Feasibility and Safety of Sildenafil to Repair Brain Injury Secondary to Birth Asphyxia (SANE-01): A Randomized, Double-blind, Placebo-controlled Phase Ib Clinical Trial.

OBJECTIVE: To test feasibility and safety of administering sildenafil in neonates with neonatal encephalopathy (NE), developing brain injury despite therapeutic hypothermia (TH). STUDY DESIGN: We performed a randomized, double-blind, placebo-controlled phase Ib clinical trial between 2016 and 2019 in neonates with moderate or severe NE, displaying brain injury on day-2 magnetic resonance imaging (MRI) despite TH. Neonates were randomized (2:1) to 7-day sildenafil or placebo (2 mg/kg/dose enterally every 12 hours, 14 doses). Outcomes included feasibility and safety (primary outcomes), pharmacokinetics (secondary), and day-30 neuroimaging and 18-month neurodevelopment assessments (exploratory). RESULTS: Of the 24 enrolled neonates, 8 were randomized to sildenafil and 3 to placebo. A mild decrease in blood pressure was reported in 2 of the 8 neonates after initial dose, but not with subsequent doses. Sildenafil plasma steady-state concentration was rapidly reached, but decreased after TH discontinuation. Twelve percent of neonates (1/8) neonates died in the sildenafil group and 0% (0/3) in the placebo group. Among surviving neonates, partial recovery of injury, fewer cystic lesions, and less brain volume loss on day-30 magnetic resonance imaging were noted in 71% (5/7) of the sildenafil group and in 0% (0/3) of the placebo group. The rate of death or survival to 18 months with severe neurodevelopmental impairment was 57% (4/7) in the sildenafil group and 100% (3/3) in the placebo group. CONCLUSIONS: Sildenafil was safe and well-absorbed in neonates with NE treated with TH. Optimal dosing needs to be established. Evaluation of a larger number of neonates through subsequent phases II and III trials is required to establish efficacy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.govNCT02812433.

Analysing and improving preoperative medication management in cardiac surgery.

AIMS: The objective of this study was to analyse the preoperative medication management within the cardiac surgery patient population and measure the effectiveness of an interprofessional intervention in routine care. METHODS: A jointly developed preoperative medication management was implemented in routine care on multiple levels (inclusion in admission letter to primary care, hotline for inquiries, pocket cards for physicians and correspondence with referring centres). The effectiveness was evaluated by analysing preoperative management before and after implementation. The primary endpoint was the number of drugs managed correctly according to the guidelines after implementation. Secondary endpoints consisted amongst others of bleeding on the intensive care unit, re-thoracotomy, postoperative infarction and cerebrovascular complications. Additionally, possible associations between the correct management and different variables were investigated by multivariate analysis. RESULTS: After the implementation, the number of drugs managed correctly according to guidelines increased from 54.0 to 73.5% (P < .001). The effect was more prominent for direct oral anticoagulants and prophylactic aspirin where the guideline adherence increased from 29.2 to 74.5% and from 78.6 to 95.1%, respectively. No difference was seen for sodium-glucose transporter-2 inhibitors, metformin, vitamin-K antagonists and dual-antiplatelet therapy. Secondary endpoints showed no safety signals with regard to bleeding or thrombotic events. In multivariate analysis, the intervention was effective (odds ratio 2.17, 95% confidence interval [1.32-3.62]) after adjusting for possible confounders. CONCLUSION: An interprofessional programme was effective to improve preoperative medication management in cardiac surgery patients. Sodium-glucose transporter-2 inhibitors, metformin and direct oral anticoagulants appear to be especially at risk for incorrect management before cardiac surgery with possible adverse events.

Effect of Clarithromycin, a Strong CYP3A and P-glycoprotein Inhibitor, on the Pharmacokinetics of Edoxaban in Healthy Volunteers and the Evaluation of the Drug Interaction with Other Oral Factor Xa Inhibitors by a Microdose Cocktail Approach.

PURPOSE: We assessed the differential effect of clarithromycin, a strong inhibitor of cytochrome P450 (CYP) 3A4 and P-glycoprotein, on the pharmacokinetics of a regular dose of edoxaban and on a microdose cocktail of factor Xa inhibitors (FXaI). Concurrently, CYP3A activity was determined with a midazolam microdose. METHODS: In an open-label fixed-sequence trial in 12 healthy volunteers, the pharmacokinetics of a microdosed FXaI cocktail (µ-FXaI; 25 µg apixaban, 50 µg edoxaban, and 25 µg rivaroxaban) and of 60 mg edoxaban before and during clarithromycin (2 x 500 mg/d) dosed to steady-state was evaluated. Plasma concentrations of study drugs were quantified using validated ultra-performance liquid chromatography-tandem mass spectrometry methods. RESULTS: Therapeutic clarithromycin doses increased the exposure of a therapeutic 60 mg dose of edoxaban with a geometric mean ratio (GMR) of the area under the plasma concentration-time curve (AUC) of 1.53 (90 % CI: 1.37-1.70; p < 0.0001). Clarithromycin also increased the GMR (90% CI) of the exposure of microdosed FXaI apixaban to 1.38 (1.26-1.51), edoxaban to 2.03 (1.84-2.24), and rivaroxaban to 1.44 (1.27-1.63). AUC changes observed for the therapeutic edoxaban dose were significantly smaller than those observed with the microdose (p < 0.001). CONCLUSION: Clarithromycin increases FXaI exposure. However, the magnitude of this drug interaction is not expected to be clinically relevant. The edoxaban microdose overestimates the extent of the drug interaction with the therapeutic dose, whereas AUC ratios for apixaban and rivaroxaban were comparable to the interaction with therapeutic doses as reported in the literature. TRIAL REGISTRATION: EudraCT Number: 2018-002490-22.

Influence of a Short Course of Ritonavir Used as Booster in Antiviral Therapies Against SARS-CoV-2 on the Exposure of Atorvastatin and Rosuvastatin.

PURPOSE: Early antiviral treatment with nirmatrelvir/ritonavir is recommended for SARS-CoV-2-infected patients at high risk for severe courses. Such patients are usually chronically ill and susceptible to adverse drug interactions caused by ritonavir. We investigated the interactions of short-term low-dose ritonavir therapy with atorvastatin and rosuvastatin, two statins commonly used in this population. METHOD: We assessed exposure changes (area under the concentration-time curve (AUC∞) and maximum concentration (Cmax)) of a single dose of 10 mg atorvastatin and 10 mg rosuvastatin before and on the fifth day of ritonavir treatment (2 × 100 mg/day) in healthy volunteers and developed a semi-mechanistic pharmacokinetic model to estimate dose adjustment of atorvastatin during ritonavir treatment. RESULTS: By the fifth day of ritonavir treatment, the AUC∞ of atorvastatin increased 4.76-fold and Cmax 3.78-fold, and concurrently, the concentration of atorvastatin metabolites decreased to values below the lower limit of quantification. Pharmacokinetic modelling indicated that a stepwise reduction in atorvastatin dose during ritonavir treatment with a stepwise increase up to 4 days after ritonavir discontinuation can keep atorvastatin exposure within safe and effective margins. Rosuvastatin pharmacokinetics were only mildly modified; ritonavir significantly increased the Cmax 1.94-fold, while AUC∞ was unchanged. CONCLUSION: Atorvastatin doses should likely be adjusted during nirmatrelvir/ritonavir treatment. For patients on a 20-mg dose, we recommend half of the original dose. In patients taking 40 mg or more, a quarter of the dose should be taken until 2 days after discontinuation of nirmatrelvir/ritonavir. Patients receiving rosuvastatin do not need to change their treatment regimen. TRIAL REGISTRATION: EudraCT number: 2021-006634-39. DRKS00027838.

Prevalence and patient-rated relevance of complexity factors in medication regimens of community-dwelling patients with polypharmacy.

PURPOSE: To describe the prevalence of complexity factors in the medication regimens of community-dwelling patients with more than five drugs and to evaluate the relevance of these factors for individual patients. METHODS: Data were derived from the HIOPP-6 trial, a controlled study conducted in 9 general practices which evaluated an electronic tool to detect and reduce complexity of drug treatment. The prevalence of complexity factors was based on the results of the automated analysis of 139 patients' medication data. The relevance assessment was based on the patients' rating of each factor in an interview (48 patients included for analysis). RESULTS: A median of 5 (range 0-21) complexity factors per medication regimen were detected and at least one factor was observed in 131 of 139 patients. Almost half of these patients found no complexity factor in their medication regimen relevant. CONCLUSION: In most medication regimens, complexity factors could be identified automatically, yet less than 15% of factors were indeed relevant for patients as judged by themselves. When assessing complexity of medication regimens, one should especially consider factors that are both particularly frequent and often challenging for patients, such as use of inhalers or tablet splitting. TRIAL REGISTRATION: The HIOPP-6 trial was registered retrospectively on May 17, 2021, in the German Clinical Trials register under DRKS-ID DRKS00025257.

Comparison of Five Lists to Identify Potentially Inappropriate Use of Non-Steroidal Anti-Inflammatory Drugs in Older Adults.

OBJECTIVE: To compare the prevalence of potentially inappropriate non-steroidal anti-inflammatory drugs (NSAIDs) among NSAIDs users defined with frequently used potentially inappropriate medication (PIM) lists and to identify the determinants of their use. DESIGN AND SETTING: Cross-sectional survey among community-dwelling older adults from Germany. SUBJECTS: N = 284 NSAIDs users aged 65-89 years. METHODS: All currently regularly or as-needed used drugs were recorded during a home visit. Multivariate logistic regression models were applied to assess the potential determinants of potentially inappropriate NSAIDs use. RESULTS: Prevalence of potentially inappropriate NSAIDs use was 54.2%, 45.4%, 29.9%, 20.4%, and 3.5% when applying the STOPP, 2019 Beers, EU(7)-PIM, FORTA, and PRISCUS list, respectively. No study participant was identified as a potentially inappropriate NSAIDs user by all five lists simultaneously. The majority (68%) were identified only by one or two lists. Merely the STOPP and Beers criteria had a moderate inter-instrument agreement. Lower pain severity, gout, peptic ulcer (PU), cardiovascular disease (CVD), and chronic kidney disease (CKD) were statistically significantly associated with potentially inappropriate NSAIDs use defined by the STOPP criteria and the latter three conditions also with the 2019 Beers criteria. CONCLUSIONS: The STOPP and Beers criteria may be superior to the other lists because they more frequently identify potentially inappropriate NSAIDs use in conditions implying a high risk for NSAIDs' adverse events (i.e., PUD, CKD and CVD). We developed a harmonized, country-independent PIM list for NSAIDs with the same advantages as observed for the STOOP and 2019 Beers criteria and recommended its use.

The impact of a computerized physician order entry system implementation on 20 different criteria of medication documentation-a before-and-after study.

BACKGROUND: The medication process is complex and error-prone. To avoid medication errors, a medication order should fulfil certain criteria, such as good readability and comprehensiveness. In this context, a computerized physician order entry (CPOE) system can be helpful. This study aims to investigate the distinct effects on the quality of prescription documentation of a CPOE system implemented on general wards in a large tertiary care hospital. METHODS: In a retrospective analysis, the prescriptions of two groups of 160 patients each were evaluated, with data collected before and after the introduction of a CPOE system. According to nationally available recommendations on prescription documentation, it was assessed whether each prescription fulfilled the established 20 criteria for a safe, complete, and actionable prescription. The resulting fulfilment scores (prescription-Fscores) were compared between the pre-implementation and the post-implementation group and a multivariable analysis was performed to identify the effects of further covariates, i.e., the prescription category, the ward, and the number of concurrently prescribed drugs. Additionally, the fulfilment of the 20 criteria was assessed at an individual criterion-level (denoted criteria-Fscores). RESULTS: The overall mean prescription-Fscore increased from 57.4% ± 12.0% (n = 1850 prescriptions) before to 89.8% ± 7.2% (n = 1592 prescriptions) after the implementation (p < 0.001). At the level of individual criteria, criteria-Fscores significantly improved in most criteria (n = 14), with 6 criteria reaching a total score of 100% after CPOE implementation. Four criteria showed no statistically significant difference and in two criteria, criteria-Fscores deteriorated significantly. A multivariable analysis confirmed the large impact of the CPOE implementation on prescription-Fscores which was consistent when adjusting for the confounding potential of further covariates. CONCLUSIONS: While the quality of prescription documentation generally increases with implementation of a CPOE system, certain criteria are difficult to fulfil even with the help of a CPOE system. This highlights the need to accompany a CPOE implementation with a thorough evaluation that can provide important information on possible improvements of the software, training needs of prescribers, or the necessity of modifying the underlying clinical processes.

Reporter cell assay-based functional quantification of TNF-α-antagonists in serum - a proof-of-principle study for adalimumab.

Quantification of therapeutic antibodies is commonly based on physico-chemical assays such as enzyme-linked immunoabsorption assays (ELISA) and lately on mass spectrometry. However, the functional integrity of evaluated immunoglobulins is yet not assessed. Consequently, a commercially available reporter cell line was used to quantify the functional concentration of the anti-tumor necrosis factor alpha (TNF-α) antibody adalimumab present in serum of a healthy beagle dog treated with 3 mg intravenous adalimumab (Humira®). HEK-Blue™-hTLR3 cells express a secreted alkaline phosphatase under the control of a nuclear factor kappa B (NF-κB) response element. Its enzymatic activity can be recorded using colorimetry, which reports activity of extracellular NF-κB stimuli such as TNF-α. Using an adalimumab concentration-response calibration curve, the functional concentration of serum adalimumab was estimated to be 4.9 ± 1.4 µg/ml, which was in excellent agreement with ELISA results (4.8 µg/ml). The obtained data suggest that this simple, easy-to-handle reporter cell assay can be used for the functional quantification of adalimumab present in samples from in vitro or pre-clinical in vivo experiments. Moreover, this assay could be used in vitro to compare the pharmacodynamics of adalimumab biosimilars or different anti-TNF-α compounds, respectively.

Pain severity and analgesics use in the community-dwelling older population: a drug utilization study from Germany.

PURPOSE: Chronic pain is common in the older population and a significant public health concern. However, comprehensive studies on analgesics use in this age group from Germany are scarce. This study aims to give a comprehensive overview on the use of the most common therapeutic groups of analgesics in community-dwelling older adults from Germany. METHODS: A cross-sectional study was carried out using data from a German cohort of 2038 community-dwelling adults aged 63-89 years. Descriptive statistics and logistic regression models were applied to assess the utilization of analgesics by age, sex, pain severity, pain duration, and locations. RESULTS: One out of four study participants was suffering from high-intensity or disabling pain. Approximately half of those taking analgesics still reported to suffer from high-intensity or disabling pain. Among analgesics users, occasional non-steroidal anti-inflammatory drugs (NSAIDs) use was the most frequent pain therapy (in 43.6% of users), followed by metamizole (dipyrone) use (16.1%), regular NSAIDs use (12.9%), strong opioids use (12.7%), and weak opioids use (12.0%). In multivariate logistic regression models, higher age, higher pain severity, longer pain duration, abdominal pain, and back pain were statistically significantly associated with opioids use. Metamizole use was also statistically significantly associated with higher pain severity but inversely associated with pain duration. CONCLUSIONS: A significant number of older German adults are affected by high-intensity and disabling chronic pain despite receiving analgesics. Long-term studies are needed to compare the effectiveness and safety of different treatments for chronic pain in older adults.

Composite midazolam and 1'-OH midazolam population pharmacokinetic model for constitutive, inhibited and induced CYP3A activity.

CYP3A plays an important role in drug metabolism and, thus, can be a considerable liability for drug-drug interactions. Population pharmacokinetics may be an efficient tool for detecting such drug-drug interactions. Multiple models have been developed for midazolam, the typical probe substrate for CYP3A activity, but no population pharmacokinetic models have been developed for use with inhibition or induction. The objective of the current analysis was to develop a composite parent-metabolite model for midazolam which could adequately describe CYP3A drug-drug interactions. As an exploratory objective, parameters were assessed for potential cut-points which may allow for determination of drug-drug interactions when a baseline profile is not available. The final interaction model adequately described midazolam and 1'-OH midazolam concentrations for constitutive, inhibited, and induced CYP3A activity. The model showed good internal and external validity, both with full profiles and limited sampling (2, 2.5, 3, and 4 h), and the model predicted parameters were congruent with values found in clinical studies. Assessment of potential cut-points for model predicted parameters to assess drug-drug interaction liability with a single profile suggested that midazolam clearance may reasonably be used to detect inhibition (4.82-16.4 L/h), induction (41.8-88.9 L/h), and no modulation (16.4-41.8 L/h), with sensitivities for potent inhibition and induction of 87.9% and 83.3%, respectively, and a specificity of 98.2% for no modulation. Thus, the current model and cut-points could provide efficient and accurate tools for drug-drug liability detection, both during drug development and in the clinic, following prospective validation in healthy volunteers and patient populations.

Evidence for underuse and overuse of antidepressants in older adults: Results of a large population-based study.

OBJECTIVES: Depression is common among elderly people. However, diagnosis and adequate treatment is frequently difficult. Research on underuse and overuse of antidepressants in elderly persons is scarce. This study investigates the utilization and appropriateness of pharmacological and psychological depression treatment in a large cohort of community-dwelling adults. METHODS: A subsample of 3117 participants (aged 55-85 y) of the third follow-up (2008-2010) of the large population-based German ESTHER study was included. Depression was assessed using the eight-item Patient Health Questionnaire (PHQ-8). In the course of a home visit, study doctors collected complete information on medication. Logistic regression analyses were conducted to determine the relationship of depression with both underuse and overuse of antidepressants. The analyses were then adjusted for socioeconomic variables, psychosomatic comorbidities, and motivation to seek help. RESULTS: One hundred sixty-three participants (5.2%; 95% confidence interval [CI], 4.5-6.1) fulfilled the criteria for major depression. Underuse of antidepressants was present in 126 depressed participants (77.3%; 70.1-83.5). Persons who were motivated to seek help, who had an established depression diagnosis, or who were taking more than five different medications had lower odds of underuse. Anxiety was associated with higher odds for underuse. Overuse of antidepressants (prescription without clinical indication) was found in 96 cases (41.7%; 35.3-48.4) of all antidepressant prescriptions. CONCLUSIONS: Depression treatment in older adults is frequently insufficient; it appears to depend on diagnosis as well as the patients' motivation to seek help. Education regarding the diagnosis of depression in the elderly as well as guidelines for appropriate treatment is needed.

Dried-Blood-Spot Technique to Monitor Direct Oral Anticoagulants: Clinical Validation of a UPLC-MS/MS-Based Assay.

Plasma concentrations of direct oral anticoagulants (DOACs) vary largely between individuals, and they correlate well with desired and adverse outcomes. Although regular concentration monitoring of DOACs is not recommended, information on DOAC exposure could be useful in situations when multiple DOAC-clearance pathways are impaired or nonadherence is suspected. Self-sampling techniques, like the use of dried-blood spots (DBSs), would be particularly useful because they enable the collection of information in ambulatory patients at relevant points in time of the dosing interval (e.g., trough). We developed and validated a DBS-based assay to quantify all currently marketed DOACs (apixaban, dabigatran, edoxaban, and rivaroxaban) in a single ultraperformance-liquid-chromatography-tandem-mass-spectrometry assay. It fulfilled all validation standards within a hematocrit range of 0.33-0.65 and was linear over the calibration ranges of 2.5-750 ng/mL (apixaban and rivaroxaban), 4.4-750 ng/mL (dabigatran), and 9.3-750 ng/mL (edoxaban). Only minor ion suppression (matrix effect ≤13%) was present, inter- and intra-assay precision was ≤13%, and inter- and intra-assay accuracies ranged between 88 and 110%. All DOACs were stable in DBSs up to 52 days at room temperature, if the DBSs were protected from light and humidity. The correlation between (whole blood) DBS and plasma concentrations was assessed in 33 patients under regular DOAC therapy. Deming-regression coefficients between simultaneously collected capillary DBSs and plasma samples were used to predict plasma concentrations from DBSs. Bland-Altman plots revealed a strong agreement between predicted and observed plasma concentrations, thus confirming the suitability of DBSs for DOAC monitoring as an important step toward the important aim of self-sampling at home.

Rivaroxaban and macitentan can be coadministered without dose adjustment but the combination of rivaroxaban and St John's wort should be avoided.

AIMS: We assessed the potential mutual interaction of oral macitentan (cytochrome P450 (CYP) 3A4 substrate) at steady-state with single-dose oral rivaroxaban (CYP3A4 and P-glycoprotein substrate) and evaluated the effect of the CYP3A and P-glycoprotein inducer St John's wort (SJW) on the pharmacokinetics of these drugs in healthy volunteers. METHODS: Twelve healthy volunteers completed this open-label, monocentre, two-period, one-sequence phase I clinical trial. The pharmacokinetics of macitentan (10 mg) was assessed on study days 3 (single dose), 15 (steady-state), 16 (impact of rivaroxaban) and 29 (after induction by oral SJW), and of rivaroxaban on days 2 (single dose), 16 (impact of macitentan at steady-state) and 29 (after induction by SJW). Concurrently, we quantified changes of CYP3A activity using oral microdoses of midazolam (30 µg). RESULTS: Rivaroxaban and macitentan did not significantly change the pharmacokinetics of each other. After induction with SJW, CYP3A activity increased by 272% and geometric mean ratios of macitentan AUC decreased by 48% and of Cmax by 45%. Concurrently, also geometric mean ratios of rivaroxaban AUC and Cmax decreased by 25%. CONCLUSIONS: There is no evidence for a relevant pharmacokinetic interaction between macitentan and rivaroxaban suggesting that these two drugs can be combined without dose adjustment. SJW strongly increased CYP3A activity and substantially reduced rivaroxaban and macitentan exposure while estimated net endothelin antagonism only decreased by 20%, which is considered clinically irrelevant. The combination of SJW with rivaroxaban should be avoided.

Prediction of Drug-Related Risks Using Clinical Context Information in Longitudinal Claims Data.

OBJECTIVES: To develop and internally validate prediction models for medication-related risks arising from overuse, misuse, and underuse that utilize clinical context information and are suitable for routine risk assessment in claims data (i.e., medication-based models predicting the risk for hospital admission apparent in routine claims data or MEDI-RADAR). METHODS: Based on nationwide claims from health-insured persons in Germany between 2010 and 2012, we drew a random sample of people aged ≥65 years (N = 22,500 randomly allocated to training set, N = 7500 to validation set). Individual duration of drug supply was estimated from prescription patterns to yield time-varying drug exposure windows. Together with concurrent medical conditions (ICD-10 diagnoses), exposure to the STOPP/START (screening tool of older persons' potentially inappropriate prescriptions/screening tool to alert doctors to the right treatment) criteria was derived. These were tested as time-dependent covariates together with time-constant covariates (patient demographics, baseline comorbidities) in regularized Cox regression models. RESULTS: STOPP/START variables were iteratively refined and selected by regularization to include 2 up to 11 START variables and 8 up to 31 STOPP variables in parsimonious and liberal selections in the prediction modeling. The models discriminated well between patients with and without all-cause hospitalizations, potentially drug-induced hospitalizations, and mortality (parsimonious model c-indices with 95% confidence intervals: 0.63 [0.62-0.64], 0.67 [0.65-0.68], and 0.78 [0.76-0.80]). CONCLUSIONS: The STOPP/START criteria proved to efficiently predict medication-related risk in models possessing good performance. Timely detection of such risks by routine monitoring in claims data can support tailored interventions targeting these modifiable risk factors. Their impact on older peoples' medication safety and effectiveness can now be explored in future implementation studies.

Pill-count and the arithmetic of risk: Evidence that polypharmacy is a health status marker rather than a predictive surrogate for the risk of adverse drug events.

With advancing age there is an increase in the disease burden and thus in the number of drugs prescribed to this patient group. It is often assumed that an increase in pill count is associated per se with an increase in the number of medication errors (e.g., potentially inappropriate prescribing, PIP) and the frequency of adverse drug events (ADE). However, prescribing more drugs can also mean more successful treatment, making it important to critically assess the benefit/risk balance of the medications prescribed in each patient. Whether a prescribed medication is appropriate depends on the clinical state of the patient (diagnoses), treatment goals, comedication/drug interactions, patient preferences, whether the patient tolerates the drug, a measure of how frail the patient is, etc. It is often argued that the number of prescribed drugs should be restricted, but we hold the view that this should only be done after careful consideration of the factors mentioned above. In our study, we remodeled the findings of two large cohort studies investigating the association between the number of drugs prescribed and clinical endpoints. The graphic illustrations obtained confirmed that targeting pill count, as a measure to reduce ADEs and mortality, fails to impact patient well-being because the number of drugs prescribed is likely determined by patient characteristics affecting drug response, namely, disease burden, patient functionality, and specific patient needs, all of which must be taken into account in order to reduce the risk of PIMs and the occurrence ADEs.
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Changes in prescribed medicines in older patients with multimorbidity and polypharmacy in general practice.

BACKGROUND: Treatment complexity rises in line with the number of drugs, single doses, and administration methods, thereby threatening patient adherence. Patients with multimorbidity often need flexible, individualised treatment regimens, but alterations during the course of treatment may further increase complexity. The objective of our study was to explore medication changes in older patients with multimorbidity and polypharmacy in general practice. METHODS: We retrospectively analysed data from the cluster-randomised PRIMUM trial (PRIoritisation of MUltimedication in Multimorbidity) conducted in 72 general practices. We developed an algorithm for active pharmaceutical ingredients (API), strength, dosage, and administration method to assess changes in physician-reported medication data during two intervals (baseline to six-months: ∆1; six- to nine-months: ∆2), analysed them descriptively at prescription and patient levels, and checked for intervention effects. RESULTS: Of 502 patients (median age 72 years, 52% female), 464 completed the study. Changes occurred in 98.6% of patients (changes were 19% more likely in the intervention group): API changes during ∆1 and ∆2 occurred in 414 (82.5%) and 338 (67.3%) of patients, dosage alterations in 372 (74.1%) and 296 (59.2%), and changes in API strength in 158 (31.5%) and 138 (27.5%) respectively. Administration method changed in 79 (16%) of patients in both ∆1 and ∆2. Simvastatin, metformin and aspirin were most frequently subject to alterations. CONCLUSION: Medication regimens in older patients with multimorbidity and polypharmacy changed frequently. These are mostly due to discontinuations and dosage alterations, followed by additions and restarts. These findings cast doubt on the effectiveness of cross-sectional assessments of medication and support longitudinal assessments where possible. TRIAL REGISTRATION: 1. Prospective registration: Trial registration number: NCT01171339 ; Name of registry: ClinicalTrials.gov; Date of registration: July 27, 2010; Date of enrolment of the first participant to the trial: August 12, 2010. 2. Peer reviewed trial registration: Trial registration number: ISRCTN99526053 ; Name of registry: Controlled Trials; Date of registration: August 31, 2010; Date of enrolment of the first participant to the trial: August 12, 2010.

Comparison of Nine Instruments to Calculate Anticholinergic Load in a Large Cohort of Older Outpatients: Association with Cognitive and Functional Decline, Falls, and Use of Laxatives.

OBJECTIVE: A patient's risk for anticholinergic adverse effects is frequently estimated by instruments evaluating the drugs included in his medication profile. It remains unknown, however, which characteristics should be included in such an assessment instrument aiming to reliably predict adverse anticholinergic outcomes. DESIGN: Cross-sectional study. SETTING: ESTHER cohort (Germany). PARTICIPANTS: Home-dwelling participants (N = 2,761) aged between 60 and 87 years. MEASUREMENTS: The association between anticholinergic load calculated with nine different instruments and four anticholinergic adverse outcomes was investigated in univariate and multivariate analyses. Therefore, linear models complemented with Kendall's tau rank correlation coefficients (ԏ) were applied for continuous outcomes and generalized linear models were used to derive odds ratios (ORs) with 95% confidence intervals (CIs) for binary endpoints. RESULTS: Based on the respective identification criteria for anticholinergic drugs, the nine instruments identified between 245 (9%) and 866 (31%) anticholinergic drug users (mean age ± SD: 73 ± 6 years; Mini-Mental State Examination [MMSE] score: 28.3 ± 2.07; Barthel Index: 97.1 ± 7.5; 291 reporting falls; 29 taking laxatives [surrogate for constipation]). In the multivariate analysis, only two instruments indicated a significant association between anticholinergic load and all four outcomes. The instrument considering the prescribed dose showed the strongest association with MMSE scores (ԏ = -0.10), falls (OR: 2.30; 95% CI: 1.50-3.52), and the use of laxatives (OR: 3.11; 95% CI: 1.04-9.36). CONCLUSIONS: Instruments most reliably predicted anticholinergicadverse events if they were either based on the drugs' serum anticholinergic activity and the suggestions of clinician experts or considered the actual prescribed dose.

How can we define and analyse drug exposure more precisely to improve the prediction of hospitalizations in longitudinal (claims) data?

BACKGROUND: Risk prediction models can be powerful tools to support clinical decision-making, to help targeting interventions, and, thus, to improve clinical and economic outcomes, provided that model performance is good and sensitivity and specificity are well balanced. Drug utilization as a potential risk factor for unplanned hospitalizations has recently emerged as a meaningful predictor variable in such models. Drug treatment is a rather unstable (i.e. time-dependent) phenomenon and most drug-induced events are concentration-dependent and therefore individual drug exposure will likely modulate the risk. This especially applies to longitudinal monitoring of appropriate drug treatment within claims data as another promising application for prediction models. METHODS AND RESULTS: To guide future research towards this direction, we firstly reviewed current risk prediction models for unplanned hospitalizations that explicitly included information on drug utilization and were surprised to find that these models rarely attempted to consider dose and frequent modulators of drug clearance such as interactions with co-medication or co-morbidities. As another example, they often presumed class effects where in fact, differences between active moieties were well established. In addition, the study designs and statistical risk analysis disregarded the fact that medication and risk modulators and, thus, adverse events can vary over time. In a simulation study, we therefore evaluated the potential benefit of time-dependent Cox models over standard binary regression approaches with a fixed follow-up period. CONCLUSIONS: Longitudinal drug information could be utilized much more efficiently both by precisely estimating individual drug exposure and by applying more refined statistical methodology to account for time-dependent drug utilization patterns.