Abstract

AIMS: Coronary artery disease is frequently diagnosed following evaluation of stable chest pain with anatomical or functional testing. A more granular understanding of patient phenotypes that benefit from either strategy may enable personalized testing. METHODS AND RESULTS: Using participant-level data from 9572 patients undergoing anatomical (n = 4734) vs. functional (n = 4838) testing in the PROMISE (PROspective Multicenter Imaging Study for Evaluation of Chest Pain) trial, we created a topological representation of the study population based on 57 pre-randomization variables. Within each patient's 5% topological neighbourhood, Cox regression models provided individual patient-centred hazard ratios for major adverse cardiovascular events and revealed marked heterogeneity across the phenomap [median 1.11 (10th to 90th percentile: 0.52-2.61]), suggestive of distinct phenotypic neighbourhoods favouring anatomical or functional testing. Based on this risk phenomap, we employed an extreme gradient boosting algorithm in 80% of the PROMISE population to predict the personalized benefit of anatomical vs. functional testing using 12 model-derived, routinely collected variables and created a decision support tool named ASSIST (Anatomical vs. Stress teSting decIsion Support Tool). In both the remaining 20% of PROMISE and an external validation set consisting of patients from SCOT-HEART (Scottish COmputed Tomography of the HEART Trial) undergoing anatomical-first vs. functional-first assessment, the testing strategy recommended by ASSIST was associated with a significantly lower incidence of each study's primary endpoint (P = 0.0024 and P = 0.0321 for interaction, respectively), as well as a harmonized endpoint of all-cause mortality or non-fatal myocardial infarction (P = 0.0309 and P < 0.0001 for interaction, respectively). CONCLUSION: We propose a novel phenomapping-derived decision support tool to standardize the selection of anatomical vs. functional testing in the evaluation of stable chest pain, validated in two large and geographically diverse clinical trial populations.