Risk and treatment effect heterogeneity: re-analysis of individual participant data from 32 large clinical trials
Risk and treatment effect heterogeneity: re-analysis of individual participant data from 32 large clinical trials
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DOI：
10.1093/ije/dyw118
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发表时间：
2016-12-01
影响因子：
7.7
通讯作者：
Hayward, Rodney A.
中科院分区：
文献类型：
--
作者：
Kent, David M.;Nelson, Jason;Hayward, Rodney A.
背景：结果风险是干预措施绝对治疗获益的数学决定因素，但这在试验人群中可能存在很大差异，从而使试验结果的解释变得复杂。方法：我们在一组大型公开随机对照试验 (RCT) 上使用 Cox 或逻辑回归开发了风险模型。我们使用极端四分位风险比（EQRR，最低风险四分位的结果率与最高风险四分位的结果率之比）评估风险异质性，并使用中位风险与平均风险比（MMRR，中位风险患者的风险与平均值的比率）评估偏度。我们还检查了不同风险层治疗效果 (HTE) 的异质性。结果：我们使用 32 项大型试验的数据描述了 39 项分析，各研究的事件发生率范围为 3% 至 63%（中位数 = 15%，第 25-75 个百分位数 = 9-29%）。风险模型的 C 统计量范围为 0.59 至 0.89（中位数 = 0.70，第 25-75 个百分位数 = 0.65-0.71）。 EQRR 范围为 1.8 至 50.7（中位数 = 4.3，第 25-75 个百分位数 = 3.0-6.1）。 MMRR 范围为 0.4 至 1.0（中位数 = 0.86，第 25-75 个百分位数 = 0.80-0.92）。随着 c 统计量的增加或总体结果发生率的降低，EQRR 预计会更高，而 MMRR 预计会更低。在 18 项具有显着总体治疗效果的比较中，只有一项在比例尺度上治疗与基线风险之间存在显着交互作用。极端风险四分位数之间绝对风险降低的差异范围为 -3.2% 至 28.3%（中位数 - 5.1%；第 25-75 个百分位数 = 0.3-10.9）。结论：临床试验中的结果风险通常存在很大差异，通常导致绝对治疗效果存在临床显着差异。大多数患者的结果风险低于总结结果中反映的试验平均值。风险分层试验分析是可行的，并且可能提供临床信息，特别是当结果可预测且不常见时。
Background: Risk of the outcome is a mathematical determinant of the absolute treatment benefit of an intervention, yet this can vary substantially within a trial population, complicating the interpretation of trial results.Methods: We developed risk models using Cox or logistic regression on a set of large publicly available randomized controlled trials (RCTs). We evaluated risk heterogeneity using the extreme quartile risk ratio (EQRR, the ratio of outcome rates in the lowest risk quartile to that in the highest) and skewness using the median to mean risk ratio (MMRR, the ratio of risk in the median risk patient to the average). We also examined heterogeneity of treatment effects (HTE) across risk strata.Results: We describe 39 analyses using data from 32 large trials, with event rates across studies ranging from 3% to 63% (median = 15%, 25th-75th percentile = 9-29%). C-statistics of risk models ranged from 0.59 to 0.89 (median = 0.70, 25th-75th percentile = 0.65-0.71). The EQRR ranged from 1.8 to 50.7 (median = 4.3, 25th-75th percentile = 3.0-6.1). The MMRR ranged from 0.4 to 1.0 (median = 0.86, 25th-75th percentile = 0.80-0.92). EQRRs were predictably higher and MMRRs predictably lower as the c-statistic increased or the overall outcome incidence decreased. Among 18 comparisons with a significant overall treatment effect, there was a significant interaction between treatment and baseline risk on the proportional scale in only one. The difference in the absolute risk reduction between extreme risk quartiles ranged from -3.2 to 28.3% (median - 5.1%; 25th-75th percentile = 0.3-10.9).Conclusions: There is typically substantial variation in outcome risk in clinical trials, commonly leading to clinically significant differences in absolute treatment effects. Most patients have outcome risks lower than the trial average reflected in the summary result. Risk-stratified trial analyses are feasible and may be clinically informative, particularly when the outcome is predictable and uncommon.