Karim Al-Azizi:
Hello everyone. I’m Karim Al-Azizi, editor-in-chief for Transcatheter Academy and an interventional cardiologist at Baylor Scott & White The Heart Hospital in Plano, Texas, USA. I’m here today with Dr William Fearon, professor of medicine and director of interventional cardiology at Stanford University School of Medicine in Stanford, California, USA, who served as the co-principal investigator for the ALL-RISE study. Welcome, Dr Fearon. We also have Dr Evan Shlofmitz, director of interventional cardiology at St Francis Hospital & Heart Center in Roslyn, New York, USA. Welcome, Evan.

Karim Al-Azizi:
So, let’s start this conversation about the ALL-RISE study, which has prompted a lot of discussion in the community, especially on the heels of prior studies, for example FAVOR China and FAVOR III Europe. Dr Fearon, as the co-PI, can you highlight for us very briefly the main findings of the ALL-RISE study?

William Fearon:
Sure, thanks, Karim. Thanks for having me.

The ALL-RISE trial was a large, multicentre, randomized study including 59 sites across the US, Europe, Japan and Israel, and 1,930 patients. Patients were randomized to either FFRangio-guided PCI using the CathWorks FFRangio system, or to standard-of-care pressure wire-based physiology, which could be FFR or a non-hyperaemic pressure ratio such as iFR or RFR. The primary outcome was the 1-year composite of death, myocardial infarction or clinically indicated revascularization, and the goal was to show that FFRangio was non-inferior to the pressure-wire strategy.

William Fearon:
At 1 year, event rates were essentially identical, about 7% in both groups, and FFRangio easily met non-inferiority. Another key finding was that workflow was facilitated with the FFRangio system: the time required to calculate the physiologic index and the overall procedure time were shorter, contrast use was lower, and radiation exposure based on fluoroscopy time was reduced. In other words, this approach was non-inferior in terms of clinical outcomes and provided a more efficient workflow.

Karim Al-Azizi:
Thank you. That was a very anticipated clinical trial, as we highlighted, and it was presented at ACC 2026 in New Orleans.

Evan, from your perspective, and as someone who also helped lead the recent consensus document together with Dr Fearon and others on angiography-derived physiology, which was published a few months ago, how do you interpret these findings? As more clinical data emerge across different angiography-derived systems that generate an FFR value, do you think we should be looking at these technologies differently, system by system, or will we treat them similarly across the board, as we have largely done with non-hyperaemic pressure ratios? Where do you think this will take us as a community in the future?

Evan Shlofmitz:
Yeah, there are some great questions in there. I think the biggest thing with ALL-RISE and its presentation at ACC is that it is really good news for the field. We have already seen growth in angiography-derived physiology in the US, and this is going to accelerate that momentum. With two large randomized controlled trials now supporting angio-derived physiology, it is very likely to be embraced as a viable option in the cath lab and will hopefully influence future US revascularization guideline updates, where there has been a gap so far.

Evan Shlofmitz:
Why I think this is so important is that we all want to move away from the subjective “it looks like a severe lesion, it looks like a 70% stenosis,” because we know there is poor accuracy in that visual approach. The goal is to incorporate more objective data.

Evan Shlofmitz:
So, even if there are differences between systems, angiography-derived physiology as a category is going to be better than relying on the oculostenotic reflex of “that looks like a bad lesion to me.”

Evan Shlofmitz:
Whether this is a class effect, I don’t think we know yet. It would be great to have head-to-head comparative studies. Until we have randomized data comparing different modalities, it is anyone’s guess whether the benefits are unique to specific technologies or represent a class effect.

Evan Shlofmitz:
One reason to be cautious about assuming a class effect is that vendors use different algorithms and modeling approaches to calculate values. They are not all derivatives of one another. There are differences in the number of angiographic views required and in the artificial intelligence and computational methods used. So each system has its own advantages and disadvantages, but what we do know is that at least one technology is reliable and reproducible, and that is the core benefit of objective data.

Evan Shlofmitz:
I think, regardless of the system, it is great to have options and to drive increased utilization of angiography-derived physiology in the US, because invasive physiologic assessment overall has been relatively flat in terms of adoption, and there is a huge number of cases where no physiology is performed. Any increase in objective physiology is going to be a benefit. I would love to see head-to-head comparisons to clarify whether there are real differences, and my suspicion is that all of them will be helpful, but in certain clinical and anatomical scenarios you may see specific advantages or disadvantages for different systems.

Karim Al-Azizi:
Thank you, Evan. I completely agree. The oculostenotic reflex is still how many operators function across the country and globally, and I think this type of evidence will help raise the bar and increase utilization of physiology.

Karim Al-Azizi:
On that note, I have a question for Bill. Between ALL-RISE and FAST III, are there clinical scenarios where physiology still has not provided a clear answer on how to assess lesions, and where you think angiography-derived physiology might help? Are there subanalyses that you are looking forward to that might push angio-derived tools beyond what wire-based physiology has already addressed?

William Fearon:
Yes. I’ll answer the second part first. There are some important substudies we are working on that should be available soon. One focuses on the left anterior descending artery, or LAD, which I think we all agree is the most important vessel, looking at how FFRangio compares with pressure-wire assessment in that setting. Another looks at cost and cost-effectiveness, which will be very important as centres consider adopting this technology. We are working on that as a substudy as well.

William Fearon:
Regarding clinical applications, both ALL-RISE and FAST III enrolled relatively few acute coronary syndrome patients, and that is an area where physiology has historically been underutilized and where we need more data. In particular, we need evidence for non-culprit vessels in STEMI, and for multivessel disease in NSTEMI where the culprit lesion is clear but there are additional moderate lesions and uncertainty about what to do. I think future randomized trials will look closely at how angio-derived systems perform in those scenarios.

Karim Al-Azizi:
Thank you, Bill.

Karim Al-Azizi:
Evan, one thing just to add to that: where I think it is going to be especially interesting to see the impact of modern physiology is in moving away from a simple red-light/green-light question, “Is there an indication for PCI?” Bill, you have led a lot of the clinical work using physiology to optimize PCI. In cases with clear-cut indications where someone is not going to do pre-PCI physiology, it is highly unlikely that the average interventionalist will then take out a pressure wire and perform post-PCI physiology. That is a huge opportunity for angio-derived physiology to be used post-PCI and intra-procedurally to tell us whether we achieved the best possible result before leaving the cath lab. I think that is a major advantage over pressure wire-based approaches.

Evan Shlofmitz:
I completely agree. And I also agree with you, Bill, that angio-derived physiology probably opens the door to answering additional questions that are easier to tackle than with wire-based studies, and may even create new lines of research beyond what has already been studied. For example, in severe valvular disease, such as severe aortic stenosis, we still do not have definitive answers on when and how to revascularize. As we move toward more multidisciplinary Heart Team discussions, these tools may also influence outcomes in patients with three-vessel disease undergoing CABG.

Evan Shlofmitz:
One signal we are already seeing in the community is that angiography-derived physiology is being increasingly accepted, even before randomized trials like ALL-RISE read out, especially in centres that did not show much uptake of wire-based physiology.

Karim Al-Azizi:
So, I would like to have some closing remarks from you both. What should we be looking forward to next?

William Fearon:
I’ll start. I think Evan is absolutely right that there are many areas where angio-derived physiology has advantages over wire-based techniques. Post-PCI physiology is one; another is pre-PCI planning, where you can quickly perform a virtual pullback along the entire vessel. That lets you evaluate serial lesions and even perform virtual PCI of a given lesion to predict the physiologic effect before you put a wire down the vessel. It can also help with stent sizing for both length and diameter. We need more data to validate these applications, but it is very exciting. I do not think this technology will just convert operators who already do pressure-wire physiology; I think it will expand the entire physiology space and bring in people who were not using physiology at all.

Evan Shlofmitz:
Yes, I definitely agree. A big point to acknowledge, particularly with the CathWorks system, is how it has evolved over the past decade into a streamlined process that is dramatically faster, with very little manual input or re-contouring required. It has become a very efficient workflow, as ALL-RISE demonstrated, and like any technology it will continue to undergo iterative improvements. As adoption expands over the next several years, it will likely become even more efficient, which should drive further uptake.

Evan Shlofmitz:
I also agree with Bill that the major promise is converting the operator who uses physiology in less than 5% of cases into someone performing physiology at an acceptable rate. And for diagnostic angiographers who do not perform interventions and previously might have had to send patients for a second diagnostic cath with invasive physiology, these tools now give them the ability to perform a comprehensive physiologic assessment using angiography-derived methods in a single session.

Karim Al-Azizi:
I completely agree. With that, I want to thank you both for taking the time to discuss this very important trial and the evolving landscape of angio-derived physiology, where we are and where we may be heading. Thank you all for your attention. To see more videos, please visit transcatheteracademy.com.