McGettigan Patricia, Han Pearline, Henry David
Discipline of Clinical Pharmacology, School of Medicine and Public Health, The University of Newcastle, New South Wales, Australia.
Br J Clin Pharmacol. 2006 Sep;62(3):358-65. doi: 10.1111/j.1365-2125.2006.02660.x.
To investigate the relationship between acute coronary syndrome (ACS) and ingested doses of selective cyclooxygenase-2 (COX-2) inhibitors and other nonsteroidal anti-inflammatory drugs (NSAIDs).
Case-control study, commenced August 2003. Cases were patients admitted to hospital with ACS (myocardial infarction/unstable angina). Controls were hospital patients admitted for reasons other than acute vascular ischaemia or conditions that are believed to be complications of treatment with COX-2 inhibitors or NSAIDs. Structured interviews were undertaken within 7 days of admission, collecting information on cardiovascular events and risk factors and all ingested drugs, including the doses of COX-2 inhibitors and NSAID consumed in the previous week and month.
An interim analysis of the data was conducted in late 2004 to inform a review of the COX-2 inhibitors by the Australian drug regulatory agency. Between August 2003 and October 2004, we recruited 328 ACS cases and 478 controls. With non-use of COX-2 inhibitors or NSAIDs as the reference the adjusted odds ratios (OR) for ACS were: celecoxib 1.11 (95% confidence interval 0.59, 2.11), rofecoxib 0.63 (0.31, 1.28) and other NSAIDs 0.67 (0.41, 1.09). Among control subjects, median daily ingested doses of celecoxib and rofecoxib were 200 mg and 13.4 mg, respectively. Using these to stratify risk, adjusted ORs for ACS were: 'low' dose (< median) 0.44 (0.19, 1.03); 'high' dose (>/= median) 1.22 (0.67, 2.21). A test for interaction across doses was statistically significant, OR 2.8 (1.0, 7.7), suggesting that at low doses, COX-2 inhibitors may be protective, becoming risk-inducing only at higher doses.
The possibility that the gradient of cardiovascular risk with COX-2 inhibitors runs from protective to risk-inducing has biological plausibility and merits further investigation.
研究急性冠状动脉综合征（ACS）与选择性环氧化酶-2（COX-2）抑制剂及其他非甾体抗炎药（NSAIDs）摄入剂量之间的关系。
病例对照研究，于2003年8月开始。病例为因ACS（心肌梗死/不稳定型心绞痛）入院的患者。对照为因急性血管缺血以外的原因或被认为是COX-2抑制剂或NSAIDs治疗并发症的疾病而入院的患者。在入院7天内进行结构化访谈，收集心血管事件、危险因素及所有摄入药物的信息，包括前一周和一个月内摄入的COX-2抑制剂和NSAIDs的剂量。
2004年末对数据进行了中期分析，为澳大利亚药品监管机构对COX-2抑制剂的审查提供信息。2003年8月至2004年10月期间，我们招募了328例ACS病例和478例对照。以未使用COX-2抑制剂或NSAIDs为参照，ACS的调整优势比（OR）为：塞来昔布1.11（95%置信区间0.59，2.11），罗非昔布0.63（0.31，1.28），其他NSAIDs 0.67（0.41，1.09）。在对照受试者中，塞来昔布和罗非昔布的每日摄入剂量中位数分别为200毫克和13.4毫克。用这些剂量分层风险后，ACS的调整OR为：“低”剂量（<中位数）0.44（0.19，1.03）；“高”剂量（≥中位数）1.22（0.67，2.21）。剂量间交互作用检验具有统计学意义，OR为2.8（1.0，7.7），表明在低剂量时，COX-2抑制剂可能具有保护作用，仅在高剂量时才会增加风险。
COX-2抑制剂导致心血管风险从保护作用转变为增加风险这一可能性具有生物学合理性，值得进一步研究。
