Tiotropium Respimat(®) vs. HandiHaler(®): real-life usage and TIOSPIR trial generalizability.

AIM: Two inhaler devices (Respimat® and HandiHaler®) are available for tiotropium, a long acting anticholinergic agent. We aimed to analyze drug utilization, off-label usage and generalizability of the TIOSPIR trial results for both devices. METHODS: Patients aged ≥18 years exhibiting at least one documented prescription of tiotropium in the database of the Association of Statutory Health Insurance Physicians, Bavaria, Germany, were included (years 2004-2008). Annual period prevalence rates (PPRs) were calculated stratified by age, gender and inhaler devices. Off-label usage (patients lacking a chronic obstructive pulmonary disease (COPD) diagnosis) and the proportion of patients meeting the inclusion and exclusion criteria of the TIOSPIR trial were analyzed. RESULTS: Between 2004 and 2008, PPRs increased and varied between 49.2 and 74.5 per 10 000 persons for HandiHaler® and between 1.5 and 9.3 per 10 000 persons for Respimat®. Small differences regarding patient characteristics existed between the two inhaler devices. Only about 30% (HandiHaler® 32.1%, Respimat® 30.0%) of the database patients receiving tiotropium could be theoretically included in the TIOSPIR trial. CONCLUSIONS: Comparing the two tiotropium devices, no clinically relevant differences regarding patient and prescribing characteristics were revealed. Results of the TIOSPIR trial were generalizable only to a minority of our study patients, underlining the need for real-life data.

Antiepileptic drugs and suicide: a systematic review of adverse effects.

BACKGROUND: Since the FDA (Food and Drug Administration) report on antiepileptic drugs (AEDs) and suicide risk was released (2008), several studies have been published on this controversial relationship. This systematic review (SR) gives an updated approach to this health issue. SUMMARY: We searched 6 databases. We ultimately included 11 publications: 4 cohort studies, 1 case-crossover study, 2 community case-control studies, and 4 SRs. Overall, 1 SR described studies already included; 3 studies reported a 2- to 4-fold overall increase in risk; 1 study reported an increased risk of suicide among epilepsy patients on AEDs with high risk of depression; 1study showed a protective effect among epilepsy patients; 2 studies were conducted with patients with bipolar disorder (1 showed a protective effect, whereas the other showed a 3-fold increase in risk of suicide), and the other 3 studies reported results for single AEDs. Several biases affected the published results. KEY MESSAGES: There is no clear evidence of an association between the use of AEDs and an increased risk of suicide because of the heterogeneity in the studies at the clinical and methodological level. A future study should cover all indications for use, retrieve information from a healthcare database, and include a defined set of covariates to avoid bias.

Anti-fibrinolytic agents in post partum haemorrhage: a systematic review.

BACKGROUND: Post partum haemorrhage is a leading cause of maternal death worldwide. It also contributes to maternal morbidity as women may require a hysterectomy to control bleeding, or may require a blood transfusion, which can transmit viral infections. Anti-fibrinolytic agents have been proposed as a treatment for post partum haemorrhage. We conducted a systematic review to assess the effectiveness and safety of anti-fibrinolytic agents in post partum bleeding. METHODS: All randomised controlled trials of anti-fibrinolytic agents given for bleeding during the postpartum period were included in this review. We searched Medline, PubMed, EMBASE, Cochrane Central Register of Controlled trials, Web of Science, metaRegister of controlled trials, LILACS, Reproductive Health Library, African healthline, POPLINE, MedCarib, CINAHL, Clinicaltrials.gov and the reference lists of eligible trials. Two authors extracted data. Methodological quality was assessed by evaluating allocation concealment. The primary outcome was maternal mortality. Secondary outcomes were blood loss, blood transfusion, hysterectomy, mean haemoglobin concentration, thrombo-embolic events and other adverse effects. RESULTS: We identified three randomised controlled trials involving 461 participants. The trials compared tranexamic acid with no treatment and reported blood loss after delivery. In all three trials, allocation concealment was either inadequate or unclear. The administration of tranexamic acid was associated with a reduction in blood loss of 92 millilitres (95%CI 76 to 109). The most frequently reported adverse effect of tranexamic acid was nausea, although the increase was easily compatible with the play of chance (RR 4.63, 95%CI 0.23 to 95.14). CONCLUSION: Tranexamic acid may reduce blood loss in post partum haemorrhage. However, the quality of the currently available evidence is poor. Adequately powered, high quality randomised controlled trials are needed.

A new risk of bias checklist applicable to randomized trials, observational studies, and systematic reviews was developed and validated to be used for systematic reviews focusing on drug adverse events.

OBJECTIVES: The objective of the study was to develop and validate an adequate tool to evaluate the risk of bias of randomized controlled trials, observational studies, and systematic reviews assessing drug adverse events. STUDY DESIGN AND SETTING: We developed a structured risk of bias checklist applicable to randomized trials, cohort, case-control and nested case-control studies, and systematic reviews focusing on drug safety. Face and content validity was judged by three experienced reviewers. Interrater and intrarater reliability were determined using 20 randomly selected studies, assessed by three other independent reviewers including one performing a 3-week retest. RESULTS: The developed checklist examines eight domains: study design and objectives, selection bias, attrition, adverse events information bias, other information bias, statistical methods to control confounding, other statistical methods, and conflicts of interest. The total number of questions varied from 10 to 32 depending on the study design. Interrater and intrarater agreements were fair with Kendall's W of 0.70 and 0.74, respectively. Median time to complete the checklist was 8.5 minutes. CONCLUSION: The developed checklist showed face and content validity and acceptable reliability to assess the risk of bias for studies analyzing drug adverse events. Hence, it might be considered as a novel useful tool for systematic reviews and meta-analyses focusing on drug safety.

Systematic Review and Meta-Analysis: Macrolides- and Amoxicillin/Clavulanate-induced Acute Liver Injury.

Antibacterials are frequently associated with idiosyncratic drug-induced liver injury (DILI). The objective of this study was to estimate the risk of macrolides and amoxicillin/clavulanate (AMC) on DILI. We conducted a systematic review (SR) and meta-analysis (MA) with studies retrieved from PubMed, Cochrane Library Plus, Web of Knowledge, clinicaltrials.gov, Livertox and Toxline (1980-2014). We searched for macrolides, AMC and MeSH and synonym terms for DILI. We included all study designs except case reports/series, all population ages and studies with a placebo/non-user comparator. We summarized the evidence with a random-effects MA. Quality of the studies was appraised with a checklist developed for SR of adverse effects. Heterogeneity and publication bias were assessed with different exploratory tools. We finally included 10 (two randomized clinical trials, six case-control, one cohort and one case-population studies) and 9 (case-population excluded) articles in the SR and MA, respectively. The overall summary relative risk of DILI for macrolides was 2.85 [95% confidence interval (CI) 1.81-4.47], p < 0.0001, I(2) = 57%. Three studies were perceived to be missing in the area of low statistical significance. Year of study and selected exposure window partly explained the variability between studies. For AMC, the risk of DILI was 9.38 (95% CI 0.65-135.41) p = 0.3, I2 = 95%. In conclusion, although spontaneous reports and case series have long established an association between macrolides and AMC with acute liver injury, these SR and MA have assessed the magnitude of this association. The low incidence of DILI and the therapeutic place of these antibiotics might tilt the balance in favour of their benefits.

Sales of macrolides, lincosamides, streptogramins, and amoxicillin/clavulanate in the in- and outpatient setting in 10 European countries, 2007-2010.

Monitoring the use of antibiotics is relevant due to the public health impact of microbial resistance, adverse effects, and costs. We present data on the consumption of macrolides, lincosamides, streptogramins and amoxicillin/clavulanate (AMC) between 2007 and 2010 in the in-and outpatient healthcare setting in 10 European countries provided by IMS Health. Antibiotics were classified according to the anatomical therapeutic chemical classification and consumption was expressed in defined daily doses/1000 inhabitants/day (DIDs). We analysed the number of prescriptions by diagnostic codes between 2008 and 2010, based on the International Classification of Diseases, 10th revision (ICD-10). These ICD-10 codes were grouped into four main categories: respiratory infections, genitourinary infections, other infections and other diagnoses. In 2010, the consumption of macrolides and lincosamides ranged from 0.45 DIDs (Sweden) to 5.46 DIDs (Italy), and from 0.04 DIDs (Denmark) to 1.00 DID (Germany), respectively. Streptogramins were available in France, Germany, Italy, Norway, Spain and United Kingdom with a consumption of <0.001 DID exclusively in the hospital setting. The consumption of AMC ranged from <0.001 DIDs (Norway) to 11.67 DIDs (Spain). During the study period, the consumption of macrolides decreased, the consumption of AMC increased in most of European countries, and lincosamides varied very slightly. Macrolides and AMC were mainly prescribed for respiratory infections in all countries but United Kingdom, where most of the prescriptions were assigned to diagnostic codes not clearly related with an infection. Lincosamides were prescribed for the respiratory infections and other infections groups. There was a wide inter-country variability in the percentage of the prescriptions assigned to each of the diagnostic categories. The inter-country differences in the consumption of these antibiotics and their prescription by diagnostic categories point to an inappropriate use of antibiotics.

Inpatient drug utilization in Europe: nationwide data sources and a review of publications on a selected group of medicines (PROTECT project).

Drug utilization (DU) studies in inpatient settings at a national level are rarely conducted. The main objective of this study was to review the general information on hospital medicine management in Europe and to report on the availability and characteristics of nationwide administrative drug consumption databases. A secondary objective was to perform a review of published studies on hospital DU of a group of selected drugs, focusing on methodological characteristics (ATC/DDD). General information on hospital drug management was retrieved from several websites, nationwide administrative drug consumption databases and reports published by governmental organizations. A PubMed search was conducted using keywords related to the selected group of drugs AND 'hospital drug utilization'. The data sources for hospital DU information varied widely and included 14 databases from 25 reviewed countries. Bulgaria, Croatia, Denmark, Estonia, Finland, France, Hungary, Iceland, Latvia, Norway and Sweden obtain information on inpatient DU at a national level from wholesalers/manufacturers. In Belgium, Italy and Portugal, drugs dispensed to patients in hospitals are registered at a national level. Data are freely available online only for Denmark and Iceland. From the PubMed search, of a total of 868 retrieved studies, only 13 studies used the ATC/DDD methodology. Although the number of DDD/100 bed-days was used in four studies, other units of measure were also used. The type of information provided for the inpatient sector allowed primarily for conducting DU research at an aggregated data level. The existence of national administrative structures to monitor hospital DU would contribute to promoting the rational use of medicines and improving the safety and quality of prescribing.

A compilation of research working groups on drug utilisation across Europe.

BACKGROUND: The assessment of the benefit-risk of medicines needs careful consideration concerning their patterns of utilization. Systems for the monitoring of medicines consumption have been established in many European countries, and several international groups have identified and described them. No other compilation of European working groups has been published. As part of the PROTECT project, as a first step in searching for European data sources on the consumption of five selected groups of medicines, we aimed to identify and describe the main characteristics of the existing collaborative European working groups. FINDINGS: Google and bibliographic searches (PubMed) of articles containing information on databases and other sources of drug consumption data were conducted. For each working group the main characteristics were recorded.Nineteen selected groups were identified, focusing on: a) general drug utilisation (DU) research (EuroDURG, CNC, ISPE'S SIG-DUR, EURO-MED-STAT, PIPERSKA Group, NorPEN, ENCePP, DURQUIM), b) specific DU research: b.1) antimicrobial drugs (ARPAC, ESAC, ARPEC, ESGAP, HAPPY AUDIT), b.2) cardiovascular disease (ARITMO, EUROASPIRE), b.3) paediatrics (TEDDY), and b.4) mental health/central nervous system effects (ESEMeD, DRUID, TUPP/EUPoMMe). Information on their aims, methods and activities is presented. CONCLUSIONS: We assembled and updated information on European working groups in DU research and in the utilisation of five selected groups of drugs for the PROTECT project. This information should be useful for academic researchers, regulatory and health authorities, and pharmaceutical companies conducting and interpreting post-authorisation and safety studies. European health authorities should encourage national research and collaborations in this important field for public health.

Inhaled beta-2-agonists/muscarinic antagonists and acute myocardial infarction in COPD patients.

OBJECTIVE: Empirical results indicate an increased risk for cardiovascular (CV) adverse drug events (ADE) in chronic obstructive pulmonary disease (COPD) patients treated with beta-2-agonists (B2A) and muscarinic antagonists (MA). A systematic review (including a meta-analysis for drug classes with sufficient sample size) was conducted assessing the association between B2A or MA and acute myocardial infarctions (MI) in COPD patients. METHODS: Comprehensive literature search in electronic databases (MEDLINE, Cochrane database) was performed (January 1, 1946-April 1, 2013). Results were presented by narrative synthesis including a comprehensive quality assessment. In the meta-analysis, a random effects model was used for estimating relative risk estimates for acute MI. RESULTS: Eight studies (two systematic reviews, two randomized controlled trials, and four observational studies) were comprised. Most studies comparing tiotropium vs. placebo showed a decreased MI risk for tiotropium, whereas for studies with active control arms no clear tendency was revealed. For short-acting B2A, an increased MI risk was shown after first treatment initiation. For all studies, a good quality was found despite some shortcomings in ADE-specific criteria. A meta-analysis could be conducted for tiotropium vs. placebo only, showing a relative risk reduction of MI (0.74 [0.61-0.90]) with no evidence of statistical heterogeneity among the included trials (I(2) = 0%; p = 0.8090). CONCLUSIONS: An MI-protective effect of tiotropium compared to placebo was found, which might be attributable to an effective COPD treatment leading to a decrease in COPD-related cardiovascular events. Further studies with effective control arms and minimal CV risk are required determining precisely tiotropium's cardiovascular risk.

Sources of European drug consumption data at a country level.

OBJECTIVES: This study aimed at outlining the characteristics of nationwide administrative databases monitoring drug consumption in Europe. METHODS: Internet and bibliographic databases (April 2010) were searched and experts in drug utilization (DU) research interviewed to find nationwide administrative medicines consumption databases in Europe, with data for the out- and inpatient healthcare sector. A questionnaire was developed to gather additional information. We collected data providers, websites, accessibility, data sources, healthcare settings, population coverage, medicines-related data, patient and prescriber data, periods covered, and linkage to other databases. RESULTS: Thirty-one administrative nationwide medicine consumption databases in 25 countries were identified. Questionnaires were responded for 20 databases. Eleven provided wholesalers' sales data, 11 on reimbursed, 5 on prescribed, and 4 on dispensing medicines. Fifteen databases provided inpatient drug consumption data, mainly wholesalers' sales. CONCLUSIONS: Nationwide administrative databases are of value to all stakeholders involved in the conduct and interpretation of post-marketing safety studies, and in the conduct of DU research. The endorsement of the anatomical therapeutic chemical/defined daily dose methodology by these databases contributes to data harmonization. However, there is still a lack of information on inpatient medicines consumption at a patient-level.