Was the thrombotic risk of rofecoxib predictable from the French Pharmacovigilance Database before 30 September 2004?

OBJECTIVES: Rofecoxib was withdrawn from the market on 30 September 2004 following the results of a randomized controlled trial. Following this sudden decision, several controversies occurred in the literature to determine whether this adverse drug reaction (ADR) could have been detected earlier. The aim of this study was to investigate whether this kind of signal could have been seen using the French Pharmacovigilance Database before this date of rofecoxib withdrawal. METHODS: Using cases registered in the French Pharmacovigilance Database from May 2000 to December 2006, we applied the case-noncase method to "serious" thrombotic ADRs reported with oral formulations of rofecoxib or celecoxib in patients older than 15 years. Cases were all notifications of thrombotic ADRs [World Health Organization Adverse Reaction Terminology (WHO-ART) codes 1300] occurred under coxib (rofecoxib, celecoxib) and noncases all other reports registered in the database (whatever the drug). We calculated a cumulative odds ratio (OR) from 20 May 2000 to 31 December 2006, with a special interest for the period before the 30 September 2004. RESULTS: Among the 50,087 "serious" ADRs registered in the database during this period, 1,127 were thrombotic ones. Rofecoxib exposure was significantly associated with high values of odds ratio (OR) [4.2 (95% CI 1.97-8.61)] for thrombotic ADRs as early as the end of 2001. The values of ADR reporting ORs remained high (3.0-3.5) until 2006. For celecoxib, a significant trend occurred only from September 2004. CONCLUSION: Despite the compulsory limits of the case/noncase methodology, this study found an association between rofecoxib exposure and the occurrence of "serious" thrombotic ADRs as early as the end of the first year of rofecoxib marketing in France. The association between celecoxib and the occurrence of such ADRs appears less clear. Our work also shows the potential use of careful analysis of pharmacovigilance databases (investigating, for example, cumulative values of risk) in the early identification of new ADRs.

Severe necrotizing soft-tissue infections and nonsteroidal anti-inflammatory drugs.

BACKGROUND: Severe necrotizing soft-tissue infection (NSTI) is a rare but potentially life-threatening condition if not recognized and treated early. The use of nonsteroidal anti-inflammatory drugs (NSAIDs) has been implicated as a contributing factor, but their role remains debated. AIMS: The aim of our study was to investigate the potential relationship between cases of NSTI recorded in the French Pharmacovigilance system and exposure to NSAIDs. METHODS: Cases of NSTI and randomly selected matched noncase controls (without skin disease) were identified in the database of the Spontaneous Reporting System in France for the period 2000-2004. Exposure to NSAIDs and other factors were investigated using conditional logistic regression. RESULTS: We found 38 cases of NSTI in 2000-04: 12 infants (0-23 months), 16 children (2-15 years) and 10 adults (>15 years), and we selected 228 controls. The median age of the sample was 4 years. Of the 38 cases, 25 were exposed to ibuprofen and 24 presented with varicella. The adjusted odds ratio for exposure to NSAIDs was 31.38 (95% CI 6.40-153.84), and 17.55 (95% CI 3.47-88.65) for viral infection. Other predisposing factors (diabetes, immunosuppression, injecting drugs) were not found to be associated, although this may have been due to the very small number of cases of NSTI/necrotizing fasciitis in adults reported in the database. CONCLUSION: Despite the limitations related to a spontaneous reporting system, this study indicates a strong association between NSAID use and NSTI. Although it was not possible to conclude if NSAIDs increase the risk of necrotizing complications in all patients, their use may mask the symptoms and delay diagnosis.

Pattern of health service utilization and predictors of readmission after a first admission for psychosis: a 2-year follow-up study.

OBJECTIVE: To explore the pattern of health service utilization over 2 years following a first admission for psychosis and the baseline characteristics predicting readmission. METHOD: Patients included in a cohort of first-admitted subjects with psychosis (n = 84) were assessed at the end of a 2-year follow-up using multiple sources of information. RESULTS: At the end of the follow-up, one of three subjects had no contact with any mental health professional, and 38% of subjects had no contact with a psychiatrist. Half of the patients were readmitted over the 2-year follow-up. The baseline characteristics independently predicting psychiatric readmission were a high number of helping contacts before first admission and persistence of psychotic symptoms at discharge. CONCLUSION: Decreasing the frequency of readmission in the early course of psychosis is a public health priority. Development of psychotherapeutic programs for subjects with early psychosis who have enduring psychotic symptoms at first discharge should be promoted.