Concordance between target trial emulation and randomised controlled trials: systematic review and meta-analysis.

Abstract

To assess the concordance of results between paired target trial emulations and their benchmarking randomised controlled trials and to explore determinants of emulation success. Systematic review and meta-analysis. Medline, EMBASE, Scopus, PsycINFO, and Web of Science (2010 to 2025). Observational studies that explicitly aimed to emulate target randomised controlled trials of a health intervention were included. Data were extracted on study domain, target population, intervention, comparator, and main outcomes for each emulation and corresponding randomised controlled trial. For 21 predefined emulation design features, concordance was assessed using Pearson correlation coefficients, standardised difference agreement, and ratio of ratios, with subgroup and regression analyses of study characteristics and concordance. Among 107 target trial emulation-randomised controlled trial pairs, the Pearson correlation coefficient was 0.59 (95% confidence interval (CI) 0.45 to 0.70), standardised difference agreement was 79% (85/107), and summary ratio of ratios was 0.96 (95% CI 0.92 to 1.01; I²=36%). In 63 pairs with closer emulation of trial design, a higher level of agreement was observed, with a Pearson correlation coefficient of 0.83 (0.73 to 0.89) and standardised difference agreement of 87% (55/63). In subgroup analysis, trial emulations tended to systematically underestimate treatment effects from randomised controlled trials for specific outcomes related to venous thromboembolism and major adverse cardiovascular events, while overestimating those for respiratory outcomes, with pooled ratio of ratios of 0.76 (0.58 to 1.00; I²=40%), 0.91 (0.86 to 0.96; I²=32%), and 1.20 (1.03 to 1.40; I²=40%), respectively. Moreover, emulations based on claims data tended to underestimate the treatment effects (ratio of ratios 0.90, 0.82 to 0.99; I²=38%). In univariate regression analyses, poorer target trial emulation-randomised controlled trial concordance was associated with emulation designs with imbalanced baseline population characteristics, treatment started in hospital, and lower outcome emulation quality. Current target trial emulations achieve moderate concordance when replicating their corresponding randomised controlled trials. Concordance could be improved by better emulation design, including better baseline and outcome emulation and leveraging multisource linked databases. PROSPERO CRD42024619811.