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Objective: Since 2014, valproate has not been recommended for use in girls and women of childbearing potential unless other treatments are ineffective or not tolerated. Risk minimization measures (RMMs) of valproate were implemented to reduce the potential risks of developmental disorders among pregnant women. A drug utilization study was carried out to assess the effectiveness of RMMs., Methods: This was a multinational, non-interventional cohort study. For the UK, existing data from the Clinical Practice Research Datalink database were used. The primary study endpoint was a change in the proportion of valproate initiations preceded by other medications relevant for valproate indications before and after implementation of RMMs., Results: The proportion of valproate initiations preceded by medications related to valproate indications increased after RMM implementation in incident female users in the UK from 66.4% to 72.4%. The proportion of incident prescriptions for epilepsy and bipolar disorder with prior medication related to valproate indications increased, from 36.2% to 44.1% and 72.9% to 77.8%, respectively. The incidence rate of valproate-exposed pregnancies decreased from 16.9 to 10.9 per 1000 person-years in the pre- and post-implementation periods, respectively., Conclusions: Results from this study indicated some improvement in physician prescribing and a potential reduction in valproate-exposed pregnancies in the UK. Given only modest improvement has been achieved, additional RMMs were implemented in 2018.

Introduction: Risk minimisation measures for valproate were implemented in Spain in 2015., Objective: The objective of this study is to assess the effectiveness of valproate risk minimisation measures in Spain intended to decrease the use of valproate as a first-line therapy, and to evaluate the prescribing patterns of valproate in women, including women of childbearing potential, in the pre- and post-implementation risk minimisation measures periods., Materials and Methods: The prescribing patterns of valproate in females and women of childbearing potential before and after risk minimisation measures implementation were examined using the longitudinal patient data database, which includes patient information from two panels: primary care physicians and neurologists/psychiatrists. Primary endpoint was the proportion of initial valproate prescriptions with at least one medication related to the valproate indications before the valproate initiation date., Results: The proportion of incident valproate prescriptions with previous use of medication related to valproate indications was 78.0% (95% CI, 73.9%; 81.5%), and 78.2% (74.5%; 81.4%) in the main pre-and post-implementation periods in the primary care physician panel. The corresponding figures for women of childbearing potential were 79.6% (73.6%; 84.5%) and 75.5% (69.7%; 80.6%), respectively. The incidence rate of pregnancies exposed to valproate (per 1,000 person-years) in women of childbearing potential decreased from 17.4 the entire pre-implementation to 8.5 in the entire post-implementation periods., Conclusion: After the implementation of risk minimisation measures for valproate in Spain, no meaningful change in prescribing was observed regarding the proportion of valproate initiations preceded by prior medication related to valproate indications. The preventative measures recommended for use of valproate in women of childbearing potential should be considered.

Objectives: This report characterizes flupirtine prescribing patterns before and after the implementation of risk minimization measures (RMM) in Germany as a complementary analysis to support previous study findings. Methods: A retrospective analysis was conducted using a patient-level longitudinal prescription database (IMS LRx) in Germany. The study population included patients who were prescribed flupirtine-containing products. One-year periods before (2012) and after (April 2015-March 2016) RMM implementation were assessed for the following measures: flupirtine use of up to two weeks, flupirtine use when other analgesics are contraindicated and concomitant use of drugs with a known potential to induce liver injury. Results: The number of flupirtine users decreased by 41.0% from 248,738 patients in the pre-RMM implementation period to 146,764 in the post-implementation period. The proportion of patients prescribed flupirtine for up to 14 days increased significantly by 22.7%, from 67.9% to 90.6% in the pre- to post-implementation periods, respectively. Over half the patients received long-term medications for conditions contraindicated with the use of other analgesics within 12 months prior to the first flupirtine prescription in the pre- and post-implementation periods (57.1% and 52.3%, respectively). Concomitant prescriptions of drugs with known potential hepatotoxic effects were recorded in 36.6% and 34.2% of flupirtine prescriptions during the pre- and post-implementation periods, respectively. Conclusions: While physicians generally restricted flupirtine prescriptions to the short-term treatment duration recommended in the labeling, the other labeling recommendations were not as stringently adopted. Findings of this investigation support a previous study conducted in an electronic medical record database.

Objective: To evaluate azilsartan medoxomil (AZM) (Edarbi ® ) utilization patterns in the primary-care setting in Germany., Materials and Methods: This is a retrospective cohort study among patients receiving AZM in the primary-care setting in Germany. Prescription patterns - including patient demographics, off-label use, use in specific populations, concomitant use of other antihypertensive drugs, and drugs potentially causing interactions with AZM - were analyzed in two periods (01/2012 - 12/2013 and 01/2014 - 11/2016) using the primary-care physician panel of German IMS ® Disease Analyzer, a patient-level electronic medical records database., Results: In total, 852 of 1,159 (74%) and 696 of 811 (86%) patients met the inclusion criteria for both periods, respectively. Approximately 25% of patients were aged ≥ 75 years; 1 patient was < 18 years old; ~ 50% were females. AZM was prescribed for the approved indication of essential hypertension in 83% and 68% of patients in the first and second period, while indication was missing in 12% and 26% of patients, respectively. AZM was coprescribed on the same day with other antihypertensive drugs in 23% (first period) and 37% (second period) of patients. Drugs that might cause an interaction with AZM were coprescribed on the same day in 3% of patients in both periods; overlapping prescription periods were detected in 14% (first period) and 8% (second period) of patients. Coprescription of AZM with angiotensin-converting enzyme (ACE) inhibitors (2%) or aliskiren (< 1%) on the same day was rare in both periods. Overlapping prescription periods with AZM decreased from 20 to 6% for ACE inhibitors and from 8 to 1% for aliskiren., Conclusion: Findings from this real-world evidence study demonstrate that AZM was generally utilized for approved indication and in accordance with the summary of product characteristics recommendations.
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What Is Known and Objective: The approved indication for trimetazidine (TMZ) was restricted to "add-on therapy for the symptomatic treatment of patients with stable angina pectoris who are inadequately controlled by or intolerant to first-line antianginal therapies" in 2012 by the Committee for Medicinal Products for Human Use (CHMP). TMZ was no longer indicated for ophthalmology and otolaryngology (ENT) indications. This drug utilization study analysed actual utilization of TMZ before and after the restriction on its indications to evaluate the effectiveness of risk minimization measures (RMM)., Methods: This was a multi-national, cross-sectional, non-interventional drug utilization study using European databases: IMS Prescribing Insights (PI) for France and Spain, National Diagnostic Index (NDI) for Romania and National Prescription Audit (NPA) for Hungary. TMZ prescriptions issued by Ear-Nose-Throat (ENT) specialists, ophthalmologists, cardiologists and General Physicians (GPs)/others were analysed during the 24-month period before (reference period) and after RMM implementation (assessment period)., Results and Discussion: During the assessment period, most of the TMZ prescriptions for ENT and ophthalmology indications (un-authorized indications) were made by GPs/others followed by ENT specialists, ophthalmologists and cardiologists in most of the countries. The proportion of TMZ prescriptions for ENT or ophthalmological indications after the restrictions on indication was reduced in Hungary (by 0.4%) and Spain (by 11.8%), remained the same in Romania and increased in France (by 3.7%)., What Is New and Conclusion: This study showed that a significant proportion of TMZ prescriptions was off-label for ENT or ophthalmological indications following the RMM implementation. More effective RMM strategies are required to reduce off-label prescriptions of TMZ., (© 2019 John Wiley & Sons Ltd.)

Introduction: Hypersensitivity reactions (HSRs) are among the known adverse events of intravenous (i.v.) iron products. Of these, particularly severe HSRs such as anaphylaxis are of great clinical concern due to their life-threatening potential., Methods: This was a retrospective pharmacoepidemiological study with a case-population design evaluating the number of reported severe HSRs following administration of the two i.v. iron products-ferric carboxymaltose and iron (III) isomaltoside 1000-in relation to exposure in European countries from January 2014 to December 2017. Exposure to both products was estimated using IQVIA MIDAS sales data in European countries. Information on spontaneously reported severe HSRs was obtained from and analysed separately for the two established safety surveillance databases EudraVigilance and VigiBase™ using the MedDRA ® Preferred Terms anaphylactic reaction, anaphylactic shock, anaphylactoid reaction and anaphylactoid shock associated with administration of either product., Results: Between 2014 and 2017, the reporting rate of severe HSRs per 100,000 defined daily doses (100 mg dose equivalents of iron) varied from 0.3 to 0.5 for ferric carboxymaltose and from 2.4 to 5.0 for iron (III) isomaltoside 1000. The reporting rate ratio for iron (III) isomaltoside 1000 versus ferric carboxymaltose was between 5.6 (95% CI 3.5-9.0) and 16.2 (95% CI 9.4-27.8)., Conclusions: Findings suggest that iron (III) isomaltoside 1000 is associated with a higher reporting rate of severe HSRs related to estimated exposure than ferric carboxymaltose in European countries. Future research investigating the occurrence of severe HSRs associated with i.v. ferric carboxymaltose and iron (III) isomaltoside 1000 is needed to broaden the evidence for benefit-risk assessment.

Objective: In response to safety concerns, risk minimization measures (RMM) for flupirtine were implemented in Europe in 2013 to reduce hepatotoxicity risk. This study aims to characterize compliance and prescribing practices of flupirtine before and after RMM implementation. Research design and methods: A retrospective pre-post design cohort study was conducted in the outpatient setting using a longitudinal electronic medical record database in Germany. The study population included patients who initiated flupirtine. One-year pre- and post-implementation periods were assessed. Main outcome measures: Six RMM elements were evaluated, including indication of acute pain, use for maximum of 2 weeks, use when other analgesics are contraindicated, no pre-existing liver disease or alcohol abuse, no concomitant drug induced liver injury, and weekly liver function tests. Results: The number of flupirtine users decreased by 34.4% from 18,291 in the pre-implementation period (2012) to 12,000 in the post-implementation period (April 2015 to March 2016). Elements of RMM with substantial improvement included flupirtine prescription duration, where the proportion of patients with duration ≤14 days increased significantly by 16.5% from 74.8% to 91.3% in the pre- and post-implementation periods, respectively. RMM with a moderate-to-high degree of compliance during the post-implementation period, although with a very small or no change from the pre- implementation period, included restriction of flupirtine prescribing to patients with acute pain when other analgesics are contraindicated, and avoiding use in patients with either pre-existing liver disease or concomitant drugs known to have a potential hepatotoxic effect. Weekly liver function tests had a low degree of compliance. Conclusions: These findings demonstrate that, while physicians restricted flupirtine prescriptions to short-term use in the target population of acute pain, not all drug labeling elements were followed to the same extent in routine practice.

Aim: To assess persistence and adherence to rivaroxaban, dabigatran, and vitamin K antagonist (VKA) treatment in primary care patients with non-valvular atrial fibrillation (AF) newly starting anticoagulant therapy., Methods and Results: Prescription data for oral anticoagulants were obtained from 7265 eligible patients from primary care practices across Germany. Persistence with and adherence to anticoagulation were assessed in anticoagulant-naïve patients with AF newly treated with dabigatran, rivaroxaban, or VKA during follow-up periods of at least 180 days, respectively 360 days after the prescription date. Persistence probabilities after 180 days were 66.0% for rivaroxaban, 60.3% for dabigatran, and 58.1% for VKA (P < 0.001 for rivaroxaban vs. VKA and P = 0.008 for rivaroxaban vs. dabigatran). After 360 days, persistence probabilities were 53.1, 47.3, and 25.5%, respectively (P < 0.001 for rivaroxaban and dabigatran vs. VKA). Considering the development over 360 days rivaroxaban demonstrated a better persistence compared with dabigatran (P = 0.026). Male gender and the presence of diabetes mellitus were associated with increased persistence, while renal impairment and antiplatelet drug use decreased persistence. High adherence (MPR ≥0.80) was observed in 61.4% of rivaroxaban users and in 49.5% of dabigatran users, with means of 0.76 [95% confidence interval (CI) 0.74-0.78] for rivaroxaban and 0.67 (95% CI 0.65-0.69) for dabigatran (P < 0.001)., Conclusions: Rivaroxaban and dabigatran demonstrated better persistence than VKA at Day 360. Furthermore, rivaroxaban was associated with better persistence and adherence than dabigatran. Further studies are needed to identify factors responsible for this difference and evaluate the impact on outcomes., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.)

Introduction: One of the most significant risk factors for the development of ovarian cancer (OC) is a genetic mutation in BRCA1 (breast cancer gene 1) or BRCA2. Here we describe the impact of previous and current guidance on BRCA testing practices and provide evidence about which characteristics best identify patients with OC and an underlying germline BRCA mutation., Methods: A search was conducted for guidelines recommending genetic testing to identify constitutional pathogenic mutations in the BRCA genes. In addition, a systematic literature search of studies published in 2003-2015 was performed to assess BRCA mutation frequency in population-based OC patients unselected for patient characteristics (personal history, family history, and Ashkenazi Jewish ethnicity) and to describe the association of patient characteristics with BRCA mutation. Exclusively, studies assessing epithelial OC or invasive epithelial OC with full-gene screening of both BRCA1 and BRCA2 mutations were evaluated., Results: Of 15 guidelines recommending genetic testing for OC patients, only 5 do not require co-occurrence of specific patient or family characteristics. Twenty-two full publications were identified that assessed germline BRCA mutation frequency in women with OC, utilizing a range of different full mutation detection methods. Germline BRCA mutation prevalence in patients with OC was 5.8-24.8%. Using criteria recommended in guidelines that are yet to be updated, we estimated that 27.5% of all germline BRCA mutations present in patients with OC may be missed because patients do not meet appropriate criteria., Conclusion: With the availability of BRCA mutation-targeted therapies, identification of patients with OC with germline BRCA mutations has potential therapeutic consequences. For identified gene carriers, predictive testing to allow cancer prevention strategies, including bilateral salpingo-oophorectomy, provides wider benefit to identifying such gene carriers. Updating guidelines will increase the opportunity for targeted treatment among patients and risk reduction in relatives., Funding: AstraZeneca.

Background: Disease modifying treatments (DMT) for MS such as interferon beta (IFNβ) have been shown to reduce the risk for disease progression. Therefore adherence to treatment is essential for treatment outcome.Here we want to evaluate if participation in a patient management program (PMP) improves adherence to DMT as well as health and cost outcomes associated with MS., Methods: In this open-label multicentre prospective observational study, German MS patients treated with once weekly intramuscular (IM) IFNβ-1a (Avonex), were offered participation in a PMP and followed for up to 12 months. The PMP included injection trainings, support and quarterly visits for up to 12 months after initiation of therapy. Utilisation of health care services was evaluated. The primary endpoint was to evaluate the direct and indirect cost associated with MS from payer, patient and societal perspective, in patients who participate in the PMP. Secondary endpoint was the clinical outcome in patients who participate in the PMP (differentiated in adherent versus non-adherent patients)., Results: In total 731 patients (mean age: 38.2, 73.7% female) were enrolled, 640 (88%) were observed for twelve months. After six months 34% of patients had participated in the PMP continuously and 21% temporarily; 39% had not participated. After twelve months, the proportions of participants were: 37% continuously and 19% temporarily; 40% had not participated. After 6 months, mean reduction in cost per patient in the participants group (€ 2151) was almost twice as high as the cost reduction amongst non-participants (€ 1131). After twelve months, the annual relapse rate was reduced by 58% compared to baseline in both the participant and non-participant groups., Conclusions: In a real-world-setting, participation in a patient management program was associated with improved medication adherence and lower total MS-related direct and indirect cost over time.

Background: Seasonal influenza is one of the most significant infectious diseases in Germany; epidemic outbreaks occur every winter and cause substantial morbidity and mortality. However, published data from Germany on the current economic burden of influenza and the costs per episode are lacking., Methods: A retrospective database analysis was conducted using a longitudinal electronic medical records database (IMS Disease Analyzer). Patients with influenza, diagnosed by German office-based physicians using ICD-10 J09-11 (International Classification of Diseases, 10(th) revision), who were observable in the database from 12 months before the index (diagnosis) date until 1 month afterwards, were included. The selection window, defined to cover two influenza seasons, was May 2010 to April 2012. Direct and indirect costs were evaluated from payer, patient and societal perspectives. Published unit costs and tariffs from Germany (2012) were used for the analysis., Results: A total of 21,039 influenza-attributable episodes in 17,836 adults, managed by primary care physicians (PCP) and 7,107 episodes in 6,288 children, managed by pediatricians, were eligible for analysis. The mean (±Standard Deviation (SD)) age of the adults with at least one episode was 46 (±18) years and 7 (±4) years in the children. The presence of clinical risk factors was documented for 39% episodes in adults and 24% episodes in children, with the most common being cardiovascular diseases in adults (29%) and chronic respiratory diseases in children (23%). Complications and severe symptoms accompanied the influenza-attributable episode (adults: 37%, children: 54%), bronchitis (adults: 16%, children: 19%) and acute upper respiratory infection (adults: 15%, children: 21%) being the most frequent. From a societal perspective, the total average mean cost (±SD) per episode was €514 (±609) in adults, where work days lost were the main cost driver (82%), and €105 (±224) in children. Complications and severe symptoms increased the cost per episode versus episodes without by 1.7 times in adults (€684 (±713) vs. €413 (±510)) and nearly 3 times in children (€149 (±278) vs. €55 (±116))., Conclusions: Based on a large patient sample derived from representative PCP and pediatricians panels, our results demonstrate that seasonal influenza is associated with substantial clinical and economic burden in Germany.

Objective: To calculate the cost-effectiveness of roflumilast in combination with a long-acting beta agonist (LABA) versus LABA as a monotherapy in patients with severe and very severe COPD in Germany., Methods: The cost-effectiveness of Roflumilast plus LABA vs. LABA as monotherapy was calculated by a long-term model (Markov). The effectiveness data are based on the clinical trials AURA and HERMES (M2-124 and M2-125). Roflumilast plus LABA compared to LABA monotherapy reduced the exacerbation rate by 20.7 % (95 % CI, -31,-9) and improved post-bronchodilator FEV1 by 46 ml (2). These data were used to calculate the mean life expectancy of the COPD cohort (start age: 64 years). Costs for the treatment of exacerbations in the inpatient setting and the outpatient setting were included in the model. Endpoints were incremental costs per avoided exacerbation and per quality adjusted life year (QALY). The input variables were addressed in sensitivity analyses. German data on epidemiology and management of COPD were to populate the model and the cost-effectiveness was analyzed from the perspective of German statutory health insurance (SHI)., Results: The model predicts a mean life expectancy of 8.1 years for patients with roflumilast plus LABA and 7.8 years for patients with LABA alone. This corresponds with a gain of 0.26 life years or 0.23 QALYs. Within this time span patients receiving roflumilast plus LABA experienced 2.43 exacerbations less than the comparator group. The incremental cost for roflumilast plus LABA is €1,852 per exacerbation avoided and €19,457 per QALY gained., Conclusion: The model calculation indicates that the cost-effectiveness of roflumilast as an add-on to LABA in patients with severe and very severe COPD is comparable to the cost-effectiveness of established and reimbursed treatment options in Germany. Analogue consideration of the cost-effectiveness of the treatment options LAMA, LABA and ICS are advisable., (© Georg Thieme Verlag KG Stuttgart · New York.)

Invasive fungal disease (IFD) causes increasing morbidity and mortality in haematological cancer patients. Reliable cost data for treating IFD in German hospitals is not available. Objective of the study was to determine the institutional cost of treating the IFD. Data were obtained by retrospective chart review in German hospitals. Patients had either newly diagnosed or relapsed acute myeloid leukaemia (AML) or myelodysplastic syndrome (MDS). Direct medical cost was calculated from hospital provider's perspective. A total of 108 patients were enrolled at 5 tertiary care hospitals, 36 IFD patients and 72 controls. The vast majority of IFD patients (74%) were diagnosed with invasive aspergillosis. On average, the hospital stay for IFD patients was 12 days longer than in control patients. All patients in the IFD group and 89% of patients in the control group received antifungal drugs. Mean direct costs per patient were €51,517 in the IFD group and €30,454 in the control group. Incremental costs of €21,063 were dominated by cost for antifungal drugs (36%), hospital stay (32%) and blood products (23%). From the perspective of hospitals in Germany the economic burden of IFD in patients with AML or MDS is substantial. Therefore, prevention of IFD is necessary with respect to both clinical and economic reasons., (© 2012 Blackwell Verlag GmbH.)

Objective: This retrospective patient data analysis was initiated to describe current treatment patterns of patients in Germany with arterial hypertension, with a special focus on compliance, persistence, and medication costs of fixed-dose and unfixed combinations of angiotensin receptor blockers (ARBs), amlodipine (AML) and hydrochlorothiazide (HCT) in Germany., Methods: The study analyzed prescription data collected by general practitioners, using the IMS Disease Analyzer database. The database was searched for patients with the diagnosis hypertension (ICD-10 code I10) and treatment data in the period 09/2009 to 08/2010. Compliance was measured indirectly based on the medication possession ratio (MPR), and persistence was defined as the duration of time from initiation to discontinuation of therapy. Medication costs were assessed from the statutory health insurance perspective in Germany., Results: In the IMS DA 406,888 observable patients in Germany were encoded with the diagnosis I10 essential hypertension. In total, 88,716 patients received prescriptions including ARBs, monotherapy (18.6%) or unfixed combinations with other anti-hypertensives (19.3%). The compliance with fixed-dose combinations of ARB with HCT, either dual or with one other anti-hypertensive drug, was significantly better, compared to unfixed combinations (mean compliance 78.1% for fixed-dose vs 71.5% for unfixed combinations of ARB with HCT, p < 0.0001; mean compliance 79.4% vs 72.0%, p < 0.0001 if an additional anti-hypertensive medication was added). Fixed-dose combinations of ARB with HCT, ARB with AML, dual only or prescribed with another anti-hypertensive medication resulted in a substantial increase of persistence, especially for patients on fixed-dose dual combinations (225.7 vs 163.6 days for ARB with HCT; 232.9 vs 178.4 days for ARB with AML, respectively). Fixed-dose combinations (varying from €1.38 to €2.20 per patient and day) were on average cheaper than unfixed combinations., Limitations: Persistence and compliance could be under- or over-estimated because their assessment was based on prescription information. For two thirds of 69,060 patients, data on compliance and persistence was missing., Conclusion: The study shows considerable variations in ARB treatment patterns among patients, with the majority of patients treated with fixed-dose or semi-fixed combination therapy. Fixed-dose combinations of ARBs with HCT and/or AML seem to result in better compliance and persistence compared to unfixed regimes of these drug classes, leading to reduction in all-cause hospitalizations, emphasizing the benefit and potential cost-savings of using fixed-dose regimes in a real-life general practice setting in Germany.

Objectives: To describe changes in costs of managing hospitalised patients with acute myeloid leukaemia (AML) after chemotherapy in Germany over 3 yr, with a special focus on prophylaxis and treatment patterns as well as resource use related to invasive fungal infections (IFI)., Methods: The study was conducted as a retrospective, single-centre chart review in patients with AML hospitalised for chemotherapy, neutropenia and infections after myelosuppressive chemotherapy from January 2004 to December 2006 in Germany. The following resource utilisation data were collected: inpatient stay, mechanical ventilation, parenteral feeding, diagnostics, systemic antifungal medication and cost-intensive concomitant medication. Direct medical costs were calculated from hospital provider perspective., Results: A total of 471 episodes in 212 patients were included in the analysis. Occurrence of IFI decreased from 5.9% in 2004 to 1.9% in 2006. Mean (± standard deviation) hospital stay decreased from 28.7 ± 17.9 d in 2004 to 22.4 ± 11.8 d in 2006. From 2004 to 2006, the use of a single antifungal drug increased from 30.4% to 46.9%, whereas the use of multiple antifungal drugs decreased from 24.4% to 13.1%. The use of liposomal amphotericin B declined between 2004 and 2006 (21.4% vs. 3.8%) and caspofungin between 2005 and 2006 (19.3% vs. 8.1%). Total costs per episode declined from €19051 ± 19024 in 2004 to €13531 ± 9260 in 2006; major reductions were observed in the use of antimycotics and blood products as well as length of hospital stay., Conclusion: Analysis of real-life data from one single centre in Germany demonstrated a change in antifungal management of patients with AML between 2004/2005 and 2006, accompanied by a decline in total costs., (© 2011 John Wiley & Sons A/S.)

Background: Rational healthcare decision-making based on clinical and economic evidence is essential to provide the best possible care for patients with atopic dermatitis (AD)., Objective: To evaluate treatment outcomes, resource use and cost associated with twice-weekly tacrolimus 0.03% ointment treatment vs. standard flare-only therapy in children with moderate-to-severe AD., Methods: In a pan-European, Phase III multicentre randomized clinical trial, children with mild-to-severe AD were randomized to 0.03% tacrolimus ointment or vehicle twice weekly for 12 months. Disease flares were treated using open-label tacrolimus 0.03% ointment twice daily. Clinical efficacy data were evaluated in a subgroup of 153 children with moderate-to-severe AD, with resource use data--collected prospectively using caregiver questionnaires--available from 146 children. Pooled costs of resource use were determined using German unit cost data. Direct and indirect costs were considered from third-party payer, patient and caregiver, and societal perspectives., Results: Twice-weekly tacrolimus ointment reduced the number of flares compared with standard therapy (P < 0.001) and prolonged time to first flare (146 vs. 17 days, P < 0.001). Mean +/- SD annual costs per patient for standard and twice-weekly therapy respectively were 2002 euro +/- 2315 vs. 1571 euro+/- 1122 for severe AD and 1136 euro +/- 1494 vs. 1233 euro +/- 1507 for moderate AD., Conclusions: In children with AD, twice-weekly treatment with tacrolimus 0.03% ointment reduces the number of flares and prolongs time spent free from flares with no additional cost in children with moderate AD, and may be cost-saving in those with severe AD.

Purpose: To evaluate treatment outcomes and resource consumption of patients with neurogenic detrusor overactivity (NDO) before and after botulinum toxin A (Botox) therapy in Germany., Methods: In a multi-center, cross-sectional, retrospective cohort study, data of patients with NDO 12 months before and after the first Botox therapy were analyzed., Results: 214 patients (mean age 38 +/- 14.8 years, 145 male, 69 female) with NDO due to spinal cord injury (81%); myelomeningocele (14%), or Multiple Sclerosis (5%) from seven hospitals were included. Mean interval between treatments was 8 months. Following treatment, mean maximum detrusor pressure, maximum cystometric capacity and detrusor compliance improved significantly. Prior to Botox therapy, 68% reported urinary tract infections (UTI), 63% had incontinence episodes, and 58% used incontinence aids. These numbers decreased significantly (p < 0.05) after treatment to 28, 33, and 28%, respectively. In patients using incontinence aids, mean costs per patient decreased from 2euro to 1euro per day, whereas the mean cost of drugs to treat UTIs per patient decreased from 163euro to 80euro per year, respectively., Conclusion: This is the first study demonstrating the clinical usefulness of Botox therapy in clinical practice. Successful treatment resulted in lower costs for NDO associated morbidity due to less need for incontinence aids and UTI medication.

This study aimed to describe health care provision, resource consumption and related costs, as well as treatment patterns and quality of life in adult patients with pulmonary arterial hypertension (PAH) in Germany. Data for this retrospective and prospective cost-of-illness-study were derived from hospitals, general practitioners and patients. Costs were evaluated from the perspective of third party payer and patient. Quality of life data were collected by using three validated instruments. A total of 167 patients were enrolled at 10 hospitals. Time period from first occurrence of symptoms to confirmed diagnosis of PAH was 2.3 years on average. Mean number of GP visits was 1.5 per patient per month, and within 15 months, inpatient stays were reported for 50% of patients. The ratio of combination therapy to single-drug therapy for endothelin receptor antagonists, phosphodiesterase-5-inhibitor and prostacyclin analogues increased significantly during 15 months. Treatment costs were, on average, euro47,400 per patient per year, arising mainly from drugs. Compared to the general population, quality of life of PAH patients was considerably impaired. This is the first study which evaluated aspects of the medical and economic consequences of PAH based on a large cohort of PAH patients in Germany., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Background: Rational health care decision-making based on outcomes and economic evidence is essential to provide the best possible care for individual patients with atopic dermatitis (AD)., Objectives: To describe treatment outcomes and to evaluate resource utilization and associated cost of maintenance use of tacrolimus ointment (MU) vs. standard use of tacrolimus ointment (SU) in adults with AD., Methods: A pan-European, phase III multicentre randomized clinical trial was conducted. Patients with mild to severe AD were randomized to tacrolimus 0.1% ointment (MU) or vehicle (SU) twice per week for 12 months. Disease exacerbations were treated by using open-label tacrolimus 0.1% ointment twice daily. Resource utilization data were collected prospectively alongside the clinical trial. Costs of pooled resource data were determined using German unit cost data. Direct and indirect costs were considered from third party payer, patient and societal perspectives., Results: All patients with moderate and severe AD were included in a subanalysis, 75 patients in the MU arm (57% moderately affected) and 59 patients in the SU arm (59% moderately affected). In patients with moderate AD, the number of disease exacerbations in the MU arm was 2.4 vs. 5.5 in the SU arm (P<0.001); in patients with severe AD corresponding figures were 2.3 vs. 7.4 (P<0.001), respectively. Mean+/-SD total annual cost per patient was euro1525+/-1081 (MU) vs. euro1729+/-1209 (SU) in patients with moderate AD and euro2045+/-2013 (MU) vs. euro2904+/-1510 (SU) in patients with severe AD., Conclusions: Maintenance treatment with 0.1% tacrolimus ointment is more effective and leads to cost savings and improved health-related quality of life in comparison with standard use of 0.1% tacrolimus ointment, especially in patients with severe AD.

Patients with acute coronary syndrome without ST-segment elevation receiving clopidogrel in addition to acetylsalicylic acid (ASA) showed a 20% risk reduction in comparison to patients receiving ASA monotherapy (CURE trial). Economic models for assessing the impact on costs exist for several countries but not for Germany on a long-term basis. The objective of this model adaptation is to assess the long-term economic impact of clopidogrel taken in addition to ASA in Germany. A Markov model with six states [at risk, first year with stroke, following years with stroke, first year with new myocardial infarction (MI), following years with MI, and death] was adapted for Germany. Model outcome was life-years saved. Effects of 1-year treatment were calculated based on the CURE trial. Resource use for the different health states was based on published data, which included costs for drugs, outpatient care, hospitalization, rehabilitation and nursing. Risk data for MI and stroke were based on Swedish data and validated for the German adaptation. The model calculates lifetime costs and survival length. Costs were estimated from the payers' perspective. A series of one-way sensitivity analyses was conducted (follow-up costs, discount rates). The Markov analysis predicts a survival of 8.89years in the placebo treatment group and 9.02 years in the clopidogrel treatment group. The cumulated costs were euro 8,548 and euro 8,953, respectively. The incremental cost-effectiveness ratio (ICER) was euro 3,113 for each life-year saved. The model was robust regarding variations in key parameters in the sensitivity analysis, resulting in a range of ICER from euro 1,338 to euro 9,322. Our results are in line with the results for other healthcare systems. Adding clopidogrel to ASA for patients with acute coronary syndrome without ST-segment elevation generated an additional life-year saved at a comparably low value of euro 3,113. One-year treatment with clopidogrel is a cost-effective treatment option in patients with acute coronary syndrome from the perspective of a third-party payer in Germany.

Background: Chemotherapy-induced nausea and vomiting (CINV) remains a major adverse effect of cancer therapy. We aimed to determine outcomes associated with use of aprepitant in outpatients undergoing highly emetogenic chemotherapy in Germany from a patient's and payer's perspective., Methods: A decision-analytic model compared an aprepitant regimen (aprepitant/ondansetron/dexamethasone) to a control regimen (ondansetron/dexamethasone) over a five days period. Clinical results and resource utilisation observed in aprepitant phase III clinical trials were assigned German unit cost data., Results: Complete response over one chemotherapy cycle was observed in 68% of patients in the aprepitant group (N=514) compared to 48% of patients in the control group (N=518). Patients were estimated to have gained an equivalent of 15 additional hours of perfect health per cycle (0.63 quality-adjusted life days) with aprepitant-based regimen compared to control regimen. Cost per quality-adjusted life year gained with aprepitant was estimated at euro28,891., Conclusions: Aprepitant substantially improved CINV-related health outcomes in patients undergoing highly emetogenic chemotherapy. Incremental benefits materialised in a cost-effective fashion.

A longitudinal study of health care-associated transmission of rotaviruses (RVs) in pediatric inpatients 0-48 months old in Austria, Germany, and Switzerland showed that almost one third of all cases occurred in patients 2 months old or younger. The effectiveness of vaccination against RV from 2 months of age onward remains to be evaluated.

Background: Atopic eczema is one of the most common skin diseases. In Germany, the economic burden is estimated to be EUR 1.2-3.5 billion yearly. The aim of this study was to show the resource utilization and costs for outpatient care and the out-of-pocket expenses for the patients., Patients and Methods: This study was a multi-center, retrospective and prospective cost-of-illness study. Patient characteristics and data on resource utilization were collected with a semi-structured patient questionnaire and by chart abstraction. 193 patients filled in the patient questionnaire; data from 169 patients were obtained by chart abstraction., Results: Average direct medical costs of a disease flare were EUR 123 per patient. Average annual total costs were EUR 1,425 per patient, increasing with severity from EUR 956 (mild) to EUR 2,068 (severe)., Conclusion: Prolongation of flare-free time and reduction in severity are not only desirable for the patients but also of economic interest.

Data on the economic burden of lower respiratory tract infections (LRTI) in young children are lacking in Germany. The objective of the cost-of-illness study was to estimate the economic impact of community-acquired LRTI and nosocomial LRTI as well as of infections due to respiratory syncytial virus (RSV), parainfluenza viruses (PIV) and influenza viruses (IV). The economic analysis is part of the PRIDE study, a prospective, multi-centre, population-based epidemiological study on the impact of LRTI in children aged 0 to 36 months in Germany. The analysis includes children with community-acquired infections (1329 cases treated as outpatients, 2039 cases treated as inpatients) and nosocomial infections (90 cases). Medical services consumed were generated by chart abstraction and parental expenses data by telephone interviews within four weeks after physician visit or hospitalisation. Costs were evaluated from following perspectives: third party payer, parent and society. Total costs for outpatient treatment are Euro 123 per LRTI case. Stratified by virus type, total costs per case are Euro 163 (RSV), Euro 100 (PIV) and Euro 223 (IV). Total costs per hospitalised LRTI case amount to Euro 2579. Stratified by virus type, total costs per case are Euro 2772 (RSV), Euro 2374 (PIV) and Euro 2597 (IV). Total costs per nosocomial case are Euro 2814. Economic burden due to LRTI is Euro 213 million annually. It is concluded that treatment of LRTI in children up to age three causes a considerable economic burden in Germany. Presented results are the first data describing the economic burden of LRTI in young children assessed by means of the incidence data for Germany. This cost-of-illness study provides basic data for further decision-making, focusing on the economic assessment of preventive strategies for RSV, PIV and IV infections.

Background: Data regarding costs of outpatient and office-based care, as well as out-of-pocket expenses, for psoriasis patients in Germany are not available. Aim of this study was to assess average annual cost and cost per flare of outpatient and office-based care for patients with moderate to severe chronic psoriasis vulgaris from several perspectives., Methods: In this multi-center, cross-sectional, retrospective and prospective cost-of-illness study, direct (medical and non-medical) and indirect costs were considered from patient, third-party payer (TPP) and societal perspectives., Results: Out of 227 patients enrolled consecutively in 17 centers, 192 cases could be analyzed. On average, TPP reimbursed 864 per patient annually, 60 % for prescribed medication and 22 % for hospitalization. Patients spent 596 yearly mainly for alternative therapies and OTC-medication/skin care products as well as for additional expenses (e. g. ultraviolet lamp, clothes or cleaning agents). Indirect costs per patient amounted to 1,440 yearly. Total annual costs per patient were 2,866 and 4,985 if treated with systemic drugs additionally. 1,173 if treated topically and/or with phototherapy., Conclusions: The relatively high average annual costs per patient indicate need for efficient control of psoriasis. This cost-of-illness study provides basic data for further decision making, including economic assessment of innovative therapies for psoriasis.

To evaluate current treatment patterns and resource utilization as well as related cost in the management of severe haemophilia patients with inhibitors in Germany, a cost-of-illness study was conducted. Generally, data were generated by structured literature search. Missing data were collected by expert interviews. All data were validated by a panel of German experts in haemophilia care. In Germany, immune tolerance therapy (ITT) is first-line therapy in inhibitor management for children in the initial year after inhibitor development, particularly for high responders (HR). In adult HR patients ITT is applied but to a remarkably lower extent than in children. To treat bleeding episodes, factor VIII (FVIII) is first-line therapy in low responders (LR). For paediatric HR patients, bleeds are mainly treated with recombinant FVIIa (rFVIIa). In adult HR patients, activated prothrombin complex concentrate (aPCC) and rFVIIa are more equally distributed as treatment options. Treatment costs were calculated for paediatric patients (15 kg) and adult patients (75 kg) from third party payers' perspective. Cost for ITT ranges from Euro 70,290 (2 months; LR) to Euro 3 812,400 (24 months; with aPCC; HR) in a paediatric patient. For an adult patient ITT cost ranges from Euro 287,500 (6 months; LR) to Euro 17,253,000 (36 months; HR). For on average 12.5 acute bleeds, average annual treatment costs amount to Euro 77,000 for a child and Euro 354,000 for an adult. Assessing the results it has been taken into consideration that ITT can last longer and annual number of bleeds can be extremely higher than on average 12.5 episodes. This indicates more health care resource consumption in some patients.

Background: Delayed chemotherapy-induced nausea and vomiting (CINV) remains a major adverse effect of cancer chemotherapy. We assessed, under current practice patterns, the occurrence and impact on healthcare resource utilization of CINV in patients receiving emetogenic chemotherapy. An additional aim of this study was to estimate costs imputable to CINV in the German healthcare environment., Materials and Methods: This prospective, multi-center, cross-sectional cost-of-illness study was conducted in three hospitals and in three office-based facilities in Germany. Consecutive patients undergoing emetogenic chemotherapy (levels 4 or 5 according to Hesketh classification of emetogenicity) were enrolled. Data were obtained from preplanned chart reviews and from self-administered patient questionnaires. Analysis of direct costs was performed from the perspectives of third party payer (statutory sick fund), provider (hospital) and patients. Indirect costs were assessed on the basis of paid workdays lost., Results: During the 5-day observation period, 134 of 208 chemotherapy cycles observed (64.4%) were associated with at least one episode of nausea or vomiting. More patients experienced delayed than acute CINV (60.7% versus 32.8%), and more patients reported nausea than vomiting (62.5% versus 26.0%). A total of 68 patients (32.6%) utilized healthcare resources due to CINV. The most frequently used resources were rescue medications and outpatient hospital and office physician visits. Only one patient required hospitalization and only three patients lost workdays due to CINV. Average costs imputable to CINV per patient (with or without CINV) per treatment cycle incurred by third party payers and hospital providers were Euro 49 and Euro 48, respectively. Patient or treatment characteristics that were associated with high costs imputable to CINV were as follows: cisplatin-containing regimen; experience of emesis; and presence of delayed CINV., Conclusions: A substantial proportion of patients continue to experience CINV. This entails not only clinical but also economic consequences, and highlights a continuing need for improved utilization of existing antiemetic agents and for new, more efficacious treatments. The greatest improvements in patient care and potential for cost offset may be realized by preventing delayed CINV.

The purpose of this study was to evaluate the cost of illness of moderate-to-severe atopic asthma and/or seasonal allergic rhinitis (SAR) in Germany from the perspective of third-party payers (TPP) and patients. Five-hundred patients (276 children/adolescents) with moderate-to-severe asthma and/or SAR were included in this cross-sectional study. Information was collected using a specific patient questionnaire and the abstraction of patient records. Overall, annual costs per patient increased with the severity of atopic asthma and if it was associated with SAR. The average annual cost of SAR was Euro1,089 per child/adolescent and Euro1,543 per adult. Annual costs of severe asthma plus SAR increased to Euro7,928 per child/adolescent and to Euro9,287 per adult. For TPPs, the main cost drivers were medication, hospitalisation, and rehabilitation. The most significant costs for patients were household modifications. For children/adolescents, 60-78% of the expenditures were direct costs, while in adults, 58% of expenditures were indirect costs. It was also observed that patients with moderate and severe asthma used inhaled corticosteroids less frequently than recommended by treatment guidelines. In summary, the total cost for patients increases with the severity of atopic asthma and/or seasonal allergic rhinitis and indirect costs represent a large proportion of the total cost.

Unlabelled: The aim of this study was to collect representative data on the incidence and clinical characteristics of community-acquired acute gastroenteritis (AGE) due to rotavirus (RV) in German children up to 4 y of age. In 20 paediatric practices in 5 German regions every child aged 0-4 y presenting with symptoms of AGE from May 1997 to April 1998 was eligible for inclusion into the study. Stool samples were tested for RV antigen by enzyme-linked immunosorbent assay and polymerase chain reaction was performed for serotyping. The course of the disease, additional diagnoses and treatment regimen were recorded. Incidences adjusted for month and region of observation were calculated by Poisson regression. Of 15,451 children under observation 3980 (26%) presented with AGE. Of 3156 stool samples available 748 (24%) proved RV positive. The incidence of AGE and RV-positive AGE was 25.2 and 4.0 per 100 children per year, respectively, with a maximum in February/March 1998. RV-positive cases were more severe than RV-negative cases (28% vs 12% severe cases, hospitalization rate 6.2% vs 2.0%, p < 0.001). The predominant genotype of RV isolated was G1/P[8] (77%), followed by G4/P[8] (17%)., Conclusion: Rotavirus accounts for a substantial part of severe cases of AGE in children up to 4 y of age. Efficient prevention, including immunization against the circulating serotypes, could save at least 122,000 children in Germany from falling ill with RV-AGE each year.

Background: The great impact of rotavirus disease on morbidity and medical health care costs in industrialized countries together with the withdrawal of the live oral rotavirus vaccine have made a reassessment of rotavirus gastroenteritis necessary. Such a reassessment should provide sufficient data for developing alternative disease prevention strategies and for allocating resources efficiently., Objectives: To compare characteristics and management of community- and nosocomially acquired rotavirus disease in Austria, Germany and Switzerland., Patients and Methods: In a prospective, population-based, trinational (Austria, Germany, Switzerland), multicenter (9 cities, 10 hospitals and 30 pediatric practices) study, a total of 174 552 children months and 78 516 hospital days were evaluated. Participants were all children 4 years of age and younger, who either presented at one of the pediatric practices with community-acquired gastroenteritis, or who had acquired gastroenteritis nosocomially. From December, 1997, to May, 1998, prospective antigen testing was done by enzyme-linked immunosorbent assay, and serotyping was done by reverse transcription polymerase chain reaction. Disease severity was scored by the Vesikari severity scale., Results: Rotavirus was detected in 29.5, 27 and 37.5% of children with community-acquired gastroenteritis and in 57, 69 and 49% of children with nosocomial gastroenteritis in Austria, Germany and Switzerland, respectively. Severity of community-acquired rotavirus gastroenteritis was more pronounced in Austria (median severity score, 11) than in Germany (median score, 9) or Switzerland (median score, 10). However, only 2% of Austrian and Swiss children compared with 12% of German children presented to their pediatricians more than four times. Nosocomially acquired rotavirus gastroenteritis was mildest in Austria but occurred within the shortest median duration of hospitalization (4 days vs. 5 and 7 in Germany and Switzerland, respectively). In a multivariant analysis age, family size, day care, breast-feeding and nationality were not predictive factors for enhanced risk to contract rotavirus infection. Alimentation was changed frequently; diet was used between 23 and 83%; special formulas were used between 10 and 57%., Conclusion: The cumulative experience from three European countries suggest that rotavirus is an important cause of diarrhea in Central Europe, but significant local differences clearly demonstrate the need for obtaining national data as a reliable basis for control and prevention of the disease.

Objective: To determine the average costs per child for rotavirus (RV) acute gastroenteritis from different perspectives, from the hospital's, third-party payer's, pediatrician's and family's perspectives as well as in summary from the societal one., Materials and Methods: This cost-of-illness study is based on data collected alongside a 6-month prospective, laboratory-confirmed epidemiologic study that evaluated the disease burden of RV infection in Austrian children < or =48 months of age. The study population at risk to contract a community- and nosocomially acquired acute gastroenteritis comprised 9,687 children. All of the 51 children with community-acquired and 33 with nosocomially acquired RV acute gastroenteritis were included in this analysis. The annual costs were estimated by means of extrapolation., Results: For community-acquired RV acute gastroenteritis, the average costs from the hospital's perspective were EURO (EUR) 97.8, from the third party payer's perspective 95.6 EUR, followed by 29.9 EUR and 9.8 EUR from the family's and pediatrician's perspectives, respectively. For nosocomially acquired RV acute gastroenteritis the average costs from the hospital's perspective were 1,494 EUR and from the third party payer's and family's perspectives 831 EUR and 116.8 EUR, respectively. In summary the average costs from the societal point of view for community-acquired RV acute gastroenteritis were 250 EUR and for nosocomial infections 2,442 EUR. After extrapolation the estimated total annual costs were 7.17 EUR million to 0.97 EUR million (13.6%) caused by community-acquired RV acute gastroenteritis and 6.2 EUR million (86.4%) caused by nosocomial RV acute gastroenteritis., Conclusion: This cost-of-illness study clearly demonstrates the great impact of RV acute gastroenteritis, mainly of nosocomially acquired infection, on medical health care costs in Austria. To cut costs efforts in disease prevention should be encouraged.

Background: In Europe information is scarce about the impact of rotavirus, probably the most important cause of acute gastroenteritis in children up to the age of 4 years. The aim of this study was to collect data on the frequency and symptoms of community-acquired rotavirus-positive acute gastroenteritis in Switzerland., Patients and Methods: In 6 paediatric practices, 3 each in the Geneva and Basle areas, every child up to the age of 48 months presenting with acute gastroenteritis between December 1997 and May 1998 was eligible for inclusion in the study. The symptoms, course of the disease and treatment were recorded in a standardized fashion after informed consent had been obtained. Stool specimens were screened for rotavirus by ELISA, and PCR was performed for serotyping in ELISA-positive samples., Results: 294 of 6672 children under observation were taken to their paediatrician because of acute gastroenteritis during the study period. Informed consent was obtained in 256 cases (mean age 19.2 months). 234 stool specimens were available of which 96 (41%) were rotavirus-positive. The incidence of rotavirus-positive acute gastroenteritis was 1.6 per 100 children and winter season. Acute gastroenteritis due to rotavirus was more severe than rotavirus-negative acute gastroenteritis, with diarrhoea and vomiting in 84% versus 54%, and dehydration in 42% versus 28%, 5% of the acute gastroenteritis cases compared to 11% of the rotavirus-positive cases were hospitalized. In the Geneva and Basle areas the predominant rotavirus types, as identified by PCR in ELISA-positive stool specimens, were G4 P[8] and G1 P[8] respectively (67% each)., Conclusion: Rotavirus infection was a relevant cause of acute gastroenteritis in our study population, resulting in more severe symptoms than rotavirus-negative acute gastroenteritis. All G-types identified in our study are included in the recently developed tetravalent vaccine. Cost-benefit analysis and ethical issues will need to be considered in evaluating the impact of the vaccine in Switzerland.