Multicenter, double-blind, randomised, placebo-controlled study in 65 patients with stable angina and single-vessel coronary disease. After image-guided PCI, an in-stent balloon was incrementally inflated until angina occurred, verified against placebo inflation; FFR-angina and RFR-angina were recorded at symptom onset, also during low- and high-intensity exercise. Median pre-PCI FFR was 0.59 (IQR 0.46-0.70). Median FFR-angina at rest was 0.29 (IQR 0.23-0.35), during low-intensity exercise 0.38, and during high-intensity exercise 0.45. RFR-angina followed parallel values: 0.22 at rest, 0.26 at low, and 0.32 at high intensity. All thresholds were significantly lower than clinical ischaemia cut-offs (p<0.001). Lower FFR-angina thresholds were associated with greater baseline angina burden and greater symptom relief from PCI. The physiological angina threshold is therefore highly individualised, varies with cardiac workload, and lies well below universal cut-offs — arguing for symptom-led, personalised revascularisation strategy.
BACKGROUND:In stable coronary artery disease, the primary goal of percutaneous coronary intervention (PCI) is symptom relief. Fractional flow reserve (FFR) and nonhyperemic pressure ratios such as resting full-cycle ratio (RFR) are used to guide revascularization. Although these indices correlate with myocardial ischemia, they have never been validated against the onset of angina. The physiological thresholds for angina (FFRanginaand RFRangina) at rest and during exercise remain undefined.METHODS:ORBITA-FIRE (Finding the Invasive Threshold for Symptom Relief in Exertional Angina) was a multicenter, double-blind, randomized, placebo-controlled study in patients with stable angina and single-vessel coronary artery disease. After imaging-guided PCI, an in-stent balloon was incrementally inflated until angina occurred at rest. This angina threshold was verified against placebo inflation, and corresponding FFRanginaand RFRanginavalues were recorded at symptom onset. The protocol was repeated during low- and high-intensity exercise to assess changes in angina thresholds with increasing cardiac workload.RESULTS:Sixty-five patients were enrolled (mean age, 63.9±8.7 years; 74% male; 69% hypertensive; 23% diabetic; 91% with Canadian Cardiovascular Society class II–III angina). Median pre-PCI FFR was 0.59 (interquartile range [IQR], 0.46–0.70) and RFR was 0.61 (IQR, 0.40–0.82). Median FFRanginaat rest was 0.29 (IQR, 0.23–0.35), increasing to 0.38 (IQR, 0.30–0.48) during low-intensity exercise and 0.45 (IQR, 0.36–0.55) during high-intensity exercise. RFRanginasimilarly increased from 0.22 (IQR, 0.16–0.30) at rest to 0.26 (IQR, 0.18–0.36) and 0.32 (IQR, 0.23–0.46) during low- and high-intensity exercise. All thresholds were significantly lower than clinical diagnostic cut points (P<0.001). Lower FFRanginaand RFRanginathresholds were associated with greater symptom reproducibility across rest, low- and high-intensity exercise conditions (FFRangina:P=0.008,P<0.001,P<0.001, respectively; RFRangina:P=0.015,P<0.001,P=0.002, respectively). Lower angina thresholds across all conditions predicted higher baseline angina burden and greater symptom relief with PCI (Pinteraction>0.999).CONCLUSIONS:Physiological thresholds for angina (FFRanginaand RFRangina) are highly individualized, vary with cardiac workload, and are consistently lower than the universal ischemia-based thresholds used to guide revascularization. These findings support integrating personalized, symptom-linked physiology to refine patient selection and to improve symptomatic response to PCI.
