Instantaneous Wave-Free Ratio for the Assessment of Intermediate Left Main Coronary Artery Stenosis: Correlations With Fractional Flow Reserve/Intravascular Ultrasound and Prognostic Implications: The iLITRO-EPIC07 Study

Background: There is little information available on agreement between fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR) in left main coronary artery (LMCA) intermediate stenosis. Besides, several meta-analyses support the use of FFR to guide LMCA revascularization, but limited information is available on iFR in this setting. Our aims were to establish the concordance between FFR and iFR in intermediate LMCA lesions, to evaluate with intravascular ultrasound (IVUS) in cases of FFR/iFR discordance, and to prospectively validate the safety of deferring revascularization based on a hybrid decision-making strategy combining iFR and IVUS. Methods: Prospective, observational, multicenter registry with 300 consecutive patients with intermediate LMCA stenosis who underwent FFR and iFR and, in case of discordance, IVUS and minimal lumen area measurements. Primary clinical end point was a composite of cardiovascular death, LMCA lesion-related nonfatal myocardial infarction, or unplanned LMCA revascularization. Results: FFR and iFR had an agreement of 80% (both positive in 67 and both negative in 167 patients); in case of disagreement (31 FFR+/iFR– and 29 FFR−/iFR+) minimal lumen area was ≥6 mm2 in 8.7% of patients with FFR+ and 14.6% with iFR+. Among the 300 patients, 105 (35%) underwent revascularization and 181 (60%) were deferred according to iFR and IVUS. At a median follow-up of 20 months, major adverse cardiac events incidence was 8.3% in the defer group and 13.3% in the revascularization group (hazard ratio, 0.71 [95% CI 0.30–1.72]; P=0.45). Conclusions: In patients with intermediate LMCA stenosis, a physiology-guided treatment decision is feasible either with FFR or iFR with moderate concordance between both indices. In case of disagreement, the use of IVUS may be useful to indicate revascularization. Deferral of revascularization based on iFR appears to be safe in terms of major adverse cardiac events. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03767621.


Decision-making algorithm based on FFR and iFR results
6 Protocol to perform a study using a pressure guidewire The patient is eligible for functional assessment in the presence of intermediate LMCA stenoses with visual estimations on the coronary angiography between 25% and 60%.
After catheterization using a guide catheter, at least, 200 µg of intracoronary nitroglycerin should be administered to keep coronary reactivity under control.
Afterwards, the intracoronary guidewire should be advanced with the sensor placed in the ostium of the guide catheter; also, pressure curves should be brought back to normal for 5 to 10 heart beats. If the lesion has an ostial location, normalization will occur by removing the guide catheter from the coronary artery and placing the guidewire into the aorta. Afterwards, the guidewire should be removed from the catheter, and coronary catheterization performed to advance the guidewire.
The pressure wire should be advanced until, at least, 3 times the diameter of the vessel beyond the most distal stenosis to be able to measure the iFR according to the standard protocol. After measuring the iFR, the guidewire should be removed with pressure curve monitorization until the inside of the guide catheter. At this point, the presence of the pressure calibration loss phenomenon (pressure drift) should be discarded. In case of overt drift (Pd/Pa measured on the catheter tip < 0.98 or > 1.02) measures should be taken again. Afterwards, FFR will be determined during hyperemia through the administration of adenosine in continuous IV infusion at doses ≥ 140 µg/kg/min for, at least, 2 minutes or an IV bolus of 0.4 mg of regadenoson. After measuring FFR, the guidewire should be removed with pressure curve monitorization until the inside of the guide catheter. At this point, the presence of pressure drift should be discarded. In case of overt drift (Pd/Pa measured on the catheter tip < 0.98 or > 1.02) measures should be taken again. 7 In case of discrepancy between the results of FFR and iFR (FFR ≤ 0.80 with iFR ≥ 0.90 or FFR ≥ 0.81 with iFR ≤ 0.89) IVUS will be performed, and the MLA determined.
Revascularization will be indicated with MLAs < 6 mm2 based on the results from the LITRO trial. 8

Protocol to conduct IVUS studies
IVUS studies will be mandatory if FFR and iFR disagree. In patients eligible for percutaneous treatment of their LMCA lesions, the IVUS is highly recommended to guide the procedure. In the remaining patients (when iFR-guided medical therapy or surgical revascularization is decided) the IVUS is recommended to establish the correlation between the iFR value and the MLA measured on the LMCA whenever possible. The IVUS system used can be mechanical or rotational with resolutions between 20 MHz and 60 MHz.
An 0.014 in intracoronary guidewire will be advanced to perform the IVUS study (it can be the same pressure guidewire used to determine the iFR) towards the left anterior descending or left circumflex coronary arteries. After the administration of 200 µg of intracoronary nitroglycerin, the IVUS catheter will be advanced distal to the LMCA bifurcation. Afterwards, the catheter will be manual or automatically removed until the ascending aorta. It is essential that the guide catheter should remain outside the coronary artery to study the left main coronary artery entirely including its ostial region.
The catheter will be placed in the left anterior descending coronary artery (preferably) or left circumflex artery or both (to conduct 2 studies with MLA determination from these positions and eventually pick the one with the lowest values).
In cases of catheter backward jump, even on manual mode (with calcified angulation) it is recommended to move the catheter forward from the aorta to acquire images of the region of interest that had not been properly assessed. 9

Technical aspects of the assessment of left main coronary artery lesions through fractional flow reserve
The study of LMCA lesions using pressure wire has some particularities that should be addressed when conducting the study: pressures when the latter is placed distal to the lesion to measure the FFR during maximum hyperemia. When the lesion is found in the LMCA distal portion and there is damage to its origin and main branches, both the distal LMCA and each one of its branches should be treated as 1 functional unit regardless of the degree of damage to these branches. To estimate the FFR, measurements are taken from the left anterior descending and left circumflex coronary arteries. The LMCA lesion is considered functionally significantly when the measurements of either one of the 2 main vessels is < 0.80. 10 In the assessment of LMCA lesions the use of an intracoronary bolus of adenosine is not recommended because, since the non-selective catheterization of the left coronary artery is required, part of the drugs administered never reach this coronary artery, which is why the induction of hyperemia can be suboptimal. For this reason, the IV administration of drugs whether adenosine (infusions of 140 µg/ kg/min for, at least, 2 minutes) or regadenoson (doses of 0.4 mg in IV bolus) is advised.

Presence of left anterior descending or left circumflex coronary artery lesions
The presence of 1 isolated LMCA lesion is not rare. A series of all-comers treated with diagnostic coronary angiography proved that, in patients with damage to the LMCA, only 9% had 1 single LMCA lesion, 17% had 1 LMCA lesion plus damage to 1 vessel, 35% had 1 LMCA lesion plus damage to 2 vessels, and 38% had LMCA disease plus damage to 3 vessels.