Determining the fractional flow reserve threshold for angina: A randomised, double-blind, placebo-controlled N-of-1 Trial

Background In stable coronary artery disease (CAD), the primary role of percutaneous coronary intervention (PCI) is symptom relief. However, clinical guidelines rely on ischaemia-based physiological thresholds to guide treatment decisions. The association between these thresholds and angina has never been studied. Purpose No placebo-controlled studies have established the fractional flow reserve (FFR) threshold that directly correlates with angina (FFRangina) at rest and on exercise. Methods A multicentre, double-blind, randomised, placebo-controlled, N-of-1 study was conducted in patients with stable angina and single-vessel CAD referred for PCI. After baseline assessment and intravascular imaging-guided PCI, an in-stent balloon was incrementally inflated in the coronary lumen until the patient developed angina at rest. This angina threshold was reproduced against placebo inflations, and FFRangina was measured at the point of symptom onset. The process was then repeated with low- and high-resistance exercise using a supine table-mounted ergometer to determine FFRangina under exertional conditions. Results Sixty-five patients were recruited (mean age 63.9 ± 8.7 years, 74% male). The median FFR improved from 0.59 (IQR 0.46 to 0.70) pre-PCI to 0.88 (0.84 to 0.92) post-PCI. At rest, FFRangina was 0.29 (0.23 to 0.35), increasing to 0.38 (0.30 to 0.48) with low-resistance exercise and 0.45 (0.36 to 0.55) with high-resistance exercise (Pr(difference)>0.99). All FFRangina thresholds were significantly lower than the clinical threshold of ≤0.80 (Pr(difference)>0.99). Conclusion The clinical FFR threshold does not correlate with symptoms. FFRangina is significantly lower than 0.80 and varies with exercise intensity. To optimise patient outcomes, clinical guidelines must adopt personalised, symptom-driven FFRangina thresholds to select patients who are most likely to derive angina relief from PCI.