Blackmores Institute, Warriewood, NSW, 2102, Australia.
School of Health and Human Sciences, Southern Cross University, Lismore, NSW, 2480, Australia.
BMC Complement Altern Med. 2017 Aug 16;17(1):408. doi: 10.1186/s12906-017-1906-x.
The public safety of α-tocopherol has been called in question by several meta-analyses which have raised concern among regulatory authorities. The objective of this study was to evaluate the Cochrane Database Systematic Review 2012 (CD007176) which concludes that α-tocopherol forms of vitamin E have a statistically significant effect on mortality, by assessing the trials and datasets used and determining their effect upon the primary outcome.The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC), a factorial design study of Finnish smokers was a pivotal paper in the Cochrane Review owing to the high mortality rate observed which resulted in a substantial weighting (42.6%) in the meta-analysis. The Cochrane meta-analysis used a 3 cell analytical method comparing all vitamin E cells (vitamin E alone plus vitamin E + β-carotene) to the placebo only cell. This had the unfortunate effect of incorrectly inflating the mortality risk attributed to vitamin E by not balancing the contribution to mortality of the β-carotene intervention. Re-analysis of the ATBC trial using data derived from the more generally accepted 'inside the table' (2 cell - vitamin E versus placebo) or 'at the margins' (4 cell - all vitamin E versus all non-vitamin E) analytical methods demonstrates a statistically non-significant result.The data from the ATBC study has been given in 5 datasets (the trial alone and four extended post-trial follow-up time periods). Using the 3 cell analysis method only the 6 and 8-year (used in the meta-analysis) follow-up periods were statistically significant. Using the 2 or 4 cell method the outcome remains non-significant over all time periods.The impartiality of excluding trials with zero mortality is also examined and questioned.This paper raises concerns overall as to the appropriateness of datasets chosen, the validity of methods and generalisability of results when using meta-analysis as a tool to determine safety. Issues raised in this paper are not unique to the Cochrane study in question. Until we have new tools, there may be a need to rely on conventional narrative systematic literature synthesis in the assessment of safety or contain our results to specific sub-populations where more conclusive results can be determined.
几项荟萃分析对 α-生育酚的安全性提出了质疑，这引起了监管机构的关注。本研究旨在评估 Cochrane 数据库系统评价 2012 年（CD007176），该评价得出结论，α-生育酚形式的维生素 E 对死亡率有统计学显著影响，方法是评估所使用的试验和数据集，并确定它们对主要结局的影响。
芬兰吸烟者的 α-生育酚、β-胡萝卜素癌症预防研究（ATBC）是 Cochrane 综述中的一篇关键论文，因为观察到的高死亡率导致荟萃分析中进行了大量加权（42.6%）。Cochrane 荟萃分析使用了 3 单元格分析方法，比较了所有维生素 E 组（单独维生素 E 加维生素 E+β-胡萝卜素）与安慰剂组。由于未平衡 β-胡萝卜素干预对死亡率的贡献，这种方法不幸地错误地夸大了归因于维生素 E 的死亡率风险。使用更广泛接受的“表内”（2 单元格 - 维生素 E 与安慰剂）或“边缘”（4 单元格 - 所有维生素 E 与所有非维生素 E）分析方法重新分析 ATBC 试验，结果显示无统计学意义。
ATBC 研究的数据已在 5 个数据集（单独的试验和四个延长的试验后随访时间段）中给出。仅使用 3 细胞分析方法，只有 6 年和 8 年（用于荟萃分析）随访期具有统计学意义。使用 2 或 4 个细胞方法，所有时间段的结果仍然无统计学意义。
排除死亡率为零的试验的公正性也受到了审查和质疑。
本文总体上对选择的数据集的适当性、方法的有效性以及使用荟萃分析作为确定安全性的工具的结果的普遍性提出了担忧。本文提出的问题不仅限于所讨论的 Cochrane 研究。在我们有新的工具之前，在评估安全性时，可能需要依赖传统的叙述性系统文献综合，或者将结果限制在可以确定更具结论性结果的特定亚人群中。
