Rationale and design of a multicenter, randomized, patients-blinded two-stage clinical trial on effects of endothelial function test in patients with non-obstructive coronary artery disease (ENDOFIND)

Abnormal peripheral and coronary endothelial function has been associated with increased risk of major adverse cardiovascular events (MACE) in cross-sectional retrospective and observational studies. However, prognostic value of routine clinical evaluation, diagnosis and treatment of endothelial dysfunction on incident MACE in patients with non-obstructive coronary artery disease (NOCAD) remains unknown. Endothelial Function Guided Management in Patients with NOCAD (ENDOFIND) is a multicenter, randomized, patients-blinded, parallel-controlled, two-stage clinical trial evaluating the impact of routine clinical peripheral endothelial function testing on initiation and/or intensification of cardiovascular preventive therapies in Stage I, and on the risk of MACE in Stage II in patients with NOCAD. One thousand participants with NOCAD on clinically indicated coronary computed tomography or invasive angiography will be enrolled and randomized 1:1, after baseline peripheral endothelial function evaluation, to either endothelial function guided treatment group or standard of care control group. In Stage I, patients will be followed for 12 months and primary outcome will be the proportion of patients receiving prescriptions for cardiovascular evidence-based lipid, blood pressure and glucose lowering medications at the clinic visit immediately after endothelial function evaluation. Secondary outcomes are change in endothelial function measured as reactive hyperemia index and patients' adherence to evidence-based medications in 12 months. Study will be extended into Stage II where sample size and follow up duration will be reevaluated to ensure statistical power, and primary outcome will be incident MACE. ENDOFIND is proof-of-concept clinical trial of a disruptive endothelial function guided clinical intervention with potential benefits to NOCAD patients. Condensed abstract: ENDOFIND is a proof-of-concept clinical trial of a disruptive endothelial function guided clinical intervention with potential benefits to patients with no obstructive coronary artery disease (NOCAD). It is a multicenter, randomized, patients-blinded, parallel controlled two-stage clinical trial to evaluate the impact of routine clinical peripheral endothelial function testing on initiation and/or intensification of cardiovascular disease preventive therapies in Stage I, and on the risk of MACE in Stage II.