2025 AHA科学声明：心导管实验室循证实践——有创心外膜冠状动脉生理评估

Practice

It is common practice to substitute NHPR metrics for FFR metrics, given that FFR requires hyperemia.

Evidence

FFR remains the reference invasive standard for physiology.$^{4}$ However, NHPR demonstrates agreement in

CLUNICAL STATEMENTS AND BIQUELINES

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$\approx80\%$ of cases using binary thresholds of 0.80 for FFR and 0.89 for NHPR.

The fundamental hemodynamic description of a sten- nosis is its pressure loss versus flow relationship. As depicted in Figure 1, net pressure loss arises from 2 components. Diffuse disease produces a linear relation- ship (as shown with the blue line), wherein doubling flow also doubles pressure loss (due to friction or viscous forces). A focal stenosis produces a quadratic relation- ship (as shown with the red line); if flow doubles, pres- sure loss quadruples (due to the turbulent exit of blood from an orifice).

The practical disagreement between FFR and NHPR varies depending on the distance from the threshold—a higher NHPR closer to 1.0 carries a decreasing rate of discordance with FFR, as does a lower NHPR closer to 0.80 (because, in general, NHPR>FFR, except for extremely low NHPR values).$^{4}$ The continuum of diagnostic performance can be represented as a pyramid (Figure 2) with increasing accuracy from coronary angiography alone to NHPR, contrast FFR (cFFR; measuring FFR after intracoronary contrast injection to produce mild hyperemia), and full hyperemic FFR at the top of the pyramid reaching 95% compared with a multitest reference standard.$^{5-7}$ A random test represents 50% accuracy.

The clinical consequences of FFR and NHPR discordance have been studied. Two large studies randomized >4500 patients to a diagnostic strategy guided by either FFR or NHPR. During 5 years of follow-up, all-cause mortality rate was significantly higher in the NHPR group (8.3% versus 6.3%).$^{8,9}$ However, the mechanism remains unclear, because there was no difference in rates of myocardial infarction (MI) or unplanned revascularization between the groups, and the increased mortality risk was primarily driven by individuals with NHPR who underwent revascularization.$^{10}$

Summary

FFR remains the reference invasive standard, with agreement between NHPR and FFR of ≈80%. A higher NHPR closer to 1.0 carries a decreasing rate of discordance with FFR, as does a lower NHPR closer to 0.80. For borderline resting gradients (eg, NHPR 0.86-0.93), a hybrid strategy of hyperemia (initial cFFR followed by vasodilator [eg, adenosine] FFR) after NHPR should be considered, especially if NHPR assessment does not reflect the clinical scenario.$^{11}$ There are several common situations when one might expect NHPR-FFR discordance: (1) high flow (proximal left anterior descending [LAD] vessel subtending a large myocardial mass) favors abnormal FFR but normal NHPR; (2) focal lesions favor abnormal FFR with normal NHPR compared with diffuse disease; and (3) low coronary flow reserve (CFR) favors normal FFR but abnormal NHPR. Most abnormal FFR/ normal NHPR disparity is due to high translesional flow during hyperemia or high CFR, whereas the converse situation (normal FFR/abnormal NHPR) is seen more frequently in diffuse coronary disease and with lower CFR. Operators should have a low threshold for the use of hyperemia given the suboptimal diagnostic performance of NHPR (accuracy 80.4%, sensitivity 78.9%, specificity 82.4%, positive predictive value 85.2%, and negative predictive value 73.3%).$^{4}$ When discordance exists between FFR and NHPR, decision-making should follow the FFR results.

FFR AND NHPR: CONTINUOUS VERSUS CATEGORICAL THRESHOLDS

Practice

It is common practice to base clinical decisions on categorical thresholds of FFR (≤0.80) and NHPR (≤0.89).

 Figure 1. Factors affecting concordance between fractional flow reserve and nonhyperemic pressure ratio.

CFR indicates coronary flow reserve; FFR, fractional flow reserve; and NHPR, nonhyperemic pressure ratio.

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 Figure 2. Pyramid of diagnostic accuracy.

FFR indicates fractional flow reserve; and NHPR, nonhyperemic pressure ratio.

Evidence

FFR values <0.75 are associated with ischemic stress testing in numerous comparative studies, with a high sensitivity (88%), specificity (100%), positive predictive value (100%), and overall accuracy (93%). FFR values >0.80 are associated with negative ischemic results with accuracy of 95%$^{7}$ with a zone of FFR with overlapping positive and negative results (0.75–0.80). Landmark clinical trials have almost exclusively used categorial thresholds when evaluating FFR or NHPR and clinical outcomes. DEFER (Deferral versus Performance of Percutaneous Transluminal Coronary Angioplasty in Patients Without Documented Ischemia)$^{12}$ used FFR ≤0.75 as the studied cutoff. FAME I (Fractional Flow Reserve versus Angiography for Multivessel Evaluation)$^{13}$ and FAME II (Fractional Flow Reserve—Guided Percutaneous Coronary Intervention Plus Optimal Medical Treatment versus Optimal Medical Treatment Alone in Patients With Stable Coronary Artery Disease)$^{14}$ increased the FFR cutoff to ≤0.80 to increase the negative predictive value. Initial trials suggested optimal agreement at iFR values of <8.86$^{15}$ to FFR ≤0.80, with further studies suggesting a gray zone with iFR of 0.86 to 0.93. Major clinical trials such as DEFINE-FLAIR (Functional Lesion Assessment of Intermediate Stenosis to Guide Revascularization)$^{16}$ and iFR-SWEDEHEART (Instantaneous Wave-Free Ratio Versus Fractional Flow Reserve in Patients With Stable Angina Pectoris or Acute Coronary Syndrome)$^{17}$ used the categorical value of iFR ≤0.89. Reliance on categorical thresholds used by these clinical trials may have practical drawbacks because reproducibility in the gray zone of FFR can be affected by clinical factors as well as variability of testing. VERIFY (Verification of Instantaneous Wave-Free Ratio and Fractional Flow Reserve for the Assessment of Coronary Artery Stenosis severity

in Everyday Practice)$^{18}$ found the variability between repeated FFR measurements to be ±0.02.

Beyond the issues with gray zone values, further clinical benefits may be overlooked when relying solely on a categorical threshold. Meta-analysis suggests that FFR demonstrates a continuous relationship with outcomes, reporting that lesions with lower FFR had a larger net benefit after revascularization with fewer clinical events.$^{19-21}$

Summary

Although categorical thresholds can be useful in clinical decision-making, solely using dichotomous FFR (≤0.80) and NHPR (≤0.89) values can limit interpretation of data in the gray zone given clinical and measurement variability. Test-retest variability in these measures is on the order of 0.02. For example, an NHPR of 0.91 on retest could yield values of 0.89 to 0.93. Thus, data continue to emerge indicating that the best decisions (Figure 3) should be coupled to the FFR or NHPR value (as a continuous measure) and considered in the clinical context of the patient's presentation, especially when the values are borderline.

FFR OR NHPR BEST PRACTICES

Route (Intracoronary Versus Intravenous) and Adenosine Dosing for Hyperemia

Practice

Although most landmark trials of FFR used adenosine continuously administered intravenously, it is a common practice to use bolus adenosine through the intracorony route.

Evidence

The goal of adenosine administration is to induce maximal vasodilation. The gold standard is intravenous adenosine administration (140 µg/kg per minute; Table 1), which is well-studied, permits time for steady-state hyperemia, and allows for standardization within and across institutions.$^{23}$ High-dose or double-dose adenosine infusion has not been demonstrated to lower the FFR value further or increase test accuracy. It reduces fluctuations, but increases patient discomfort.$^{24}$ On the other hand, intracoronary administration limits systemic side effects in exchange for a shorter steady-state plateau and loss of ability to perform an accurate slow pullback gradient measurement.

Conventional intracoronary adenosine dosing is 200 µg for the left and 100 µg for the right coronary artery.$^{25}$ Some studies have suggested that higher intracoronary doses may be needed for an equivalent hyperemic response to intravenous infusion. FFR measurements with escalating intracoronary doses up to 800 µg resulted in an increased frequency of abnormal FFR

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 Figure 3. Relationship between fractional flow reserve as a continuous measure and risk of cardiovascular events.

with reasonable safety.$^{26}$ In a meta-analysis of 12 studies, FFR values were significantly lower with intravenous adenosine than with intracoronary adenosine. Intracoronary adenosine was associated with a higher incidence of atrioventricular block, whereas angina or systemic symptoms were more frequent with intravenous adenosine.$^{27}$

Summary

For FFR measurement, the administration of adenosine through the intravenous route is preferred. Although intracoronary adenosine has quicker onset, is associated with fewer systemic effects, and is less expensive than intravenous administration in the United States, it may not always induce maximal hyperemia (Table 2). In most cases, higher intracoronary adenosine (200 µg for the left coronary, 100 µg for the right coronary) provides a similar FFR result to intravenous adenosine. If there is concern about insufficient hyperemia with intracoronary adenosine, higher doses can be given, or a switch to intravenous adenosine can be made.

cFFR Has Greater Accuracy Than NHPR

Practice

The translesional coronary pressure ratio immediately after an injection of iodinated radiographic contrast (cFFR)) exceeds the diagnostic accuracy of NHPR.$^{5}$ However, in clinical practice, NHPR is commonly used without any hyperemia.

Evidence

Intracoronary injection of iodinated radiographic contrast increases coronary blood flow by ≈60%,$^{5}$ likely through several mechanisms. Transient myocardial ischemia produces an oxygen debt that is repaid by increased flow.$^{25}$ An additional contributor to contrast-induced hyperemia is different osmolality and temperature compared with blood (eg, contrast is colder, because it is stored at room temperature). Moreover, intracoronary injection

Table 1. Suggested Practices for Invasive Coronary Physiologic Assessment

|Preprocedure| |---| |Caffeine intake before FFR measurement using intracoronary adenosine does not significantly affect measurement.$^{22}$ The hyperemic effect of intravenous adenosine may be blunted.| |Intraprocedure| |Use guiding catheters (≥5F) without side holes.| |Ascertain coaxial guide position in the coronary ostium.| |Disengage the guiding catheter from the ostium for pressure calibration, equalization, and recording.| |Equalize pressure with the pressure sensor located just outside the tip of the guiding catheter.| |Before equalization of pressures and for all pressure measurements, flush the guide catheter to remove the viscous contrast agent. Flushing the guide catheter is not recommended during cFFR measurement.| |Before equalization of pressures and for all pressure measurements, remove the introducer needle.| |Preinductor intracoronary nitroglycerin before advancement of the wire in the coronary to prevent coronary spasm.| |Place the wire in the distal third of the vessel being measured.| |For hyperemia:| |Intravenous adenosine 140 µg/kg per min or regadenoson 400 µg undiluted; intravenous route preferred for patients with an aorto-ostial lesion| |Intracoronary adenosine (typically 100 µg for the RCA and 200 µg for the LCA)| |Intracoronary papaverine (typically 8 mg for the RCA and 12 mg for the LCA)| |For cFFR: use the typical amount of contrast (6-10 mL) to opacify the artery| |Postprocedure| |Assess for drift.| |If post-PCI physiology is abnormal (FFR <0.90 or NHPR <0.95), consider FFR or NHPR pullback or intravascular imaging to identify residual areas of ischemia.|

cFFR indicates contrast fractional flow reserve; FFR, fractional flow reserve; LCA, left coronary artery; NHPR, nonhyperemic pressure ratio; and RCA, right coronary artery.

transiently increases coronary Doppler peak velocity above baseline,$^{25}$ indicating a temporary mechanical component from increased injection pressure or endothelial shear forces before autoregulatory mechanisms restore homeostasis.

Two large trials compared the diagnostic performance of cFFR against NHPR using the reference standard of FFR.$^{28,29}$ Both studies demonstrated superior binary agreement for cFFR over the whole-cycle ratio between mean distal pressure and mean proximal pressure (Pd/Pa) and subcycle NHPR. The binary accuracy of cFFR generally equals 85% to 90% versus standard FFR, depending on the specific cohort and chosen binary threshold (the typical binary threshold is between 0.83 and 0.85 for cFFR). In addition, serial measurements are more repeatable for cFFR than for NHPR.$^{5}$ Prognostic information regarding binary discordances between cFFR and standard FFR has suggested similar outcomes, albeit in a modestly sized,

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Table 2. Intravenous Versus Intracoronary Adenosine for FFR Measurement

|Adenosine route|Advantages|Disadvantages| |---|---|---| |Intravenous|Gold standard and used in most validation studies|Expensive| |Intravenous|More reliable hyperemia|Higher incidence of systemic side effects| |Intravenous|Stable hyperemia for pullback|Longer procedural duration| |Intravenous|Reduced incidence of atrioventricular block|Infusions associated with variability over respiratory cycles| |Intravenous|Ideal for all lesion types including serial lesions and aort-oostial lesions|| |Intracoronary|Avoids systemic hypotension and discomfort|Higher incidence of atrioventricular block| |Intracoronary|Avoids bronchospastic reaction|Not suitable for pullback/ assessment of serial lesions| |Intracoronary|Shorter procedural duration|Not suitable for aorto-ostial lesions| |Intracoronary|Less expensive|Variability in hyperemia depending on dose administered|

FFR indicates fractional flow reserve.

retrospective series.$^{30}$ In the pyramid of diagnostic test accuracy, cFFR is therefore higher than NHPR and below FFR (Figure 2). Limitations of cFFR are that, like intracoronary adenosine, it does not permit measurement of pressure pullback FFR given the short duration of hyperemia and also that an additional 6 to 10 mL of contrast might be a concern for patients with advanced kidney disease.

Summary

cFFR outperforms NHPR and whole-cycle resting Pd/Pa for predicting FFR. It provides a practical and repeatable option for operators wishing to increase agreement with FFR while avoiding adenosine-induced hyperemia (Figure 2)$^{5}$ cFFR (≤0.83) can be considered in patients with borderline NHPR, especially when the clinical scenario is discordant with the NHPR measurement. The volume of contrast should be between 6 and 10 mL and injected as per a routine coronary angiogram.$^{28}$ Flushing the catheter with saline is not necessary and might miss the peak hemodynamic effect that arrives within about 10 seconds and lasts only a few seconds.

Disengagement of the Guide Catheter

Practice

The guide catheter typically is engaged during FFR or NHPR measurement unless there is concern for aortostotal stenosis.

Evidence

Studies have shown FFR or NHPR to be significantly lower when measured with the guide catheter disengaged when compared with measurement with the catheter engaged. The mean $\Delta$ FFR was 0.05±0.04 in a study of 25 patients.$^{31}$ FFR, Pd/Pa, and resting full-cycle ratio (RFR) values shifted across the decisional thresholds after guide catheter disengagement in 17%, 14%, and 12%, respectively, in another study of 166 patients.$^{32}$ There was no correlation between ostial vessel diameter and differences in FFR or NHPR with guide catheter disengagement.$^{32}$

Summary

Routine guide catheter disengagement is reasonable during measurement of FFR or NHPR for more accurate measurement.

Ideal Starting Position of the Pressure Sensor Within the Vessel When Performing Functional Assessment

Practice

There is variability in positioning the distal sensor in the coronary artery before measurement of invasive physiology. Whether the pressure sensor should be just distal to the lesion or further into the distal third of the vessel is unclear.

Evidence

Studies have shown differences in FFR values based on the location of the distal sensor.$^{33-36}$ Documents highlighting the standardization of FFR measurements have advocated that the pressure wire be positioned at least 20 to 30 mm (ie, 10× artery diameter) distal to the location of the lesion at a point where laminar flow should be restored, but ideally in the distal part of the vessel beyond the region that a “coronary bypass might be inserted.”$^{37}$ Mean FFR measurements were significantly lower with measurements obtained in the distal vessel compared with measurements 20 to 30 mm distal to the stenoses (0.78±0.09 versus 0.84±0.08; P<0.0001), with a greater proportion of abnormal FFR measurements when compared with placing the sensor in a more proximal location (42% versus 13%). Similar results have been shown with NHPR.$^{38}$

Summary

Based on the available evidence, invasive pressure measurements should be obtained with the sensor in the distal third of the coronary artery, and at least 20 to 30 mm distal to the lesion. This provides the best physiologic estimation for the artery from all lesions in series proximal to the pressure sensor. A pull-back pressure assessment should be performed routinely to assess for gradients across serial lesions. Caution is warranted in tortuous vessels or a smaller distal artery to avoid vessel injury such as dissection or perforation.

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Assessing for Pressure Signal Drift

Practice

Assessment for pressure signal drift on wire pullback is not routinely done in clinical practice.

Evidence

Pressure signal drift refers to a shift of the initial pressure during calibration (ie, zeroing) to another value after the measurement—either up or down—which may lead to misclassification of lesion severity. Piezoelectric sensors (such as Abbott PressureWire X, Philips OmniWire, or Insight LifeTech TruePhysio) have more drift than optical pressure wire sensors (such as Boston COMET II, Haemonetics OptoWire III, or ACIST Navvus II). Pressure drift of ±0.02 is arbitrarily considered an acceptable threshold in which repeat equalization and physiologic assessment are not necessary. A simple way to identify drift is to note the pressure ratio when the sensor approaches the coronary ostium during pullback. A Pd/Pa value should be 1.0.

Six key factors can be addressed to decrease this potential source of error. First, measurements should be made after removing the wire introducer if equalization was performed without it. Second, the catheter should be flushed with saline before any measurements are started, because contrast or blood in the catheter produces damped pressure tracings, and flushing the system with saline ensures accurate pressure fidelity. Third, deep intubation of the guide catheter should be avoided, because this can dampen the aortic pressure signal and lead to false-negative FFR or NHPR values. Fourth, the pressure wire transducer should be saturated in saline to reduce drift; the wire should remain in its package tubing flushed with saline before insertion in the guide catheter, the transducer should be zeroed at the approximate level of the aortic valve, and the table should not be independently adjusted after calibration. Fifth, guide catheters with side holes may cause a pressure gradient between the side holes and the catheter lumen; the guide catheter should be disengaged from the coronary ostium to adjust for the side holes. Sixth, the piezoelectric pressure wire connector should be kept free of thrombus or blood, which can interfere with the Pd reading.$^{39}$

Summary

Stenosis misclassification can occur in up to a third of patients when there is significant drift (>0.02).$^{39,40}$ Expert consensus has previously used a threshold of ±0.05 and pressure wire manufacturers have used drift thresholds of up to ±0.07.$^{41,42}$ A good time point to verify absence of drift is at the end of any pullback measurements. If the FFR is highly abnormal (<0.75), or normal (>0.85), small degrees of drift can be ignored. If significant drift is detected, the corrective measures listed previously should be instituted and FFR or NHPR remeasured.

FFR OR NHPR IN SELECT LESION SUBSETS

Acute Coronary Syndromes

Practice

There are concerns about the accuracy of FFR or NHPR in nonculprit vessels in patients with acute MI.$^{43}$

Evidence

The concern about reduced accuracy of FFR or NHPR in the early stages of acute MI is based on transient reduction in coronary vasodilatory function (interstitial edema, microvascular vasoconstriction, intramyocardial hemorrhage, and distal embolization) in both the infarcted and potentially the noninfarcted myocardial regions$^{44}$ and changes in hemodynamics that might affect resting coronary flow. It is understood that FFR or NHPR are not accurate in the culprit vessel at the time of acute coronary syndromes, but there has also been concern about the accuracy in nonculprit vessels. However, in a study$^{45}$ of 101 patients with acute MI (75% with ST-segment-elevation MI), FFR measurements in the nonculprit vessel taken at the time of the culprit vessel percutaneous coronary intervention (PCI) were similar to repeat measurements taken 35±4 days afterwards. Furthermore, the index of microcirculatory resistance measured in the noninfarct artery was found to be normal in 11 of 14 (79%) patients, and this value did not significantly change in follow-up. Similar results have been shown with NHPR$^{46,47}$

Several trials have been performed using physiologic guidance to assess the nonculprit artery in acute MI,$^{48-53}$ many of which were performed during the index procedure.$^{48,50,52}$ Brief episodes of arteriovenous conduction delay and transient drop in blood pressure have been reported when performing FFR at the time of the index procedure, but major adverse events related to FFR were infrequent (0.25%).$^{48}$ However, studies comparing physiology-guided with angiography-guided complete PCI have reported mixed results,$^{5,0,51}$ and the role of physiologic assessment of the nonculprit artery to guide complete revascularization remains uncertain. COMPLETE-2 (Physiology-Guided versus Angiography-Guided Noncul-prit Lesion Complete Revascularization for Acute MI and Multivessel Disease), an international study of patients with ST-segment-elevation MI or non-ST-segment-elevation MI and multivessel disease, will evaluate a strategy of physiology-guided complete revascularization compared with angiography-guided complete revascularization.

Summary

Physiologic measures of the nonculprit lesion taken at the time of an acute MI show adequate correlation with measures taken at a time remote from the infarction. It is reasonable to believe that physiology-guided assessment of the noninfarct artery performed either at the time of the infarct artery PCI or at a time remote from the event can guide revascularization.

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Severe Aortic Stenosis

Practice

Invasive physiologic assessment of coronary lesions in the setting of severe aortic stenosis (AS) is performed in clinical practice. However, there is limited evidence to support its accuracy in the setting of severe AS.

Evidence

In patients with severe AS, resting and hyperemic coronary flow are affected to different degrees. To compensate for increased oxygen demand from the hypertrophied left ventricle, the resting coronary flow is increased (decreasing NHPR and potentially overestimating hemodynamic severity).$^{54}$ Moreover, patients with severe AS have high left ventricular end diastolic pressure, elevated microvascular resistance, fibrosis, and capillary rarefaction, all of which can lead to higher FFR across a specific stenosis. In the COSMIC-AS study (Coronary and Microcirculatory Measurements in Patients With Aortic Valve Stenosis) of 116 patients, FFR or NHPR discordance was seen in 42.3% of patients. After transcatheter aortic valve replacement, FFR decreased and NHPR increased, and the discordance was reduced.$^{54}$ The study found an FFR ≤0.83 and an NHPR ≤0.85 to have better accuracy to predict myocardial ischemia.$^{54}$ In an observational study, the concordance between pre- and post-transcatheter aortic valve replacement FFR was higher (92.8%) compared with Pd/Pa (75.4%) and RFR (73.8%)$^{55}$ The safety and tolerability of intravenous and intracoronary adenosine in the setting of AS has been demonstrated in multiple studies.$^{56-59}$

Summary

Although FFR or NHPR measurements are used to determine the hemodynamic significance of intermediate coronary lesions in patients without severe AS, the evidence to support their accuracy is limited. Overall, FFR may underestimate lesion severity and NHPR may overestimate lesion severity. Therefore, a low FFR ≤0.80 in severe AS likely indicates a significant lesion, whereas a high NHPR >0.89 likely indicates an insignificant lesion (Figure 4). With an FFR or NHPR in the gray zone, one should be aware that the value may change, leading to a different decision after treatment of the AS. A recent study has suggested an FFR ≤0.83 and NHPR ≤0.85 to have better accuracy to predict myocardial ischemia. Randomized trials are ongoing that will help determine the utility of these physiologic measurements in patients with severe AS.$^{60}$

FFR or NHPR Can Predict Nonviable Myocardium

Practice

Some operators measure FFR or NHPR in an attempt to distinguish infarcted from viable myocardium.

Evidence

No definitive relationship should be expected between intracoronary pressure measurements and the extent of myocardial infarction distal to an epicardial stenosis. A transmural infarction still receives blood flow at baseline$^{61}$ and global vasodilators like adenosine can increase flow to a variable extent, even to the infarcted region.

Two distinct measures have been explored: FFR, and the change between resting Pd/Pa and FFR. Of the 2 largest series examining FFR, no significant relationship was found with myocardial viability.$^{62,63}$ The other 2 series from the same single center identified FFR thresholds of 0.71 and 0.74.$^{64,65}$ Generally a difference between rest Pd/Pa and FFR of 0.10 identified viability in 2 modestly sized cohorts,$^{66,67}$ albeit one in the acute MI setting and using a complex methodology.$^{67}$ However, the data are limited.

Summary

FFR or NHPR measures cannot reliably identify viable versus infarcted myocardium, and are not recommend for this purpose.

Donor Vessel Supplying Collaterals

Practice

Invasive physiologic assessment of an intermediate coronary lesion in a vessel supplying collaterals (donor vessel) to a vessel with a chronic total occlusion (CTO) has lower accuracy.

Evidence

FFR or NHPR can be used to assess the physiologic significance of an intermediate lesion in a donor vessel before CTO intervention, multiple factors have been found that might lead to changes in the FFR or NHPR after CTO revascularization (if performed). These include lesion characteristics in the donor vessel, the degree of collaterals, the effect of collateral steal, microvascular dysfunction, and the viability of the myocardium.$^{68}$ Multiple clinical studies have investigated the cumulative effect of these factors on FFR and NHPR in the donor vessel and have shown an immediate and long-term significant increase in donor vessel FFR after CTO PCI.$^{69-71}$ Studies of NHPR have shown a similar increase in the iFR value after CTO PCI (0.86±0.10 to 0.88±0.10; P=0.012), leading to a re-classification of the predominant donor vessel from ischemic to nonischemic in 25% of the cases.$^{72}$

Summary

FFR or NHPR measurements can be used to determine the severity of intermediate lesions in donor vessels in patients with a vessel with a CTO, but caution must be taken in interpreting the results because of the potential for increase in FFR or NHPR in the donor vessel if the CTO were to be revascularized. In patients with normal FFR (>0.80) or NHPR (>0.90), revascularization of the donor

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 Figure 4. Fractional flow reserve and nonhyperemic pressure ratio assessment in patients with severe aortic stenosis.

AS indicates aortic stenosis; FFR, fractional flow reserve; LAD, left anterior descending; LCx, left circumflex; and NHPR, nonhyperemic pressure ratio.

vessel can be deferred. Revascularization of the donor vessel can be considered if the donor vessel FFR is <0.70 or NHPR <0.80.$^{68}$ In patients with a donor FFR or NHPR between these 2 values, CTO PCI should be performed first (if planned) and physiologic assessment of the donor vessel should be repeated subsequently (Figure 5).$^{68}$

to vessel foreshortening and overlap. Measuring FFR or NHPR across the LM can provide functional information, improving decision-making.

Evidence

FFR or NHPR to assess the significance of LM stenosis has challenges related to guide catheter obstruction (for ostial lesions), exacerbation of FFR or NHPR discordance due to proximal location of the lesion supplying a large myocardial territory, and effect of hemodynamic crosstalk of downstream LAD or left circumflex (LCx) stenosis on the accuracy of pull-back assessment of LM stenosis. Intravenous adenosine is preferred because it

Left Main Stenosis

Practice

Coronary angiography alone is notoriously poor at identifying significant left main (LM) coronary disease due

 Figure 5. Fractional flow reserve for assessment of donor vessel supplying a collateral.

CTO indicates chronic total occlusion; FFR, fractional flow reserve; LAD, left anterior descending; LCx, left circumflex; PCI, percutaneous coronary intervention; and RCA, right coronary artery.

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allows unseating of the guide catheter and avoids ostial obstruction during hyperemia. LM measurement should be made with the pressure wire first in the LAD and then again in the LCx. The measurement in both branches is important when one or the other has a stenosis and thus the effect of the combined LM and downstream lesion can be separated. For example, across an LM with no downstream disease in either LAD or LCx, FFR or NHPR will accurately reflect the LM narrowing, confirmed by both branch FFR values. However, if there is disease in one branch (eg, the LAD), then an abnormal

FFR or NHPR value indicates that either the LM or the LAD lesion is significant. Measuring FFR in the LCx can be helpful, as it is not substantially affected by the LAD disease unless the LAD disease is severe (FFR <0.50).$^{73}$ If there is substantial downstream disease in both branch vessels (LAD and LCx), one should consider intravascular imaging to obtain anatomic information (Figure 6). A recent study suggested that in isolated LM disease, the FFR/NHPR is significantly lower when measured in the LAD compared with the LCx.$^{74}$ It is unclear how much of this difference was related to undetected ostial LAD

 Figure 6. Fractional flow reserve for assessment of left main lesion.

FFR indicates fractional flow reserve; LAD, left anterior descending; LCx, left circumflex; LM, left main; and PCI, percutaneous coronary intervention.

CLUNICAL STATEMENTS AND GUDELINES

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disease or the effect of hydrostatic pressure; however, based on these results, one should default to the FFR/NHPR value in the LAD, especially if the LCx is negative.

A number of observational studies have demonstrated the safety of deferring revascularization in patients with intermediate LM disease and a negative FFR (>0.75-0.80).$^{75-77}$ Emerging data support the role of NHPR for identifying LM lesions that can be treated medically.$^{78}$ However, the concordance between FFR and NHPR is modest (80%). In the iLITRO-EPIC07 study (Concordance Between FFR and iFR for the Assessment of Intermediate Lesions in the Left Main Coronary Artery: A Prospective Validation of a Default Value for iFR), of lesions with negative iFR, 46% had LM minimal luminal area <6 mm$^{2}$ on intravascular imaging (see Accuracy of NHPR Compared With FFR), suggesting reduced accuracy of NHPR. Moreover, in a study evaluating the accuracy of pressure wire-derived indices in comparison with quantitative perfusion cardiac magnetic resonance-derived myocardial perfusion reserve, FFR was superior to NHPR at detecting functionally significant LM disease.$^{79}$

Summary

FFR or NHPR are useful for evaluating the functional significance of intermediate LM disease. A negative value (especially for FFR) indicates that revascularization can be safely deferred. Strategies for FFR or NHPR measurement for isolated LM stenosis and for LM stenosis with concomitant disease in one or both downstream branches are outlined in the preceding text and summarized in Figure 6. The concordance between FFR and NHPR is modest (80%) and additional testing including FFR and intravascular imaging should be considered based on the clinical presentation if the NHPR is negative, given that the LM typically supplies a greater amount of myocardium, which can exacerbate FFR-NHPR discordance.

Tandem Lesions

Practice

In patients with serial or tandem lesions, it can be challenging to determine which lesion is hemodynamically significant, or whether both lesions are significant.

Evidence

In patients with serial lesions, there may be hemodynamic interdependence, meaning that one lesion affects flow across the other. For example, if the pressure sensor is placed between the 2 lesions in an attempt to measure the FFR of only the proximal lesion, the distal lesion can impair maximal flow across the proximal lesion, resulting in a smaller pressure gradient and a higher FFR than would be present if the distal lesion were absent. This hemodynamic crosstalk occurs most often during

hyperemia (ie, with FFR), but can also be seen at rest with NHPRs, particularly diastolic NHPRs such as iFR, dPR, and RFR, and becomes more pronounced as the lesions become more severe.$^{80}$

When measuring FFR or NHPR in a vessel with tandem lesions, the first step is to place the pressure sensor beyond both lesions to establish the hemodynamic significance of the two combined. If the distalmost FFR is not significant, revascularization can be deferred. If the FFR or NHPR is abnormal beyond both lesions, then the pressure sensor should be slowly pulled back to determine which lesion is responsible for producing most of the pressure gradient. The most significant lesion should then be stented, and the remaining lesion remeasured. If the 2 narrowings are close enough together, both can be stented with one long stent. If not, the FFR or NHPR of the remaining lesion must be reassessed and, if still abnormal, a second stent can be placed. Moreover, pullback pressure gradients and coregistration with intravascular imaging can sharpen lesions specific localization. Novel, angiography-derived methods for assessing coronary physiology without a pressure wire allow for virtual stenting of one tandem lesion and assessment of the remaining lesion before any actual PCI is performed.$^{81}$ Data are limited.

Summary

Assessing the hemodynamic significance of tandem coronary lesions with invasive wire-based physiology remains a challenge. With careful measurement from a slow pullback of the pressure wire and, if necessary, repeat measurement after stenting one lesion, operators can safely and effectively use physiologic measures to guide PCI of tandem lesions (Figure 7).

Ostial Lesions

Practice

In patients with aorto-ostial lesions, there is a concern that FFR or NHPR may not be accurate.

Evidence

Angiographic assessment of ostial lesions can be difficult due to vessel overlap, angulation, and foreshorting. Intravascular imaging for ostial lesions may be difficult to interpret due to catheter jump. Moreover, invasive physiologic measurement of aorto-ostial lesions is challenging due to guide catheter pressure wave dampening, which can reduce Pa and falsely elevate FFR or NHPR.

Summary

Invasive physiologic measurement of aorto-ostial lesions is challenging due to guide catheter dampening resulting in falsely negative FFR or NHPR values. Use of a guide catheter without side holes, meticulous guide catheter handling technique (eg, disengagement strictly required, flushing, coaxial positioning) during pressure

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Invasive Epicardial Coronary Physiologic Assessment

 Figure 7. Physiologic assessment of tandem lesions.

FFR indicates fractional flow reserve.

wire measurements, and use of intravenous adenosine will support physiologic measurements. Standard FFR or NHPR thresholds apply. Given that aorto-ostial lesions typically supply greater amounts of myocardium, which can exacerbate FFR-NHPR discordance, a negative NHPR should be followed by FFR based on the clinical presentation.

FFR or NHPR in Saphenous Vein Grafts

Practice

In routine clinical practice, saphenous vein graft (SVG) hemodynamic assessment using FFR or NHPR is rarely performed because there is uncertainty regarding its accuracy.

Evidence

There are limited data to guide the use of FFR or NHPR in SVG. In a small study of 10 patients with SVG lesions who had stress myocardial perfusion imaging before referral for PCI, the negative predictive value of FFR <0.75 to predict ischemia on myocardial perfusion imaging was 85%.$^{82}$ Studies show that a non-ischemic FFR carries a significantly worse prognosis in SVG compared with non-SVG lesions.$^{83}$ These findings can be attributed to multiple considerations pertaining to SVG. SVG FFR is a result of the SVG flow, native flow, and flow through collaterals, which can result in a normal FFR despite severe SVG stenosis. More importantly, the variable rate of progression of SVG lesions hinders the utility of a negative physiologic assessment to predict clinical outcomes.$^{84}$ A factor to consider when performing FFR in an SVG is whether the native coronary is patent or occluded. If the native vessel is occluded, the procedure and interpretation of the result would be the same as in a native coronary. However, if the native vessel is patent, then the sensor of the pressure wire should be placed distal to the distal anastomosis site to truly account for the cumulative effect of the atherosclerotic burden on perfusion of the downstream myocardial area and a pullback performed to assess the area of stenosis.$^{85}$

Summary

The evidence to support the use of FFR or NHPR in SVGs is limited. The available evidence points toward a lack of clinical benefit to guide revascularization decisions in these patients, finding similar outcomes compared with angiographic guided interventions. A positive FFR or NHPR in a diseased vein graft indicates ischemia and warrants revascularization, if feasible, but a negative FFR or NHPR may progress more rapidly with medical therapy alone, compared with native coronary disease. Further clinical trials are needed to provide more conclusive evidence.

Myocardial Bridging

Practice

The accuracy of FFR or NHPR and their relative accuracy (FFR versus NHPR) in the setting of myocardial bridging (MB) is uncertain given the dynamic compression.

Evidence

MB is a common, often benign, congenital coronary anomaly in which a segment of epicardial coronary artery traverses through the myocardium for a portion of its length.$^{86}$ MB causes dynamic stenoses that vary with cardiac cycle, heart rate, and sympathetic vascular tone. Although chiefly considered a systolic phenomenon, intravascular ultrasound studies have demonstrated a delay in the increase in luminal diameter during diastole.

Given the dynamic nature of MB, standard pressure wire techniques are inadequate for the accurate assessment of MB severity, In general, the goal of pressure-wire techniques in the accurate assessment of MB is to assess compromised diastolic blood flow, because systolic over-shooting of distal pressure can occur. FFR is calculated by comparing mean pressures by default and is considered inadequate for this purpose, because the mean pressure difference might be affected by the systolic overshooting.$^{87,88}$ However, a FFR value of <0.75 is likely to predict ischemia in a vessel with MB.$^{89}$ Diastolic FFR is the preferred method of FFR and should be measured with dobutamine or exercise to induce maximal systolic compression

GLINICAL STATEMENTS AND GUIDELINES

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Invasive Epicardial Coronary Physiologic Assessment

across the MB segment. A diastolic FFR value of ≤0.76 has been identified as a cutoff to predict those with MB-related ischemia during dobutamine challenge.$^{90}$

Summary

Standard pressure-wire techniques are inadequate for the accurate assessment of MB severity. Diastolic FFR is the preferred method of FFR and should be measured with dobutamine or exercise to induce maximal systolic compression across the MB segment. Because diastolic FFR is not commercially available, we recommend that NHPR during dobutamine be measured instead. The preferred intracoronary hemodynamic measurements should include dobutamine challenge (up to 50 µg/kg per minute and use of atropine as needed to achieve 85% of maximum predicted heart rate) along with measurement of diastolic

physiology (either iFR/RFR or diastolic FFR with a threshold of ≤0.76). iFR and RFR during dobutamine infusion may be particularly advantageous in the assessment of MB, as supported by comparison with diastolic FFR.$^{91}$

POST-PCI PHYSIOLOGY MEASUREMENT

Practice

Measurement of FFR or NHPR after PCI is not routine in clinical practice and its utility and value are unknown.

Evidence

A substantial proportion of patients with angiographically successful PCI have suboptimal post-PCI FFR values,

 Figure 8. Physiologic assessment of intermediate coronary lesions.

cFFR indicates contrast fractional flow reserve; LAD, left anterior descending; and LCx, left circumflex.

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Invasive Epicardial Coronary Physiologic Assessment

defined previously as post-PCI FFR <0.90. Post-PCI FFR values <0.90 or iFR <0.95 have been shown to correlate with poor long-term outcomes.$^{92}$ Post-PCI physi-ology measurement can be performed according to the standard techniques after PCI. Studies indicate that both the absolute post-PCI FFR value and the relative degree of FFR gain are associated with symptom improvement, quality of life improvement, and reduced adverse events after PCI.$^{93}$ Well-accepted gain or desirable threshold to reach after PCI have not been well-established. A δFFR gain of <0.10 may be associated with a higher rate of major adverse cardiovascular events, although there is an obvious interaction with presence of diffuse disease outside the target lesion.$^{94}$

Causes of abnormal FFR or NHPR after PCI include stent underexpansion, edge dissections, additional disease proximal or distal to the stented segment, coronary spasm, and wire-based pseudostenes due to the interaction between the pressure wire and tortuous vessels (ie, straightening artifact).$^{95}$

Summary

Abnormal post-PCI FFR (<0.90) and NHPR (<0.95) should prompt additional interrogation (including intravascular imaging) of the diseased vessel segment. Pressure pullback can identify stent-related issues, overlooked lesions, and diffuse disease. Whereas diffuse disease mandates aggressive optimal medical therapy, focal pressure drops during pullback indicate the need for postdilatation if within the stented segment or additional stent implantation.$^{96}$

Disclosures

Writing Group Disclosures

|Writing group member|Employment|Research grant|Other research support|Speakers' bureau/honoraria|Expert witness|Ownership interest|Consultant/ advisory board|Other| |---|---|---|---|---|---|---|---|---| |Sripal Bangalore|New York University School of Medicine|None|None|None|None|None|None|None| |Morton J. Kern|Long Beach Veterans Administration Hospital|None|None|Acist*; Abiomed*; Cathworkst; OpSenst; Zollt|None|None|Medtronic, Inc*; CathWorks, Inc*|None| |George D. Dangas|Icahn School of Medicine at Mount Sinai Cardiovascular Institute|None|None|None|None|None|None|None| |William F. Fearon|Stanford University Medical Center|Abbott Vascular†; Medtronict (all institutional research support)|None|None|None|None|ShockWave*; Edwards LifeSciences*; SpectraWAVE, Inc*|None| |Setri Fugar|Northwest Health Medical Group|None|None|None|None|None|None|None|

(Continued)

CLIVICAL STATEMENTS GLIMICAL STATEMENTS

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Invasive Epicardial Coronary Physiologic Assessment

Writing Group Disclosures Continued

|Writing group member|Employment|Research grant|Other research support|Speakers' bureau/ honoraria|Expert witness|Ownership interest|Consultant/ advisory board|Other| |---|---|---|---|---|---|---|---|---| |Sohah Iqbal|Shore Medical Center/ Massachusetts General Hospital|None|None|None|None|None|None|None| |Nils P. Johnson|McGovern Medical School at UThHealth|Neovasc/Shockwave (institutional research support: PET core lab for COSIRA-Il trial [NCT05102019])†|None|Boston Scientific (all honoraria to institution)*|None|Institutional patent application for methods to correct pressure tracings from fluid-filled catheters*|None|None| |David Power|Icahn School of Medicine at Mount Sinai, Zena and Michael A. Wiener Cardiovascular Institute|None|None|None|None|None|None|None| |Jacqueline Tamis-Holland|Cleveland Clinic|None|None|None|None|None|None|None|

This table represents the relationships of writing group members that may be perceived as actual or reasonably perceived conflicts of interest as reported on the Disclosure Questionnaire, which all members of the writing group are required to complete and submit. A relationship is considered to be "significant" if (a) the person receives ≥$5000 during any 12-month period, or ≥5% of the person's gross income; or (b) the person owns ≥5% of the voting stock or share of the entity, or owns ≥5000 of the fair market value of the entity. A relationship is considered to be "modest" if it is less than "significant" under the preceding definition.

*Modest.

†Significant.

Reviewer Disclosures

|Reviewer|Employment|Research grant|Other research support|Speakers' bureau/honoraria|Expert witness|Ownership interest|Consultant/ advisory board|Other| |---|---|---|---|---|---|---|---|---| |Somiot S. Brar|University of California, Los Angeles|None|None|None|None|None|None|None| |Konstantinos Charitakis|University of Texas Health Science Center|None|None|None|None|None|None|None| |Adhir Shroff|University of Illinois at Chicago|None|None|None|None|None|None|None| |Nadia R. Sutton|Vanderbilt University Medical Center|SCAI Early Career (research on invasive microvascular dysfunction testing and cardiac MRI-based microvascular testing assessment)†|None|Abbott; Zoll†|None|None|Philips*|None| |Jose Wiley|Tulane University School of Medicine|None|None|None|None|None|None|None|

This table represents the relationships of reviewers that may be perceived as actual or reasonably perceived conflicts of interest as reported on the Disclosure Questonnaire, which all reviewers are required to complete and submit. A relationship is considered to be "significant" if (a) the person receives ≥$5000 during any 12-month period, or ≥5% of the person's gross income or (b) the person owns ≥5% of the voting stock or share of the entity, or owns ≥$5000 of the fair market value of the entity. A relationship is considered to be "modest" if it is less than "significant" under the preceding definition.

*Modest.

†Significant.

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