Determining the Physiological Threshold for Angina (ORBITA-FIRE): A Double-Blind, Randomized, Placebo-Controlled Study
Abstract
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, FFR angina and RFR angina , 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 FFR angina and RFR angina values 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 FFR angina at 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. RFR angina similarly 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 FFR angina and RFR angina thresholds were associated with greater symptom reproducibility across rest, low- and high-intensity exercise conditions (FFR angina : P =0.008, P <0.001, P <0.001, respectively; RFR angina : 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 (probability of interaction >0.999). CONCLUSIONS: Physiological thresholds for angina, FFR angina and RFR angina , 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.
Article Details
Authors (30)
Fiyyaz Ahmed-Jushuf
National Heart and Lung Institute, Imperial College London, UK (F.A.-J., M.J.F., S.C., C.A.R., D.W., F.A.S., K.M., K.C., S.M., S.S.N., H.S., J.P.H., D.P.F., M.J.S.-S., R.K.A.-L.).
Michael J. Foley
National Heart and Lung Institute, Imperial College London, UK (F.A.-J., M.J.F., S.C., C.A.R., D.W., F.A.S., K.M., K.C., S.M., S.S.N., H.S., J.P.H., D.P.F., M.J.S.-S., R.K.A.-L.).
Shayna Chotai
National Heart and Lung Institute, Imperial College London, UK (F.A.-J., M.J.F., S.C., C.A.R., D.W., F.A.S., K.M., K.C., S.M., S.S.N., H.S., J.P.H., D.P.F., M.J.S.-S., R.K.A.-L.).
Christopher A. Rajkumar
National Heart and Lung Institute, Imperial College London, UK (F.A.-J., M.J.F., S.C., C.A.R., D.W., F.A.S., K.M., K.C., S.M., S.S.N., H.S., J.P.H., D.P.F., M.J.S.-S., R.K.A.-L.).
Danqi Wang
Florentina A. Simader
National Heart and Lung Institute, Imperial College London, UK (F.A.-J., M.J.F., S.C., C.A.R., D.W., F.A.S., K.M., K.C., S.M., S.S.N., H.S., J.P.H., D.P.F., M.J.S.-S., R.K.A.-L.).
Krzysztof Macierzanka
National Heart and Lung Institute, Imperial College London, UK (F.A.-J., M.J.F., S.C., C.A.R., D.W., F.A.S., K.M., K.C., S.M., S.S.N., H.S., J.P.H., D.P.F., M.J.S.-S., R.K.A.-L.).
Kayla Chiew
National Heart and Lung Institute, Imperial College London, UK (F.A.-J., M.J.F., S.C., C.A.R., D.W., F.A.S., K.M., K.C., S.M., S.S.N., H.S., J.P.H., D.P.F., M.J.S.-S., R.K.A.-L.).
Sannidhya Misra
National Heart and Lung Institute, Imperial College London, UK (F.A.-J., M.J.F., S.C., C.A.R., D.W., F.A.S., K.M., K.C., S.M., S.S.N., H.S., J.P.H., D.P.F., M.J.S.-S., R.K.A.-L.).
Rupert Williams
St George’s, University of London and St. George’s University Hospitals NHS Foundation Trust, UK (R.W., J.C.S.).
Klio Konstantinou
Essex Cardiothoracic Centre, Mid and South Essex NHS Foundation Trust, Basildon, UK (K.K., S.R.M., T.R.K., J.R.D., G.C., J.N.D.).
Jehangir N. Din
Essex Cardiothoracic Centre, Mid and South Essex NHS Foundation Trust, Basildon, UK (K.K., S.R.M., T.R.K., J.R.D., G.C., J.N.D.).
Shah R. Mohdnazri
Essex Cardiothoracic Centre, Mid and South Essex NHS Foundation Trust, Basildon, UK (K.K., S.R.M., T.R.K., J.R.D., G.C., J.N.D.).
Peter D. O’Kane
University Hospitals Dorset NHS Foundation Trust, Bournemouth, United Kingdom
Peter Haworth
Portsmouth Hospitals University NHS Trust, UK (P.H.).
Sukhjinder S. Nijjer
National Heart and Lung Institute, Imperial College London, UK (F.A.-J., M.J.F., S.C., C.A.R., D.W., F.A.S., K.M., K.C., S.M., S.S.N., H.S., J.P.H., D.P.F., M.J.S.-S., R.K.A.-L.).
Henry Seligman
National Heart and Lung Institute, Imperial College London, UK (F.A.-J., M.J.F., S.C., C.A.R., D.W., F.A.S., K.M., K.C., S.M., S.S.N., H.S., J.P.H., D.P.F., M.J.S.-S., R.K.A.-L.).
Thomas R. Keeble
Essex Cardiothoracic Centre, Mid and South Essex NHS Foundation Trust, Basildon, UK (K.K., S.R.M., T.R.K., J.R.D., G.C., J.N.D.).
John R. Davies
Mid and South Essex NHS Foundation Trust, Basildon, United Kingdom
Gerald Clesham
Essex Cardiothoracic Centre, Mid and South Essex NHS Foundation Trust, Basildon, UK (K.K., S.R.M., T.R.K., J.R.D., G.C., J.N.D.).
Jonathan Hinton
University Hospitals Dorset NHS Foundation Trust, Bournemouth, UK (J.N.D., P.D.O., J.H.).
James C. Spratt
Department of Cardiology, City St. George’s, University of London, London
Jason N. Dungu
Essex Cardiothoracic Centre, Mid and South Essex NHS Foundation Trust, Basildon, UK (K.K., S.R.M., T.R.K., J.R.D., G.C., J.N.D.).
Daniel Knight
Royal Free London NHS Foundation Trust, UK (D.K., T.K.).
Tushar Kotecha
Royal Free London NHS Foundation Trust, UK (D.K., T.K.).
Frank E. Harrell
Vanderbilt University School of Medicine, Nashville, TN (F.E.H.).
James P. Howard
National Heart and Lung Institute, Imperial College London, UK (F.A.-J., M.J.F., S.C., C.A.R., D.W., F.A.S., K.M., K.C., S.M., S.S.N., H.S., J.P.H., D.P.F., M.J.S.-S., R.K.A.-L.).
Darrel P. Francis
Matthew J. Shun-Shin
National Heart and Lung Institute, Imperial College London, UK (F.A.-J., M.J.F., S.C., C.A.R., D.W., F.A.S., K.M., K.C., S.M., S.S.N., H.S., J.P.H., D.P.F., M.J.S.-S., R.K.A.-L.).
Rasha K. Al-Lamee
National Heart and Lung Institute, Imperial College London, UK (F.A.-J., M.J.F., S.C., C.A.R., D.W., F.A.S., K.M., K.C., S.M., S.S.N., H.S., J.P.H., D.P.F., M.J.S.-S., R.K.A.-L.).