Utility of 18F-Flurpiridaz PET Relative Flow Reserve in Differentiating Obstructive from Nonobstructive Coronary Artery Disease

Abstract Background Absolute quantification of myocardial blood flow (MBF) on PET perfusion imaging improves the identification of coronary artery disease (CAD). However, distinguishing MBF impairment due to obstructive CAD from nonobstructive CAD remains challenging. We aimed to evaluate the incremental diagnostic value of PET-derived relative flow reserve (RFR) in the diagnosis of obstructive CAD. Methods This is a post hoc analysis of the multicenter phase-III trial of 18 F-flurpiridaz PET ( NCT01347710 ). Patients with available MBF quantification were included. Reduced stress MBF (sMBF) was defined as sMBF below the median (2.2 mL/min/g). Obstructive CAD on quantitative invasive coronary angiography (ICA) was defined as > 70% stenosis. RFR was calculated as a ratio of the minimal segment sMBF over the highest reference vascular territory sMBF. RFR performance for predicting obstructive CAD was evaluated through Receiver Operating Characteristic (ROC) analysis and the net reclassification index (NRI) of multivariable regression models. Results The study included 231 patients (71% male; 56% with established CAD) drawn from the original cohort of 755 trial participants. No patients had three-vessel CAD. In a per vessel-based analysis, 82% of vessels with reduced sMBF had no obstructive CAD on ICA. RFR was significantly lower for vessels with obstructive CAD (0.55 vs 0.80, p<0.0001). In vessels with reduced sMBF, RFR was independently associated with obstructive CAD even after accounting for sTPD and MFR (OR 3.08, 95% CI: 1.49–6.38; p = 0.002). While the addition of RFR did not significantly improve discrimination (AUC 0.806 vs. 0.822, p = 0.11), it significantly improved reclassification of vessels with and without obstructive CAD (NRI: 0.93, p < 0.0001). Conclusions RFR provides complementary diagnostic information beyond existing PET parameters and may help refine the diagnosis of obstructive CAD in patients with reduced flows. Clinical Perspective A major diagnostic dilemma in cardiac PET/CT perfusion imaging is determining whether reductions in stress myocardial blood flow and/or myocardial flow reserve are caused by obstructive or nonobstructive coronary artery disease (CAD), leading to uncertainty about whether invasive angiography is needed. Our study demonstrates that incorporating PET-derived relative flow reserve (RFR) adds meaningful diagnostic information beyond existing PET perfusion and flow parameters. RFR does not substantially increase overall discrimination between obstructive and nonobstructive CAD, but it significantly improves reclassification of individual cases, indicating that RFR can help refine decision-making, particularly in borderline cases. These data suggest that selective integration of RFR with existing PET metrics could improve patient selection for invasive procedures and guide more targeted medical therapy for nonobstructive CAD. Future research is needed to confirm these findings across a broader patient population, including higher-risk cohorts and women, as well as with other PET radiotracers.