Emulating the EPIC trial using VetCompass primary-care data: causal effects of pimobendan in UK dogs with grade IV/VI heart murmurs

Abstract

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.