Generalizing data from randomized trials to predict long-term treatment outcomes in older populations

项目总结/摘要 随机对照试验（RCT）被认为是评估治疗效果的金标准。 然而，典型RCT的两个特征限制了它们对患者、提供者和其他决策者的效用。 首先，随机对照试验通常集中在狭窄的患者人群中，以增加内部效度。这就限制了 随机对照试验结果针对老年和病情较重的目标人群，特别是当治疗效果异质性（HTE） 存在。第二，许多随机对照试验的随访时间很短，尽管他们评估的许多治疗方法都是 打算长期使用。尽管RCT在研究期间提供了关于治疗疗效的证据， 随访，估计治疗的长期影响是困难的。随着患者年龄的增长，他们的疾病状态可能 他们可以发展新的和恶化的条件，改变治疗的效果。因此，我们认为， RCT期间观察到的平均治疗效果可能无法准确反映长期治疗 结果。由于这些局限性而缺乏普遍性，导致在翻译RCT结果时存在不确定性， 临床实践，尤其是在上市后的早期阶段。迫切需要制定方法 这可以使试验结果对患者、临床医生和其他决策者更有用。我们提出了一种新 将RCT结果扩展到更广泛的患者人群和更长时间的方法， HTE。该方法使用来自个体水平RCT数据和个体水平 模拟模型，以估计适用于外部目标人群特征的影响，例如 老年人。来自三项具有里程碑意义的RCT的现有个体水平数据将用作病例研究， 评价将RCT结果推广到老年患者的可行性和应用 在现有的医疗保险数据中确定：长期抗凝治疗的随机评价（RE- LY）试验，ARNI与ACEI的前瞻性比较，以确定对全球死亡率的影响， 心力衰竭（PARADIGM-HF）患者的死亡率，以及LCZ 696与缬沙坦相比对 射血分数保留的心力衰竭患者的发病率和死亡率（PARAGON-HF）。我们 假设RCT中关于HTE的信息可以用来预测治疗结果 在更大的目标人群和更长的时间段比研究的随机对照试验。

Project Summary/Abstract Randomized controlled trials (RCTs) are considered the gold standard for assessing efficacy of treatments. However, two characteristics of typical RCTs limit their utility for patient, providers, and other decision-makers. First, RCTs often focus on narrow patient populations to increase internal validity. This limits generalizability of the RCT results to older and sicker target populations, especially when heterogeneity of treatment effect (HTE) is present. Second, many RCTs have short follow-up even though many treatments that they evaluate are intended to be used for a long time. Although RCTs provide evidence about treatment efficacy during the study follow-up, estimating the long-term impact of treatment is difficult. As patients age, their disease state can change and they can develop new and worsening conditions that modify the effect of a treatment. Therefore, the average treatment effect observed during an RCT may not accurately reflect long-term treatment outcomes. Lack of generalizability due to these limitations causes uncertainty in translating RCT findings in clinical practice, especially in the early post-marketing stages. There is an urgent need to develop methods that can make trial results more useful to patients, clinicians, and other decision-makers. We propose a novel approach to expand RCT results to broader patient populations and over longer periods in the presence of HTE. The approach uses evidence about HTE derived from individual-level RCT data and an individual-level simulation model to estimate effects applicable to the characteristics of external target populations, such as older individuals. Existing individual-level data from three landmark RCTs will be used as case studies to evaluate the feasibility and application of the proposed approach for generalizing RCT results to older patients identified in existing Medicare data: the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE- LY) trial, the Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF), and the Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction (PARAGON-HF). Our hypothesis is that information about HTE in the RCTs can be leveraged to predict treatment outcomes in a larger target population and over longer time periods than studied in the RCTs.