Validity of ICD-9 and ICD-10 codes used to identify acute liver injury: a study in three European data sources

This is the peer reviewed version of the following article: Forns, J. [et al.]. Validity of ICD-9 and ICD-10 codes used to identify acute liver injury: a study in three European data sources. "Pharmacoepidemiology and drug safety", 6 Juny 2019, vol. 28, núm. 7, p. 965-975, which has been published in final form at 10.1002/pds.4803. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving."Purpose Validating cases of acute liver injury (ALI) in health care data sources is challenging. Previous validation studies reported low positive predictive values (PPVs). Methods Case validation was undertaken in a study conducted from 2009 to 2014 assessing the risk of ALI in antidepressants users in databases in Spain (EpiChron and SIDIAP) and the Danish National Health Registers. Three ALI definitions were evaluated: primary (specific hospital discharge codes), secondary (specific and nonspecific hospital discharge codes), and tertiary (specific and nonspecific hospital and outpatient codes). The validation included review of patient profiles (EpiChron and SIDIAP) and of clinical data from medical records (EpiChron and Denmark). ALI cases were confirmed when liver enzyme values met a definition by an international working group. Results Overall PPVs (95% CIs) for the study ALI definitions were, for the primary ALI definition, 84% (60%-97%) (EpiChron), 60% (26%-88%) (SIDIAP), and 74% (60%-85%) (Denmark); for the secondary ALI definition, 65% (45%-81%) (EpiChron), 40% (19%-64%) (SIDIAP), and 70% (64%-77%) (Denmark); and for the tertiary ALI definition, 25% (18%-34%) (EpiChron), 8% (7%-9%) (SIDIAP), and 47% (42%-52%) (Denmark). The overall PPVs were higher for specific than for nonspecific codes and for hospital discharge than for outpatient codes. The nonspecific code “unspecified jaundice” had high PPVs in Denmark. Conclusions PPVs obtained apply to patients using antidepressants without preexisting liver disease or ALI risk factors. To maximize validity, studies on ALI should prioritize hospital specific discharge codes and should include hospital codes for unspecified jaundice. Case validation is required when ALI outpatient cases are considered.Peer ReviewedPostprint (author's final draft

Impact of EMA regulatory label changes on systemic diclofenac initiation, discontinuation, and switching to other pain medicines in Scotland, England, Denmark, and The Netherlands

Purpose: In June 2013 a European Medicines Agency referral procedure concluded that diclofenac was associated with an elevated risk of acute cardiovascular events and contraindications, warnings, and changes to the product information were implemented across the European Union. This study measured the impact of the regulatory action on the prescribing of systemic diclofenac in Denmark, The Netherlands, England, and Scotland. Methods: Quarterly time series analyses measuring diclofenac prescription initiation, discontinuation and switching to other systemic nonsteroidal anti-inflammatory (NSAIDs), topical NSAIDs, paracetamol, opioids, and other chronic pain medication in those who discontinued diclofenac. Absolute effects were estimated using interrupted time series regression. Results: Overall, diclofenac prescription initiations fell during the observation periods of all countries. Compared with Denmark where there appeared to be amore limited effect, the regulatory action was associated with significant immediate reductions in diclofenac initiation in The Netherlands (−0.42%, 95% CI, −0.66% to −0.18%), England (−0.09%, 95% CI, −0.11% to −0.08%), and Scotland (−0.67%, 95% CI, −0.79% to −0.55%); and falling trends in diclofenac initiation in the Netherlands (−0.03%, 95% CI, −0.06% to −0.01% per quarter) and Scotland (−0.04%, 95% CI, −0.05% to −0.02% per quarter). There was no significant impact on diclofenac discontinuation in any country. The regulatory action was associated with modest differences in switching to other pain medicines following diclofenac discontinuation. Conclusions: The regulatory action was associated with significant reductions in overall diclofenac initiation which varied by country and type of exposure. There was no impact on discontinuation and variable impact on switching

Identification of potential carcinogenic and chemopreventive effects of prescription drugs : a protocol for a Norwegian registry-based study

Introduction Surveillance of unintended effects of pharmaceuticals (pharmacovigilance or drug safety) is crucial, as knowledge of rare or late side effects is limited at the time of the introduction of new medications into the market. Side effects of drugs may involve increased or decreased risk of cancer, but these typically appear after a long induction period. This fact, together with low incidences of many cancer types, limits the usefulness of traditional pharmacovigilance strategies, primarily based on spontaneous reporting of adverse events, to identify associations between drug use and cancer risk. Postmarketing observational pharmacoepidemiological studies are therefore crucial in the evaluation of drug-cancer associations. Methods and analysis The main data sources in this project will be the Norwegian Prescription Database and the Cancer Registry of Norway. The underlying statistical model will be based on a multiple nested case-control design including all adult (similar to 200 000) incident cancer cases within the age-range 18-85 years from 2007 through 2015 in Norway as cases. 10 cancer-free population controls will be individually matched to these cases with respect to birth year, sex and index date (date of cancer diagnosis). Drug exposure will be modelled as chronic user/non-user by counting prescriptions, and cumulative use by summarising all dispensions' daily defined doses over time. Conditional logistic regression models adjusted for comorbidity (National Patient Register), socioeconomic parameters (Statistics Norway), concomitant drug use and, for female cancers, reproduction data (Medical Birth Registry), will be applied to identify drug-use-cancer-risk associations. Ethics and dissemination The study is approved by the regional ethical committee and the Norwegian data protection authority. Results of the initial screening step and analysis pipeline will be described in a key paper. Subsequent papers will report the evaluation of identified signals in replication studies. Results will be published in peer-reviewed journals, at scientific conferences and through press releases.Peer reviewe

Impact of EU regulatory label changes for diclofenac in people with cardiovascular disease in four countries:interrupted time series regression analysis

Objective: Due to cardiovascular safety concerns, the European Medicines Agency (EMA) recommended new contraindications and changes to product information for diclofenac across Europe in 2013. This study aims to measure their impact among targeted populations. Method: Quarterly interrupted time series regression (ITS) analyses of diclofenac initiation among cohorts with contraindications (congestive cardiac failure [CHF], ischaemic heart disease [IHD], peripheral arterial disease [PAD], cerebrovascular disease [CVD]) and cautions (hypertension, hyperlipidaemia, diabetes) from Denmark, the Netherlands, England and Scotland. Results: The regulatory action was associated with significant immediate absolute reductions in diclofenac initiation in all countries for IHD (Denmark −0.08%, 95%CI −0.13, −0.03; England −0.09%, 95%CI −0.13 to −0.06%; the Netherlands −1.84%, 95%CI −2.51 to −1.17%; Scotland −0.34%, 95%CI −0.38 to −0.30%), PAD and hyperlipidaemia, the Netherlands, England and Scotland for hypertension and diabetes, and England and Scotland for CHF and CVD. Post-intervention there was a significant negative trend in diclofenac initiation in the Netherlands for IHD (−0.12%, 95%CI −0.19 to −0.04), PAD (−0.13%, 95%CI −0.22 to −0.05), hypertension, hyperlipidaemia and diabetes, and in Scotland for CHF (−0.01%, 95%CI −0.02 to −0.007%), IHD (−0.017, 95%CI −0.02, −0.01%), PAD and hypertension. In England, diclofenac initiation rates fell less steeply. In Denmark changes were more strongly associated with the earlier EMA 2012 regulatory action. Conclusion: Although significant reductions in diclofenac initiation occurred, patients with contraindications continued to be prescribed diclofenac, the extent of which varied by country and target condition. Understanding reasons for such variation may help to guide the design or dissemination of future safety warnings

Core concepts in pharmacoepidemiology : Measures of drug utilization based on individual-level drug dispensing data

Background Drug utilization studies are essential to facilitate rational drug use in the society. Aim In this review, we provide an overview of drug utilization measures that can be used with individual-level drug dispensing data, referencing additional reading on the individual analysis. This is intended to serve as a primer for those new to drug utilization research and a shortlist from which researchers can identify useful analytical approaches when designing their drug utilization study. Results and Discussion We provide an overview of: (1) basic measures of drug utilization which are used to describe changes in drug use over time or compare drug use in different populations; (2) treatment adherence measures with specific focus on persistence and implementation; (3) how to measure drug combinations which is useful when assessing drug-drug interactions, concomitant treatment, and polypharmacy; (4) prescribing quality indicators and measures to assess variations in drug use which are useful tools to assess appropriate use of drugs; (5) proxies of prescription drug misuse and skewness in drug use; and (6) considerations when describing the characteristics of drug users or prescribers