Sven Schmiedl

Potentially Inappropriate Medications in the Elderly: The PRISCUS List

BACKGROUND Certain drugs are classified as potentially inappropriate medications (PIM) for the elderly because they carry an increased risk of adverse drug events in this patient group. PIM lists from other countries are of limited usefulness in Germany because different drugs are on the market in each country and prescribing practices vary as well. Thus, a list of potentially inappropriate medications for the elderly was developed specifically for use in Germany. METHODS A preliminary PIM list suitable for the German market was created on the basis of a selective literature search and a qualitative analysis of published international PIM lists. The final German PIM list was developed by means of a comprehensive, structured expert survey in two rounds (a so-called Delphi process). RESULTS 83 drugs in a total of 18 drug classes were rated as potentially inappropriate for elderly patients. For 46 drugs, the experts came to no clear decision after the second Delphi round. For cases in which the administration of a PIM is clinically necessary, the final PRISCUS list contains recommendations for clinical practice, e.g. monitoring of laboratory values and dose adaptation. Therapeutic alternatives are also listed. CONCLUSION Potentially inappropriate medications carry the risk of causing adverse drug events in the elderly. A drawback of using a Delphi process to generate a PIM list, as was done for the new German list, is that little scientific evidence is currently available for the evaluation of active substances, potential therapeutic alternatives, and indicated monitoring procedures. Thus, the validity and practicability of the PRISCUS list remain to be demonstrated (and the same holds for PIM lists already published in other countries). It should be used as a component of an overall concept for geriatric pharmacotherapy in which polypharmacy and interacting medications are avoided, and doses are regularly re-evaluated.

Adverse drug reactions in Germany: direct costs of internal medicine hospitalizations

German hospital reimbursement modalities changed as a result of the introduction of Diagnosis Related Groups (DRG) in 2004. Therefore, no data on the direct costs of adverse drug reactions (ADRs) resulting in admissions to departments of internal medicine are available. The objective was to quantify the ADR‐related economic burden (direct costs) of hospitalizations in internal medicine wards in Germany.

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

Studies on drug utilization usually do not allow direct cross‐national comparisons because of differences in the respective applied methods. This study aimed to compare time trends in BZDs prescribing by applying a common protocol and analyses plan in seven European electronic healthcare databases.

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

The annual prevalence of antiepileptic drug (AED) prescribing reported in the literature differs considerably among European countries due to use of different type of data sources, time periods, population distribution, and methodologic differences. This study aimed to measure prevalence of AED prescribing across seven European routine health care databases in Spain, Denmark, The Netherlands, the United Kingdom, and Germany using a standardized methodology and to investigate sources of variation.

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.

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

There is widespread concern about increases in antibiotic use, but comparative data from different European countries on rates of use are lacking. This study was designed to measure and understand the variation in antibiotic utilization across five European countries.

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 tiotropiums cardiovascular risk.

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

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

Fingerhut ein alter Hut? Eine Analyse stationärer Aufnahmen durch digitalisassoziierte unerwünschte Arzneimittelwirkungen

ZusammenfassungHintergrund:Obwohl der klinische Nutzen einer Digitalistherapie bei Herzinsuffizienz begrenzt ist, wurden in Deutschland im Jahre 2004 ca. 255 Mio. Tagesdosen Digitalisglykoside (DGs) verordnet.Methodik:Für den Zeitraum 2000–2004 analysierten die Autoren zur stationären Aufnahme führende unerwünschte Arzneimittelwirkungen (UAWs) der nationalen Pharmakovigilanzzentren, deren Zusammenhang mit einer DG-Therapie als mindestens „wahrscheinlich“ bewertet wurde.Ergebnisse:Von 3 092 Patienten mit aufnahmebedingender UAW lag bei 314 Patienten (10,2%, 244 Frauen) eine DG-assoziierte UAW vor. Patienten mit DG-assoziierter UAW waren signifikant älter und leichter als Patienten mit anderen UAWs. Die Inzidenz [95%-CI] betrug 1,9 [1,0; 3,3] pro 1 000 DG-Exponierte je Quartal. Von 296 Patienten (228 Frauen) mit oraler Digitoxintherapie erhielten 70,6% der Frauen, aber nur 29,3% der Männer eine zu hohe tägliche Dosis, d.h. > 1 μg/kg Körpergewicht. Bei Frauen fanden sich signifikant höhere körpergewichtsbezogene Digitoxintagesdosen und Digitoxinserumspiegel. Bei Patienten mit nicht erhöhten Digitoxinspiegeln waren häufig pharmakodynamische Medikamenteninteraktionen (z.B. β-Blocker) entscheidend für die UAW-Entstehung. 42,4% der DG-UAWs wurden als vermeidbar eingeschätzt.Schlussfolgerung:Die Verschreibung einer körpergewichtsadaptierten Digitoxindosis ist wesentlich für die Verhinderung vermeidbarer DG-UAWs, insbesondere bei älteren, leichten Frauen. Regelmäßige Serumspiegelkontrollen sind auch aufgrund einer möglicherweise verlängerten Halbwertszeit bei sehr alten Patienten wichtig, ebenso die Beachtung pharmakodynamischer und pharmakokinetischer Interaktionen.AbstractBackground:Although the value of digitalis glycosides in the treatment of heart failure is limited, approximately 255 million DDDs of digitalis glycosides (DGs) were prescribed in Germany in 2004.Method:The authors analyzed data from adverse drug reactions (ADRs) resulting in hospitalization in the four German Pharmacovigilance Centers (PVCs) associated with DGs between 2000 and 2004. All patients with an at least “probable” ADR were included. Results:Out of 3,092 ADR patients, in 314 patients (10.2%, 244 women) admission was caused by a DG-related ADR. Patients with DG-related ADR had a significantly lower body weight and were significantly older than patients with other ADRs. Per 1,000 patients exposed to DGs the incidence [95% CI] was calculated to 1.9 [1.0; 3.3] ADRs per 3 months exposition. Oral digitoxin was involved in 296 patients (228 women). 70.6% of women but only 29.3% of men were overdosed (> 1 μg/kg body weight per day). Women received significantly higher body weight-related digitoxin doses and had significantly higher digitoxin plasma levels than men. ADRs in patients with nonelevated digitoxin serum level were mainly caused by pharmacodynamic drug-drug interactions (e.g., β-blockers). Overall, 42.4% of the ADRs were supposed to be preventable.Conclusion:Body weight-adapted dosing of digitoxin is essential for preventing DG-ADRs, particularly in elderly women with low body weight. Beyond giving attention to pharmacodynamic and pharmakokinetic drug-drug interactions, regular measurements of digitoxin plasma concentrations are crucial accounting for the increased half-life of digitoxin in the very old.

Utilisation and Off-Label Prescriptions of Respiratory Drugs in Children

Respiratory drugs are widely used in children to treat labeled and non-labeled indications but only some data are available quantifying comprehensively off-label usage. Thus, we aim to analyse drug utilisation and off-label prescribing of respiratory drugs focusing on age- and indication-related off-label use. Patients aged ≤18 years documented in the Bavarian Association of Statutory Health Insurance Physicians database (approx. 2 million children) between 2004 and 2008 were included in our study. Annual period prevalence rates (PPRs) per 10,000 children and the proportion of age- and indication-related off-label prescriptions were calculated and stratified by age and gender. Within the study period, highest PPRs were found for the fixed combination of clenbuterol/ambroxol (between 374–575 per 10,000 children) and the inhaled short acting beta-2-agonist salbutamol (between 378–527 per 10,000 children). Highest relative PPR increase was found for oral salbutamol (approx. 39-fold) whereas the most distinct decrease was found for oral long-acting beta-2-agonist clenbuterol (−97%). Compound classes most frequently involved in off-label prescribing were inhaled bronchodilative compounds (91,402; 37.3%) and oral beta-2-agonists (26,850; 22.5%). The highest absolute number of off-label prescriptions were found for inhaled salbutamol (n = 67,084; 42.0%) and oral clenbuterol/ambroxol (fixed combination, n = 18,897; 20.7%). Off-label prescribing due to indication was of much greater relevance than age-related off-label use. Most frequently, bronchodilative compounds were used off-label to treat respiratory tract infections. Highest off-label prescription rates were found in the youngest patients without relevant gender-related differences. Off-label prescribing of respiratory drugs is common especially in young children. Bronchodilative drugs were most frequently used off-label for treating acute bronchitis or upper respiratory tract infections underlining the essential need for a more rational prescribing in this area.