Chapters Transcript Non-invasive Imaging of Coronary Atherosclerosis Trials, Tribulations and Transformations Back to Symposium David Newby, MD, PhD, FRSE, FMedSci, discusses non-invasive imaging of coronary atherosclerosis. any update on cardiovascular disease. I'm very grateful to Sanjay for inviting me and giving me the honor of presenting to you today. I'm sorry that I can't be there in person. These are my conflicts of interest and in red are the ones that are pertinent to this presentation. What I want to do today is to talk to you about non invasive imaging, Corey atherosclerosis and principally about ct korean geography. There are other modalities such as pets and I'm not going to talk about today. But what I wanted to share with you is our experience of conducting trials in this area with reference to other trials. And then some of the perhaps feedback that we received in presenting the study and then finally to go into where I think the future of ct angiography lies. So first of all, I was the chief investigator of the Scott Heart trial and this was a trial that was set out across the whole of Scotland and recruited around 4000 patients. These patients were in the cardiology outpatients clinic being assessed for chest pain. These were in 21 centers with three imaging centers. We approached patients once they'd been assessed by the cardiologists clinician in the clinic. So the patients would have been had an examination uh clinical history. They usually went on to have an exercise treadmill test there and then in the clinic, that's the structure that we tend to do and then the management plan of whether they needed a nuclear test invasive angiography and an initial treatment drug treatment and management plan decided then when all of that had been decided where they approached whether they'd like to take part in the study and they were randomized to a risk or that's to the probability of having a cardiovascular event or a C. T. Angiogram. So approximately 2000 and just over 2000 were randomized. ACT scan and 2000 to the standard of care are which included a risk score. So what did we find? The primary endpoint of the study was the diagnosis of angina due to quarantine because that's why they're there and that's why we're doing an extra test. And what we found was that certainly ct cory and increased the certainty of whether someone did or did not have coronary heart disease. And actually the frequency crept up a little bit so a little bit higher than anticipated. Which is probably as you would predict. But when it came to the primary endpoint of angina due to current disease, the certainty again nearly doubled. But the frequency actually slipped a little bit and found. And I think that's because the CT scan gives us that extra information as to whether someone did or didn't have current disease and prevented as over treating people. And I think we tend to perhaps over treat people a little bit just because we're anxious of missing someone with significant disease. So did that change how we manage the patients? Certainly change some of the investigations which I come on too. But it certainly changed the therapy. So in keeping with what I've just told you about the diagnosis preventative treatments were increased. Overall more new treatments were started than those that were canceled. They were canceling people had normal cory arteries. And the reverse was true for anti angina therapy. So more was start more was canceled. That was started in line with the fact that the frequency of the diagnosis of angina fell. Now. These were temporary changes in treatment you can see here this is five year prescribing data in the patients that took part and the increase in anti platelet and statin therapy persisted over the five year period. And did it change how we treat people in terms of coronary revascularization? Well yes it did. And there's a 20% increase in coronary revascularization in the first year. And this is often held up as a criticism of CT angiography of course the more disease you find the more you're going to treat. We've seen that with the drug therapy. So it's not surprising therefore that actually that that coronary revascularization was increased. Um But what you notice is after the first year when all the additional reeve asks that have been initiated by the C. T. Have passed you actually find a flipping over such that C. T. Was associated with less uh revascularization long term where standard care had a higher rate and that probably reflects a unrecognized disease than becoming manifest. But also unrecognized disease not being treated. And so I think overall over the five years there was no difference in riva scrapes yet despite that we did see a difference in the rate of fatal and nonfatal myocardial infarction. As you can see here. One thing that perhaps I agonized over is that we couldn't get the CT scans done that quickly. It took us a couple of weeks from the randomization to getting the C. T. Scan. And then of course he had to be reported results sent to the cardiologist and the cardiologist right to the general practitioner of the patient to initiate therapy so that all caused a delay over one or two months. And so I thought this was a bit of a flaw in the study but in some senses it's a virtue because you can see the capital markers do not change. So the ct scan is not a therapy. We know that's a diagnostic test is only when the therapy changes. Do we see a change in the trajectory of the capital my curves, which to me makes it certainly sounds sort of internally consistent finding. So overall we improve the diagnosis in one in four we change the diagnosis one in four, we changed treatments in investigations investigations in one of the extremes in one in four and overall nearly half the rates of my cardio function. So having done many clinical trials and finally had one that was positive I was delighted to have found this application for C. T. Which I think is a potential transformation. This did generate a lot of interest. Certainly when we published the five year outcome data and generated some controversy because I think this was something that people were not necessarily anticipating. We had some interesting social media comments john Monroe of course who's promoted himself as on the social media of cardiology came up with various comments along these lines uh actually slightly misled because he didn't read the full protocol properly. But there's a lot of exercise testing going on. And even if the exercise test was inconsistent you could go on and do nuclear studies which was actually planned in around one in 51 in 10 of the patients. Some of the criticisms where we had too many endpoints in there and it was an open label trial. What's their case ascertainment bias. So we took all these on the chin I suppose. But I would like to take you through some of the arguments as to why I don't think that's particularly right. Um Certainly in terms of open label and being what was this a real effect? Well of course um we then had patients who went on to have an invasive cats and what we found as indeed the uh promised trial which was also reported around initially around the first time the scott heart trial was reported. Um you see that the rates of normal korean geography. When you go to the invasive cath lab greatly reduced halved in nearly halved in promise two thirds reduced in scott heart. And the problem with that is that the people that did get in the Cath lab had more actionable disease. So around 30% were more likely to have obstructive disease in both the promise and the scott Atran and that's why we saw the early rise in intervention but then that subsequent fall, which is intriguing. We also know from individual patient data, meta analysis that Mark jewish group in Berlin and scott heart contributed around 500 patients. This meta analysis that actually, if you try to find obstructive disease CTE is pretty pretty accurate sensitivity is nearly 100% specificity is 1000.87 but is often said if you show to interventional college the same invasive coriander gram and they always agree 100% and arguably just as variable as one of the show cts. And I suppose the final thing that I would say about accuracy is that actually recently had the discharge trial which looks at comparing head to head invasive cast versus cT coriander grameen people referred for invasive calf and of course as alumina graham invasive cast can often miss plaque in the wall. And so actually C. T. If you're looking for Korea aroma is the gold standard because it's not aluminum graham actually can see the plaque in the wall. And as you can see here um it gives you much higher rates of a detectable corn aroma. The other issue that perhaps is often flagged is that myocardial perfusion imaging is the gold standard for risk stratification. This is against scott hard data on the right. You can see risk stratification in terms of exercise E. C. G. The humble exercise E. G. G. And as you can see it does indeed predict outcome of fatal and nonfatal M. I. 23 fold between normal and abnormal. Um But when we looked at the patients only only a third of the ones that went on to have an M. I actually were in the BCG positive group compared that to the ct normal cory arteries hardly any. And in fact when we looked at the ones that did happen there most of those were in um scans that had a lot of motion and we probably missed a little bit of that aroma. But putting that aside and you can see is an 11 fold difference between those with normal and obstructive disease. And what you also see is there's an awful lot of non obstructive disease. And over around half of the mls and scott heart trial happened in those that had non obstructive disease and of course non obstructive disease by definition you should be able to detect by a stress test. Now you might say well this is the humble P. C. G. David. Or do you expect. But this is the promised data. Same sorts of plots here. They 70 80% where nuclear and stress echo scans not humble treadmill and we see exactly the same thing. So here is a roughly fourfold risk from normal to severely abnormal. They graded the severity of abnormality here And over 50% of the subsequent M. i. S. happened in those that had a normal functional test. And again when it came to C. T. There was over a tenfold difference in normal to severely abnormal and over 50% of the M. I. S. Over 50% of the M. I. Had non obstructive disease. So really reinforcing that. And there's been recent data out from ischemia trial showing exactly the same thing that stress echo was greatly inferior to the C. T. In terms of risk stratification. Now the next criticism that's been leveled is the promise trial was neutral and scott heart was positive and are they really comparable etcetera. But if you use the same endpoint and this is buried in the supplement that promised trial and then you uh if you look at one year death nonfatal myocardial infarction they have almost the identical hazard ratio confidence intervals and indeed p. Value. Um So this is not a bolt out of the blue. This is not keeping with other trials. And indeed various metro analyses have shown this consistently observational social showing this consistently that there is a reduction in their mind. And I think this has a lot to do with finding non obstructive disease and treating it appropriately with preventative therapies, lifestyle interventions etcetera. Of course we also have had the discharge I've always mentioned. And indeed when you look at hard endpoints by invasive cath which is a huge uh a really tough thing to be event rates. Okay, that wasn't statistically significantly different but it was slightly lower in the C. T. Arm and I'm a great fan of compounding or layering um safety outcomes with efficacy outcomes. But if you do add in as indeed the promise trial did actually they did layer efficacy and safety outcomes. And if you layer those together then you see quite a dramatic difference in terms of outcome in favor of C. T. Because you get less complications. And in the discharge trial, I should also highlight that in terms of outcomes, there were less reve asks in the CTR. And similar rates of angina and only 20% of those who had a CC first went on to a very invasive cats in the end. So really quite remarkable. And I do think that putting aside even is a stress test versus a functional test, it's now getting to visit an invasive coriander gram or a ct coriander graham. And I think we're now increasingly seeing that that this is being taken up. And of course in the UK, the nice guidelines have recommended C. T. Is the first line test of choice in people with possible angina and uh and I'll show you some data related to that in a minute um european and north american guidelines now both give C. T. A. Class one indication. I think the american guidelines are actually more accurate. They stick to the data and they recommend for intermediate to high risk patients with stable chest pain and no known cory ostracize the ct coriander graham and that's done to risk stratify them and for guiding treatment decisions. Whereas the european guidelines give it a one B which I disagree with for reasons already mentioned and actually give equal weight as a stress test, which I think is unfortunate because that's not really following the evidence. Are people listening to the guidelines? Well this is UK data, Jonathan will mccall in Cambridge, did this in the whole data from England and even the english are listening to the Scottish data. Um and as you can see, the first scott heart promised publications came out in 2015 and you can see an upward trend almost immediately in ct angiography there the great dotted line is when the nice guidelines were Published, although there was between 2016 and throughout 2016 really there were draft guidelines for consultation and before the ultimate publication at the end of that year. And what you can see is the trends of testing. Now I think in purple there is his spect scanning and you can see that is been historically declining. And the converse of that stress M. R. Which has been slowly rising given its popularity in the UK. But what you can see is a nice genuflection of C. T. Really ramping up from around the time of the trials coming out in the guidelines. Nice guideline coming out. But at the very top you can see invasive coronary angiography and you can see a very subtle starting to decline. And that is actually just uh statistically significant decline that you're seeing the invasive cat that we're seeing across the UK really reinforcing what we're seeing from the discharge trial. And then Jonathan went on to do perhaps a slightly provocative analysis where we looked at cardiovascular mortality and looked at each of the regions across the UK and those that were early adopters and using a lot more CT and changed to C. T. During the time course the 10 year time course that we looked at. What we found was that the greatest reductions in cardiovascular mortality we're seeing in regions that were early adopters and users of ct korean geography and those regions had the greatest rise in CT numbers had the greatest fall in the mortality associated cardiovascular disease. Now there are many confound is here and I'm not saying that the C. T. Is the only explanation because of course regions that are investing in cardiovascular investigations, maybe better regions that are treating patients better etcetera, etcetera. But this is in line with what we've certainly seen in the trials. So that's where we are, where we're going. Well of course. Ct angiography gives us a lot more information than just obstructive and non obstructive. This is one of the seminal papers from 15 years ago and Mighty armies paper looking at patients with acute coronary syndromes and stay by Joanna petrus and looking at plaque characteristics and what you can see is that patients with acute current syndromes are have positively model plaque, non calcified plaque and spotty calcification within the plaque. Whereas large areas of macro classification actually imply stability. And so these various features possibly modeling low attenuation plaque spotty calcification and the napkin ring sign. Which is a very particular type of quite a nasty low attenuation plaque are all associated with adverse events. And we certainly looked at this in the scott heart trial, Michelle Williams did this work. And if you have any of those features, then you have quite a marked difference in adverse outcome on the right hand side. You can see the corollary with obstructive disease and showing very similar differentials. And I want to come back to that in a moment. But this is qualitative, this is what it looks like. What about quantitative plaque analysis And without any day. And see the Sinai using her very uh imaginative software. We've looked at Connery plaque in terms of its composition. Total plaque volume plaque. Non calcified plaque, calcified plaque and lower, low attenuation plaque. The necrotic core type plaque. What we find is that when you look at how these things are interrelated, there's a very strong interrelationship risk courts don't do very well. But area stenosis correlates with a lot of these plaque burdens and that should not be a surprise because of course to get a static Corey artery, you have to have positive remodeling. That then is the plaque is going is growing so much that it overcomes that positive remodeled segment of the artery and then causes a Luminal stenosis. So having a stenosis is actually a marker of having a lot of plaque. But beyond just that, even when you don't have to notice and you have a lot of positive remodeling and that is a high risk factor. And when we looked at all the different things, the thing that came out in multi variable analysis was the lower density, low attenuation plaque within the arteries which showed a five fold difference in outcome. So really, I think we're moving into an era now going beyond to notice severity when we're trying to predict infarction, looking low density, low attenuation plaque and these irish plant features. Now I'm just going to briefly mention some of the other areas that are in development, you'll be familiar with Harris. Santa needs work in oxford looking at peri vascular fat. We're looking at inflammation around the artery, in the adipose tissue. And he's certainly gone on to show that in the christmas, et studying some german cohorts that this inflammation around the artery does appear to be a great risk predictor. We've looked at this both in terms of the plaque characterization I've just described and the perico very flat. And when we put those two together, we do find that both predicted the low attenuation plaque does seem to add value, that the pericardial fat does appear to add some value. And when you put them together it does seem to be that the low attenuation plaque is the dominant factor, but there is a slight additive value in the two. And we're going to see how that pans out in the future. I think we need more studies on this prospective studies and external validation of it. And then finally, it's getting really complicated in there. We need, you know, doing plaque analysis takes, you know, half an hour to an hour to do patients. Is that really clinically possible damage? Has certainly developed her auto plaque with Ai algorithms to do this automatically charis charis Antoniades has taken even further in doing radio mics, not just the pericardial fat, but all the other features that we can and can't see with the naked eye. And this is getting really complex, but you can get quite spectacular results with this radio mics approach and this is actually we shared within the scott heart to be analyzed. All the scans and we can see is that this radio mics approach can really dramatically hell of ratio of it alone in terms of the outcome and the high risk plaque. And this radio mics approach certainly seems to have synergistic value again. So I've hopefully given you an insight into my view of ct cory angiography assessment, noninvasive assessment of Korie atherosclerosis. Take you through some of the trial data. Some of the criticism, comments and some of them have not addressed in the talk will be delighted to do so in the discussion and hopefully seeing where Seti korean geography is going in the future. So it just leads me to thank scott Heart trialist and acknowledge my co workers here in the UK International and of course in the U. S. Thank you. Created by Related Presenters David Newby, MD, PhD, FRSE, FMedSci British Heart Foundation Duke of Edinburgh Chair of CardiologyProfessor, University of Edinburgh, Scotland British Heart Foundation Duke of Edinburgh Chair of CardiologyProfessor, University of Edinburgh, Scotland
