Epidemiology and demographic patterns of cardiovascular diseases and neoplasms deaths in Western Europe: a 1990-2019 analysis.

OBJECTIVES: Cardiovascular diseases (CVDs) and neoplasms have been considered as public health concerns worldwide. This study aimed to estimate the epidemiological patterns of death burden on CVDs and neoplasms and its attributable risk factors in Western Europe from 1990 to 2019 to discuss the potential causes of the disparities. STUDY DESIGN AND METHODS: We collected data on CVDs and neoplasms deaths in 24 Western European countries from the Global Burden of Disease Study. We analyzed patterns by age, sex, country, and associated risk factors. The results include percentages of total deaths, age-standardized death rates per 100,000 population, and uncertainty intervals (UIs). Time trends were assessed using annual percent change. RESULTS: In 2019, CVDs and neoplasms accounted for 33.54% and 30.15% of Western Europe's total deaths, with age-standardized death rates of 128.05 (95% UI: 135.37, 113.02) and 137.51 (95% UI: 142.54, 128.01) per 100,000. Over 1990-2019, CVDs rates decreased by 54.97%, and neoplasms rates decreased by 19.54%. Top CVDs subtypes were ischemic heart disease and stroke; top cancers for neoplasms were lung and colorectal. Highest CVD death burdens were in Finland, Greece, Austria; neoplasm burdens in Monaco, San Marino, Andorra. The major risk factors were metabolic (CVDs) and behavioral (neoplasms). Gender differences revealed higher CVDs death burden in males, while neoplasms burden varied by risk factors and age groups. CONCLUSION: In 2019, CVDs and neoplasms posed significant health risks in Western Europe, with variations in death burdens and risk factors across genders, age groups, and countries. Future interventions should target vulnerable groups to lessen the impact of CVDs and neoplasms in the region.

Metabolic syndrome in adults with autistic traits: associated psychological, behavioral, and biological factors in females and males - a PharmLines initiative.

Background: While cardiovascular diseases is highly prevalent and an important cause of mortality in autistic adults, knowledge on their increased cardiovascular risk is limited. Hence, this study aimed to investigate psychological, behavioral, and physical factors associated with metabolic syndrome (MetS) in adults with autistic traits. Methods: In total, 17,705 adults from the Lifelines Cohort were included and categorized using Autism Spectrum Quotient-10 sum-scores. The quartiles with highest (HQ-traits-group females: n = 2,635; males: n = 1803) and lowest levels of autistic traits (LQ-traits-group, n = idem) were analyzed. Using multivariable logistic regression, the associations between MetS and (self-reported and interviewed) psychological, behavioral, and physically measured factors in these stratified groups were investigated. Results: Among females, MetS was more common in the HQ-traits-group than in the LQ-traits-group (10.0% versus 7.5%, p < 0.01), while this was not the case among males (HQ-traits-group 13.8% versus LQ-traits-group 13.1%, p = 0.52). In both the female and male HQ-traits-group, the presence of MetS was associated with poorer self-reported health, less daily physical activity, and altered leukocyte counts. Conclusion: These findings underline the relevance of adequate cardiovascular prevention in adults with higher levels of autistic traits. Future research could gain more insight into the relationship between cardiovascular risk and autistic traits in females, and into tailored cardiovascular prevention.

In utero antidepressant exposure not associated with ADHD in the offspring: A case control sibling design.

Recent studies have reported an association between antidepressant (AD) use during pregnancy and the risk to develop attention-deficit/hyperactivity disorder (ADHD) in the offspring. However, the association might be confounded by risk factors in the pregnant parent. To control for unmeasured factors between pregnancies carried by the same parent, we set up a case-control sibling study using the University of Groningen prescription database IADB.nl. Children receiving medication for ADHD (cases) before the age of 16 years were matched to siblings not receiving such medication (controls). Exposure was defined as at least two prescriptions for any AD during pregnancy, i.e., the period of 39 weeks before the birth date of the offspring. Secondary analyses were performed to assess the effects of the degree of exposure (the amount of Defined Daily Doses) and the type of AD exposed to. Univariate and multivariate logistic regression was used to estimate odds ratios (ORs) with corresponding 95% confidence intervals (CI). In total, 2,833 children (1,304 cases and 1,529 controls) were included in the analysis. Exposure rate to ADs among cases and controls was 2.2% and 2.4%, respectively. After adjusting for the birth date of the child (as a proxy for the date of pregnancy), age of the pregnant parent at birth, use of psychostimulants, opioids, and antiepileptic drugs by the pregnant parent in the 15 months before birth of the child, an adjusted OR of 1.11 (95% CI 0.67-1.83) was found for the risk of ADHD in the offspring when exposed in utero to ADs. This indicates no increased risk of ADHD in offspring following in utero exposure to ADs. The secondary analyses revealed no statistically significant associations either. The present study provides further evidence that an association between in utero AD exposure and ADHD in offspring might not exist. This perceived association may be caused (at least partially) by confounding by indication. The extent to which depression in the pregnant parent could cause mental disorders such as ADHD in offspring, and the mechanisms involved, should be investigated in further studies.

The long-term safety of chronic azithromycin use in adult patients with cystic fibrosis, evaluating biomarkers for renal function, hepatic function and electrical properties of the heart.

Background: Azithromycin maintenance therapy is widely used in cystic fibrosis (CF), but little is known about its long-term safety. We investigated whether chronic azithromycin use is safe regarding renal function, hepatic cell toxicity and QTc-interval prolongation.Methods: Adult CF patients (72 patients using azithromycin for a cumulative period of 364.8 years and 19 controls, 108.8 years) from two CF-centers in the Netherlands with azithromycin (non)-use for at least three uninterrupted years were studied retrospectively.Results: There was no difference in mean decline of estimated glomerular filtration rate (eGFR), nor in occurrence of eGFR-events. No drug-induced liver injury could be attributed to azithromycin. Of the 39 azithromycin users of whom an ECG was available, 4/39 (10.3%) had borderline and 4/39 (10.3%) prolonged QTc-intervals, with 7/8 patients using other QTc-prolonging medication. Of the control patients 1/6 (16.7%) had a borderline QTc-interval, without using other QTc-prolonging medication. No cardiac arrhythmias were observed.Conclusion: We observed no renal or hepatic toxicity, nor cardiac arrythmias during azithromycin use in CF patients for a mean study duration of more than 5 years. One should be aware of possible QTc-interval prolongation, in particular in patients using other QTc-interval prolonging medication.

Rates, determinants and success of implementing deprescribing in people with type 2 diabetes: A scoping review.

BACKGROUND: Individualizing goals for people with type 2 diabetes may result in deintensification of medication, but a comprehensive picture of deprescribing practices is lacking. AIMS: To conduct a scoping review in order to assess the rates, determinants and success of implementing deprescribing of glucose-, blood pressure- or lipid-lowering medications in people with diabetes. METHODS: A systematic search on MEDLINE and Embase between January 2007 and January 2019 was carried out for deprescribing studies among people with diabetes. Outcomes were rates of deprescribing related to participant characteristics, the determinants and success of deprescribing, and its implementation. Critical appraisal was conducted using predefined tools. RESULTS: Fourteen studies were included; eight reported on rates, nine on determinants and six on success and implementation. Bias was high for studies on success of deprescribing. Deprescribing rates ranged from 14% to 27% in older people with low HbA1c levels, and from 16% to 19% in older people with low systolic blood pressure. Rates were not much affected by age, gender, frailty or life expectancy. Rates were higher when a reminder system was used to identify people with hypoglycaemia, which led to less overtreatment and fewer hypoglycaemic events. Most healthcare professionals accepted the concept of deprescribing but differed on when to conduct it. Deprescribing glucose-lowering medications could be successfully conducted in 62% to 75% of participants with small rises in HbA1c . CONCLUSIONS: Deprescribing of glucose-lowering medications seems feasible and acceptable, but was not widely implemented in the covered period. Support systems may enhance deprescribing. More studies on deprescribing blood pressure- and lipid-lowering medications in people with diabetes are needed.

Clinical and economic impact of medication non-adherence in drug-susceptible tuberculosis: a systematic review.

BACKGROUND: Despite considerable efforts to globally eradicate TB, and the availability of effective antibiotics, TB elimination goals are falling behind. While non-adherence to TB drug regimens may compromise effective treatment, its full impact is still unknown.OBJECTIVE: To determine the clinical and economic impact of non-adherence to TB medication on treatment outcomes in drug-susceptible TB patients (DS-TB).METHODS: A systematic review was performed using PubMed and Embase for studies published between 2009 and 2019 reporting associations between adherence and WHO-defined TB treatment outcomes and economic outcomes in DS-TB patients.RESULTS: A total of 14 studies were included. Eight focused on the association between non-adherence and death, 2 on treatment failure, 1 study on successful treatment outcome, 1 study on both successful and unsuccessful treatment outcomes and 2 on cost outcomes. Most studies (71.4%) were retrospective cohort or case-control studies. The results showed that non-adherence to TB drug regimens was associated with death, treatment failure and lower cure rates.CONCLUSION: Non-adherence to TB drugs has a profound impact on both clinical and economic TB outcomes. To reach WHO TB elimination goals, preventing non-adherence and the implementation of cost-effective intervention programmes should receive the highest priority.

Predictors for treatment outcomes among patients with drug-susceptible tuberculosis in the Netherlands: a retrospective cohort study.

OBJECTIVES: We evaluated treatment outcomes and predictors for poor treatment outcomes for tuberculosis (TB) among native- and foreign-born patients with drug-susceptible TB (DSTB) in the Netherlands. METHODS: This retrospective cohort study included adult patients with DSTB treated from 2005 to 2015 from a nationwide exhaustive registry. Predictors for unsuccessful treatment outcomes (default and failure) and TB-associated mortality were analysed using multivariate logistic regression. RESULTS: Among 5674 identified cases, the cumulative incidence of unsuccessful treatment and mortality were 2.6% (n/N = 146/5674) and 2.0% (112/5674), respectively. Although most patients were foreign-born (71%; 4042/5674), no significant differences in these outcomes were observed between native- and foreign-born patients (p > 0.05). Significant predictors for unsuccessful treatment were aged 18-24 years (odds ratio (OR), 2.04; 95% CI 1.34-3.10), homelessness (OR, 2.56; 95% CI 1.16-5.63), prisoner status (OR, 5.39; 95% CI 2.90-10.05) and diabetes (OR, 2.02; 95% CI 1.03-3.97). Furthermore, predictors for mortality were aged 74-84 years (OR, 5.58; 95% CI 3.10-10.03) or ≥85 years (OR, 9.35, 95% CI 4.31-20.30), combined pulmonary and extra-pulmonary TB (OR, 4.97; 95% CI 1.42-17.41), central nervous system (OR, 120, 95% CI 34.43-418.54) or miliary TB (OR, 10.73, 95% CI 2.50-46.02), drug addiction (OR, 3.56; 95% CI 1.34-9.47) and renal insufficiency/dialysis (OR, 3.23; 95% CI 1.17-8.96). CONCLUSIONS: Native- and foreign-born patients exhibited similar TB treatment outcomes. To further reduce disease transmission and inhibit drug resistance, special attention should be given to high-risk patients.

[Upward trend in the use of psychostimulants by adults]. / Stijgende lijn in het gebruik van psychostimulantia door volwassenen.

OBJECTIVE: To gain insight into the trends in the use of psychostimulants among adults. DESIGN: Retrospective database study. METHODS: We selected data on adults (≥ 18 years) who had had a minimum of 2 prescriptions for a psychostimulant drug within 1 year from IADB.nl, a Netherlands database of filled prescriptions (59 public pharmacies, approximately 600,000 patients). We calculated both the number of new users and the total number of users of psychostimulants per year in the period 2004-2014. We also assessed which agent was the most commonly prescribed psychostimulant drug and who had initiated treatment. RESULTS: The number of adults who were prescribed psychostimulants (methylphenidate, dexamphetamine and amphetamine) increased from 1.5 per 1000 adults in 2004 to 7.8 per 1000 adults in 2014. Users were mainly male (63.0%) and methylphenidate was the most frequently prescribed agent (85.7%). The number of new users of these agents increased from 0.5 to 1.5 per 1000 adults, and the greatest increase was observed among young adults (< 30 years). The increase in new users seems to have stabilized since 2012. Around 40% of new treatments were initiated by the GP. CONCLUSION: The large increase in the number of adults who are prescribed psychostimulants seems mainly to be the result of an increase in the number of new users, especially among young adults. As psychostimulants are only approved for the treatment of ADHD in children from 6 years of age and in adolescents, short- and long-term effects and side effects of these drugs need to be better assessed in the adult population.

[Effectiveness of influenza vaccine in the Netherlands: predominant circulating virus type and vaccine match are important conditions]. / Effectiviteit van influenzavaccinatie in Nederland.

OBJECTIVE: To investigate the relationship between circulating influenza virus A types and subtypes and influenza B lineages, their match with the vaccine and the effectiveness of the influenza vaccine (IVE). DESIGN: Test negative case control study. METHOD: We used data from the Dutch Sentinel Practices of the Netherlands Institute for Health Services Research (NIVEL) Primary Care Database. Participating general practitioners took nose and throat swabs for viral studies from patients with influenza-like illness or another acute respiratory infection. Cases were those patients whose samples were positive for an influenza virus and controls were those whose samples were negative for influenza virus. We determined the IVE of 11 influenza seasons 2003/2004 to 2013/2014, for all seasons together and stratified by influenza virus type and to vaccine match or mismatch. RESULTS: Over all seasons, the IVE was 29% (95% CI:11-43). In seven of the 11 seasons there was a mismatch between vaccine and circulating virus type. The IVE was 40% (95% CI: 18-56) for those seasons in which there was a vaccine match, and 20% (95% CI: - 5-38) for seasons with a mismatch. When the influenza A/H3N2 virus was dominant, the IVE was 38% (95% CI: 14-55). The IVE against the influenza virus A/H1N1, A/H1N1/pdm09 and against both influenza B lineages was 77% (95% CI: 37-92), 47% (95% CI: 22-64) and 64% (95% CI: 50-74), respectively. CONCLUSION: The IVE was particularly low when there was a mismatch between the vaccine and the circulating virus type and when A/H3N2 was the dominant influenza subtype.

An explorative study of school performance and antipsychotic medication.

BACKGROUND: Antipsychotic therapy can reduce severe symptoms of psychiatric disorders, however, data on school performance among children on such treatment are lacking. The objective was to explore school performance among children using antipsychotic drugs at the end of primary education. METHODS: A cross-sectional study was conducted using the University Groningen pharmacy database linked to academic achievement scores at the end of primary school (Dutch Cito-test) obtained from Statistics Netherlands. Mean Cito-test scores and standard deviations were obtained for children on antipsychotic therapy and reference children, and statistically compared using analyses of covariance. In addition, differences in subgroups as boys versus girls, ethnicity, household income, and late starters (start date within 12 months of the Cito-test) versus early starters (start date > 12 months before the Cito-test) were tested. RESULTS: In all, data from 7994 children could be linked to Cito-test scores. At the time of the Cito-test, 45 (0.6 %) were on treatment with antipsychotics. Children using antipsychotics scored on average 3.6 points lower than the reference peer group (534.5 ± 9.5). Scores were different across gender and levels of household income (p < 0.05). Scores of early starters were significantly higher than starters within 12 months (533.7 ± 1.7 vs. 524.1 ± 2.6). CONCLUSION: This first exploration showed that children on antipsychotic treatment have lower school performance compared to the reference peer group at the end of primary school. This was most noticeable for girls, but early starters were less affected than later starters. Due to the observational cross-sectional nature of this study, no causality can be inferred, but the results indicate that school performance should be closely monitored and causes of underperformance despite treatment warrants more research.

[Antidepressant guidelines poorly adhered to in young people]. / Antidepressivarichtlijnen slecht nageleefd bij jeugd.

OBJECTIVE: To examine if Dutch physicians adhere to the national guidelines on the treatment of depression in children and adolescents. DESIGN: Retrospective database research. METHOD: Data on children and adolescents aged between 6 and 17 years were selected from the IADB, a Dutch database of filled prescriptions. We examined whether children and adolescents were prescribed fluoxetine as recommended by the guideline, and whether the starting dose was in accordance with the guideline. RESULTS: Of 2942 children and adolescents in whom antidepressant treatment was initiated, the proportion prescribed fluoxetine increased from 10.1% in 1994-2003 to 19.7% in 2010-2014. However, paroxetine (1994-2003) and citalopram (2004-2014) were the most frequently prescribed antidepressants. Starting doses were guideline-concordant in 58% of children, 31% of preadolescents and 16% of adolescents. Sixty percent of all adolescents were prescribed an adult starting dose. CONCLUSION: Guideline adherence was poor. In contrast to the guidelines, physicians preferred citalopram to fluoxetine in children and adolescents with depression. Furthermore, adolescents often received an adult starting dose. These results suggest that dedicated effort is necessary to improve guideline adherence.

Antibiotic use during pregnancy and asthma in preschool children: the influence of confounding.

BACKGROUND: A recent study suggested that early-life intestinal microbiota may play an important role in the development of childhood asthma, indicating that antibiotics taken during early life or in late pregnancy may be associated with childhood asthma. OBJECTIVE: This study aims to assess the association between prenatal antibiotic use and asthma in preschool children using data from the prescription database IADB.nl. To assess the influence of potential confounding, we conducted both a case-sibling and a case-control study and compared the results. METHODS: We conducted a case-sibling study in which 1228 children with asthma were compared to 1228 siblings without asthma, using data from the prescription database IADB.nl. In addition, a case-control study was conducted. Asthma in preschool children was defined as ≥ 3 prescriptions for anti-asthma medication within a year before the fifth birthday. Conditional logistic regression was used to estimate crude and adjusted odds ratios (aORs). RESULTS: In both the case-sibling and case-control analysis, the use of antibiotics in the third trimester of pregnancy was associated with an increased risk of asthma in preschool children (aOR 1.37; 95% CI 1.02-1.83 and aOR 1.40; 95% CI 1.15-1.47). Time-trend analyses showed that results were not influenced by a time trend in antibiotic exposure. A significant association between exposure to antibiotics in any trimester of pregnancy and the development of asthma in preschool children was observed in the case-control analysis only (aOR 1.46; 95% CI 1.34-1.59). CONCLUSION: Antibiotic use in the third trimester of pregnancy was associated with a small increased risk of asthma in preschool children. This association was robust to time-invariant confounding or exposure time trends, further supporting the important role for early-life intestinal microbiota in the development of childhood asthma.

Prescribing patterns, adherence and LDL-cholesterol response of type 2 diabetes patients initiating statin on low-dose versus standard-dose treatment: a descriptive study.

AIMS: The aim of this study was to describe and compare treatment modifications and discontinuation, adherence levels and response to treatment in patients with type 2 diabetes initiating on low-dose vs. standard-dose statin treatment. METHODS: A 2-year follow-up cohort study was performed using data from the Groningen Initiative to Analyse Type 2 Diabetes Treatment (GIANTT) database in patients with type 2 diabetes initiating statin treatment between January 2007 and December 2012. First, we determined whether there were differences in treatment modifications and discontinuation after statin initiation between patients starting on a low-dose vs. standard-dose. Second, we looked at differences in adherence and LDL-cholesterol response after 2 years follow-up between these groups. RESULTS: Around 22% of patients initiated statin treatment on a dose lower than recommended. More than half of them remained on a low dose during a 2-year follow-up period, whereas less than 15% received a dose increase. Of the patients initiating on standard-dose, also more than half remained on the same treatment during this period, whereas 8% received a dose decrease without subsequent increase. Over 25% of patients starting on low-dose or standard-dose treatment discontinued treatment, often within the first 180 days after initiation or after a first treatment change. Patients on low-dose treatment had lower adherence levels and were less likely to have adequate LDL-cholesterol response compared with patients on standard-dose after 2 years follow-up. CONCLUSIONS: Current patterns of statin treatment in patients with type 2 diabetes are suboptimal, with discontinuation, inadequate adherence levels and lack of treatment intensification seen in those who had inadequate LDL-cholesterol response after 2 years of follow-up. Patients starting on low-dose had more treatment modifications, discontinuation and adherence problems as compared with those starting on standard-dose treatment, which calls for a closer look at the rationale of starting patients on low-dose statin treatment.

Relation between CYP2D6 Genotype, Phenotype and Therapeutic Drug Concentrations among Nortriptyline and Venlafaxine Users in Old Age Psychiatry.

Objectives: To determine relations between drug concentrations and the cytochrome P450-CYP2D6 genotype or phenotype among elderly patients treated with nortriptyline or venlafaxine. Methods: A post-hoc analysis of a clinical trial was performed. Patients were grouped into phenotypes according to the metabolite/mother compound ratio. Genotypes were assessed by the CYP2D6 *3 and *4 alleles. Results: Data was available from 81 patients (41 nortriptyline, 40 venlafaxine) with a mean age of 72 years. No phenoconversion from poor metabolizers (PM) to extensive metabolizers (EM), or vice versa, was found. However, we did find phenoconversion from PM to intermediate metabolizers (IM), IM to EM, or vice versa in 36% of observations. Among nortriptyline users, patients with a PM or IM genotype had more supra-therapeutic blood levels, although this did not reach statistical significance. In exploratory analyses we found men were more likely (RR: 2.4; 95% CI: 1.14-5.07) to display phenoconversion from an IM genotype to EM phenotype. In addition, compared to non-PMs, PMs were found to have higher risk (RR: 1.56; 95% CI: 1.03-2.37) on non-response, although this was only significant when response was measured on the Hamilton Rating Scale for Depression and not on the Montgomery Åsberg Depression Rating Scale. Conclusion: Patients phenoconversed, but we did not observe phenoconversion from PM to EM or vice versa. Genotype information could be used as a valuable tool, in addition to therapeutic drug monitoring, to prevent supratherapeutic drug levels of nortriptyline or venlafaxine in elderly patients with a PM genotype.

Identification of Dutch children diagnosed with atopic diseases using prescription data: a validation study.

PURPOSE: The aim of this study is to validate medication proxies for the identification of children diagnosed with atopic disorders that can be applied in various types of epidemiological research. METHODS: Records of 7439 children, aged between 0 and 10 years, in the period 2001 until 2010, were retrieved from the Registration Network Groningen database, a general practitioners database in the north-eastern part of the Netherlands. The sensitivity and positive predictive value (PPV) of 22 medication proxies for the identification of children diagnosed with atopic disorders (asthma, atopic dermatitis, and allergic rhinitis) were computed using the registered diagnoses as gold standards. In addition, different capture periods (1 year, half year, and length of study period) for the detection of prescriptions were tested for all the medication proxies. RESULTS: The highest PPV (0.84, 95 % CI 0.81-0.87) in combination with a sufficient sensitivity value (0.54, 95 % CI 0.50-0.57) for the identification of children diagnosed with asthma was yielded for the medication proxy, ≥2 prescriptions for anti-asthma medication within 1 year, including 1 inhaled steroid. PPV and sensitivity were even higher in the age group 6-10 years. The proxies designed for the identification of children diagnosed with atopic dermatitis and allergic rhinitis yielded only high PPVs (≥0.75) in combination with low sensitivity values (≤0.22). Altering the capture period for the detection of prescriptions to half a year or the length of the study period only affected sensitivity values. CONCLUSION: Children diagnosed with asthma can be identified reliably with a range of medication proxies. The use of prescription data for the identification of children diagnosed with atopic dermatitis and allergic rhinitis is questionable.

Adherence to standard-dose or low-dose statin treatment and low-density lipoprotein cholesterol response in type 2 diabetes patients.

OBJECTIVE: To determine the association between adherence, dose and low-density lipoprotein (LDL) cholesterol response in patients with type 2 diabetes initiating statin treatment. RESEARCH DESIGN AND METHODS: This cohort study was performed using data for 2007-2012 from the Groningen Initiative to Analyse Type 2 Diabetes Treatment (GIANTT) database. The association between adherence to a standard-dose statin and LDL cholesterol response was assessed using linear regression, adjusting for covariates. The effect of low-dose versus standard-dose was assessed in a propensity-score matched cohort. Adherence rates, defined as the proportion of days covered (PDC), were estimated between statin initiation and LDL outcome measurement. MAIN OUTCOME MEASURE: LDL cholesterol level at follow-up. RESULTS: The effect of adherence on LDL cholesterol response, measured in 2160 patients, was dependent on the baseline LDL cholesterol level. For patients with a baseline LDL cholesterol of 3.7 mmol/l and an adherence rate of 80%, a 40% reduction in LDL cholesterol was predicted. In the matched sample of 1144 patients, the treatment dose showed a difference in impact on the outcome for adherence rates higher than 50%. It was estimated that a patient with a baseline LDL cholesterol of 3.7 mmol/l will need an adherence rate of at least 76% on low-dose and 63% on standard-dose treatment to reach the LDL cholesterol target of 2.5 mmol/l. LIMITATIONS: Adherence was measured as the PDC, which is known to overestimate actual adherence. Also, we were not able to adjust for lifestyle factors. CONCLUSIONS: We determined the concurrent effect of treatment adherence and dose on LDL cholesterol outcomes. Given the adherence levels seen in clinical practice, diabetes patients initiating statin treatment are at high risk of not reaching the recommended cholesterol target, especially when they start on a low-dose statin.

Predictors of response in initial users of metformin and sulphonylurea derivatives: a systematic review.

AIM: To provide an overview of factors predicting metformin and sulphonylurea treatment response. BACKGROUND: A large variability between individuals in treatment response to metformin and sulphonylurea derivatives exists. Understanding which factors determine response to these drugs may pave the way for more individualized therapy. METHODS: We conducted a systematic search in the MEDLINE, Cochrane and EMBASE databases, between 2003 and 2012 for articles assessing demographic and clinical prediction factors of treatment response in initial users of metformin or sulphonylurea. A literature search of articles referenced within the studies identified was also performed. Treatment response was defined as change in HbA1c level, reaching target HbA1c levels or time to treatment change. Studies were assessed on quality, sample size and type of analysis. Results were summarized by tabulating positive, null and negative associations observed for included predictors. RESULTS: A total of 10 articles (six trial reports and four cohort studies) were obtained, including three of sufficient quality. For metformin, baseline HbA1c , older age, lower BMI and shorter disease duration were found to be predictors of better treatment response in at least three studies of sufficient quality. For sulphonylurea derivatives, baseline HbA1c and shorter duration were identified as predictors of better treatment response in at least two studies of sufficient quality. Race, smoking status, lipid levels, blood pressure, kidney function and comorbidities were not significantly associated with treatment response. CONCLUSIONS: Several demographic and clinical factors were identified as possible predictors of response to metformin and sulphonylurea, but the number of studies with sufficient quality was small. Generally, early treatment seems important for achieving better glycaemic outcomes.

A simple dried blood spot method for therapeutic drug monitoring of the tricyclic antidepressants amitriptyline, nortriptyline, imipramine, clomipramine, and their active metabolites using LC-MS/MS.

Therapeutic drug monitoring (TDM) of tricyclic antidepressants (TCAs) is considered useful in patients with major depressive disorder, since these drugs display large individual differences in clearance, and the therapeutic windows of these drugs are relatively small. We developed an assay for determination of amitriptyline (ATP), nortriptyline (NTP), imipramine (IMP), desipramine (DSP) clomipramine (CMP) and desmethyl-clomipramine (DCMP) in dried blood spots (DBS). A fast and robust LC-MS/MS method was developed and analytically validated for simultaneous determination of ATP, NTP, IMP, DSP, CMP, and DCMP in DBS. Six mm circles were punched out from DBS collected on Whatman DMPK-C paper and mixed with acetonitrile: methanol 1:3 containing the internal standard. The extract was analyzed by LC-MS/MS. Total LC-MS/MS runtime was 4.8 min. The assay was linear in the range 20-500 µg/L for all compounds. Overall-assay accuracy and precision were<20% for the lower limit of quantification (LLOQ), except for CMP (CV=22.3%), and <15% at other concentrations. The initial LLOQ was 20 µg/L however for CMP and DMCP it was increased to 40 µg/L. The blood volume per spot did not influence the results, but a low hematocrit (≤ 30%) was associated with a >15% negative bias for all compounds. Punching at the perimeter of the blood spot instead of the center was associated with a positive bias. A good correlation was found between patients plasma and DBS samples of ATP, NTP and DMCP, but not for CMP. In addition, proportional differences were found. This LC-MS/MS method was analytically validated for determination of TCAs in DBS. Future validation will focus on the clinical application of the method.

2012/13 influenza vaccine effectiveness against hospitalised influenza A(H1N1)pdm09, A(H3N2) and B: estimates from a European network of hospitals.

While influenza vaccines aim to decrease the incidence of severe influenza among high-risk groups, evidence of influenza vaccine effectiveness (IVE) among the influenza vaccine target population is sparse. We conducted a multicentre test-negative case-control study to estimate IVE against hospitalised laboratory-confirmed influenza in the target population in 18 hospitals in France, Italy, Lithuania and the Navarre and Valencia regions in Spain. All hospitalised patients aged ≥18 years, belonging to the target population presenting with influenza-like illness symptom onset within seven days were swabbed. Patients positive by reverse transcription polymerase chain reaction for influenza virus were cases and those negative were controls. Using logistic regression, we calculated IVE for each influenza virus subtype and adjusted it for month of symptom onset, study site, age and chronic conditions. Of the 1,972 patients included, 116 were positive for influenza A(H1N1)pdm09, 58 for A(H3N2) and 232 for influenza B. Adjusted IVE was 21.3% (95% confidence interval (CI): -25.2 to 50.6; n=1,628), 61.8% (95% CI: 26.8 to 80.0; n=557) and 43.1% (95% CI: 21.2 to 58.9; n=1,526) against influenza A(H1N1) pdm09, A(H3N2) and B respectively. Our results suggest that the 2012/13 IVE was moderate against influenza A(H3N2) and B and low against influenza A(H1N1) pdm09.

Does a cardiovascular event change adherence to statin treatment in patients with type 2 diabetes? A matched cohort design.

OBJECTIVE: To be effective, adherence to statin treatment is essential. We assessed the effect of an apparent first cardiovascular event on statin adherence rates in type 2 diabetes patients. RESEARCH DESIGN AND METHODS: A matched cohort study was conducted among type 2 diabetes patients initiating statin treatment for primary prevention in the Groningen University IADB.nl pharmacy database. Patients who had a drug-treated cardiovascular event (index date) after statin initiation were matched to a reference patient without such an event with similar gender, age at statin initiation, initiation date, follow-up period and adherence level before the event. Adherence rates were measured as percentages of days covered (PDC), and shifts in adherence levels (non-adherent/partially adherent/fully adherent) and rates around the event were evaluated. RESULTS: We could match 375 of the 855 eligible index patients to a reference patient. Index patients had on average a PDC of 81% after the index date; reference patients had a PDC of 71% (p < 0.001) while both had a PDC of 79% before the index date. Index patients were 4.5 times more likely than reference patients to shift from non-adherent to fully adherent (95% CI 1.1-18.8) and 1.8 times more likely to shift from partially adherent to fully adherent (95% CI 1.2-2.6). In the index group, 26% of patients became more adherent after the first cardiovascular event. In contrast, 20% of patients became less adherent. LIMITATIONS: Medication proxies were used, which could have caused misclassification. Furthermore, a substantial group of index patients could not be matched to a reference patient due to small ranges in matching criteria. CONCLUSIONS: The occurrence of a drug-treated cardiovascular event appeared to avert the declining statin adherence rate observed in diabetes patients without such an event. On the other hand, one in five patients became less adherent after the event, indicating that there are still important benefits to achieve.