Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, the Netherlands.
Drug Saf. 2011 Sep 1;34(9):783-92. doi: 10.2165/11590470-000000000-00000.
Naproxen, ibuprofen and diclofenac are frequently used as comparators in randomized controlled trials (RCTs) on the safety and efficacy of cyclooxygenase (COX)-2 inhibitors. Different comparator doses may influence the results of RCTs. It has been hypothesized that RCTs of COX-2 inhibitors where different doses were administered resulted in different conclusions about the cardiovascular safety of COX-2 inhibitors. High comparator doses may let COX-2 inhibitors look better in terms of safety, while low comparator doses may result in the opposite.
The aim of the study was to compare doses of COX-2 inhibitors and comparator drugs used in RCTs, and to investigate dose changes over time.
We searched the Cochrane Central Register of Controlled Trials, The Cochrane Library for published Cochrane reviews, Clinicaltrials.gov and PubMed, for RCTs between 1995 and 2009 in which celecoxib or rofecoxib were compared with naproxen, ibuprofen or diclofenac. All articles labelled as RCTs mentioning rofecoxib or celecoxib and one or more of the comparator drugs in the title and/or abstract were included. We extracted information on doses of both non-selective NSAIDs and selective COX-2 inhibitors used in the RCTs, and study year. The Mann-Whitney test was used to compare the difference in median dose in rofecoxib and celecoxib RCTs. Linear regression was performed to evaluate trends in dosage over time. For comparisons between COX-2-inhibitors, celecoxib trials after the 2004 market withdrawal of rofecoxib were excluded.
Median defined daily dose (DDD) of celecoxib (2.00) was higher than the median DDD of rofecoxib (1.00; p < 0.001), whereas non-selective NSAID doses were comparable in rofecoxib (2.00) and celecoxib (2.00; p = 0.988) studies. In both groups, the non-selective NSAID doses decreased over time (B [regression coefficient] = -0.07; p = 0.28, and B = -0.054; p = 0.09, respectively). In contrast, the DDDs of rofecoxib increased slightly over time (B = 0.037; p = 0.28), whereas the celecoxib DDDs decreased over time (B = -0.081; p = 0.09). In due course, the contrasts between DDDs of COX-2 inhibitors and non-selective NSAIDs converged, both in rofecoxib and celecoxib RCTs; therefore, doses have become more comparable in recent years because of differences in steepness of two decreasing dose trends in the case of celecoxib, and opposing dose trends in the case of rofecoxib.
Although the dose trends over time differed for RCTs comparing rofecoxib and celecoxib with diclofenac, ibuprofen or naproxen, the results of our study do not support the hypothesis that dose trends influenced the decision to continue marketing celecoxib after the withdrawal of rofecoxib because the overall median DDD of celecoxib was substantially higher than the median DDD of rofecoxib, while non-selective NSAID DDDs were comparable.
在环氧化酶（COX）-2 抑制剂安全性和疗效的随机对照试验（RCT）中，萘普生、布洛芬和双氯芬酸经常被用作对照药物。不同的对照药物剂量可能会影响 RCT 的结果。据推测，使用不同剂量的 COX-2 抑制剂进行 RCT 可能会导致关于 COX-2 抑制剂心血管安全性的不同结论。高剂量的对照药物可能会使 COX-2 抑制剂在安全性方面表现得更好，而低剂量的对照药物则可能会产生相反的效果。
本研究旨在比较 COX-2 抑制剂和 RCT 中使用的对照药物的剂量，并研究剂量随时间的变化。
我们检索了 Cochrane 对照试验中心注册库、Cochrane 图书馆的已发表 Cochrane 综述、Clinicaltrials.gov 和 PubMed，以寻找 1995 年至 2009 年间进行的 RCT，其中塞来昔布或罗非昔布与萘普生、布洛芬或双氯芬酸进行了比较。所有标有 RCT 并在标题和/或摘要中提到罗非昔布或塞来昔布以及一种或多种对照药物的文章均被纳入。我们提取了 RCT 中使用的非选择性 NSAIDs 和选择性 COX-2 抑制剂的剂量信息，以及研究年份。使用 Mann-Whitney 检验比较罗非昔布和塞来昔布 RCT 中中位数剂量的差异。进行线性回归以评估剂量随时间的趋势。对于 COX-2 抑制剂之间的比较，在罗非昔布市场撤出后进行的塞来昔布试验被排除在外。
塞来昔布（2.00）的定义日剂量（DDD）中位数高于罗非昔布（1.00；p<0.001），而非选择性 NSAID 剂量在罗非昔布（2.00）和塞来昔布（2.00）研究中相似（p=0.988）。在这两组中，非选择性 NSAID 剂量随时间减少（B[回归系数]=-0.07；p=0.28，B=-0.054；p=0.09）。相反，罗非昔布的 DDD 随时间略有增加（B=0.037；p=0.28），而塞来昔布的 DDD 随时间减少（B=-0.081；p=0.09）。随着时间的推移，COX-2 抑制剂和非选择性 NSAID 的 DDD 之间的差异逐渐缩小，无论是在罗非昔布还是塞来昔布 RCT 中都是如此；因此，由于塞来昔布剂量下降趋势陡峭，罗非昔布剂量下降趋势相反，近年来剂量变得更加可比。
尽管比较罗非昔布和塞来昔布与双氯芬酸、布洛芬或萘普生的 RCT 中剂量随时间的变化趋势不同，但我们的研究结果并不支持剂量趋势影响罗非昔布撤出后继续销售塞来昔布的决定的假设，因为塞来昔布的总体中位数 DDD 明显高于罗非昔布的中位数 DDD，而非选择性 NSAID 的 DDD 相似。
