Penn Medicine’s Cardiology department invited Dr. Sripal Bangalor, Professor of Medicine and the Director of the Cardiac Cath Lab at New York University to discuss the Ischemia Trial and the implications for decision making in patients with SIHD.
Twitter @PennMDForum Mhm. Mhm. Mhm. All right. Good morning, everybody. Welcome, Thio pen, cardiology, grand rounds. Very excited for today's talk. He ischemia. Trial was a huge endeavor that took years of planning, and I'm sure, countless hours of hard work. It's one of the pivotal studies of cardiology and will be discussed and quoted for years to come. The results were presented late last year. The final manuscript came out this spring. Unfortunately, this was around the time of the early days of the Cove it pandemic, and I feel that in many ways that overshadowed the skinny. A trial in the results and focus shifted towards the covert situation, and we weren't able to discuss and dives deep into this. Try Eliza's we wanted to. So today I'm very excited to announce Doctor Sri Paul Bangalore. There was a professor of medicine at N Y. U. He's the director of the cardiac cath Lab complex Coronary interventions and Cath Lab research at N. Y. U. Triple has an amazing resume, including countless publications, grants and has been very pivotal in the ischemia tri ALS, as well as multiple other cardiology, interventional based trials. He is the primary investigator for the ischemia trial, Um, ckd sub study. And today we'll be talking about the ischemia trial. This trial has been interpreted differently by both non invasive and invasive cardiologists, and I'm very excited to get RuPaul's insight because of his involvement in the trial, especially as a P I in the sub study and as an interventional cardiologists. Unfortunately, CMI code. I don't have it just yet, but we will place it in the chat feature, hopefully during his talk. And as with past ground rounds, please feel free. Leave any questions or comments, uh, in the queue in the chat section or the Q. And a section will try to leave the last 10 to 15 minutes for a discussion with Dr Bangalore. So with that, Sri Paul, thank you very much. And, uh, I'll let you take over and share your screen and get started. Thank you very much. And thanks for having me on. Um I'm going to share my slides, so hopefully you guys can see my slides. So, uh, eso I've titled this as this commute, trial and perspective and really dwelling into implications for decision making and patients with stable ischemic heart disease. So these are some off my disclosures as it's relevant to this stock. I have grand support from NHL B I for the scheme unity, ischemia, see Katie trial and I'm the p I for this Kimia CKD tri ALS. So maybe let's come. Let's first start with the fundamental question eso inpatient with stable ischemic heart disease. And again, I want to emphasize that what we're going to discuss today is Onley relevant to patients with stable ischemic heart disease, not acute coronary syndromes. So the fundamental question is, why do we revascularization? Why do we consider revascularization in patients who have stable ischemic heart disease? So some of the potential goals are it would be great if you can improve survival by revascularization. Um, it also really great if revascularization can prevent other cardiovascular events and also to improve quality of life And of course, um, the preference, whether it improves one or all of these goals, um, it remains to be seen, But, you know, let's go through all of these and see well, what is the data to support each of this and patients who have stable ischemic heart disease? So if you look at the data leading up to the ski me A trial from a randomized clinical trials randomize strategy trials off revascularization versus, uh, initial medical therapy strategy. One consistent message has been there has been no difference in mortality with revascularization. So if you look at the courage trial, there was no difference in death. Barry to retrial, no difference in death, whether it was the PC I stratum or the Cabbage Stratum and even more recently, the fame to trial, even though it's being touted as a positive trial. If you look at that point of death, there was indeed no difference in death between a strategy of revascularization compared to medical therapy alone. So the question then is why randomized trials have not demonstrated survival benefit for revascularization in sht. So I think this is an interesting slide. Looking at what happens with severe obstruction versus those with the mild obstruction, patients with severe obstruction generally present with the angina. There is usually no rupture, so this is kind of the classic pathway for patients. Stable ischemic heart disease. They're severe fibra tick plaque, severe obstruction, no lipid fibrosis, calcification they usually present with exertion of angina. And of course, you can consider anti vaginal therapy and revascularization. On the other hand, if you look at mild obstruction, these patients generally don't present with angina but more likely to present as a rupture of the plaque, especially if it is a vulnerable plaque. And we know from data back in the seventies and eighties that most of their minds are caused by ruptured off a plaque, which are 50% or less in terms of damages. Diagnosis there usually lipid cap Liverpool, rich with the thin cap on the presentation, is usually acute. Um, I unstable engineers are on death, of course. I mean, we know from a number of randomized trials for this group of patients revascularization specifically with the P C. I, um, is a significant benefit that reducing cardiovascular events, including production in death Or am I So if you go back to design limitations of prior trials prior tiles of stable ischemic heart disease, some of the design limitations are low risk patients were included. Um, and revascularization was not optimal in the courage and body to D, because there was little d s use and no FFR used, there was, ah reference bias. We randomize ing after cat. I think this is critically important because the prior trials enrolled patients after they had a diagnostic cat. And one can imagine that if a patient as severe proximal a lady stenosis, it is likely that the referent would have said, Oh, no, no, this is not a trial candidate. Let's not randomize thes patients. And of course, there was a small sample size. So the remaining gap when we started to think about the ischemia, try a Liz. Are there any high this group off stable s comic heart disease patients in whom revascularization improves data on my in their off modern medical therapy? Of course, when we think off high risk group, we generally think off an atomic subsets. For example, approximately lady. So this is data about approximately lady from the Courage Trial, looking at patients who had approximately ladies diagnosis 50 to 69 also 70 to 89. And you can see patients randomized Theo MTR in the hash lines and the patients were randomized to PC. I are in the solid lines. One thing to note is approximately. Lady was not in effect modifier. There was no it originated treatment effect based on approximately lady stenosis in in the courage trial. Or, of course, if you look approximately lady stenosis 70 to 89. So there's 63 patients in the PC I group and 77 patients in the OMT group. So a small subgroup of patients, But at least it does show that there was no significant difference in debt and my or our a non est elevation SCS based on proximity status. What about other high risk and atomic subsets, for example, triple vessel disease. Again, this is data from courage trial. Looking at PC, I was this, uh, optimal medical therapy again, the same trend eyes seen for triple vessel disease. And no significant difference in this composite and point between PC I and optimal medical therapy. So can we think of other high risk upset? So, um, what about ischemia? Um, so this is data from Rory. A comment which groups looking at person, myocardial ischemia, my cardio myocardial ischemia and the interplay between revascularization and medical therapy. Of course, this is, um, observational data off 10,000 patients known on coronary artery disease. The follow up off two years on what they showed in this analysis was there was an inflection point around the 10% myocardial ischemia, where if you had 10% of greater myocardial ischemia, revascularization was associated significant reduction in cardiac death when compared to medical therapy alone. Or, of course, if you're ischemia is less than a 10% you see that the relationship is actually flipped numerically higher event rates with revascularization compared to medical therapy alone. So this and few other studies were the reason, uh, we decided to ask the question, uh, in the scheme a trial, so in, uh, in brief, this slide shows the design of the scheme a trial in the scheme, a trial. We took patients, stable patients who had moderate or severe ischemia as determined by the site. And these were all read by a core lab. And after our stressed, as the patients were CCT eligible. So in other words, patients whose Jaafar was 60 or greater, um, or they're gonna coronary anatomy was not previously defined. Underwent a blinded coronary ct. The blinded coronary CT was done, um, for two reasons. One is thio, of course, blind the sites for anatomy so that there isn't a referral bias into who gets into the trial. Um, the C C T a core lab looked at the C. T s for two reasons. One is to make sure that they had obstructive disease and it was The obstructive disease was defined on corny cts, 50% of greatest diagnosis, and second, to make sure to rule out left main disease, eso on the sites were basically told whether they were eligible. So if they were eligible, that would mean that they had obstructive disease in C c. T. A. On did not have left main disease. And, of course, in the subset of patients were not CCT eligible. They were randomized directly after rest as stress test patients were randomized to an invasive strategy off optimal medical therapy, cat and optimal revascularization or the conservative strategy. We started with the OMT alone with cat reserved for OMT failure. So the skin mystic 80 trial started Ah ah, Year after the ski mia trial started enrolling in this trial enrolled patients with monitor severe ischemia, But the geo far less than 30 or analysis um, just to quickly talk about this. Um, as you know, from all of the prior trials, courage body to retrial fame to etcetera the consistently and excluded patients with CKD. So this is the only dedicated trial in in this CKD space. So in this trial we took the patients who had a similar amount of ischemia but lower Jaafar and given the fact that they're lower g f r C C T A was not required and patients. And when the war randomized immediately, soon after a stress test to an invisible a conservative strategy the primary and point for the schema See Kitty trial was a composite of death or am I? And the primary and point for ischemia was a five point composite. So this slide shows the eligibility criteria for the ischemia trial. Um, and we went through a most of it. This has the definition of moderate or severe ischemia based on different stress test modality. So nuclear 10% of greater ischemia echo three greater segment. Stress induced monitor severe. Uh, I poke unnecessary kindness CMR e t t and so forth. So, um, just like any other trial, it's critically important. Thio recognized which patients were actually not enrolled in ischemia trial. So some of our, uh, important exclusion criteria were if a patient at the A. C s within two months. That was an exclusion criteria. If less than 35% anyway, check class three or four heart failure and if you if the patient and unacceptable angina despite medical therapy. So in other words, uh, they were already maxed out on their medical therapy, they were really, um, not satisfied with their medical therapy and wanted to pass authorization. They were not enrolled in the trial. And if the patient at PCR cabbage within one year there were also not enrolled in the trial. So these air the patients that the skin material results does not apply to. So there has been much discussion in social media and elsewhere about the fact that we allowed exercise treadmill test to be one of the entry criteria. In fact, a quarter of the patients enrolled in ischemia at the distressed US morality as an exercise treadmill test. So just to be clear about what was the criteria, so for exercise treadmill test, the criteria was you needed to have 1.5 millimeters SD depression or greater in two or more leads, or I should should have two millimeters to depression in a single lead. But the U K G criteria alone was not sufficient, and they needed to have these e k g changes within seven Mets off exercise on this was not enough. They also needed to have angina. I did a history of angina or angina during this treadmill stress test, and even this was not enough on the patient. Finally, absolutely. I turned the ghost a coronary CT on the coronary CT had to show a 70% of greatest gnosis, an approximate or mid vessel. So you can imagine this Utd criteria is fairly strict. And of course, I mean took a ah lot of discussion to come up with this criteria on the reason we had all these stringent criteria was to make sure that we're capturing patients who have have significant stenosis in approx are mid vessel. Um so this was the eligibility criteria. The other question to ask is, now that the schema travel is Aziz enrolled being published? Did ischemia actually enroll the high risk cohort that we started to enroll? So these were the results the qualifying stressed as based on core lab interpretation. So for the patients, the 5179 patients randomized in ischemia. More than half of the patient as severe ischemia based on Colaba interpretation, a third of them at modern ischemia and 12% and mild or none. And the rest were un interpret double. So, um, in terms of enrolling, high risk group of patients, I mean, initially, when I started on the trial, I was thinking that this is gonna be a trial off modern ischemia. I was pleasantly surprised that more than half the patients enroll in ischemia at severe ischemia. What about anatomy again, Going with the theme of Did the skinny actually enroll a higher score of patients? Eso This is anatomy based on anatomy based on coronary ct on based on colony and geography. So, as you can see here, based on coronary CT, 76% of patients and multi vessel disease on the same was true for the subset of patients who underwent coronary angiography. 71% at coronary multi vessel colonial to disease. Um, and if you look at the type of anatomy um, seen, um, 87% of patients based on corn e c t at ah, lady stenosis. In fact, close to half of them approximately lady stenosis and in a subset of patients and then underwent cornea and geography. You see somewhat similar relationships. 76% of the ladies diagnosis on 36% of them had approximately ladies diagnosis. And finally, if you look at the symptoms status of these patients so these are baseline health status quality of life in the patients who are enrolling the ischemia trial, um, as we can see here 21% 1 in five patients at the daily or weekly an engineer, 44% at angina several times a month, and a third of these patients at no Angela eso this kind of war, the categories of angina based on the Sakha engine of frequencies care. So now we're going into revascularization eso in the patients who are randomized invasive strategy. 80% of those patients underwent revascularization, so among the 20% with Noto revascularization to third at insignificant decision colony angiogram and the third and extensive disease unsuitable for any more of revascularization. So among the 80% who underwent revascularization, 74% were was by PC I and 26% by cabbage, and of course, you see that there was a very high proportion, you know, use of drug eluting stents and lima graphs. Um, in this trial, eso there is a popular miss perception that they great ischemia trial to PC I but 26% of them also underwent cabbage Something Thio keep in mind. So this slide shows the cat cardiac catheterization both in the invasive strategy and conservative strategy. So if you focus on the conservative strategy eso indication for cat in the conservative strategy. So we had it on 28% of patients at the end of four years who underwent cats in the conservative strategy, I think the more important number to note is the revascularization. So 23% of them underwent revascularization in the conservative strategy for years. But if you look at, um, uh, revascularization not proceeded, but I primary and point event it was 16% of four years. So in other words, the other, um 7% was mainly because of events which had already counted in the primary and point so 16% of four years around 4% a year. Three vascular ization in the conservative strategy. So now coming to the primary and point. So this is the primary and point of the scheme a trial. So this is a five point composite CV debt that my hospitalization for unstable angina or heart failure resuscitated cardiac arrest. So the relationship is a complex. And of course, as we can see on the slide, there's no significant difference between invasive and conservative strategy for this endpoint. But the curves did cross around two year time point, uh, initially upfront. At six months, there was, ah, higher hazard with the invasive strategy, and at four years there was, uh, more benefit with invasive strategy even compared thio conservative strategy. If you look at the major secondary point of CV death that, um, I again we see similar relationship no significant difference between invasive conservative strategy curves cross around the two year time point offered up front as erred and late benefit with invasive and compared to the conservative strategy and quickly looking at the results of the ischemia, CKD tri als um, as stated before this enrolled Ugo far less than 30 or on dialysis, no Corrin e c T patients who were randomized. We enrolled around be randomized 777 patients, and we took a lot of measures to optimize revascularization in these group of patients. For all patients who randomized invasive strategy, we provided a customized hydration protocol, and this hydration protocol was based on the Poseidon trial. So, in other words, for the patient was randomized, we would send them, uh, worksheet, which would provide hydration based on patient's body weight on also, while off contrast that they can use for heart stop, we strongly increased the heart kidney approach, including an apologist for decision making for these patients and which train sites to use ultra low volume zero contrast PC I techniques for for these patients to minimize outfront risk. Now, if you look at the baseline characteristics off the schema trial, sorry, this is the schema CKD trial. So we see that 92% of patients had hypertension, 57% of the patient that diabetes and just over a half of the patients were on dialysis. And among patients not analysis, uh, security Stage four was in 86% of patients security. Stage five was on 14% of patients, and these were the key stressed US and and geographic characteristics in the scheme. Masticated trial, severe ischemia was seen in 38% of patients, modern ischemia and 62% of patients on these air. The categories off percent an atomic stenosis in the patients who were randomized to invasive strategy. Zero vessel disease in 26% of patients multi vessel disease in just over 50% off patients. This is a court of patients who did not undergo coronary CT. So we did see that 2% of patients and left main disease on coronary angiogram on these are the results of this community Katie Trial No significant difference between, uh, invasion of conservative strategy for the endpoint of data. And my what I want to point out is the three year event rates. So this is, ah, hard composite of data. Um, I The event rates around 36%. So one in three had a primary endpoint event at the end of three years. If you look at the major secondary and point which is a five point composite again, no significant difference between visual and conservative strategy. And of course, the Beijing analysis is very consistent with the frequent its approach showing not no not significant difference between the two treatment strategies. So now when we combine both the schematics schema, security trial, we see that we have data across the spectrum of security stages security Stage one to stage five and dialysis. Andres were some of the results that I presented earlier this year as a late breaker at a C. C. So you see the breakdown of the patient numbers there. So if you look at all of the sea Katie stages and look at the end point So this is data and my no significant difference between invasive conservative strategy. If you look at the Trojan ity based on CKD stage, this is not statistically significant. So the results were consistent across all of the security stages. This is also true for the major. Secondly, and point no difference between invasive conservative strategy on the results were consistent across security stages. So you know this, in brief, is what the schema trialing showed. But now let's use that data and put it into clinical practice. Eso let's see our best. Can we use this thio manage for decision making in patients with stable ischemic heart disease. So now going back to the drawing board of why we're a vascular is patients with stable ischemic heart disease. Let's see Thio. Let's see if there is a data. There are data to support, uh, revascularization to improve survival. As we saw from data from prior trials. The trial trials have consistently shown no difference in mortality between revascularization medical therapy. And if you look at this scheme and ischemia, CKD trial and specifically, you know I want toe emphasize this in the scheme a trial. If you look at the end point of death, there is no crossing curves. I mean these these curves are superimposed on each other. No difference in debt between invasive and conservative strategy on this is also true for conservative strategy for the Eskimos CKD trial a death rate close to around 28% of three years. And we saw that this is also true across the security stages. No. A Trojan idea of treatment effect based on security stages nominal interaction P value 0.8 million different by security stage four. But given the number of analysis, this could be a play of chance. Um, okay, for some odd reason, this is not showing up but eso We recently published meta analysis of all randomized trials in circulation. Off routine revascularization was initial medical therapy. So this particular analysis included 14 randomized trials, 15,000 patients with average follow up off, put on 4.5 years with 65,000 patient years of follow up on what we showed in this particular analysis, if you look at what death, there is no significant difference between routine revascularization was this initial medical therapy for the endpoint of debt? The point estimate is a 0.0.99 and these, uh, figures are stratified by no stent trials or sustained trials. And so there was no interaction between no stand two assistant trials. In other words, older trial versus more recent trials. And in fact, if you just look at the more recent trials, the story is very consistent. No significant difference in death between the two strategies. In fact, we used ah clinical trialing design methodology using stopping boundaries to see Do we have enough sample size to rule out a significant difference in death. And what we showed was our analysis with robust enough to rule out a 10% rather to risk reduction for death. As you can see here, this is the accumulating evidence from all randomized trials. In fact, accumulating evidence crosses the futility boundary so we can say with confidence that there is the absence of for 10% relative risk reduction for death that revascularization when compared to medical therapy alone. What about the endpoint of cardiovascular death again? So there was no significant difference between revascularization. Was this medical therapy for then point of cardiovascular debt interaction based on older versus newer trials? Results are not significant. And if you just focus on newer trials again, no significant difference in cardiovascular death between the two strategies So But if you do go back to the guidelines, a CCH guidelines for revascularization to improve survival, the CCH guidelines do recommend revascularization in certain subsets of patients. For example, patients with triple vessel disease or two vessel disease with approximately lady disease. Um, these air indications for improving service revascularization for improving survival. So are there other high risk subgroup of patients where revascularization can actually improve survival in high risk group of patients, for example, left main disease, LV dysfunction, triple vessel disease, proxy lady and extensive ischemia. Now, if you look at the data for left main disease. So this is the data for left main disease. Um, looking at cat trials of cabbage was just no cabbage done in the 19 eighties. So there were three trials. And this this is ah, meth analysis by Salim Yousef off those three trials combining cabbage comparing cabbage, which is no cabbage. So in these trials, cabbage was associated with a significant improvement in survival extensive and survival by 20 months in the subset of patients who had left main disease. But of course, this was back in the seventies and eighties. Onda. The total number of patients in all of these three trials was 150 patients with left main disease. But at least this data seems to suggest that, um, revascularization improves survival, uh, in patients with the left main disease. But within that's upset. For example, the V a cooperative study did show that the left main severity potentially place an impact, um, on the outcomes. For example, in the V, a cooperative study in patients who had a greater than 75% left main destino sis the absolutely reduction or the absolute benefit off improvement in survival was greater when compared to patients who had 50 to 75% stenosis, although the interaction P value was not the significant eso clearly, um, in patients with left main disease, that is significant improvement in survival based on all the trials. And, of course, all subsequent trials have excluded patients that left main disease. What about patients with the systolic dysfunction on? Of course. As the stitch trialing addressed this question, Enrolling patients with ischemic cardiomyopathy randomize ing them to cabbages is, uh, medical therapy. Uh, okay, so there is some issue with my slide here. I don't, uh it z not showing up. But as we know from the data from the stitches trial, there was significant reduction in mortality with cabbage when compared. Thio medical therapy alone in patients that the ischemic cardiomyopathy, the number needed to treat if only 14 patients there was also signify introduction and hospitalization for heart failure in these group of patients. So as such in patients who have will be dysfunction, that is extension improvement in survival with revascularization. What about patients with triple vessel disease? So this is, uh, data comparing back in the day trials in 19 eighties to present. So in the 19 eighties, cabbage roses, no cabbage. This is the data from Salim Yusuf's group. Of what we have seen was in the three trials in patients with triple vessel disease. Cabbage actually improved survival compared to know, cabbage extension of survival close to around 6 to 8 months. But now, if you look at batty to D trial against with some odd reason, my, uh this slide is not showing, but I can see it on the screen here. But anyway, so on the bed, in the body to retrial. Even if you look at the cabbage trata, there is no significant difference between cabbage with this medical therapy for extension of survival. Improvement of survival in patients with triple vessel disease. Uh, I'm trying to see. Looks like my slides air not showing up. So maybe maybe, let me ask you, Do you see a graph there on the slide? No, unfortunately, probably see the title of the slide. Um, but the actual graphs or not showing up, some of them are. But this one, for example, is not Yeah, I do see that the rest of the slides it's doing the same thing. Um, give me one second. I'll try to use the pdf version of this. Yes. I'm sorry about that. So I hope you can see this, Um, so in the body to retrial. So, as you can see here, even in patients with triple vessel disease, if you look at cabbage versus medical therapy, there was actually no difference in survival. I wish I can just go. Okay. So what about triple vessel disease? And they ski me a trial. So this is the data based on the number of vessel disease, and they schema trial between in measurement conservative strategy. So, as you can see here, one vessel to on three vessel disease. In fact, in the scheme a trial, this is based on corn e c t. 45% of patients at triple vessel disease. And if you look at the end point that this is a primary endpoint based on number of vessel disease, Noah Trojan idea of treatment effect based on a number of vessel disease, and again, no difference even in the three vessels of group patients. So this is some data we presented earlier this year at a C. C. looking at Duke score of six but mainly comprising of patients with triple vessel disease looking for, then point off survival. Um, in point of mortality. Again, we see investment conservative strategy no difference in survival in patients with the triple vessel disease. What about approximately lady disease in the scheme? Trial eso in patients with or without approximately lady disease? Approximately Lady disease itself was not an effect modifier. This is for the primary and point, which is a five point composite. 46% of patients at approximately lady disease. No it originality of treatment effect based on approximately lady disease. What about survival? So this is again data presented at a CC this year. Although we use the Duke score of five. This also included a significant proportion of patients approximately lady disease on the messages Consistent. No survival benefit based on proximal lady disease status. What about expenses of survival based on a schema? Severity. So in ischemia trial, the entry threshold was moderate or severe. Ischemia did severe ischemia. Was that an effect modifier? And of course, as we can see here, over close to 55% of patients at severe ischemia and for the primary five point composite. There was no it originated treatment effect based on the degree amount of ischemia in the ischemia trial. And this is again some data we presented earlier this year. A day. See, See if you look at severe, moderate or mild or no ischemia and mortality, and specifically for severe ischemia. You see that the curves is still superimposed. No difference in survival between invasive on conservative strategy. So if you go back to the drawing board to improve survival, the revascularization to improve survival is only supported for certain subgroup of patients. For example, those who left main disease and, uh, those who have LV systolic dysfunction. What about to prevent other cardiovascular events? So in the scheme, retrial invasive strategy was associated with significant increase in procedural in mind, but a significant decrease in spontaneous and mind. So, in fact, that spontaneous and my was reduced by 33% with invasive strategy when compared to a conservative strategy. So on this effect, the effect on procedural non procedural um, I was actually consistent across the Katie stages, so higher hazard of procedural and my and benefit of reducing non procedural Am I In fact, in our meta analysis for the overall m I, we found that there was no significant difference in order. All of my between the vascular station was this medical therapy. But the test for interaction with significance is that in the newer trials there was an 11% decrease in overall Um, I with the routine revascularization when compared to medical therapy. And this was again The results are consistent. Increasing procedural, my decreasing spontaneous and my revascularization also reduced unstable angina with no difference in heart failure or stroke. So the other questions that's being asked is, can PC I actually reduce semi on in the scheme a trial. We found that there was a 35 33% reduction in spontaneous semi. But if you look at the complete trial, which is only P C. I, the effect off reduction in spontaneous and I was very consistent 32% reduction in spontaneous and my in the complete trial off stem E and P C multi vessel P C I. And in fact, we presented this result earlier at a CC this year, looking at conservative strategy in blue invasive strategy with P. C. I and cabbage Onda None. As you can see here, both PC and cabbage reduces taipan in my when compared toe the conservative strategy alone. And this is also a data with which we presented earlier this year looking at the prognostic implication off procedural versus non procedural, am I? So this is for the endpoint of all cause death, as you can see, procedural, Am I? The line crosses the line of unity. The confidence interval crosses the line of unity, whereas, uh, the type one, um, I the non procedural, um I is significantly associated with all cause. Death on this is also true for cardiovascular that this is a manuscript which is in, uh, preparation, so it will be published very soon. So at least in this analysis, we showed that, uh, non procedural a mile prognostic lee important when compared toa procedural m I. And finally, the other reason to consider revascularization to improve quality of life. So one thing that we showed in ischemia, which is kind of different from the prior trials in prior courage in Bari to re trials there, was implemented in the quality of life with the invasive strategy when compared to conservative strategy. But the effect was short lasting. For example, in the Barry to deal with PC I after one year, there was no significant difference within PC I and medical therapy on in the Courage trial. After three years, there was no statistically significant difference between PC and medical therapy for improvement in quality of life. The difference in ischemia is that we showed significant improvement in quality of life with an invasive strategy compared to conservative strategy, and this benefit was durable for up to four years in this trial on this was true for whether you looked at the sac somebody score angina, frequency score or the quality of life scale and in fact, what we showed in this trial as if a patient has daily or weekly angina, you only need to treat three patients to increase the probability of Noah Engineer have been compared to conservative strategy Onda along the same lines if your patients with no engineer. So there is no significant difference between in Beijing and conservative strategy for the outcomes off, probably of no angina, and in fact, this relationship was consistently seen through the length of the trial. Um, if you This is the quality of life for the ischemia CKD trial. So in the CKD trial, the difference between the domain and the CKD trial was that, uh, the proportion of patients with angina with no engineer was actually 50% so half of the patients did not have angina. And in this group of patients, although the trend was similar, invasive strategy was associated with the improvement in quality of life score compared to conservative strategy. This did not reach statistical significance. The probability of any benefit with the invasive strategy in the c. K. D cohort was hired in the first three months, but after three months, it, uh, it decrease with time. So in our meth analysis, looking at angina is an endpoint. Again, the message was consistent significant improvement in, uh, angina with revascularization when compared to medical therapy alone and just thio emphasize. So this is all of the data from randomized trials of routine revascularization? Was this initial medical therapy? It's important to recognize that these trials mainly under patient within the year for 35% or greater patients who had CCS class 1 to 2 and no left main disease, and if they were randomized to routine revascularization. 71% of them underwent pc I 16% and when cabbage on 12.5% under at the medical therapy and no revascularization in the patient to randomize thio, initial medical therapy or a duration of 4.5 years of follow up. It's important to recognize that 32% of them crossed over and underwent. Uh, some form off revascularization either PC ir cabbage. So in conclusion, I wanted to spare plenty of time so that we can have some discussion. So if you if you look at this meta analysis So we had data from 65,000 patient years of follow up from randomized trials off routine revascularization with this initial medical therapy and this suggests that nearly one in three in the initial medical therapy undergo revascularization over 4.5 years of follow up. There was similar survival between routine revascularization. Was this initial medical therapy routine revascularization reduced non procedural and my unstable and angina? There was greater freedom from angina at the expense of increase in procedural and my and so if you look at the overall conclusion in patients with CHD revascularization to improve survival is only supported by left main disease. But of course, this is not that there is no con temporary data. It's also supported for patients. It'll be systolic dysfunction, but for other substance of patients three vessel disease, approximately 80 and extensive ischemia. Data from ischemia trial does not suggest improvement in survival for those group of patients. So what are the other reasons to consider revascularization in such patients? And of course, we have clearly shown that revascularization produces a durable, benefited to reducing angina related quality of life. And there is also reduction in spontaneous and my aunt. I think the key to emphasize his patient preference matters in these decision making. Thank you for your attention, Sri Paul. Fantastic talk on. But I really congratulate you and the other investigators for the persistence in pulling off this trial. I know it's been years and years of hard work and planning, and to complete this and to offer this insight into stable ischemic heart disease is fantastic. So I really congratulate you and the other investigators and thank you again for coming to speak. Um, there's some questions that are popping in, but I'm going to start with a few, and I'm going to start with the big one that I'm sure you get all the time. Does ischemia even matter anymore? Why do we do a stress test? And this whole idea of wrist ratifying patients with mild, moderate, severe ischemia is that out the door now? So we just go based on symptoms and medical therapy? Yeah, you know, So that's a great question. And I think this is a question is going to be debated for, like, I think, the next couple of years as to what best to do. You know, my my short answer to that is you know, this Give me a trial itself was not designed to dio decide whether you should start with an atomic testing Was dysfunctional testing. Of course, there are other trials, the promise and the Scott. Uh, Scott hard trial, which, which addressed that you know, my bias towards what to choose. Um, you know, I lean more towards the nice guidelines in their recommendation is what should be the first line. So if you have a patients with no known coronary artery disease, I rather prefer an atomic testing like colony C t uh, to better define because even in the scheme a trial in in this upset with monitor severe ischemia, 20% were screened out because even after a stresses should monitor severe ischemia, their non obstructive disease and 10% of them I had left main disease. So I kind of leaned towards an atomic testing for that reason. And secondly, I think, uh, it really depends on the institutional strength. Um, so I think you know when one has to tailor it based on an institution strength. But again, I mean, in terms of how do you apply this? If you have a patient who is very symptomatic and it prefers thio, you prefer to revascularization strategy You no one can make an argument that why do all of these tests You can, uh, refer them for a revascularization to begin with. If you choose a conservative strategy, you need to make sure that as we showed in our trial, 20% of non obstructed sees 10% of lameness is so you have to make sure that, uh, you're not protect medically managing those group of patients. My next question. What is stable ischemic heart disease in 2020. What I mean by that if a patient gets angina after they go on a hike on DNA now they're getting angina on a walk around the block. But they're not getting anything at rest. Does that count? Is unstable angina progressing? Does that count a stable ischemic heart disease? Um, how do you view? And yeah, so I think you know that That's a great question. I mean, off course. I know. I always tell my fellows that you know all of this symptom, symptom mythology. It depends on how you ask a question to the patient. And, you know, you can have the same patient you can, you know, classify angina in many different ways on by thinking along these lines, I think the stable ischemic heart disease guidelines the A c c h A. I think there's a pretty good job a defining what is a low risk, unstable angina. So if the symptoms they're not lasting more than 20 minutes, if you don't have e k g changes, you can still consider those lotus can stable engine and manage them similar toe stable ischemic heart disease. So I do agree with that s so I think it's a more off trying to figure out how your patient is doing over the next couple of days. Will there be longer term follow up? And the reason I bring this up is what patients start with a stable lesion. Let's say like you show them that angiogram in 80 90% R C. A lesion that progresses and a third of you know, plus patients race and dramatic. So if we go natural history, I think it's a lot of us can conceive the idea that that artery will slowly progress to 100%. They will develop collaterals at the same time. It may never have simple, but what you and I see now in the cath lab is when somebody comes in with an M I. The ones that are really sick are the ones that have now assert Parnelli d m I. But they've had a chronic total inclusion of another vessel. So does this really answer in 4 to 5 year period, the long term effects of medical therapy and letting some of these lesions potentially progressed? The CTO s Yeah, I think that's a great question. And to add to that and we all know that compliance with medical therapy decreases with time. Eso, uh, along those lines have some good news that we have bean funded for, ah, extension of follow up. So we'll be following these patients up for another A t east five years. I think the maximum duration of follow up will be 10 years. So we have started the process. Um, so we will have some data on long term follow up. I mean, we're discussing the endpoints, but at least we will get data on survival, uh, for a long term follow up for 10 years for these patients. So you know, John Spertus, um, talks a lot about quality of life. And there have been a lot of discussions going around on patients preference and having to take a number of medications. Is mortality really the best outcome for these types of studies, or should we be looking Atmore quality of life, patient preference outcomes? Um, yeah. So I think that's critically important. And I think you know so to me personally, what ischemia trial does is, um, you know, there was a period of time. I'm sure you have seen this too. So If you have a patient with severe ischemia, the patients will be referred immediately to the cath lab. I mean, there will be referred from the stress test lab saying that Oh, this patient has ah lot of ischemia. He needs to go to the cath lab today. And at least this trial will say, Look, I mean, you're not killing these patients. I mean, there is no rush to do that, Um, so I think along those lines. So at least in ah subset of people's minds, severe ischemia is equated to increase death. So I at least this trial says, Oh, by the way, that is not going to be amortality difference. And, of course, then you have to weigh in everything else That's important for the patient, you know? So is it quality of life and and on The way I see it is, you can have two patients with the same symptoms on 1 may prefer medical management, and this trial will tell me that if he chooses medical therapy, it's not a bad option, is not going to drop dead. And, of course, that those patients will have to be closely monitored to see do they actually respond to medical therapy. And if medical therapy doesn't work, you have to take the next step off. You know, the vascular izing, those patients. So absolutely, I don't think I think as of now we have enough data for stable ischemic heart disease that it's not going to impact mortality. And so we do need to focus on other endpoints. Triple A question about Perry procedural and my and complications. This is coming up for the ischemia trial that's coming up when we talk about left main disease with Excel, Um, and P C I vs cabbage. So the procedural complication rate of 3 to 4% does that affect the bottom line and the outcomes? Yeah, So you know that this is a very important and controversial topic. And in fact, I can tell you, with the design of this trial we've been debating, I mean, it feels like it's a long debate for like, 10 years about what to do with this and what should be the threshold for it. And, as you know, the schema trial, we had a very stringent definition for procedural. And my, um, you're not only needed by market elevation. You needed to have some symptoms you can t changes are and geographic evidence. Um and, uh and, you know, even with that stringent definition, what we're seeing now is that the non procedural my is prognostic Lee. More important, at least for the five year time point than procedural. Um, I there are trends, Onda. Of course. I mean, on the clinical aspect of it is if you look at the data I mean, I think there was data published 10 years ago. How many people actually check by Marcus routinely And it was like 8% across the country. And I'm sure I and currently that it's it's very low. I think it's lower than 5% check routine by markers. So you're not going to see that in clinical practice? But one thing to be mindful is, uh, if you do revascularization the bad way, So if you lose a side branch, no flow, etcetera. So you're gonna pay a price at some point? I mean, it may not. It's, you know, the studies are all over the place. There are some studies showing any biomarker valuation post PCs associated with outcomes, and, of course, then Many of them are confounded by what competitive use. But this the debate off PC, I I mean, the very procedures spontaneous, I would think will continue for the reason that I mean, there are also other people would say, Oh, you know, you shouldn't give a free pass for bad revascularization. Three About how good is medical therapy right now in the courage trial, the event rate? Um, one of the questions says about 19%. While the ischemia trial, it was 11%. Um, do you have data on what medical therapy these patients were on? For example, what l d l they got to blood pressure. They got to their A one c. Yeah, that's good. Now, yeah, eso. The short answer is the medical therapy is definitely better. Andi, I think if you look at the conservative strategy event rates, as you just pointed out, it's definitely less than other trials, despite the fact that we enroll the high risk group of patients. Um, the longer and of course I mean, we have data on achievement of LDL goals and BP goals, etcetera. I think the idea less than 70% was over 70% of patients achieve that goal. Um, but if you look at the composite so we had a five point OMT composite goal attainment rate and it was just over 50%. So despite whatever we did, um, you know, on the way we achieved this I mean, this is very important. I mean, we did phone calls two sides to say, Oh, by the way, your patient x as not achieve this goal on. And we were constantly on the sides to make sure that they do this Medical therapy optimized medical therapy for these patients. Despite that, one in two patients did not achieve all of the goals. And, of course, if you look at individual goals, the goal attainment is much higher. But if you look at overall attainment of all goals, it's one into did not attend the goals despite the fact that there was heavy, uh, in a way, supervision and monitoring of these cases. So it just goes to show, you know, optimum medical therapy takes effort. Um, of course. I mean, we're looking at various different aspects of it, and as we know, regardless, even if the patient is randomized, revascularization, optimum medical therapies, critically important triple for for left main disease. You know, the teaching for a long time was anything more than 50% should be revascularization. And, you know, historically that's been by cabbage here in the US as we move in the era of FFR in really making sure legion is functionally significant. Do we have data? Um, that 50 to 70% left. Mainz may not need to be revascularization the whole. The reason I'm asking is that the idea of the c t. A and the ischemia trial was really to rule out left main disease. Yeah, Good question. Immediate lesions. Yeah, it's a good question. And I think, you know, unfortunately, we are stuck with this paradigm off considering 50% of greater left main disease as significant. Um, and as you know, So the previous trials use that it's based on 150 patients from randomized trials. And, uh, left Main tends to be one of those emotional subgroups. Unless somebody does a random maestro lie, I don't think anything is going to change with left. Mainz. Andi, I think we were very careful because I could tell you that one of the things that people were concerned is even one single left main. You know, if there is if patients were randomized in the trial and on the C T. C. C. T. Has said no left main disease and on invasion angiogram that was left main disease. It was a big issue, so we wanted to. We would get the coronary CT core lab and and your core lab to look at the same thing together and then speak to the side because you can imagine people lose faith if if if you start seeing left main disease when the seas Colony City said no. And of course, when we did all of this, which it was fascinating to know that, um in in most instances both were right. Both the current E c T guys were right and the and Yuko labral right, because we're looking at the same patients, but in different aspects of it. I mean, one is Lumina Graham, and many times the corny CT guys would say, Yeah, that it's plaque starting from the left main. But it's mainly in the hostel, a lady. So it's it's those kind of things that we were seeing. What is the proposed mechanism of decreased M I type one m I in the re vascular eyes group commented early about the vulnerable plaque versus the diagnosis. Yeah, so that's so That's a great question. So the quick short answer is we all know with cabbage cabbage bypasses 50 millimeters of the artery. So if there is a plaque rupture in the 1st 15 millimeters you protected. So that's the mechanism for cabbage reintroducing type one and my for PC I. It's interesting that the paradigm I talked about the, uh, in the seventies and eighties, where most plaque rupture because off plaque rupture from 50% are lesser stenosis. Now from Prospect and other studies, we know that even severe lesions 70% of greater lesions, especially if they're lipid plaque rich. So they also are causal in causing type one m I S O. I think it's more off. It's less to do with the degree of stimulus and more to do with vulnerable to your plaque. And what prospect and other studies are showing is, uh, even if you have an an geographically significant stenosis that can cause the type one m I, mainly because of its Olympic plaque and thin cap. So I think fixing those lesions with P. C. I is likely the mechanism production of M I both in the scheme a trial and also in the complete trial. Um, can you comment on the cost effective analysis that z underway? Yeah, that's a great question. So we're working on it, and I think we'll have some of the results in the next couple of months. All right, um, any role for stress testing in asymptomatic patients with known C A d, either with or without revascularization in the past. And I assume this is getting at is the amount of ischemia that we see with that matter? Yeah. So, unfortunately, I can tell you that based on what we have seen so far, you know, it ideally should not change management. So if you are truly a symptomatic beyond, um, primary or secondary prevention measures, uh, there isn't true role for revascularization. So there shouldn't be the amount of stress testing them for asymptomatic patients Should radios that being said, you know, there are importance of group of patients that are excluding all of these trials and specifically around the area's off, you know, Peri operatively, stratification and stuff, you know? So I think that that field needs to move forward to the randomized trials. Although there are few randomized trials that have addressed that. But, you know, in my opinion, stress testing for asymptomatic patients should definitely be big. Should be read used. Um Well, fantastic. Look sharp. I'm sure you've got to get Thio the cath lab here. Azaz. Well, so I want to thank you again. Fantastic talk. Fantastic insight into the ischemia trial and its implications. I think this is a debate that's going to continue on down. I know you guys are working hard and we're gonna learn more and more from the data that's already been collected. A s'more Publications come out. So once again, Thank you. And congratulations on the fantastic study. Thank you. Thank you very much. Thanks for having me on. All right. Take care. You too. Thank you. Bye bye.