Impact of varying outcomes and definitions of suicidality on the associations of antiepileptic drugs and suicidality: comparisons from UK Clinical Practice Research Datalink (CPRD) and Danish national registries (DNR).

PURPOSE: The purpose of this study is to quantify the impact of the different outcomes and definitions of suicidality on the association between antiepileptic drugs (AEDs) and suicidality. METHODS: Retrospective cohort studies of selected AEDs (carbamazepine, gabapentin, lamotrigine, phenytoin, pregabalin, topiramate and valproate) using data from UK Clinical Practice Research Datalink (CPRD) alone and linked to UK Hospital Episode Statistics (HES) and UK Office of National Statistics (ONS), and from Danish national registries (DNR). Follow-up started at initiation of one of the study AEDs, divided into exposure periods, a maximum 90-day post-exposure period, and the reference period starting the day after the 90-day post-exposure period ended. Primary outcomes were completed suicide (SUI)/suicide attempt (SA) for CPRD and SUI/deliberate self-harm (DSH) for DNR. We applied adjusted Cox regression analyses and sensitivity analyses with varying outcome definitions. RESULTS: We analyzed 84,524 AED users from CPRD-HES-ONS (1188 SUI/SA; 96 SUI) and 258,180 users from DNR (7561 SUI/DSH; 781 SUI). The adjusted hazard ratios (HRs) on SUI/SA ranged between 1.3 (95% confidence interval (CI): 0.84-2.00) for lamotrigine and 2.7 (1.24-5.81) for phenytoin in CPRD-HES-ONS, and between 0.9 (0.78-1.00) for valproate and 1.8 (1.10-3.07) for phenytoin on SUI/DSH in DNR. HRs for the primary outcomes varied consistently across exposure periods and data sources. HRs for SUI were in general lower, more stable and similar for periods of exposure and the 90-day post-exposure period. CONCLUSION: Applying different outcomes and definitions of suicidality had an impact on the relative risks of suicidality associated with the investigated AEDs with results for SUI being most consistent and reliable.

Prevalence of antibiotic use: a comparison across various European health care data sources.

PURPOSE: There is widespread concern about increases in antibiotic use, but comparative data from different European countries on rates of use are lacking. This study was designed to measure and understand the variation in antibiotic utilization across five European countries. METHODS: Seven European healthcare databases with access to primary care data from Denmark, Germany, the Netherlands, Spain and the UK were used to measure and compare the point and 1-year-period prevalence of antibiotic use between 2004 and 2009. Descriptive analyses were stratified by gender, age and type of antibiotic. Separate analyses were performed to measure the most common underlying indications leading to the prescription of an antibiotic. RESULTS: The average yearly period prevalence of antibiotic use varied from 15 (Netherlands) to 30 (Spain) users per 100 patients. A higher prevalence of antibiotic use by female patients, the very young (0-9 years) and old (80+ years), was observed in all databases. The lowest point prevalence was recorded in June and September and ranged from 0.51 (Netherlands) to 1.47 (UK) per 100 patients per day. Twelve percent (Netherlands) to forty-nine (Spain) percent of all users were diagnosed with a respiratory tract infection, and the most common type of antibiotic prescribed were penicillin. CONCLUSION: Using identical methodology in seven EU databases to assess antibiotic use allowed us to compare drug usage patterns across Europe. Our results contribute quantitatively to the true understanding of similarities and differences in the use of antibiotic agents in different EU countries.

Exposure to benzodiazepines (anxiolytics, hypnotics and related drugs) in seven European electronic healthcare databases: a cross-national descriptive study from the PROTECT-EU Project.

PURPOSE: Studies on drug utilization usually do not allow direct cross-national comparisons because of differences in the respective applied methods. This study aimed to compare time trends in BZDs prescribing by applying a common protocol and analyses plan in seven European electronic healthcare databases. METHODS: Crude and standardized prevalence rates of drug prescribing from 2001-2009 were calculated in databases from Spain, United Kingdon (UK), The Netherlands, Germany and Denmark. Prevalence was stratified by age, sex, BZD type [(using ATC codes), i.e. BZD-anxiolytics BZD-hypnotics, BZD-related drugs and clomethiazole], indication and number of prescription. RESULTS: Crude prevalence rates of BZDs prescribing ranged from 570 to 1700 per 10,000 person-years over the study period. Standardization by age and sex did not substantially change the differences. Standardized prevalence rates increased in the Spanish (+13%) and UK databases (+2% and +8%) over the study period, while they decreased in the Dutch databases (-4% and -22%), the German (-12%) and Danish (-26%) database. Prevalence of anxiolytics outweighed that of hypnotics in the Spanish, Dutch and Bavarian databases, but the reverse was shown in the UK and Danish databases. Prevalence rates consistently increased with age and were two-fold higher in women than in men in all databases. A median of 18% of users received 10 or more prescriptions in 2008. CONCLUSION: Although similar methods were applied, the prevalence of BZD prescribing varied considerably across different populations. Clinical factors related to BZDs and characteristics of the databases may explain these differences.

Antiepileptic drug use in seven electronic health record databases in Europe: a methodologic comparison.

OBJECTIVE: The annual prevalence of antiepileptic drug (AED) prescribing reported in the literature differs considerably among European countries due to use of different type of data sources, time periods, population distribution, and methodologic differences. This study aimed to measure prevalence of AED prescribing across seven European routine health care databases in Spain, Denmark, The Netherlands, the United Kingdom, and Germany using a standardized methodology and to investigate sources of variation. METHODS: Analyses on the annual prevalence of AEDs were stratified by sex, age, and AED. Overall prevalences were standardized to the European 2008 reference population. RESULTS: Prevalence of any AED varied from 88 per 10,000 persons (The Netherlands) to 144 per 10,000 in Spain and Denmark in 2001. In all databases, prevalence increased linearly: from 6% in Denmark to 15% in Spain each year since 2001. This increase could be attributed entirely to an increase in "new," recently marketed AEDs while prevalence of AEDs that have been available since the mid-1990s, hardly changed. AED use increased with age for both female and male patients up to the ages of 80 to 89 years old and tended to be somewhat higher in female than in male patients between the ages of 40 and 70. No differences between databases in the number of AEDs used simultaneously by a patient were found. SIGNIFICANCE: We showed that during the study period of 2001-2009, AED prescribing increased in five European Union (EU) countries and that this increase was due entirely to the newer AEDs marketed since the 1990s. Using a standardized methodology, we showed consistent trends across databases and countries over time. Differences in age and sex distribution explained only part of the variation between countries. Therefore, remaining variation in AED use must originate from other differences in national health care systems.

YKL-40 and mast cells are associated with detrusor fibrosis in patients diagnosed with bladder pain syndrome/interstitial cystitis according to the 2008 criteria of the European Society for the Study of Interstitial Cystitis.

AIMS: Bladder pain syndrome/interstitial cystitis (BPS/IC), diagnosed according to the new 2008 criteria of the European Society for the Study of Interstitial Cystitis (ESSIC), may lead to detrusor fibrosis. In some inflammatory diseases, fibrosis is related to YKL-40. The aims were to examine YKL-40 antigenic expression in bladder tissue and levels in serum and urine in BPS/IC and to evaluate whether YKL-40 could be a non-invasive, prognostic biomarker for bladder fibrogenesis and treatment intensity. METHODS AND RESULTS: Immunohistochemistry, immunoelectron microscopy and enzyme-linked immunosorbent assay (ELISA) analyses in 45 patients showed YKL-40 expression in detrusor mast cell granules and submucosal macrophages, and elevated YKL-40 levels in serum and urine compared to healthy individuals (median 72 versus 7 µg/l, P < 0.001). Clinicopathological parameters showed associations of detrusor fibrosis with YKL-40-positive cells (P = 0.001), mast cells (P = 0.014) and urine YKL-40 (P = 0.009). Bladder capacity correlated inversely with YKL-40-positive cells (P < 0.001) and mast cells (P = 0.029). Treatment intensity was not associated with YKL-40. CONCLUSION: Serum and urine levels of YKL-40 may be used as non-invasive biomarkers in BPS/IC for the evaluation of bladder fibrogenesis.

Bladder pain syndrome/interstitial cystitis in a Danish population: a study using the 2008 criteria of the European Society for the Study of Interstitial Cystitis.

OBJECTIVE: To characterize and evaluate a Danish patient population with bladder pain syndrome/interstitial cystitis (BPS/IC), using a working definition for BPS/IC incorporating six variables, and a set of criteria defined by the European Society for the Study of Interstitial Cystitis (ESSIC); to describe the clinical course and treatment intensity in relation to these variables. PATIENTS AND METHODS: Clinical data were obtained retrospectively from medical records for 349 consecutive patients with IC referred to the Department of Urology, Copenhagen University Hospital Herlev, Denmark between 1966 and 2008. The median (range) age at diagnosis was 53 (16-88) years; 64% were followed for at least 2 years. The outcome was expressed in terms of treatment intensity and was correlated with clinical data (pain, nocturnal frequency, bladder capacity, mucosal glomerulations, detrusor mastocytosis, detrusor intrafascicular fibrosis, IFF). RESULTS: All patients had pain and 75% had nocturia at least twice. The bladder capacity estimated under general anaesthesia was <500 mL in 42%; 53% presented with detrusor mastocytosis (> or =28 mast cells/mm(2)) and 50% with IFF. The detrusor mast cell count (P < 0.001), IFF (P = 0.004) and nocturnal frequency (P = 0.043) had statistically significant prognostic value for treatment intensity, whereas bladder capacity and glomerulations were not significant. CONCLUSION: Nocturia, detrusor mastocytosis and IFF are associated with multiple treatments and presumed failure of standard urological therapy in patients with BPS/IC, while bladder capacity and glomerulations are not. Valid conclusions cannot be drawn because of numerous limitations to the study.

Body surface area determined by whole-body CT scanning: need for new formulae?

Calculation of the estimated body surface area (BSA) by body height and weight has been a challenge in the past centuries due to lack of a well-documented gold standard. More recently, available techniques such as 3D laser surface scanning and CT scanning may be expected to quantify the BSA in an easier and more accurate way. This study provides the first comparison between BSA obtained from post-mortem whole-body CT scans and BSA calculated by nine predictive formulae. The sample consisted of 54 male cadavers ranging from 20 to 87 years old. 3D reconstructions were generated from CT scans using Mimics software, and BSA values were automatically extracted from the program. They were compared with nine predictive equations from the literature. Remarkably, close correlations (r > 0·90) were found between BSA values from CT scans and those from the predictive formulae. A mean BSA of the 54 cadavers of 1·84-1·87 m2 was calculated by all formulae except one, SD values varying between 0·171 and 0·223 m2 . T-tests revealed significant differences between mean BSA values calculated with CT and three of the formulae. Regression analyses showed intercepts >(0;0) and slopes <1·0 using all predictive equations, with the CT scan determination as gold standard. It is concluded that DuBois and DuBois' equation can be safely used in normal-weight male subjects with high accuracy, but it seems likely that BSA is underestimated in underweight subjects and overestimated in overweight individuals. Creation of new formulae specific for overweight subjects and children may be needed.

Time trends of period prevalence rates of patients with inhaled long-acting beta-2-agonists-containing prescriptions: a European comparative database study.

BACKGROUND: Inhaled, long-acting beta-2-adrenoceptor agonists (LABA) have well-established roles in asthma and/or COPD treatment. Drug utilisation patterns for LABA have been described, but few studies have directly compared LABA use in different countries. We aimed to compare the prevalence of LABA-containing prescriptions in five European countries using a standardised methodology. METHODS: A common study protocol was applied to seven European healthcare record databases (Denmark, Germany, Spain, the Netherlands (2), and the UK (2)) to calculate crude and age- and sex-standardised annual period prevalence rates (PPRs) of LABA-containing prescriptions from 2002-2009. Annual PPRs were stratified by sex, age, and indication (asthma, COPD, asthma and COPD). RESULTS: From 2002-2009, age- and sex-standardised PPRs of patients with LABA-containing medications increased in all databases (58.2%-185.1%). Highest PPRs were found in men ≥ 80 years old and women 70-79 years old. Regarding the three indications, the highest age- and sex-standardised PPRs in all databases were found in patients with "asthma and COPD" but with large inter-country variation. In those with asthma or COPD, lower PPRs and smaller inter-country variations were found. For all three indications, PPRs for LABA-containing prescriptions increased with age. CONCLUSIONS: Using a standardised protocol that allowed direct inter-country comparisons, we found highest rates of LABA-containing prescriptions in elderly patients and distinct differences in the increased utilisation of LABA-containing prescriptions within the study period throughout the five European countries.

Patient characteristics among users of analgesic over-the-counter aspirin in a Danish pharmacy setting.

BACKGROUND: Use of over-the-counter (OTC) high-dose acetylsalicylic acid (ASA) is a risk factor for experiencing gastric bleeding. However, more detailed knowledge on the characteristics of users of OTC ASA is needed. OBJECTIVE: To characterise users of OTC high-dose ASA in a Danish pharmacy setting. METHOD: We conducted an interview based survey among users of OTC high-dose ASA. Questions were asked regarding: (1) demographic characteristics; (2) use patterns; (3) knowledge about adverse events; (4) risk factors for experiencing gastric bleeding; (5) reasons for choosing an ASA-containing medicine; and (6) whether their GP was informed on their use of high-dose ASA. RESULTS: One-hundred-seventeen interviews were completed. Nineteen percent and 37 % used high-dose ASA on a daily or weekly basis respectively. Sixty-eighth percent found high-dose ASA to be more effective than other analgesics. Fourty-seven percent had one or more risk factors for experiencing ulcer bleeding, most commonly age >60 years (32 %) and previous peptic ulcer (9 %). The most well-known adverse events were abdominal pain (32 %) and peptic ulcer (26 %). The most common source of information was friends and family (32 %). CONCLUSION: A large proportion of users of high-dose ASA have risk factors for experiencing gastric bleeding. Health-care professionals needs to provide more information on potential adverse events.

Different initiatives across Europe to enhance losartan utilization post generics: impact and implications.

INTRODUCTION: There is an urgent need for health authorities across Europe to fully realize potential savings from increased use of generics to sustain their healthcare systems. A variety of strategies were used across Europe following the availability of generic losartan, the first angiotensin receptor blocker (ARB) to be approved and marketed, to enhance its prescribing vs. single-sourced drugs in the class. Demand-side strategies ranged from 100% co-payment for single-sourced ARBs in Denmark to no specific measures. We hypothesized this heterogeneity of approaches would provide opportunities to explore prescribing in a class following patent expiry. OBJECTIVE: Contrast the impact of the different approaches among European countries and regions to the availability of generic losartan to provide future guidance. METHODOLOGY: Retrospective segmented regression analyses applying linear random coefficient models with country specific intercepts and slopes were used to assess the impact of the various initiatives across Europe following the availability of generic losartan. Utilization measured in defined daily doses (DDDs). Price reductions for generic losartan were also measured. RESULTS: Utilization of losartan was over 90% of all ARBs in Denmark by the study end. Multiple measures in Sweden and one English primary care group also appreciably enhanced losartan utilization. Losartan utilization actually fell in some countries with no specific demand-side measures. Considerable differences were seen in the prices of generic losartan. CONCLUSION: Delisting single-sourced ARBs produced the greatest increase in losartan utilization. Overall, multiple demand-side measures are needed to change physician prescribing habits to fully realize savings from generics. There is no apparent "spill over" effect from one class to another to influence future prescribing patterns even if these are closely related.

Bridging differences in outcomes of pharmacoepidemiological studies: design and first results of the PROTECT project.

BACKGROUND: Observational pharmacoepidemiological (PE) studies on drug safety have produced discrepant results that may be due to differences in design, conduct and analysis. PURPOSE: The pharmacoepidemiology work-package (WP2) of the Pharmacoepidemiological Research on Outcomes of Therapeutics by a European ConsorTium (PROTECT) project aims at developing, testing and disseminating methodological standards for design, conduct and analysis of pharmacoepidemiological studies applicable to different safety issues using different databases across European countries. This article describes the selection of the safety issues and the description of the databases to be systematically studied. METHODS: Based on two consensus meetings and a literature search, we selected five drug-adverse event (AE) pairs to be evaluated in different databases. This selection was done according to pre-defined criteria such as regulatory and public health impact, and the potential to investigate a broad range of methodological issues. RESULTS: The selected drug-AE pairs are: 1) inhaled long-acting beta-2 agonists and acute myocardial infarction; 2) antimicrobials and acute liver injury; 3) antidepressants and/or benzodiazepines and hip fracture; 4) anticonvulsants and suicide/suicide attempts; and 5) calcium channel blockers and malignancies. Six European databases, that will be used to evaluate the drug-AE pairs retrospectively, are also described. CONCLUSION: The selected drug-AE pairs will be evaluated in PE studies using common protocols. Based on consistencies and discrepancies of these studies, a framework for guiding methodological choices will be developed. This will increase the usefulness and reliability of PE studies for benefit-risk assessment and decision-making.

Impact of delisting ARBs, apart from losartan, on ARB utilisation patterns in Denmark: implications for other countries.

INTRODUCTION: Renin-angiotensin inhibitor drugs have been a target for health authority initiatives across Europe with the potential for substantial savings once generic angiotensin-converting enzyme inhibitors (ACEIs) became available without compromising care. Recently, losartan was the first angiotensin receptor blocker (ARB) to lose its patent. In Denmark, the authorities removed all other ARBs from the reimbursement list, apart from losartan, as they were all seen as essentially similar for the management of hypertension or congestive heart failure at appropriate doses, but more expensive. Similarly, all other ARB fixed-dose combinations (FDCs), apart from losartan, were removed from the reimbursement list. OBJECTIVE: The aims of the study were to (i) assess the impact of these reimbursement changes on the subsequent utilisation of losartan and other ARBs alone or as FDCs; (ii) assess changes in the prices of losartan and other ARBs post-generic losartan to calculate potential savings; and (iii) compare the impact of the policies in Denmark with other European countries to provide guidance. METHODOLOGY: This was a retrospective segmented regression analysis of an interrupted time-series design comparing utilisation patterns before and after the changes in ARB reimbursement status. Utilisation was measured in defined daily doses (DDDs). Changes in total expenditure and expenditure/DDD were also assessed over time. RESULTS: Losartan utilisation grew from 31 to 33 % of total single ARB utilisation before generic losartan, to 93 % by October 2011. There was a corresponding decrease in the utilisation of all other ARBs. Both changes were significant (p < 0.001). Total expenditure on single ARBs in 2011 was 77 % below 2009 levels despite a 16 % increase in utilisation. Estimated savings were 290.5 million Danish Kroner (DKK). A similar trend was seen for losartan FDCs, which was also significant (p < 0.001). DISCUSSION: Losartan utilisation grew appreciable following the changes. The change was much greater than seen in countries that had eased prescribing restrictions for losartan but not the other ARBs. Active therapeutic switching programmes plus education and financial incentives also significantly enhanced losartan utilisation following generics in two countries and regions; however, the increase in losartan utilisation was less than that seen in Denmark.

Osteoporosis among Fallers without Concomitant Fracture Identified in an Emergency Department: Frequencies and Risk Factors.

We aimed to determine whether the Emergency Department (ED) is a suitable entrance point for osteoporosis screening among fallers without concomitant fracture compared to referral from general practice. Furthermore, to identify factors associated with osteoporosis among fallers. Methods. Patients aged 50-80 years sustaining a low-energy fall without fracture were identified from an ED (n = 199). Patients answered a questionnaire on risk factors and underwent osteodensitometry. Data was compared to a group of patients routinely referred to osteodensitometry from general practice (n = 201). Results. Among the 199 included fallers, 41 (21%) had osteoporosis. Among these, 35 (85%) reported either previous fracture or reduced body height (>3 cm). These two risk factors were more frequent among fallers with osteoporosis compared to fallers with normal bone mineral density or osteopenia (previous fracture P = .044, height reduction P = .0016). The osteoporosis frequency among fallers from ED did not differ from a similarly aged patient-group referred from general practice (P = .34). Conclusion. Osteodensitometry should be considered among fallers without fracture presenting in the ED, especially if the patient has a prior fracture or declined body height. Since fallers generally have higher fracture risk, the ED might serve as an additional entrance to osteodensitometry compared to referral from primary care.

Axillary sentinel node identification in breast cancer patients: degree of radioactivity present at biopsy is critical.

BACKGROUND: The radioactivity present in the patient (Act(rem) ) at sentinel node (SN) biopsy will depend on injected activity amount as well as on the time interval from tracer injection to biopsy, which both show great variations in the literature. The purpose of this study was to analyse the influence of varying Act(rem) levels on the outcome of axillary SN biopsy in patients with breast cancer (BC). MATERIAL AND METHODS: Eight hundred and fifty-eight patients with BC were consecutively referred to SN biopsy, 21% for a same-day and 79% of the patients for a 2-day procedure. Four hundred and nineteen patients underwent scintigraphy and 439 did not. For same-day procedures, 50 MBq (99m) Tc-nanocolloid (Nanocoll(®) ) was injected, and for 2-day procedures 110 MBq. For the analysis of SN biopsy outcome, the patients were divided into three Act(rem) groups: <10 (56% of the patients), 10-20 (23%), and >20 MBq (21%). During surgery, SNs were located using a hand-held gamma probe supported by image information when available and blue dye injection. Pathology included haematoxylin-eosin staining followed by immunohistochemistry. RESULTS: The number of SNs removed (mean value 1·87 versus 2·14, P = 0·0003) and the probability of finding a malignant SN (P = 0·034) were lower in the <10 MBq group of patients compared with higher Act(rem) >20 MBq. Of the 25 patients with SN non-detection, 20 patients had an Act(rem) <10 MBq. Imaging had no significant influence on the number of patients with a malignant SN (P = 0·48). CONCLUSION: Act(rem) above 10 MBq for nanocolloid tracer appears important for appropriate identification of SNs in patients with BC.

The study design and characteristics of the Danish national health interview surveys.

AIMS: The Danish National Institute of Public Health, University of Southern Denmark has carried out national representative health interview surveys among adult Danes in 1987, 1994, 2000 and 2005. The aim of this study is to describe the characteristics of the design, including the response rates of the four surveys. METHODS: The samples in 1987 and 1994 are based on simple random sampling. The samples in 2000 and 2005 are based on stratified random sampling. In addition, all invited to the survey in 1994 were re-invited in both 2000 and 2005. Data were collected via face-to-face interview at the respondent's home. Following the interview in 1994, 2000 and 2005, all respondents were asked to complete a self-administered questionnaire. RESULTS: The response rate for the face-to-face interview fell from 79.9% in 1987 to 66.7% in 2005 and the response rate for the self-administered questionnaire from 68.1% in 1994 to 51.5% in 2005. The decrease is particularly marked among the young. The mean interview length has increased from 33.3 minutes in 1987 to 50.2 minutes in 2005. CONCLUSIONS: The declining response rate in the surveys is a major concern and can pose problems in generalizing data from the surveys to the Danish population. However, these surveys are essential, as the information collected cannot be gathered by means of official statistical registers. Hence, efforts to increase the response rate will be important in the forthcoming surveys.