Adherence to Direct Oral Anticoagulants in Patients With Non-Valvular Atrial Fibrillation: A Cross-National Comparison in Six European Countries (2008-2015).

Aims: To describe and compare the adherence to different direct oral anticoagulants (DOACs) in eight European databases representing six countries. Methods: Longitudinal drug utilization study of new users (≥18 years) of DOACs (dabigatran, rivaroxaban, apixaban) with a diagnosis of non-valvular atrial fibrillation (2008-2015). Adherence was examined by estimating persistence, switching, and discontinuation rates at 12 months. Primary non-adherence was estimated in BIFAP and SIDIAP databases. Results: The highest persistence rate was seen for apixaban in the CPRD database (81%) and the lowest for dabigatran in the Mondriaan database (22%). The switching rate for all DOACs ranged from 2.4 to 13.1% (Mondriaan and EGB databases, respectively). Dabigatran had the highest switching rate from 5.0 to 20.0% (Mondriaan and EGB databases, respectively). The discontinuation rate for all DOACs ranged from 16.0 to 63.9% (CPRD and Bavarian CD databases, respectively). Dabigatran had the highest rate of discontinuers, except in the Bavarian CD and AOK NORDWEST databases, ranging from 23.2 to 64.6% (CPRD and Mondriaan databases, respectively). Combined primary non-adherence for examined DOACs was 11.1% in BIFAP and 14.0% in SIDIAP. There were differences in population coverage and in the type of drug data source among the databases. Conclusion: Despite the differences in the characteristics of the databases and in demographic and baseline characteristics of the included population that could explain some of the observed discrepancies, we can observe a similar pattern throughout the databases. Apixaban was the DOAC with the highest persistence. Dabigatran had the highest proportion of discontinuers and switchers at 12 months in most databases (EMA/2015/27/PH).

Incidence of medically treated depression in Denmark among individuals 15-44 years old: a comprehensive overview based on population registers.

OBJECTIVE: Examine the overall incidence of medically treated depression in Denmark among individuals 15-44 years old, and estimate the 5-year cumulative incidence of psychiatric hospital care among individuals treated first in non-hospital-based care. METHODS: We followed all individuals born in Denmark between 1969 and 1998 from age 15 or 2006 (whichever came first) until first depression treatment; death; emigration; or December 31, 2013. Incidence rates were estimated using Poisson regression. Cumulative incidence of hospital care following treatment in non-hospital care was estimated using Kaplan-Meier curves. RESULTS: In this sample of 2 014 760 individuals, incidence rates of depression in non-hospital and hospital-based care in 2012-2013 were 6.6 (95% Confidence Interval: 6.5-6.7) per 1000 person-years and 1.5 (95% CI: 1.5-1.6) per 1000 person-years, respectively. Overall, 85-90% of first medical treatment for depression took place outside of psychiatric hospitals, but a quarter (26.3%) of individuals treated for depression received hospital care initially or within 5 years. Incidence of hospital care was higher in women and younger individuals. CONCLUSIONS: Most medical treatment for depression in Denmark takes place in non-hospital settings. Women and younger individuals are more likely to receive hospital care both initially and within 5 years after first antidepressant treatment.

C-reactive protein and white blood cell levels in schizophrenia, bipolar disorders and depression - associations with mortality and psychiatric outcomes: a population-based study.

BACKGROUND: Mental disorders have been associated with increased levels of inflammatory markers, which can affect disease trajectories. We aimed to assess levels of C-reactive protein (CRP) and white blood cells (WBC) across individuals with schizophrenia, bipolar disorder, and depression, and to investigate associations with subsequent psychiatric admission and mortality. METHODS: We identified all adults in the Central Denmark Region during 2000-2012 with a first diagnosis of schizophrenia, bipolar disorder, or depression and a baseline measurement of CRP and/or WBC count. We followed these individuals until outcome of interest (psychiatric admission or death), emigration or December 31, 2012, using Cox regression analysis to estimate hazard ratios (HRs). RESULTS: Baseline median CRP differed significantly between mental disorders (P=0.01) being highest in individuals with bipolar disorder (3.5mg/L) (particularly during manic states, 3.9mg/L), followed by schizophrenia (3.1mg/L), and depression (2.8mg/L), while baseline WBC count did not differ (median 7.1×109/L). Elevated CRP levels were associated with increased all-cause mortality by adjusted HRs of 1.56 (95% CI: 1.02-2.38) for levels 3-10mg/L and 2.07 (95% CI: 1.30-3.29) for levels above 10mg/L compared to individuals with levels below 3mg/L. WBC counts were not associated with all-cause mortality. No association was observed between levels of the inflammatory markers and subsequent psychiatric admissions. CONCLUSIONS: People with severe mental disorders had increased inflammatory markers at first diagnosis, and elevated CRP levels were associated with increased mortality. Thorough screening for physical diseases is of utmost importance among individuals who are diagnosed with severe mental disorder.

Psychopharmacological drug utilization patterns in pregnant women with bipolar disorder - A nationwide register-based study.

BACKGROUND: Bipolar disorder is often associated with a lifetime indication for treatment with psychotropic drugs, thus pregnant women face the dilemma whether to continue treatment or not. This study describes the psychopharmacological drug utilization patterns among women with bipolar disorder from 12 months preconception to 12 months postpartum. METHODS: We conducted a register-based cohort study among all Danish women aged 15-55 with a diagnosis of bipolar disorder, who gave birth to their first and singleton child between January 1997 and December 2012. Psychotropic drug use was determined by prescriptions obtained from the Danish National Prescription Registry. RESULTS: We identified 336 women. The proportion of women redeeming prescriptions for any psychotropic drug decreased during pregnancy, from 54.8% in the 3 months preconception to 36.6% in the third trimester (p<0.001). Lithium dosing increased significantly during pregnancy. A total of 35 (41.2%) of the women on psychotropic monotherapy and 37 (50.0%) of the women on psychotropic polypharmacy used an antidepressant without concomitant use of a mood-stabilizer at some time during pregnancy. LIMITATIONS: Only redemption of prescriptions was assessable, thus we were not able to assess compliance and discontinuation of treatment before the end of the treatment duration. There was no information on drug use during hospitalizations. CONCLUSIONS: We found a decrease in the proportion of women redeeming prescriptions during pregnancy. There was a high prevalence of antidepressant use without a mood-stabilizer, potentially putting women at risk for a switch to mania - although this is still debated. This calls for further investigation.

Infections and exposure to anti-infective agents and the risk of severe mental disorders: a nationwide study.

OBJECTIVE: Severe infections are associated with increased risks of mental disorders; however, this is the first large-scale study investigating whether infections treated with anti-infective agents in the primary care setting increase the risks of schizophrenia and affective disorders. METHOD: We identified all individuals born in Denmark 1985-2002 (N = 1 015 447) and studied the association between infections treated with anti-infective agents and the subsequent risk of schizophrenia and affective disorders during 1995-2013. Cox regression analyses were adjusted for important confounders. RESULTS: Infections treated with anti-infective agents were associated with increased risks of schizophrenia by a hazard rate ratio (HRR) of 1.37 (95%-CI = 1.20-1.57) and affective disorders by a HRR of 1.64 (95%-CI = 1.48-1.82), fitting a dose-response and temporal relationship (P < 0.001). The excess risk was primarily driven by infections treated with antibiotics, whereas infections treated with antivirals, antimycotics, and antiparasitic agents were not significant after mutual adjustment. Individuals with infections requiring hospitalization had the highest risks for schizophrenia (HRR = 2.05; 95%-CI = 1.77-2.38) and affective disorders (HRR = 2.59; 95%-CI = 2.31-2.89). CONCLUSION: Infections treated with anti-infective agents and particularly infections requiring hospitalizations were associated with increased risks of schizophrenia and affective disorders, which may be mediated by effects of infections/inflammation on the brain, alterations of the microbiome, genetics, or other environmental factors.

Cardiovascular drug use and mortality in patients with schizophrenia or bipolar disorder: a Danish population-based study.

BACKGROUND: Cardiovascular (CV) co-morbidity is one of the major modifiable risk factors driving the excess mortality in individuals with schizophrenia or bipolar disorder. Population-based studies in this area are sparse. METHOD: We used Danish population registers to calculate incidence rate ratios (IRRs) for CV drug use, and mortality rate ratios comparing subjects with schizophrenia or bipolar disorder with subjects with no prior psychiatric hospitalization. RESULTS: IRRs for CV prescriptions were significantly decreased in patients with schizophrenia or bipolar disorder compared with the general population. Among persons without previous myocardial infarction (MI) or cerebrovascular disease, persons with schizophrenia or bipolar disorder had an up to 6- and 15-fold increased mortality from all causes or unnatural causes, respectively, compared with the general population, being most pronounced among those without CV treatment (16-fold increase). Among those with previous MI or cerebrovascular disease, excess all-cause and unnatural death was lower (up to 3-fold and 7-fold increased, respectively), but was similar in CV-treated and -untreated persons. CONCLUSIONS: The present study shows an apparent under-prescription of most CV drugs among patients with schizophrenia or bipolar disorder compared with the general population in Denmark. The excess of mortality by unnatural deaths in the untreated group suggests that the association between CV treatment and mortality may be confounded by severity of illness. However, our results also suggest that treatment of CV risk factors is neglected in these patients.

Prevalence of antidepressant use and contacts with psychiatrists and psychologists in pregnant and postpartum women.

OBJECTIVE: We aimed to study prevalence of antidepressant drug use from 12 months prior childbirth to 12 months postpartum and to compare the prevalences with those in a group of women of similar age who did not give birth. We additionally studied prevalences of contacts with private practicing psychiatrists and psychologists during a similar time period. METHOD: Our study population comprised of pregnant women, and their controls were drawn from a 25% sample of the entire Danish population. Information on redeemed prescriptions for antidepressants and referrals to psychiatrists and psychologists was extracted. The outcome measure was period prevalence calculated in 3-month intervals from 12 months before childbirth to 12 months postpartum. RESULTS: In the 2-year observation period around childbirth, 2733 (3.17%) women had one or more prescriptions for an antidepressant and 935 (1.18%) and 1399 (1.76%) were referred to consultations with a psychiatrist or psychologist, respectively. Women giving birth had a markedly lower use of antidepressants compared to controls, with the largest observed difference during third trimester of pregnancy (0.6% vs. 2.20%). CONCLUSION: We found that the prevalence of redeemed prescriptions for antidepressants decreased during pregnancy and increased postpartum. Similar patterns were observed for contacts with private practicing psychiatrists and psychologists.

Secondary medical prevention among Danish patients hospitalised with either peripheral arterial disease or myocardial infarction.

OBJECTIVE: We compared the use of secondary prevention among patients with a first-time hospitalisation for peripheral arterial disease (PAD) of the lower limb with that among patients with a first-time hospitalisation for myocardial infarction (MI). DESIGN AND MATERIALS: Population-based follow-up study between 1997 and 2003 using registry data from the counties of Northern Jutland, Aarhus and Viborg, Denmark. RESULTS: Between 1997 and 2003, within 180 days after hospital discharge, 26% of patients with lower limb PAD (n=3,424) used antiplatelet drugs, 10% statins, 22% ACE-inhibitors/AT-II receptor antagonists and 13% betablockers compared with 55%, 46%, 42% and 78% respectively among patients with MI (n=11,927). Patients with PAD were substantially less likely than patients with MI to use antiplatelet drugs [adjusted relative risk (RR)=0.39 (95% confidence interval (CI): 0.36-0.41)], statins [adjusted RR=0.21 (95% CI: 0.19-0.23)], ACE-inhibitors/AT-II receptor antagonists [adjusted RR=0.43 (95% CI: 0.40-0.47)] and beta-blockers [adjusted RR=0.10 (95% CI: 0.09-0.11). Between 1997 and 2003 secondary prevention increased considerably in both patient groups, but the disparity in treatment persisted. CONCLUSIONS: Efforts to further increase secondary prevention among patients with PAD are needed urgently.

The frequency of inappropriate tablet splitting in primary care.

INTRODUCTION: We assessed the frequency and determinants of tablet splitting in primary care in Germany and evaluated the quality of information on divisibility in the Summary of Product Characteristics (SPCs) and in the Package Leaflet (PL) as legal sources of information for health care providers and patients. METHODS: We performed a cross-sectional questionnaire survey among patients of 59 general practitioners in the German Federal State Saxony-Anhalt in 2005 in order to collect detailed information on all drugs of patients maintained on more than three drugs. RESULTS: The response rate was 82.1% (n=905) and 3,158 drugs (tablets and dragées) were included in the analyses. Of all drugs, 24.1% were split (762 of 3,158): 8.7% of all split tablets were unscored (66 of 762) and 3.8% of all split tablets were not allowed to be split (29 of 762). Tablets of the higher price categories and higher strengths were twice as likely to be split. Only 22.5% of the SPCs (9 of 40) of the split unscored tablet brands contained explicit information on divisibility and only 36.4% of the PLs (8 of 22) of the split brands that were not allowed to be split stated that splitting was not appropriate. CONCLUSION: The splitting of tablets in primary care is a frequent habit likely driven by medical and economic considerations. Almost 1% of all tablets are split that must not be fragmented. However, the SPC and PL provide only limited information on divisibility stressing the need to improve this information promptly to avoid medication errors.

[Search for new anti-angiogenic agents with structural analogy with thalidomide]. / Recherche de nouveaux agents anti-angiogéniques: analogues structuraux de la thalidomide.

Despite its teratogenic effects, thalidomide has been reintroduced in human anticancer treatment for its anti-angiogenic activity, especially observed in patients with multiple myeloma. Here, we report the synthesis of new analogues designed to increase the thalidomide anti-tumour properties. The anti-angiogenic activity of the compounds was tested on EA.hy 926 endothelial cell lines. In this model, that is easier to manipulate than HUVEC cells, thalidomide is active in a similar dose range as reported on HUVEC cells and one of our compounds is more efficient.

Assessing hypertension management in the community: trends of prevalence, detection, treatment, and control of hypertension in the MONICA Project, Augsburg 1984-1995.

OBJECTIVE: To assess trends in prevalence and detection, treatment and control of hypertension in a German population between 1984 and 1995. SETTING AND PARTICIPANTS: Independent random samples of the population were examined in cross-sectional surveys with identical methods in 1984/85 (age range 25 to 64 years, n = 4022 participants), 1989/90 (age range 25 to 74 years, n = 4940) and 1994/95 (age range 25 to 74 years, n = 4856). MAIN OUTCOME MEASURES: Prevalence of hypertension and proportions of hypertensives detected, treated and controlled. Hypertension was defined as blood pressure above 140/90 mm Hg or taking antihypertensive medication. RESULTS: The prevalence of hypertension did not change significantly over the 10 years (25--64 years, age-standardised 1984/85: 37.8% in men and 24.6% in women; 1994/95: 39.3% and 24.8%, respectively). Rates of detection, treatment and control of hypertension did not change much either. Of all hypertensives in 1994/95, 54% were detected in men and 64% in women, the treatment rates were 23% and 32%, and the proportions of those with controlled hypertension (below 140/90 mm Hg with treatment) were as low as 7% and 13%, respectively. Rates were higher in the older age groups, however, control rates never exceeded 20% at any age. CONCLUSIONS: Despite considerable changes in the pharmacological treatment of hypertension there was a disappointing stagnation with regard to the management of this important risk factor in the community. The reasons for this unfavourable trend need clarification and appropriate public health action. Journal of Human Hypertension (2001) 15, 27-36

Incidence of first-time idiopathic seizures in users of tramadol.

STUDY OBJECTIVE: To assess the risk of idiopathic incident seizures among patients who ever took tramadol. DESIGN: Nested case-control design. SETTING: General Practice Research Database from November 1996-August 1998. PATIENTS: Eleven thousand three hundred eighty-three patients. INTERVENTION: Comparison of risks of idiopathic incident seizures during exposed and unexposed times among patients who had ever taken tramadol and other analgesics with 90-day follow-up. MEASUREMENTS AND MAIN RESULTS: Among the 11,383 subjects we identified 21 cases of idiopathic seizures, 10 of which were categorized as definite cases and 11 categorized as possible cases. Three patients were exposed to tramadol alone in the previous 90 days, 10 to opiates, three to both tramadol and opiates, one to other analgesics, and four to no analgesics. CONCLUSION: The risk of idiopathic seizures was similarly elevated in each analgesic exposure category compared with nonusers, suggesting that the risk for patients taking tramadol was not increased compared with other analgesics.

Population trends in antihypertensive drug use: results from the MONICA Augsburg Project 1984 to 1995.

Trends in antihypertensive drug use were assessed among 25- to 64-year-old participants of three independent surveys of the MONICA Augsburg region in 1984/85, 1989/90, and in 1994/95. Despite constant prevalences of hypertension, the percentage of hypertensives taking medication increased over the study period. The latter was mainly due to significant rises in antihypertensive monotherapy. By contrast, the use of combination treatments with two or more agents remained constant; however, although combinations composed of only two drugs were taken more often in 1995, those with three or more agents and fixed-dose preparations decreased substantially. Beta-blockers were most frequently, and with a rising tendency, taken as antihypertensive monotherapy. Newer drug classes like calcium channel blockers and ACE-inhibitors were introduced as monotherapy more hesitantly. Diuretics persisted as the basis of antihypertensive combination therapy. The use of combination therapies containing obsolete drugs, like reserpine, declined significantly with corresponding increases in drug combinations of, in particular, calcium channel blockers or ACE-inhibitors. We conclude that monotherapies account for most of the rising antihypertensive treatment rates and probably reflect intensified therapy of borderline hypertensives. The trends in antihypertensive drug classes and treatment regimens reflect a less rapid adoption of novel therapeutic concepts but a fairly close adherence to national and international guidelines.