Patricia Tennis

Sudden Unexplained Death in Epilepsy: Observations from a Large Clinical Development Program

Summary: Purpose: The present study was conducted to determine the rate of sudden unexplained death in epilepsy (SUDEP) in a well‐defined cohort of patients included in the lamotrigine (LTG) clinical development database.

Cohort Study of Incidence of Sudden Unexplained Death in Persons with Seizure Disorder Treated with Antiepileptic Drugs in Saskatchewan, Canada

Summary: To measure the incidence of sudden unexplained death in treated persons with epilepsy (SUDEP) and to identify risk factors for SUDEP, a cohort of 6,044 persons aged 15–49 years with more than four prescriptions for antiepileptic drugs (AEDs) was identified from the Saskatchewan Health prescription drug file. To exclude subjects whose sudden deaths (SUDs) might be misattributed to another chronic underlying disease, subjects with hospitalizations for cancer or heart problems were excluded. To exclude subjects without epilepsy, subjects with >2‐year AED treatment followed by AED‐free time and subjects receiving < 1 U/day were excluded. The final cohort consisted of 3,688 subjects. Follow‐up was started at the first AED prescription listed in the prescription drug file and ended at the earliest of the following: age 50 years, death, or last registration in the Saskatchewan Health. For 153 of 163 deaths occurring in the cohort, copies of anonymized death certificates were obtained and copies of anonymized autopsy reports of potential SUDEP cases were examined. There were 18 definite/probable SUDs and 21 possible SUDEPs, yielding a minimum incidence of 0.54 SUDEP per 1,000 person‐years and a maximum of 1.35 SUDEP per 1,000 person‐years. SUDEP incidence increased with male sex, number of AEDs ever prescribed, and prescription of psychotropic drugs and was highest in males with a history of treatment with three or more AEDs and four or more psychotropic drug prescriptions. Poisson regression showed a 1.7‐fold increase in risk of SUDEP for each increment in maximum number of AEDs administered, a likely surrogate for severity and persistence of seizures.

Lamotrigine and the risk of malformations in pregnancy.

Objective: To report the frequency of major malformations in lamotrigine-exposed pregnancies from September 1, 1992, through March 31, 2004, in the International Lamotrigine Pregnancy Registry. Methods: Health care professionals throughout the world can voluntarily enroll lamotrigine-exposed pregnancies in this observational study. Only pregnancies with unknown outcomes at the time of enrollment were included in the analysis. The percentage of outcomes with major birth defects was calculated as the total number of outcomes with major birth defects divided by the sum of the number of outcomes with major birth defects + the number of live births without defects. Results: Among 414 first-trimester exposures to lamotrigine monotherapy, 12 outcomes with major birth defects were reported (2.9%, 95% CI 1.6% to 5.1%). Among the 88 first-trimester exposures to lamotrigine polytherapy including valproate, 11 outcomes with major birth defects were reported (12.5%; 95% CI 6.7% to 21.7%). Among 182 first-trimester exposures to lamotrigine polytherapy excluding valproate, 5 outcomes with major birth defects were reported (2.7%, 95% CI 1.0% to 6.6%). No distinctive pattern of major birth defects was apparent among the offspring exposed to lamotrigine monotherapy or polytherapy. Conclusions: The risk of all major birth defects after first-trimester exposure to lamotrigine monotherapy (2.9%) was similar to that in the general population and in other registries enrolling women exposed to antiepileptic monotherapy (3.3% to 4.5%). However, the sample size was too small to detect any but very large increases in specific birth defects.

Monitoring pregnancy outcomes after prenatal drug exposure through prospective pregnancy registries: A pharmaceutical company commitment

OBJECTIVE Glaxo Wellcome becomes aware of prenatal exposures to its medications as early as the clinical trial phase of development. An international process for monitoring prenatal exposure to all Glaxo Wellcome medicines has been developed. For specific products there are prospective pregnancy registries. STUDY DESIGN The registries are observational, case-registration, and follow-up studies designed to detect evidence of teratogenicity associated with specific medications. After prenatal exposure to the registry medication, pregnancies are registered prospectively, through voluntary reports by health care providers. An advisory committee of independent scientists for each registry reviews data and advises in dissemination of information. Risk of birth defects, as defined by the Centers for Disease Control and Prevention, is compared with published risks both in women in the general population and in women with the underlying condition being treated, if available. RESULTS The following data show results from the prospective first-trimester exposures registered since establishment of each registry. The published risk of birth defects in the general population range is 3% to 5%, and the risk in women with epilepsy is 6% to 9%. The proportions of outcomes with birth defects are as follows: in the Acyclovir (antiviral medication) Pregnancy Registry (1984-1998) (19/581), 3.3% (95% confidence interval, 2.0%-5.2%); in the Lamotrigine (monotherapy and polytherapy antiepileptic medication) Pregnancy Registry (1992-September 1998) (8/123), 6.5% (95% confidence interval, 3.1%-12.8%); in the Sumatriptan (migraine medication) Pregnancy Registry (1996-October 1998) (7/183), 3.8% (95% confidence interval, 1.7%-8.0%). The Valacyclovir, Bupropion, and Naratriptan registries have insufficient data for analysis. CONCLUSION None of the registries has provided a risk estimate exceeding that expected in the disorder treated, and no pattern of defects has been observed. Whereas information from the larger registries is reassuring regarding risk, these studies cannot rule out possible small excess risks from use of these drugs in pregnancy. Data obtained through these registries are shared with the medical community as a supplement to animal toxicology studies to assist in weighing potential risks and benefits of treatment for individual patients. The success of the registries depends on the continued willingness of the obstetrics and gynecology community to notify the registries of prenatal exposures.

Delayed initiation of subcutaneous insulin therapy after failure of oral glucose-lowering agents in patients with Type 2 diabetes: a population-based analysis in the UK

Aims  The aim of this retrospective cohort study was to estimate the time to insulin initiation in patients with Type 2 diabetes inadequately controlled on oral glucose‐lowering agents (OGLAs).

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.

Preliminary results on pregnancy outcomes in women using lamotrigine

Summary:  Purpose: In 1992, the International Lamotrigine Pregnancy Registry was initiated to enroll prospectively and to monitor pregnancies exposed to lamotrigine (LTG) for the occurrence of major birth defects. This study presents results as of September 2001 on 168 outcomes exposed to LTG monotherapy and 166 outcomes after pregnancies exposed to LTG polytherapy during the first trimester.

Sudden Unexplained Death Among Subjects with Refractory Epilepsy

Summary: Purpose: To address concerns about possible increases in rates of sudden unexplained death (SUD) after use of new anticonvulsants, more information on the rate of SUD among subjects with refractory epilepsy is needed to provide a comparison.

RECORD LINKAGE TO CONDUCT AN EPIDEMIOLOGIC STUDY ON THE ASSOCIATION OF RHEUMATOID ARTHRITIS AND LYMPHOMA IN THE PROVINCE OF SASKATCHEWAN, CANADA

The objective of this effort was to assess the utility of the large automated database in Saskatchewan as a resource for pharmacoepidemiologic studies. To this end a study was undertaken to test the hypothesis that rheumatoid arthritis (RA) increases the risk of cancer, especially lymphoma. This was done by performing a retrospective cohort study based on record linkage data from Saskatchewan Health. From hospital discharge diagnoses in the hospital file an exposed group (RA) and two comparison groups matched to the RA group by age and sex were identified: (1) the RA group consisted of people with a discharge diagnosis of rheumatoid arthritis; (2) the osteoarthritis (OA) group consisted of people with OA discharge diagnoses; and (3) a comparison (CN) group consisted of hospitalized people with no discharge diagnoses of arthritis. Drug exposures were determined by linkage with the Prescription Drug File, cancer outcomes were determined by linkage with the Cancer Foundation file, and length of eligibility in the health plan and demographics information were determined by linkage with the registration file. The data were checked for quality of linkages across files and consistency with study definitions. Of 13,333 identified subjects, 2.8% were excluded because of apparent incorrect assignment to study group or age group or because of ineligibility in health plan during the study period. In order to decrease the possibility of misclassification of exposure (rheumatoid arthritis), hospital discharge diagnoses were used to exclude subjects with any inflammatory rheumatic diseases (IRD) from the CN (7.8%) and OA (8.3%) groups and subjects with IRD other than rheumatoid arthritis (4.6%) from the RA group. To decrease selection bias, those who had cancer within 1 year of enrollment (to exclude those in hospital because of symptoms of undiagnosed cancer) were excluded. Because RA subjects hospitalized by a rheumatologist were most likely to have valid rheumatoid arthritis diagnoses, each analysis was run twice: once with the entire RA group (N = 1210) and once with those in the RA group who were rheumatologist-hospitalized (N = 646). Logistic regression of incidence was used to control for age, sex, and use of individual disease-modifying anti-rheumatoid drugs (DMARDs). For the rheumatologist-hospitalized RA group compared to the CN group, a significant 4-fold greater risk for lymphoma/myeloma was detected when DMARD use was not controlled for, and a 3.4-fold increase in risk was detected even when use of individual DMARDs was controlled for.(ABSTRACT TRUNCATED AT 400 WORDS)

VALIDITY OF RHEUMATOID ARTHRITIS DIAGNOSES LISTED IN THE SASKATCHEWAN HOSPITAL SEPARATIONS DATABASE

A Saskatchewan hospital separations database was compared to abstracted hospital records to determine the reliability of the database (i.e. accuracy with which the computer data reflect the charts from which they were coded) and the validity of classifying rheumatoid arthritis status with the database (i.e. the extent to which rheumatoid arthritis mentioned in the database reflected the condition of the patient). A sample of hospitalized subjects fell into three categories: 144 who never had a database diagnosis of any arthritis, 146 who had a database diagnosis of osteoarthritis, and 142 who had a database diagnosis of rheumatoid arthritis. These 432 people experienced 1717 hospitalizations eligible to match a hospital database listing by date, and 1618 matched. Of the remaining 99, 35 were relatively recent and probably had not yet been entered into the database, 39 were possibly entered incorrectly, and 25 could not be matched in any way. Of 150 hospitalizations with a database diagnosis of rheumatoid arthritis, this diagnosis was in the hospital record for 125. Chart documentation of rheumatoid arthritis status was greatest for subjects who, according to the database, were hospitalized by a rheumatologist: of 73 subjects in this category, abstractions showed 69.9% met > or = 5 American Rheumatism Association criteria, 15.1% met < 5 criteria but had a rheumatologists diagnosis of rheumatoid arthritis, 1.3% met < 5 criteria and had a rheumatoid arthritis diagnosis by a non-rheumatologist, and 13.7% had no mention of rheumatoid arthritis or its symptoms in any medical record abstracted. In summary, reliability of the database was excellent, but validity depended on the source of diagnosis.