Risk of death and cardiovascular outcomes with thiazolidinediones: a study with the general practice research database and secondary care data.

OBJECTIVE: To describe the likely extent of confounding in evaluating the risks of cardiovascular (CV) events and mortality in patients using diabetes medication. METHODS: The General Practice Research Database was used to identify inception cohorts of insulin and different oral antidiabetics. An analysis of bias and incidence of mortality, acute coronary syndrome, stroke and heart failure were analysed in GPRD, Hospital Episode Statistics and death certificates. RESULTS: 206,940 patients were identified. The bias analysis showed that past thiazolidinedione users had a lower mortality risk compared to past metformin users. There were no differences between past users of rosiglitazone and pioglitazone (adjusted RR of 1.04; 95% CI 0.93-1.18). Current rosiglitazone users had an increased risk of death (adjusted RR 1.20; 95% CI 1.08-1.34) and of hospitalisation for heart failure (adjusted RR of 1.73; 95% CI 1.19-2.51) compared to current pioglitazone users. Risk of mortality was increased two-fold shortly after starting rosiglitazone. Excess risk of death over 3 years with rosiglitazone was 0.3 per 100 in those aged 50-64 years, 2.0 aged 65-74, 3.0 aged 75-84, and 7.0 aged 85+. The cause of death with rosiglitazone was more likely to be due to a disease of the circulatory system. CONCLUSIONS: Higher risks for death (overall and due to cardiovascular disease) and heart failure were found for rosiglitazone compared to pioglitazone. These excess risks were largest in patients aged 65 years or older. The European regulatory decision to suspend rosiglitazone is supported by this study

Patterns of risk of cancer in patients with metal-on-metal hip replacements versus other bearing surface types: a record linkage study between a prospective joint registry and general practice electronic health records in England.

BACKGROUND: There are concerns that metal-on-metal hip implants may cause cancer. The objective of this study was to evaluate patterns and timing of risk of cancer in patients with metal-on-metal total hip replacements (THR). METHODS: In a linkage study between the English National Joint Registry (NJR) and the Clinical Practice Research Datalink (CPRD), we selected all THR surgeries (NJR) between 2003 and 2010 (n = 11,540). THR patients were stratified by type of bearing surface. Patients were followed up for cancer and Poisson regression was used to derive adjusted relative rates (RR). RESULTS: The risk of cancer was similar in patients with hip resurfacing (RR 0.69; 95% Confidence Interval [CI] 0.39–1.22) or other types of bearing surfaces (RR 0.96; 95% CI 0.64–1.43) compared to individuals with stemmed metal-on-metal THR. The pattern of cancer risk over time did not support a detrimental effect of metal hip implants. There was substantial confounding: patients with metal-on-metal THRs used fewer drugs and had less comorbidity. CONCLUSIONS: Metal-on-metal THRs were not associated with an increased risk of cancer. There were substantial baseline differences between the different hip implants, indicating possibility of confounding in the comparisons between different types of THR implants

Risk of Mortality (including Sudden Cardiac Death) and Major Cardiovascular Events in Users of Olanzapine and Other Antipsychotics: A Study with the General Practice Research Database.

Objective. Assess risk of cardiac events and mortality among users of olanzapine and other antipsychotics relative to nonusers. Methods. The General Practice Research Database was used to identify cohorts of antipsychotic users and nonusers with psychiatric illness. Outcomes included cardiac mortality, sudden cardiac death (SCD), all-cause mortality (excluding suicide), coronary heart disease (CHD), and ventricular arrhythmias (VA). Results. 183,392 antipsychotic users (including 20,954 olanzapine users) and 193,920 psychiatric nonusers were identified. There was a significantly higher rate of cardiac mortality (adjusted RR [aRR]: 1.53, CI, 1.12-2.09) in olanzapine users relative to psychiatric nonusers, consistent with findings for both atypical and typical antipsychotics. Relative to psychiatric nonusers, no increased risk of all-cause mortality was observed among olanzapine users (aRR: 1.04, CI, 0.93-1.17), but elevated all-cause mortality risk was observed when compared to all antipsychotic users (aRR: 1.75, CI, 1.64-1.87). There was no increased risk of CHD or VA among olanzapine users relative to psychiatric nonusers, consistent with findings for atypical but not typical antipsychotics. SCD cases were uncommon. Conclusions. Use of antipsychotic agents was associated with increased risk of all-cause and cardiac mortality. Patients treated with olanzapine were found to be at increased risk of cardiac mortality versus psychiatric nonusers

Коректність задачі Коші для нескінченної системи нелінійних осциляторів, розміщених на двовимірній решітці

Стаття присвячена вивченню нескінченної системи диференціальних рівнянь, яка описує нескінченний ланцюг лінійно зв’язаних нелінійних осциляторів. Отримано результати про існування та єдиність локального та глобального розв’язків задачі Коші.The article deals with infinite systems of differential equations that describe infinite system of nonlinear oscillators on 2D–lattice. It is obtained results on existence and uniqueness of local and global solutions to the Cauchy problem

The Imperfective Past

The objective of our study was to investigate whether use of antipsychotics is associated with hip/femur fractures and whether pharmacological differences between antipsychotics are related to the occurrence of fractures.A case-control study was conducted, in which cases were defined as patients with a hip/femur fracture. Each patient was matched to one control patient. The association between use of antipsychotics and the occurrence of hip/femur fractures was evaluated using conditional logistic regression.The study included 44,500 patients from 683 general practices from different geographical areas in the UK, registered within the General Practice Research Database (GPRD). Exposure to antipsychotics was categorized as “no use”, “current use” and “prior use”.Both current and prior use of antipsychotics were associated with an approximately two-fold increased risk of fractures. After adjustment for possible confounders, a small significant effect remained (Odds Ratios (OR) of 1.3). We did not find an association between dose of antipsychotics, or between the degree of blockade of the alpha-1 adrenoceptor or histamine-1 receptor and risk of fractures. The total number of days of antipsychotic use was significantly associated with an increased risk of hip/femur fractures.We conclude that there is a small increased risk of hip/femur fractures associated with the use of antipsychotics. This risk increases with long-term use

General practitioners' accounts of negotiating antibiotic prescribing decisions with patients: a qualitative study on what influences antibiotic prescribing in low, medium and high prescribing practices

Background Antimicrobial resistance (AMR) is high on the UK public health policy agenda, and poses challenges to patient safety and the provision of health services. Widespread prescribing of antibiotics is thought to increase AMR, and mostly takes place in primary medical care. However, prescribing rates vary substantially between general practices. The aim of this study was to understand contextual factors related to general practitioners’ (GPs) antibiotic prescribing behaviour in low, high, and around the mean (medium) prescribing primary care practices. Methods Qualitative semi-structured interviews were conducted with 41 GPs working in North-West England. Participants were purposively sampled from practices with low, medium, and high antibiotic prescribing rates adjusted for the number and characteristics of patients registered in a practice. The interviews were analysed thematically. Results This study found that optimizing antibiotic prescribing creates tensions for GPs, particularly in doctor-patient communication during a consultation. GPs balanced patient expectations and their own decision-making in their communication. When not prescribing antibiotics, GPs reported the need for supportive mechanisms, such as regular practice meetings, within the practice, and in the wider healthcare system (e.g. longer consultation times). In low prescribing practices, GPs reported that increasing dialogue with colleagues, having consistent patterns of prescribing within the practice, supportive practice policies, and enough resources such as consultation time were important supports when not prescribing antibiotics. Conclusions Insight into GPs’ negotiations with patient and public health demands, and consistent and supportive practice-level policies can help support prudent antibiotic prescribing among primary care practices

Drug therapy for alcohol dependence in primary care in the UK:A Clinical Practice Research Datalink study

AIM:To evaluate drug therapy for alcohol dependence in the 12 months after first diagnosis in UK primary care. DESIGN:Open cohort study. SETTING:General practices contributing data to the UK Clinical Practice Research Database. PARTICIPANTS:39,980 people with an incident diagnosis of alcohol dependence aged 16 years or older between 1 January 1990 and 31 December 2013. MAIN OUTCOME MEASURE:Use of pharmacotherapy (acamprosate, disulfiram, naltrexone, baclofen and topiramate) to promote abstinence from alcohol or reduce drinking to safe levels in the first 12 months after a recorded diagnosis of alcohol dependence. FINDINGS:Only 4,677 (11.7%) of the cohort received relevant pharmacotherapy in the 12 months following diagnosis. Of the 35,303 that did not receive pharmacotherapy, 3,255 (9.2%) received psychosocial support. The remaining 32,048 (80.2%) did not receive either mode of treatment in the first 12 months. Factors that independently reduced the likelihood of receiving pharmacotherapy included: being male (Odds Ratio [OR] 0.74; 95% CI 0.69 to 0.78); older (65-74 years: OR 0.61; 95% CI 0.49 to 0.77); being from a practice based in the most deprived quintile (OR 0.58; 95% CI 0.53 to 0.64); and being located in Northern Ireland (OR 0.78; 95% CI 0.67 to 0.91). The median duration to initiation of pharmacotherapy was 0.80 months (95% CI 0.70 to 1.00) for acamprosate and 0.60 months (95% CI 0.43 to 0.73) for disulfiram. Persistence analysis for those receiving acamprosate and disulfiram revealed that many patients never received a repeat prescription; persistence at 6 months was 27.7% for acomprosate and 33.2% for disulfiram. The median duration of therapy was 2.10 months (95% CI 1.87 to 2.53) for acamprosate and 3.13 months (95% CI 2.77 to 3.36) for disulfiram. CONCLUSION:Drug therapy to promote abstinence in alcohol dependent patients was low, with the majority of patients receiving no therapy, either psychological or pharmacological. When drug therapy was prescribed, persistence was low with most patients receiving only one prescription. Our data show that treatment for alcohol dependence is haphazard, and there is an urgent need to explore strategies for improving clinical management of this patient group

The Association of Oral Bisphosphonate Use With Mortality Risk Following a Major Osteoporotic Fracture in the United Kingdom:Population-Based Cohort Study

OBJECTIVES: Bisphosphonates (BPs) might have extra benefits in reducing mortality because of their anti-atherosclerotic effects, but studies reported conflicting results. We investigated the association between oral BP use and mortality risk following a major osteoporotic fracture (MOF) in the United Kingdom. DESIGN: This was a population-based cohort study. SETTING AND PARTICIPANTS: In total, 163,273 adults aged 50 years and older with an MOF between 2000 and 2018 from the Clinical Practice Research Datalink in the United Kingdom. METHODS: Cox proportional hazards models were used to estimate the risk of all-cause mortality in current (0‒6 months), recent (7‒12 months), and past (>1 year) exposures to oral BPs after nonhip MOF and hip fracture. In addition, stratification by sex, BP type, and duration of follow-up was performed. RESULTS: Compared with never users of oral BPs, current BP use was associated with a 7% higher all-cause mortality risk after nonhip MOF, whereas a 28% lower all-cause mortality risk was observed after hip fracture. Past BP exposure was associated with a 14% and 42% lower risk after nonhip MOF and hip fracture, respectively. When considering only the first 5 years of follow-up, mortality risk associated with current BP use was significantly lower for both fracture groups, and the greatest reduction in mortality risk was observed within the first year. Women had slightly lower risk compared with men. CONCLUSIONS AND IMPLICATIONS: We found a slight increased risk of all-cause mortality with current BP exposure after a nonhip MOF; however, a protective effect was observed following a hip fracture. Both the timing and the effect size of an association based on the anti-atherosclerotic hypothesis of BPs are not supported by our results. The decreasing trend of the mortality risk with shorter durations of follow-up suggests that the observed association is likely due to unknown distortion or unknown pleiotropic properties of BPs

Impact of sample size on the stability of risk scores from clinical prediction models: a case study in cardiovascular disease

From Springer Nature via Jisc Publications RouterHistory: received 2020-02-25, accepted 2020-08-12, registration 2020-08-13, pub-electronic 2020-09-09, online 2020-09-09, collection 2020-12Publication status: PublishedFunder: Medical Research Council; doi: http://dx.doi.org/10.13039/501100000265; Grant(s): MR/N013751/1Abstract: Background: Stability of risk estimates from prediction models may be highly dependent on the sample size of the dataset available for model derivation. In this paper, we evaluate the stability of cardiovascular disease risk scores for individual patients when using different sample sizes for model derivation; such sample sizes include those similar to models recommended in the national guidelines, and those based on recently published sample size formula for prediction models. Methods: We mimicked the process of sampling N patients from a population to develop a risk prediction model by sampling patients from the Clinical Practice Research Datalink. A cardiovascular disease risk prediction model was developed on this sample and used to generate risk scores for an independent cohort of patients. This process was repeated 1000 times, giving a distribution of risks for each patient. N = 100,000, 50,000, 10,000, Nmin (derived from sample size formula) and Nepv10 (meets 10 events per predictor rule) were considered. The 5–95th percentile range of risks across these models was used to evaluate instability. Patients were grouped by a risk derived from a model developed on the entire population (population-derived risk) to summarise results. Results: For a sample size of 100,000, the median 5–95th percentile range of risks for patients across the 1000 models was 0.77%, 1.60%, 2.42% and 3.22% for patients with population-derived risks of 4–5%, 9–10%, 14–15% and 19–20% respectively; for N = 10,000, it was 2.49%, 5.23%, 7.92% and 10.59%, and for N using the formula-derived sample size, it was 6.79%, 14.41%, 21.89% and 29.21%. Restricting this analysis to models with high discrimination, good calibration or small mean absolute prediction error reduced the percentile range, but high levels of instability remained. Conclusions: Widely used cardiovascular disease risk prediction models suffer from high levels of instability induced by sampling variation. Many models will also suffer from overfitting (a closely linked concept), but at acceptable levels of overfitting, there may still be high levels of instability in individual risk. Stability of risk estimates should be a criterion when determining the minimum sample size to develop models

Risk of mortality (including sudden cardiac death) and major cardiovascular events in atypical and typical antipsychotic users: a study with the general practice research database.

Objective. Antipsychotics have been associated with increased cardiac events including mortality. This study assessed cardiac events including mortality among antipsychotic users relative to nonusers. Methods. The General Practice Research Database (GPRD) was used to identify antipsychotic users, matched general population controls, and psychiatric diseased nonusers. Outcomes included cardiac mortality, sudden cardiac death (SCD), all-cause mortality (excluding suicide), coronary heart disease (CHD), and ventricular arrhythmias (VA). Sensitivity analyses were conducted for age, dose, duration, antipsychotic type, and psychiatric disease. Results. 183,392 antipsychotic users (115,491 typical and 67,901 atypical), 544,726 general population controls, and 193,920 psychiatric nonusers were identified. Nonusers with schizophrenia, dementia, or bipolar disorder had increased risks of all-cause mortality compared to general population controls, while nonusers with major depression had comparable risks. Relative to psychiatric nonusers, the adjusted relative ratios (aRR) of all-cause mortality in antipsychotic users was 1.75 (95% CI: 1.64-1.87); cardiac mortality 1.72 (95% CI: 1.42-2.07); SCD primary definition 5.76 (95% CI: 2.90-11.45); SCD secondary definition 2.15 (95% CI: 1.64-2.81); CHD 1.16 (95% CI: 0.94-1.44); and VA 1.16 (95% CI: 1.02-1.31). aRRs of the various outcomes were lower for atypical versus typical antipsychotics (all-cause mortality 0.83 (95% CI: 0.80-0.85); cardiac mortality 0.89 (95% CI: 0.82-0.97); and SCD secondary definition 0.76 (95% CI: 0.55-1.04). Conclusions. Antipsychotic users had an increased risk of cardiac mortality, all-cause mortality, and SCD compared to a psychiatric nonuser cohort