Abstract Background Identifying and targeting established modifiable risk factors such as hyperlipidaemia, blood pressure, smoking, and diabetes have led to a successful reduction in poor outcomes from coronary artery disease (CAD) at the population-level. However, up to one-in-four patients who present with ST elevation myocardial infarction do so in the absence of such risk factors. There is a significant unmet need for new diagnostic strategies independent of these factors to detect CAD in its subclinical phase. Polygenic risk scores (PRS) have demonstrated an ability in cohort studies to improve risk prediction models independent of traditional risk factors and self-reported family history. However, there is a lack of data from implementation and interventional studies demonstrating efficacy, participant and provider experience, and cost effectiveness of utilising PRS. Aim The aim of this study is to examine the incorporation of a CAD PRS during primary care-based cardiovascular disease (CVD) risk assessments to identify low or intermediate risk individuals with newly diagnosed CAD and subsequent impact on shared treatment decisions, participant experience, and provider experience. Our hypothesis is that incorporating a CAD PRS-based decision tool for a coronary calcium scan into CVD risk assessments will identify new, potentially missed individuals with subclinical CAD. Methods The ESCALATE study is a 12-month, prospective, multi-centre implementation study incorporating CAD PRS into otherwise standard primary care CVD risk assessments, identifying patients at increased lifetime CAD risk, for non-invasive CT coronary imaging. 1,000 eligible participants aged 45-65 years old will enter the PPP-CAD Diagnostic Pathway, which applies CAD PRS to those considered low or moderate 5-year absolute CVD risk based on traditional risk factors and triages those with CAD PRS ≥80% for a coronary calcium scan (Figure 1). The primary outcome will be the identification of subclinical CAD, defined as a coronary artery calcium score (CACS) >0 Agatston units (AU). Multiple secondary outcomes will be assessed, including baseline CACS ≥100 AU or ≥75th age-/sex-matched percentile, medical management strategies, cholesterol and blood pressure levels, health-related quality of life (HRQOL), and patient experience. Results Study recruitment was initiated recruitment in August 2022 and is actively recruiting across Australia. 298 participants have been enrolled as of 27th February 2022. Conclusion The ESCALATE study is the first prospectively registered clinical trial testing the ability of a CAD PRS to: a) identify individuals with subclinical CAD by non-invasive coronary imaging; and b) measure the impact of this diagnostic strategy on personalised diagnosis and shared decision-making. The top-line study results are expected in mid-2025.