Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA.
Department of Non-invasive Cardiology, Harvard Medical School, Boston, MA, USA.
Contemp Clin Trials. 2020 Mar;90:105937. doi: 10.1016/j.cct.2020.105937. Epub 2020 Jan 23.
The per-protocol effect provides important information in randomized trials with incomplete adherence. Yet, because valid estimation typically requires adjustment for prognostic factors that predict adherence, per-protocol effect estimates are often met with skepticism. In placebo-controlled trials, however, the validity of adjustment can be indirectly verified by demonstrating no association between adherence and the outcome among the placebo arm. Here, we describe a two-stage procedure in which we first adjust for time-varying adherence in the placebo arm and then use a similar procedure to estimate the per-protocol effect.
We use the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) randomized trial. First, we compare adherers versus non-adherers in the placebo arm, adjusting for pre- and post-randomization variables. Second, we use models validated in the placebo arm to estimate the per-protocol effect of adherence to candesartan versus placebo in the full trial.
We successfully estimated no association between adherence and mortality in the placebo arm; hazard ratio: 0.91 (95% CI: 0.51, 2.52). We then estimated the per-protocol effect under two sets of protocol-defined stopping criteria after adjustment for post-randomization confounders. The mortality hazard ratio estimates ranged from 0.91 to 0.93 for the per-protocol effect estimates, similar to the intention-to-treat effect estimates.
Adherence adjustment in the CHARM trial is feasible when appropriate assumptions about missing data and confounding are made. These assumptions cannot be verified but can be supported through the use of placebo-arm adherence assessment.
在不完全依从的随机试验中，方案内效应提供了重要信息。然而，由于有效估计通常需要调整预测依从性的预后因素，因此方案内效应估计常常受到质疑。然而，在安慰剂对照试验中，通过证明在安慰剂组中依从性与结局之间没有关联，可以间接验证调整的有效性。在这里，我们描述了一种两阶段的方法，我们首先调整安慰剂组中随时间变化的依从性，然后使用类似的程序来估计方案内效应。
我们使用坎地沙坦治疗心力衰竭：降低死亡率和发病率评估（CHARM）随机试验。首先，我们比较了安慰剂组中依从者与不依从者，调整了随机化前后的变量。其次，我们使用在安慰剂组中验证的模型来估计在整个试验中坎地沙坦对安慰剂的依从性的方案内效应。
我们成功地估计了在安慰剂组中，依从性与死亡率之间没有关联；风险比：0.91（95%CI：0.51，2.52）。然后，我们在调整了随机化后混杂因素后，根据两组方案定义的停止标准，估计了方案内效应。在经过调整后，方案内效应的死亡率风险比估计值在 0.91 到 0.93 之间，与意向治疗效应估计值相似。
当对缺失数据和混杂因素做出适当的假设时，CHARM 试验中的依从性调整是可行的。这些假设不能被验证，但可以通过使用安慰剂组的依从性评估来支持。
