CI). In addition, three case-reports from the VigiBase were studied in detail. Results: We identified 327 reports of PMR/AT as cases and 1635 reports of other ADRs as non-cases. Among cases statins were more frequently reported as suspected agent (29.4%) compared to non-cases (2.9%). After adjustment for several covariates, statins were statistically significantly associated with reports of PMR/AT (ROR 14.21; 95% CI 9.89-20.85). Conclusions: The result of this study underlines findings of the case reports that the use of statins may be associated with the occurrence of PMR/AT.Background: In The Netherlands, the largest outbreak of Q fever worldwide is ongoing. A particular risk group concerns pregnant women in which the infection is mostly asymptomatic. Q fever during pregnancy may cause both obstetric complications as well as chronic infection in the mother. Long term antibiotic treatment of infected women may reduce the risk of complications. Objectives: A clustered randomized controlled trial to assess the effects of screening for Q fever during pregnancy is ongoing (trial register number NL30340.042.09). The primary endpoint is a maternal or obstetric complication in Q fever positive women. Methods: Midwife centers in high-risk Q fever areas were randomized to recruit pregnant women for the screening or control strategy. In both groups a blood sample was taken between 20 and 32 weeks of gestation. In the screening group this sample was immediately analyzed with indirect immunofluorescence assay for the detection of IgG and IgM antibodies. Every positive sample was fully titrated. In case of acute or chronic infection antibiotic treatment advice was given. In the control group serum was frozen for analysis after delivery. Results: In all, 55 of 99 eligible midwife centers were randomized. They recruited 1222 pregnant women from which a blood sample was taken; 534 for the screening group and 688 for the controle group. Fourteen percent in both groups had serologic evidence for an acute or previous Q fever infection. Only 7 participants in the intervention group had evidence for an acute infection and were treated with antibiotics (erythromycin or cotrimoxazole). Three of them experienced side-effects, mainly gastro-intestinal, of which one consulted the gynecologist due to the side-effects. Since a part of the participants still have to deliver, data collection on clinical outcome is still ongoing. Conclusions: Fourteen percent of the pregnant women in high-risk Q fever areas have evidence of Q fever infection. Only a very small part has an acute infection, in which treatment is though to be needed. Clinical outcome data and cost-effectiveness analyses are expected in spring and will be presented.