Interview + Case Report

The Future of Physiological Assessment

Ziad Ali, MD, DPhil1,2

1New York Presbyterian Hospital / Columbia University Medical Center, New York, New York; 2Cardiovascular Research Foundation, New York, New York  

Ziad Ali, MD, DPhil1,2

1New York Presbyterian Hospital / Columbia University Medical Center, New York, New York; 2Cardiovascular Research Foundation, New York, New York  

What are the benefits of using physiological assessment such as fractional flow reserve (FFR) to assess the hemodynamic significance of lesions?

Intermediate diameter stenosis coronary lesions are common in interventional cardiology and represent a diagnostic dilemma. Inappropriately treating or deferring these lesions may lead to harm. Randomized trials using a pressure wire-based system demonstrate clinical benefit for FFR-guided revascularization versus angiographic guidance alone, helping solve this clinical dilemma. Basic physiological assessment is appropriate when there is an intermediate lesion without a corresponding stress test showing ischemia in the same territory. For example, if there is an 80% narrowing in a proximal left anterior descending (LAD) coronary artery with a stress test showing ischemia in the same territory, it would be a little foolish to perform physiological assessment to determine whether or not that lesion is significant. 

However, during that same percutaneous coronary intervention (PCI) of the proximal LAD, if the operator saw an intermediate lesion in the right coronary artery, one may consider doing a physiological assessment in that situation.

FFR requires the use of a hyperemic agent. What are the challenges involved with use of this agent?

There are three predominant pitfalls or limitations to FFR. One is that the patients don’t like it, because a significant number of patients develop symptoms with intravenous administration of adenosine. Symptoms are much more limited with intracoronary administration, but worldwide, the most common method of administration is intravenous. The second limitation is the time related to procuring the adenosine. This may include contacting the pharmacy, mixing adenosine, setting up an infusion pump and delivering the drug. The third limitation has been its associated cost. While that may seem trivial in some geographies, in others, it’s not. For example, in some geographies, adenosine is quite expensive, such as when it needs to be procured from the pharmacy, incurring a pharmacy charge. 

What is angio-derived FFR and what are its potential benefits?

Angio-derived FFR is basically an extension of computational fluid dynamics, whereby a computational algorithm creates a virtual FFR by evaluating certain parameters of the angiogram, such as the length of the lesion, diameter of the stenosis, and the territory in which the lesion is located. By creating a contour of the artery and simulating a tube-like structure from a reconstruction of the angiogram, it can simulate the FFR. What are the advantages of angio FFR? Of course, it eliminates the need for adenosine or a hyperemic agent, but it also eliminates the need for instrumentation. And while the overall rate of device-related events by a pressure wire are relatively low, the event rate is not zero. The only risk incurred from an angio-based FFR is the potential use of additional contrast, so it is invariably safer than FFR. Angio FFR is also going to be much faster, because it eliminates the need to mix drugs or put a wire across the lesion. Theoretically, it could be cheaper, as it certainly won’t require any hardware. What happens in an angio-based FFR is DICOM images that have been stored as part of the angiogram in at least two different views without moving the camera are used to reconstruct a three-dimensional (3D) structure out of the 2D images. That 3D structure is then computationally converted into a tube. The flow patterns of that tube are used to determine a potential pressure drop across a stenosis and that pressure drop is then correlated to create a virtual FFR. It does provide a number, referred to as the virtual FFR (vFFR), and the cutoffs for virtual FFR are the same as for conventional hyperemic FFR. 

How can an angio-derived FFR measurement (vFFR) help with assessing lesion significance?

Angio-derived FFR is used in the same clinical scenarios as hyperemic  FFR: an intermediate lesion of unclear physiological significance. However, angio FFR can provide a measurement for multivessel disease in a fraction of the time required by FFR via a pressure wire. Angio FFR does not require the operator to place a wire in all three arteries and eliminates the use of two different guide catheters. One could envision that as time goes on, virtual FFR would become a part and process of the angiogram, offering physiological assessment of each coronary artery as standard of care to help guide decision making. It’s imminently doable. Right now, in order to perform an angio-based FFR or virtual FFR, you need a view of the coronary artery from at least two different angles, at least 30 degrees apart. If you focus on the lesion and are able to see it in two different views, virtual FFR could be done in any artery you want: the left anterior descending (LAD), circumflex, right coronary, or any combination thereof. For example, in situations where you don’t have a stress test or don’t have a computed tomography (CT) FFR on a patient coming into the lab, if the patient has typical symptoms or not, an angio FFR could be done on all three vessels very, very quickly, allowing one to determine which lesion would be the most likely culprit for that patient.

What data are available for angio-derived FFR?

The studies that have been done so far have been comparator studies, whereby a pressure wire is placed in the coronary artery, FFR is performed, that number is stored as a blinded assessment, and then angio FFR is performed, also blinded. A core lab then compares the blinded two numbers for correlation and diagnostic accuracy, including sensitivity and specificity. The diagnostic accuracy overall has really been very strong, in the low 90s, which means that essentially it’s about 92% as accurate as FFR (as the gold standard). 

Could angio-derived FFR replace invasive FFR?

I think so. There are some technical hurdles with integrating new technology into older x-ray equipment. As new x-ray equipment becomes available, as systems are upgraded across the country and across the world, angio-derived FFR is going to be an established, integral part of all cath labs of the future. As angio FFR is integrated into these systems, I would expect that wire-based systems would be used for more niche assessments, such as the microvasculature or assessment of flow.

How does it compare to the resting indices like Pd/Pa or iFR?

Right now, angio FFR is compared to FFR. The comparison of angio FFR to resting indices is less well-described, and the diagnostic accuracy of angio FFR against Pd/Pa or iFR (or resting full-cycle ratio [RFR] or diastolic pressure ratio [dPR]) is lower than against angio FFR. Of course, that result is very predictable. If you design a technology based on FFR, and then compare that technology to another assessment method that has an 80% accuracy against FFR, of course, it will not perform as well, so it’s not unexpected. As this field continues to evolve, it is likely that there will be similar assessments against resting indices. But whether the assessment is against FFR or whether it is against a resting index, it really is a moot point. I think that comparison against one physiological assessment is really the key.

What will be needed to establish vFFR as a gold standard?

There needs to be more data available. Currently, in the literature, angio FFR’s total experience probably includes about 2500 patients. In comparison, the resting indices and FFR have data incorporating tens of thousands of patients with very long-term follow-up. We need more short-term data in terms of diagnostic accuracy, and then ultimately, we need clinical outcomes trials to show that angio FFR is able to do the same thing that FFR was able to do in the FAME 1 and FAME 2 trials; that is, to improve the outcomes of these patients. There is such a trial, called FAVOR III, currently randomizing patients in China. Patients are randomized to quantitative flow ratio (QFR), which is one version of angio FFR, against angiography-based PCI with clinical outcome. We look forward to the results. It is likely that angio-based FFR will be an integral part of the cath lab in the future.

What’s the impact you envision now that vFFR can be offered in partnership with an imaging company such as Siemens Healthineers?

This is an exciting partnership. Pie Medical Imaging (offering vFFR) is a leader in the field of medical imaging software and Siemens is a major player in cath labs all across the world. Integrating vFFR into Siemens systems should alleviate any of the current limitations to integration of angio-FFR, namely, the logistical challenges of image transfer and integration into the imaging system within the cath lab. 

Read the accompanying case report:

Virtual FFR: A Simple, Reliable, Angiography-Based Method to Assess Physiological Lesion Severity in the Cath Lab

This article is supported by Siemens Healthineers.

Disclosures: Dr. Ali reports grants from National Heart, Lung, and Blood Institute during the conduct of the study; grants and personal fees from Abbott Vascular, grants and personal fees from Cardiovascular Systems, Inc., personal fees from Amgen, AstraZeneca, Abiomed, Boston Scientific, Cardinal Health, OpSens Medical, and ACIST Medical; and other from Shockwave Medical, outside the submitted work. 

Ziad A. Ali, MD, DPhil, can be contacted at