Alejandro Arana

Suicide-related events in patients treated with antiepileptic drugs.

BACKGROUND A previous meta-analysis of data from clinical trials showed an association between antiepileptic drugs and suicidality (suicidal ideation, behavior, or both). We used observational data to examine the association between the use or nonuse of antiepileptic drugs and suicide-related events (attempted suicides and completed suicides) in patients with epilepsy, depression, or bipolar disorder. METHODS We used data collected as part of the clinical care of patients who were representative of the general population in the United Kingdom to identify patients with epilepsy, depression, or bipolar disorder and to determine whether they received antiepileptic drugs. We estimated the incidence rate of suicide-related events and used logistic regression to compute odds ratios, controlling for confounding factors. RESULTS In a cohort of 5,130,795 patients, the incidence of suicide-related events per 100,000 person-years was 15.0 (95% confidence interval [CI], 14.6 to 15.5) among patients without epilepsy, depression, bipolar disorder, or antiepileptic-drug treatment, 38.2 (95% CI, 26.3 to 53.7) among patients with epilepsy who did not receive antiepileptic drugs, and 48.2 (95% CI, 39.4 to 58.5) among patients with epilepsy who received antiepileptic drugs. In adjusted analyses, the use of antiepileptic drugs was not associated with an increased risk of suicide-related events among patients with epilepsy (odds ratio, 0.59; 95% CI, 0.35 to 0.98) or bipolar disorder (1.13; 95% CI, 0.35 to 3.61) but was significantly associated with an increased risk among patients with depression (1.65; 95% CI, 1.24 to 2.19) and those who did not have epilepsy, depression, or bipolar disorder (2.57; 95% CI, 1.78 to 3.71). CONCLUSIONS The current use of antiepileptic drugs was not associated with an increased risk of suicide-related events among patients with epilepsy, but it was associated with an increased risk of such events among patients with depression and among those who did not have epilepsy, depression, or bipolar disorder.

Prescription patterns for asthma medications in children and adolescents with health care insurance in the United States

To cite this article: Arellano FM, Arana A, Wentworth CE, Vidaurre CF, Chipps BE. Prescription patterns for asthma medications in children and adolescents with health care insurance in the United States. Pediatr Allergy Immunol 2011; 22: 469–476.

Hepatic disorders in patients treated with COX-2 selective inhibitors or nonselective NSAIDs: a case/noncase analysis of spontaneous reports.

BACKGROUND Hepatic adverse events associated with the use of nonaspirin drugs and NSAIDs are uncommon, but the widespread use of these drugs may impact public health. OBJECTIVE We conducted a case/noncase analysis of spontaneous reports to compare the hepatic safety profile of cyclooxygenase (COX)-2 selective inhibitors with that of nonselective NSAIDs. METHODS This case/noncase analysis was conducted using the US Food and Drug Administration Freedom of Information (FDA/FOI) database (through quarter 1, 2003) and the World Health Organization Uppsala Monitoring Centre (WHO/UMC) database (through quarter 3, 2003). Council for International Organizations of Medical Sciences and WHO Adverse Reaction Terminology preferred terms were used to classify hepatic disorders with broad and specific case definitions. After reports involving established hepatotoxic drugs (bromfenac, nimesulide, sulindac) were excluded, the proportion of reports (PRs) of each case definition was calculated for each NSAID. Crude and adjusted reporting odds ratios (RORs) were used to compare the overall proportions of hepatic disorders and hepatic failure of celecoxib and rofecoxib versus nonselective NSAIDs. RESULTS A total of 158,539 and 185,253 reports of NSAIDs were identified in the FDA/FOI and WHO/UMC databases and 25% and 16%, respectively, involved other hepatotoxic drugs. The PRs of hepatic disorders for all COX-2 selective inhibitors and non-selective NSAIDs were 3.0% in the FDA/FOI database and 2.7% in the WHO/UMC database. In the FDA/FOI and WHO/UMC databases, respectively, mmesulide (16.7% and 14.4%), bromfenac (12.0% and 20.7%), diclofenac (8.1% and 4.7%), and sulindac (6.1 % and 9.9%) were reported to be associated with higher proportions of overall hepatic disorders compared with those of other NSAIDs. Crude and adjusted RORs for the prevalences of overall hepatic disorders and hepatic failure with celecoxib and rofecoxib versus the other NSAIDs were <1 (indicating that the proportion was not higher than that of the comparator) in both databases. The interpretation of the results was unchanged when bromfenac, nimesulide, and sulindac were excluded from the analysis. CONCLUSIONS In this case/noncase analysis, bromfenac, nimesulide, sulindac, and diclofenac had higher proportions of reports of hepatic disorders compared with those of other NSAIDs in the FDA/FOI and WHO/UMC databases. The analysis did not raise a safety concern for celecoxib or rofecoxib versus NSAIDs for overall hepatic disorders and hepatic failure.

Infliximab paediatric crohn's disease educational plan a European, cross-sectional, multicentre evaluation:

Background: The infliximab (Remicade®; Schering-Plough, Kenilworth, NJ, USA) Risk Management Plan included the development, execution and tracking of an education programme directed towards prescribers of infliximab for patients with paediatric Crohn’s disease (the Infliximab Paediatric Crohn’s Disease Educational Plan). The programme content consisted of educational materials and communications aimed at educating prescribers on the risks associated with infliximab use.Objective: To evaluate the effectiveness of the risk minimization plan.Methods: Evaluation focused on two components: documentation of training of sponsors’ personnel, and evaluation of awareness among prescribing physicians in European countries. Treating physicians, identified both independently of the sponsor (6 countries) and by the sponsor (24 countries), were surveyed using a structured questionnaire.Results: Training of internal staff on the educational programme was performed and completed by every person designated an appropriate candidate for the programme in all European countries. The independent survey conducted in Germany, France, Italy, Spain, Sweden and the UK indicated that around 90% of the physicians were either paediatric gastroenterologists (57%) or paediatricians (33%). The great majority (96%) of the interviewed physicians were currently treating paediatric Crohn’s disease, and most were currently using infliximab in their treatment of the disease. More specifically, 82% of gastroentrologists treating paediatric Crohn’s disease were using infliximab; among paediatricians, the proportion was lower (42%).Ninety-six percent of paediatric gastroenterologists or gastroenterologists declared themselves aware of the benefits and risks of using infliximab for the treatment of paediatric Crohn’s disease; in comparison, fewer paediatricians (82%) declared themselves aware of these benefits and risks. The majority initially gained awareness through congresses and workshops, and at the time of the survey only 25% declared that they were made aware of the benefits and risks through the educational programme. However, the majority of physicians reported that they had been approached by the sponsor’s personnel in France (98%), Italy (100%), Spain (83%) and Sweden (70%). In Germany and the UK this proportion was 42%.Almost all physicians were aware of the need to perform tuberculosis (TB) and cancer screening prior to initiating therapy with infliximab, and to screen for hypersensitivity reactions before, during and after treatment. Ninety percent of the physicians were aware of the need to update immunization therapy before initiating therapy and, except in Italy (92% aware), around 50% of the physicians were aware of the need to provide patients with the infliximab Patient Alert Card.In the other European countries where the survey took place among physicians identified by the sponsor, 99% of paediatric gastroenterologists and 90% of gastroenterologists or paediatricians declared themselves aware of the benefits and risks of using infliximab for the treatment of paediatric Crohn’s disease, and all of them were aware of the risk of TB and opportunistic infections and the need to perform TB and cancer screening prior to initiating therapy with infliximab.Conclusions: Overall, the results of the evaluation of the Infliximab Paediatric Crohn’s Disease Educational Plan were satisfactory. The objective of education of internal personnel of the pharmaceutical companies distributing infliximab was completely achieved; over 90% of physicians reported being aware of the benefits and risks of infliximab for the treatment of paediatric Crohn’s disease. Further work should be carried out across all countries to educate physicians on providing patients with the infliximab Patient Alert Card. In Germany and the UK in particular, where <50% of physicians reported having been approached by the sponsor’s personnel, further work is needed to raise awareness of the educational programme.

Validity of the codes of suicidality in the THIN database

The quality of suicide recording in the THIN database has been questioned. We recently performed a study of the incidence of suicide in patients with epilepsy in THIN and investigated the validity of the suicide and suicidality recording in the database. The THIN database is representative of the UK general population covering over 6.7million patients. THIN data are entered by 314 general practitioners’ (GP) offices within the National Health System in the UK and collected from the daily record keeping of these general practices. Medical events are automatically coded at entry using the Read coding system. We defined cases of ‘‘suicidality’’ as presence of codes of suicides, attempted suicides, and intentional self-inflicted injuries (codes are available online). We defined completed suicide as an episode coded as above followed by a code of death in the following month and a final enrollment date of the patient in the database within 6months following the code of suicide. When patients had a suicide code and a death code within a month but an end of enrollment date after the 6months following suicide we reviewed the patients’ profile. Within them, those whose last medical or health related code was within 1month following the suicide date were also considered completed suicides. There were 8212 patients who were identified as attempting suicide. We selected a random sample of 218 cases of suicidality (86 suicides and 132 attempts) for validation to determine the positive predictive value (PPV) of the diagnoses used. The validation process included a questionnaire sent to the general practitioner (GP), as well as a review of the patients’ medical records and death certificate (DC) when available (a copy of the questionnaire is available online). The questionnaires and records were reviewed by one of the investigators (FMA), blinded for exposure to the medications object of the original study. Conduct of the study was approved by the South East Multicenter Research Ethics Committee. We received information on 177 questionnaires (response rate 81% [95% CI 75–86%]), the rest (41) did not respond or the questionnaire was deemed invalid (4). Of the 177 valid questionnaires received, five cases were not confirmed cases of suicidality and the rest (172) were considered valid cases of suicidality (PPV 97% [95% CI 93–99%]). There were 86 cases of completed suicide investigated, of which we received 74 responses (response rate 86% [95% CI 77–93%]). Of the 74 cases with additional information, 65 were confirmed suicides (PPV 88% [95% CI 78–94%]), DCs were available in 57 of them. There were 132 cases of suicidality that were not considered completed suicides; we received 103 responses during the validation procedure (response rate 78% [95% CI 70–85%]). Eleven cases were found to be completed suicides (11% [95% CI 5–18%]); four of them with a DC. The predictive value of the absence of a death code was 89% (95% CI 82–95%). The sensitivity of the algorithm to determine death from suicide among suicidal patients was [65/(65þ 11)] 86% (95% CI 76–93%), and the specificity of the algorithm for suicide attempt not resulting in death was [92/(92þ 9)] 91% (95% CI 84–96%) (Table 1). Hall in her study described that suicide was often not reported in THIN even when a cause of death was listed, with only one of seven found directly. We did not study the proportion of patients with suicidality among those not identified as such after electronic record review, and cannot confirm that finding. The codes and the algorithm used to identify suicidality had a very high predictive value. However, the PPVof the algorithm to identify suicide was not as high and 14% (95% CI 7–24%) [11/(65þ 11)] of true, completed suicides were not identified as having died. Likewise 12% (95% CI 6–22%) (9/74) of patients identified as dying from suicide died due to other causes within the month after attempting suicide (Table 1). Thus those performing studies on suicidality in THIN and using an algorithm similar to pharmacoepidemiology and drug safety 2010; 19: 1316–1317 Published online in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/pds.1998

Ophthalmic nepafenac use in the Netherlands and Denmark

To describe nepafenac use in the Netherlands and Denmark with reference to its approved indications. For context, we also describe the use of ketorolac and diclofenac.

Cancer Incidence after Initiation of Antimuscarinic Medications for Overactive Bladder in the United Kingdom: Evidence for Protopathic Bias

To estimate the incidence of 10 common cancers among patients treated with antimuscarinic medications for overactive bladder (AMOABs).

Suicide-related events in patients treated with antiepileptic drugs: not an example of time-window bias.

n engl j med 363;19 nejm.org november 4, 201

Characterization of new users of cilostazol in the UK, Spain, Sweden, and Germany

To describe the characteristics of new users of cilostazol in Europe with the aim to support the evaluation of its benefit/risk as used in regular clinical practice before the implementation of labeling changes recommended by the European Medicines Agency.

Validation of cancer cases using primary care, cancer registry, and hospitalization data in the UK:

Background: In the United Kingdom, hospital or cancer registry data can be linked to electronic medical records for a subset of general practices and years. Methods: We used Clinical Practice Research Datalink data (2004–2012) from patients treated for overactive bladder. We electronically identified provisional cases of 10 common cancers in General Practitioner Online Database data and validated them by medical profile review. In practices with linkage to Hospital Episodes Statistics and National Cancer Data Repository (2004–2010), we validated provisional cancer cases against these data sources. This linkage also let us identify additional cancer diagnoses in individuals without cancer diagnosis records in the General Practitioner Online Database. Results: Among 50,840 patients, 1,486 provisional cancer cases were identified in the General Practitioner Online Database for 2004–2012. Medical profile review confirmed 93% of 661 cases in nonlinked practices (range, 100% of non-Hodgkin lymphomas and uterine cancer to 77% of skin melanomas) and 96% of 825 cases in linked practices (100% of kidney and uterine cancers to 92% of melanomas). In the subset of linked practices, for 2004–2010, 720 cases were confirmed, of which 68% were identifiable in the General Practitioner Online Database (range, 90% of breast to 36% of kidney cancers). Conclusions: Most cases of cancer identified electronically in the General Practitioner Online Database were confirmed. A substantial proportion of cases, especially of cancer types not typically managed by general practitioners, would be missed without Hospital Episodes Statistics and National Cancer Data Repository data (and are likely missed in nonlinked practices). See video abstract at, http://links.lww.com/EDE/B315. Registration (before study conduct): European Union electronic Register of Post-Authorisation Studies (EU PAS Registry) number EUPAS5529, http://www.encepp.eu/encepp/viewResource.htm?id=11107.