Sommet A, Grolleau S, Bagheri H, Lapeyre-Mestre M, Montastruc J L
Laboratoire de Pharmacologie Médicale et Clinique, Unité de Pharmacoépidémiologie, EA 3696, Université de Toulouse, Faculté de Médecine, 37 allées Jules-Guesde, Toulouse, France.
Eur J Clin Pharmacol. 2008 Aug;64(8):829-34. doi: 10.1007/s00228-008-0497-3. Epub 2008 May 29.
Rofecoxib was withdrawn from the market on 30 September 2004 following the results of a randomized controlled trial.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.
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.
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.
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.
在一项随机对照试验得出结果后，罗非昔布于2004年9月30日退出市场。这一突然决定之后，文献中出现了一些争议，以确定这种药物不良反应（ADR）是否能够更早被发现。本研究的目的是调查在罗非昔布退出市场之前，使用法国药物警戒数据库是否能发现这类信号。
利用2000年5月至2006年12月在法国药物警戒数据库中登记的病例，我们将病例-非病例方法应用于15岁以上患者中口服罗非昔布或塞来昔布报告的“严重”血栓性ADR。病例为所有在昔布类药物（罗非昔布、塞来昔布）使用下发生的血栓性ADR的报告[世界卫生组织不良反应术语（WHO-ART）编码1300]，非病例为数据库中登记的所有其他报告（无论使用何种药物）。我们计算了2000年5月20日至2006年12月31日的累积比值比（OR），特别关注2004年9月30日之前的时间段。
在此期间数据库中登记的50087例“严重”ADR中，1127例为血栓性ADR。早在2001年底，罗非昔布暴露与血栓性ADR的高比值比（OR）值[4.2（95%CI 1.97-8.61）]显著相关。ADR报告OR值在2006年之前一直保持较高（3.0-3.5）。对于塞来昔布，仅从2004年9月开始出现显著趋势。
尽管病例/非病例方法存在一定局限性，但本研究发现早在罗非昔布在法国上市的第一年年底，罗非昔布暴露与“严重”血栓性ADR的发生之间存在关联。塞来昔布与这类ADR发生之间的关联似乎不太明确。我们的工作还表明，仔细分析药物警戒数据库（例如调查风险累积值）在早期识别新的ADR方面具有潜在用途。
