John G. Weil

Prophylactic aspirin and risk of peptic ulcer bleeding

Abstract Objective: To determine the risks of hospitalisation for bleeding peptic ulcer with the current prophylactic aspirin regimens of 300 mg daily or less. Design: A case-control study with hospital and community controls. Setting: Hospitals in Glasgow, Newcastle, Nottingham, Oxford, and Portsmouth. Subjects: 1121 patients with gastric or duodenal ulcer bleeding matched with hospital and community controls. Results: 144 (12.8%) cases had been regular users of aspirin (taken at least five days a week for at least the previous month) compared with 101 (9.0%) hospital and 77 (7.8%) community controls. Odds ratios were raised for all doses of aspirin taken, whether compared with hospital or community controls (compared with combined controls: 75 mg, 2.3 (95% confidence interval 1.2 to 4.4); 150 mg, 3.2 (1.7 to 6.5); 300 mg, 3.9 (2.5 to 6.3)). Results were not explained by confounding influences of age, sex, prior ulcer history or dyspepsia, or concurrent non-aspirin non-steroidal anti-inflammatory drug use. Risks seemed particularly high in patients who took non-aspirin non-steroidal anti-inflammatory drugs concurrently. Conclusion: No conventionally used prophylactic aspirin regimen seems free of the risk of peptic ulcer complications. Key messages Key messages This finding applies to doses in common use of 75, 150, and 300 mg daily Despite these results, overall benefits of treatment are likely considerably to outweigh possible risks

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

Final results from 18 years of the International Lamotrigine Pregnancy Registry

Objective: To monitor for a signal for major teratogenicity following in utero lamotrigine exposure. Methods: Health care providers reported lamotrigine exposure during pregnancy, and subsequent outcomes, on a voluntary basis. Prospective reporting early in pregnancy was encouraged. Major congenital malformations (MCMs) were classified according to the Centers for Disease Control and Prevention (CDC) criteria and were reviewed by a pediatrician on the Registrys Scientific Advisory Committee. The proportion of infants with MCMs was calculated by trimester and therapy type and descriptively compared to population-based reference estimates. Results: Over an 18-year period, 35 infants with MCMs were observed among 1,558 first-trimester monotherapy exposures: 2.2%(95% confidence interval [CI] 1.6%–3.1%). This was similar to estimates from general population-based cohorts. The observed proportion of infants with MCMs among 150 lamotrigine/valproate polytherapy exposures was 10.7% (95% CI 6.4%–17.0%) and was 2.8% (95% CI 1.5%–5.0%) among 430 infants exposed to lamotrigine polytherapy without valproate. No consistent pattern of malformation type, or malformation frequency by dose, was observed. Discussion: The Registry did not detect an appreciable increase in MCM frequency following first-trimester lamotrigine monotherapy exposure. With over 1,500 first-trimester monotherapy exposures, the Registry was powered to detect major teratogenicity. The proportion of infants with MCMs following lamotrigine/valproate polytherapy exposure was high, but similar to that previously reported with valproate monotherapy. The Registry failed to observe an increased MCM frequency with increasing lamotrigine dose. Monitoring of specific malformations among lamotrigine-exposed pregnancies will continue through case-control surveillance in the European Congenital Anomalies and Twins Registers network.

Safety of MF59-adjuvanted A/H1N1 influenza vaccine in pregnancy: a comparative cohort study

OBJECTIVE The 2009-2010 A/H1N1 pandemic provided a unique setting to study the safety of MF59-adjuvanted vaccination in pregnancy. STUDY DESIGN This was an observational cohort study of the safety of an MF59-adjuvanted A/H1N1 vaccine (Focetria) conducted among 4508 pregnant women (2295 vaccinated vs 2213 unvaccinated), with 3 month follow-up of neonates. RESULTS No maternal deaths or abortions occurred among the vaccinated women. No differences between the vaccinated and unvaccinated cohorts were observed for gestational diabetes, preeclampsia, stillbirth, low birthweight, neonatal deaths, or congenital malformations. The risk of premature birth was significantly decreased among the vaccinated women (adjusted proportional hazard, 0.69; 95% confidence interval, 0.51-0.92). No differences were observed in rates of congenital malformations after vaccination in the first (2.1%), second (2.7%), or third (2.1%) trimesters. CONCLUSION There was no evidence of a safety risk for MF59-adjuvanted A/H1N1 vaccination in pregnant women; protection was observed against premature birth.

Incidence of New-Onset Seizures in Mild to Moderate Alzheimer Disease

OBJECTIVE To estimate the incidence rate and predictors of seizures in patients with mild to moderate Alzheimer disease (AD). DESIGN Cohort study of patients with mild to moderate AD in clinical trials. Risk factors for potential seizures were evaluated by stratified descriptive statistics and univariable and multivariable Cox proportional hazards regressions. SETTING Pooled patient-level data from 10 Alzheimer Disease Cooperative Study clinical trials in mild to moderate AD from 1995 to 2010. PATIENTS Three thousand seventy-eight subjects randomized to the treatment or placebo arms of 10 AD clinical trials. Screening Mini-Mental State Examination scores ranged between 10 and 28. RESULTS Eighteen seizures were reported in 3078 randomized subjects, with an incidence rate of 484 per 100 000 person-years (95% CI, 287-764). Statistically significant independent risk factors for seizure were younger age (adjusted hazard ratio, 0.80; 95% CI, 0.69-0.93 per every 5 years of age), greater cognitive impairment at baseline (adjusted hazard ratio, 2.79; 95% CI, 1.06-7.33 for Mini-Mental State Examination scores <18 compared with Mini-Mental State Examination scores ≥18), and antipsychotic use at baseline (adjusted hazard ratio, 3.47; 95% CI, 1.33-9.08). CONCLUSIONS Seizure rates in patients with mild to moderate AD in clinical trials are similar to rates observed in longer observational cohort studies, but they are greater than expected in the general elderly population. Younger age, greater degree of cognitive impairment, and history of antipsychotic use were independent risk factors for new-onset seizures in AD.

Data resources for investigating drug exposure during pregnancy and associated outcomes: The General Practice Research Database(GPRD) as an alternative to pregnancy registries

Pregnancy registries are the most commonly used data resource for the post-marketing surveillance of drug teratogenicity. However, the limited sample size and potential selection bias in these registries has led us to investigate the potential of the UK General Practice Research Database (GPRD) as an alternative data source for monitoring drug safety during pregnancy. In addition, a literature review identified further observational data sources that monitor pregnancy outcomes for future evaluation.Initial feasibility studies focused on the ability of the GPRD to capture pregnancy outcomes for a range of drug class exposures, all of which are currently under investigation in pregnancy registries, during pregnancy. The comparator pregnancy registries were identified via a MEDLINE search, whilst eligible pregnancies, in which women received one or more prescriptions for the drug of interest during pregnancy, were identified in the GPRD using the mother-baby link. The number of pregnancy outcomes following exposure to medication for arange of conditions with varying prevalence, including depression, migraine, epilepsy, herpes simplex and HIV, captured by the two data sources were compared. For depression, a relatively prevalent condition, the GPRD recorded the same number of mean annual intrauterine exposures to fluoxetine as the pregnancy registry (118 exposures/year). Ascertainment of intrauterine exposure to drug treatments for less prevalent conditions was found to be higher for the pregnancy registries than the GPRD; for the older antiepileptic drugs (valproate and carbamazepine), the pregnancy registry recorded between four and five times as many mean annual exposures as the GPRD. Virtually no antiretroviral exposures (three) were identified during the time period of interest on the GPRD, compared with 3946 in the Antiretroviral Pregnancy Registry.Data from the GPRD meet established criteria for evaluating outcomes of pregnancy. For prevalent conditions, it has the potential to replace or work alongside standard pregnancy registries and the alternative data sources identified. Further studies are now needed to assess its ability to replicate known teratogenic associations.

Bridging Differences in Outcomes of Pharmacoepidemiological Studies: Design and First Results of the PROTECT Project

Background: Observational pharmacoepidemiological (PE) studies on drug safety have produced discrepant results that may be due to differences in design, conduct and analysis. Purpose: The pharmacoepidemiology work-package (WP2) of the Pharmacoepidemiological Research on Outcomes of Therapeutics by a European ConsorTium (PROTECT) project aims at developing, testing and disseminating methodological standards for design, conduct and analysis of pharmacoepidemiological studies applicable to different safety issues using different databases across European countries. This article describes the selection of the safety issues and the description of the databases to be systematically studied. Methods: Based on two consensus meetings and a literature search, we selected five drug-adverse event (AE) pairs to be evaluated in different databases. This selection was done according to pre-defined criteria such as regulatory and public health impact, and the potential to investigate a broad range of methodological issues. Results: The selected drug-AE pairs are: 1) inhaled long-acting beta-2 agonists and acute myocardial infarction; 2) antimicrobials and acute liver injury; 3) antidepressants and/or benzodiazepines and hip fracture; 4) anticonvulsants and suicide/suicide attempts; and 5) calcium channel blockers and malignancies. Six European databases, that will be used to evaluate the drug-AE pairs retrospectively, are also described. Conclusion: The selected drug-AE pairs will be evaluated in PE studies using common protocols. Based on consistencies and discrepancies of these studies, a framework for guiding methodological choices will be developed. This will increase the usefulness and reliability of PE studies for benefit-risk assessment and decision-making.

Identifying major congenital malformations in the UK general practice research database (GPRD): A study reporting on the sensitivity and added value of photocopied medical records and free text in the GPRD

AbstractBackground: Postmarketing teratogen surveillance is essential and requires a data source that can reliably capture a wide range of congenital malformations. The UK General Practice Research Database (GPRD) may have the potential to be used for this kind of surveillance. Objective: To assess the extent to which this database can be used to accurately identify major congenital malformations. Methods: This study was carried out as part of a broader study to compare data on anticonvulsant use and safety in pregnancy between the GPRD and a pregnancy registry. The study period ran from 1 January 1990 until 31 December 2006. Mother-baby pairs where the mother had a record of epilepsy, seizure or convulsion were identified using the GPRD computerized medical records. Infants of mother-baby pairs who had a record of a major congenital malformation were identified. Full photocopied paper medical records were requested from the infant’s general practitioner and where this was not possible any data entries consisting of uncoded comments, so-called ‘free text’, in the electronic GPRD record were requested from the database provider. This additional information was then reviewed in order to determine the extent to which the congenital malformation diagnoses identified via the computerized records could be confirmed or rejected and then classified as being major or minor. Results: Within the study population of 3869 live mother-baby pairs, 188 potentially major congenital malformations were identified from the GPRD computerized record relating to 161 unique individuals. Using a combination of photocopied medical records and free text it was possible to verify 160 malformations (85.1%) as the malformation indicated by the computerized records; this ranged from 91.7% of those cases verified using photocopied medical records and 77.9% of cases verified using free text. Of the verified congenital malformations, using a combination of computerized data, photocopied medical records and free text, it was possible to classify 78.1% as being major and 15.0% as minor, and this percentage was found to be the same for those cases reviewed by photocopied records and those where free text was used. The proportions of malformations that could be verified and those that could be classified as major or minor were found to vary by malformation class. Conclusions: The GPRD can be used to ascertain a wide range of congenital malformations. In many cases, when a malformation is identified in the GPRD via the computerized medical records, the malformation is likely to exist. However, in this study a small proportion of identified cases had to be excluded because they had been coded incorrectly or diagnostically ruled out. Therefore, depending on the congenital malformation of interest, verification of such malformations using photocopied medical records or free text is generally recommended.