Target trial emulation: Do antimicrobials or gastrointestinal nutraceuticals prescribed at first presentation for acute diarrhoea cause a better clinical outcome in dogs under primary veterinary care in the UK?

Abstract

Target trial emulation applies design principles from randomised controlled trials to the analysis of observational data for causal inference and is increasingly used within human epidemiology. Veterinary electronic clinical records represent a potentially valuable source of information to estimate real-world causal effects for companion animal species. This study employed the target trial framework to evaluate the usefulness on veterinary observational data. Acute diarrhoea in dogs was used as a clinical exemplar. Inclusion required dogs aged ≥ 3 months and < 10 years, presenting for veterinary primary care with acute diarrhoea during 2019. Treatment strategies were: 1. antimicrobial prescription compared to no antimicrobial prescription and 2. gastrointestinal nutraceutical prescription compared to no gastrointestinal nutraceutical prescription. The primary outcome was clinical resolution (defined as no revisit with ongoing diarrhoea within 30 days from the date of first presentation). Informed from a directed acyclic graph, data on the following covariates were collected: age, breed, bodyweight, insurance status, comorbidities, vomiting, reduced appetite, haematochezia, pyrexia, duration, additional treatment prescription and veterinary group. Inverse probability of treatment weighting was used to balance covariates between the treatment groups for each of the two target trials. The risk difference (RD) of 0.4% (95% CI -4.5% to 5.3%) was non-significant for clinical resolution in dogs treated with antimicrobials compared with dogs not treated with antimicrobials. The risk difference (RD) of 0.3% (95% CI -4.5% to 5.0%) was non-significant for clinical resolution in dogs treated with gastrointestinal nutraceuticals compared with dogs not treated with gastrointestinal nutraceuticals. This study successfully applied the target trial framework to veterinary observational data. The findings show that antimicrobial or gastrointestinal prescription at first presentation of acute diarrhoea in dogs causes no difference in clinical resolution. The findings support the recommendation for veterinary professionals to limit antimicrobial use for acute diarrhoea in dogs.

Fig 1. Directed acyclic graph (DAG) based on existing evidence and expert knowledge to estimate our assumptions regarding the overall effect of prescription of antimicrobials for acute diarrhoea in dogs on clinical resolution.

Fig 2. Flowchart depicting the study design and data analysis process.

Fig 3. Nonparametric estimation of time-to-event curves for treatment escalation in dogs attending primary-care practices in the UK prescribed antimicrobials (A = 1) and dogs not prescribed antimicrobials (A = 0) at first presentation for acute diarrhoea.

Fig 4. Nonparametric estimation of time-to-event curves for treatment escalation in dogs attending primary-care practices in the UK prescribed gastrointestinal nutraceuticals (GN = 1) and dogs not prescribed gastrointestinal nutraceuticals (GN = 0) at first presentation for acute diarrhoea.

Fig 5. Estimation of time-to-event curves via IP weighted hazards model (and 95% confidence intervals calculated via bootstrapping) for treatment escalation in dogs attending primary-care practices in the UK prescribed antimicrobials (A = 1) and dogs not prescribed antimicrobials (A = 0) at first presentation for acute diarrhoea.

Fig 6. Estimation of time-to-event curves via IP weighted hazards model (and 95% confidence intervals calculated via bootstrapping) for treatment escalation in dogs attending primary-care practices in the UK prescribed gastrointestinal nutraceuticals (G = 1) and dogs not prescribed gastrointestinal nutraceuticals (G = 0) at first presentation for acute diarrhoea.