Department of Vascular Medicine University Medical Center Utrecht Utrecht the Netherlands.
Department of Cardiology Amsterdam University Medical CenterAcademic Medical Center/University of Amsterdam Amsterdam the Netherlands.
J Am Heart Assoc. 2022 Jan 4;11(1):e017605. doi: 10.1161/JAHA.120.017605. Epub 2021 Dec 22.
Background For translating an overall trial result into an individual patient's expected absolute treatment effect, differences in relative treatment effect between patients need to be taken into account. The aim of this study was to evaluate whether relative treatment effects of medication in 2 large contemporary trials are influenced by multivariable baseline risk of an individual patient. Methods and Results In 9361 patients from SPRINT (Systolic Blood Pressure Intervention Trial), risk of major adverse cardiovascular events was assessed using a newly derived risk model. In 18 133 patients from the RE-LY (Randomized Evaluation of Long-Term Anticoagulant Therapy) trial, risk of stroke or systemic embolism and major bleeding was assessed using the Global Anticoagulant Registry in the Field-Atrial Fibrillation risk model. Heterogeneity of trial treatment effect was assessed using Cox models of trial allocation, model linear predictor, and their interaction. There was no significant interaction between baseline risk and relative treatment effect from intensive blood pressure lowering in SPRINT (=0.92) or from dabigatran compared with warfarin for stroke or systemic embolism in the RE-LY trial (=0.71). There was significant interaction between baseline risk and treatment effect from dabigatran versus warfarin in the RE-LY trial (<0.001) for major bleeding. Quartile-specific hazard ratios for bleeding ranged from 0.40 (95% CI, 0.26-0.61) to 1.04 (95% CI, 0.83-1.03) for dabigatran, 110 mg, and from 0.61 (95% CI, 0.42-0.88) to 1.20 (95% CI, 0.97-1.50) for dabigatran, 150 mg, compared with warfarin. Conclusions Effect modification of relative treatment effect by individual baseline event risk should be assessed systematically in randomized clinical trials using multivariate risk prediction, not only in terms of treatment efficacy but also for important treatment harms, as a prespecified analysis. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01206062.
将总体试验结果转化为个体患者预期的绝对治疗效果时，需要考虑患者间相对治疗效果的差异。本研究旨在评估 2 项大型当代试验中药物的相对治疗效果是否受个体患者多变量基线风险的影响。
在 SPRINT（收缩压干预试验）的 9361 例患者中，使用新推导的风险模型评估主要不良心血管事件的风险。在 RE-LY（长期抗凝治疗随机评价）试验的 18333 例患者中，使用全球抗凝注册-房颤风险模型评估卒中或全身性栓塞及大出血的风险。使用试验分配、模型线性预测及其交互作用的 Cox 模型评估试验治疗效果的异质性。强化降压治疗对 SPRINT 中血压的影响（=0.92）或与 RE-LY 试验中达比加群酯与华法林相比对卒中或全身性栓塞的相对治疗效果（=0.71）与基线风险之间无显著交互作用。RE-LY 试验中达比加群酯与华法林相比，主要出血的基线风险与治疗效果之间存在显著交互作用（<0.001）。出血风险的四分位数特异性危险比范围为达比加群酯 110mg 组为 0.40（95%CI，0.26-0.61）至 1.04（95%CI，0.83-1.03），达比加群酯 150mg 组为 0.61（95%CI，0.42-0.88）至 1.20（95%CI，0.97-1.50），与华法林相比。
使用多变量风险预测，在随机临床试验中系统评估个体基线事件风险对相对治疗效果的影响修饰，不仅要考虑治疗效果，还要考虑重要的治疗危害，作为预先指定的分析。
