Measurement of Fractional Flow Reserve Predicts the Functional Significance of Peripheral Arterial Lesions in the Ischaemic Leg

Introduction: The current mainstay for investigating peripheral arterial disease (PAD) uses duplex ultrasound (DUS) and visual assessment of lesions by either computed tomography (CTA)/magnetic resonance (MRA) or invasive angiography (IA). In coronary vessels, Fractional Flow Reserve (FFR) measures the trans-stenotic pressure loss during maximum flow to determine the ‘functional’ significance and inform revascularisation. This study (i) investigated the relationship between anatomical (diameter stenosis, DS%) and functional (FFR) severity of peripheral arterial stenoses and (ii) correlated these parameters to limb tissue perfusion. Methods: Patients with short-distance claudication (IC) and critical limb ischaemia (CLI) underwent DUS and CTA. Pre-procedural blood oxygenation level-dependent cardiovascular magnetic resonance (BOLD-CMR; 3.0T Ach- ieva, Philips Healthcare) was performed in both legs at rest and during reactive hyperaemia. T2* signal gradient during reactive hyperemia (Grad) of the calf muscles was recorded. During elective angioplasty/stenting, an 0.014” Doppler-flow and pressure-sensing guidewire (Combo- Wire XT!, Philips Healthcare) was used to measure the trans-stenotic pressure index (distal lesion pressure[Pd]/ aortic pressure[Pa]) at rest (“Pd/Pa”) and during hyper- aemia (“FFR”). Intra-arterial adenosine was used to provoke hyperaemia, which was confirmed by measuring the resting-to-hyperaemic change in average peak velocity (APV) and microvascular resistance (MVR, calculated as Pd/APV). Quantitative Vessel Analysis (Philips Allura Xper FD20, Philips Healthcare) was used to calculate percentage diameter stenosis (DS%) from CTA and IA. Follow up with DUS determined primary patency, defined as <50% restenosis in the treated segment. Results: Fifty-two stenoses (iliac n1⁄433; femoral n1⁄419) in 41 patients were evaluated; 59% had IC and 41% had CLI. Median DS% by DUS, CTA, and IA were 70% (IQR 60-86), 67% (52-77) and 61% (48-73), respectively. Pd/ Pa and FFR were successfully measured in all patients with no complications. There was a significant increase in APV (14.9 cm/s (8.5-20.7) to 30 cm/s (18.2-44.8); p<0.0001) and reduction in MVR (6.8 (4.5-9.2) to 2.7 (1.7-3.9); p<0.0001) following adenosine administration. Median pre-treatment Pd/Pa was 0.91 (0.78-0.97) and FFR was 0.70 (0.52-0.87), which improved to 0.94 (0.86-0.98; p1⁄40.001) and 0.90 (0.80-0.95; p<0.0001) after angioplasty/stenting, respectively. FFR correlated poorly with CTA and IA-DS% (R21⁄40.57-0.60; p<0.0001) and had a stronger association with clinical severity (CLI vs IC; AUC 0.96, p<0.0001). Perfusion in 18 ischaemic limbs (14 patients) was assessed with BOLD-CMR. FFR strongly correlated with Grad (R21⁄40.63; p<0.0001), whereas DS% (DUS, R21⁄40.18 [p1⁄40.85]; CTA, R21⁄40.45 [p1⁄40.001] and IA, R21⁄40.41 [p1⁄40.003]) were poor predictors of limb perfusion. Forty patients (98%) were followed up for a median of 3 (1.8-4.1) months. A post- treatment FFR cut-off of 0.88 demonstrated a sensitivity and specificity of 75% for predicting primary patency (AUC 0.852). Conclusion: FFR appears to be a useful index of functional severity and ischaemic burden related to peripheral arterial stenoses, and for predicting successful intervention. Clinical trials will determine whether it will become, as it has in the coronary circulation, the gold standard for making treatment decisions.