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

The PHARMO System

Pharmacoepidemiology, the study of the effects of drugs in large numbers of people, is a relatively new discipline that applies the methods of epidemiology to clinical pharmacology. Premarketing clinical trials remain the only way to scientifically determine whether a drug is causally effective, yet these trials do not provide information that allows for estimates about rare, late, or off-label toxicities associated with the drug in question. Increasing concern about common and debilitating adverse effects of medications has highlighted the need for enhanced postmarketing surveillance to follow up on clinical trials. There is a further concern regarding the broader issue of the risk-benefit ratio of certain medications. Computerized databases are a good source of information on which to lay the foundations of postmarketing research. A system of cross-linked computerized medical records may better enable researchers and physicians to realistically monitor postmarketing safety and incorporate monitoring benefits. The same research could also elucidate the net public health effect of regulatory decisions. The Veterans Affairs database in the United States and PHARMO in the Netherlands may represent good models on which to base future postmarketing surveillance studies. In this expert roundtable supplement, Brian L. Strom, MD, provides an overview of the appropriate use of large computer databases in pharmacoepidemiology studies. Philip Wang, MD, DrPH, discusses the advantages of pharmacoepidemiologic studies over clinical trials in correctly detecting drug safety issues. Francesca Cunningham, PharmD, reviews a large computer database that is currently in use within the VA healthcare system, and Ron M.C. Herings, PharmD, PhD, discusses the development of the PHARMO system in the Netherlands

Pharmacy-Based Medical Record Linkage Systems

In this chapter the Dutch PHARMO (PHARmacoMOrbidity linkage system), the Danish OPED (Odense University Pharmacoepidemiologic Database), and the Danish AUPD (Aarhus University Prescription Database) are discussed as selected examples of pharmacy-based medical linkage systems. Each system uses its own unique patient identifiers to link exposure (pharmacy dispensing), outcomes, and other relevant characteristics and events. The design of these databases, their strengths, weaknesses, similarities, and differences are presented. The content of the drug exposure files is discussed, as well as methods of linking to other sources, including cancer registries, hospital databases, clinical laboratories, and birth registries. Examples of how these linkages have been used in pharmacoepidemiologic, epidemiologic, and outcomes studies are provided

Concomitant drug use among patients on cardiac glycosides

Cardiac glycosides are among the drugs most commonly used in elderly patients and constitute approximately 3% of all prescriptions filled by these patients. Recipients of digitalis usually show high levels of concomitant drug use. In this study 1,128 users of cardiac glycosides users were matched 1:1 by age, gender and community to non-users. Concomitant drug use patterns in the users group were compared with such patterns in the non-users group. Utilization data were drawn from a sample of pharmacy records (population size: n=74,445). Digoxin accounted for 99% of all digitalis prescriptions. Digoxin use seems to be an important predictor for high morbidity levels and consequent drug use. The prevalence of use of anticoagulants, thyroid drugs, anti-diarrheals, anti-diabetics, anti-hypertensives and diuretics was 2–4 times higher in the digitalis group. Concomitant drug use patterns in naturally occurring groups of patients may provide an important source of information on the health status of recipients of digoxin

Twenty-year trends in the use of anti-seizure medication among pregnant women in the Netherlands

Background: Anti-seizure medications (ASMs) are used to treat conditions such as epilepsy and bipolar disorder. Some of these drugs are associated with an increased risk of congenital malformations and adverse developmental outcomes. Objectives: To examine trends in use of ASMs among pregnant women in the Netherlands according to medication safety profile. Methods: Using population-based data from the PHARMO Perinatal Research Network, we assessed trends in use of ASMs among pregnant women in the Netherlands between 1999 and 2019, stratified by medication safety profile. Individual treatment patterns were also assessed. Results: In total, 671,709 pregnancies among 446,169 women were selected, of which 2405 (3.6 per 1000) were ASM-exposed. Over the study period, a significant increase was observed for use of known safest ASMs (0.7–18.0 per 10,000 pregnancies) as well as for those with uncertain risk (5.3–13.4 per 10,000 pregnancies). Use of ASMs with higher risk of congenital malformations decreased significantly (24.8–14.5 per 10,000 pregnancies), except for topiramate (0–6.7 per 10,000 pregnancies). Switches between ASM safety risk categories before and during pregnancy were uncommon; women rather discontinued treatment or switched within the same category. There was no clear change for the proportion using polytherapy during pregnancy (12% overall), however a non-significant trend toward inclusion of known safest ASMs was observed over time (1.9–3.6%). Conclusions: Over the last two decades, there has been an increase in use of known safest ASMs among pregnant women, together with a trend toward newer ASMs with uncertain risk. Only a small proportion of women switched to a safer alternative before or during pregnancy. Altogether, this highlights the need for an expansion of ASM risk knowledge and communication to healthcare providers and women of reproductive age to improve preconception counseling

Psoriasis may not be an independent predictor for the use of cardiovascular and anti-diabetic drugs: A 5-year prevalence study

Most studies investigating the association between psoriasis and cardiovascular disease have shown a significant relationship. This comparison study investigated the association between psoriasis and prevalent use of cardiovascular drugs. Drug exposure data for 1998 to 2006 were extracted from the Dutch PHARMO-Record Linkage System database. Psoriasis patients were selected using an algorithm of hospitalization and drug dispensing records specific for psoriasis and matched with controls for gender, age and time-period. From the records of 2.5 million Dutch residents, 9,804 (0.4%) psoriasis patients and 15,288 (0.6%) controls were selected. Psoriasis patients used significantly more anti-hypertensives, anti-coagulant and anti-platelet agents, digoxin, nitrates, lipid-lowering and anti-diabetic drugs than the reference population during a 5-year period observation. In a multiple linear regression model adjusting for the number of unique drugs used, psoriasis was no longer significantly associated with any of these drug classes. Psoriasis patients used more cardiovascular-related drugs, but surveillance bias appears to affect this association considerably

A population-based linked cohort of cancer and primary care data: A new source to study the management of cancer in primary care

Objective: Insight into the management of cancer in the primary care setting is pivotal to improve early recognition and survival of cancer patients. Therefore, the Netherlands Cancer Registry (NCR) was linked to the General Practitioner (GP) Database of the PHARMO Database Network to make this research possible. Methods: The NCR collects tumour data on all newly diagnosed cancer patients, whereas the GP Database comprises data from electronic patient records registered by GPs. Databases were linked using a probabilistic record linkage technology. Results: Through record linkage of the NCR and the GP Database, we have established a large population-based cohort (NCR-PHARMO GP cohort) of 135,868 cancer patients. Data are available on demographics, tumour characteristics, primary health care use before and after cancer diagnosis including medication use, medical conditions, laboratory tests, and referrals. Data can be used for a number of different studies, for example, to study the diagnostic pathway in the primary care setting in order to identify possibilities for early recognition. Conclusion: The NCR-PHARMO GP cohort provides rich data on the primary care management of cancer facilitating large-scale observational cancer research in the primary care setting. The patient-level linkage allows for long-term follow-up of cancer patients, with ongoing annual updates

Impact of Osteoporosis Treatment Adherence on Fracture Rates in North America and Europe

Fragility fractures associated with osteoporosis constitute a significant public health concern. Clinical trials have shown that a variety of agents-bisphosphonates, raloxifene, calcitonin, hormone replacement therapy, teriparatide, and strontium ranelate-can reduce the risk of osteoporosis-related fragility fractures. However, low levels of compliance and persistence in the real-life setting mean that efficacy benefits observed in clinical trials with these agents may not translate into equivalent effectiveness in daily practice. The aim of this review is to provide a comprehensive evaluation of compliance and persistence data from retrospective/observational studies, with particular reference to studies that consider the effects on fracture rates. PubMed of the National Center for Biotechnology Information (NCBI) and Web of Science databases were searched for publications detailing observational or retrospective analyses of adherence, compliance, and persistence with osteoporosis therapies. In addition, authors provided relevant studies that were not retrieved using the search criteria. In total, 17 unique publications were identified. Analysis of the publications indicated that low compliance and persistence rates for osteoporosis therapies in the real-life setting result in increased rates of fragility fractures. The results emphasize the importance of good treatment compliance and persistence with osteoporosis therapies in order to achieve a significant therapeutic benefit and thereby reduce the burden that osteoporosis and associated fractures place on individuals and healthcare systems