Angiographically-derived fractional flow reserve and optical coherence tomography findings after coronary stenting

In the early days of percutaneous coronary interventions (PCI), pressure gradients were obtained to confirm lesion severity before and after interventions [[1], [2], [3]]. Then, coronary angiography was consolidated as the best tool to assess PCI results and compare the efficacy of different coronary interventions. However, angiography has well-recognized, inherent, limitations in assessing coronary artery disease (CAD) as it only provides a 2-dimensional lumenogram unable to disclose the atheroma burden at the vessel wall. The advent of intracoronary imaging (ICI) revolutionized the field by directly visualizing atheromatous coronary plaques. ICI revealed that angiography systematically underestimated the extent and severity of CAD, due to unrecognized diffuse disease and remodeling phenomena. Alternatively, early physiological studies also demonstrated a poor correlation between the angiographically derived lesion severity and its functional significance [[1], [2], [3]]. Fractional flow reserve (FFR) consolidated as the gold standard to assess the functional significance of epicardial coronary lesions [[1], [2], [3]]. The idea that “anatomy is not physiology” represented a major paradigm shift and, since then, the use of intracoronary physiology is recommended by clinical practice guidelines to guide revascularization decisions [4].

More recently, the notion that coronary anatomy is unable to predict the functional significance of coronary lesions has been critically challenged in a “back to the future” journey [[5], [6], [7], [8], [9], [10]]. Technological advances currently allow an unprecedented accuracy in the assessment of coronary anatomy using different techniques (i.e., angiography, ICI, CT-angiography) relying on detailed 3D reconstructions. Powerful sophisticated artificial intelligence (AI) algorithms are used to process this advanced anatomic information, sometimes enriched by surrogate markers of hemodynamic conditions or coronary flow [[5], [6], [7], [8], [9], [10]], to accurately predict coronary physiology. However, obtaining good correlations is only part of the equation, because accuracy, precision and reproducibility remain critical to ensure that these results may be translated into the clinical area to inform the decision-making process in individual patients. Where are we now in the conundrum linking coronary anatomy and physiology?

Present study:

This study by Ziedses des Plantes et al [11] sought to define the association between post-PCI angiographically-derived vessel FFR (vFFR) and optical coherence tomography (OCT) findings, in patients with intermediate coronary lesions. Complete post-PCI OCT and vFFR data were available for 109 vessels (100 patients) in the FAST OCT study. Post-PCI assessment included two orthogonal angiographic projections after intracoronary injection of nitrates and aortic pressure recording. On OCT vessel minimal lumen area (MLA) was identified both anywhere along the entire pullback and within the stent. Post-PCI vFFR was 0.93, vessel MLA 3.48 mm² and in-stent MLA 5.37 mm². On multivariable analysis, a significant association was found between post-PCI vFFR and vessel MLA. The optimal cutoff of post-PCI vFFR to detect an MLA ≤ 4.5 mm² was 0.92 (sensitivity 60 %, specificity 88 %). Of interest, the proximal vFFR gradient showed a good diagnostic performance to detect proximal residual disease, whereas the diagnostic performance obtained to detect stent underexpansion or residual vessel disease at other locations (edge dissections or plaque) was poor [11].

vFFR has recently emerged as an accurate alternative to pressure-wire based FFR [[7], [8], [9], [10],12,13]. With this technique, gradients at proximal and distal coronary segments and across the stent may be readily analyzed. The present study suggests a significant correlation between vFFR and MLA post-PCI. These findings are of clear interest but addressing some issues will be of value.

First, the primary aim of the FAST OCT study was to assess the association between pre-PCI vFFR and OCT findings. The present analysis [11] is a pre-specified, yet small, sub-study where only selected patients −half of the initial population- with adequate post-PCI angiograms and final OCT studies, were included. This should be considered as might be a potential source of bias.

Second, the interplay between MLA and in-stent MLA was not clarified. The main objective of the present study was to investigate the association between OCT-detected MLA and vFFR post-PCI. Surprisingly, no significant associations were observed between post-PCI vFFR and the presence of stent underexpansion, residual lesions or presence of stent edge dissections. Further studies, including a large number of patients, are indeed warranted to further refine the clinical implications of vFFR during PCI.

Third, selecting a post-PCI vessel MLA of 4.5 mm² as an absolute criterium does not consider the vessel size. Relative indexes of stent expansion are more appealing from a pathophysiological standpoint than absolute MLA values. However, most previous studies have been unable to demonstrate a superior predictive value for clinical events of the relative indexes of stent expansion as compared with absolute values of in-stent MLA. Of note, in diffuse lesions current OCT measurement algorithms permit assessing the extent of stent expansion considering the natural tapering of the vessel and the side branches. Moreover, further insights on the correlation between physiology and anatomy could have been unveiled by comparing vFFR with MLA or relative stent expansion criteria as continuous variables.

Fourth, the potential implications of the status of the microcirculation in these patients remained elusive. Previous studies have shown that the amount and viability of the subtended myocardium may affect physiological results. One-fourth of patients in this study had a previous myocardial infarction and 2/3 of lesions were located in the left anterior descending coronary artery. Additional information on the potential implications of the selected vessel and status of the subtended myocardium would have been helpful to better understand the value and limitations of vFFR as a surrogate of the wire-determined FFR. Unfortunately, in this study wire-based FFR values were not available.

Finally, optimization procedures were performed to correct initially suboptimal OCT results, thus a small number of patients with OCT-detected suboptimal results was analyzed.

Other important issues:

ICI has shown a major value to guide and optimize stent implantation. The use of both OCT and intravascular ultrasound (IVUS), particularly in complex lesions, has been associated not only with better anatomic results but also with superior clinical outcomes and, recently, has received a IA recommendation by the ESC clinical practice guidelines [4]. Alternatively, post-PCI FFR has also shown to be able to predict clinical outcomes. Therefore, both sub-optimal OCT and FFR post-PCI are associated with adverse events. In case of concordant sub-optimal results the case for additional optimization efforts is clear. However, the implications of suboptimal OCT findings associated with satisfactory FFR results or, conversely, abnormal FFR results despite optimal OCT results, remain unclear.

As discussed, many previous studies have used invasive angiography to predict wire-based FFR [[7], [8], [9], [10],12,13]. The use of computational flow dynamics and, AI in particular, have been instrumental to foster this field. These studies differ in the assumptions made by the models, the selected boundary conditions and the additional information requested (single vs. orthogonal projections, aortic pressure, TIMI frame count) to estimate FFR [[7], [8], [9], [10],12,13]. However, it is still unclear which methodology to determine angiographically-derived FFR will provide better diagnostic accuracy or will be more easily implemented in real world clinical practice.

Notably, vFFR provides a fast and accessible method to identify patients with a suboptimal post-PCI result who may benefit from additional OCT evaluation to identify mechanical issues and optimize final results [[8], [9], [10],12,13]. The findings of the present work are aligned with the results from the FFR SEARCH study, which found an association between wire-detected FFR and MLA, whereas no association was detected between FFR and stent expansion or the presence of a residual lesion on IVUS [14]. However, the enthusiasm for angiographically-based physiology was recently partially tempered by the negative results of the FAVOR-III Europe trial [15]. In this pivotal randomized clinical trial , including 2,000 patients with intermediate coronary lesions, the quantitative flow ratio (an angiography-based computational method for the estimation of FFR), failed to meet noninferiority for clinical events at 1 year compared with wire-based FFR.

Conclusions:

It is clear that “anatomy is not physiology”. It is also clear that surrogate non-invasive indexes of functional significance are still not perfectly aligned with invasive-FFR results. However, it is also evident that soon, using currently available technology and the invaluable help of AI, a comprehensive and throughout anatomic analysis of intermediate lesions will be able to reliably predict the related physiological implications.