Anna K. Jönsson

Risk of venous thromboembolism due to antipsychotic drug therapy.

An increasing number of reports suggest a link between venous thromboembolism (VTE) and the use of antipsychotics. To better understand this association the available body of evidence has been critically scrutinised. Relevant articles were identified in the databases Scopus and PubMed. Several observational studies using different methodologies show an increased risk of VTE in psychiatric patients. This elevated risk seems to be related to the use of antipsychotic medication and in particular to the use of clozapine and low-potency first-generation drugs. Many studies investigating the association have, however, methodological limitations. The biological mechanisms involved in the pathogenesis of this possible adverse reaction are largely unknown but several hypotheses have been suggested such as drug-induced sedation, obesity, increased levels of antiphospholipid antibodies, enhanced platelet aggregation, hyperhomocysteinemia and hyperprolactinemia. The association may also be related to underlying risk factors present in psychotic patients. Physicians need to be aware of this possible adverse drug reaction. Although supporting evidence has not been published they should consider discontinuing or switching the antipsychotic treatment in patients experiencing VTE. In addition, although data is lacking, the threshold for considering prophylactic antithrombotic treatment should be low when risk situations for VTE arise, such as immobilisation, surgery and so on.

Spontaneously reported adverse reactions in association with complementary and alternative medicine substances in Sweden

Although the safety information is limited, use of complementary and alternative medicine (CAM) products is not without risks. Spontaneous reporting systems may be used in the surveillance of these products. We describe the pattern of spontaneously reported CAM related adverse reactions submitted to the Swedish Medical Products Agency (MPA) and highlight areas of safety concern.

Tramadol dependence : a survey of spontaneously reported cases in Sweden.

Tramadol is a weak opioid analgesic, which is generally considered to be safe. However, conflicting data exist on the dependence potential of tramadol.

Caffeine fatalities--do sales restrictions prevent intentional intoxications?

Objective. Caffeine is widely available in beverages and in different over-the-counter products, including tablets containing 100 mg caffeine. Because intentional fatal intoxications with caffeine occur, the maximum quantity of caffeine tablets that can be bought over the counter in a single purchase was restricted from 250 to 30 in Sweden in the year 2004. The objective of this article was to study the effect of this decision on the number of fatal caffeine intoxications. Method. In Sweden 95% of all cases undergoing forensic autopsy are screened for a number of drugs including caffeine. All cases during January 1993–September 2009 with a caffeine concentration above 80 μg/g blood were recorded. Results. During the study period toxicological investigations were performed in 83,580 forensic autopsies. Caffeine contributed to the fatal outcome in 20 cases (0.02%). Thirteen (65%) of these fatalities occurred before the introduction of the sales restriction. However, no fatal intoxications where caffeine contributed to the cause of death was recorded between May 2007 and September 2009. Conclusion. Overdoses of tablets containing caffeine can be fatal, suicides as well as accidents occur. Restricting the maximum quantity of caffeine tablets available over the counter seemed to be effective in preventing suicides because of caffeine although some time elapsed until the effect was noted. Further monitoring is required to ensure that the observed lower caffeine mortality is a sustained effect.

Venous Thromboembolism in Recipients of Antipsychotics : Incidence, Mechanisms and Management

Since chlorpromazine was introduced to the market in the early 1950s, the use of antipsychotic drugs has been associated with venous thromboembolism (VTE) in a number of reports. During the last decade the evidence has been strengthened with large epidemiological studies. Whether all antipsychotics increase the risk for VTE or the risk is confined to certain drugs is still unclear. The aim of this article is to present an updated critical review focusing on the incidence, mechanisms and management of VTE in users of antipsychotics. After searching the databases PubMed and Scopus for relevant articles we identified 12 observational studies, all of which were published after the year 2000. In most of these studies an elevated risk of VTE was observed for antipsychotic drugs, with the highest risk for clozapine, olanzapine and low-potency first-generation antipsychotics. The risk seems to be correlated with dose. The elderly, who mainly use lower doses, do not show an increased risk of VTE to the same extent as younger subjects.The underlying biological mechanisms explaining the association between antipsychotic medication and VTE are to a large extent unknown. Several hypotheses have been proposed, such as body weight gain, sedation, enhanced platelet aggregation, increased levels of antiphospholipid antibodies, hyperprolactinaemia and hyperhomocysteinaemia. The risk of VTE in schi-zophrenia and other psychotic disorders may also be related to the underlying disease rather than the medication.Very limited evidence exists to guide how cases of VTE in subjects using antipsychotics should be handled. An attempt to compile an algorithm where the patients’ individual risk of VTE is assessed and preventive clinical measures are suggested has been published recently. Strong consideration should be given to discontinuation of the offending antipsychotic drug in patients experiencing a VTE, and another antipsychotic drug with a presumably lower risk should be chosen if antipsychotic drug treatment is still indicated. It is essential that physicians and patients are aware that VTE may be an adverse drug reaction to the antipsychotic treatment so the condition is identified early and treated appropriately.

A comparison of two methods for estimating refill adherence to statins in Sweden: the RARE project.

To analyse and compare refill adherence to statins estimated with two different methods with a focus on sensitivity to definitions.

Antipsychotics and risk of venous thromboembolism: A population-based case-control study

During the last decade, the risk of venous thromboembolism (VTE) has been reported in users of antipsychotic drugs. However, the reports have been inconclusive. This study aimed to determine the relative risk of VTE in antipsychotic drug users. Using data from medical databases in North Jutland and Aarhus Counties, Denmark, and the Danish Civil Registration System, we identified 5,999 cases with a first-time diagnosis of VTE and, based on risk set sampling, 59,990 sex- and age-matched population controls during 1997–2005. Users of antipsychotic drugs were identified from population-based prescription databases and categorized based on filled prescriptions prior to admission date for VTE or index date for controls as current (at least one prescription within 90 days), recent (at least one prescription within 91–180 days), former (at least one prescription within 181–365 days) or nonusers (no recorded prescription within 365 days). Compared with nonusers, current users of any antipsychotic drugs had an increased risk of VTE (adjusted relative risk [ARR]: 1.99, 95% confidence interval [CI]: 1.69–2.34). Former users of any antipsychotic drugs had a nonsignificant elevated risk of VTE compared with nonusers (ARR: 1.54, 95% CI: 0.99–2.40, p-value: 0.056). In conclusion, users of antipsychotic drugs have an increased risk of VTE, compared with nonusers, which might be due to the treatment itself, to lifestyle factors, to the underlying disease, or to residual confounding.

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.

Cost of illness of patient-reported adverse drug events: a population-based cross-sectional survey.

Objectives To estimate the cost of illness (COI) of individuals with self-reported adverse drug events (ADEs) from a societal perspective and to compare these estimates with the COI for individuals without ADE. Furthermore, to estimate the direct costs resulting from two ADE categories, adverse drug reactions (ADRs) and subtherapeutic effects of medication therapy (STE). Design Cross-sectional study. Setting The adult Swedish general population. Participants The survey was distributed to a random sample of 14 000 Swedish residents aged 18 years and older, of which 7099 responded, 1377 reported at least one ADE and 943 reported an ADR or STE. Main outcome measures Societal COI, including direct and indirect costs, for individuals with at least one self-reported ADE, and the direct costs for prescription drugs and healthcare use resulting from self-reported ADRs and STEs were estimated during 30 days using a bottom-up approach. Results The economic burden for individuals with ADEs were (95% CI) 442.7 to 599.8 international dollars (Int