Hip/femur fractures associated with the use of benzodiazepines (anxiolytics, hypnotics and related drugs): a methodological approach to assess consistencies across databases from the PROTECT-EU project.

BACKGROUND: Results from observational studies may be inconsistent because of variations in methodological and clinical factors that may be intrinsically related to the database (DB) where the study is performed. OBJECTIVES: The objectives of this paper were to evaluate the impact of applying a common study protocol to study benzodiazepines (BZDs) (anxiolytics, hypnotics, and related drugs) and the risk of hip/femur fracture (HFF) across three European primary care DBs and to investigate any resulting discrepancies. METHODS: To measure the risk of HFF among adult users of BZDs during 2001-2009, three cohort and nested case control (NCC) studies were performed in Base de datos para la Investigación Farmacoepidemiológica en Atención Primaria (BIFAP) (Spain), Clinical Practice Research Datalink (CPRD) (UK), and Mondriaan (The Netherlands). Four different models (A-D) with increasing levels of adjustment were analyzed. The risk according to duration and type of BZD was also explored. Adjusted hazard ratios (cohort), odds ratios (NCC), and their 95% confidence intervals were estimated. RESULTS: Adjusted hazard ratios (Model C) were 1.34 (1.23-1.47) in BIFAP, 1.66 (1.54-1.78) in CPRD, and 2.22 (1.55-3.29) in Mondriaan in cohort studies. Adjusted odds ratios (Model C) were 1.28 (1.16-1.42) in BIFAP, 1.60 (1.49-1.72) in CPRD, and 1.48 (0.89-2.48) in Mondriaan in NCC studies. A short-term effect was suggested in Mondriaan, but not in CPRD or BIFAP. All DBs showed an increased risk with the concomitant use of anxiolytic and hypnotic drugs. CONCLUSIONS: Applying similar study methods to different populations and DBs showed an increased risk of HFF in BZDs users but differed in the magnitude of the risk, which may be because of inherent differences between DBs.

Understanding inconsistency in the results from observational pharmacoepidemiological studies: the case of antidepressant use and risk of hip/femur fractures.

PURPOSE: Results from observational studies on the same exposure-outcome association may be inconsistent because of variations in methodological factors, clinical factors or health care systems. We evaluated the consistency of results assessing the association between antidepressant use and the risk of hip/femur fractures in three European primary care databases using two different study designs. METHODS: Cohort and nested case control studies were conducted in three European primary care databases (Spanish BIFAP, Dutch Mondriaan and UK THIN) to assess the association between use of antidepressants and hip/femur fracture. A common protocol and statistical analysis plan was applied to harmonize study design and conduct between data sources. RESULTS: Current use of antidepressants was consistently associated with a 1.5 to 2.5-fold increased risk of hip/femur fractures in all data sources with both designs, with estimates for SSRIs generally higher than those for TCAs. In general, risk estimates in Mondriaan, the smallest data source, were higher compared to the other data sources. This difference may be partially explained by an interaction between SSRI and age in Mondriaan. Adjustment for GP-recorded lifestyle factors and matching on general practice had negligible impact on adjusted relative risk estimates. CONCLUSION: We found a consistent increased risk of hip/femur fracture with current use of antidepressants across different databases and different designs. Applying similar pharmacoepidemiological study methods resulted in similar risks for TCA use and some variation for SSRI use. Some of these differences may express real (or natural) variance in the exposure-outcome co-occurrences.

Exposure to benzodiazepines (anxiolytics, hypnotics and related drugs) in seven European electronic healthcare databases: a cross-national descriptive study from the PROTECT-EU Project.

PURPOSE: Studies on drug utilization usually do not allow direct cross-national comparisons because of differences in the respective applied methods. This study aimed to compare time trends in BZDs prescribing by applying a common protocol and analyses plan in seven European electronic healthcare databases. METHODS: Crude and standardized prevalence rates of drug prescribing from 2001-2009 were calculated in databases from Spain, United Kingdon (UK), The Netherlands, Germany and Denmark. Prevalence was stratified by age, sex, BZD type [(using ATC codes), i.e. BZD-anxiolytics BZD-hypnotics, BZD-related drugs and clomethiazole], indication and number of prescription. RESULTS: Crude prevalence rates of BZDs prescribing ranged from 570 to 1700 per 10,000 person-years over the study period. Standardization by age and sex did not substantially change the differences. Standardized prevalence rates increased in the Spanish (+13%) and UK databases (+2% and +8%) over the study period, while they decreased in the Dutch databases (-4% and -22%), the German (-12%) and Danish (-26%) database. Prevalence of anxiolytics outweighed that of hypnotics in the Spanish, Dutch and Bavarian databases, but the reverse was shown in the UK and Danish databases. Prevalence rates consistently increased with age and were two-fold higher in women than in men in all databases. A median of 18% of users received 10 or more prescriptions in 2008. CONCLUSION: Although similar methods were applied, the prevalence of BZD prescribing varied considerably across different populations. Clinical factors related to BZDs and characteristics of the databases may explain these differences.

Incidence of second primary malignancies in relapsed/refractory B-cell non-Hodgkin's lymphoma patients in England.

BACKGROUND: Treatments for relapsed/refractory (r/r) B-cell non-Hodgkin's lymphoma (NHL) may be associated with an increased risk of second primary malignancies (SPMs). Currently available SPM incidence benchmarks are unreliable due to small sample sizes. METHODS: The Cancer Analysis System (CAS), a population-level cancer database in England, was used to identify patients with incident B-cell NHL diagnosed during 2013-2018 with evidence of r/r disease. Incidence rates (IRs) of SPMs after r/r disease diagnosis were calculated per 1000 person-years (PYs) and stratified by age, sex, and SPM type. RESULTS: We identified 9444 patients with r/r B-cell NHL disease. Of those who were eligible for SPM analysis, nearly 6.0% (470/7807) developed at least one SPM after r/r disease diagnosis (IR: 44.7; 95% confidence interval [CI]: 40.9-48.9). Of note, 205 (2.6%) had a non-melanoma skin cancer (NMSC) SPM. IR of SPMs was the highest for patients with r/r chronic lymphocytic leukemia/small lymphocytic leukemia (80.0) and lowest for diffuse large B-cell lymphoma (DLBCL) (30.9). Patients with DLBCL had the shortest overall survival after r/r disease diagnosis. CONCLUSIONS: This real-world data study suggests that the IR of SPM among patients with r/r B-cell NHL is 44.7 per 1000 PY and that most SPMs diagnosed after r/r disease diagnosis are NMSCs, establishing a basis for the comparison of safety outcomes for new treatments being developed for r/r B-cell NHL.

Multiple sclerosis and risk of venous thromboembolism: a population-based cohort study.

BACKGROUND: Multiple sclerosis (MS) patients may be at increased risk of venous thromboembolism (VTE), but evidence is limited. OBJECTIVES: To examine long-term risk of VTE among MS patients. PATIENTS AND METHODS: We conducted a population-based cohort study among 17,418 Danish MS patients and 87,090 comparison cohort members from the general population. Data on MS, VTE and comorbidities were obtained from the Danish National Registry of Patients including all admissions to Danish hospitals since 1977. We computed cumulative risks for VTE and adjusted incidence rate ratios (IRRs). RESULTS: A total of 34 (0.2%) MS patients and 36 (0.04%) comparison cohort members had a deep venous thrombosis (DVT) within 1 year following the date of initial MS diagnosis/index date [adjusted IRR = 3.02 (95% CI: 2.14-4.27)]. During this period, 16 (0.09%) MS patients and 26 (0.03%) comparison cohort members had a documented pulmonary embolism (PE) [adjusted IRR = 2.85 (95% CI: 1.72-4.70)]. During the subsequent up to 29 years, 315 (1.9% of MS patients alive at year 1) MS patients had a record of a DVT [adjusted IRR = 2.28 (95% CI: 2.01-2.59)] and 129 (0.8%) had PE [IRR = 1.58 (95% CI: 1.31-1.92]. CONCLUSION: MS is a risk factor for VTE, but the absolute risk is low.

Risk of arterial cardiovascular diseases in patients with multiple sclerosis: a population-based cohort study.

BACKGROUND: Patients with multiple sclerosis (MS) may have a higher risk of cardiovascular diseases (CVD) than the general population, but data are limited. METHODS: We conducted a population-based cohort study involving Danish citizens diagnosed with MS (n = 13,963) from 1977 to 2006 and an age- and sex-matched population cohort (n = 66,407) using data on MS, arterial CVD and comorbidity from the Danish National Registry of Patients. We calculated the risk of arterial CVD for all subjects and computed adjusted incidence rate ratios (IRRs). RESULTS: During the first year of follow-up, the risk of myocardial infarction (MI) was 0.2% among patients with MS (adjusted IRR = 1.84; 95% confidence interval, CI: 1.28-2.65, compared with population cohort members), whereas the 1-year risk of overall stroke was 0.3% (adjusted IRR = 1.96; 95% CI: 1.42-2.71). IRRs were 1.92 (95% CI: 1.27-2.90) for heart failure and 0.77 (95% CI: 0.42-1.39) for atrial fibrillation/flutter. During the subsequent 2-30 years of follow-up, IRRs remained elevated for overall stroke (1.23; 95% CI: 1.10-1.38) and heart failure (1.53; 95% CI: 1.37-1.71) but decreased for acute MI (1.10; 95% CI: 0.97-1.24). CONCLUSION: In this Danish cohort, the risk of CVD among MS patients was low, but greater than that in the general population, particularly in the short term.

A systematic scoping review on the consequences of stress-related hyperglycaemia.

BACKGROUND: Stress-related hyperglycaemia (SHG) is commonly seen in acutely ill patients and has been associated with poor outcomes in many studies performed in different acute care settings. We aimed to review the available evidence describing the associations between SHG and different outcomes in acutely ill patients admitted to an ICU. Study designs, populations, and outcome measures used in observational studies were analysed. METHODS: We conducted a systematic scoping review of observational studies following the Joanna Briggs methodology. Medline, Embase, and the Cochrane Library were searched for publications between January 2000 and December 2015 that reported on SHG and mortality, infection rate, length of stay, time on ventilation, blood transfusions, renal replacement therapy, or acquired weakness. RESULTS: The search yielded 3,063 articles, of which 43 articles were included (totalling 536,476 patients). Overall, the identified studies were heterogeneous in study conduct, SHG definition, blood glucose measurements and monitoring, treatment protocol, and outcome reporting. The most frequently reported outcomes were mortality (38 studies), ICU and hospital length of stay (23 and 18 studies, respectively), and duration of mechanical ventilation (13 studies). The majority of these studies (40 studies) compared the reported outcomes in patients who experienced SHG with those who did not. Fourteen studies (35.9%) identified an association between hyperglycaemia and increased mortality (odds ratios ranging from 1.13 to 2.76). Five studies identified hyperglycaemia as an independent risk factor for increased infection rates, and one identified it as an independent predictor of increased ICU length of stay. DISCUSSION: SHG was consistently associated with poor outcomes. However, the wide divergences in the literature mandate standardisation of measuring and monitoring SHG and the creation of a consensus on SHG definition. A better comparability between practices will improve our knowledge on SHG consequences and management.

Potential paraneoplastic syndromes and selected autoimmune conditions in patients with non-small cell lung cancer and small cell lung cancer: A population-based cohort study.

BACKGROUND: Little is known about the occurrence and distribution of types of paraneoplastic syndromes (PNS) in patients with lung cancer. Identification of autoimmune PNS is particularly important for discerning them from immune-related adverse events of novel immunotherapies. We estimated the occurrence of PNS among patients with lung cancer and compared it with that in the general population. METHODS: In this registry-based cohort study in Denmark, we identified all patients with incident primary lung cancer between 1997 and 2010, and in a general-population comparison cohort matched on calendar time, sex, age, and residence. Among patients with non-small cell lung cancer (NSCLC) and small-cell lung cancer (SCLC), we estimated prevalence of potential PNS and selected autoimmune conditions and compared their incidence rates with those of equivalent conditions in the general population cohort, using hazard ratios (HRs) adjusted for baseline comorbidity. RESULTS: There were 35,319 patients with NSCLC and 6,711 patients with SCLC. The incidence rates per 1000 person-years (95% confidence interval) of any potential PNS or selected autoimmune disorders were 135.4 (131.9-139.1) among NSCLC patients and 237.3 (224.4-250.5) among SCLC patients. Adjusted HRs for any potential PNS or selected autoimmune disorders were 4.8 (4.7-5.0) for NSCLC and 8.2 (7.6-8.8) for SCLC. CONCLUSION: Incidence rate of any potential PNS or selected autoimmune disorders among patients with lung cancer was greater than that in the general population and was greater after SCLC than after NSCLC. IMPACT: These results provide context to discerning PNS from adverse effects of novel immunotherapies during the clinical course of NSCLC and SCLC.

Psoriasis and risk of incident cancer: an inception cohort study with a nested case-control analysis.

Psoriasis has been associated with lymphohematopoietic and solid cancers; however, reports have been inconsistent. Cancer incidence was compared between psoriasis and psoriasis-free patients, and the roles of psoriasis duration and treatment were explored in this observational study using the UK General Practice Research Database. Among 67,761 patients, 1,703 patients had incident cancer; of whom 54% had a history of psoriasis. Incidence rate ratios for lymphohematopoietic and pancreatic cancers were 1.81 (95% confidence interval (CI) 1.35-2.42) and 2.20 (95% CI 1.18-4.09), respectively. In a nested case-control analysis, adjusted odds ratios (ORs) for cancer overall were 1.50 (95% CI 1.30-1.74) for psoriasis of >or=4 years duration and 1.53 (95% CI 0.97-2.43) for patients receiving systemic treatment (marker of disease severity). Lymphohematopoietic malignancy risk was highest in patients with systemic treatment. The OR for patients without systemic treatment was 1.59 (95% CI 1.01-2.50) for psoriasis of <2 years and 2.12 (95% CI 1.45-3.10) for that of >or=2 years duration. Risks of bladder/kidney and colorectal cancers were increased with longer-duration psoriasis. Psoriasis patients may have an increased overall risk of incident cancer (mainly lymphohematopoietic and pancreatic). Longer-term psoriasis and more severe disease may increase the risk of some cancers. These observations need further confirmation, particularly because of the potential of findings by chance in observational studies with subgroup analyses.

Prevalence of glucose metabolism abnormalities and cardiovascular co-morbidity in the US elderly adult population.

PURPOSE: To estimate the prevalence of glucose metabolism abnormalities, including diabetes, and its associated cardiovascular risk factors and co-morbidity in the US elderly population. METHODS: Cross-sectional analysis of data from the Third National Health and Nutrition Examination Survey (NHANES III, 1988-1994) in adults aged 65 years and more. The 1997 American Diabetes Association (ADA) and the 1998 World Health Organization (WHO) criteria were used to classify the subject's glucose metabolism status. The 2-hour oral glucose tolerance test (OGTT) was performed only among those participants aged 40 to 74 years. RESULTS: The age-adjusted prevalence of diagnosed diabetes was 12.5% (95% CI: 11.4%-13.6%) among US adults aged 65 years or more. According to the ADA definition 40% of men and 28% of women were affected by some degree of glucose metabolism impairment. According to the WHO definition, 55% of men and 50% of women aged 65 to 74 years were affected by glucose metabolism abnormalities. Mexican-Americans were the most affected under both definitions (51% and 77%, respectively). Overall, 72% of elderly diagnosed diabetics had hypertension, 28% had coronary heart disease (CHD), 47% suffered from cardiovascular disease and 80% of them presented known CHD or multiple coronary risk factors, other than age, level of LDL-cholesterol and diabetes. Under both definitions, a trend towards a worsening coronary risk profile with increased glucose metabolism impairment was observed. CONCLUSION: A notable proportion of elderly people is affected by some degree of glucose metabolism impairment which in turn is associated with cardiovascular co-morbidity.