Prescribers' compliance with Summary of Product Characteristics of dabigatran, rivaroxaban and apixaban - a European comparative drug utilization study

Despite a tremendous increase of direct oral anticoagulants (DOACs) prescriptions in recent years, only few data are available analysing prescribers' adherence to Summary of Product Characteristics (SmPC). We aimed to assess adherence to registered indications, contraindications, special warnings/precautions, and potential drug-drug interactions for three DOAC compounds (dabigatran, rivaroxaban, apixaban) in six databases of five European countries (The Netherlands, United Kingdom, Spain, Denmark, Germany). We included adult patients (≥18 years) initiating DOACs between 2008 and 2015. For several SmPC items, broad definitions were used due to ambiguous SmPC terms or lacking data in some databases. Within the study period, a DOAC was initiated in 407,576 patients (rivaroxaban: 240,985 (59.1%), dabigatran: 95,303 (23.4%), apixaban: 71,288 (17.5%)). In 2015, non-valvular atrial fibrillation was the most common indication (>60% in most databases). For the whole study period, a substantial variation between the databases was found regarding the proportion of patients with at least one contraindication (inter-database range [IDR]: 8.2%-55.7%), with at least one special warnings/precaution (IDR: 35.8%-75.2%), and with at least one potential drug-drug interaction (IDR: 22.4%-54.1%). In 2015, the most frequent contraindication was 'malignant neoplasm' (IDR: 0.7%-21.3%) whereas the most frequent special warnings/precaution was 'prescribing to the elderly' (≥75 years; IDR: 25.0%-66.4%). The most common single compound class interaction was 'concomitant use of non-steroidal anti-inflammatory drugs' (IDR: 3.0%-25.3%). Contraindications, special warnings/precautions, and potential drug-drug interaction were present in a relevant number of new DOAC users. Due to broad definitions used for some SmPC terms, overall proportions for contraindications are prone to overestimation. However, for unambiguous SmPC terms documented in the databases sufficiently, the respective estimates can be considered valid. Differences between databases might be related to 'true' differences in prescription behaviour, but could also be partially due to differences in database characteristics

Стратегії та підходи до реструктуризації підприємств сфери ЖКГ в умовах реформування власності України

Наведено результати дослідження існуючих підходів до стратегічних напрямів реструктуризації підприємств сфери ЖКГ в умовах реформування власності. Ключові слова: стратегія реструктуризації, ЖКГ України, реструктуризація підприємства, антикризове управління, стратегічний менеджмент.Приведены результаты исследования существующих подходов в стратегических направлениях реструктуризации предприятий сферы ЖКГ в условиях реформирования собственности. Ключевые слова: стратегия реструктуризации, ЖКХ Украины, реструктуризация предприятия, антикризисное управление, стратегический менеджмент.The paper presents the results of studying the approaches in strategic directions of restructuring of housing and communal enterprises under property reformation in Ukraine. Keywords: strategy of restructuring, housing and communal facilities of Ukraine, restructuring of enterprise, anti-crisis management, strategic management

Concomitant medication use and its implications on the hazard pattern in pharmacoepidemiological studies: example of antidepressants, benzodiazepines and fracture risk

Background: Antidepressants and benzodiazepines are often co-prescribed and both associated with an increased fracture risk, albeit with distinctive hazard patterns. Timing of initiation of one with respect to the other and duration of use may influence the combined fracture hazard. The objective of our study was to describe patterns of concomitant use of benzodiazepine and antidepressants in terms of timing of initiation and duration and to illustrate the potential impact of various scenarios of timing of co-use on hip fracture hazard. Methods: Patients initiating antidepressant therapy (2002-2009) were identified from the Netherlands Primary Care Research Database. Concomitant benzodiazepine use was assessed according to the start time of benzodiazepine with respect to antidepressant therapy start. Duration of concomitant use was estimated relative to the length of antidepressant treatment episode.  Results: Among 16,087 incident antidepressant users, 39.0% used benzodiazepines concomitantly during their first antidepressant treatment episode. The time of initiation of benzodiazepine use was variable (64.4% starting before, 13.7% simultaneous and 21.9% after antidepressants). Duration of concomitant use in the three groups varied.  Conclusions: Co-prescribed medications with a common adverse event, may not only require accounting for concomitant use, but also the timing of start and duration of use as the overall hazard may vary accordingly

New-user and prevalent-user designs and the definition of study time origin in pharmacoepidemiology: a review of reporting practices

Background Guidance reports for observational comparative effectiveness and drug safety research recommend implementing a new-user design whenever possible, since it reduces the risk of selection bias in exposure effect estimation compared to a prevalent-user design. The uptake of this guidance has not been studied extensively.Methods We reviewed 89 observational effectiveness and safety cohort studies published in six pharmacoepidemiological journals in 2018 and 2019. We developed an extraction tool to assess how frequently new-user and prevalent-user designs were reported to be implemented. For studies that implemented a new-user design in both treatment arms, we extracted information about the extent to which the moment of meeting eligibility criteria, treatment initiation, and start of follow-up were reported to be aligned.Results Of the 89 studies included, 40% reported implementing a new-user design for both the study exposure arm and the comparator arm, while 13% reported implementing a prevalent-user design in both arms. The moment of meeting eligibility criteria, treatment initiation, and start of follow-up were reported to be aligned in both treatment arms in 53% of studies that reported implementing a new-user design. We provided examples of studies that minimized the risk of introducing bias due to unclear definition of time origin in unexposed participants, immortal time, or a time lag.Conclusions Almost half of the included studies reported implementing a new-user design. Implications of misalignment of study design origin were difficult to assess because it would require explicit reporting of the target estimand in original studies. We recommend that the choice for a particular study time origin is explicitly motivated to enable assessment of validity of the study.Clinical epidemiolog

Drug exposure misclassification in pharmacoepidemiology: sources and relative impact

Background Drug exposure assessment based on dispensing data can be misclassified when patients do not adhere to their therapy or when information about over-the-counter drugs is not captured in the study database. Previous research has considered hypothetical sensitivity and specificity values, whereas this study aims to assess the impact of literature-based real values of exposure misclassification. Methods A synthetic cohort study was constructed based on the proportion of exposure theoretically captured in a database (range 0.5-1.0) and the level of adherence (0.5-1.0). Three scenarios were explored: nondifferential misclassification, differential misclassification (misclassifications dependent on an unmeasured risk factor doubling the outcome risk), and nondifferential misclassification in a comparative effectiveness study (RRA and RRB both 2.0 compared to nonuse, RRA-B 1.0). Results For the scenarios with nondifferential misclassification, 25% nonadherence or 25% uncaptured exposure changed the RR from 2.0 to 1.75, and 1.95, respectively. Applying different proportions of nonadherence or uncaptured use (20% vs. 40%) for subgroups with and without the risk factor, an RR of 0.95 was observed in the absence of a true effect (i.e., true RR = 1). In the comparative effectiveness study, no effect on RR was seen for different proportions of uncaptured exposure; however, different levels of nonadherence for the drugs (20% vs. 40%) led to an underestimation of RRA-B (0.89). Discussion All scenarios led to biased estimates, but the magnitude of the bias differed across scenarios. When testing the robustness of findings of pharmacoepidemiologic studies, we recommend using realistic values of nonadherence and uncaptured exposure based on real-world data.Clinical epidemiolog

Tell me what you want, what you really really want: Estimands in observational pharmacoepidemiologic comparative effectiveness and safety studies

PURPOSE: Ideally, the objectives of a pharmacoepidemiologic comparative effectiveness or safety study should dictate its design and data analysis. This paper discusses how defining an estimand is instrumental to this process. METHODS: We applied the ICH-E9 (Statistical Principles for Clinical Trials) R1 addendum on estimands - which originally focused on randomized trials - to three examples of observational pharmacoepidemiologic comparative effectiveness and safety studies. Five key elements specify the estimand: the population, contrasted treatments, endpoint, intercurrent events, and population-level summary measure. RESULTS: Different estimands were defined for case studies representing three types of pharmacological treatments: (1) single-dose treatments using a case study about the effect of influenza vaccination versus no vaccination on mortality risk in an adult population of ≥60 years of age; (2) sustained-treatments using a case study about the effect of dipeptidyl peptidase 4 inhibitor versus glucagon-like peptide-1 agonist on hypoglycemia risk in treatment of uncontrolled diabetes; and (3) as needed treatments using a case study on the effect of nitroglycerin spray as-needed versus no nitroglycerin on syncope risk in treatment of stabile angina pectoris. CONCLUSIONS: The case studies illustrated that a seemingly clear research question can still be open to multiple interpretations. Defining an estimand ensures that the study targets a treatment effect that aligns with the treatment decision the study aims to inform. Estimand definitions further help to inform choices regarding study design and data-analysis and clarify how to interpret study findings

Tell me what you want, what you really really want: estimands in observational pharmacoepidemiologic comparative effectiveness and safety studies

Purpose: Ideally, the objectives of a pharmacoepidemiologic comparative effectiveness or safety study should dictate its design and data analysis. This paper discusses how defining an estimand is instrumental to this process.Methods: We applied the ICH-E9 (Statistical Principles for Clinical Trials) R1 addendum on estimands - which originally focused on randomized trials - to three examples of observational pharmacoepidemiologic comparative effectiveness and safety studies. Five key elements specify the estimand: the population, contrasted treatments, endpoint, intercurrent events, and population-level summary measure.Results: Different estimands were defined for case studies representing three types of pharmacological treatments: (1) single-dose treatments using a case study about the effect of influenza vaccination versus no vaccination on mortality risk in an adult population of =60 years of age; (2) sustained-treatments using a case study about the effect of dipeptidyl peptidase 4 inhibitor versus glucagon-like peptide-1 agonist on hypoglycemia risk in treatment of uncontrolled diabetes; and (3) as needed treatments using a case study on the effect of nitroglycerin spray as-needed versus no nitroglycerin on syncope risk in treatment of stabile angina pectoris.Conclusions: The case studies illustrated that a seemingly clear research question can still be open to multiple interpretations. Defining an estimand ensures that the study targets a treatment effect that aligns with the treatment decision the study aims to inform. Estimand definitions further help to inform choices regarding study design and data-analysis and clarify how to interpret study findings.Clinical epidemiolog

Bias in observational studies on the effectiveness of in hospital use of hydroxychloroquine in COVID-19

Purpose: During the first waves of the coronavirus pandemic, evidence on potential effective treatments was urgently needed. Results from observational studies on the effectiveness of hydroxychloroquine (HCQ) were conflicting, potentially due to biases. We aimed to assess the quality of observational studies on HCQ and its relation to effect sizes. Methods: PubMed was searched on 15 March 2021 for observational studies on the effectiveness of in-hospital use of HCQ in COVID-19 patients, published between 01/01/2020 and 01/03/2021 on. Study quality was assessed using the ROBINS-I tool. Association between study quality and study characteristics (journal ranking, publication date, and time between submission and publication) and differences between effects sizes found in observational studies compared to those found in RCTs, were assessed using Spearman's correlation. Results: Eighteen of the 33 (55%) included observational studies were scored as critical risk of bias, eleven (33%) as serious risk and only four (12%) as moderate risk of bias. Biases were most often scored as critical in the domains related to selection of participants (n = 13, 39%) and bias due to confounding (n = 8, 24%). There were no significant associations found between the study quality and the characteristics nor between the study quality and the effect estimates. Discussion: Overall, the quality of observational HCQ studies was heterogeneous. Synthesis of evidence of effectiveness of HCQ in COVID-19 should focus on RCTs and carefully consider the added value and quality of observational evidence

Unintended impact of pharmacovigilance regulatory interventions: A systematic review

AIMS: Studies assessing the impact of pharmacovigilance regulatory interventions often focus on the expected (or intended) outcomes, while any possible unintended impact may be overlooked. The update of the Good Pharmacovigilance Practice guideline in 2017 elaborated on impact assessment, emphasizing the need also to assess possible unintended impact. This systematic literature review investigated how often the unintended impact of regulatory interventions was considered in publications of studies investigating pharmacovigilance regulatory interventions in Europe. METHODS: We conducted a systematic review of the literature on MEDLINE and EMBASE from 1 January 2012 to 28 February 2022 to identify publications that investigated the impact of regulatory interventions in Europe. The primary outcome of the study was the number of publications reporting assessments of unintended impact. In addition, we studied the characteristics of these publications, including the type of outcomes assessed, the analytical methods applied and the type of data used. RESULTS: In total, 96 publications were included in the analysis. The unintended impact of pharmacovigilance regulatory interventions was investigated in 23 of 96 publications (24%). The drug classes most frequently studied in the publications assessing unintended impact of regulatory interventions were oral glucose-lowering drugs (n = 6, 26%), opioids (n = 4, 17%), antidepressants (n = 4, 17%) and antipsychotics (n = 3, 13%). The reported methods to assess the unintended impact were interrupted time series (n = 10, 43%) and descriptive statistics with or without significance testing (n = 2 [9%] and n = 9 [39%], respectively). The outcomes selected for unintended impact assessments included the use of other drugs (n = 16, 70%), health outcomes (n = 8, 35%) and behavioural changes (n = 4, 17%). Most of the publications reported on the use of electronic health record databases (n = 13, 57%) or claims databases (n = 13, 57%), while registries were used in 4 publications (17%). CONCLUSION: The unintended impact of pharmacovigilance regulatory interventions was reported in only a quarter of identified publications. There was no apparent increase in attention to unintended impact assessments after the update of the Good Pharmacovigilance Practice guidelines