Pegram Camilla, Diaz-Ordaz Karla, Brodbelt Dave C, Chang Yu-Mei, Boswood Adrian, Wilshaw Jenny, Reep Carmen A T, Balling Sarah, Sahota Jaya, Church David B, O'Neill Dan G
Pathobiology and Population Sciences, The Royal Veterinary College, Hatfield, United Kingdom.
University College London, Department of Statistical Science, London, United Kingdom.
PLoS One. 2025 Jun 18;20(6):e0325695. doi: 10.1371/journal.pone.0325695. eCollection 2025.
Target trial emulation applies design principles from randomised controlled trials (RCTs) to the analysis of observational data, potentially replicating RCT results in real-world settings. The EPIC trial reported that pimobendan delays the onset of congestive heart failure (CHF) and extends survival in dogs with preclinical degenerative mitral valve disease (DMVD). The current study aimed to explore the extent to which target trial emulation approximates the EPIC trial results in a primary-care setting. Grade IV/VI murmur diagnosis was defined as the treatment intervention stage. There were 928 dogs ≥ 6 years and ≤ 15 kg at first grade IV/VI murmur diagnosis recorded from January 1, 2016, to December 31, 2018 in the VetCompass database included in the study. A causal inference "target trial emulation" approach using VetCompass anonymised clinical data was designed to replicate the EPIC trial with adaptation for a primary-care setting and to address immortal time bias, confounding bias and loss to follow-up. After bias adjustments to establish causal effects using observational data, the 5-year CHF cumulative incidence was lower in dogs prescribed pimobendan (34.1%, 95% CI 26.5-42.0) than dogs not prescribed pimobendan (56.3%, 95% CI 52.8-59.8). Dogs prescribed pimobendan had 311 fewer days of health lost to CHF (95% CI 224-395 days) within 5 years. Dogs prescribed pimobendan lived longer (adjusted mean survival time 1051 days, 95% CI 967-1125) than dogs not prescribed pimobendan (905 days, 95% CI 871-940 days). This study demonstrates that target trial emulation within veterinary research can replicate findings from RCTs. Clinically, the current findings suggest that preclinical grade IV murmur diagnosis may offer an appropriate intervention stage to begin pimobendan therapy in dogs with presumed DMVD.
目标试验模拟将随机对照试验（RCT）的设计原则应用于观察性数据的分析，有可能在现实环境中复制RCT的结果。EPIC试验报告称，匹莫苯丹可延迟充血性心力衰竭（CHF）的发作，并延长患有临床前退行性二尖瓣疾病（DMVD）犬的生存期。本研究旨在探讨在初级保健环境中，目标试验模拟在多大程度上接近EPIC试验的结果。IV/VI级杂音诊断被定义为治疗干预阶段。研究纳入了VetCompass数据库中2016年1月1日至2018年12月31日首次记录IV/VI级杂音诊断时年龄≥6岁且体重≤15千克的928只犬。使用VetCompass匿名临床数据的因果推断“目标试验模拟”方法旨在针对初级保健环境进行调整后复制EPIC试验，并解决不朽时间偏倚、混杂偏倚和失访问题。在使用观察性数据进行偏倚调整以确定因果效应后，服用匹莫苯丹的犬5年CHF累积发病率（34.1% , 95% CI 26.5 - 42.0）低于未服用匹莫苯丹的犬（56.3% , 95% CI 52.8 - 59.8）。服用匹莫苯丹的犬在5年内因CHF而损失健康的天数减少311天（95% CI 224 - 395天）。服用匹莫苯丹的犬比未服用匹莫苯丹的犬寿命更长（调整后平均生存时间1051天，95% CI 967 - 1,125）（905天，95% CI 871 - 940天）。本研究表明，兽医研究中的目标试验模拟可以复制RCT的结果。临床上，目前的研究结果表明，临床前IV级杂音诊断可能为疑似DMVD的犬开始匹莫苯丹治疗提供一个合适的干预阶段。
