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... Show morePurpose: 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. Show less
Hempenius, M.; Rijken, S.; Groenwold, R.H.H.; Hek, K.; Boer, A. de; Klungel, O.H.; Gardarsdottir, H. 2022
Aim Primary nonadherence (PNA) is defined as not filling the first prescription for a drug treatment. PNA can lead not only to poor patient outcomes but also to exposure misclassification in... Show moreAim Primary nonadherence (PNA) is defined as not filling the first prescription for a drug treatment. PNA can lead not only to poor patient outcomes but also to exposure misclassification in written prescription databases. This study aims to estimate PNA in primary care in the Netherlands and to investigate associated factors. Methods Patients from the Nivel Primary Care Database (Nivel-PCD) who received a new prescription (>1 year not prescribed) from a general practitioner in 2012 were linked to pharmacy dispensing information of consenting pharmacies based on sex, year of birth, four-digit postal code and at least 50% matching Anatomical Therapeutic Classification codes. PNA was defined as not having a prescription dispensed within 30 days from the prescribing date. PNA was assessed overall and per drug class. The associations between PNA and several patient- and prescription-related characteristics were assessed using mixed-effects logistic regression models. Results After matching 86 361 of 396 251 subjects (21.8%) in the Nivel-PCD records to the pharmacy records, this study included 65 877 subjects who received 181 939 new drug prescriptions. Overall, PNA was 11.5%. PNA was lowest for thyroid hormones (5.5%) and highest for proton pump inhibitors (12.8%). Several factors were associated with PNA, such as having comorbidities (odds ratio [OR] 1.46, 95% confidence interval [CI] 1.37-1.56 for >3 active diagnoses, compared to no active diagnoses) or reimbursement status (OR 2.78, 95% CI 2.65-2.92 for not reimbursed drugs compared to fully reimbursed drugs). Conclusions A total of 11.5% of newly prescribed drugs were not dispensed. This can lead to overestimation of the actual drug exposure status when using written prescription databases. Show less
Hempenius, M.; Groenwold, R.H.H.; Boer, A. de; Klungel, O.H.; Gardarsdottir, H. 2021
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... Show moreBackground 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. Show less
Hempenius, M.; Groenwold, R.H.H.; Souverein, P.C.; Boer, A. de; Klungel, O.H.; Gardarsdottir, H. 2021
Aims Drug exposure status based on routinely collected data might be misclassified when the database contains only prescriptions from 1 type of prescriber (e.g. general practitioner and not... Show moreAims Drug exposure status based on routinely collected data might be misclassified when the database contains only prescriptions from 1 type of prescriber (e.g. general practitioner and not specialist). This study aims to quantify the impact of such exposure misclassification on the risk of major bleeding and stroke/transient ischaemic attack (TIA)associated with direct oral anticoagulants (DOACs) vs. vitamin K antagonists (VKAs).Methods Incident anticoagulant users (>12 mo free of anticoagulation use) in the Dutch PHARMO Database Network between 2008 and 2017 were included. Drug exposure was assessed using pharmacy dispensing information. The risks of hospital admission of major bleeding for DOAC vs. VKA users was assessed with Cox regression analysis, where exposure was based on all dispensings, on general practitioner (GP)-prescribed dispensings only or on specialist-prescribed dispensings only. Hazard ratios (HRs) were estimated also for hospitalization for gastrointestinal bleeding, intracranial bleeding and stroke/TIA.Results We included 99 182 VKA-initiators and 21 795 DOAC-initiators. Use of DOAC was associated with a lower risk of major bleeding compared to VKA use; HR 0.79 (95% confidence interval 0.70-0.90), 0.78 (0.68-0.91) and 0.62 (0.50-0.76), for exposure based on complete dispensing information, only GP- and only specialist-prescribed dispensings, respectively. Similar results were found for the other bleeding outcomes. For stroke/TIA the HRs were 0.96 (0.84-1.09), 1.00 (0.84-1.18) and 0.72 (0.58-0.90), respectively.Conclusion Including only GP-prescribed anticoagulant dispensings in this case did not materially impact the effect estimates compared to including all anticoagulant dispensings. Including only specialist-prescribed dispensings, however, strengthened the effect estimates. Show less
Hempenius, M.; Luijken, K.; Boer, A. de; Klungel, O.; Groenwold, R.; Gardarsdottir, H. 2020
Purpose Exposure definitions vary across pharmacoepidemiological studies. Therefore, transparent reporting of exposure definitions is important for interpretation of published study results. We... Show morePurpose Exposure definitions vary across pharmacoepidemiological studies. Therefore, transparent reporting of exposure definitions is important for interpretation of published study results. We aimed to assess the quality of reporting of exposure to identify where improvement may be needed.Method We systematically reviewed observational pharmacoepidemiological studies that used routinely collected health data, published in 2017 in six pharmacoepidemiological journals. Reporting of exposure was scored using 11 items of the ISPE-ISPOR guideline on reporting of pharmacoepidemiological studies.Results Of the 91 studies included, all studies reported the type of exposure (100%), while most reported the exposure risk window (85%) and the exposure assessment window (98%). Operationalization of the exposure window was described infrequently: 16% (14/90) of the studies explicitly reported the presence or absence of an induction period if applicable, 11% (5/47), and 35% (17/49) reported how stockpiling and gaps between exposure episodes were handled, respectively, and 35% (17/49) explicitly mentioned the exposure extension. Switching/add-on was reported in 62% (50/81). How switching between drugs was dealt with and specific drug codes were reported in 52 (57%) and 24 (26%) studies, respectively.Conclusion Publications of pharmacoepidemiological studies frequently reported the type of exposure, the exposure risk window, and the exposure assessment window. However, more details on exposure assessment are needed, especially when it concerns the operationalization of the exposure risk window (eg, the presence or absence of an induction period or exposure extension, handling of stockpiling and gaps, and specific codes), to allow for correct interpretation, reproducibility, and assessment of validity. Show less
