An observational post-authorization safety study (PASS) of naloxegol drug utilization in four European countries.

PURPOSE: Naloxegol has been shown to be an efficient alternative to treat opioid-induced constipation (OIC). This study aimed at describing the characteristics of naloxegol users and assessing patterns of naloxegol use and associated factors. METHODS: This drug utilization cohort study used observational registry data on patients newly prescribed naloxegol in four European countries. Patient characteristics and patterns of naloxegol use and associated factors were described. RESULTS: A total of 17 254 naloxegol users were identified across the countries. Their median age was 56-71 years, and each country had a majority of women (ranging 57.5%-62.9%). Multiple comorbidities, including cancer, were common. Natural opium alkaloids and osmotically acting laxatives (excluding saline) were the most frequently used opioids and laxatives. Overall prior use of opioids ranged from 91.9% to 99.6% and overall prior use of laxatives ranged from 69.9% to 92.4%. Up to 77.7% had prior use of medications with interaction potential, and up to 44.5% used them concurrently with naloxegol. Naloxegol was discontinued by 55.1%-90.9% of users, typically during the first 30 days. Approximately 10%-30% switched to or augmented the treatment with another constipation medication or restarted naloxegol after discontinuation. Augmentation with another constipation medication was relatively common, suggesting that naloxegol was used for multifactorial constipation. CONCLUSION: The present study reflects real-world clinical use of naloxegol, including in vulnerable patient groups. Some naloxegol users lacked laxative or regular opioid use within six months before index date or used naloxegol concomitantly with medications presenting an interaction potential.

Prenatal exposure to pregabalin, birth outcomes and neurodevelopment - a population-based cohort study in four Nordic countries.

INTRODUCTION: Pregabalin is an antiepileptic drug frequently prescribed to pregnant women. Risks of adverse birth and postnatal neurodevelopmental outcomes following prenatal exposure to pregabalin are uncertain. OBJECTIVE: To investigate the association between prenatal exposure to pregabalin and the risks of adverse birth and postnatal neurodevelopmental outcomes. METHODS: This study was conducted using population-based registries in Denmark, Finland, Norway, and Sweden (2005-2016). We compared pregabalin exposure against no exposure to antiepileptics and against active comparators lamotrigine and duloxetine. We obtained pooled propensity score-adjusted estimates of association using fixed-effect and Mantel-Haenszel (MH) meta-analyses. RESULTS: The total number of pregabalin-exposed births was 325/666,139 (0.05%) in Denmark, 965/643,088 (0.15%) in Finland, 307/657,451 (0.05%) in Norway, and 1275/1,152,002 (0.11%) in Sweden. The adjusted prevalence ratios (aPRs) with 95% confidence interval (CI) following pregabalin exposure versus no exposure were 1.14 (0.98-1.34) for major congenital malformations and 1.72 (1.02-2.91) for stillbirth, which attenuated to 1.25 (0.74-2.11) in MH meta-analysis. For the remaining birth outcomes, the aPRs were close to or attenuated toward unity in analyses using active comparators. Adjusted hazard ratios (95% CI) contrasting prenatal pregabalin exposure versus no exposure were 1.29 (1.03-1.63) for ADHD and attenuated when using active comparators, 0.98 (0.67-1.42) for autism spectrum disorders, and 1.00 (0.78-1.29) for intellectual disability. CONCLUSIONS: Prenatal exposure to pregabalin was not associated with low birth weight, preterm birth, small for gestational age, low Apgar score, microcephaly, autism spectrum disorders, or intellectual disability. On the basis of the upper value of the 95% confidence interval, increased risks greater than 1.8 were unlikely for any major congenital malformation and ADHD. For stillbirth and most groups of specific major congenital malformations, the estimates attenuated in MH meta-analysis.

Metformin in pregnancy and risk of abnormal growth outcomes at birth: a register-based cohort study.

INTRODUCTION: We previously reported an increased risk of being small for gestational age (SGA) and a decreased risk of being large for gestational age (LGA) after in utero exposure to metformin compared with insulin exposure. This follow-up study investigated if these observations remain when metformin exposure (henceforth, metformin cohort) is compared with non-pharmacological antidiabetic treatment of gestational diabetes mellitus (GDM; naïve cohort), instead of insulin. RESEARCH DESIGN AND METHODS : This was a Finnish population register-based cohort study from singleton children born during 2004-2016. Birth outcomes from metformin cohort (n=3964) and the naïve cohort (n=82 675) were used in the main analyses. Additional analyses were conducted in a subcohort, restricting the metformin cohort to children of mothers with GDM only (n=2361). Results were reported as inverse probability of treatment weighted OR (wOR), with the naïve cohort as reference. RESULTS  : No difference was found for the outcome of SGA between the cohorts in the main analyses (wOR 0.97, 95% CI 0.73 to 1.27) or in the additional analyses (wOR 1.01, 95% CI 0.75 to 1.37). No difference between the cohorts was found for the risk of LGA (wOR 0.91, 95% CI 0.75 to 1.11) in the main analyses but a decreased risk was observed in the additional analyses (wOR 0.72, 95% CI 0.56 to 0.92). CONCLUSIONS : This follow-up study found no increase in the risk of SGA or LGA after in utero exposure to metformin, compared with drug-naïve GDM. The decreased risk of LGA in mothers with GDM may suggest residual confounding. The lack of increased SGA risk aligns with findings from studies using metformin in non-diabetic pregnancies. In contrast, lower birth weight and increased SGA birth risk were observed in GDM pregnancies for metformin versus insulin. Metformin should be avoided with emerging growth restriction in utero. The interplay of intrauterine hyperglycemia and pharmacological treatments needs further assessment.

Healthcare costs of adverse drug reactions and potentially inappropriate prescribing in older adults: a population-based study.

OBJECTIVES: To describe the distribution of costs based on potentially inappropriate prescribing (PIP) and adverse drug reaction (ADR) status in terms of total direct costs and costs caused by ADRs, among older adults. DESIGN: A retrospective cohort study was conducted among older adults, identified from a random sample of the general Swedish population. PIP was identified based on the Screening Tool of Older Persons' Prescriptions (STOPP) criteria and ADRs were identified using the Howard criteria. Causality between PIP and ADRs was evaluated using Hallas' criteria. Prevalence-based direct healthcare costs were calculated for the 3-month study period, including the total cost for healthcare and drugs, and the cost caused by ADRs. SETTING: All care levels, including primary care, other outpatient care and inpatient care. PARTICIPANTS: 813 adults ≥65 years. PRIMARY OUTCOME MEASURES: The prevalence and cost of PIP and ADRs. RESULTS: Total direct cost for persons with PIP was approximately twice the total cost of those without PIP (€1958 (€1428-€2616) vs €881 (€817-€1167), p=0.0020). The costs caused by ADRs was 10 times higher among persons with PIP, compared with those without PIP (€270 (€86-€545) vs €27 (€10-€61), p=0.047). For persons with ADRs caused by PIP, total direct costs were €4646 (€2617-€7931). This group represented 8% of the study population and used 25% of the costs. The main cost driver in all studied patient groups was healthcare contacts. CONCLUSIONS: Older persons with PIP and ADRs had high healthcare costs, particularly when ADRs were caused by PIP. Since these costs appear to be substantial, the potential savings by preventing their occurrence may, to a certain degree, cover the added cost of such activities. Further studies should be undertaken to provide further evidence on the costs of PIP, ADRs and ADRs caused by PIP.

Metformin in pregnancy and risk of adverse long-term outcomes: a register-based cohort study.

INTRODUCTION: This study aimed to investigate if maternal pregnancy exposure to metformin is associated with increased risk of long-term and short-term adverse outcomes in the child. RESEARCH DESIGN AND METHODS : This register-based cohort study from Finland included singleton children born 2004-2016 with maternal pregnancy exposure to metformin or insulin (excluding maternal type 1 diabetes): metformin only (n=3967), insulin only (n=5273) and combination treatment (metformin and insulin; n=889). The primary outcomes were long-term offspring obesity, hypoglycemia, hyperglycemia, diabetes, hypertension, polycystic ovary syndrome, and challenges in motor-social development. In a sensitivity analysis, the primary outcomes were investigated only among children with maternal gestational diabetes. Secondary outcomes were adverse outcomes at birth. Analyses were conducted using inverse- probability of treatment weighting (IPTW), with insulin as reference. RESULTS  : Exposure to metformin or combination treatment versus insulin was not associated with increased risk of long-term outcomes in the main or sensitivity analyses. Among the secondary outcomes, increased risk of small for gestational age (SGA) was observed for metformin (IPTW-weighted OR 1.65, 95% CI 1.16 to 2.34); increased risk of large for gestational age, preterm birth and hypoglycemia was observed for combination treatment. No increased risk was observed for neonatal mortality, hyperglycemia, or major congenital anomalies. CONCLUSIONS : This study found no increased long-term risk associated with pregnancy exposure to metformin (alone or in combination with insulin), compared with insulin. The increased risk of SGA associated with metformin versus insulin suggests caution in pregnancies with at-risk fetal undernutrition. The increased risks of adverse outcomes at birth associated with combination treatment may reflect confounding by indication or severity.

Prevalence of adverse pregnancy outcomes after exposure to interferon beta prior to or during pregnancy in women with MS: Stratification by maternal and newborn characteristics in a register-based cohort study in Finland and Sweden.

BACKGROUND: Previous studies reported no increase in the prevalence of adverse pregnancy outcomes after exposure to interferon-beta (IFN-beta). However, no study has investigated if the prevalence of these outcomes after IFN-beta exposure is modified by maternal and newborn characteristics. Our objective was to describe the stratified prevalence of adverse pregnancy outcomes among women with multiple sclerosis (MS) exposed only to IFN-beta or unexposed to any MS disease modifying drugs (MSDMDs). METHODS: This population-based cohort study using Finnish (1996-2014) and Swedish (2005-2014) register data included pregnancies of women with MS exposed only to IFN-beta 6 months before or during pregnancy (n=718) or unexposed to MSDMDs (n=1397). The outcome prevalences were described stratified by maternal and newborn characteristics, with 95% confidence intervals (CIs). Confounder-adjusted analyses were performed if the prevalence results indicated modified effect of IFN-beta in specific strata. RESULTS: The stratified analysis indicated that the prevalence of serious (anomaly or stillbirth) and other adverse pregnancy outcomes was similar among the exposed and unexposed, with no statistically significant difference. Among women treated for MS >5 years, serious adverse pregnancy outcomes occurred in 4.3% (95%CI: 1.9-8.3%) of pregnancies exposed only to IFN-beta 6 months before or during pregnancy and in 2.7% (95%CI: 1.2-5.0%) of unexposed pregnancies. The confounder adjusted analyses did not support the hypothesis that MS treatment duration before pregnancy would modify the risk of adverse pregnancy outcomes after exposure to IFN-beta 6 months before or during pregnancy. CONCLUSION: The prevalence of adverse pregnancy outcomes was not increased after IFN-beta exposure, when pregnancies of women with MS were stratified by maternal and newborn characteristics. The stratified results were similar to the unstratified results in the same population.

Pregnancy outcomes after exposure to interferon beta: a register-based cohort study among women with MS in Finland and Sweden.

BACKGROUND: Our aim was to estimate and compare the prevalence of adverse pregnancy outcomes among pregnant women with multiple sclerosis (MS) exposed to interferon beta (IFNB) and among women with MS unexposed to any MS disease-modifying drug (MSDMD). METHODS: This cohort study used Finnish (1996-2014) and Swedish (2005-2014) national register data. Women with MS having IFNB dispensed 6 months before or during pregnancy as the only medication were considered as IFNB exposed (only IFNB-exposed), whereas women with MS unexposed to any MSDMD were considered unexposed (MSDMD-unexposed). Prevalence was described and compared using log-binomial or logistic regression and adjusted for potential confounders including maternal age and comorbidity. RESULTS: Among 2831 pregnancies, 2.2% of the only IFNB-exposed and 4.0% of the MSDMD-unexposed women had serious adverse pregnancy outcomes [elective termination of pregnancy due to foetal anomaly (TOPFA), major congenital anomaly (MCA) in live, or stillbirth]. After adjustments, the prevalence of serious adverse pregnancy outcomes was lower among the only IFNB-exposed compared with the MSDMD-unexposed [relative risk 0.55, 95% confidence interval (CI) 0.31-0.96]. The prevalence of individual outcomes, including MCA, spontaneous abortions, and stillbirths was not increased with IFNB exposure. Women with MS exposed to IFNB appeared more likely to terminate their pregnancy for reasons other than foetal anomaly, compared with MSDMD-unexposed pregnant MS patients (odds ratio 1.71, 95% CI 1.06-2.78). CONCLUSION: In this large cohort study, no increase in the prevalence of adverse pregnancy outcomes was observed in women with MS exposed to IFNB compared with MS patients unexposed to any MSDMDs. This study together with other evidence led to a change in the labels of the IFNB products in September 2019 in the European Union, and IFNB use today may be considered during pregnancy, if clinically needed.

Observational evidence from patients diagnosed with chronic lymphocytic leukaemia (CLL) in Finland between 2005-2015 show improved survival over time.

OBJECTIVES: We aimed to describe treatment patterns of chronic lymphocytic leukaemia (CLL) patients in routine practice settings, compare overall survival and time-to-next-treatment among patients treated in different time periods (2005-2008, 2009-2013, 2014-2015), and explore associated factors. METHODS: This retrospective cohort study included adult CLL patients from the Finnish Hematology Registry. RESULTS: In total, 124 and 64 CLL patients received first- and second-line treatments, respectively. The use of first- and second-line treatments with bendamustine-rituximab (BR) increased, while chlorambucil-based treatments decreased over time. Patients treated in more recent years showed a trend towards longer first- and second-line survival. A trend towards inferior overall survival was detected in first- and second-line treatment with B/BR. First-line time-to-next-treatment was longer for patients treated in the later years towards 2015, while second-line time-to-next-treatment did not improve over time. CONCLUSIONS: This study identified that improved treatment outcomes over time were likely influenced by patient characteristics and treatments, but also through other factors unexplored in this study. Hence, further research on the factors influencing patients' survival over time is needed. In particular, research on using B/BR in clinical practice is warranted.

Comparing Methods for Estimating Direct Costs of Adverse Drug Events.

OBJECTIVES: To estimate how direct health care costs resulting from adverse drug events (ADEs) and cost distribution are affected by methodological decisions regarding identification of ADEs, assigning relevant resource use to ADEs, and estimating costs for the assigned resources. METHODS: ADEs were identified from medical records and diagnostic codes for a random sample of 4970 Swedish adults during a 3-month study period in 2008 and were assessed for causality. Results were compared for five cost evaluation methods, including different methods for identifying ADEs, assigning resource use to ADEs, and for estimating costs for the assigned resources (resource use method, proportion of registered cost method, unit cost method, diagnostic code method, and main diagnosis method). Different levels of causality for ADEs and ADEs' contribution to health care resource use were considered. RESULTS: Using the five methods, the maximum estimated overall direct health care costs resulting from ADEs ranged from Sk10,000 (Sk = Swedish krona; ~€1,500 in 2016 values) using the diagnostic code method to more than Sk3,000,000 (~€414,000) using the unit cost method in our study population. The most conservative definitions for ADEs' contribution to health care resource use and the causality of ADEs resulted in average costs per patient ranging from Sk0 using the diagnostic code method to Sk4066 (~€500) using the unit cost method. CONCLUSIONS: The estimated costs resulting from ADEs varied considerably depending on the methodological choices. The results indicate that costs for ADEs need to be identified through medical record review and by using detailed unit cost data.

Direct and indirect costs for adverse drug events identified in medical records across care levels, and their distribution among payers.

BACKGROUND: Adverse drug events (ADEs) cause considerable costs in hospitals. However, little is known about costs caused by ADEs outside hospitals, effects on productivity, and how the costs are distributed among payers. OBJECTIVE: To describe the direct and indirect costs caused by ADEs, and their distribution among payers. Furthermore, to describe the distribution of patient out-of-pocket costs and lost productivity caused by ADEs according to socio-economic characteristics. METHOD: In a random sample of 5025 adults in a Swedish county, prevalence-based costs for ADEs were calculated. Two different methods were used: 1) based on resource use judged to be caused by ADEs, and 2) as costs attributable to ADEs by comparing costs among individuals with ADEs to costs among matched controls. Payers of costs caused by ADEs were identified in medical records among those with ADEs (n = 596), and costs caused to individual patients were described by socio-economic characteristics. RESULTS: Costs for resource use caused by ADEs were €505 per patient with ADEs (95% confidence interval €345-665), of which 38% were indirect costs. Compared to matched controls, the costs attributable to ADEs were €1631, of which €410 were indirect costs. The local health authorities paid 58% of the costs caused by ADEs. Women had higher productivity loss than men (€426 vs. €109, p = 0.018). Out-of-pocket costs displaced a larger proportion of the disposable income among low-income earners than higher income earners (0.7% vs. 0.2%-0.3%). CONCLUSION: We used two methods to identify costs for ADEs, both identifying indirect costs as an important component of the overall costs for ADEs. Although the largest payers of costs caused by ADEs were the local health authorities responsible for direct costs, employers and patients costs for lost productivity contributed substantially. Our results indicate inequalities in costs caused by ADEs, by sex and income.

Potentially inappropriate prescribing and adverse drug reactions in the elderly: a population-based study.

PURPOSE: Potentially inappropriate prescriptions (PIPs) criteria are widely used for evaluating the quality of prescribing in elderly. However, there is limited evidence on their association with adverse drug reactions (ADRs) across healthcare settings. The study aimed to determine the prevalence of PIPs, defined by the Screening Tool of Older Persons' potentially inappropriate Prescriptions (STOPP) criteria, in the Swedish elderly general population and to investigate the association between PIPs and occurrence of ADRs. METHOD: Persons ≥65 years old were identified from a random sample of 5025 adults drawn from the Swedish Total Population Register. A retrospective cohort study was conducted among 813 elderly with healthcare encounters in primary and specialised healthcare settings during a 3-month period in 2008. PIPs were identified from the Swedish Prescribed Drug Register, medical records and health administrative data. ADRs were independently identified by expert reviewers in a stepwise manner using the Howard criteria. Multivariable logistic regression examined the association between PIPs and ADRs. RESULTS: Overall, 374 (46.0 %) persons had ≥1 PIPs and 159 (19.5 %) experienced ≥1 ADRs during the study period. In total, 29.8 % of all ADRs was considered caused by PIPs. Persons prescribed with PIPs had more than twofold increased odds of experiencing ADRs (OR 2.47; 95 % CI 1.65-3.69). PIPs were considered the cause of 60 % of ADRs affecting the vascular system, 50 % of ADRs affecting the nervous system and 62.5 % of ADRs resulting in falls. CONCLUSION: PIPs are common among the Swedish elderly and are associated with increased odds of experiencing ADRs. Thus, interventions to decrease PIPs may contribute to preventing ADRs, in particular ADRs associated with nervous and vascular disorders and falls.

Adherence to Antihypertensive Therapy and Elevated Blood Pressure: Should We Consider the Use of Multiple Medications?

BACKGROUND: Although a majority of patients with hypertension require a multidrug therapy, this is rarely considered when measuring adherence from refill data. Moreover, investigating the association between refill non-adherence to antihypertensive therapy (AHT) and elevated blood pressure (BP) has been advocated. OBJECTIVE: Identify factors associated with non-adherence to AHT, considering the multidrug therapy, and investigate the association between non-adherence to AHT and elevated BP. METHODS: A retrospective cohort study including patients with hypertension, identified from a random sample of 5025 Swedish adults. Two measures of adherence were estimated by the proportion of days covered method (PDC≥80%): (1) Adherence to any antihypertensive medication and, (2) adherence to the full AHT regimen. Multiple logistic regressions were performed to investigate the association between sociodemographic factors (age, sex, education, income), clinical factors (user profile, number of antihypertensive medications, healthcare use, cardiovascular comorbidities) and non-adherence. Moreover, the association between non-adherence (long-term and a month prior to BP measurement) and elevated BP was investigated. RESULTS: Non-adherence to any antihypertensive medication was higher among persons < 65 years (Odds Ratio, OR 2.75 [95% CI, 1.18-6.43]) and with the lowest income (OR 2.05 [95% CI, 1.01-4.16]). Non-adherence to the full AHT regimen was higher among new users (OR 2.04 [95% CI, 1.32-3.15]), persons using specialized healthcare (OR 1.63, [95% CI, 1.14-2.32]), and having multiple antihypertensive medications (OR 1.85 [95% CI, 1.25-2.75] and OR 5.22 [95% CI, 3.48-7.83], for 2 and ≥3 antihypertensive medications, respectively). Non-adherence to any antihypertensive medication a month prior to healthcare visit was associated with elevated BP. CONCLUSION: Sociodemographic factors were associated with non-adherence to any antihypertensive medication while clinical factors with non-adherence to the full AHT regimen. These differing findings support considering the use of multiple antihypertensive medications when measuring refill adherence. Monitoring patients' refill adherence prior to healthcare visit may facilitate interpreting elevated BP.

Pharmacoepidemiology at Nordic School of Public Health NHV: Examples from 1999 to 2014.

BACKGROUND: Pharmacoepidemiology is a branch of public health and had a place at the Nordic School of Public Health. Courses, Master's theses and Doctorates of Public Health (DrPH) in Pharmacoepidemiology were a relatively minor, but still important part of the school's activities. METHODS: This paper gives a short background, followed by some snapshots of the activities at NHV, and then some illustrative case-studies. These case-studies list their own responsible co-authors and have separate reference lists. RESULTS: In the Nordic context, NHV was a unique provider of training and research in pharmacoepidemiology, with single courses to complete DrPH training, as well as implementation of externally-funded research projects. CONCLUSIONS: With the closure of NHV at the end of 2014, it is unclear if such a comprehensive approach towards pharmacoepidemiology will be found elsewhere in the Nordic countries.

The impact of a changed legislation on reporting of adverse drug reactions in Sweden, with focus on nurses' reporting.

PURPOSE: In March 2007, a legislative amendment was issued in Sweden compelling nurses to report all suspected adverse drug reactions (ADRs) to the national pharmacovigilance system. The aims of this study were to describe the status of ADR reporting, before and after the implementation of the legislative changes, and to describe the general characteristics of suspected ADRs reported by nurses. METHODS: The Swedish pharmacovigilance system during the study period constituted six regional centres responsible for the handling of all spontaneous ADR reports within their region. In this study, we identified all individual ADR reports from 2005 and 2010, analysed in depth the ADR reports from two regional centres and collated information about the reporter and the nature of the reported ADR. RESULTS: From the two regional centres, a total of 898 and 1074 reports were submitted in 2005 and 2010 respectively. Nurses submitted 31% (275 reports) of the reports in 2005 and 24% (260 reports) in 2010. Nurses' reporting of serious ADRs was 3% (seven reports) in 2005 and 7% (17 reports) in 2010 with reporting of unlabelled ADRs at 4% (11 reports) in 2005 and 17% (45 reports) in 2010. Most of the serious and/or unlabelled reactions were related to vaccine administration (14 reports in 2005 and 36 reports in 2010). CONCLUSIONS: The overall ADR reporting by nurses did not appear to increase after the change in reporting legislation. The proportion of serious and/or unlabelled ADRs reported by nurses did however appear to increase during the same period. Taken together, our data suggests that further pro-active measures should be considered in order to involve nurses in the reporting of suspected ADRs.

Economic impact of adverse drug events--a retrospective population-based cohort study of 4970 adults.

BACKGROUND: The aim was to estimate the direct costs caused by ADEs, including costs for dispensed drugs, primary care, other outpatient care, and inpatient care, and to relate the direct costs caused by ADEs to the societal COI (direct and indirect costs), for patients with ADEs and for the entire study population. METHODS: We conducted a population-based observational retrospective cohort study of ADEs identified from medical records. From a random sample of 5025 adults in a Swedish county council, 4970 were included in the analyses. During a three-month study period in 2008, direct and indirect costs were estimated from resource use identified in the medical records and from register data on costs for resource use. RESULTS: Among 596 patients with ADEs, the average direct costs per patient caused by ADEs were USD 444.9 [95% CI: 264.4 to 625.3], corresponding to USD 21 million per 100 000 adult inhabitants per year. Inpatient care accounted for 53.9% of all direct costs caused by ADEs. For patients with ADEs, the average societal cost of illness was USD 6235.0 [5442.8 to 7027.2], of which direct costs were USD 2830.1 [2260.7 to 3399.4] (45%), and indirect costs USD 3404.9 [2899.3 to 3910.4] (55%). The societal cost of illness was higher for patients with ADEs compared to other patients. ADEs caused 9.5% of all direct healthcare costs in the study population. CONCLUSIONS: Healthcare costs for patients with ADEs are substantial across different settings; in primary care, other outpatient care and inpatient care. Hence the economic impact of ADEs will be underestimated in studies focusing on inpatient ADEs alone. Moreover, the high proportion of indirect costs in the societal COI for patients with ADEs suggests that the observed costs caused by ADEs would be even higher if including indirect costs. Additional studies are needed to identify interventions to prevent and manage ADEs.

Prevalence, nature and potential preventability of adverse drug events - a population-based medical record study of 4970 adults.

AIMS: To estimate the 3 month prevalence of adverse drug events (ADEs), categories of ADEs and preventable ADEs, and the preventability of ADEs among adults in Sweden. Further, to identify drug classes and organ systems associated with ADEs and estimate their seriousness. METHODS: A random sample of 5025 adults in a Swedish county council in 2008 was drawn from the Total Population Register. All their medical records in 29 inpatient care departments in three hospitals, 110 specialized outpatient clinics and 51 primary care units were reviewed retrospectively in a stepwise manner, and complemented with register data on dispensed drugs. ADEs, including adverse drug reactions (ADRs), sub-therapeutic effects of drug therapy (STEs), drug dependence and abuse, drug intoxications from overdose, and morbidities due to drug-related untreated indication, were detected during a 3 month study period, and assessed for preventability. RESULTS: Among 4970 included individuals, the prevalence of ADEs was 12.0% (95% confidence interval (CI) 11.1, 12.9%), and preventable ADEs 5.6% (95% CI 5.0, 6.2%). ADRs (6.9%; 95% CI 6.2, 7.6%) and STEs (6.4%; 95% CI 5.8, 7.1%) were more prevalent than the other ADEs. Of the ADEs, 38.8% (95% CI 35.8-41.9%) was preventable, varying by ADE category and seriousness. ADEs were frequently associated with nervous system and cardiovascular drugs, but the associated drugs and affected organs varied by ADE category. CONCLUSIONS: The considerable burden of ADEs and preventable ADEs from commonly used drugs across care settings warrants large-scale efforts to redesign safer, higher quality healthcare systems. The heterogeneous nature of the ADE categories should be considered in research and clinical practice for preventing, detecting and mitigating ADEs.

Refill adherence and self-reported adverse drug reactions and sub-therapeutic effects: a population-based study.

PURPOSE: To assess refill adherence to dispensed oral long-term medications among the adult population and to investigate whether the percentages of self-reported adverse drug reactions (ADRs) and sub-therapeutic effects (STEs) differed for medications with adequate refill adherence, oversupply, and undersupply. METHOD: Survey responses on self-reported ADRs and STEs were linked to the Swedish Prescribed Drug Register in a cross-sectional population-based study. Refill adherence to antihypertensive, lipid-lowering, and oral anti-diabetic medications was measured using the continuous measure of medication acquisition (CMA). The percentages of self-reported ADRs and STEs were compared between medications with adequate refill adherence (CMA 0.8-1.2), oversupply (CMA > 1.2), and undersupply (CMA < 0.8). RESULTS: The study included 1827 persons, and the refill adherence was measured for 3014 antihypertensive, 839 lipid lowering, and 253 oral anti-diabetic medications. Overall, 65.7% of the medications had adequate refill adherence, 21.9% oversupply, and 12.4% undersupply. The percentages of self-reported ADRs and STEs were respectively 2.6%, 2.7%, and 2.1% (p > 0.5) for ADRs and 1.1%, 1.6%, and 1.5% (p > 0.5) for STEs. CONCLUSIONS: Adequate refill adherence was found in two thirds of the medication therapies. ADRs and STEs were unexpectedly equally commonly reported for medications with adequate refill adherence, oversupply, and undersupply. These results suggest that a better understanding of patients' refill behaviors and their perceived medication adverse outcomes is needed and should be considered in improving medication management. The impact of individual and healthcare factors that may influence the association between refill adherence and reported medication adverse outcomes should be investigated in future studies.

Prevalence and perceived preventability of self-reported adverse drug events--a population-based survey of 7099 adults.

PURPOSE: Adverse drug events (ADEs) are common and often preventable among inpatients, but self-reported ADEs have not been investigated in a representative sample of the general public. The objectives of this study were to estimate the 1-month prevalence of self-reported ADEs among the adult general public, and the perceived preventability of 2 ADE categories: adverse drug reactions (ADRs) and sub-therapeutic effects (STEs). METHODS: In this cross-sectional study, a postal survey was sent in October 2010 to a random sample of 13 931 Swedish residents aged ≥ 18 years. Self-reported ADEs experienced during the past month included ADRs, STEs, drug dependence, drug intoxications and morbidity due to drug-related untreated indication. ADEs could be associated with prescription, non-prescription or herbal drugs. The respondents estimated whether ADRs and STEs could have been prevented. ADE prevalences in age groups (18-44, 45-64, or ≥65 years) were compared. RESULTS: Of 7099 respondents (response rate 51.0%), ADEs were reported by 19.4% (95% confidence interval, 18.5-20.3%), and the prevalence did not differ by age group (p>0.05). The prevalences of self-reported ADRs, STEs, and morbidities due to drug-related untreated indications were 7.8% (7.2-8.4%), 7.6% (7.0-8.2%) and 8.1% (7.5-8.7%), respectively. The prevalence of self-reported drug dependence was 2.2% (1.9-2.6%), and drug intoxications 0.2% (0.1-0.3%). The respondents considered 19.2% (14.8-23.6%) of ADRs and STEs preventable. Although reported drugs varied between ADE categories, most ADEs were attributable to commonly dispensed drugs. Drugs reported for all and preventable events were similar. CONCLUSIONS: One-fifth of the adult general public across age groups reported ADEs during the past month, indicating a need for prevention strategies beyond hospitalised patients. For this, the underlying causes of ADEs should increasingly be investigated. The high burden of ADEs and preventable ADEs from widely used drugs across care settings supports redesigning a safer healthcare system to adequately tackle the problem.

Modelling drug-related morbidity in Sweden using an expert panel of pharmacists'.

BACKGROUND: Drug-related morbidity (DRM) is common and to some extent preventable, and associated with considerable costs in patients attending hospital. In outpatients and in the general public corresponding data are limited, but pharmacists' expert opinion has suggested high rates of DRM also in US ambulatory care. It is unknown if the results are applicable in Sweden today. OBJECTIVE: To estimate the proportions of patients with DRM and preventable DRM and the cost-of-illness (COI) of DRM in Sweden based on pharmacists' expert opinion. SETTING: Swedish healthcare. METHOD: The study applied a conceptual model of DRM based on a decision tree. An expert panel of pharmacists determined the probabilities of therapeutic outcomes of medication therapy. The COI analysis included direct costs from the healthcare perspective. Sensitivity analyses were performed for variations in probabilities and pathway costs. MAIN OUTCOME MEASURE: DRM included new medical problems (adverse drug reactions, drug dependence and intoxications) and therapeutic failures (insufficient effects of medicines and morbidity due to untreated indication). RESULTS: The expert panel estimated that 61 ± 14 % (mean ± SD) of all patients attending healthcare suffered from DRM, of which 29 ± 8 % suffered from new medical problems, 18 ± 6 % from therapeutic failures, and 15 ± 7 % from a combination of both. The DRM was considered preventable in 45 ± 15 % of the patients with DRM. The estimated COI was EUR 997 per patient attending healthcare, corresponding to an annual cost of EUR 6,600 million to the Swedish healthcare system. The COI ranged from EUR 490 to EUR 1,314 when varying the participants' probabilities of DRM and clinical outcomes from the first to the third quartile. Of the pathway costs, the COI was most sensitive to variation in the cost of prolonged hospital stay (COI range EUR 953-1,306). CONCLUSION: According to pharmacists' expert opinion, a large proportion of patients in Sweden experience DRM and preventable DRM, and the estimated COI of DRM is extensive. Since observational studies have not addressed the burden of DRM to the general public, this study adds the pharmacists' perception on DRM. Other healthcare professionals' perceptions on DRM need to be investigated in future studies.

Modelling drug-related morbidity in Sweden using an expert panel of physicians.

PURPOSE: In modelling studies using pharmacists' opinions, drug-related morbidity (DRM) and preventable DRM have been more common than in observational studies, and the resulting costs are extensive. Modelling studies' estimates may vary depending on informants' profession. The purpose of this modelling study was to estimate the proportion of patients with DRM and preventable DRM and the cost of illness (COI) of DRM in Sweden based on physicians' expert opinions. METHOD: A conceptual model of DRM was modified from previous studies. Using a modified Delphi technique, a panel of physicians (n = 19) estimated the probabilities of DRM, preventable DRM, and clinical outcomes of DRM separately for outpatients and inpatients. DRM included new medical problems (adverse drug reactions, drug dependence, and intoxications by overdose) and therapeutic failure (insufficient effects of medicines, and morbidity due to untreated indication). A COI analysis included the direct costs of DRM. RESULTS: Physicians estimated that 51 ± 22% [mean ± standard deviation (SD)] of outpatients experience DRM and 12 ± 8% preventable DRM. Of inpatients, 54 ± 17% was estimated to experience DRM and 16 ± 7% preventable DRM. Of outpatients with DRM, 24 ± 11% was estimated to experience preventable DRM, whereas this proportion for inpatients was 31 ± 15%. The estimated COI was 376 euros per outpatient and 838 euros per inpatient. CONCLUSIONS: Swedish physicians estimated that every other outpatient and inpatient experiences DRM, which is often preventable and costly. As physicians' estimates on the proportion of patients with DRM were higher than in observational studies in restricted subpopulations, DRM may be more common in the general population than observational studies suggest.