Impact of stenosis resistance and coronary flow capacity on fractional flow reserve and instantaneous wave-free ratio discordance: a combined analysis of DEFINE-FLOW and IDEAL

Background The pressure-derived parameters fractional flow reserve (FFR) and the emerging instantaneous wave-free ratio (iFR) are the most widely applied invasive coronary physiology indices to guide revascularisation. However, approximately 15–20% of intermediate stenoses show discordant FFR and iFR, and therapeutical consensus is lacking. Aims We sought to associate hyperaemic stenosis resistance index, coronary flow reserve (CFR) and coronary flow capacity (CFC) to FFR/iFR discordance. Methods We assessed pressure and flow measurements of 647 intermediate lesions (593 patients) of two multi-centre international studies. Results FFR and iFR were discordant in 15% of all lesions (97 out of 647). FFR+/iFR− lesions had similar hyperaemic average peak velocity (hAPV), CFR and CFC as FFR−/iFR− lesions, whereas FFR−/iFR+ lesions had similar hAPV, CFR and CFC as FFR+/iFR+ lesions (p > 0.05 for all). FFR+/iFR− lesions were associated with lower baseline stenosis resistance, but not hyperaemic stenosis resistance, compared with FFR−/iFR+ lesions (p < 0.001). Conclusions Discordance with FFR+/iFR− is characterised by maximal flow values, CFR, and CFC patterns similar to FFR−/iFR− concordance that justifies conservative therapy. Discordance with FFR−/iFR+ on the other hand, is characterised by low flow values, CFR, and CFC patterns similar to iFR+/FFR+ concordance that may benefit from percutaneous coronary intervention. Supplementary Information The online version of this article (10.1007/s12471-023-01796-x) contains supplementary material, which is available to authorized users.


Introduction
The accuracy of coronary angiography (CAG) in assessing functional stenosis significance is poor [1,2], and additional coronary physiology assessment improves the identification of haemodynamically relevant stenosis [3,4].Among these are the coronary pressure-derived fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR).Both indices are translesional pressure ratios, but FFR is calculated from averaged whole cycle hyperaemic pressure measurements, while iFR is calculated from selective diastolic non-hyperaemic pressure measurements.Disagreement occurs in up to 20% of vessels [5][6][7], but comparisons with independent reference standards have documented equivalent diagnostic efficiency between the two techniques [8].In addition, two large randomised clinical trials reported non-inferiority of iFR-guided intervention to FFR-guided intervention with respect to adverse cardiovascular events [9,10].Interestingly, revascularisation rates were lower in the iFR-guided strategy arm, but no difference in 1-year major cardiac event (MACE) rates was apparent between the two strategies [11].With FFR and iFR now used interchangeably in clinical practice, or even together in the same patient, the frequent discordance and intriguing findings on revascularisation rates warrant detailed insights into disagreement between the techniques.Previous studies have suggested that measurements of coronary flow reserve (CFR) can provide valuable insight into the origin of iFR/FFR discordance [12][13][14], but comprehensive physiological assessment using basal and hyperaemic stenosis resistance index, stenosis-specific markers of physiological severity, and coronary flow capacity (CFC), a comprehensive myocardial perfusion marker, may allow more detailed insight into the origin and consequences of iFR/FFR discordance.Therefore, we sought to describe the origin of iFR/FFR disagreement with respect to physiological stenosis severity and myocardial perfusion impairment to guide the combined use of iFR and/or FFR in clinical practice.

Patient population
This analysis included patients from two international multi-centre studies on comprehensive invasive physiological stenosis assessment: the IDEAL registry, and the DEFINE-FLOW study (NCT02328820).Rationale and design of DEFINE-FLOW [15] and the results of IDEAL [16] have been published elsewhere.From DEFINE-FLOW, solely measurements approved by the core laboratory were used in this subanalysis, since the required physiological data for hyperaemic stenosis resistance and CFC calculations were only available in cases in which core lab data were reported.

Cardiac catheterisation and physiological assessment
Intracoronary nitroglycerin (100-300 µg) was administered at the beginning of the procedure, and repeated every 30 min if necessary.After diagnostic coronary angiography, a 0.014 dual pressure and Doppler flow velocity sensor tipped guidewire (ComboWire XT; Philips Volcano, San Diego, CA) was zeroed to atmospheric pressure, and subsequently calibrated to aortic pressure at the ostium of the guiding catheter.Afterwards, the guidewire was positioned at least five vessel diameters distal to the lesion.After obtaining a stable flow signal, wire position was recorded fluoroscopically and adenosine was administered by an intracoronary bolus injection of 60-150 µg, or intravenous infusion of adenosine at a dose of 140 μg/kg/min to induce hyperaemia [17,18].After obtaining the measurements, the guidewire was pulled back to the guiding catheter to assess pressure drift.
FFR was calculated as the mean distal to aortic pressure at peak hyperaemia.CFR was calculated as the ratio of hyperaemic (hAPV) to baseline (bAPV) average peak flow velocity.iFR was calculated by dividing distal resting pressure by aortic pressure in the diastolic wave-free period.Baseline stenosis resistance was calculated as the ratio of mean transstenotic pressure gradient to bAPV with a cut-off value of 0.66 [19], whereas hyperaemic stenosis resistance was calculated as the ratio of mean trans-stenotic pressure gradient to hAPV, with a cut-off value of 0.80 [20].Binary iFR ≤ 0.89, FFR ≤ 0.8, and hyperaemic stenosis resistance ≥ 0.8 mm Hg/cm/s were considered abnormal.Normal CFC was defined as a CFR ≥ 2.8 and an hAPV of ≥ 49.0 cm/s.Mildly reduced CFC was defined as a CFR <2.8 but >2.1 and an hAPV of < 49.0 but > 33.0 cm/s.Moderately reduced CFC was defined as a CFR ≤ 2.1 and > 1.7, and an hAPV of ≤ 33.0 and > 26.0 cm/s.Finally, severely reduced CFC was defined as a CFR ≤ 1.7, and an hAPV of ≤ 26.0 cm/s [21].Abnormal CFC was defined as a moderately to severely reduced CFC.

What's new?
Discordance with abnormal FFR and normal iFR is characterised by maximal flow values, similar to concordant normal FFR and iFR lesions.In patients with abnormal FFR and normal iFR, conservative therapy may be justified.Discordance with normal FFR and abnormal iFR is characterised by low flow values, similar to concordant abnormal FFR and iFR values.Patients with normal FFR and abnormal iFR may benefit from intervention.

Statistical analysis
All analyses were performed at the lesion level, except for baseline patient characteristics.Continuous data were presented as mean ± standard deviation or median (first, third quartile [Q1, Q3]), and were compared by using the paired Kruskal-Wallis test.Analyses across iFR/FFR concordance and discordance groups were compared with 1-way ANOVA, Kruskal-Wallis, χ 2 or Fisher's exact test.Receiver operating characteristic (ROC) curves were computed to compare the diagnostic efficiency of each invasive physiological index against severely or moderately reduced CFC by the area under the ROC curve (ROCAUC).ROCAUC was calculated using DeLong's method.Using the clinically established FFR and iFR cut-off values (≤ 0.80 for FFR and ≤ 0.89 for iFR), diagnostic agreement, sensitivity, specificity, positive predictive value, and negative predictive value were evaluated between FFR and iFR.Applicable tests were 2-tailed and p < 0.05 was considered statistically significant.For all statistical analyses, the STATA version 15.1 (StataCorp, College Station, Texas) software package was used.

Results
A total of 593 patients with 647 lesions were analysed; 281 patients with 281 measurements from IDEAL, and 312 patients with 366 measurements from DE-FINE FLOW.Mean age was 65 ± 10 years, and 77% of patients were male (Tab.1).Physiologic and angiographic characteristics are summarised in Tab. 2.

Association between iFR, FFR and baseline and hyperaemic flow
Lesion and physiology characteristics across FFR/iFR groups are summarised in Tab.S1 in ESM.bAPV and hAPV were not significantly different between the discordant groups (p = 0.202 and p = 0.09 respectively) (Fig. 2a).CFR was significantly different across groups (p = 0.0001).Lesions with FFR+/iFR-discordance had similar hAPV and CFR compared with lesions with FFR-/iFR-concordance (hAPV 31 2b,c).

iFR, FFR, CFC and stenosis resistance across FFR/iFR groups
Figure 3 shows the distribution of lesions across the CFC categories within each of the FFR/iFR groups.Lesions with FFR+/iFR-discordance had abnormal CFC in 22% of cases, similar to lesions with FFR-/iFRconcordance where 21% of cases had abnormal CFC (p = 0.64).Lesions with FFR-/iFR+ discordance had Values are reported as n (%) or mean ± SD MI myocardial infarction, PCI percutaneous coronary intervention, RAAS renin-angiotensin-aldosterone system, SD standard deviation  abnormal CFC in 55% of cases, similar to lesions with FFR+/iFR+ concordance where 63% of lesions had abnormal CFC (p = 0.28).

Discussion
The main finding of this study is that discordance between FFR and iFR, in terms of stenosis severity classification, is explained by the magnitude in maximal

Impact of coronary flow and stenosis resistance on FFR/iFR discordance
Similar to previous reports, discordance between FFR and iFR occurred in 15% of cases in the current analysis [6].As depicted in Tab.S1 in ESM, the main difference between the discordance groups is reflected by the delta APV, CFR and hyperaemic stenosis resistance.This indicates the direct relationship of the discordance between FFR and iFR to the delta APV per interrogated vessel and the proportionally linear relationship between pressure and flow across a stenosis [22].This relationship can be described by the quadratic equation of the form ΔP = Av + Bv 2 ; where ΔP is the pressure drop across the stenosis, v is the flow velocity and A and B are stenosis-specific coefficients.As such, the pressure drop is quadratically dependent of the flow through it and this could explain the differences between the discordance groups.In the FFR+/iFR-group, the intermediate lesions are characterised by a higher epicardial resistance (hyperaemic stenosis resistance) and increased CFR as a larger delta APV results in a larger pressure drop across that lesion during hyperaemia compared to the resting conditions, and thus, an abnormal FFR in the presence of a normal iFR.In comparison, within the FFR-/iFR+ group, the delta APV is limited and together with a lower hyperaemic stenosis resistance results in a limited pressure drop during hyperaemia compared with that at rest, resulting in a normal FFR in the presence of an abnormal iFR (Tab.S1 in ESM).

Comparison with previous studies
The present study confirms, and expands on, previous studies on flow characteristics in FFR/iFR discordance.Petraco et al. [23] and Cook et al. [5] were the first to provide insights in the origin of FFR/iFR discordance.The shared finding of these studies was that vessels with FFR+/iFR-have higher hyperaemic flow and CFR compared with FFR-/iFR+ vessels.Our findings provide further evidence for the role of maximal flow values in FFR/iFR discordance (Tab.S1 in ESM).Patients in the present study with FFR-/iFR+ discordance were significantly older than patients with FFR+/iFR-discordance (mean age 66 ± 10 versus 62 ± 10; p = 0.02) and tended to have a higher prevalence of diabetes (p = 0.08).Increasing age and diabetes are associated with a diminished response to a potent vasodilator, consequently leading to lower maximal flow values, impacting FFR/iFR discordance as described above [1,24,25].Since non-hyperaemic stenosis physiology, assessed by baseline stenosis resistance, was similar across the two discordance patterns, the physiological origin of FFR/iFR discordance lies in hyperaemic vessel flow characteristics that are not related to stenosis severity.This is further supported by the distribution of CFC across the FFR/iFR groups (Fig. 3).High hyperaemic flow and CFR are predictors of benign long-term clinical outcomes, even when FFR ≤ 0.80 [14].The previously reported reports from the DEFINE-FLOW study and the ILIAS-registry indicated that patients with vessels with normal CFR and abnormal FFR in whom revascularisation was deferred, have outcomes similar to those patients who were treated with revascularisation [26].Moreover, low CFR is independently associated with poor long-term clinical outcome [12,[27][28][29].Hence, iFR seems efficient in identifying those stenoses that are associated with impaired flow characteristics since the current data confirm in detail that FFR/iFR discordance occurs on the basis of variable maximal flow values that are generally more benign in iFRvessels without differences in stenosis severity.In this population, this efficiency was not increased by additional measurement of FFR.These findings should trigger further evaluation of the prognostic impact of FFR/iFR discordance, on which evidence remains scarce [30].From the comprehensive perspective of coronary haemodynamics provided by CFC, FFR/iFR discordance due to abnormal FFR is associated with normal or mildly reduced CFC in nearly 80% of cases.This may explain the lower revascularisation rates noted in the iFR arms of the DEFINE-FLAIR and iFR SWEDEHEART which, as noted above, were not associated with worse outcomes than the FFR-based strategy.Alternatively, FFR/iFR discordance due to normal FFR might look worrisome: around 50% of these cases have moderately or severely reduced CFC.The prognostic implications of this finding have been highlighted in previous works [21].It remains unclear if revascularisation of stenosis included in this category would be associated with improved patient outcomes.Moreover, other causes of iFR/FFR discordance have been suggested: lesion location and severity, heart rate, age and beta blocker use affect mainly FFR and should be taken into account [31].
It was suggested that non-hyperaemic indices may be less reliable in proximal LAD lesions, since these supply a large amount of subtended myocardial mass [32].However, this physiological consideration is based on the relationship between larger subtended myocardial mass and higher maximal hyperaemic flow across the stenosis, which leads to higher pressure gradients across a given stenosis.As discussed above, this phenomenon is indeed associated with discordance between iFR and FFR, but also with benign coronary flow characteristics.This is supported by clinical outcome data from a combined analysis of DEFINE-FLAIR and iFR-SWEDEHEART as well, documenting a lower incidence of adverse events for LAD lesions deferred based on iFR measurements compared with LAD lesions deferred based on FFR measurements.

Clinical implications
In clinical practice, borderline iFR values will be followed by FFR measurements for clinical decisionmaking.In general, a borderline iFR value with an abnormal FFR value will be interpreted as an indication for percutaneous coronary intervention, while percutaneous coronary intervention will be postponed in case of a normal FFR.The present study, including the ROC analysis comparing iFR and FFR, indicates an opposite interpretation: a patient may benefit from an intervention in case of iFR+/FFR-, while conservative therapy may be justified in case of iFR-/FFR+.In case of doubt, performing CFR measurements may provide a more robust answer whether it is safe to defer a certain lesion of intermediate severity, since hyperaemic flow is significantly different between FFR+/iFR-and FFR-/iFR+ lesions, where FFR+/iFR-lesions are associated with higher CFR and thus benign long-term clinical outcomes.

Limitations
The total number of discordant iFR/FFR lesions in the DEFINE-FLOW and IDEAL is small, but these two studies combined provide the largest multi-centre analysis of patients with intermediate coronary lesions undergoing invasive physiological interrogation by combined pressure and flow velocity measurements.Second, clinical follow-up after coronary physiological assessment was not routinely performed in IDEAL, prohibiting the evaluation of clinical outcomes.

Conclusion
Discordance between iFR and FFR is an inevitable phenomenon, occurring in 15% of cases in this analysis, and is explained by the magnitude in maximal flow in the evaluated coronary artery unrelated to stenosis severity.

Fig. 3
Fig. 3 Prevalence of CFC categories for each FFR/iFR group (FFR fractional flow reserve, iFR instantaneous wave-free ratio, CFC coronary flow capacity)

Table 1
Baseline characteristics

Table 2
Physiologic and angiographic characteristics iFR 0.92 [0.85, 0.96] Values are reported as n or median [Q1, Q3] Reported percentages are excluding missing values LV left ventricular, MI myocardial infarction, PCI percutaneous coronary intervention, LAD left anterior descending artery, LCX left circumflex artery, RCA right coronary artery, FFR fractional flow reserve, CFR coronary flow reserve, iFR instantaneous wave-free ratio

Table 3
Study population characteristics of the FFR/iFR discordant lesions groups