Methodology of the brodalumab assessment of hazards: a multicentre observational safety (BRAHMS) study.

INTRODUCTION: Safe and effective pharmacological treatment is of paramount importance for treating severe psoriasis. Brodalumab, a monoclonal antibody against interleukin (IL) 17 receptor A, was granted marketing authorisation in the EU in 2017. The European Medicines Agency requested a postauthorisation safety study of brodalumab to address potential safety issues raised during drug development regarding major adverse cardiovascular events, suicidal conduct, cancer and serious infections. METHODS AND ANALYSIS: BRodalumab Assessment of Hazards: A Multinational Safety is a multicentre observational safety study of brodalumab running from 2017 to 2029 using population-based healthcare databases from Denmark, Sweden, Norway, Netherlands, Germany and three different centres in Italy. A distributed database network approach is used, such that only aggregate data are exchanged between sites.Two types of designs are used: a case-time-control design to study acute effects of transient treatment and a variation of the new user active comparator design to study the effects of transient or chronic treatment. As comparators, inhibitors of TNF-α, inhibitors of IL-12 and IL-23, and other inhibitors of cytokine IL-17A are included.In the self-controlled case-time-control design, the risk of developing the outcome of interest during periods of brodalumab use is compared within individuals to the risk in periods without use.In the active comparator cohort design, new users of brodalumab are identified and matched to new users of active comparators. Potential baseline confounders are adjusted for by using propensity score modelling. For outcomes that potentially require large cumulative exposure, an adapted active comparator design has been developed. ETHICS AND DISSEMINATION: The study is approved by relevant authorities in Denmark, Norway, Sweden, the Netherlands, Germany and Italy in line with the relevant legislation at each site. Data confidentiality is secured by the distributed network approach. Results will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: EUPAS30280.

Characterization and cholesterol management in patients with cardiovascular events and/or type 2 diabetes in the Netherlands.

OBJECTIVE: To describe clinical characteristics and cholesterol management of patients with cardiovascular events (CVEs) and/or type 2 diabetes mellitus (T2DM) with high low-density lipoprotein cholesterol (LDL-C) > 1.8 mmol/L in the Netherlands. RESEARCH DESIGN AND METHODS: From the PHARMO Database Network a cross-sectional cohort was constructed. The descriptive study included patients on lipid modifying therapy (LMT) in 2009, classified as high cardiovascular risk based on a history of T2DM or CVE, with 2010 LDL-C levels above 1.8 mmol/L (2011 European Society of Cardiology [ESC] target). Sub-cohorts were created: T2DM + CVE from the T2DM cohort and multiple CVE from the CVE only cohort. MAIN OUTCOME MEASURES: Clinical characteristics and drug treatment were determined at the time of the last LDL-C measurement in 2010. RESULTS: Of 10,864 very high risk patients, 66% had T2DM, 37% of whom also had CVE. In the CVE only cohort (34%), 18% had multiple events. More regular check-ups skewed inclusion towards diabetes patients. T2DM vs. CVE cohort characteristics were: 53% vs. 63% male, 42% vs. 27% obese, 19% vs. 24% current smoker, 54% vs. 51% systolic blood pressure <140 mmHg, with similar proportions in the sub-cohorts. Proportions reaching the Dutch guideline LDL-C target of <2.5 mmol/L were 56% (T2DM), 57% (T2DM + CVE), 48% (CVE only) and 53% (multiple CVE only). Frequencies of high intensity dose statin (simvastatin ≥80 mg, atorvastatin ≥40 mg or rosuvastatin ≥20 mg) were 6% (T2DM), 9% (T2DM + CVE, CVE only) and 14% (multiple CVE only); 1-2% received additional ezetimibe and 3-5% received non-statin LMT only, including ezetimibe. CONCLUSION: Despite LMT, >40% of the patients above ESC target also failed to reach the less stringent Dutch target, even in the higher risk groups. Therefore, management of hypercholesterolemia after CVE or T2DM should be optimized to improve cardiovascular outcomes. There is substantial room for improving other cardiovascular risk factors.

Quick assessment of drug-related admissions over time (QUADRAT study).

PURPOSE: To develop a computerized prescreening procedure for the identification of possible/probably Hospital Admissions potential Related to Medications (HARMs). METHOD: Pairs of drugs and reasons for hospitalization (generated automatically from the PHARMO record linkage database by using two data mining techniques) were assessed manually to determine whether they represented pharmacologically plausible adverse drug events (PP-ADEs). Two crude samples of these PP-ADEs (from 2005 and 2008) were examined manually to establish causality and preventability on the basis of hospital discharge letters plus medication dispensing data. The results were used to calculate the positive predictive value (PPV) of the crude causality PP-ADEs, the net percentage of possible/probably HARMs, and their potential preventability. RESULTS: Data mining by Gamma Poisson Shrinkage and trend analysis produced 1330 and 2941 significant drug-event pairs, respectively. After manual assessment, 307 different PP-ADEs remained. The annual prevalence of these PP-ADEs was stable at approximately 8% throughout 2000-2009. Manual assessment of two samples of crude PP-ADEs showed that their causality PPV was 53.7% (95%CI: 52.7%-54.7%) in 2005 and 47.9% (95%CI: 46.9%-49.0%) in 2008. The net contribution of possible/probably HARMs to all acute admissions was 4.6% (95%CI: 4.5%-4.8%) in 2005 and 3.9% (95%CI: 3.8%-4.0%) in 2008. The potential preventability of all possible/probably HARMs in the two samples was 19.3% (95%CI: 18.5-20.1). CONCLUSION: Automated pre-selection of PP-ADEs is an efficient way to monitor crude trends. Further validation and manual assessment of the automatically selected hospitalizations is necessary to get a more detailed and precise picture.

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.

Assessing the determinants of the potential for cost-effectiveness over time: the empirical case of COPD.

OBJECTIVES: The objective of this study was to assess the potential for cost-effectiveness of new technologies for chronic obstructive pulmonary disease (COPD) over the period from 2001 to 2010. METHODS: Lung function outcomes and drug prices were observed for a UK COPD population over the period from 2001 to 2010. Cost-effectiveness was assessed at regular intervals on the basis of an established cost-effectiveness model, and the maximum price a technology providing cure could achieve under the current cost-effectiveness rules was estimated. RESULTS: The results of this study show that although the scope for clinical improvement in COPD was still considerable, during the 10 years studied, the potential for cost-effectiveness at each point in time was dependent on momentary market characteristics, such as the changing price of comparators and improvements in clinical effectiveness. As a result, the analysis demonstrates that the future cost-effectiveness of a technology in development depends on the manner pricing and clinical effectiveness evolve throughout time. CONCLUSIONS: Because any predictions will be short-lived and dependent on a number of uncertain factors, we conclude that producing accurate forecasts on the potential for cost-effectiveness of new therapies earlier during the development process is especially difficult under the current static cost-effectiveness framework.

Prescribing of rosiglitazone and pioglitazone following safety signals: analysis of trends in dispensing patterns in the Netherlands from 1998 to 2008.

BACKGROUND: Relevant safety signals in the EU are regularly communicated in so-called 'Direct Healthcare Professional Communications' (DHPCs) or European Medicines Agency (EMA) press releases. Trends of a decrease in the use of rosiglitazone following regulatory safety warnings have been described in the US. In the EU, however, relatively little is known about dispensing patterns following DHPCs or other safety signals such as EMA press releases. OBJECTIVE: The objective of this study was to analyse trends in dispensing patterns of rosiglitazone and pioglitazone following DHPCs and EMA press releases in the EU member state, the Netherlands. METHODS: Data for this study were obtained from the PHARMO Record Linking System, which includes drug dispensing records from community pharmacies of approximately 2.5 million individuals in the Netherlands. Over the period 1998-2008 an auto-regressive, integrated, moving average model (ARIMA) was fitted. The DHPC letters or EMA press releases were used as determinants. Adjustments were made for publication of certain literature. Stratification was performed for dispensings prescribed by general practitioners (GPs) and those prescribed by specialists. RESULTS: For rosiglitazone, four EMA press releases and two DHPCs were issued; for pioglitazone, one DHPC was issued. The number of rosiglitazone dispensings prescribed by GPs decreased significantly after publication of DHPCs and EMA press releases concerning the risk of macular oedema and risk of fractures (both p-values 0.001). The number of rosiglitazone dispensings decreased statistically significantly after publication of EMA press releases 2 and 3 concerning cardiovascular risks but not for EMA press release 4. Adjustment for certain publications in the literature reduced the effect of communicated safety issues on the proportion of dispensings. CONCLUSIONS: Although it is difficult to disentangle the effect of DHPCs and EMA press releases from the effect of reports published in the literature, our results suggest that prescribers may react to such safety communications.

Antihypertensive drugs: a perspective on pharmaceutical price erosion and its impact on cost-effectiveness.

OBJECTIVE: When comparators' prices decrease due to market competition and loss of exclusivity, the incremental clinical effectiveness required for a new technology to be cost-effective is expected to increase; and/or the minimum price at which it will be funded will tend to decrease. This may be, however, either unattainable physiologically or financially unviable for drug development. The objective of this study is to provide an empirical basis for this discussion by estimating the potential for price decreases to impact on the cost-effectiveness of new therapies in hypertension. METHODS: Cost-effectiveness at launch was estimated for all antihypertensive drugs launched between 1998 and 2008 in the United Kingdom using hypothetical degrees of incremental clinical effectiveness within the methodologic framework applied by the UK National Institute for Health and Clinical Excellence. Incremental cost-effectiveness ratios were computed and compared with funding thresholds. In addition, the levels of incremental clinical effectiveness required to achieve specific cost-effectiveness thresholds at given prices were estimated. RESULTS: Significant price decreases were observed for existing drugs. This was shown to markedly affect cost-effectiveness of technologies entering the market. The required incremental clinical effectiveness was in many cases greater than physiologically possible so, as a consequence, a number of products might not be available today if current methods of economic appraisal had been applied. CONCLUSIONS: We conclude that the definition of cost-effectiveness thresholds is fundamental in promoting efficient innovation. Our findings demonstrate that comparator price attrition has the potential to put pressure in the pharmaceutical research model and presents a challenge to new therapies being accepted for funding.

Costs of hospital events in patients with metastatic colorectal cancer.

BACKGROUND: In the last decade, the number of new agents, including monoclonal antibodies, being developed to treat metastatic colorectal cancer (mCRC) increased rapidly. While improving outcomes, these new treatments also have distinct and known safety profiles with toxicities that may require hospitalizations. However, patterns and costs of hospitalizations of toxicities of these new 'targeted' drugs are often unknown. OBJECTIVE: This study aimed to estimate the costs of hospital events associated with adverse events specified in the 'Special Warnings and Precautions for Use' section of the European Medicinal Agency Summary of Product Characteristics for bevacizumab, cetuximab, and panitumumab, in patients with mCRC. METHODS: From the PHARMO Record Linkage System (RLS), patients with a primary or secondary hospital discharge code for CRC and distant metastasis between 2000-2008 were selected and defined as patients with mCRC. The first discharge diagnosis defining metastases served as the index date. Patients were followed from index date until end of data collection, death, or end of study period, whichever occurred first. Hospital events during follow-up were identified through primary hospital discharge codes. Main outcomes for each event were length of stay and costs per hospital admission. RESULTS: Among 2964 mCRC patients, 271 hospital events occurred in 210 patients (mean [SD] duration of follow-up: 34 [31] months). The longest mean (SD) length of stay per hospital admission were for stroke (16 [33] days), arterial thromboembolism (ATE) (14 [21] days), wound-healing complications (WHC), acute myocardial infarction (AMI), congestive heart failure (CHF), and neutropenia (all 9 days; SD 5-15). Highest mean (SD) costs per admission were for stroke (€13,500 [€28,800]), ATE (€13,300 [€18,800]), WHC (€10,800 [€20,500]). LIMITATIONS: Although no causal link could be identified between any specific event and any specific treatment, data from this study are valuable for pharmacoeconomic evaluations of newer treatments in mCRC patients. CONCLUSIONS: Inpatient costs for events in mCRC patients are considerable and vary greatly.

A dynamic perspective on pharmaceutical competition, drug development and cost effectiveness.

Limited healthcare budgets result in payers adopting policies at national, regional or local level to achieve allocative efficiency in drug spending. Some of these aim at creating a link between pharmaceutical prices and the value they provide by setting a cost effectiveness (CE) threshold as the maximum acceptable ratio between incremental costs and effects of new drugs. The clinical effectiveness of the comparator used in those CE analyses tends to be greater over time, whilst, due to market competition and loss of exclusivity, their price is expected to be lower. At the same time, research and development (R&D) costs increase with inflation and with efforts to address regulation towards increased safety concerns. As effective patent times decrease, a minimum price constraint raises for the new entrant. These features occur at different rates across disease areas and are expected to result in differently shaped innovation curves. In this scenario, we demonstrate that a general arbitrary threshold may prevent further efficient R&D. Investment may be withdrawn before the optimum innovation point is reached and affordable clinical effectiveness may be lost. We conclude that disease-specific characteristics are an additional consideration in CE decision rules to accommodate the particularities of innovation across disease areas.

Glycemic control and long-acting insulin analog utilization in patients with type 2 diabetes.

INTRODUCTION: The objective was to compare glycemic control, insulin utilization, and body weight in patients with type 2 diabetes (T2D) initiated on insulin detemir (IDet) or insulin glargine (IGlar) in a real-life setting in the Netherlands. METHODS: Insulin-naïve patients with T2D, starting treatment with IDet or IGlar between January 1, 2004 and June 30, 2008, were selected from the PHARMO data network. Glycemic control (hemoglobin A1c [HbA1c]), target rates (HbA1c <7%), daily insulin dose, and weight gain were analyzed comparing IDet and IGlar for patients with available HbA1c levels both at baseline and at 1-year follow-up. Analysis of all eligible patients (AEP) and a subgroup of patients without treatment changes (WOTC) in the follow-up period were adjusted for patient characteristics, propensity scores, and baseline HbA1c. RESULTS: A total of 127 IDet users and 292 IGlar users were included in the WOTC analyses. The mean HbA1c dropped from 8.4%-8.6% at baseline to 7.4% after 1 year. Patients at HbA1c goal increased from 9% at baseline to 32% for IDet and 11% to 35% for IGlar, which was not significantly different (OR 0.75, 95% CI 0.46, 1.24). Weight gain (n=90) was less among IDet users (+0.4 kg) than among IGlar users (+1.1 kg), albeit not significant. The AEP analysis (252 IDet + 468 IGlar users) showed similar results with 33%-36% at goal (OR 0.81, 95% CI 0.57, 1.16), and median daily insulin doses of 25 IU/day (P=0.70). CONCLUSION: There was no significant difference between users of IDet and IGlar with respect to glycemic control and insulin dose in a real-life setting. The low proportion of patients on target at baseline may indicate that insulin therapy is initiated too late. Moreover, the observation that one-third of the patients reached HbA1c target at follow-up may indicate that basal insulin analogs are not titrated intensively enough.

Large impact of antidiabetic drug treatment and hospitalizations on economic burden of diabetes mellitus in The Netherlands during 2000 to 2004.

OBJECTIVE: To estimate the burden of diabetes mellitus (DM) and its complications in The Netherlands. METHODS: The PHARMO Record Linkage System comprised among others linked drug dispensing, hospital and clinical laboratory data from approximately 2.5 million individuals in The Netherlands. Patients with DM (type 1 and type 2) were included in the study cohort from 2000 to 2004 if they used antidiabetic drugs or had HbA1c >or= 6.5 mmol/L or had a hospitalization for DM or a diabetic complication in the measurement year or in the preceding year. Controls, defined as subjects without a diagnosis of DM and/or subjects not prescribed glucose-lowering medication, were 1:1 matched to patients with diabetes, on birth year, zip code, and gender. Complications (hospitalizations and dispensings for cardiovascular disease/eye problems/amputations) were classified into stages. Complications attributed to DM were estimated as complication stages 1 and 2 among patients minus those among controls. Drug costs were extrapolated to The Netherlands by direct standardization. RESULTS: Among the total population in The Netherlands, the prevalence of DM increased from 2.8% in 2000 to 4.0% in 2004. Severe cardiovascular complications attributed to DM increased from 18,000 to 39,000 patients. Per DM patient the cost of direct treatment attributed to DM increased from Euro 974 in 2000 to Euro 1283 in 2004. Per 100 members of the total population, this increase was from Euro 2764 in 2000 to Euro 5140 in 2004. Most of these costs (65% in 2004) were because of hospitalizations. CONCLUSION: Drug treatment, hospitalizations, and cost attributed to diabetes mellitus have almost doubled between 2000 and 2004, but so did the "background" costs in the general population, perhaps because of preventive efforts.

Extent of uncontrolled disease and associated medical costs in severe asthma--a PHARMO study.

OBJECTIVE: Asthma is a major public health problem with considerable economic impact. The highest costs being observed in patients with severe asthma. Furthermore, despite the use of recommended therapies, asthma control can still be poor. Therefore, the objective of this study was to assess the extent of uncontrolled disease and associated medical costs in severe asthma. METHODS: The PHARMO Record Linkage System includes among others drug dispensing and hospitalizations for > or = 2 million subjects in The Netherlands. Severe asthma patients used long-acting beta-agonists and inhaled corticosteroids for over 200 days and short-acting beta-agonists for at least 100 days in 2004. Severe uncontrolled asthma was defined as a hospitalization for asthma or use of multiple short courses of oral corticosteroids assessed in 2004. Reimbursed costs of asthma drugs and hospitalizations were calculated during this year. A matched nested-case control study was performed to identify treatment-related risk factors for uncontrolled disease. Information on clinical diagnosis of (severity of) asthma was not available. RESULTS: About 17% of patients with severe asthma aged 12-49 years (N = 1158) showed lack of control. Excess drug costs for severe uncontrolled asthma with hospitalization mounted up to 700 Euro per patient per year and 300 Euro per patient per year for patients without hospitalization. Including hospital admission costs, excess costs mounted up to over 10,000 Euro per patient per year. Lack of control did not seem to be caused by under-treatment. CONCLUSION: Poor control of severe asthma leads to disproportionately increased direct costs compared to severe controlled asthma, especially when hospital admission is required.

Large-scale stopping and switching treatment with COX-2 inhibitors after the rofecoxib withdrawal.

PURPOSE: To compare treatment changes after the rofecoxib withdrawal with changes occurring normally and to re-assess 12 months afterwards. METHODS: The PHARMO database comprised medication and hospital discharge records of over 3 million inhabitants in the Netherlands. The Study cohort included chronic coxib users with a coxib prescription on 30th September 2004; the Reference cohort others with a coxib prescription on 1st June 2004. Initial treatment changes were based on first new prescription since cohort entry. Twelve-month changes were studied within the Study cohort only. RESULTS: The Study cohort (n = 6974) and Reference cohort (n = 5393) had similar demographics, stratified on type of coxib. In the Study cohort, 3341 (48%) initially stopped coxibs, of whom 1121 (16%) stopped all analgesic, versus 13 and 5% in the Reference cohort (p < 0.001). Among 'other coxib' users 32% stopped coxibs, and 15% stopped all analgesics, versus 14% and 4%, p < 0.001 in the Reference cohort. Among those who stopped coxibs, 34% switched to non-selective non-steroidal anti-inflammatory drug (nsNSAID) without PPI, 21% to nsNSAID with PPI, and 45% stopped NSAID treatment (Reference cohort: 35, 20, and 44%, respectively). These rates for 'other coxib users' were: switching to nsNSAID without PPI 23% (Study Cohort) versus 35% (Reference Cohort), 13 versus 28%, and 64 versus 37% respectively (p < 0.001). Twelve months later, stopping NSAID increased to 43%, stopping all analgesics to 32%. Rheumatologists continued coxibs more frequently than other caregivers (87, 65, 54%, respectively). CONCLUSIONS: The rofecoxib withdrawal resulted in a large proportion of patients who discontinued analgesic treatment altogether regardless of original coxib therapy.

Quality of life of patients with irritable bowel syndrome is low compared to others with chronic diseases.

BACKGROUND: Irritable bowel syndrome (IBS) is a prevalent functional gastrointestinal dysmotility disorder. This study aimed to estimate the burden of illness of a Dutch population of community dwelling patients suffering from IBS. METHODS: Patients identified at community pharmacies, using mebeverine as a proxy for IBS, were administered a questionnaire regarding (1) the Rome II criteria for IBS, (2) predominant type of stool during complaints, (3) severity of symptoms (abdominal pain and discomfort), (4) generic and disease-specific quality of life, (5) current health status (utilities), and (6) loss of productivity. RESULTS: Three hundred and seventy-five users of mebeverine were identified of which 169 patients met the Rome II criteria for IBS, and were included in the study. More than half (58%) of the IBS patients reported severe abdominal pain and complaints. Generic and disease-specific quality of life outcomes showed impairment on all dimensions. Current health status in IBS patients, calculated on the basis of the EQ-5D VAS, was perceived on 62% of full health (95% CI, 60-66%). A calculation of health status in these patients based on the SF-6D algorithm showed a comparable score of 0.67 (1 is full health; 95% CI, 0.65-0.68). The loss in productivity of IBS patients was 1.8 days (95% CI, 1.1-2.5) per month. CONCLUSIONS: This study confirmed that the burden of illness of IBS in the Netherlands is substantial. IBS patients treated with mebeverine experienced low quality of life and suffered from severe pain. Based on these results, more attention for the diagnosis and treatment of IBS seems to be justified.

Inappropriate initial treatment of secondary intra-abdominal infections leads to increased risk of clinical failure and costs.

AIMS: The objective of this population-based, retrospective cohort study was to investigate the incidence and initial antibiotic treatment of secondary intra-abdominal infections (sIAI) and to assess whether inappropriate initial antibiotic therapy affects patient outcomes. METHODS: All patients hospitalized for sIAI (1995-1998) were identified in the PHARMO Record Linkage System, a patient-centric database including pharmacy dispensing records from community pharmacies linked to hospitalization records in the Netherlands. Complementary in-hospital antibiotic drug use was obtained from the computerized inpatient pharmacy files. The patient outcomes considered were switch to second-line antibiotic treatment, re-operation, and death. In addition, a composite variable clinical failure was constructed based on the above-mentioned outcomes. Furthermore, the effect of clinical failure on length of hospital stay and costs of hospitalization was assessed. Associations between appropriateness of initial antibiotic treatment and outcomes were estimated using multivariate logistic and linear regression models. RESULTS: In the source population of 228,000 persons, 175 cases were classified as sIAI (mean age 49.3 +/- 24.5, 50.9% male) resulting in an incidence of 2.3/10,000 person-years [95% confidence interval (CI) 2.0, 2.7]. Initial antibiotic treatment was appropriate for 84% of the cases. The risk of clinical failure was 17.1%. Inappropriate initial antibiotic treatment increased the risk of clinical failure 3.4-fold (95% CI 1.3, 9.1). Length of hospital stay and costs of hospitalization were significantly increased for patients with clinical failure. CONCLUSIONS: Inappropriate choice of initial antibiotic therapy in sIAI patients leads to more clinical failure resulting in a longer hospital stay and higher costs of hospitalization compared with appropriate initial antibiotic therapy.

Treatment patterns and health care costs of mebeverine-treated IBS patients: a case-control study.

BACKGROUND: Irritable bowel syndrome (IBS) is a functional disorder affecting the quality of life of patients. In the Netherlands, mebeverine is currently the only medical treatment registered for IBS, although its efficacy is considered disputable. OBJECTIVE: To assess treatment patterns and associated health care cost in mebeverine users relative to matched controls. METHODS: A matched case-control study was performed using pharmacy data. Cases were mebeverine users as proxy for IBS patients. Controls were non-mebeverine users and matched to cases by age, gender and pharmacy. Prevalence and incidence of mebeverine use, concomitant drug use and hospitalizations were assessed in 3431 cases and 3431 controls. Concomitant drug use and hospitalizations was also assessed in a subgroup of 1222 users of mebeverine and laxatives (proxy for constipation-IBS) and their controls. RESULTS: Twelve per 1000 residents were ever-dispensed mebeverine in 1998. One-third of these mebeverine users used laxatives concomitantly. Concomitant drug use and hospitalizations were increased in mebeverine users. The odds ratio for hospitalizations for gastrointestinal reasons was increased predominantly in mebeverine users with concomitant laxative use (OR:8.7; 95%CI [4.3-17.3]). Excess yearly costs for all concomitant medications were 94 Euros [95%CI 79 Euros-109 Euros] and for hospital admissions 120 Euros [74 Euros-166 Euros] per mebeverine user. In mebeverine users with concomitant laxative use these costs were 136 Euros and 251 Euros respectively. CONCLUSIONS: In treated IBS patients, concomitant drug use and hospitalizations are increased relative to matched controls. Medical resource use and associated health care costs are particularly increased in mebeverine users using laxatives. The total mean excess cost per patient per year is 482 Euros.

The costs of benzodiazepine-associated hospital-treated fall Injuries in the EU: a Pharmo study.

OBJECTIVE: To estimate the hospitalisation costs of accidental fall injuries in the EU resulting from the use of benzodiazepines. METHODS: Risk and exposure data were obtained from the Dutch Pharmo system, a population-based register of drug-dispensing records and hospital records. The population attributable risk (PAR) was calculated using the age-specific prevalence estimates of benzodiazepine use and the corresponding relative risk (RR), obtained from a case-control study in community-dwelling inhabitants over 55 years of age in defined areas of The Netherlands covering the period 1985-2000. Annual hospitalisation costs of benzodiazepine-related fall injuries were based on the age-specific PARs and extrapolated to the European population using accident and demographic data of the EU. All analyses were performed from the perspective of a third-party payer. RESULTS: Fall injuries in the study population were significantly associated with benzodiazepine use (RR 1.6, 95% CI 1.4-1.7), especially in those aged over 85 years (RR 3.6, 95% CI 2.9-4.5). The total annual hospital direct medical costs in 2000 of fall-related injuries attributable to benzodiazepine use were Euro 1.8 billion (95% CI Euro 1.5-2.2 billion) in the EU. CONCLUSIONS: The estimated costs of hospitalisations of accidental-fall injuries related to benzodiazepine use in the EU varied between Euro 1.5 and Euro 2.2 billion each year. More than 90% of these costs were in the elderly, with hip fractures as the major contributor. Discontinuing benzodiazepines in the elderly and/or substituting them with other drugs not associated with the risk of falls in the elderly will to a large extent prevent these accidents.

Increased risk of achilles tendon rupture with quinolone antibacterial use, especially in elderly patients taking oral corticosteroids.

BACKGROUND: In several case reports, the occurrence of Achilles tendon rupture has been attributed to the use of quinolones, but the epidemiologic evidence for this association is scanty. METHODS: We conducted a population-based case-control study in the General Practice Research Database in the United Kingdom during the period 1988 through 1998. Cases were defined as all persons who had a first-time recording of an Achilles tendon rupture, and who had at least 18 months of valid history before the index date. As a control group, we randomly sampled 50 000 patients with at least 18 months of valid history who were assigned a random date as index date. RESULTS: We identified 1367 cases that met the inclusion criteria. The adjusted odds ratio (OR) for Achilles tendon rupture was 4.3 (95% confidence interval [CI], 2.4-7.8) for current exposure to quinolones, 2.4 (95% CI, 1.5-3.7) for recent exposure, and 1.4 (95% CI, 0.9-2.1) for past exposure. The OR of Achilles tendon rupture was 6.4 (95% CI, 3.0-13.7) in patients aged 60 to 79 years and 20.4 (95% CI, 4.6-90.1) in patients aged 80 years or older. In persons aged 60 years and older, the OR was 28.4 (95% CI, 7.0-115.3) for current exposure to ofloxacin, while the ORs were 3.6 (95% CI, 1.4-9.1) and 14.2 (95% CI, 1.6-128.6) for ciprofloxacin and norfloxacin, respectively. Approximately 2% to 6% of all Achilles tendon ruptures in people older than 60 years can be attributed to quinolones. CONCLUSIONS: Current exposure to quinolones increased the risk of Achilles tendon rupture. The risk is highest among elderly patients who were concomitantly treated with corticosteroids.