Trial emulations in observational data analyses can complement findings from randomized clinical trials, inform future trial designs, or generate evidence when randomized studies are not feasible due to resource constraints and ethical or practical limitations. Importantly, trial emulation designs facilitate causal inference in observational data analyses by enhancing counterfactual thinking and comparisons of real-world observations (e.g. Mendelian Randomization) to hypothetical interventions. In order to enhance credibility, trial emulations would benefit from prospective registration, publication of statistical analysis plans, and subsequent prospective benchmarking to randomized clinical trials prior to their publication. Confounding by indication, however, is the key challenge to interpreting observed intended effects of an intervention as causal in observational data analyses. We discuss the target trial emulation of the REDUCE-AMI randomized clinical trial (ClinicalTrials.gov ID NCT03278509; beta-blocker use in patients with preserved left ventricular ejection fraction after myocardial infarction) to illustrate the challenges and uncertainties of studying intended effects of interventions without randomization to account for confounding. We furthermore directly compare the findings, statistical power, and clinical interpretation of the results of the REDUCE-AMI target trial emulation to those from the simultaneously published randomized clinical trial. The complexity and subtlety of confounding by indication when studying intended effects of interventions can generally only be addressed by randomization.

观察数据分析中的试验模拟可以补充随机临床试验的结果，为未来的试验设计提供信息，或者在随机研究由于资源限制和伦理或实践限制而不可行时生成证据。重要的是，试验模拟设计通过增强反事实思维以及现实世界观察（例如孟德尔随机化）与假设干预措施的比较，促进观察数据分析中的因果推断。为了提高可信度，试验模拟将受益于前瞻性注册、统计分析计划的发布以及随后在发布之前对随机临床试验进行前瞻性基准测试。然而，指示混淆是将观察到的干预预期效果解释为观察数据分析中的因果关系的关键挑战。我们讨论了 REDUCE-AMI 随机临床试验（ClinicalTrials.gov ID NCT03278509；β-受体阻滞剂在心肌梗死后左心室射血分数保留的患者中的使用）的目标试验模拟，以说明研究干预措施预期效果的挑战和不确定性随机化以考虑混杂因素。此外，我们还直接将 REDUCE-AMI 目标试验模拟结果的发现、统计功效和临床解释与同时发表的随机临床试验的结果进行比较。在研究干预措施的预期效果时，指示混淆的复杂性和微妙性通常只能通过随机化来解决。