Ross Joseph S, Madigan David, Hill Kevin P, Egilman David S, Wang Yongfei, Krumholz Harlan M
Department of Geriatrics and Palliative Medicine, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1070, New York, NY 10029, USA.
Arch Intern Med. 2009 Nov 23;169(21):1976-85. doi: 10.1001/archinternmed.2009.394.
In September 2004, rofecoxib was voluntarily withdrawn from the worldwide market. Our objective was to determine whether and when analysis of published and unpublished placebo-controlled trials could have revealed cardiovascular risk associated with rofecoxib before its withdrawal as an example to inform future postmarket pharmaceutical safety surveillance efforts.
We conducted a cumulative subject-level pooled analysis of data from all randomized, placebo-controlled trials of rofecoxib conducted by the manufacturer before September 2004. Our main outcome measurement was incidence of any investigator-reported death from any cause or cardiovascular thromboembolic (CVT) adverse event.
We identified 30 randomized, placebo-controlled trials of rofecoxib that enrolled a combined 20 152 subjects. Trial duration ranged from 4 weeks to 4 years; enrollment ranged from 17 to 2586 subjects prescribed either rofecoxib or placebo; and rofecoxib dose ranged from 12.5 mg to 50 mg. As of December 2000, 21 of these trials had been completed (70%), and the risk of a CVT adverse event or death was greater among subjects assigned to the rofecoxib group (rate ratio [RR], 2.18; 95% confidence interval [CI], 0.93-5.81) (P = .07), raising concerns from a safety standpoint. Subsequently collected data through June 2001 showed that rofecoxib was associated with a 35% increased risk of a CVT adverse event or death (RR, 1.35; 95% CI, 1.00-1.96) (P = .05). Analyzing data available as of April 2002, we found a 39% increased risk (RR, 1.39; 95% CI, 1.07-1.80) (P = .02), and using data available as of September 2004, we found a 43% increased risk (RR,1.43; 95% CI, 1.16-1.76) (P < .001).
Cumulative pooled analysis of all randomized, placebo-controlled trials demonstrates a trend toward increased cardiovascular risk associated with rofecoxib compared with placebo as early as December 2000, the comparison reaching a P value of .05 by June 2001, nearly 3(1/2) years before the manufacturer's voluntary market withdrawal.
2004年9月，罗非昔布主动退出全球市场。我们的目的是确定已发表和未发表的安慰剂对照试验分析能否在罗非昔布退出市场之前揭示其心血管风险，以此为例为未来的上市后药品安全监测工作提供参考。
我们对制造商在2004年9月之前进行的所有罗非昔布随机、安慰剂对照试验的数据进行了累积个体水平的汇总分析。我们的主要结局指标是任何研究者报告的任何原因导致的死亡或心血管血栓栓塞（CVT）不良事件的发生率。
我们确定了30项罗非昔布随机、安慰剂对照试验，共纳入20152名受试者。试验持续时间从4周到4年不等；入组人数从17人到2586名服用罗非昔布或安慰剂的受试者不等；罗非昔布剂量从12.5毫克到50毫克不等。截至2000年12月，这些试验中有21项已经完成（70%），罗非昔布组受试者发生CVT不良事件或死亡的风险更高（率比[RR]，2.18；95%置信区间[CI]，0.93 - 5.81）（P = 0.07），从安全性角度引发了担忧。随后截至2001年6月收集的数据显示，罗非昔布与CVT不良事件或死亡风险增加35%相关（RR，1.35；95% CI，1.00 - 1.96）（P = 0.05）。分析截至2002年4月可得的数据，我们发现风险增加39%（RR，1.39；95% CI，1.07 - 1.80）（P = 0.02），使用截至2004年9月可得的数据，我们发现风险增加43%（RR，1.43；95% CI，1.16 - 1.76）（P < 0.001）。
对所有随机、安慰剂对照试验的累积汇总分析表明，早在2000年12月，与安慰剂相比，罗非昔布就呈现出心血管风险增加的趋势，到2001年6月该比较的P值达到0.05，比制造商主动退出市场提前了近3年半。
