David J. Webb

Epilepsy, suicidality, and psychiatric disorders: a bidirectional association.

A study was undertaken to determine whether psychiatric disorders associated with suicide are more common in incident epilepsy than in matched controls without epilepsy, before and after epilepsy diagnosis.

Use of antiepileptic drugs and risk of fractures Case–control study among patients with epilepsy

Objective: To study the association between use of antiepileptic drugs (AEDs) and risk of fractures. Methods: The authors obtained data from the General Practice Research Database (GPRD). A case–control study was nested within a cohort of patients with active epilepsy. Cases were patients with a first fracture after cohort entry. Up to four controls were matched to each case by practice, sex, year of birth, timing of first epilepsy diagnosis, index date, and duration of GPRD history. Cumulative exposure to AEDs was assessed by summing the duration of all AED prescriptions. A distinction was made between AEDs that induce the hepatic cytochrome P-450 enzyme system and AEDs that do not. Medical conditions and drugs known to be associated with bone metabolism or falls were evaluated as potential confounders. Conditional logistic regression analysis was used to calculate odds ratios (ORs) and 95% CIs. Results: The study population comprised 1,018 cases and 1,842 matched controls. The risk of fractures increased with cumulative duration of exposure (p for trend < 0.001), with the strongest association for greater than 12 years of use: adjusted OR 4.15 (95% CI 2.71 to 6.34). Risk estimates were higher in women than in men. There was no difference between users of AEDs that induce and AEDs that do not induce the hepatic cytochrome P-450 system. Conclusions: Long-term use of AEDs was associated with an increased risk of fractures, especially in women. More research on mechanisms of AED-induced bone breakdown and female vulnerability to the effects of AEDs on bone health is warranted.

Incidence of fractures among epilepsy patients: a population-based retrospective cohort study in the General Practice Research Database.

Summary:u2002 Purpose: To compare the incidence of various fractures in a cohort of patients with epilepsy with a reference cohort of patients not having epilepsy.

Modelling estimates of the burden of Respiratory Syncytial virus infection in adults and the elderly in the United Kingdom

BackgroundGrowing evidence suggests respiratory syncytial virus (RSV) is an important cause of respiratory disease in adults. However, the adult burden remains largely uncharacterized as most RSV studies focus on children, and population-based studies with laboratory-confirmation of infection are difficult to implement. Indirect modelling methods, long used for influenza, can further our understanding of RSV burden by circumventing some limitations of traditional surveillance studies that rely on direct linkage of individual-level exposure and outcome data.MethodsMultiple linear time-series regression was used to estimate RSV burden in the United Kingdom (UK) between 1995 and 2009 among the total population and adults in terms of general practice (GP) episodes (counted as first consultation ≥28xa0days following any previous consultation for same diagnosis/diagnostic group), hospitalisations, and deaths for respiratory disease, using data from Public Health England weekly influenza/RSV surveillance, Clinical Practice Research Datalink, Hospital Episode Statistics, and Office of National Statistics. The main outcome considered all ICD-listed respiratory diseases and, for GP episodes, related symptoms. Estimates were adjusted for non-specific seasonal drivers of disease using secular cyclical terms and stratified by age and risk group (according to chronic conditions indicating severe influenza risk as per UK recommendations for influenza vaccination). Trial registration NCT01706302. Registered 11 October 2012.ResultsAmong adults aged 18+ years an estimated 487,247 GP episodes, 17,799 hospitalisations, and 8,482 deaths were attributable to RSV per average season. Of these, 175,070 GP episodes (36xa0%), 14,039 hospitalisations (79xa0%) and 7,915 deaths (93xa0%) were in persons aged 65+ years. High- versus low-risk elderly were two-fold more likely to have a RSV-related GP episode or death and four-fold more likely be hospitalised for RSV. In most seasons since 2001, more GP episodes, hospitalisations and deaths were attributable to RSV in adults than to influenza.ConclusionRSV is associated with a substantial disease burden in adults comparable to influenza, with most of the hospitalisation and mortality burden in the elderly. Treatment options and measures to prevent RSV could have a major impact on the burden of RSV respiratory disease in adults, especially the elderly.

Risk of ischaemic cardiovascular events from selective cyclooxygenase‐2 inhibitors in osteoarthritis

Most previous observational studies assessing cardiovascular risk associated with Cox‐2 inhibitors (Cox‐2is) used a case control approach, limiting the assessment of absolute risk by disease group and effect of duration of exposure. We conducted a retrospective cohort study in patients with osteoarthritis.

Occurrence and Recurrence of Attempted Suicide Among People With Epilepsy

IMPORTANCEnPeople with epilepsy have a 5-fold increased risk of suicide. Less is known about attempted suicide and whether psychiatric disorders and antiepileptic drugs modify the risk of attempted suicide.nnnOBJECTIVESnTo estimate the magnitude of the association between attempted suicide and epilepsy by comparing a first suicide attempt and a second suicide attempt (hereafter referred to as a recurrent suicide attempt) among people before they received a diagnosis of epilepsy (case patients) with a first suicide attempt and a recurrent suicide attempt among people without epilepsy (control patients), and to evaluate the effect of comorbid psychiatric disorders and the exclusion of antiepileptic drug prescriptions on this association.nnnDESIGN, SETTING, AND PARTICIPANTSnPopulation-based retrospective cohort study in the United Kingdom of case patients with incident epilepsy and control patients without a history of epilepsy in a general practice setting using Clinical Practice Research Datalink. The case patients with incident epilepsy were identified between 1987 and 2013 and were 10 to 60 years of age. The control patients for each case patient were 4 randomly selected people who did not receive a diagnosis of epilepsy before the case patients epilepsy was diagnosed (the index date), matched by year of birth, sex, and general practice for a control to case ratio of 4 to 1.nnnMAIN OUTCOMES AND MEASURESnHazard ratio for incident and recurrent suicide attempts among case patients with epilepsy compared with control patients without.nnnRESULTSnFor 14,059 case patients (median age, 36 years [range, 10-60 years]) who later had an onset of epilepsy vs 56,184 control patients (median age, 36 years [range, 10-60 years]), the risk was increased 2.9-fold (95% CI, 2.5- to 3.4-fold) for a first suicide attempt during the time period before the case patients received a diagnosis of epilepsy. For 278 case patients (median age, 37 years [range, 10-61 years]) who later had an onset of epilepsy vs 434 control patients (median age, 35 years [range, 11-61 years]), the risk was increased 1.8-fold (95% CI, 1.3- to 2.5-fold) for a recurrent suicide attempt up to and including the day that epilepsy was diagnosed. Exclusion of antiepileptic drugs prescribed before the index date did not meaningfully alter the findings, nor did separate analyses of patients with and patients without diagnosed psychiatric disorders.nnnCONCLUSIONS AND RELEVANCEnSuicide attempts and recurrent suicide attempts are associated with epilepsy even before epilepsy manifests, suggesting a common underlying biology. Our findings indicate that both incident and recurrent suicide attempts are associated with incident epilepsy in the absence of antiepileptic drugs and in the absence of diagnosed psychiatric disorders, further strengthening the evidence for a common underlying etiology with an as-yet-unknown mechanism.

Risk of cancer in patients exposed to gabapentin in two electronic medical record systems.

High doses of gabapentin were associated with pancreatic acinar cell tumors in male Wistar rats, but there is little published epidemiological data regarding gabapentin and carcinogenicity. We explored the association between gabapentin and cancer in a US medical care program and followed up nominally significant associations in a UK primary care database.

Risk factors for antiepileptic drug regimen change in patients with newly diagnosed epilepsy

This study aimed to investigate the evolution of treatment within patients with newly diagnosed epilepsy identified from a large US commercial health care database. Postdiagnosis, patient follow-up was divided into observation units defined by consecutive antiepileptic drug (AED) prescriptions. Consecutive prescriptions were compared to assess whether a change in AED regimen had occurred. Factors associated with a regimen change were explored using a logistic regression model with subject random effects. Among 5930 patients with newly diagnosed epilepsy, there was a median of one regimen change in the first year. However, patients prescribed polytherapy regimens early in the course of disease were at a substantially greater risk of a regimen change (polytherapy vs monotherapy odds ratio=10.2, 95% confidence interval=9.2-11.3). Although a seizure during the preceding 90 days significantly increased the risk of a regimen change, it was beyond the scope of the study to determine the proportion of changes directly attributable to uncontrolled seizures.

Do case‐only designs yield consistent results across design and different databases? A case study of hip fractures and benzodiazepines

The case‐crossover (CXO) and self‐controlled case series (SCCS) designs are increasingly used in pharmacoepidemiology. In both, relative risk estimates are obtained within persons, implicitly controlling for time‐fixed confounding variables.

Study investigating the generalisability of a COPD trial based in primary care (Salford Lung Study) and the presence of a Hawthorne effect

Introduction Traditional phase IIIb randomised trials may not reflect routine clinical practice. The Salford Lung Study in chronic obstructive pulmonary disease (SLS COPD) allowed broad inclusion criteria and followed patients in routine practice. We assessed whether SLS COPD approximated the England COPD population and evidence for a Hawthorne effect. Methods This observational cohort study compared patients with COPD in the usual care arm of SLS COPD (2012–2014) with matched non-trial patients with COPD in England from the Clinical Practice Research Datalink database. Generalisability was explored with baseline demographics, clinical and treatment variables; outcomes included COPD exacerbations in adjusted models and pretrial versus peritrial comparisons. Results Trial participants were younger (mean, 66.7 vs 71.1 years), more deprived (most deprived quintile, 51.5% vs 21.4%), more current smokers (47.5% vs 32.1%), with more severe Global initiative for chronic Obstructive Lung Disease stages but less comorbidity than non-trial patients. There were no material differences in other characteristics. Acute COPD exacerbation rates were high in the trial population (98.37th percentile). Conclusion The trial population was similar to the non-trial COPD population. We observed some evidence of a Hawthorne effect, with more exacerbations recorded in trial patients; however, the largest effect was observed through behavioural changes in patients and general practitioner coding practices.