Clinical Trial Update

Evaluating Post-PCI iFR and Optimal Revascularization in DEFINE PCI: Use of physiology with Philips iFR, OmniWire, and iFR Co-registration with upcoming DEFINE GPS

Allen Jeremias, MD, MSc*

Director of Interventional Cardiology Research and Associate Director, Cardiac Catheterization Laboratory, St. Francis Heart Center, Roslyn, New York; Director, Physiology Core Lab, Cardiovascular Research Foundation; New York, New York.
*Dr. Jeremias is the Principal Investigator for DEFINE PCI and DEFINE GPS, clinical studies sponsored by Philips.

Ziad A. Ali, MD, DPhil

Director of the DeMatteis Cardiovascular Institute and Investigational Interventional Cardiology, St. Francis Heart Center, Roslyn, New York; Director of the Angiographic Core Lab, Cardiovascular Research Foundation, New York, New York. Dr. Ali is an Investigator for DEFINE PCI and DEFINE GPS, clinical studies sponsored by Philips.

Allen Jeremias, MD, MSc*

Director of Interventional Cardiology Research and Associate Director, Cardiac Catheterization Laboratory, St. Francis Heart Center, Roslyn, New York; Director, Physiology Core Lab, Cardiovascular Research Foundation; New York, New York.
*Dr. Jeremias is the Principal Investigator for DEFINE PCI and DEFINE GPS, clinical studies sponsored by Philips.

Ziad A. Ali, MD, DPhil

Director of the DeMatteis Cardiovascular Institute and Investigational Interventional Cardiology, St. Francis Heart Center, Roslyn, New York; Director of the Angiographic Core Lab, Cardiovascular Research Foundation, New York, New York. Dr. Ali is an Investigator for DEFINE PCI and DEFINE GPS, clinical studies sponsored by Philips.

The DEFINE PCI (Physiologic Assessment of Coronary Stenosis Following PCI) study1 suggests that percutaneous coronary intervention (PCI) guided by instantaneous wave-free ratio (iFR) can improve outcomes and reduce angina for patients more effectively than treatment guided by angiography alone. The trial assessed the level of residual ischemia found in patients following PCI using a blinded iFR pullback measurement. At one year, patients with a post-PCI iFR measurement ≥0.95 had improved outcomes and less recurrent angina. A post-PCI iFR of ≥0.95 was also associated with improved event-free survival at 1 year and 68% fewer clinical events at 1 year compared with patients with less than optimal post-PCI iFR values (1.8% vs 5.7%, P=.04). DEFINE PCI also revealed that 24% of patients with angiographically successful PCI had residual ischemia, and in approximately 82% of these patients, it was the result of a focal, potentially treatable lesion.

Why is the DEFINE PCI study important?

Allen Jeremias, MD, MSc: When you measure physiology (Table 1), you can do either a spot measurement in the distal vessel in order to determine the physiology of the entire vessel for that myocardial territory or, as was done in DEFINE PCI, add a slow pullback of the pressure guidewire. Doing a pullback allows you to see the step-ups in the vessel, with each step-up basically representing an obstruction (which is why you have a pressure drop). The pullback allows the operator to quantify why there is abnormal physiology. In DEFINE PCI, we found that 24% of patients still had abnormal physiology after what looked angiographically to be a successful procedure. When we did the pullback, we could determine the reasons for the abnormal physiology. That is novel, as well as the key to finding out how we can make the procedure better in the future. One blinded iFR measurement was performed at the end of the procedure, the operator did not do any additional intervention, and then the patient was followed out to a year to see how they did. Post-PCI iFR measurement has never been studied in a blinded fashion. DEFINE PCI is important because it highlights the pitfalls of angiography alone and the advantages of invasive physiology in identifying the exact location of flow limitations within the artery. Also, it gives us a target to try and achieve post PCI to get optimal outcomes.

Ziad A. Ali, MD, DPhil: Not only did we focus acutely on whether ischemia was left behind that was missed by the angiogram, but because the trial was blinded, we were also able to evaluate the impact of that residual ischemia on patients in the long term. It is unique that DEFINE PCI had a one-year follow-up with clinical endpoints to determine how patients with residual ischemia did compared to those without. One of the take-home messages from the one-year DEFINE PCI data is that patients with a post-PCI iFR of 0.95 or above did exceptionally well compared to those that were below 0.95.

Post-PCI physiology seems intuitive. Why do you think it isn’t performed more often?

Dr. Ali: One of the first problems with the adoption of physiology in general, not just post PCI, is that the physical properties of pressure wires have made it difficult to guide the wire where you want. In actual fact, a pressure wire is not a solid wire, but is a hypo tube with wiring that goes inside. As you can imagine, compared to a standard workhorse guidewire, which has a solid metal core, such as nitinol, a typical pressure wire is harder to manipulate. That makes it difficult to get into tortuous anatomy or way down a coronary artery. The second problem in obtaining physiologic measurements is that whenever you are measuring these pressures in the artery, the results have an inherent amount of error over the time of an entire case. For example, if you buy a stopwatch, after a little while, it may not be perfect on the time; maybe it will be 3 minutes ahead. The problem is that when you use a tool with a similar propensity in the body, those small changes or errors on the part of the pressure wire can significantly impact decision making, because the iFR cut point of 0.89 is so close to being normal at 1.0. That loss of measurement accuracy is called drift. A third problem comes if you want to obtain a post-PCI physiologic measurement after putting in a stent. Getting the pressure wire back in becomes much more difficult. It has already been used in the artery, so it’s already banged up, and now there is metal in the way.

The OmniWire pressure guide wire (Philips) is a major step forward, because it is constructed and handles more like a workhorse wire, really more than any other available pressure guide wire on the market, and it has a minimal drift. For both pre and post PCI iFR measurement, the OmniWire has been a major improvement. It performs very similar to a workhorse wire, which means the OmniWire can actually be used as your primary wire. Not so long ago, we used to put the wire down and only expect a simple answer: “Is there ischemia or not?” We then would fix the problem with a regular guidewire, based on the angiogram. We are now asking our physiology to do more.

Can you share a case example?

Dr. Jeremias: If you look at Figure 1, it shows overall abnormal distal iFR with severe left anterior descending (LAD) coronary artery disease. The iFR pullback also revealed severe left main disease that is angiographically occult. The traditional methodology would be to put your wire down and check the iFR. Obviously, here it is abnormal. You would then remove the wire, put your normal workhorse wire down, and fix whatever blockages you think angiographically are most critical. We did a pressure wire pullback through all of these lesions and as you can see, there is often a mismatch between the angiogram and the pressure gradient. An iFR pullback also allows you to identify diffuse disease (Figure 2). Perhaps there is no focal lesion, but the pressure drops throughout the vessel. Maybe those patients don’t do well with stents and maybe we have to treat them with bypass or something else. This scenario would be in contrast to a pullback showing a big, sharp step up, where you know that if you put a stent there, you will have a huge benefit. Doing an iFR pullback identifies the physiologic impact of the distribution pattern of atherosclerosis in a particular vessel. We have a road map so we know where the lesions are. It is not adding a lot of time, but it adds accuracy to the procedure. With a better wire like the OmniWire, it is made a hundred times easier. You do lose your wire position by doing the pullback, so you have to readvance it. Going through a tight lesion with a bad wire three times is not great, and so you want to have better equipment. iFR Co-registration allows us to plan the procedure on the angiogram. It shows you the pullback pressure drops with yellow dots and also displays the pressure gradients directly onto the angiogram. You can also use the virtual stenting tool to draw a line to figure out the impact of stenting: “If I use a 38 millimeter stent, then I can improve the iFR by 16 units.” You can add the 16 units to the iFR measurement, and it estimates what your iFR measurement will be after the procedure. iFR Co-registration allows you to plan out the whole procedure ahead of time and then do a guided PCI.

Dr. Ali:  Using the OmniWire with iFR Co-registration is a lot different than putting a pressure wire down the vessel and making a FFR measurement. The best way to put it is that we used to use physiology to determine whether to treat. Now we use physiology to determine how to treat.

You have described the OmniWire as similar to a workhorse wire. Can you talk more about the wire handling?

Dr. Jeremias:  A solid core wire allows you to torque the wire with an almost 1-to-1 translation. Pressure wires, on the other hand, typically have electrical cables running through the wire to the pressure sensor in the distal wire. As a result, traditional hypotube style pressure wires limit core diameter, consequently limiting torque transmission. The technology hasn’t significantly improved in 20 years.

OmniWire’s solid core design is a gamechanger for pressure wire technology.

It sounds like the time added to the procedure is minimal.

Dr. Jeremias: It is literally 15 seconds to do the pullback, and then another maybe 10 seconds to complete the iFR Co-registration.

Dr. Ali: We expect times to become even shorter as the entire culture surrounding this technology adapts. We will move from the expectation of a difficult-to-navigate pressure wire to the use of a pressure wire to perform the entire intervention. Getting this physiology wire to a workhorse level means the time that you can use it just like a workhorse. You need to wire the artery to deliver the balloons and stents, you can do that on OmniWire, and because the OmniWire has very little drift, you can do the post PCI physiology on the same wire, with minimal impact on workflow. The time added is really to turn on the device. In this regard, I think both Allen and I would give tremendous credit to Philips, who has focused on making this technology truly plug-and-play as much as possible in comparison to the other industry leaders. It can be integrated into clinical practice with a minimal disruption in workflow. As a pressure guidewire that handles much closer to a workhorse wire, we can ask the OmniWire to guide the entire PCI, which will be the strategy in DEFINE GPS.

What is the connection between DEFINE PCI and DEFINE GPS?

Dr. Jeremias: DEFINE PCI determined that the angiogram alone is suboptimal, that invasive physiology can overcome its major limitations by pinpointing the most important narrowing, and also, the optimal iFR post procedure. DEFINE GPS (Distal Evaluation of Functional Performance with Intravascular Sensors to Assess the Narrowing Effect: Guided Physiologic Stenting) will be a large-scale, prospective, randomized, controlled trial of 3000+ patients at nearly 100 sites worldwide which tests whether these findings improve patient outcomes in a head-to-head randomization. We are going to test the hypothesis that doing the iFR pullback, planning the procedure, and aiming for a post-PCI iFR of 0.95 or greater will result in better outcomes than just a standard angiographically-guided strategy. The DEFINE GPS trial will also assess the clinical effectiveness of iFR Co-registration guidance to minimize post-PCI ischemia in patients.

Dr. Ali: What the angiogram is missing, which is considerable, is what the pressure wire pullback will pick up: lesions essentially hiding in plain sight that could potentially impact the patient’s long-term outcome. The goal of DEFINE GPS is to see whether an iFR pullback and aiming for a post-PCI iFR measurement of 0.95 or greater truly does improve outcomes, as was suggested in DEFINE PCI.

How would imaging modalities like intravascular ultrasound (IVUS) interact with the use of iFR and iFR Co-registration?

Dr. Ali:  They are complementary technologies. One of the downsides to this technology is that you cannot look at the plaque morphology. It is telling you whether or not there is a physiological change at any site within the coronary artery. Evaluating something like vulnerable plaque would still involve imaging. Ideally, we would say that a combination of imaging and physiology-guided PCI allows you to optimally treat. First of all, treat the lesions that need to be treated. Place the stent in the appropriate position, optimize that stent, and finally, make sure that you have done a good job. We are trying to move towards the concept that these technologies are not mutually exclusive. In fact, quite the opposite — they are synergistic.

This article is supported by Philips.

Dr. Ali can be contacted at zali@crf.org

Dr. Jeremias can be contacted at allen.jeremias@chsli.org

Drs. Ziad Ali and Allen Jeremias have a consulting arrangement with Philips.

More information on DEFINE PCI can be found on the Philips website.

References
  1. Jeremias A, Davies JE, Maehara A, Matsumura M, Schneider J, Tang K, Talwar S, Marques K, Shammas NW, Gruberg L, Seto A, Samady H, Sharp A, Ali ZA, Mintz G, Patel M, Stone GW. Blinded physiological assessment of residual ischemia after successful angiographic percutaneous coronary intervention: the DEFINE PCI study. JACC Cardiovasc Interv. 2019 Oct 28;12(20):1991-2001. doi: 10.1016/j.jcin.2019.05.054.
  2. Li SJ, Ge Z, Kan J, et al. Cutoff value and long-term prediction of clinical events by FFR measured immediately after implantation of a drug-eluting stent in patients with coronary artery disease: 1- to 3-year results from the DKCRUSH VII registry study. JACC Cardiovasc Interv. 2017 May 22; 10(10): 986-995. doi: 10.1016/j.jcin.2017.02.012
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