Publications
scientifiques

IMPORTANCE: Levetiracetam is a commonly used antiepileptic drug, yet psychiatric adverse effects are common and may lead to treatment discontinuation. OBJECTIVE: To derive prediction models to estimate the risk of psychiatric adverse effects from levetiracetam use. DESIGN, SETTING, AND PARTICIPANTS: Retrospective open cohort study. All patients meeting the case definition for epilepsy after the Acceptable Mortality Reporting date in The Health Improvement Network (THIN) database based in the United Kingdom (inclusive January 1, 2000, to May 31, 2012) who received a first-ever prescription for levetiracetam were included. Of 11 194 182 patients registered in THIN, this study identified 7400 presumed incident cases (66.1 cases per 100 000 persons) over a maximum of 12 years' follow-up. The index date was when patients received their first prescription code for levetiracetam, and follow-up lasted 2 years or until an event, loss to follow-up, or censoring. The analyses were performed on April 22, 2018. EXPOSURE: A presumed first-ever prescription for levetiracetam. MAIN OUTCOMES AND MEASURES: The outcome of interest was a Read code for any psychiatric sign, symptom, or disorder as reached through consensus by 2 authors. This study used regression techniques to derive 2 prediction models, one for the overall population and one for those without a history of a psychiatric sign, symptom, or disorder during the study period. RESULTS: Among 1173 patients with epilepsy receiving levetiracetam, the overall median age was 39 (interquartile range, 25-56) years, and 590 (50.3%) were female. A total of 14.1% (165 of 1173) experienced a psychiatric symptom or disorder within 2 years of index prescription. The odds of reporting a psychiatric symptom were significantly elevated for women (odds ratio [OR], 1.41; 95% CI, 0.99-2.01; P = .05) and those with a preexposure history of higher social deprivation (OR, 1.15; 95% CI, 1.01-1.31; P = .03), depression (OR, 2.20; 95% CI, 1.49-3.24; P < .001), anxiety (OR, 1.74; 95% CI, 1.11-2.72; P = .02), or recreational drug use (OR, 2.02; 95% CI, 1.20-3.37; P = .008). The model performed well after stratified k = 5-fold cross-validation (area under the curve [AUC], 0.68; 95% CI, 0.58-0.79). There was a gradient in risk, with probabilities increasing from 8% for 0 risk factors to 11% to 17% for 1, 17% to 31% for 2, 30% to 42% for 3, and 49% when all risk factors were present. For those free of a preexposure psychiatric code, a second model performed comparably well after k = 5-fold cross-validation (AUC, 0.72; 95% CI, 0.54-0.90). Specificity was maximized using threshold cutoffs of 0.10 (full model) and 0.14 (second model); a score below these thresholds indicates safety of prescription. CONCLUSIONS AND RELEVANCE: This study derived 2 simple models that predict the risk of a psychiatric adverse effect from levetiracetam. These algorithms can be used to guide prescription in clinical practice.

OBJECTIVE: To assess the incidence of hip fracture and all major osteoporotic fractures (MOF) in patients with chronic obstructive pulmonary disease (COPD) compared with non-COPD patients and to evaluate the use and performance of fracture risk prediction tools in patients with COPD. To assess the prevalence and incidence of osteoporosis. DESIGN: Population-based cohort study. SETTING: UK General Practice health records from The Health Improvement Network database. PARTICIPANTS: Patients with an incident COPD diagnosis from 2004 to 2015 and non-COPD patients matched by age, sex and general practice were studied. OUTCOMES: Incidence of fracture (hip alone and all MOF); accuracy of fracture risk prediction tools in COPD; and prevalence and incidence of coded osteoporosis. METHODS: Cox proportional hazards models were used to assess the incidence rates of osteoporosis, hip fracture and MOF (hip, proximal humerus, forearm and clinical vertebral fractures). The discriminatory accuracies (area under the receiver operating characteristic [ROC] curve) of fracture risk prediction tools (FRAX and QFracture) in COPD were assessed. RESULTS: Patients with COPD (n=80 874) were at an increased risk of fracture (both hip alone and all MOF) compared with non-COPD patients (n=308 999), but this was largely mediated through oral corticosteroid use, body mass index and smoking. Retrospectively calculated ROC values for MOF in COPD were as follows: FRAX: 71.4% (95% CI 70.6% to 72.2%), QFracture: 61.4% (95% CI 60.5% to 62.3%) and for hip fracture alone, both 76.1% (95% CI 74.9% to 77.2%). Prevalence of coded osteoporosis was greater for patients (5.7%) compared with non-COPD patients (3.9%), p<0.001. The incidence of osteoporosis was increased in patients with COPD (n=73 084) compared with non-COPD patients (n=264 544) (adjusted hazard ratio, 1.13, 95% CI 1.05 to 1.22). CONCLUSION: Patients with COPD are at an increased risk of fractures and osteoporosis. Despite this, there is no systematic assessment of fracture risk in clinical practice. Fracture risk tools identify those at high risk of fracture in patients with COPD.

BACKGROUND: Diagnosis of Parkinson's disease (PD) is typically preceded by nonspecific presentations in primary care. OBJECTIVES: The objective of this study was to develop and validate a prediction model for diagnosis of PD based on presentations in primary care. SETTING: The settings were general practices providing data for The Health Improvement Network UK primary care database. METHODS: Data from 8,166 patients aged older than age 50 years with incident diagnosis of PD and 46,755 controls were analyzed. Likelihood ratios, sensitivity, specificity, and positive and negative predictive values for individual symptoms and combinations of presentations were calculated. An algorithm for risk of diagnosis of PD within 5 years was calculated using multivariate logistic regression analysis. Split sample analysis was used for model validation with a 70% development sample and a 30% validation sample. RESULTS: Presentations independently and significantly associated with later diagnosis of PD in multivariate analysis were tremor, constipation, depression or anxiety, fatigue, dizziness, urinary dysfunction, balance problems, memory problems and cognitive decline, hypotension, rigidity, and hypersalivation. The discrimination and calibration of the risk algorithm were good with an area under the curve of 0.80 (95% confidence interval 0.78-0.81). At a threshold of 5%, 37% of those classified as high risk would be diagnosed with PD within 5 years and 99% of those who were not classified as high risk would not be diagnosed with PD. CONCLUSION: This risk algorithm applied to routine primary care presentations can identify individuals at increased risk of diagnosis of PD within 5 years to allow for monitoring and earlier diagnosis of PD. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

OBJECTIVE: Compare outcomes of intensive treatment of SBP to less than 120 mmHg versus standard treatment to less than 140 mmHg in the US clinical Systolic Blood Pressure Intervention Trial (SPRINT) with similar hypertensive patients managed in routine primary care in the United Kingdom. METHODS: Hypertensive patients aged 50-90 without diabetes or chronic kidney disease (CKD) were selected in SPRINT and The Health Improvement Network (THIN) database. Patients were enrolled in 2010-2013 and followed-up to 2015 (SPRINT N = 4112; THIN N = 8631). Cox's proportional hazards regressions were fitted to estimate the hazard of all-cause mortality or CKD (main adverse effect) associated with intensive treatment, adjusted for sex, age, ethnicity, smoking, blood pressure, cardiovascular disease, aspirin, statin, number of antihypertensive drugs at baseline, change in number of antihypertensive drugs at trial entry, and clinical site. RESULTS: Almost half of the patients had intensive treatment (43-45%). In SPRINT, intensive treatment was associated with a decreased hazard of mortality of 0.63 (0.43-0.92), while in THIN with an increased hazard of 1.66 (1.28-2.15). In THIN, this effect was time-dependent. Intensive treatment was associated with an increased hazard of CKD of 2.67 (1.74-4.11) in SPRINT and 1.35 (1.08-1.70) in THIN. In THIN, this effect differed by the number of antihypertensive drugs prescribed at baseline. CONCLUSION: It appears that intensive treatment of SBP may be harmful in the general population where all have access to routine healthcare as with the UK National Health Services, but could be beneficial in high-risk patients who are closely monitored.

OBJECTIVE: Obesity is very common in patients with obstructive sleep apnoea (OSA) and polycystic ovary syndrome (PCOS). Longitudinal studies assessing OSA risk in PCOS and examining the role of obesity are lacking. Our objective was to assess the risk of OSA in women with vs without PCOS and to examine the role of obesity in the observed findings. DESIGN: Population-based retrospective cohort study utilizing The Health Improvement Network (THIN), UK. METHODS: 76 978 women with PCOS and 143 077 age-, BMI- and location-matched women without PCOS between January 2000 and May 2017 were identified. Hazard ratio (HR) for OSA among women with and without PCOS were calculated after controlling for confounding variables using multivariate Cox models. RESULTS: Median patient age was 30 (IQR: 25-35) years; median follow-up was 3.5 (IQR: 1.4-7.1) years. We found 298 OSA cases in PCOS women vs 222 in controls, with incidence rates for OSA of 8.1 and 3.3 per 10 000 person years, respectively. Women with PCOS were at increased risk of developing OSA (adjusted HR = 2.26, 95% CI: 1.89-2.69, P < 0.001), with similar HRs for normal weight, overweight and obese PCOS women. CONCLUSIONS: Women with PCOS are at increased risk of developing OSA compared to control women irrespective of obesity. Considering the significant metabolic morbidity associated with OSA, clinicians should have a low threshold to test for OSA in women with PCOS. Whether OSA treatment has an impact on PCOS symptoms and outcomes needs to be examined.

BACKGROUND & AIMS: There are few data on the incidence of upper and lower gastrointestinal bleeding (UGIB and LGIB) from observational studies of low-dose aspirin users. We aimed to estimate incidence rates of UGIB and LGIB in a large cohort of new users of low-dose aspirin in the United Kingdom, with subanalyses of hospitalization status and fatalities. METHODS: We performed a population-based study of 199,079 new users of low-dose aspirin (median age, 64.0 years) identified from the Health Improvement Network primary care database (2000-2012). Individuals were followed for a median 5.4 years (maximum, 14 years) to identify new cases of UGIB and LGIB. Following multistep validation, we calculated overall and age- and sex-specific incidence rates; we performed subanalyses for health care use and death within 30 days of GIB. We also estimated rates within a matched (1:1) cohort of nonusers of low-dose aspirin at the start of the follow-up period. RESULTS: The low-dose aspirin users had 1115 UGIB events and 1936 LGIB events; most subjects with UGIB events (58.9%) were hospitalized, whereas most subjects with LGIB events were referred to secondary care (72.8%). Crude incidence rates of GIB per 1000 person-years were 0.97 for subjects with UGIB (95% CI, 0.91-1.02) and 1.68 for subjects with LGIB (95% CI, 1.60-1.75). Incidence rates per 1000 person-years for patients hospitalized for GIB were 0.57 for UGIB (95% CI, 0.53-0.61) and 0.45 for LGIB (95% CI, 0.42-0.49); for referred (but not hospitalized) cases, these values were 0.39 for UGIB (95% CI, 0.36-0.43) and 1.22 for LGIB (1.16-1.29). Incidence rates per 1000 person-years were 0.06 for fatal UGIB (95% CI, 0.04-0.07), 0.01 for fatal LGIB (95% CI, 0.01-0.02), 0.91 for nonfatal UGIB (95% CI, 0.86-0.97), and 1.66 for nonfatal LGIB (95% CI, 1.59-1.74). Among nonusers of low-dose aspirin, incidence rates per 1000 person-years were 0.67 (95% CI, 0.63-0.75) for UGIB and 0.76 (95% CI, 0.72-0.82) for LGIB. CONCLUSION: In a population-based study of low-dose aspirin users, the incidence of LGIB was higher than the incidence of UGIB. However, incidence rates of hospitalized GI bleeds and 30-day mortality rates were lower for LGIB than for UGIB. These estimates are valuable for benefit-risk assessments of low-dose aspirin for cardiovascular and colorectal cancer prevention.

BACKGROUND: Elevated vitamin B12 levels (B12) are associated with increased short-term cancer risk. However, the implications for early cancer detection in primary care have not been assessed. METHODS: Individuals with plasma B12 measurements were sampled from The Health Improvement Network primary care database, UK. Persons with low B12 levels were excluded together with persons with cancer or B12 treatment before date of B12 measurement. Incident cancer was the outcome of interest and was identified through Read codes. Individuals were disaggregated according to plasma B12 levels (unit: pmol/L): 150-600 (reference range values), 601-800, 801-1,000, and >1,000. RESULTS: Among the 757,185 persons who met the inclusion criteria, we identified 33,367 incident cancers during 2,874,059 years of follow-up. We found a higher 1-year cancer risk among the 25,783 (3.4%) persons with elevated B12 levels compared with those with normal B12 levels. After multivariable adjustment for lifestyle factors and social deprivation, persons with B12 >1,000 pmol/L had a 1-year incidence rate ratio of 4.72 (95% confidence interval: 3.99-5.58). The association showed a nonlinear dose-response pattern, and it remained robust in stratified analyses, including when reducing the risk of confounding by indication in subanalyses. The risks were particularly elevated for liver cancer, pancreas cancer, and myeloid malignancies among persons with elevated B12 levels. CONCLUSIONS: Elevated plasma B12 levels were associated with a higher 1-year cancer risk than normal B12 levels among persons seen in UK primary care, suggesting that some cancers may affect B12 metabolism. IMPACT: Elevated B12 may mark occult cancer.

IMPORTANCE: Alopecia areata (AA) is an autoimmune disease characterized by hair loss that can impose a substantial psychological burden on patients, including major depressive disorder (MDD), yet many patients report mental health symptoms prior to the onset of AA. As such, there may be an association between MDD and AA that acts in both directions. OBJECTIVE: To assess the bidirectional association between MDD and AA. DESIGN, SETTING, AND PARTICIPANTS: This population-based retrospective cohort study included patients 10 to 90 years of age registered with The Health Improvement Network in general practices in the United Kingdom between January 1, 1986, and May 16, 2012. Statistical analysis was conducted from August 17, 2017, to April 23, 2018. To assess the risk of AA, the following 2 cohorts were defined: patients with an incident diagnosis of MDD (exposure) and a reference general population cohort. To assess the risk of MDD, the following 2 cohorts were defined: patients with an incident diagnosis of AA (exposure) and a reference general population cohort. Person-time was partitioned into unexposed and exposed time in the exposure cohorts. MAIN OUTCOMES AND MEASURES: In the analysis of the risk of AA, development of incident AA during follow-up was considered the main outcome measure. In the analysis of the risk of MDD, development of incident MDD during follow-up was considered the primary outcome measure. RESULTS: In the analysis of the risk of AA, 405 339 patients who developed MDD (263 916 women and 141 423 men; median age, 36.7 years [interquartile range, 26.6-50.5 years]) and 5 738 596 patients who did not develop MDD (2 912 201 women and 2 826 395 men; median age, 35.8 years [interquartile range, 25.3-52.6 years]) were followed up for 26 years. After adjustment for covariates, MDD was found to increase the risk of subsequently developing AA by 90% (hazard ratio, 1.90; 95% CI, 1.67-2.15; P < .001). Antidepressants demonstrated a protective effect on the risk of AA (hazard ratio, 0.57; 95% CI, 0.53-0.62; P < .001). In the analysis of the risk of MDD, 6861 patients who developed AA (3846 women and 3015 men; median age, 31.5 years [interquartile range, 18.2 years]) and 6 137 342 patients who did not develop AA (3 172 371 women and 2 964 971 men; median age, 35.9 years [interquartile range, 27.0 years]) were followed up for 26 years. After adjustment for covariates, AA was found to increase the risk of subsequently developing MDD by 34% (hazard ratio, 1.34; 95% CI, 1.23-1.46; P < .001). CONCLUSIONS AND RELEVANCE: These temporal analyses suggest that, while patients with AA are at risk for subsequently developing MDD, having MDD also appears to be a significant risk factor for development of AA, with antidepressant use confounding this risk.

INTRODUCTION: We aimed to compare risk of stillbirth between maternal smokers and those prescribed nicotine replacement therapy (NRT) during pregnancy. AIMS AND METHODS: We conducted a cross-sectional analysis on a pregnancy cohort of 220,630 singleton pregnancies ending in live or stillbirth between 2001 and 2012 from The Health Improvement Network UK general practice database. Women were categorized into three groups: NRT (prescribed during pregnancy or 1 month before conception); smokers; and controls (nonsmokers without a pregnancy NRT prescription). We calculated Odds ratios (OR) and corresponding 95% confidence intervals (CI) for stillbirth in the NRT group and smokers compared to controls. RESULTS: A total of 805 pregnancies ended in stillbirth (3.6/1000 births). Absolute risks of stillbirth in NRT and smoker groups were both 5/1000 births compared with 3.5/1000 births in the control group. Compared with the control group, the adjusted odds of stillbirth in the NRT group was not statistically significant (OR = 1.35, 95% CI 0.91 to 2.00), although it was similar in magnitude to that in the smokers group (OR = 1.41, 95% CI 1.13 to 1.77). CONCLUSIONS: We found no evidence of a statistically significant association between being prescribed NRT during pregnancy and odds of stillbirth compared with nonsmoking women. Although our study had much larger numbers than any previously, an even larger study with biochemically validated smoking outcome data and close monitoring of NRT use throughout pregnancy is required to exclude effects on findings of potential exposure misclassification.

BACKGROUND: The annual health check (AHC) programme, as part of a Directed Enhanced Service, offers an incentive to general practitioners in England to conduct health checks for people with intellectual disabilities (IDs). The aim of this analysis was to estimate the impact on health care costs of AHCs in primary care to the National Health Service in England by comparing adults with ID who did or did not have AHCs using data obtained from The Health Improvement Network. METHODS: Two hundred eight records of people with ID from The Health Improvement Network database were analysed. Baseline health care resource use was captured at the time the first AHC was recorded (i.e. index date), or the earliest date after 1 April 2008 for those without an AHC. We examined the volume of resource use and associated costs that occurred at the time AHCs were performed, as well as before and after the index date. We then estimated the impact of AHCs on health care costs. RESULTS: The average cost of AHC was estimated at £142.57 (95%CI £135.41 to £149.74). Primary, community and secondary health care costs increased significantly after the index date in the no AHC group owing to higher increase in resource utilisation. Regression analysis showed that the expected health care cost for those who have an AHC is 56% higher than for those who did not have an AHC. Age and gender were also associated with increase in expected health care cost. CONCLUSION: The level of resource utilisation increased in both (AHC and no AHC) groups after the index date. Although the level of resource use before index date was lower in the no AHC group, it increased after the index date up to almost reaching the level of resource utilisation in the AHC group. Further research is needed to explore if the AHCs are effective in reducing health inequalities.

BACKGROUND: our aim was to study the relationship between HbA1c and cardiovascular morbidity and all-cause mortality among older insulin-treated patients with type 2 diabetes (T2D) after adjustment for multiple confounders. METHODS: data for 4589 adults with T2D (>65 years) on insulin treatment were sourced from 532 UK General Practices via the Health Improvement Network (THIN) database. Cox proportional hazard models and Kaplan-Meier estimators were fitted to derive the hazards of all-cause mortality by HbA1c categories (<6.5, 6.5-7.4, 7.5-8.4, 8.5-9.4, 9.5-10.4, 10.5-11.4%; and 11.5% and above) after 5 years of follow-up following insulin initiation. RESULTS: we observed a U-shaped relationship between all-cause mortality and HbA1c, with the lowest risk seen in the HbA1c range of 6.5-7.4% and marked increased in risk with HbA1c > 11%. The highest mortality risks of 31 and 40% were significantly associated with the lowest (<6.5%) and highest (11.5% and above) HbA1c categories: aHR: 1.31; (95%CI: 1.10-1.56; P = 0.002) and aHR: 1.40; (95%CI: 1.01-1.96; P = 0.039), respectively. CONCLUSIONS: both low and high HbA1c were associated with increased all-cause mortality, among older patients with insulin-treated T2D. This cohort study supports the need for individualisation of care and suggests better outcomes with HbA1c levels around 6.5-7.4% and markedly excess risk with HbA1c > 11.

Risks of low-dose aspirin-associated upper and lower gastrointestinal bleeds (UGIB/LGIB) may vary by severity and presence of cardiovascular disease (CVD). No study has quantified these risks for UGIB and LGIB in the same real-world study population. Using UK primary care data, 199,049 new users of low-dose aspirin (75-300 mg/day) and 1:1 matched non-users were followed to identify incident UGIB (  = 1843)/LGIB (  = 2763) cases. Nested case-control analyses compared current low-dose aspirin vs. non-use on UGIB/LGIB risk. Adjusted incidence rate ratios (ORs; 95% CIs) were 1.62 (1.42-1.86) for non-fatal UGIB, 1.63 (1.47-1.81) for non-fatal LGIB, 0.77 (0.51-1.16) for fatal UGIB, 1.29 (0.50-3.36) for fatal LGIB. For hospitalizations, adjusted ORs (95% CIs) were 1.55 (1.32-1.81) for UGIB and 1.89 (1.58-2.27) for LGIB; for referred only cases, they were 1.52 (1.26-1.84) for UGIB and 1.54 (1.37-1.73) for LGIB. In primary CVD prevention, adjusted ORs (95% CI) were 1.62 (1.38-1.90) for UGIB and 1.60 (1.42-1.81) for LGIB; in secondary CVD prevention, they were 1.16 (0.89-1.50) for UGIB and 1.67 (1.34-2.09) for LGIB. Low-dose aspirin was associated with increased risks of non-fatal but not fatal UGIB/LGIB. Key message Low-dose aspirin is associated with an increased risks of non-fatal UGIB/LGIB but not fatal UGIB/LGIB.

OBJECTIVE: To assess the relationship between Intimate partner violence (IPV) (a highly prevalent form of domestic abuse) with the subsequent development of temporomandibular joint disorder (TMD). METHODS: A retrospective open cohort study using a UK primary care database was undertaken. 18,547 women exposed to IPV were matched by age to 74,188 unexposed women. Defined through clinical codes the outcome of interest was TMD, and adjusted incidence rates (aIRR) were used to describe the relationship after considering covariates of interest. RESULTS: 94 individuals in the exposed group were clinically coded with TMD during the study period translating to an incidence rate (IR) or 1.59 per 1000 person years. This was in comparison to 342 outcomes in the unexposed group (IR 1.21 per 1000 person years). The unadjusted IRR was 1.31 (95% CI 1.04-1.65; p < 0.020) and after adjustment for important covariates increased to 1.45 (95% CI 1.14-1.84; p < 0.002). CONCLUSION: Our results suggest that the development of TMD may be associated with exposure to IPV in women. CLINICAL SIGNIFICANCE: In the first cohort to do so, we have identified a moderate association between Intimate partner violence exposure and subsequent development of TMD. This highlights an opportunity for screening of abuse in individuals presenting with TMD.

BACKGROUND: A low estimated glomerular filtration rate (eGFR) and an increased urinary albumin-to-creatinine ratio (ACR) are well-recognised prognostic markers of cardiovascular (CV) risk, but their individual and combined relationship with CV disease and total mortality among insulin-treated type 2 diabetes (T2D) patients in routine clinical care is unclear. METHODS: We analysed data for insulin users with T2D from UK general practices between 2007 and 2014 and examined the association between mortality rates and chronic kidney disease [categorised by low eGFR (< 60 mL/min/1.73 m ), high eGFR (≥60 mL/min/1.73 m ), low ACR (< 300 mg/g); and high ACR (≥300 mg/g) at insulin initiation] after a 5-year follow-up period using Cox proportional hazard models. RESULTS: A total of 18,227 patients were identified (mean age: 61.5 ± 13.8 years, mean HbA1c: 8.6 ± 1.8%). After adjusting for confounders, when compared to adults on insulin therapy with an eGFR < 60 and an ACR ≥300 (low eGFR + high ACR) after a follow-up period of 5 years, patients with an eGFR < 60 and an ACR < 300 (low eGFR + low ACR) had a 6% lower mortality rate (aHR: 0.94; 95% CI 0.79-1.12); those with an eGFR > 60 and an ACR ≥300 (high eGFR + high ACR) had a 20% lower mortality rate (aHR: 0.80; 95% CI 0.68-0.96); and those with an eGFR > 60 and an ACR < 300 (high eGFR + low ACR) had the lowest death rate (28% less; aHR: 0.72; 95% CI 0.59-0.87). CONCLUSION: This study shows that among a large cohort of insulin-treated T2D patients in routine practice, the combination of reduced eGFR with increased ACR was associated with the greatest risk of premature death, followed closely by those with reduced eGFR and normal ACR levels. Adoption of aggressive CV risk management strategies to reduce mortality in patients with a low eGFR and albuminuria is essential in high-risk patients with T2D.

IMPORTANCE: An American Academy of Orthopaedic Surgeons guideline recommends tramadol for patients with knee osteoarthritis, and an American College of Rheumatology guideline conditionally recommends tramadol as first-line therapy for patients with knee osteoarthritis, along with nonsteroidal anti-inflammatory drugs. OBJECTIVE: To examine the association of tramadol prescription with all-cause mortality among patients with osteoarthritis. DESIGN, SETTING, AND PARTICIPANTS: Sequential, propensity score-matched cohort study at a general practice in the United Kingdom. Individuals aged at least 50 years with a diagnosis of osteoarthritis in the Health Improvement Network database from January 2000 to December 2015, with follow-up to December 2016. EXPOSURES: Initial prescription of tramadol (n = 44 451), naproxen (n = 12 397), diclofenac (n = 6512), celecoxib (n = 5674), etoricoxib (n = 2946), or codeine (n = 16 922). MAIN OUTCOMES AND MEASURES: All-cause mortality within 1 year after initial tramadol prescription, compared with 5 other pain relief medications. RESULTS: After propensity score matching, 88 902 patients were included (mean [SD] age, 70.1 [9.5] years; 61.2% were women). During the 1-year follow-up, 278 deaths (23.5/1000 person-years) occurred in the tramadol cohort and 164 (13.8/1000 person-years) occurred in the naproxen cohort (rate difference, 9.7 deaths/1000 person-years [95% CI, 6.3-13.2]; hazard ratio [HR], 1.71 [95% CI, 1.41-2.07]), and mortality was higher for tramadol compared with diclofenac (36.2/1000 vs 19.2/1000 person-years; HR, 1.88 [95% CI, 1.51-2.35]). Tramadol was also associated with a higher all-cause mortality rate compared with celecoxib (31.2/1000 vs 18.4/1000 person-years; HR, 1.70 [95% CI, 1.33-2.17]) and etoricoxib (25.7/1000 vs 12.8/1000 person-years; HR, 2.04 [95% CI, 1.37-3.03]). No statistically significant difference in all-cause mortality was observed between tramadol and codeine (32.2/1000 vs 34.6/1000 person-years; HR, 0.94 [95% CI, 0.83-1.05]). CONCLUSIONS AND RELEVANCE: Among patients aged 50 years and older with osteoarthritis, initial prescription of tramadol was associated with a significantly higher rate of mortality over 1 year of follow-up compared with commonly prescribed nonsteroidal anti-inflammatory drugs, but not compared with codeine. However, these findings may be susceptible to confounding by indication, and further research is needed to determine if this association is causal.

OBJECTIVE: Supplementing the Spontaneous Reporting System (SRS) with Electronic Health Record (EHR) data for adverse drug reaction detection could augment sample size, increase population heterogeneity and cross-validate results for pharmacovigilance research. The difference in the underlying data structures and terminologies between SRS and EHR data presents challenges when attempting to integrate the two into a single database. The Observational Health Data Sciences and Informatics (OHDSI) collaboration provides a Common Data Model (CDM) for organizing and standardizing EHR data to support large-scale observational studies. The objective of the study is to develop and evaluate an informatics platform known as ADEpedia-on-OHDSI, where spontaneous reporting data from FDA's Adverse Event Reporting System (FAERS) is converted into the OHDSI CDM format towards building a next generation pharmacovigilance signal detection platform. METHODS: An extraction, transformation and loading (ETL) tool was designed, developed, and implemented to convert FAERS data into the OHDSI CDM format. A comprehensive evaluation, including overall ETL evaluation, mapping quality evaluation of drug names to RxNorm, and an evaluation of transformation and imputation quality, was then performed to assess the mapping accuracy and information loss using the FAERS data collected between 2012 and 2017. Previously published findings related to vascular safety profile of triptans were validated using ADEpedia-on-OHDSI in pharmacovigilance research. For the triptan-related vascular event detection, signals were detected by Reporting Odds Ratio (ROR) in high-level group terms (HLGT) level, high-level terms (HLT) level and preferred term (PT) level using the original FAERS data and CDM-based FAERS respectively. In addition, six standardized MedDRA queries (SMQs) related to vascular events were applied. RESULTS: A total of 4,619,362 adverse event cases were loaded into 8 tables in the OHDSI CDM. For drug name mapping, 93.9% records and 47.0% unique names were matched with RxNorm codes. Mapping accuracy of drug names was 96% based on a manual verification of randomly sampled 500 unique mappings. Information loss evaluation showed that more than 93% of the data is loaded into the OHDSI CDM for most fields, with the exception of drug route data (66%). The replication study detected 5, 18, 47 and 6, 18, 50 triptan-related vascular event signals in MedDRA HLGT level, HLT level, and PT level for the original FAERS data and CDM-based FAERS respectively. The signal detection scores of six standardized MedDRA queries (SMQs) of vascular events in the raw data study were found to be lower than those scores in the CDM study. CONCLUSION: The outcome of this work would facilitate seamless integration and combined analyses of both SRS and EHR data for pharmacovigilance in ADEpedia-on-OHDSI, our platform for next generation pharmacovigilance.

BACKGROUND: Many studies have found an increased risk of pulmonary tuberculosis (PTB) among those with diabetes mellitus (DM). However, evidence on whether the association is bidirectional remains sparse. This study investigates DM rates among those with and without prior tuberculosis (TB) disease as well as the reverse. METHODS: Data on a UK general practice population, between 2003 and 2009, were obtained from The Health Improvement Network database. A series of retrospective cohort studies were completed. Individuals were successively classified as 'exposed' or 'unexposed' to TB, PTB, extrapulmonary TB (EPTB) or DM. Multivariate negative binomial regression was used to calculate incidence rate ratios (IRR) among each exposure group for outcomes of interest (TB, PTB, EPTB or DM in turn) adjusting for plausible confounding variables (age, sex, region, Townsend quintile and smoking status). Potential confounding due to ethnicity was adjusted for using McNamee's external method. RESULTS: DM risk was substantially raised among individuals with a history of TB disease (IRR 5.65 (95% CI 5.19 to 6.16)), PTB (IRR 5.74 (95% CI 5.08 to 6.50)) and EPTB (IRR 4.66 (95% CI 3.94 to 5.51)) compared with those without; results were attenuated after external adjustment for ethnicity (IRR 2.33 (95% CI 2.14 to 2.53)). TB risk was raised modestly among individuals with DM (IRR 1.50 (95% CI 1.27 to 1.76)) and was attenuated slightly after adjustment for ethnicity (IRR 1.26 (95% CI 1.07 to 1.48)). CONCLUSION: DM risk was raised among those with previous TB disease; this finding has implications for follow-up and screening of patients with TB, who may be at high risk of developing DM or related complications.

BACKGROUND: In vitro and animal studies have suggested that trazodone, a licensed antidepressant, may protect against dementia. However, no studies have been conducted to assess the effect of trazodone on dementia in humans. This electronic health records study assessed the association between trazodone use and the risk of developing dementia in clinical practice. METHODS AND FINDINGS: The Health Improvement Network (THIN), an archive of anonymised medical and prescribing records from primary care practices in the United Kingdom, contains records of over 15 million patients. We assessed patients from THIN aged ≥50 years who received at least two consecutive prescriptions for an antidepressant between January 2000 and January 2017. We compared the risk of dementia among patients who were prescribed trazodone to that of patients with similar baseline characteristics prescribed other antidepressants, using a Cox regression model with 1:5 propensity score matching. Patients prescribed trazodone who met the inclusion criteria (n = 4,716; 59.2% female) were older (mean age 70.9 ± 13.1 versus 65.6 ± 11.4 years) and were more likely than those prescribed other antidepressants (n = 420,280; 59.7% female) to have cerebrovascular disease and use anxiolytic or antipsychotic drugs. After propensity score matching, 4,596 users of trazadone and 22,980 users of other antidepressants were analysed. The median time to dementia diagnosis for people prescribed trazodone was 1.8 years (interquartile range [IQR] = 0.5-5.0 years). Incidence of dementia among patients taking trazodone was higher than in matched users of other antidepressants (1.8 versus 1.1 per 100 person-years), with a hazard ratio (HR) of 1.80 (95% confidence interval [CI] 1.56-2.09; p < 0.001). However, our results do not suggest a causal association. When we restricted the control group to users of mirtazapine only in a sensitivity analysis, the findings were very similar to the results of the main analysis. The main limitation of our study is the possibility of indication bias, because people in the prodromal stage of dementia might be preferentially prescribed trazodone. Due to the observational nature of this study, we cannot rule out residual confounding. CONCLUSIONS: In this study of UK population-based electronic health records, we found no association between trazodone use and a reduced risk of dementia compared with other antidepressants. These results suggest that the clinical use of trazodone is not associated with a reduced risk of dementia.