Multi-Jurisdictional CAC Meeting - Coronary Intravascular Lithotripsy (IVL) - August 20, 2025 - JE Part B

Dr. Gina Mullen:

Hi, everyone. Good afternoon. My name is Gina Mullen. It's nice to meet you all or see you all virtually. We know your schedules are full, so thank you for taking time today to attend our Evidentiary CAC Meeting, discussing coronary intravascular lithotripsy. Our goal today is simple. We want to hear the expertise from our esteemed subject-matter experts and examine the evidence together.

Dr. Meredith Loveless:

Good afternoon, Dr. Mullen. Thank you for being here. We're excited for a panel that represents a variety of different practice settings, academic and private practice, as well as a representation geographically from across the country. We do ask that we keep the comments concise and evidence anchored, and when possible, to please reference specific trials, registries or guidelines. And if you disagree with the expert who's presenting, that's fine. We just ask that you share your rationale and the data that informs your view.

Dr. Gina Mullen:

Yep. And a few quick housekeeping notes. This session is recorded. Please avoid sharing any patient identifying information. The raise hand feature is available for SMEs. This is not an open meeting, so only the speakers on the recorded line will be able to speak, as well as the contract medical directors asking questions. When answering a question, please state your name for the record.

Dr. Meredith Loveless:

And if you've had any changes to your conflicts of interest since your disclosure, please state that before your first comment. We are aiming for about five minutes for the initial response, so we can cover all of the questions today. We may gently try to keep this on track. We do understand that some questions may take a little more time and others less time, and we do look forward to it there at the session, but we want to hear from everyone.

Dr. Gina Mullen:

Yes. So how we'll run today each question has an assigned moderator and suggested SMEs to take this call. Other SMEs, and SMEs stands for subject-matter experts, are welcome to add brief reactions or comments. Our objective today is to review and critically evaluate the literature on cardiac intravascular lithotripsy, what it demonstrates and where uncertainties remain, so we can clearly articulate definitions, patient and lesion selection, technique, outcomes, safety, and how IVL appropriately fits relative to other calcium modification strategies.

Dr. Meredith Loveless:

And with that, thank you for your time and candor. Let's briefly review today's agenda and move directly to question one.

Dr. Gina Mullen:

All right. So, we want to recognize the medical - the Medicare Administrative Contractors joining us today and thank them for moderating and contributing to the discussion. We have National Government Services, CGS administrators, Palmetto GBA, Noridian Healthcare Solutions, Wisconsin Physicians Service Insurance Corporation, Novitas Solutions, and First Coast Service Options. And while Novitas Solutions and First Coast Service Options are represented today, they are unable to read questions during the meeting today.

Our SMEs, Subject Matter Experts, contributing today are Dr. James Blankenship, Professor of Medicine, Director of Cardiac Catheterization Laboratory, and Director of Division of Cardiology at University of New Mexico - Albuquerque, New Mexico, with training in internal medicine, interventional cardiology, cardiovascular diseases, and nuclear cardiology. He had no conflicts of interest to disclose.

The next is Dr. Abdul Hafiz. He is a tenured Associate Professor for Internal Medicine, Director of SIU, Advanced Structural Heart Disease Program, Associate Program Director of the Cardiology Fellowship Program at Southern Illinois University School of Medicine in Springfield, Illinois. He has training in internal medicine, cardiology, interventional cardiology, and structural heart disease. Conflicts of interest that was disclosed is that Shockwave will fund an unrelated clinical trial in the future, and he was a past three-core medical consultant.

Dr. Korpas is next. He is an Interventional Cardiologist at Pioneer Heart Institute in Lincoln, Nebraska, with training in internal medicine and interventional cardiology, with no conflicts of interest to disclose. Dr. David Winchester is a tenured Professor of Medicine at University of Florida College of Medicine and Senior Medical Advisor for Veterans Health Administration, Office of Integrated Veterans Care. He has training in internal medicine, interventional cardiology, cardiovascular diseases, nuclear cardiology, cardiovascular computed tomography, and echocardiography. He had no conflicts to disclose.

Dr. Meredith Loveless:

Can you hear me now? You are not loud.

Dr. Gina Mullen:

Yes.

Dr. Meredith Loveless:

Okay. Dr. Barry Bertolet, Interventional Cardiologist, Director of the Chest Pain Evaluation Unit and Staff Cardiologist at North Mississippi Medical Center in Tupelo, Mississippi, trained in internal medicine, interventional cardiology, cardiovascular disease, endovascular and vascular medicine, congestive heart failure, and transplant trained, and is on the Speaker Bureau in the past for Shockwave. And are you getting enough audio?

Dr. Gina Mullen:

A little bit, yes.

Dr. Meredith Loveless:

Okay. Well, I will get back to you, and I'll try to fix my audio.

Dr. Gina Mullen:

Okay. No problem. So, I think she just read Dr. Bertolet, Dr. Edward Tuohy is an attending physician at Bridge port Hospital in Bridgeport, Connecticut, Milford Hospital in Milford, Connecticut, and Danbury Hospital in Danbury, Connecticut. He has training in internal medicine, interventional cardiology, and endovascular intervention, cardiovascular diseases, nuclear cardiology, as well as adult comprehensive echocardiography, you know. I'm so sorry. No conflicts of interest to disclose.

Dr. Tanveer Raab is a Professor of Medicine of interventional cardiology in the division of cardiology and eminent physician for department of medicine at Emory University School of Medicine. He's also the Section Chief of Cardiology and Director of interventional cardiology and cardiac catheterization laboratory at Emory Decatur Hospital, as well as a Master Interventionalist of Society of Cardiovascular Angiography and Intervention. His training includes internal medicine, interventional cardiology, cardiovascular diseases, and he is a registered physician in vascular interpretation for the American Registry for Diagnostic Medical Sonography. He has no conflicts of interest to disclose. So, we will start with question number one and turn the floor over to Dr. Moynihan.

Dr. Eileen Moynihan:

Hi, everybody. Eileen Moynihan for Noridian Healthcare Solutions. This question is for Dr. Bertolet. Does the evidence demonstrate that intravascular lithotripsy is effective for the treatment of severely calcified coronary vessels? And is there evidence for use in moderately severe calcified coronary vessels?

Dr. Barry Bertolet:

Yes. Thank you for the opportunity to address tonight - today. So, the short answer is, yes. There is nice evidence. This has been demonstrated in a series of trials called the Disrupt trials. The first Disrupt I trial was a smaller trial looking at 60 patients in the United States and Europe that were treated with IVL. There was a device success rate of 95.5% with a very low risk of any kind of complication. So, freedom from any kind of complication was 95%. And in this initial trial, it showed that the mechanism of action was actually fracturing of the calcified plaque as the primary mechanism of action.

In the Disrupt II, this was a post-market study that was done with real world population in the United States and Europe. This was 120 patients. So, 94% of these patients were judged to have severe calcification, meaning that six had moderate calcification. And then IVL delivery success for a treatment was 100% here with reduction of the stenosis that was being treated down to 8% after the IVL. And again, a very high freedom from any kind of complication.

Disrupt III was the pivotal trial in the United States, and this was 431 patients. This was performed in the United States and in Europe. And with this, again, there was a high success rate at 92.4% in delivering the device. When we looked at OCT imaging in a large number of these patients, we saw that fractures were demonstrated in 67%. So again, softening up this calcified plaque.

And importantly, when we looked at these patients, looking at the ability to expand the stent completely, which I believe is a good mark of success, that the stent expansion was 101% of the stent size. So, pretty phenomenal there. And again, we see that it was a low complication rate. And then finally, when we go outside the United States, there was the Disrupt CAD IV study that was done primarily in Japan. And then this showed very favorable results as compared to what we got from Europeans than in the United States in the CAD I, CAD II, and CAD III studies.

These results are summarized in Table 3 of Reference 4 in your packet, and it shows very good consistency amongst the different clinical trials looking at an experimental and real-world population and looking at different populations of people, whether they be from Europe, from North America, or from, maybe, in Asia. Now - and this is my own opinion. I looked at the ORBIT II study, and the study designed for the CAD III was quite similar to ORBIT.

And in this, when we look at it, we see that there were similar outcomes with perhaps less enigmatic kind of issues that we see. Now, one of the nice things that we did learn from the Disrupt CAD III study is that there was a run-in population that was looked at. And when we looked at this, we found that the patients that did their first several procedures basically did not have a learning curve. And so, their outcomes at procedure 1, 2, and 3 was the same as it was at 11, 12, and 13. And that's important because it tells us that this technology is intuitive.

And then, when we looked at the CAD III post-market approval study, we actually found that when we opened this up to a real-world population that we got better, if not equal, results in a somewhat safer population and a sicker population. And I say sicker because it looks like the calcium in the lesions was a bit more complex, as well as the lesions were a bit more stenotic. And then, finally, there is a nice reference from Dr. Moussa, who looked at IVL versus rotablator, and so another technology to treat calcified arteries. And he found that there were trends toward maybe better outcomes, lower complication rates. But what was significant is that there was shorter fluoroscopy time. And so, that means that there was less time spent in the cath lab in order to achieve a good outcome from this.

And so, in summary, from the severe, we do see that there was exceptional procedural success anywhere from 90% to 100%. Very favorable stent profile with a very low risk of perforation, which is contrary to what we may do with athrectomy. And there seems to be durable results. We have followed in the CAD III patients out now beyond two years with durable results. And then, the final question for that is, "what about in moderately severe calcification?" And that has been looked at specifically in a reference that we will add later. This was for Aksoy. This was in Circulation Cardiovascular Interventions, Volume 12, Issue 11 in November of 2011.

And he looked at a population of patients that had both moderate and severe calcification treated with IVL. And what he found here is that IVL was very feasible. It was safe in treating these patients that had both moderate and severe calcification. So, it was a useful tool in that population of patients as well. And so, while there's not as much data with the moderately calcified, there is some that is in the literature that would support its use in moderately calcified vessels.

Dr. Gina Mullen:

Thank you.

Dr. Barry Bertolet:

I will be happy to answer questions. Thank you.

Dr. Gina Mullen:

Thank you so much. Are there any responses to that? I'm sorry, Eileen. I was trying to do a one-minute warning, and then, kind of, it was like playing double dutch. So, I'll be a little better next time. And - but - yes, any - if any of you want to comment on that, I will unmute. Thank you.

Dr. Eileen Moynihan:

I think Dr. Bertolet was very complete. Thank you. Should we move on hearing no other comments?

Dr. Gina Mullen:

Yes.

Dr. Eileen Moynihan:

Dr. Tuohy, how do we classify the severity of the plaque that is moderate or severe in an objective way? For example, we've seen calcium angles, plaque without motion. What definitions should be used? And does it make a difference in the outcomes?

Dr. Edward Tuohy:

Yes. Hi. Thank you for allowing me to participate in the forum today. And I appreciate the question. I'll try to be brief. Typically, we look at calcification where a moderate level is developed by an angle or an arc of calcium within the vessel of less than 270 degrees and a length of less than 5 millimeters, an absence of nodular calcification, and not an extensive amount of circumferential involvement.

And severe calcification would be a progression of that, where the arc is greater than 270 degrees, often 360 degrees, circumferential calcium, and a length greater than 5 millimeters, so extensive areas of restrictive calcification. Presence of calcified nodules, which is another separate indicator where it's not circumferential in terms of the arc, but a large nodule compressing the artery and reducing your ability to expand stents as present. And smaller vessel diameters as well, certainly I think vessels that are less than 3-1/2 millimeters.

And we've focused the literature in terms of those types of lesions, because the calcium arc in there - if the calcium arc is greater than 270, and there's 360 degree calcification - nodular calcification, or small vessels, those are vessels that are at high risk of stent under-expansion. And in all of the studies - and Dr. Bertolet did a great job of going over all of that disrupt data, but that's been the corollary to inappropriate stent expansion and negative outcomes. So, those are the definitions that I believe are relatively uniform throughout the literature with the moderate degrees of calcification being able to be treated with non-compliant balloons or a cutting balloon, with more moderate to severe calcification requiring treatment with either lithotripsy or rotational athrectomy. Thank you.

Dr. Eileen Moynihan:

Do any of the other speakers have any additional comments?

Dr. Tanveer Rab:

Hi. This is Tanveer. Thank you, Dr. Tuohy. I did add two references for you all, because what Dr. Tuohy has described was described by Fugino in your intervention 2018, that it stated an OCT-based calcium scoring system, and also an article by Shockwave in CERC interventions from 2020 regarding intravascular image-guided PCI and a universal approach for optimization stent application. Both of these articles are important in supporting the question number two. So, I think Dr. Mullen, I think will give those references to you.

Dr. Gina Mullen:

Thank you, Dr. Rab.

Dr. Eileen Moynihan:

Thank you, Dr. Rab.

Dr. Eileen Moynihan:

Anyone else?

Dr. Denes Korpas:

It's Denes Korpas. Can you hear me. Hello?

Dr. Edward Tuohy:

Yes, we hear you.

Dr. Eileen Moynihan:

Yes. We can hear you.

Dr. Denes Korpas:

Yes. I'm sorry. So, I just want to add that, you know, you guys, I mean, nicely kind of described the calcium here, but most of these descriptions are based on intravascular imaging, OCT and IVUS. And I think in most labs, you know, typically don't do that routine-based, especially, you know, outside trial settings. So - and the definition of severe calcification in geographic imaging is typically it's a calcium that's encompassed both cells vessel and you can see that without cardiac motion. So, that's typically, you know, in the literature is also classified as severe calcium. Moderate is typically a calcium that you can see with cardiac motion. So, just to add on, you know, if you don't have intravascular imaging techniques, those are definitions just, you know, based on fluoroscopy.

Dr. Eileen Moynihan:

So, would they all come out to be similar measurements? Because if you have a bunch of studies and this is all measured in a different way, does that all mean the same thing to you?

Dr. Tanveer Rab:

Let me answer that because I think for guidelines, they're encouraging class one recommendations for these complex procedures, which for the most part should not be done in a bread and butter hospital. Remember, calcification can be on the surface of the artery and still be severe within the artery. But I think we're going to do a procedure for stent optimization. You do need imaging. And I think the current definition of standard care really based on IVUS and OCT imaging to define what has already been described by Dr. Tuohy. So, I think - yes. I mean, that a lot of people have calcium on their coronaries, if you look at it, just to make sure about fluoroscopy. That alone does not measure to the depth of what we want to do with complex PCI using any kind of athrectomy and maybe IVL.

Dr. Denise Nachodsky:

Thank you so much, Dr. Rab. Hi. This is Denise Nachodsky from WPS. So, therefore, what would you prefer as, do you think it's more of the gold standard that we should be using? There's multiple articles that might be using IVUS, some use OCT, and then some others have suggested non-imaging. So, as we are trying to find what is the best for us, what might be guideline that you suggest?

Dr. Tanveer Rab:

Dr. Tuohy, do you want to answer or do you want me to answer that, please?

Dr. Edward Tuohy:

I mean, I can - I think I can field it. I think the availability of high-definition IVUS and OCT is relatively prevalent throughout more of the labs that are doing higher risk cases and using this technology. And I think we have - I've seen - we have high-definition IVUS in our lab. We don't have OCT. Yale, the mothership has OCT available, but they don't use it all the time for this.

If you look at all of the literature that was attached to the packet, there's a variance in whether you're using IVL and OCT, and both of them are using artificial intelligence-enhanced analyses. And I think it should just be standard that intracardiac imaging is used, whatever technology that you have in association with these procedures, because I think it correlates with better outcomes, and it definitely correlates with more appropriate use of the devices.

Dr. Denise Nachodsky:

Thank you so much for that. The buzzword of the intracardiac imaging is very helpful, I think, for us.

Dr. Edward Tuohy:

Of course. Thank you.

Dr. Gina Mullen:

And Dr. Moynihan, can you see that Dr. Bertolet and Dr. Rab have their hands up? I'm going to defer to you. I just wanted to - I didn't know if you could see their hands up.

Dr. Eileen Moynihan:

No, I can't see them. Sorry.

Dr. Gina Mullen:

You can't? Okay, no problem. I'm happy to let you know. But Dr. Bertolet is off mute if he wants to go in the next Dr. Rab?

Dr. Barry Bertolet:

Yes. Thank you very much. I don't disagree with my colleagues and what they've said there. I think we do want to be careful at mandating that IVUS needs to be used prior to IVL, because it may be that if we are using ultrasound or we're using OCT is that it may not be necessary to determine it's a severely calcified vessel in every case, and I'd hate to see that we mandate that as a precursor procedures. I do think it's useful in the optimization of the post-procedure, but just that definition of calcification, I would lean toward what Dr. Korpas said earlier.

Dr. Tanveer Rab:

So, what I would like to say is that, you know, for 20 years, we have stayed behind what intravascular imaging adds, but the good news is that from 20% activity, we've gone up to close to 65% or 70% in this country, putting us again in more complicated cases. So, IV imaging is - has increased, and there are algorithms like M-O-D Max OCT and a similar algorithm for IVUS that helps guide your therapy. So, I think we need to look forward that imaging is here to stay and is going to continue on, because guidelines have given us last minute indications that it's here in Europe and I think that will be the path we take in defining all this in therapy.

Dr. Denes Korpas:

I agree with that. And then it's Dr. Korpas, however, if you're looking at the safety of the procedure and the future of maybe moving this into a ASC setting, I think a lot of those centers will not have imaging - intravascular imaging. So, I think I would also be cautious and careful to tie this definition only to intravascular imaging. So, I think, you know, as IVL will hopefully penetrate, you know, with faith and into everyday practice, I think it's unrealistic to really say that you don't have to IVUS and OCT every lesion. And then the definition from fluoroscopy in a private practice clinical setting, outpatient setting still can be valid.

Dr. Eileen Moynihan:

Hey, Gina, do you see anybody else?

Dr. Gina Mullen:

I don't, thank you.

Dr. Eileen Moynihan:

All right. I think we can move on at this point. Thank you, everyone, for your responses. This one is for Dr. Blankenship. What's the best success measurement for this procedure, as it does not seem to be measured consistently in literature? We see flow pressure across the width of the stent, residual diameter, stenosis less than 50% or less than 30% or less than 20%. Can you comment?

Dr. James Blankenship:

Well, thanks for the question. It's an interesting question. Generally, in interventional cardiology, criteria for a successful procedure are lack of complications during the procedure. By that, I mean things like perforation and severe dissection, and a final residual stenosis, which is less than - and then you fill in the blank with a percent. So, it's fairly easy to define when you see a perforation, when you see a severe dissection.

The question here seems to get to the question of physiology. In other words, do you need a measure such as a fractional flow reserve to judge success? And I think the answer to that is clearly no. In terms of flow, we generally would say that normal flow, which would be in the language TIMI Grade 3 flow would be a prerequisite, although acknowledging in some cases you get slow flow or no flow. But in general, TIMI Class 3 would be a prerequisite.

And then the - probably the key question here is what would be the acceptable residual diameter? I think usually the stent's less than 10% residual instant compared to the adjacent normal arterial wall would be a criteria for kind of normal stenting. I think given the fact that we are dealing with a particular situation with severe calcification, it's more appropriate to loosen that up a little bit. So, I think 20% to 30% would be an appropriate criterion.

Dr. Eileen Moynihan:

I lost my microphone there for a second. Does anyone - Thank you. Does anyone have anything to add? All right. Then I think I will turn it over to the next CMD.

Dr. Jennifer Abrams:

Good afternoon, everybody. I'm Jennifer Abrams. I am one of the CMDs from Palmetto GBA. Thank you for being here today. My first question will be to Dr. Winchester, and it is a subject that we have already started to touch upon, but perhaps you can expand a little bit more on what the best methods are to evaluate a lesion prior to needing IVL. For example, FFR, CT, invasive, optical coherence tomography, the OCT, or intravascular ultrasound. These are all measured by different techniques in the different articles that we've seen, and do the different techniques utilized - do they make a difference in the results that we're seeing?

Dr. David Winchester:

Thanks very much. This is David Winchester. I'm just going to summarize a couple of the definitions that were used in the studies. In the Disrupt CAD studies, the methods described lesions that needed to be severely - "severely calcified de novo lesions of less than 32 millimeters to 40 millimeters in length and with at least 50% to 70% stenosis."

Looking deeper into the supplemental materials for those studies, it was further defined as, "Evidence of calcification at the lesion site by A, angiography with fluoroscopic radio opacity is noted without cardiac motion prior to contrast injection involving both sides of the arterial wall, and in at least one location and total length of calcium of at least 15 millimeters extending partially into the target lesion, or by B, IVUS or OCT with presence of greater than 270 degrees of calcium on at least one cross-section."

Then from the BENELUX IVL registry, we have the following definition. Intravascular ultrasound score 360 degree calcification, calcium extending over 270 degrees, measuring at least 5 millimeters in length, detection of a calcified nodule or vessel diameter less than 3-1/2 millimeters, or OCT score two points for a maximum angle greater than 180, and one point for a maximum thickness greater than 0.5, one point for a length greater than 5 millimeters.

If intravascular imaging was not available, severity of calcification was assessed angiographically. Radiopaque density is visible without cardiac motion before contrast injection affecting both sides of the coronary artery wall or considered a hallmark of severe calcification. So, in summary and in my assessment, while the trials did use several techniques, I think that they had fairly consistent definitions between them. I think more importantly as it relates to outcomes, I could not find where the trials broke out the results based on the different techniques that were applied. And in my opinion, I do not think that the different techniques would make much difference in terms of patient outcomes.

Dr. Jennifer Abrams:

Thank you very much. Are there any follow-up questions or comments before we move on?

Dr. Meredith Loveless:

Can you hear me?

Dr. Jennifer Abrams:

Yes, ma'am.

Dr. Meredith Loveless:

Okay. This is Dr. Loveless. Just I - if angiography underestimates the calcium in the coronary arteries, from what I understand up to 40% of the time, is there anything that should be - like should both IV ultrasound or OCT be done to help with patient selection and understanding which patients help predict which patients may have successful stent expansions before the procedure?

Dr. David Winchester:

Yes, I think you bring up an important question, although the problem, I think, at least in terms of the data as it was reported, is I didn't see where they broke out the difference between angiographically-based severe calcification versus some of the invasive imaging options. I do see that a couple of our other experts - at the outset I was - it was suggested I had interventional cardio - interventional training, and I don't. So, let me go ahead and pause here and defer to some of my other colleagues on the call who do have experience in the cath lab.

Dr. Gina Mullen:

Dr. Blankenship, and then Dr. Bertolet?

Dr. James Blankenship:

I think one point that is brought out by the question here, there's really two questions. One, is it appropriate to undertake an intervention on a procedure? And then the second question is, how to do it. And I think the suggestion that fractional flow reserve by CT or invasive techniques, that really gets to the question of should a procedure of any sort be done? And then the second question is, if you're going to do it, how do you decide what tools to use? And that's where the Optical coherence tomography and intravascular ultrasound come into play.

And they're useful in helping to determine whether, you know, what technique you use. And then a final criteria that I think hasn't been brought up yet is that if you guess wrong and you think that you don't need intravascular lithotripsy, you inflate a balloon and you can't get the lesion dilated with the balloon. In other words, you blow up the balloon and there's still a big dent in it where the calcium is. And that's an indication that you might need the intravascular lithotripsy.

Dr. Barry Bertolet:

Yes, I was just going to echo the exact same point that Dr. Blankenship just concluded with, is that if we do choose an alternative path, such as balloon angioplasty to begin with, and we see that there's initial failure that we always can go back to doing the IVL therapy. So, it's not like you have to pick up front. You can start with a balloon. If you get failure there, you could go to IVL.

Dr. James Blankenship:

And could I just add to that as I'm sure that Dr. Bertolet knows better than I, that, again, if you guess wrong and put a stent in and you can't fully dilate the stent, then even then you can deploy IVL. And that's been proven to be a very effective remediation when you can't get full stent expansion.

Dr. Jennifer Abrams:

Dr. Rab?

Dr. Tanveer Rab:

Yes. So, let me discuss the question. Let me just say that about CT, as a main measure of evaluation, that has not been studied at trials. Trials are ongoing. Agree with the future, and of the added reference. It was just published in JSCAI by the group from Minneapolis. It was part of what do you call it, 4F study, that Sandoval et all published it in JSCAI just this year. But it's not the standard yet, because it's still part of trials. And I think if you want any measurement, per se. Still probably the goal tends to be imaging and with OCT arrivals. The CT has not yet taken off, but probably will be available in the future, because more CT angiograms will be done, and people will need CT-guided TCI.

Dr. Jennifer Abrams:

Thank you very much, everyone. I appreciate it. If there are no other comments, I'll move on to my next question. My next question is going to be directed toward Dr. Hafiz. The evidence does not necessarily compare the same artery to the same artery. Are there any standards on which the arteries are appropriate for treatment based upon current evidence?

Dr. Abdul Hafiz:

I was muted. Can you guys hear me?

Dr. Jennifer Abrams:

Yes, sir.

Dr. Abdul Hafiz:

Thank you for the question. So, I'll break this down, but the short answer is probably no. But here's an explanation. So, at the risk of sounding very, very simplistic, and probably more common geared towards the non-cardiologists in the meeting, there are four main blood vessels in the heart. The left main on the left, the branch of two vessels, the LAD and the circumflex, and on the right side, the right coronary artery.

So, to rephrase the question, if there is any individual artery-to-artery outcome measures, the answer that I found is no, not necessarily. Are there any studies explaining if there are, per protocol, selective use of IVL in a particular vessel and how that affects the outcomes? Again, the answer is probably no. Do any studies break down the use of IVL in different vessels? Yes. Well, all - most studies do report the percentage of the different use frequencies in different vessels.

And in terms of the frequency, the LAD was the most common vessel, and the left main was the least common vessel. And the right coronary artery and the circumflex, depending on the study, they can go back and forth. Another way to answer this question is, are there any characteristics chosen to target the vessels, as the other speakers have spoken in great detail? Yes, there are, and some of my comments will be overlapping theirs. But the size of the vessel, the length of the coronary artery calcification, the length of the target lesion, the degree of the calcification, these are all characteristics which will define success in a particular vessel, and that's particularly the vessel itself.

So, the first one will be the size of the vessel. So, by definition, the technology uses a balloon sizing of one-to-one, unlike the other athrectomy devices, which are downsized. So, you have to pick an IVL catheter which is the appropriate size, and technology comes in 2.5 millimeter to 4 millimeter vessels. So, the target lesion in the vessel has to be in that range to be treated for the reference vessel diameter. And the lesion severity, as indicated by others, has to be at least 50% or more than 70%, depending on which trial you look at.

The length of the target lesion was chosen in the most prospective studies, including Disrupt studies. But many prospective studies left it to the operator, essentially. And there's a lot of heterogeneity in what studies are defined afterwards. The longer the lesion calcific zone, the less compliant we know the vessel will be in making delivery difficult. Therefore, when it was chosen what lesions to go after, there were different cutoffs that were chosen. For example, they varied from 10-millimeter to 15 millimeter, and a maximum of 32 millimeter to 40 millimeter. And the references are in my reference that were emailed, depending on the study.

So, there were several follow-up real-world studies that looked at this, and the criteria were not strictly met. Of note, to determine both the above criteria, intravascular imaging was done initially mostly with OCT, and later operators did not use OCT, and they used mostly IVUS. And the follow-up studies would have what we observed in the real world, and many labs don't have OCT. For example, even our lab does not have OCT, but we do use heavily intravascular ultrasound imaging.

Each - also, OCT one can add more contrast, and there are scenarios where you cannot use it. Moving on to calcification, calcification is, as the others have defined, there is a very specific criteria for calcium. You define severity, there's length, there is the arc of - angle of calcium, there's the depth of the calcium, and all those have been already - so I'll skip, because they've been defined.

So, in conclusion, IVL is performed and can be performed in any of the coronary artery with a baseline TIMI-3 flow, although it has been used in the CTO instances. IVL can be safely delivered to target lesion in a vessel that fits the device one-to-one sizing fashion, regardless of the proximal, mid, or the distal location, and a full analysis of Disrupt I to IV trials. It was heavily - highly effective in achieving residual stenosis less than 30% in 92.4% patients with in-hospital MACE of only 6.5%, which is pretty remarkable. And this MACE was mostly driven by non-QA microinfarction versus death or STEMI.

The target lesion failure was also less than 10% of 30 days, specifically 7.2%, and less than 1% stent thrombosis, which is also very remarkable. Studies have shown varying outcomes based on the baseline profile of the patient, such as the outcomes are generally worse if you use it in acute coronary syndrome versus stable angina, or if you use it in bifurcation situations, or if you use it as a bailout. But again, I'm not aware of individual artery-to-artery comparison. All four vessels have been targeted. All distal, proximal, or mid locations have been targeted. I have given references one to four, and my response via email.

Dr. Jennifer Abrams:

Thank you very much. Does anyone else have anything to add, or any follow-up questions?

Dr. Denes Korpas:

It's Dr. Korpas. The only thing I want to add that and this is beautiful presentation, but, you know, the IVL catheter or balloon that comes in different sizes, you know, it's kind of 2.5 and higher, and, you know, 4 is the highest number, so. And the vessels of less than 2.5, you know, currently cannot be treated with IVL.

Dr. Jennifer Abrams:

Thank you. Anyone else? Then I will move on to the next question, which is being directed to Dr. Korpas. Are there standards set on the techniques for current standard of care procedures, such as rotational or laser, athrectomy, cutting balloons, high-pressure balloons, et cetera? And do those standards affect the outcomes of these procedures?

Dr. Denes Korpas:

Sure. Thank you for that. But, you know, I don't have the video, since my Wi-Fi is not that great, so I'm just going to use the microphone. So, I would start with the traditional balloons, you know, high-pressure balloons, you know, so-called non-compliant balloons. You know, we use them every day. Obviously, you know, regular balloons have a burst pressure of lower atmospheres. These balloons, high-compliance balloons, cannot - can be up to 20 atmospheres before they burst. As a matter of fact, there are balloons that go up to 40. Typically, you know, we use this as first-line treatments, you know, to try to dilate harder lesions, such as calcified lesions.

Techniques are pretty much similar to regular balloon procedure delivery and inflation. Most of us would actually move on to something else if you see the balloon is not completely deployed. Cutting balloons and scoring balloons have come to the forefront few years ago. They are hard to deliver. Sometimes calcified lesions could be, you know, treated with that with some initial data showing that there's a better luminal cross-sectional area. However, the shortcomings of these balloons are mostly that they deliver them to a calcified lesion, even with body-wide techniques, a lot of techniques that are hard. So, if you look at the outcomes of these balloons and high-compliance balloons there have been no difference in several studies. So, I think, you know, these are first-line treatments, but also did not add significant amount of ease and positive outcomes to the procedures.

Rotational selecting of a rotablator has been approved since 1996. I would just go for the approval an indication, which was in lesions that can be crossed with a guide wire and calcified. We have been using this, you know, with good success. Most of us would go to a rotablation if the balloon cannot cross the lesions. That's the primary indication nowadays for a rotablator. They come in different sizes, 1.25 to up to 2. And as far as the question with regards to complications, there has been little correlation between size and operating experience with regards to complication. The bigger the burst size, the higher complication rate, such as perforation.

And the operating experience is obviously, is also a significant factor here. Fewer cases, more complications, as with many other procedures, more cases are less complications. So, I would say, as a standard rotablator would be used if the wire can cross the lesion, but the balloon cannot cross the lesion, or there's severe, heavy calcification. We'll talk about later in this presentation. Yes. No comment in use of rotablator and IVL.

Moving on to laser athrectomy, this doesn't mean a thing, you know, for better indication, typically in lesions that cannot be crossed, so this is actually a modality that can be used for lesions that cannot be crossed. Also, in acute myocardial infarction situation, and also under-expanded and instantly stenotic lesions, and also vein grafts that's approved. You know, the use of laser cannot be used less than 2.5 vessels as well, so there's a limitation there as well. I think I would speak for the community of cardiology and rheumatology that these laser procedures are not as common as they - initially we thought they would be. So, I would say that, typically, a laser is reserved to situations where there's an occlusion or stent problem, stent restenosis or expanded stent - on the expanded stent since this laser does significant amount of pressure that will facilitate stent expansion.

And just the last one, a quick comment on orbital athrectomy, which, you know, it typically was the same indication as IVL rotablator initially in the studies. However, if you look at the data, there's a higher rate of perforations, complications than rotablators, so this typically is not as favorably looked at as rotablation. And if you look at real- world data with a concomitant use of IVL, and - or athrectomy, typically a rotablator would be the choice with concomitant use.

Dr. Jennifer Abrams:

Thank you very much. Dr. Blankenship, you have something to add?

Dr. James Blankenship:

That was quite a comprehensive answer, and thank you for that. I'm trying to look at what the intent of the question is, maybe the question is, are there standards that should be set for the technique of intra-coronary lithotripsy? And when I try to think of, are there any standards that should be set for its use, I think it's probably nothing more than just noting that the recommended inflation pressure is four atmospheres and probably should not exceed that. I don't think there's any reason to under usual practices.

And then, of course, the - you want to get the device across the lesion, but I can't think of any other standards that I would want to set. I mean, there are certainly standards for other devices that are very important for their safe use, but I can't think of anything else for lithotripsy. Thank you.

Dr. Jennifer Abrams:

Thank you. Dr. Rab?

Dr. Tanveer Rab:

So, a little tangent to this, just about IVL, let me just let you know, there are four of the devices there, so that is the market is going to get better and better because the safety profile of IVL compared to other mechanical abstractive devices, such as rotablator or atherectomy. In terms of Shockwave, they have a device that does not have a balloon on it known as javelin, which appears to cross lesions a little better than the current balloons. This does not have a balloon on it, instead it just has a vibratory core at the end to create a passage similar to what rotablator is, especially clinical trials, here it's already had some approval in Europe, but the technology continues to evolve because there's safety in this device.

Dr. Jennifer Abrams:

Thanks for the comments.

Dr. Denes Korpas:

Yes. Thanks for the comment. I thought the question was, you know, other modalities except for IVL, that's why I didn't address the IVL. It looks like, you know, it was actually the current standard, which, you know, was other abstractive devices.

Dr. Meredith Loveless:

That's correct. Thank you.

Dr. Abdul Hafiz:

I just want to add a comment about the inflation pressure. According to IFU that I'm aware, after four atmospheres, they do want you to go to six atmospheres and then come down and no greater than six atmospheres, just an addendum to what was already said.

Dr. Jennifer Abrams:

Dr. Hafiz, did you have anything to say?

Dr. Gina Mullen:

Just as a housekeeping reminder, if you could just state your name before you speak, just so we have record of it, but thank you so much, Dr. Hafiz.

Dr. Denes Korpas:

Yes. You know, just a quick comment of just - of that, if you look at the current recommendation from the company, the studies did show that six atmosphere inflation, that's what the standard. Right now, they do not recommend necessarily that, you know, that post-inflation, so just go to four and then pause it and come down.

Dr. Jennifer Abrams:

Thank you, Dr. Korpas. Anyone else? If not, then I will pass the banner on to Dr. Nachodsky, who will be taking over.

Dr. Denise Nachodsky:

Thank you so much. I'm Denise Nachodsky, and I'm one of the CMDs at WPS. From the start, I just really would like to echo what my colleagues have said here, that thank you so very much for your time that you're taking from your busy schedules to provide your expert insight to this procedure, its safety, and its clinical utility compared to the current cardiac calcium debulking interventions. So, my question - actually my first question goes to Dr. Rab. Can you please define, and I know we're kind of getting the flavor of what we should be doing, but can you please define: A, the patient population; and B, the angiographic criteria for which lithotripsy would be the preferred procedure or alternative to the current procedures that we have available, such as rotational or laser athrectomy, the cutting balloons, the high-pressure balloons, et cetera for these heavily calcified lesions.

And when you explain that to us, could you please define it in context to these two points that are of concern to me? The Shockwave coronary lithotripsy system, which got approval, the PMA approval, was based on the DISRUPT CAD III trial, okay? And the approval of this device and the procedure is indicated for lithotripsy-enabled, low-pressure balloon dilatation, severely calcified, and a de novo lesion prior to stenting. That is what is required.

The PMA also has very detailed inclusion and exclusion criteria, such as the lesion site. It cannot be an osteolesion. You cannot have left main. It cannot be a total occluded lesion. The target vessel diameter cannot be - it has to be within 2.5 to 4.0 centimeters. The length is not to exceed 40 millimeters. And other criteria about the patient, such as the patient can't have Class 3 or 4 heart failure, cannot be on dialysis. The creatinine level cannot be elevated beyond 2.5. The EF has to be greater than 25% on these patients. So, with these very strict criteria, my concern in reading these articles is that the approval suggests that it's allowed on a much more low-risk patient population and a low-risk procedure compared to the other calcium debulking procedures that we have right now that are currently available.

And my second concern that I have is, in regards to the FDA supplemental approval for this device in 2022 said that they're going to increase the maximum pulse count from 180 to 120 when using lithotripsy. What literature or data supported in this supplemental version that need to increase from 80 to 120 bursts? Has this changed the outcome? Has this changed the safety profile in regards to this procedure? So, thank you.

Dr. Tanveer Rab:

Thank you very much. It's a very broad-based question. I think what we need to look at is, is this going to be regarding IVL? It should be not just focused to what you want to do today, but looking forward because IVL is here to stay. Now, all these criteria that are there, the issue that accompanies when it first came out and released to the market, of course, everybody wanted to be safe with it. But I think if you look at - let's answer each one at a time. So a patient population, I think all comers. I don't think no injection fractions necessary preclude lithotripsy because in terms of safety, the degree generated by rotational athrectomy or orbital athrectomy can actually stun the ventricle to the point that it decompensates the patient.

Whereas, you know, lithotripsy is just a balloon, you know, it just does not cause the dis-normalization of disruption of flow of dis-normalization like the other devices do. So, it's safer. In terms of calcified coronary lesions, yes, it is there for calcified coronary lesions, but I think most of us do not use any of the other devices including lithotripsy if they did not have a full arc of calcium, at least an arc of calcium based on imaging, which is more than 180 degrees. So, that is some of the criteria that should be used.

And the third thing that's not mentioned is most of us would do a balloon test that if a lesion did not yield to high pressure balloon inflation, but even a non-confined balloon, then there is indication of some kind of plaque modification, either by an inspecting procedure or lithotripsy. Now, a lot of these things were based, the indication is based on clinical trials, particularly Disrupt trials and trials out of Japan. But I think we have broadened that. This is device safety. I think - and these are coming off registries and other data, not listed trials. We have broadened the use because the device is safe. It does not cause perforations. It can be used in patients with low ejection fractions, does not cause dis-normalization.

In many instances, it's a first-line therapy of plaque modification now. And very commonly it is used also after rotational abstraction, but as I indicated before, the newer generation devices that are being developed, including one from Shockwave where they don't have a balloon on it, will allow passage of a device which is specifically thought to be balloon uncrossable. Okay. So, the ideal device is coming to balloon uncrossable lesions, and they are being developed and currently are in trial.

Now, in terms of use in left-main stenosis, including osteocyte branch, they're no longer exclusion because it's being used in registries right now all over the world to be used in that kind of setting. And it's safe. Now, the 120 pulse count, again, it's safe. Otherwise, the FDA would not have approved it. It's safe. It's used now for the - you know, previously we had a limited pulse count up to 60. Now, it's 120. Because they are resistant lesions that do not - that actually even after rotational abstraction or orbital abstraction or after high-pressure balloon, do not yield.

In particular, in the instance restenosis, where there's a calcified plaque outside the stent boundary, which is not getting modified, 120 pulse is quite reasonable to use to get that benefit. So, it is safe. So, I think that in terms of going back to your question, patient population outcome is no longer low in ejection fraction. And I think it is a reasonable alternative. And I think if devices get modified, it might be first-line therapy, putting in devices that would be crossable and those defined as balloon and crossable lesions. Thank you.

Dr. Denise Nachodsky:

I think, Dr. Bertolet, you may have an additional comment.

Dr. Barry Bertolet:

Yes. I wanted to address the comment about the exclusion criteria. And this was actually preset because when they designed DISRUPT CAD III, it was designed after ORBIT 2. So, it had to mirror, and the FDA sort of enforced this, it had to mirror the inclusion-exclusion criteria of ORBIT 2. And so, the criteria here that were - exclusion criteria in that DISRUPT III were not because of the catheter, would not - or this device wouldn't work there. It was because this was an FDA mandate.

And in fact, in many of these circumstances, this is the utility of the device. And so - and in fact my very first patient that I did was a patient that was on dialysis that had had frequent admissions into hospital and had heavily calcified coronary disease that was turned down for bypass surgery, not a candidate for other procedures, athrectomy procedures, because of the low ejection fraction. And we had to require impella support to do that. So again, this is the beauty of this catheter is that we're able to help people that present technology doesn't allow it. So, these exclusion criteria were only for the study in a scientific study, because of previous studies and are not directed at the catheter per se.

Dr. Denise Nachodsky:

Thank you so much. My follow-up to this, though, is - oh, I forgot my follow-up to this, you know guys, which is too interesting. The question that I have, though, kind of as a follow-up, though, is, where is it - do you have data or literature? I would just like to know, I mean, one of the results was - as I said is, it went from 80 to 120. And it's fine. It wouldn't have been otherwise allowed to go up to 120 if it wasn't safe. But why did we need to do that? Is there study - do you have literature that says, now using the 120, that the safety profile is okay, that there's not worse outcomes. And if you have any literature to send to us so that we can use it as a reference when we are writing policy.

Dr. Tanveer Rab:

(All) I think that most of these came from resistance using that are not - for instance - for example, that they're not yielding to traditional therapies, including abstracting devices or high-pressure balloon. And it was felt that if we had more pulses, we probably could get that effect. Rarely in de novo lesions do you have that kind of situation. But certainly very hard resistance lesions, at least, for instance, restenosis, it's felt that more pulses would give you the benefit because then you'd have to switch out the device to maybe a laser, even to take out the plaque behind the stent. For example, it just was felt that we kept this, you know, longer and gave more pulses, you could have a better benefit than one with laser. So, in terms of trials, and really no trials per se, but I think there's a lot of literature and anecdotal results and registries to suggest that there's a benefit. Okay.

Dr. Denes Korpas:

I would also add, you know, I agree with all that. I would add that this balloon length is only 12 millimeters. There's lesions that we're treating that are longer than 12 millimeters. So, I think the ability to give you more pulses, more pulses per - you know, per lesion, you will actually enable you to treat longer, you know, lesions and more calcified lesions. So, I would say that probably as a post-market cases were coming in, since we established safety of this procedure, I think, you know, by going up by, you know, like 40 more impulses, I think we're able to treat the more calcified, the nodular lesions and the longer lesions.

Dr. Tanveer Rab:

Thank you for pointing that out. I was going to say that. You could use that, you know, if there's longer lesions, you'd have to change out and put a fresh device in, which is very costly. And adding these pulses gives you an opportunity to do more areas rather than one focused area in longer lesions.

Dr. Meredith Loveless:

I think this has been a great discussion, but I'm going to encourage us to wrap it up to move to the next question so we can continue on, since we still have so many questions.

Dr. Denise Nachodsky:

Thank you. And for the two that still had their hand up, I think Dr. Blankenship as well as Dr. - I'm not sure who the other one was. If you just want to write in or give us your resources, it'd be greatly appreciated. My next question is, will lithotripsy be an alternative or an adjunct to the established current procedures at the same time as the initial procedure for these severely calcified stenotic lesions? And I guess some of you alluded to it. I have a question in regards to when you're in a cath lab and you're going to do your intervention, okay?

Do you change or combine other calcium debulking procedures? Will you use laser and a cutting balloon, et cetera? And if not, why would lithotripsy be an exception where we can use it as an adjunct to other current procedures? Because currently it's only that I've seen in the studies that were international, not the U.S., that lithotripsy could be an adjunct to the current procedures.

Dr. James Blankenship:

So, thank you for the question. And the answer is yes, both. And so, I think that we'll see this used, as you know, as a primary strategy in a lot of patients. And then we'll also see it as an adjunct or sort of bailout. And there may be different reasons why. So, let's talk about just from a primary adjunct. In the DISRUPT-CAD III study is that this was used as a primary modality in 384 of the 431 patients that were studied. And so, this can be used as an initial strategy for debulking or softening up the calcium there with, in the study, very proven good success, low complication rates, and then with no additional debulking needed in the majority of the cases.

This may be an advantage in several of the cases, particularly if we're talking about instant restenosis of a heavily calcified lesion, or perhaps even in bifurcation lesions, is that this may be a primary choice in lesion characteristics. Again, this may be used as an adjunct or a bailout in certain situations. Some of these were alluded to earlier. So, if we went in with a high-pressure balloon or if we did atherectomy, and we failed to get the stent the - I'm sorry, the vessel expansion that we needed in order to deploy a stent, is that using this as an adjunct would be helpful.

And then finally is that if we did place a stent in a calcified lesion, and we were not able to expand it appropriately, is that we could then follow with the shockwave balloon or the IVL balloon in order to assure good stent expansion, which means a better outcome for the patient in the long term. So, the short answer, again, to repeat that would be, I think we'll see it both. Primary strategy in many cases, but also as an adjunct strategy in those where we need it for failed other strategies. So, thank you.

Dr. Denise Nachodsky:

Thank you so much. Any follow-up from anyone else? I don't see hands up. So, for the sake of time, I'm going to go on to my last question. And this question is for Dr. Tuohy, as well as, I guess, Dr. Winchester. And you alluded to this multiple times, so for saving of time, just brief opinions if you can. Are there different considerations for treatment depending upon the location of the coronary artery calcification, that is, in which artery is affected? How does the IVL compare to CABG for left main calcification? And is there evidence to show that IVL is safe now for use in left main - considering it was not - that's not one of the inclusion criteria?

Dr. David Winchester:

Dr. Tuohy?

Dr. Edward Tuohy:

Yes. You want what do you want to do here?

Dr. David Winchester:

You can.

Dr. Edward Tuohy:

Okay. So, I mean, there are differences depending on the location of the coronary calcification between left main and, you know, the remainder. Each vessel has its own unique characteristics, and there's advantages over using IVL versus rotational atherectomy in the right coronary artery, for example, and not needing a pacemaker. The left main coronary artery has separate distinctions, whether it's a protected left main or an unprotected left main, having had previous coronary bypass grafting surgeries.

I was unaware of, you know, comparative data, or I couldn't glean out from the studies any comparative data of CABG versus left main disease per se, but a number of the studies went over left main disease use within the population that they studied, and some compared it to the others, and some just included it. So, I'll go over that very quickly. The DISRUPT series actually had very few left main cases. Only DISRUPT III had six left main cases, but it was safe and effective there. In the AXOI study, propensity scoring comparison of IVL versus noncompliant PTCA, they demonstrated there was an equivalent rate of MACE, whether you used intravascular list with tripsy or used noncompliant balloon angioplasty in those left main lesions, with a predominance of using NC balloons there.

In all of this study, there were 59 patients who had left main with 1-year follow-up, and they were compared to 450 non-left main patients, and similar procedural success with similar TBR, death, and MACE at 1 year were exhibited. IVUS study also, 1 year out, only 11 patients, which was 23% of the total study, but they demonstrated in that that there was utility and high risk in ACS patients, and those patients, as they evolved over time, had low MACE rates, despite being higher risk patients. That was redoubled in Wong's study, real-world IVL use in South Korea versus rotational atherectomy. Again, small numbers, 16 absolute patients getting IVL, but they had less no-reflow, less contrast use, less fluoroscopy use, and less incidence of piece of purple ACEs in the coronaries.

The Gupta's study showed safety and efficacy of IVL for nodular calcium, another area that we've touched on, but a unique advantage for Shockwave in that significant nodular calcium is present at the left main bifurcation, going into the LAD, ramus, and/or circumflex, and about a third of the patients in this study were left main bifurcation nodules, and there were zero deaths at 30 days with about just under 10% rate of cardiovascular death at 1 year in this high-risk population. The van Oort study showed in 454 patients over 5 years, of which 57 were left mains, that there was a low complication rate, under 1%.

The overall MACE at 1 year was 13%, and did not differ between the two groups. McInerney also looked at a small number of left main nodular calcium in significant numbers. Again, similar success and low MACE rates were seen as the DISRUPT III trial. And finally, Rola's study had 131 consecutive uses of IVL, again, about 20% of the cases in this were left main, so a low MACE rate. But overall, I think there's substantial evidence that using this in left main disease is safe, and, you know, we've added in these higher-risk patients over time, and been able to do patients who were surgical turndowns for coronary artery bypass grafting with protected PCI using Impella support and low-EF.

And we've actually been able to get away with cases, at least in our practice, of doing it in unprotected left mains with normal ventricular function and careful, judicious use of the pulses, and be able to do left main bifurcation angioplasty in those cases. David, add-on stuff? I hope I left some time.

Dr. David Winchester:

No. I think you covered it completely. I don't have anything to add.

Dr. Edward Tuohy:

Thanks.

Dr. Denise Nachodsky:

Thank you so much for that very thorough presentation with the list of all the studies to help us. Very much appreciated. I'm going to go on to my last question, which...

Dr. Edward Tuohy:

Thanks.

Dr. Denise Nachodsky:

will be for Dr. Hafiz. And this is more so just for long-term outcome data. Most of the studies that we have seen or read are really based upon you have data one year out, maybe for some out to 2 years, but it's - the numbers are so small in the study. So, is there long-term outcome data that you have seen in your practices where coronary lithotripsy is sufficient to support this procedure? And please apply on any of the long-term outcome data regarding the restenosis rates, the frequency that you might need a repeat cardiac intervention versus going to a CABG or MACE compared to the other current procedures that are calcium devolving procedures.

Dr. Abdul Hafiz:

Thanks for the question. In my research of this topic, I found the coronary IVL was approved by the FDA in February 2021. And that's from the time where most of the commercial use started getting used. And this is based on the DISRUPT trials. The pivotal trial to DISRUPT-CAD III, single-arm perspective multicenter trial, and had a primary safety endpoint of freedom from MACE at 30 days post-PCI with efficacy of having treating less than 50% visual stenosis. And this is similar to what others have said, similar to the ORBIT II trial for orbital atherectomy. The DISRUPT-CAD I trial wasn't done in the 2015-2016 era. So, we're looking at a very relatively recent technology and the grand scheme of things that we've done in the international cardiology world.

IVL is still considered relatively new, although there's about a decade of experience now with it. Most long-term data published in the literature is in the 1- to 2-year range from my research of this topic. And there have been significant changes in how IVL is practiced now compared to the initial DISRUPT trials, such as use of rotational atherectomy, RotaTripsy, i.e., what we call it, use of IVL in instant restenosis, which was not studied in initial trials. Sometimes a very low rate of intravascular imaging, or IVL used as a bailout instead of the upfront use of the trial technology itself. This was done either after stent was delivered and the stent was found to be under dilated, and this is what the real-world registries demonstrate.

To me, this data is slightly difficult to replicate and compare with various studies versus the initial DISRUPT studies. So, you cannot really make a one-to-one comparison. Also, the DISRUPT studies did not have a control arm, and this was based on what others have said, being based on other trials which preceded DISRUPT studies and developed prospective single-arm trials. With these caveats, data so far shows robust and durable safety and efficacy, the biggest advantage being its ease of use, as others have said, very similar to a basic work-in-intervention technique. So, you basically deliver a balloon over a wire and start doing your IVL and inflate the balloon target legion, requiring no significant training, compared with atherectomy devices such as rotational or orbital atherectomy or eczema laser, by which the supporting medical staff also needs to be trained.

And not only that, they need to maintain their competence, and not all labs can do these kind of interventions compared to IVL, which is much simpler. There is a European registry which tracked 273 patients from 2018 to 2021, despite the above-mentioned caveats and showed success of 99% at a median 2-year follow-up, approximately cardiac death of 5%, and MACE, major adverse cardiac events, of 11%, with a target legion reaching also 6%. The shorter follow-up, there was a Polish registry of 131 patients in NA-TVR under expended stents treated with IVL, showed at 6 months, the MACE rate was 7.9, and TLR was like legion revascularization with 3.8%. I'm not aware of CABG explicitly being a target for outcomes post-IVL, as by definition, it is mostly used for single legion vessel problems, and that was objective of the Disrupt I to IV trials.

And it's unusual for CABG to be done for a single legion failure, especially after, given the lower incidence of left-main IVL in these trials, now for which CABG would be the upfront strategy. So, CABG preexisted in about 9% of the population of the Disrupt III trials. Multi-vessel CAD was not the target population they were studying, especially given the SYNTAX score, which determines the overall burden of the coronary disease, and the score ranged from 15, 20, 22, and 23, which is in the low-to-intermediate range, by definition, and favors non-multi-vessel PCI treatment rather than CABG.

In acute coronary syndrome patients with IVL, it was used - IVL was used as bailout or courtesy, you know, Polish registry of 15 patients. Every SYNTAX score was just about 20, and MACE rate was 13 at 6 months. Follow-up with any revascularization for this particular population was 33%, with a target legion failure of 6.7% in this high-risk population, which is different from what the Disrupt trials have studied. Despite these high-risk cases, the 6-month MACE rates were remarkably low overall and very comparable across different trials. Even when PCI with IVL is done in unprotected left-main, in a majority-stable angina, and in STEMI population, hematurin after revascularization at 1 year unspecified by PCI or CABG, you could do both, was only 6.8%, while cumulative MACE was in the 10% range, and death was only 4%.

Studies comparing head-to-head different coronary decalcification modalities are rare, again, to my knowledge. Only comparisons are based on historical cohorts of the registry data. There is a study group from Netherlands that compared rotational atherectomy to IVL and recorded 6-month follow-up in balloon-crossable legions that were heavily calcified. By definition, you cannot deliver IVL if it's not balloon-crossable. It found no statistically significant difference in procedural success. 82% was 92% in 6 months, and the MACE was 12% versus 6% on similar outcomes. Even though numerically IVL favored, but in the study sample of 101 patients, IVL had a significant lower fluoroscopy time as it was mentioned earlier by the speaker, which holds up to the ease-of-use case scenario that has been described and a shorter learning curve for IVL compared to other traditional atherectomy devices.

The OCT subset of the sub-trials that showed that calcium modification is circumferential. It's unaffected by viral bias, unlike rotational or orbital atherectomy. Although the IVL compared to all other CAC modification devices, including scoring balloons, affects deep wall calcium, which is very different from other modalities, and this avoids severe trauma that happens. It also avoids heat generation. It is little to no surprise that the DISRUPT trials consistently, all of them, show very low incidence of target lesion. Overflow, slow flow, perforation are serious. Top of the section had D to F. I'm finishing my little monologue here.

A different, ever-suspective study mentioned about comparing IVL versus rotational atherectomy in less male population, again, found no difference in cumulative one-year MACE, which was the FMI revascularization, which is driven by ischemia. A group for Emory mentioned, by the way, I'm speaking for Emory here, reported findings from a 50-patient retrospective study comparing IVL versus rotational atherectomy in less male calcific disease, and more than half of them had bifurcation lesions, reported significantly higher technical success without MACE in IVL versus rotational atherectomy, 98% versus 86%. This was statistically significant, but lower procedural complication with the IVL group. A recent study comparing IVL and rotational atherectomy in CTOs from a multi-center registry showed no significant difference between the technical success, procedural success, MACE.

However, there were more perforations in the rotational atherectomy, 9.5% versus 3.2%, and this was highly statistically significant, besides lower procedure time, and so on and so forth. So, similar themes observed in other studies. There was a study from Singapore which showed similar findings. So, in conclusion, number 1, long-term data is limited to only 30 days, 16 months, 6 months, and 1-year data, mostly, and shows several procedural success with MACE, around 10%, with most reporting it lower than the DISRUPT CAD protocol patients. MACE starts rising if you start using it as a bailout rather than as a front or in acute coronary syndrome population, but it still stays less than 15%.

Number 2, repeat revascularization, regardless of how or why it is done with PCI or CABG, is a rare phenomenon in the majority of IVL patients. Number 3, rotational atherectomy and IVL provide similar outcomes in most retrospective studies with trends toward better outcomes with IVL and balloon-crossable lesions, but shorter procedure time, less complication, and in my study, actually superior with IVL, although no direct prospective randomized trials exist. Thank you.

Dr. Denise Nachodsky:

Thank you so very much for that detailed presentation, and I see that Dr. Blankenship handed up for any additional comments.

Dr. James Blankenship:

Well, that was quite a tour de force, and congratulations to Dr. Hafiz. I think one perspective that might be valuable to think about here is that, in a sense, you know, when you're starting to dig a hole, it doesn't matter if you start with a pickaxe or a shovel. You want to get the hole to the right size, and kind of like this, no matter what you start with, you want to get that final stent that goes in fully expanded. And I think it doesn't matter too much which of these techniques you use as long as you get that final end result of an excellent stent expansion, and I think what we're hearing is that the IVL does this as well as any of the other procedures. It's not better, and probably more safely.

Dr. Denise Nachodsky:

Thank you so much, Dr. Blankenship. And I think, Dr. Rab, your hand is up for a comment.

Dr. Tanveer Rab:

Yes. So, we suddenly have a best day. That's excellent, Dr. Hafiz. I listened at you. So, the risk and loss rates are lower, or at least comparable to other devices. At least in our experience, when we talk about modification lesions, there are people, patients who are not going to be candidates for going out and about the grafts in a variety of lesions, and you know, things like balloon, previous bifurcation side branch, or rotator cuff technique, or other devices, does not give an optimum result at the off-stream of the side branch. It really looks so complex. The shockwave seems to, or IVL seems to, work well in that area in modifying the plaque and the bifurcation so that you have better stent expansion, okay? And lower risk and loss rates. So, that's what we've discovered and published in that article, that if you're wanting lower risk and loss rates, you're going to get bifurcation, IVL may be a better therapy.

Dr. Denise Nachodsky:

Thank you, gentlemen. Your expertise is very much appreciated here. And at this point, I'm going to turn over to my next colleague, which I believe is Dr. Loveless.

Dr. Meredith Loveless:

Hi. This is Dr. Loveless from CGS, and my first question, we've already touched on this, so I'm just going to see if Dr. Winchester has any additional - if any measures attributable - of the intravascular ultrasound, and should there be something like a point system for patient selection?

Dr. David Winchester:

Thank you. I was a little unclear on some of the elements of the question, so I'll start with what I had prepared as my comments. So, I looked at this in a couple of different ways. The first way that I looked at it was comparing IV - comparing PCI with and without IVL. And I think that one of the key elements here is because of the capacity for how IVL modifies plaque as compared to other options that are available to interventional operators, this has - that this particular technology has the potential advantage of making PCI in heavily calcified vessels safer than other strategies like rotational atherectomy or high-pressure balloon systems of some sort.

And that's got to do with how the technology works as compared to what other systems are doing. I did note that there was one review article that specifically commented on IVL with and without the use of embolic filters and noted no difference in outcomes if those safety devices were or were not used. And then I took the broader picture to comment that, you know, as new technologies like these come to market, you know, I think it's obviously important that operators who are no longer in a training environment have expectations and opportunities to participate in, you know, the appropriate level of proctoring.

We also have a fair amount of post-approval monitoring data, and it may or may not be worthwhile to continue some of those as these products become more frequently used in the clinical setting. That said, I would be - I would welcome any other comments from the other reviewers if they had any of the thoughts about what specifically might be done to improve the general safety of this system.

Dr. Meredith Loveless:

I don't see any hands up, so I think that you covered - I think you must have covered it well. So, we'll move to the next question, and for Dr. Blankenship, and this is - and we've also discussed a lot of this in our discussion, but we're, again, comparing intravascular lithotripsy to other calcium modification techniques. And is there certain factors that you would consider when choosing the calcium modification? And I think that, I think what - I'm going to take this a different direction just because we've already discussed this. So, I think one of the challenges that we have here is that we've got the DISRUPT studies, which are - if we have a perspective single arm multi-center trials with one and two being fairly small sample sizes and three being large sample sizes and four being a small sample size in a non-U.S. population.

And so, we have, with 30-day outcomes with the exception of the follow-up on CAD-III. So, you know, typically, these perspective single arm studies are going to be considered low to moderate in terms of their quality depending on sample size and bias risk. And then, when we're comparing the intravascular lithotripsy to other procedures, the majority of our data is retrospective. And when we're in Medicare and we're, by law, required to make policy decisions based on evidence and meeting that reasonable and necessary criteria, it gets challenging when we are dealing with largely low-quality evidence. So, that's where I'm trying to tease out where the evidence supports this over another procedure and where the evidence is supporting the advantages that you're discussing of the ILP compared to some of the procedures, which you've clearly defined as more risky.

Dr. James Blankenship:

Okay. Well, thank you for that question. And I think I'm going to compare it to each one of several different modalities, but I think we've moved beyond that. I think one of the limitations is that these other modalities have patient selection factors. For instance, you can't do rotational atherectomy on every case. So, you carefully select the cases that you're going to do rotational atherectomy on. So, any trial with rotational atherectomy is going to be, say, limiting the types of lesions and the situations you can use it in.

By contrast, I think intravascular lithotripsy can be used in pretty much a wide spectrum of different patient situations, like stable disease, even STEMI or acute coronary syndromes, and a very wide selection of different kinds of lesions. And just as one example, for instance, you would avoid using rotational atherectomy on a severe bend. But with intravascular lithotripsy, if you can get the catheter around the bend, it should be as safe as anywhere else. So, I think that when you look at some of these, even retrospective studies, and you see that has - you know, they succeed in delivering the stent 98% to 100% of the time, what that means is that once you decide to pull the lithotripsy catheter out of your toolbox and deploy it, you have a very high likelihood of success at a very low risk.

And a lot of those cases are ones where you would not pull a rotational atherectomy catheter out. You would leave it in your toolbox and say, well, this is not - it's either too dangerous, or it's not anatomically suitable for this particular modality. Does that get to your question?

Dr. Meredith Loveless:

Yes. And I appreciate your description that a non-cardiologist can understand. So, thank you. So, then that leads me to, if you're able to do this on patients that you may not be able to utilize other calcium modification techniques, is there any long-term risk? Would that be taking a patient that might have proceeded with a surgical intervention or a more aggressive intervention into a stent, and does that have equal success long-term? Basically, I'm trying to understand, are we putting patients potentially at any increased risk that would have gone on to a more aggressive therapy that we're delaying because of this, or is it providing them an alternative to avoid that? And the biggest concern, I think, is that our data is so short-term that I don't know if we know 3, 5 years out what's going on.

Dr. David Blankenship:

Well, I guess one could argue that the technology is so relatively easy, safe, and effective that you might pull it out in the case of a person who perhaps would have been better served with bypass surgery, somebody with three-vessel disease and diabetes with heavy calcification, and you would normally say, well, they're better served with bypass surgery, and that's probably true whether you tried it with stenting or intracranial lithotripsy followed by stenting, but the lithotripsy might make it so easy that people would be tempted to do what ultimately is not in the patient's best interest.

But I think that's about the only situation I can think of where that would be so. Sometimes you talk about when you do a full metal jacket with a stent, in other words, you stent from the top to the bottom of the artery, you're cutting off the option of doing bypass surgery later because the surgeon has no place to put a graft in because it's all been stented. You don't find that here. Again, it goes back to that idea that if your final goal is to get a well-deployed stent, it doesn't matter how you get it there, and any one of these technologies that is effective in getting the stent well-expanded at the right spot, I think is equally effective and in most situations does not limit further interventions down the road.

Dr. Meredith Loveless:

That is so helpful. Thank you. I just want to see if any - if there's any other comments on this before we move. Dr. Rab?

Dr. Tanveer Rab:

Very quickly, you mentioned the cost issue and that's obviously a concern for all of us through CMS. But remember, just like when rotational atherectomy started, you know, it's 25 years plus, the costs have come down. This particular device has four competitors already out there. So, the cost of the device will come down with time. That's one of the concerns. But the device is really here to stay. Thank you.

Dr. Meredith Loveless:

I just want to clarify that we actually don't consider cost in the Medicare reasonable and necessary criteria. So, we focus on patient outcomes and safety and does it improve long-term outcomes. And I - Dr. Hafiz?

Dr. Abdul Hafiz:

Yes. This is Dr. Hafiz. So, my comments are what we have known is calcium - chlorine and calcium is getting worse. And I think this is across different commenters who have mentioned this. We see more and more of it, more length of chlorine and calcium lesions. We need adequate tools that are modern to deal with it. Atherectomy and orbital or rotational atherectomy are based on mechanical debulking, which is one of the older ways of treating this lesion. And this is a brand-new technology with a completely different philosophy of how they're treated. Not only does this address a different subset of calcium, which is deep calcium, which is superficial, but also big nodules are better treated with this lesion. And also the most important cause of sense failure is underdeployment. So, did that - so my comment is also that this technology can be used in a lot more hands than atherectomy and orbital or rotational atherectomy. So, you can use this in smaller labs with less experience and less staffing expertise.

Dr. Denise Nachodsky:

Thank you. I just have one question for CMD to echo Dr. Loveless' concerns. It is that part of our role, though, is looking at the clinical evidence to support doing this. The numbers are very low in many of these trials. The patient population numbers are very low and the follow-up is shorter. And that is where I think we're struggling to say you're saying it's great. You in practice, you've mentioned a lot about registries. Where can we get data like that to say, okay, we're looking at the clinical trials and the literature out there, but it's short term and it's small numbers. And is that safe enough just on this low level of evidence to support that this is a procedure we should be going with? You all do that in your practice. Out in the real world, everything is evidence-based and looking at big trials. And, you know, if you're faced with the fact that there's only, you know, maximum 100 patients or 60 patients or 12 patients with left-main, for us to write a policy, is it very safe for us to do that?

Dr. Meredith Loveless:

And I see Dr. Korpas.

Dr. Denes Korpas:

Yes. So I agree with everything that has been said. I think, you know, Dr. Hafiz, I agree with you. So, the calcification is getting worse. So, we have an increasing population that's aging. We have, you know, prevalence in diabetes, you know, failure at things, you know, is going to get worse. I think, at this point, you know, we're looking at, you know, as Dr. Blankenship said, you know, we're not looking at IVL as an endpoint, as a tool to deploy a stent. The endpoint is an optimal stent deployment, which will confer, you know, an optimal deployment to less risk stenosis and stent thrombosis. So, that's the ultimate endpoint.

And I think to go back and compare, you know, the modality is going to be probably not feasible as we have such a good safety endpoint. So, I think we'll have to rely on these registries, and I think registries are the way to go. And, you know, I think, you know, there's some coming in Europe, you know, that over 400, you know, we mentioned that the Netherlands registered over 400 patients. A high percentage of those patients had ACS, and their outcomes were excellent. So, I think going forward, there's evidence, you know, cannot be randomized prospective studies, but I think the registries and the number of patients with safe treatments will be probably the, you know, way to actually, you know, look at the evidence.

Dr. Barry Bertolet:

This is Dr. Berry Bertolet. Just to add on to your question there, is that when I look back at the ORBIT II study, which was orbital atherectomy, which followed the same regulatory pathway that IVL has followed that same regulatory pathway, in that study, there was 443 patients. And so, again, when we look at Disrupt III, that was 431 patients. And so, when we're looking at the size of these studies for this type of disease that's out there, is that these studies and the population's numbers that are out there are appropriate to gain regulatory support.

Dr. Meredith Loveless:

Yes. And I do want to clarify that FDA approval and coverage are not the same. So, what - you know, we, in addition to the safety and the efficacy that the FDA pathway looks at, we also have to look at patient outcomes, the long term. And so, that's where I'm just trying to tease out where the data aligns.

Dr. Barry Bertolet:

And just to echo that, and what I mean by that is, you do now pay for artherectomy. And so, it's the same thing here, is that the same number of patients were studied, and you approve that technology. Now, we have the same number of patients, and you're hearing from the people that use it, is that we get similar results, and probably more safe. So, this is something that I think that the numbers in the clinical trial, but also what you're hearing from us, should support its coverage.

Dr. Meredith Loveless:

Yes. I appreciate that and the expertise. And I think that what we're trying to understand is that unlike orbital atherectomy, where it seems to be applied to a fairly specific lesion, ILP is easier to have a shorter learning curve. So, it's in the hands of a lot more cardiologists and some of these more advanced technologies like the orbital artherectomy, and being used off-label from the indication in - with a much higher volume than those. So, we're just trying to understand and seeking your all guidance and what is the evidence support and not support in terms of these off-label use and the rapid expansion of the technology. And we can - so it just - I see Dr. Rab after your comment, and then we can just keep that in mind as we continue to work our way through the question.

Dr. Tanveer Rab:

So, Medicare supports ASCs, and, you know, the device safety, this very device, as far as people who use ASCs, because it's safer to get better outcomes for the patient.

Dr. Gina Mullen:

Okay. Dr. Loveless, you're on mute if you're talking.

Dr. Meredith Loveless:

Oh, okay. I apologize.

Dr. Gina Mullen:

No worries. Mm-hm.

Dr. Meredith Loveless:

We can continue with Dr. Rab for the next question. And this one is that regarding the comparators and does having different comparators impact the outcomes?

Dr. Tanveer Rab:

So, my response is going to be brief. You know, it really does not impact the devices per se, because in all the studies that you've mentioned or coded so far, the safety profile is comparable to post-rotation or rotational atherectomy. And it's probably safer because the number of perforations are much lower with this device. In some studies, almost zero compared to rotational atherectomy. So, that's the best answer I can give you looking at all the studies that have been coded so far.

Dr. Meredith Loveless:

Great. Thank you. And if there's no other comments on this one, we'll move to the next question, which is for Dr. Hafiz and Dr. Korpas. And the technology is FDA-approved for severely calcified de novo coronary lesions prior to stenting. And this is going back to that off-label use. And I'm really interested in focusing on the evidence. Is there a way - is there evidence - I guess, really, in the absence of evidence, these would be limitations. So, is there evidence to say these should not be limitations?

Dr. Denes Korpas:

Do you want to take the first three and I'll take the last three?

Dr. Abdul Hafiz:

Sure. You want me to start, Dr. Korpas?

Dr. Denes Korpas:

Sure.

Dr. Abdul Hafiz:

Okay. So, I'll start with the first point. Yes. So, the answer is I have answered most of these in my responses to the first question that I did. For the record the question number - the second question I answered, the reference that I have in email, there were 16 references to that question answered. So, the combined with other circumferential catheter modification devices, yes.

As we mentioned, RotaTripsy, which is a term where you combine rotational athrectomy with IVL is a well-described technique and is data-supportive to use. In addition, one retrospective study, (unintelligible) score matched the study, did compare IVL with high-pressure balloons and coronary calcified lesions and reported significantly higher rate of procedural success with IVL versus non-compliant balloons with a pressure of greater than 16 atmospheres deployed. Mean pressure achieved was 29 atmospheres in the latter group.

So, procedural success was significantly higher with the IVL group versus NC group, and this was 82.5% versus 61.4%, and the P-value was less than 0.05. Although the 12-month MACE was similar in the two groups at 10.5% versus 11.5%, and overall complications were less than 1% in either group. About 20% of patients, though, had moderate coronary calcification study. Conclusion data for IVL versus other modalities exists, but is only retrospective registry-based, as has been pointed out. And no high-quality propensity, respectively, randomized data exists. Based on limited compared data, IVL has unique advantages that has already been discussed extensively, but hard outcomes data is largely similar across modalities. You can take the next one, if you would like, Korpas.

Dr. Denes Korpas:

So nice one, a better procedure would stand in place. I think there's some data suggesting that late instant restenosis even actually early under-deployment, actually has significant benefits from IVL. There was a study that utilized 100 patients, and out of those were - 55% of those patients (unintelligible) patients who actually old stent placement procedures, you know, such as instant restenosis, you know, who's but 45% of those patients, 34% were actually acute under-deployed stents.

And IVL was utilized in both patient populations, and the success rate was actually very similar. So, the question was, you know, what is the mechanism here? And typically, you know, with the immediate under-deployment, there is calcification outside the stent, and that those calcium deposits can be fractured by IVL. And the concern of the study was, obviously, is there any damage to the polymer by the shock acoustic waves, and that did not translate into a significant restenosis.

So, the conclusion of an acute stent under-deployment situation is that IVL is effective. It can break up calcium outside the stent without the damage of the polymer. Also note, you know, the stent layer didn't matter, so if it was actually two or three stent layers, the efficacy was actually a lot less. The late data, again, 55 patients out of 100 in that study were actually late instant restenosis patients who were actually calcium was inside the vessel. The mechanism there was actually similar to, you know, the lesions, you know, breaking up calcium deposits in the scar tissue inside the stent, and that also actually was, you know, quite favorable outcome with regards to the MACE procedures at 30 days and one year. So, there is evidence that actually IVL can be used in stent restenosis as well as under-deployed stents in acute setting as well with safe outcomes.

Dr. Abdul Hafiz:

I will take the next two briefly, and then I'll let you continue to Korpas. So, this we are talking about the off-level and limited limitation to the technology. So, this C part of the question is anatomical locations, bifurcation or lesmene. Yes, there are numerous studies supporting the use in lesmene, and one specifically reports outcome in bifurcations. We have discussed this earlier. Having said this, generally bifurcations in the non-lesmene lesions tend to have worse outcomes, and that necessarily is not a limitation of technology. It's just the nature of the disease. Whether you use IVL or don't use IVL.

Acute coronary syndrome, the DISRUPT III Study excluded NSTEMI and STEMI is within 30 days if it had occurred, but subsequent registry and retrospective data, as mentioned earlier in response to question number 10, included acute coronary syndrome patients across the spectrum on stable angina and STEMI - or STEMI, with the latter being the smallest subset. Outcomes were not compared separately, to my knowledge, between ACS and non-ACS groups directly.

In a 2021 meta-analysis by (unintelligible)., the ACS varied from 26% to 45% across the studies in their analysis and the references provided. A similar number was reported by International European (unintelligible) Registry at 44%, which found an increasing trend in ACS patients treated with IVL at the cost of decreased use of other CSU modalities, coronary calcium modalities. More - most were NSTEMI, 25% patients, followed by unstable angina 12%, and STEMI was the least common at 7%, while just over half were still chronic chest pain patients at 56%. IVL use rose from 33% in ACS to 48% from early to the later part of that registry.

Both technical and procedural success, usually defined as technical success without any adverse MACE events, was high at 91% and 89% respectively, while MACE rates in one year were relatively low at 13%, despite the inclusion of ACS patients, some of which were bailout IVL, which is known to have higher rates of MACE, and only 8% clinically driven revascularization events, and 4% mortality within a year. Very briefly, in responses, lesion size, and total occlusion, this has already been discussed in my earlier discussion. Back to you, Dr. Korpas.

Dr. Denes Korpas:

I'll just read some comments on the eight-point syndrome. The registry that you mentioned that had 14% MACE rate, if you look at the other Texas registry or study, at nine months, you know, the MACE rate was 24% with rotational athrectomy of the similar patient population. So, again, looking at real-world high prevalence of ACS, 14% versus 24%, again, not a direct comparison, but similar patient population between IVL and (unintelligible). Lesion size, we mentioned that briefly. Obviously, catheter comes in different sizes, in the 2.5 up to 4, which is currently a treatable vessel size.

If you look at lesion size, we did mention the balloon length is about 12 millimeters, but with increasing pulses, we can actually treat lesions that are longer in the disrupt studies. You know, lesions have to be less than 40 millimeters, as we mentioned before. And, again, I think the third three-dimensional aspect of lesion size is deep calcium. Deep calcium typically is defined with OCT or IVUS of calcium that's more than 0.5 millimeters inside the, you know, in the vessel. Now, those lesions actually have deep calcium, are effectively treated with IVL. It's been shown that both superficial and deep calcium are fractured about, you know, 70% of the cases on the intervascular imaging.

So, lesion size's limitations are the vessel size, the length, and the calcification. Again, those are the treatment options for IVL. Pelvic lesion, per se, obviously, is not feasible to treat with IVL. You have to cross the lesion with a wire. However, if you have a successful crossing, you can use IV techniques such as, you know, rotation athrectomy, and then IVL can be safely utilized. However, again, of occlusion by same use of IVL is not indicated.

Dr. Abdul Hafiz:

Just a comment about the calcium depth, 5 millimeter, and then probably best seen with OCT, but OCT is not always employed. Thank you.

Dr. Meredith Loveless:

Thank you very much, everyone for the excellent education with your answers. And I'm going to turn things over to Dr. Barre.

Dr. Luke Barre:

Yes. Thank you. And I think that we're now in a couple of questions that we have touched on with a few of your really excellent answers. But this question is directed to Dr. Rab. And it is, does the use of calcium modification devices improve percutaneous coronary intervention outcomes? And the follow-on to that is, for what duration is outcome data available?

Dr. Tanveer Rab:

Thank you. So, if you have a calcified plaque or any plaque, the goal here is to get the maximum benefits of stenting with the widest stent area and with very little indentation of the body of the stent. And the whole goal is that you prevent the scar tissue formation coming back or the growth of the calcified nodule through the stent's trough. So, the patient does not keep on coming back with recurrent cardiac events or acute cardiac syndrome.

So, the goal with any percutaneous intervention is an optimal result. And whatever device you want to use to modify plaque is absolutely essential and important to get to the optimal goal for optimal stent expansion. So yes, yes, calcium modification optimizes stent expansion and reduces MACE and instant resubmersion. There's plenty, plenty of data out there. And if there are some optimal results and if the stent is not well expanded, the lesions will keep on coming back and haunting you. Now, in terms of trials, most trials looked at outcome data at 30 days. And so, according to the ideal literature, most of the initial trial data was at 30 days. That works well for all orbital rotation aspects. Thank you.

Dr. Luke Barre:

Thank you, Dr. Rab. Sorry, I had trouble getting myself off mute for a second there. So, moving on to the other speakers, did anyone else have anything to add?

Dr. Abdul Hafiz:

I just want to add a brief comment. IVL is a new innovation. And as we've seen on the structural cardiology side, TAVR, for example, and they keep innovating different new technologies. And the follow-up is going to need time and probably same will happen with IVL, just a matter of time before the studies have long-term data. It's just that the technology doesn't have - hasn't existed for so long.

Dr. Luke Barre:

Thank you. I If any other comments before hand, we can move to the next item, question 16. So again, this touches very specifically on another question that was asked, question nine, but adds on a little bit in terms of the percentage failures and this is directed towards Dr. Blankenship. The prompt here is, are there different considerations for treatment depending on the location of the calcification, i.e., which artery is affected? How does lithotripsy compare to bypass for left main calcification? The follow-on to that is whether there is evidence to show that lithotripsy is safe for use in left main disease. And so, those are the elements that were specifically touched on. And the more specific question, if you'd like to add to it, is what are the percentage failures at 1, 5, and 10 years?

Dr. James Blankenship:

This is Jim Blankenship. Is the question about percentage failures specific to left main or in general?

Dr. Luke Barre:

Yes, it is directed towards left main.

Dr. James Blankenship:

Okay. So, I think the answer is yes, there are some different considerations for treatment depending on the which artery is affected. One example would be that rotational athrectomy, for instance, can cause what's called, again, no reflow, which, if you use it in the left main, can be catastrophic, and which always makes us pretty nervous when we use it in the left main, and in some cases, we would use impello support to do it safely.

In contrast, the IVL requires you to blow up the balloon in the left main for a short period of time, which, in somebody with normal left ventricular function, at least, is generally reasonably well-tolerated and produces a predictable result, as opposed to the catastrophe that you sometimes see with rotational athrectomy. So, that's one example when one might faced with a left main lesion, prefer to use lithotripsy as opposed to, again, my favorite alternative, which is rotational athrectomy. So, that's one example of differential use of it.

And I mentioned previously, there are some types of lesions in some arteries where the other modalities either can't cross a lesion or can't be safely employed. So, there is evidence that it's safe. There are retrospective studies that looked at left main. I can supply references, but the evidence there basically is that the lithotripsy is at least as safe as the other calcium modification modalities. So, I think the answer to left main disease is yes, it is safe. There's always a little more risk with left main disease, because if anything goes wrong, of course, and it can be catastrophic, but that's true for any of these modalities. And again, I think the lithotripsy is more reliable.

Percentage failures, we've talked about follow-up. We don't really have follow-up beyond two years. The follow-up at two years is generally pretty good. There's different ways of looking at failure. One is target lesion failure, which is specifically usually defined as thrombosis or restenosis within the treated lesion requiring revascularization or causing a complication such as myocardial infarction. And then there's overall major adverse cardiac event rates for the patient, which generally run for one year at about 5% and 10% respectively, and for two years generally run at about 8% and 16% respectively. And the data for lithotripsy and bypass - or the data for lithotripsy generally falls into those ranges.

Dr. Luke Barre:

I see Dr. Bertolet has his hand up.

Dr. Barry Bertolet:

Yes, sir. So, just wanted to add to that very nice answer. A couple of things is that when we look at left as compared to bypass surgery directly, just looking at that, there's been no difference in mortality and outcomes when you look at those different procedures. The big thing I think it's important to understand is that oftentimes this is not an either or, but it may be that if somebody has left main disease that we oftentimes now use a heart team approach where we will consult with our surgical colleagues and we'll decide what's the best way to approach a certain patient.

And using that heart team approach, a lot of times these patients are denied CABG or they're denied the opportunity for that. And so, if we did not have technologies like this that were available to us, then that would provide either no option for the patient or a very dangerous option for the patient as outlined by Dr. Blankenship earlier. So, I wanted to add some color commentary to what he added. Thank you.

Dr. Luke Barre:

Thank you both for those excellent responses. Are there any other comments from our subject-matter experts? Okay. So, I think we can move to the next item, which is again going to be directed towards Dr. Bertolet. This does touch on some of the limitations that were discussed earlier, but I think it's phrased differently enough to make it worth asking, which is what are the contraindications for intravascular lithotripsy?

Dr. Barry Bertolet:

So I think this will be a quick answer. So, the contraindications are few. So, the first contraindication would be you can't get the balloon there. And so if you can't cross it with the IVL balloon, then you can't do the procedure. So, that would be a contraindication. So, if it's - you can't get a wire across, you can't get the - a balloon across, then you can't do the procedure.

I believe that there is evidence of active thrombus. That would be likely for me an absolute contraindication. At least for now, utilization in bypass grafts unstudied in that arena there. And so I think that would be an absolute contraindication. So, for relative contraindications, as mentioned earlier, there - these balloons come in certain sizes.

So, I think that if we were to try to use this in a vessel that was beyond the size range, the size matrix that is presently available that would be a relative contraindication. And perhaps if we were retrying a vessel where there was a previous perforation or a bad dissection, that may make it, I'd say, something to think about from a relative contraindication standpoint. But I would limit it to just those few. Thank you.

Dr. Luke Barre:

Thank you very much, Dr. Bertolet. Did any of the other subject matter experts want to opine on either relative or absolute contraindications in their opinions? Thank you, Dr...

Dr. Abdul Hafiz:

I just wanna comment this.

Dr. Denes Korpas:

Yes. This is Dr. Denes Korpas. Having just a brief mention about down this phenomenon of ventricle capture, you know, we haven't talked about this, but this rate of shock waves is about one pulse per second. So, it turns out to be a 60 beats per minute heart rate. It has been shown actually in some studies that there's some ventricle capture that's actually observed in patients.

Mostly have the heart rate less than 60 mil patients and, you know, it's correlated with the number of impulses. And again, speaking for the safety of this procedure, it did not translate into any high-grade arrhythmias. So, I think, you know, if you look at, you know, someone with a lower heart rate, you could anticipate capture of the ventricle. But again, it's safe. It did not actually increase any risk of arrhythmias, definite, you know, ventricle fibrillation. Just to be mentioned, that is an expected, not a complication, but a feature. And it's safe, again, should not be a contraindication if someone's heart rate is lower than 60.

Dr. Luke Barre:

Thank you, Dr. Korpas. I saw Dr. Hafiz had a comment as well.

Dr. Abdul Hafiz:

Just a comment about the ventricle capture. I add that the only thing that was observed was transient hypertension and that did not have any clinical relevant outcome. The other thing was a comment about the CTOs. There is actually a utilization and there has been a couple of comments about chronic total occlusions. There was a registry which did specifically study that this device has been used in CTOs, probably best after the lesion is crossed, but it cannot be used up front as the lesion cannot be crossed.

Dr. Edward Tuohy:

Thank you, Dr. Hafiz. Do any other subject matter experts have a comment before we move to the next item? Okay. So with that, I will pass it over - back over to Dr. Mullen.

Dr. Gina Mullen:

Thank you. So, Dr. Hafiz, is it appropriate to perform these procedures in ambulatory surgery or office space centers without surgical backup? And if so, who, if any, would or would not be eligible?

Dr. Abdul Hafiz:

Thank you for the question. This will be a brief answer. A fundamental modality of coronary calcification, IVL, is the simplest one to use from a technical aspect. It is a low-risk intervention with excellent safety profile, as has been discussed by other speakers, when performed per protocol that was used in DISRUPT 1 to 4. If you follow the exact protocol, you're going to have - you're going to be very safe place, but very low risk of perforation, slow flow, no reflow, and so on and so forth.

And we discussed this in detail in my response earlier. More time modifications have been made to techniques that are used with IVL as has been discussed earlier, which slightly elevate the risk of MACE, but reduce the procedure time. In some cases, compared to rotational atherectomy actually reduce complications in the short term.

There's this guide document, which is an expert consensus document on PCI without on-site surgical backup. The reference is provided. And it suggests the IVL can actually be used in an ambulatory setting with no on-site surgical backup. However, typically, these sites will not have other modalities such as inpatient atherectomy and orbital atherectomy devices to be used as urgent if needed.

While the document suggests that other scenarios to avoid an ASCs, such as low EF, CTOs, calcified lesions, unprotected left vein, gen vein grafts, or high bleeding risk patients, there is little data to guide as to which specific coronary calcified lesions are best suited for IVL and ASCs.

In general IVL, should be used or should be available in ASCs, especially for bailout scenarios. However, best practice would generally dictate that severe calcium, the broad spectrum of severe calcium that we see on a day-to-day basis is best treated on a surgical on-site backup facility with full-spectrum devices capable and technical staff who can handle those strategies and where there's logistical support. Having said that, I think it's very appropriate to leave it, and it is covered for ASCs.

Dr. Gina Mullen:

Thank you. And Dr. Rab.

Dr. Tanveer Rab:

So, at the present time, we know at a lot of levels two, many centers which do not have surgical backup. The safety of the device in most communities, IVL has been used there without surgical backup. So, there's quite a bit of data now from all over the country that this is kind of practiced particularly when people are concerned about rotation of the atherectomy. And we do need atherectomy in a lot of the centers in the country now routinely. I think in the Atlanta metro area, most of the level two hospitals have IVL without surgical backup.

Dr. Gina Mullen:

Thanks, Dr. Rab. Dr. Korpas, next question for you. Please opine on the additional training and certification requirements for physicians and medical staff.

Dr. Denes Korpas:

Sure. My opinion that the training requirement is minimal and my opinion is supported by evidence, mostly in the DISRUPT III study when looked at the safety and efficacy of this procedure. It was similar rates of success and safety in 47 centers that had a first case compared to the subsequent three IA4 cases that were done.

So, pretty much, you know, the operator experience is given by the standard techniques of building a balloon. So, specifically no additional training is required for physicians. I just confirm with the company, this, you know - that allow - also for staff, they typically have an in-service one time when they come to the cath lab. They, you know, teach them device hookup, you know, just the balloon prepping. And typically they support the next couple of cases, but typically, you know, it's a one time in-service for the staff. There's some CMEs, CEUs that can be done as well. But typically the requirement for, you know - for training is minimal.

Dr. Gina Mullen:

Thank you. And just to clarify, you said you reached out to the company to confirm the on - in-service, is that correct? I just wanted to make sure I understood.

Dr. Denes Korpas:

Yes. Correct.

Dr. Gina Mullen:

Okay. Thank you. And Dr. Tuohy, what ICD-10...

Dr. Edward Tuohy:

Yes.

Dr. Gina Mullen:

.diagnosis codes do you think are appropriate for this technology?

Dr. Edward Tuohy:

Yes. So, I think in this case, it's very similar to the standard PCI codes. So, it would include the I-20 series for angina, as well as I-21 on - and I-25 series for both acute myocardial infarction and atherosclerotic heart disease as well as the I-11 and I-50 series involving hypertensive heart disease as a potential cause of angina chest pain as well as the I-50 heart failure series for patients who have compromised ventricular function related to their underlying coronary artery disease. But basically similar to those. I don't - I poured through some of the other diagnosis codes and did not see anything that was compelling. I don't know if my colleagues have anything that they would add specifically to that list.

Dr. Tanveer Rab:

If you look at the - and I did a search on Google and AI and all this stuff. There's also a series of codes like 02F03VV, 02F13VV, 02F23VV, and 02F33VV. I think those come from the abstract community chart and not anything else.

Dr. Edward Tuohy:

Yes. I think those are not like current codes that we'd be using routinely. I don't know if you have any insight into that, Dr. Blankenship, my RUC guru.

Dr. James Blankenship:

No. I can't answer that.

Dr. Edward Tuohy:

If I - yes, like, I code - right the - ICD codes don't have usually ZZZ in it, right? That's kind of subtext for some of what we do in the RUC for the global periods and the - I don't know. But I think that's an adequate list.

Dr. Gina Mullen:

Yes.

Dr. Tanveer Rab:

Well, Blankenship's expert here, he's the guru here, so.

Dr. Edward Tuohy:

Yes. He's the mentor.

Dr. Gina Mullen:

Oh, well, thank you guys so much. That was our final question. Before we close, are there any closing comments? I know we are over by 10 minutes and I do apologize. So, I do want to open the floor if there are any comments that you guys would like to make just for a few minutes.

Dr. Edward Tuohy:

I think it's amazing it's only 10 minutes over. I congratulate my colleagues on their brevity assessment and learning curve during the course of questions.

Dr. James Blankenship:

Yes. I learned a lot and I congratulate staff on keeping it on track. Good going.

Dr. Edward Tuohy:

Yes. I think it was a good team effort by everyone.

Dr. Gina Mullen:

Everyone, thank you. Dr. Hafiz, one second.

Dr. Denise Nachodsky:

When you put a group of cardiologists in the same room, just remember from cath conferences and all that, everyone will come up with a different stenosis of that lesion and a different answer. So to have a group of experts like you in the room able to answer 20 questions that were complex, okay? It's totally amazing and totally love what y'all did for us.

Dr. Gina Mullen:

Yes. Thank you, Dr. Nachodsky. Dr. Hafiz, you were going to say something as well.

Dr. Abdul Hafiz:

Yes. I just want to end the session by saying thank you everybody. And it goes back to what I mentioned, Dr. Mullen and of course I heard about this conference is IVL. It is a game changer for us who have been introduced to technology, have known how difficult and cumbersome the other technologies have been. So, with that in mind, I don't have any other questions and thanks everybody. This has been an incredibly learning experience.

Dr. Gina Mullen:

Yes. Thanks from me as well. Please feel free to send any additional literature, written comments, written answers, supplemental answers to my email or the NGS CAC email within the next two weeks. We're grateful for the substantial effort you devoted to reviewing the evidence and for your very thoughtful contributions today.

Dr. Meredith Loveless:

And just second our appreciation for your time and expertise. And I learned a lot, I'm sure everyone did and this concludes our meeting.

Dr. Tanveer Rab:

Thank you very much for asking us to be part of this.

Dr. Edward Tuohy:

Thank you.

Dr. Abdul Hafiz:

Thank you guys for being here.

Dr. Edward Tuohy:

Thanks to everyone.

Dr. Gina Mullen:

Thank you.

Dr. Barry Bertolet:

Thank you.

Dr. Denes Korpas:

Thank you.

Dr. Gina Mullen:

Have a great evening.

Dr. Denise Nachodsky:

Thanks.

Dr. Gina Mullen:

Thank you.

Dr. Barry Bertolet:

Bye bye.

END