Risk of Incident Osteoarthritis of the Hand in Statin Initiators: A Sequential Cohort Study.

OBJECTIVE: To investigate the association between statin therapy initiation and incident hand osteoarthritis (OA). METHODS: We performed a propensity score-matched cohort study using data from the UK-based Clinical Practice Research Datalink. Statin initiators had ≥1 statin prescription between 1996 and 2015 and were matched 1:1 on their propensity score to noninitiators within 10 sequential 2-year cohort entry blocks. After a 180-day run-in period, patients were followed in an as-treated approach until a recorded diagnosis of hand OA or until censoring (change in exposure status, development of an exclusion criterion, or maximum follow-up of 5.5 years). We applied Cox proportional hazard regression to calculate hazard ratios (HRs) with 95% confidence intervals (95% CIs) overall and in subgroups of sex, age, statin dose, statin agent, preexisting dyslipidemia, and treatment duration. To compare results, we ran all analyses with negative and positive control outcomes and assessed generalized OA as a secondary outcome. We further performed the overall analysis with an active comparator (topical glaucoma therapy initiators). RESULTS: Among 233,608 statin initiators and the same number of noninitiators, we observed an overall HR for hand OA of 0.98 (95% CI 0.88-1.09). The observed null result remained unchanged in all subgroups. Results were highly similar for generalized OA and negative control outcomes. In addition, the active comparator analysis showed a null result with an HR for hand OA of 0.85 (95% CI 0.56-1.29). Previously known associations with positive control outcomes were observed. CONCLUSION: There was no association between statin initiation and incident hand OA in this study.

Adverse events profile of oral corticosteroids among asthma patients in the UK: cohort study with a nested case-control analysis.

BACKGROUND: To evaluate the adverse events profile of oral prednisolone among adult asthma patients in the UK. METHODS: Using data from the UK-based Clinical Practice Research Datalink, we conducted a series of cohort studies to quantify incidence rates and incidence rate ratios, and a series of nested case-control analyses to estimate crude and adjusted odds ratios, of 11 different potential corticosteroid-related adverse events (bone-related conditions, hypertension, peptic ulcer, severe infections, herpes zoster, diabetes mellitus type 2, cataract, glaucoma, chronic kidney disease, affective disorders, and cardiovascular events). RESULTS: Between 165,900 and 269,368 asthma patients were included in each of the 11 cohorts, of whom between 836 and 16,192 developed an outcome of interest. Incidence rates per 1000 person-years of potential corticosteroid-related adverse events in patients with new current use of oral prednisolone ranged from 1.4 (95% confidence interval [CI], 1.0-1.8) for peptic ulcer to 78.0 (95% CI, 74.8-81.2) for severe infections. After adjusting for confounding, current oral prednisolone use was most strongly associated with an increased risk of severe infection, compared with non-use of prednisolone; OR 2.16 (95% CI, 2.05-2.27). There were smaller elevated risks of peptic ulcer, affective disorders, and cataract at higher doses, and marginally increased risks of herpes zoster, cardiovascular events, diabetes mellitus type 2, and bone related conditions, compared with non-use of prednisolone. We did not observe an association between oral prednisolone use and glaucoma, chronic kidney disease, or hypertension. CONCLUSION: Oral prednisolone use is associated with infections, gastrointestinal, neuropsychiatric, ocular, cardiovascular, metabolic, and bone-related complications among adult asthma patients.

Parkinson disease and the risk of epileptic seizures.

OBJECTIVE: To assess the association between incident Parkinson disease (PD) and subsequent incident epileptic seizures. METHODS: We conducted a retrospective cohort study with a nested case-control analysis using data from the U.K. Clinical Practice Research Datalink. We identified patients aged ≥40 years with an incident diagnosis of PD between 1995 and 2016 and a matched comparison group of PD-free individuals. We calculated crude incidence rates (IRs) with 95% confidence intervals (CIs) of epileptic seizures in PD patients and the PD-free comparison group, and corresponding crude incidence rate ratios (IRRs). In the nested case-control analysis, we calculated adjusted odds ratios (adj. ORs) of incident PD among cases with incident epileptic seizures and seizure-free controls overall and stratified by various seizure-provoking comorbidities. RESULTS: Among 23,086 incident PD patients and 92,343 PD-free individuals, we identified 898 patients with incident epileptic seizures. The crude IR of epileptic seizures in PD patients was 266.7/100,000 person-years (95% CI = 235.6-297.7), and in PD-free individuals it was 112.4/100,000 person-years (95% CI = 103.5-121.3; IRR = 2.37, 95% CI = 2.06-2.73). The adj. OR of epileptic seizures was 1.68 (95% CI = 1.43-1.98) in PD patients compared with PD-free individuals. PD patients with comorbid brain disorders (adj. OR = 12.36, 95% CI = 8.74-17.48) or with > 1 seizure-provoking comorbidity (adj. OR = 13.24, 95% CI = 10.15-17.25) were at the highest risk of epileptic seizures compared with PD-free individuals with no seizure-provoking comorbidities. INTERPRETATION: This study suggests that incident PD is associated with an increased risk of incident epileptic seizures. Ann Neurol 2018;83:363-374.

Lifestyle factors, psychiatric and neurologic comorbidities, and drug use associated with incident seizures among adult patients with depression: a population-based nested case-control study.

To investigate risk factors for incident seizures among adult patients with depression. We conducted a nested case-control analysis in adult patients with newly diagnosed depression, using data from the U.K.-based Clinical Practice Research Datalink. Among cases with incident seizures and matched controls, we estimated odds ratios (ORs) with 95 % confidence intervals (CIs) of potential risk factors for seizures as reported from data of the general population: underweight (body mass index <18.5 kg/m2), smoking, alcoholism, drug abuse, psychiatric or neurologic comorbidities, and concomitant use of drugs. Of 186,540 patients with depression, 1489 developed a seizure during follow-up. Being underweight (OR 1.67 [95 % CI 1.23-2.26]), a current smoker (OR 1.45 [95 % CI 1.26-1.67]), having alcoholism (OR 2.98 [95 % CI 2.56-3.47]), and drug abuse (OR 2.51 [95 % CI 1.94-3.24]), were associated with increased risks of seizures compared to normal weight, non-smoking, no alcoholism, and no drug abuse, respectively. Previous stroke/transient ischemic attack (OR 6.07 [95 % CI 4.71-7.83]) or intracerebral bleeding (OR 8.19 [95 % CI 4.80-13.96]), and comorbid dementia (OR 6.83 [95 % CI 4.81-9.69]), were strongly associated with seizures. Current use of cephalosporins (OR 2.47 [95 % CI 1.61-3.78]) and antiarrhythmics (OR 1.59 [95 % CI 1.26-2.01]) was associated with an increased risk of seizures compared to non-use. Among adult patients with depression, being underweight, smoking, alcoholism, and drug abuse, were associated with seizures. Remote stroke and comorbid dementia were strong risk factors for seizures. Current use of cephalosporins or antiarrhytmics was associated with an increased risk of seizures compared to non-use.

Risk of Seizures Associated with Antidepressant Use in Patients with Depressive Disorder: Follow-up Study with a Nested Case-Control Analysis Using the Clinical Practice Research Datalink.

INTRODUCTION: Antidepressant use has been associated with an increased risk of seizures. Evidence on the association between antidepressant use at therapeutic doses and seizures mainly comes from clinical trials that were not designed to investigate this potential relationship. OBJECTIVE: The objective of this study was to assess the risk of first-time seizures in association with exposure to antidepressants in patients with depressive disorders. METHODS: We conducted a retrospective follow-up study with a nested case-control analysis between 1998 and 2012, using data from the UK-based Clinical Practice Research Datalink (CPRD). We estimated crude incidence rates with 95 % confidence intervals (CIs) of seizures in depressed patients who used selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), 'other antidepressants', no antidepressants, or who had used antidepressants in the past. To adjust for potential confounding, we estimated odds ratios of antidepressant drug use among cases with seizures and matched controls in a nested case-control analysis. RESULTS: Of 151,005 depressed patients, 619 had an incident seizure during follow-up. Incidence rates per 10,000 person-years were 12.44 (95 % CI 10.67-14.21) in SSRI users, 15.44 (95 % CI 8.99-21.89) in SNRI users, 8.33 (95 % CI 4.68-11.98) in TCA users, 9.33 (95 % CI 6.19-12.46) in non-users of antidepressants, and 5.05 (95 % CI 4.49-5.62) in past users of antidepressants. In the case-control analysis, relative risk estimates for seizures were increased in current users of SSRIs (adjusted odds ratio 1.98, 95 % CI 1.48-2.66) and SNRIs (adjusted odds ratio 1.99, 95 % CI 1.20-3.29), but not TCAs (adjusted odds ratio 0.99, 95 % CI 0.63-1.53), compared with non-users. CONCLUSION: Current use of SSRIs or SNRIs was associated with a twofold increased risk of first-time seizures compared with non-use, while current use of TCAs (mostly low dose) was not associated with seizures. Treatment initiation in SSRI and SNRI users was associated with a higher risk of seizures than longer-term treatment.

Antipsychotic drug use and the risk of seizures: follow-up study with a nested case-control analysis.

OBJECTIVE: To investigate the association between antipsychotic drug use and the development of first-time seizures in patients with schizophrenia, affective disorders, or dementia. METHODS: We used data from the UK-based Clinical Practice Research Datalink database to conduct a follow-up study with a nested case-control analysis between 1998 and 2013. We identified patients with schizophrenia, affective disorders, or dementia, and estimated incidence rates of seizures among users of four antipsychotic drug subclasses, defined according to existing hypotheses on their seizure-inducing potential (1, olanzapine or quetiapine; 2, amisulpride, aripiprazole, risperidone, or sulpiride; 3, low-to-medium potency first-generation antipsychotic drugs [chlorpromazine, zuclopenthixol, flupenthixol, pericyazine, promazine, thioridazine]; 4, medium-to-high potency first-generation antipsychotic drugs [haloperidol, prochlorperazine, trifluoperazine]), and among those who did not use antipsychotic drugs. To adjust for confounding, we estimated odds ratios for seizures separately among patients with affective disorders or dementia, stratified by antipsychotic drug use and timing of use. RESULTS: In the total cohort of 60,121 patients (who had schizophrenia, affective disorders, or dementia), the incidence rate of seizures per 10,000 person-years was 32.6 (95 % confidence interval [CI] 22.6-42.6) in users of olanzapine or quetiapine, 24.1 (95 % CI 13.2-34.9) in users of amisulpride, aripiprazole, risperidone, or sulpiride, 49.4 (95 % CI 27.7-71.0) in users of low-to-medium potency antipsychotic drugs, 59.1 (95 % CI 40.1-78.2) in users of medium-to-high potency antipsychotic drugs, and 11.7 (95 % CI 10.0-13.4) in non-users of antipsychotic drugs. Patients with dementia had significantly higher incidence rates of first-time seizures compared with patients with affective disorders, irrespective of antipsychotic drug use. In patients with affective disorders, current use of medium-to-high potency first-generation antipsychotic drugs was associated with an increased risk of seizures (adjusted odds ratio 2.51 [95 % CI 1.51-4.18]) compared with non-use, while use of other antipsychotic drugs was not associated with seizures. In patients with dementia, current use of olanzapine or quetiapine (adjusted odds ratio 2.37 [95 % CI 1.35-4.15]), low-to-medium potency first-generation antipsychotic drugs (adjusted odds ratio 3.08 [95 % CI 1.34-7.08]), and medium-to-high potency first-generation antipsychotic drugs (adjusted odds ratio 2.24 [95 % CI 1.05-4.81]) was associated with an increased risk of seizures compared with non-use, but current use of amisulpride, aripiprazole, risperidone, or sulpiride (adjusted odds ratio 0.92 [95 % CI 0.48-1.75]) was not. Use of antipsychotic drugs in patients with schizophrenia could not be investigated because of small numbers. CONCLUSIONS: Current use of medium-to-high potency first-generation antipsychotic drugs was associated with a 2.5-fold increased risk of seizures compared with non-use of antipsychotic drugs in patients with affective disorders. In these patients, current use of all other antipsychotic drug subclasses was not associated with seizures. In patients with dementia, current and past use of all antipsychotic drug subclasses, except amisulpride, aripiprazole, risperidone, or sulpiride, was associated with an increased risk of seizures.

Bone fractures in children with autistic spectrum disorder.

BACKGROUND: Bone fractures in children represent a source of significant disability and morbidity. Are children with autistic spectrum disorder (ASD) at an altered risk of fractures compared with typically developing children? METHODS: Using the General Practice Research Database, the authors assessed the prevalence of fractures in boys with ASD diagnosed between 2 and 8 years. A cross-sectional design was used to compare the prevalence of fractures among children with ASD and age-matched controls, conditional logistic regression to explore the relative risk of having a fracture in association with diagnosed ASD. RESULTS: The study population comprised 3,219 boys with a first-time diagnosis of ASD and 12,265 matched controls. ASD was associated with a significantly decreased risk of developing a fracture at any time in childhood (odds ratio [OR], 0.68, 95% confidence interval [CI], 0.59-0.77, p < .0001). The relative risk estimates were lower for the time period after ASD diagnosis (OR, 0.56, 95% CI, 0.48-0.66, p < .0001) but were not different for the time period before ASD diagnosis (OR, 0.96, 95% CI, 0.78-1.18, p = .6866). Adjusting for use of different drugs did not change the estimates. CONCLUSION: The relative risk of experiencing a fracture at any time in childhood is lower for boys with ASD compared with healthy boys.

Malaria chemoprophylaxis regimens: a descriptive drug utilization study.

BACKGROUND: Mefloquine belongs to the priority chemoprophylaxis drugs for travelers to malaria endemic regions. We aimed to assess the prescribing patterns for mefloquine and other antimalarials. METHODS: We conducted a descriptive drug utilization study using the U.K. Clinical Practice Research Datalink (CPRD). We assessed characteristics of individuals with a first-time antimalarial prescription for mefloquine, atovaquone/proguanil, chloroquine and/or proguanil, or doxycycline between 2001 and 2012. RESULTS: Of 165,218 individuals with a first-time antimalarial prescription, 108,344 (65.6%), 25,294 (15.3%), 23,195 (14.0%), and 8385 (5.1%) were prescribed atovaquone/proguanil, mefloquine, doxycycline, and chloroquine and/or proguanil, respectively. Among mefloquine users, 7.5% had a history of a neuropsychiatric disorder (versus 12.6%-13.7% among other antimalarial users) and 0.04% had a history of severe liver disease (versus 0.04%-0.1% among other antimalarial users). A total of 19.4% mefloquine users were children younger than 12 years (versus 0.4%-15.8% among other antimalarials), and 1.3% pregnant or postpartum women (versus 0.4%-1.4% among users of other antimalarials). CONCLUSIONS: The most frequently prescribed antimalarial chemoprophylaxis was atovaquone/proguanil. Mefloquine was occasionally prescribed for patients with comorbidities listed as contraindications, but most practitioners observed contraindications. Mefloquine was often prescribed for children and pregnant women.