Dr. Douglas T riffon discusses the role inflammation plays in the development of cardiovascular disease and reviews several clinical trial outcomes related to available treatment options.
sure. Okay, so now our next speaker is somebody everybody uh already knows Well from this morning is dr Douglas Trip in. He is the only speaker today that dr cork and I had asked to actually to give to talks. Um I also want to add in uh DR trip in clearly seems to be paying attention. During one of our breaks. I went down the hallway and went into his office and he was using a stepper right after my exercise talk. So I was pretty honored that he paid attention and started to get chris. Anyway, so uh so uh as the leader, as one of the leaders in the field of dis epidemiologic felt doctor Trip in, it was just the right person to speak on inflammation. And that's why we asked him back to give this this talk on an update on inflammation and novel biomarkers for atherosclerosis. So, without further ado I'd like to welcome back dr Douglas Trip in. Thank you again, chris. And thank you, David. And then let's get control of the screen. Yeah. Oh so residual risk and cardiac patients remains high even on guideline directed medical therapy even with LDL at goal. And again it's due to these other risk factors that we've been hearing about LP Little, a genetic small dense LDL oxidized LDL. Try this right remnants diabetes, smoking bad diet. Um poor exercise but also inflammation plays a role. So this lecture we're going to key on the residual risk from inflammation and how that plays in concert with LBO risk. These are my disclosures haven't changed since this morning. So we know from the last 20 years that there's a lot of bench science research on inflammation and that inflammation plays a role in all stages of arts grosses from the initiation of art sclerosis propagation and then the acute event plaque rupture. So this has been well established. But the question is, can we take this to the clinic, is this something that you can actually start implementing in patients that you're seeing in the office? We're not. So we're looking at dual targets, we're looking at a dual target of an SDL of 70 Or crp under two and the data is surprising that they're equal and risk. The hazard ratio for an elevated LDL is 1.7 and most trials has aggression for an elevated Hs cRP over two mg. Odessa is also 1.7 and we see this in many of the statin trials. We see this in the regression trials. If you leave CRP over to and you get your LDL nice and low, you don't get regression. It says is if it's as if you left the LDL high and untreated. So for every residual LDL risk, We have three people with residual inflammatory risk. So we often don't check Crp Hs CRP LDL was chucked a lot more frequently. So we're missing a lot of these people who haven't met this dual target. This is then a nice study from Jack showing that as we up the ante as we go from modern dose statin to high dose statin, improve it as we go from hindustan adding on his state of mind. As we then add on PCS Key nine, We see in the orange residual cholesterol risk is shrinking from 14% to 7. But look at residual inflammatory risk. It goes up 29 33 37. So with most of our guideline directed therapy, even our new algorithms or leaving inflammatory risk again getting worse and worse as we add on more LDL treatment. So again, in the final analysis we won't have to targets will have many targets cholesterol, crp residual traumatic risk, remnant risk, LP. A. Risk, diabetes risk, exercise risk, diet risk, stress risk etcetera. So recognizing that there are multiple targets but we're going to focus on just this dual target. So again, I think what we often forget when we're talking about this is that we do have a wealth of data with statins that they do handle these dual targets. So we've seen from care after Apotex caps prove it reversal. A TZ jupiter hard protection in ascot that higher dose statin that controls both LDL and HS CRP actually has incremental benefit and lowering risk more than just an LDL centric approach. This is shown here. So in the prove at trial which is of course moderate dose statin with pravastatin versus high dose statin with the tortilla Staten in the red do goals, achieved Much lower event rate 10% vs 5%. But if neither hall achieved again high risk. If he only achieved one, it doesn't matter which one you leave untreated, it's the same residual risk. High LDL is just as bad as leaving crp high. So if you have not reached a dual goal you can bump your statin up to higher potency. That is a way to get more people at the dual goal. Now, from the improvement trial, we also saw on top of high dose high potent statin, We can add on a set of mind and it did give you a greater absolute risk reduction, 2% in the overall trials and mentioned earlier on improve it. But now, if you get both goals attained you have a 10% absolute risk reduction. And so as a demigod can further lower crp Again it lowers LDL and improve at 24% crp nine or 10% And the absolute drop in CRP was .3 mg per deciliter. And again in the right patient that can be enough to achieve dual role. But it's another card in your back pocket to use. If you've got residual risk here from inflammation, this is then digging deeper in the prove it and say what is the change in hs CRP. When you push to high dose high potency sten and again you had an additional 0.8 mg were desolate or drop in crp going from monitor high dose N and if you combine this with the said imaging then Get a 1.2 mg for dust leader, which is a little more robust. Drop and get more people to do target and again shown to lower events. So when we're talking about inflammation and there's all these sexy new drugs, don't forget the drugs we already have. They do have outcomes and they do have efficacy. Saw this in jupiter. The extent of cRP reduction correlates with the event reduction As well as an ascot getting under most trials under two mg per deciliter. But here we had 1.83 but lower was important to achieve to lower events. Now the trial had absolutely proved the inflammatory hypothesis was the cantos trial. And in Cantos we had patients with CRP started over two. It was four point to an average LBO 82 And they were given Kenya Kenya mab in three doses And only one dose actually worked. It was the 150 mg dose every three months. There was no change in L deal. So a pure drop inn I owe six or the marker of I. 06 Hs CRP did drop events, absolute risk reduction 60.600 patient years. It was a small absolute risk reduction Number need to treat was 166 3 7 years of the trial, there was a 35 to 40% drop in HS CRP. But there was a higher risk in fatal infection. Sepsis 400.13 per 100 patient years. There was also a dramatic drop in lung cancer. So it actually dropped lung cancer 75%. So it seemed better as an anti cancer than as an in a coronary event truck. But it did prove the point lowering inflammation only. Not lowering LDL did lower events is in stabs, lower both. And so you couldn't really tease out how much was the LDL lowering in the CRP as cleanly is in this trial? So it proved the point. Now. They then went back and looked at the cantos and said, okay, does the event reduction correlate with the amount of CRP reduction? And the answer was yes, it did. So, in those patients in Cannes does who were given The 150 mg dose And did not get their crp under two because they started with a very high CRP. Some started with the crp of eight and they did not have any of that reduction here in the blue line, no different from placebo. So again, much as we saw in the PCS canine trials, just because you're on the drug, it didn't mean that at work you had to perform, you have to get that syrupy under two. Those patients who did get a therapy under two had a 25% drop in advance, they also dropped cardiovascular death 31% and all cause mortality 31%. So it was much more robust and I think this is a lesson in these trials is that we have to have a magnitude of benefit in the inflammatory marker before we're going to have transition into cardiovascular event reduction. So kenya kenya mab was not approved for use because of its cost and the question about increase in fatal infections. So then we turn to the trials on the old drug culture scene. One of the first trials was the cold cocked trial. And this is not an acute coronary syndrome trial. This is a trial in patients who are within 30 days of an M. I. But again not acute in mind. Then they were randomized to receive a lower dose than we have in this country. 0.5 mg of culture scene. Today we have 0.6 in this country or placebo. Importantly, they had a high CRP at intake, which makes sense If you're treating residual inflammatory risk, you want to have it in the study that's not always seen as well. Get to later in other trial designs and they had a composite mace for outcome and it was a positive trial. They had here A 23% drop in events And significant over the 22 months of the trial positive trial. They did not though reduce death, they did not reduce michael infarction, they did reduce stroke, they did reduce urgent hospitalizations for unstable angina and revascularization. That's going to be a common theme in all of the culture scene trials. They definitely prevent revascularization and there was a trend, curious trend we're going to see in all trials of a decrease in a fib wasn't significant but an interesting trend. So following suit then was a second trial with culture scene and this is the Lodo co trial pro design small trial and like small trials probably overestimates the benefit which I think it did Same dose around three years and follow up Mace as an outcome. And they found, you know, a 67% drop in events. And again this isn't going to be the event reduction that we see in Meta analysis. It's going to be more like 32% event reduction in an absolute risk reduction of 2.8. But small trial tend to overestimate benefit at a 10.7 absolute risk reduction number to treat of nine four deaths and coach the intent and placebo too small. The number to really be meaningful but a very significant event reduction. And interesting they had reduction in non stent related A. CS. So we know after an A. C. S. You put a stent in 50% of the time. The next event is from the non culprit vessel because the patients, an unstable patient is many unstable plaques, not just the one you stinted. And so again it's more likely that you're going to have an A. C. S. From one of these non culprit vessels for your next A. CS. And culture scene was effective in preventing it in this trial. So this was such a compelling trial. They decided to do it again in larger numbers. And so we have the Lodo Co two trial. So this time instead of 538 patients, we have 5,522 patients same dose 28 months. And they had to have corn disease on calf or C. T. A. Or as I mentioned in my talk this morning based on the new study in Jack Imaging. If you had a calcium score over 400, that was the same event rate as obstructive single vessel disease. They included that and they had mace for their outcome And they have this 31% drop in events, which is going to be more what we're going to see in meta analysis. So this is kind of the take home number to keep in your mind, absolute risk reduction to eight number to treat us 36 And again, not to compete with PCS canines, but just as a comparison, This is more powerful. In the same time period as the PCS canine trials, they had a 15% drop relative in outcomes and an absolute risk reduction about 1.6. And again, not that you can't use both and that that's where this research would suggest what if we have synergism here, shouldn't that be evaluated since PCSK nine inhibitors do not lower cRP. And for the right patient type, might this be a nice synergism for the future of cardiovascular management? Certainly, future trials would have to prove that to be the point. So, in the Lodo Co two trial, we did have a reduction of emi larger trial, esky mia revascularization, but not in stroke, not in death. And again, there was this trend towards reduction in atrial fibrillation. Non significant trend. There was an increase in biology because culture scene interferes with statin metabolism and you can set patients up for statin toxicity and myopathy. And so they did see a 15% increase in that signal with my algebra. There was a annoying signal of an increase in non cardiovascular death. There's not well worked out. Could it be from infection? Could be from pneumonia. Didn't really see it in the trial. So that has been a question and I think is area of need for further understanding, you know, in the use of focusing in coronary patients. I did this quick and dirty summary of the trial. This is all the outcome events reporting the trials and the the average is again a 29% relative risk reduction in absolute risk reduction of 2.5. Look at a Canadian meta analysis where they pretty much showed the same thing. But these are the take home numbers. What do you expect from culture scene? You know, and patients with stable corner disease or reason to my but not acute. Um, I and this is the take home numbers here. Now here's a study in acute um I so starting in hospital with acute coronary syndrome was a negative trial. So for reasons we don't understand giving culture scene early on didn't seem to be a win. There was another trial called Culture CNPC. I also was a negative trial. There was a 23% decrease in events. That was a non significant trend. But we really don't have rigorous scientific evidence. The acute um I and acute in the hospital is when you start Certainly 30 days post and in stable coronary patients. I think that is true. What we also don't have in these culture scene trials is no one's done the study. What was the entry HS crp, what was the achieved? HS CRP and didn't correlate with event reduction. Is that really the test of efficacy? And that analysis has been done and I think it needs to be done so that we know who would be the failure with these drugs and you know, when do not use them again. This is a meta analysis from europe raising at least to question. Is there a safety concern that needs further studied? I'll show you the Canadian and met analysis where they have more studies and they found that it wasn't significant trend, but it's still a trend. So again, it's something we need more evidence to know. Should we not be using it in certain age groups? Since we know immunity wanes, A certain age groups is a greater risk of sepsis and pneumonia. We don't know this. So this is the Canadian med analysis. They also looked at the side effects, but the Canadian Canadian met analysis, there was a reduction of them. I there was a reduction of stroke. There was a reduction of the recurrent urgent revascularization. So these are the areas where it seems to be the most robust and where we would use it. So we would think of using it in that patient. Maybe he was already on PCS can inhibit you got there LDA on the floor. But as I showed in my earlier talk, you can have an LDL of 20 honest PCSK nine inhibitor and have a high HS CRP and still have a 13% event rage, you know, in a year. And so you may not have that patient protected if he has recurrent events. Is this perhaps the patient where we would use culture scene? And then I mentioned that you dash prevent dot com website. If you go in there and look at the benefit, you'll often see that with really low LDL fifties, forties, the incremental benefit that it will show you. It will compute it and we'll show you that in the piece is an inhibitor. Didn't lower events. Very much interestingly enough. In reference to Dr Einhorn lecture, they have SGL T two in this algorithm. You can see whoa There's a great drop in cardiovascular events in these patients with that goal LDL adding an S. U. L. T. Two. But also they have culture scene in there and you can see you get this 30% drop in events. And so it really helps you tailor treatment for your patient when you might be thinking. You know, just just beat the LDL down to zero and that's as good as I can do what we have data. We can do more than that. We can add SGL T two, we can add GLP one, we can add culture scene. So another trial as a field trial. So this was a methotrexate trial and in this trial they recruited people history of M. I. Multi vessel coronary disease with diabetes metabolic syndrome. But they didn't have inflammation. They didn't have residual inflammation. So why would you design this trial knowing from the results of cantos? That the drop in CRP had to be 50%. And in the statin trials for an event reduction. So not surprisingly, this was a negative trial. If you didn't have residual restroom inflammation and you tried to lower it with methotrexate once a week, there was no benefit. Now. Whether methotrexate would work. If the CRP was four in this trial, we'll probably never know. I doubt this will be redone. So it's an unanswered question. And at this point we would say methotrexate doesn't have any benefit in lowering cardiovascular events. And there was an increase non death from any cause as well in this trial suggesting that there is a cost to inhibiting inflammation and maybe again with increasing inflammatory risk. So I'll get back to the conclusions here, let's talk about another inflammatory markers serra minds. So ceremonies are a single lipid and their increased with metabolic syndrome, diabetes, insulin resistance and inflammation. And there are better market than HS CRP. This is from search to and it shows that these ceremonies ratios are more powerful than all the risk factors we know and love. And curious as to what I mentioned this morning. Look at HDL cholesterol failing but look at HBO particle being superior. As I mentioned surprisingly, LPL early wasn't as strong as serra mites. But again, it may depend on the entry average LPL early in the population. That may not be true if your L. P. A. Is in the 89th percentile. This is then looking at combining biomarkers in what's called the cert to algorithm where they looked at multiple trials and they back tested and they found that high sensitivity troponin T had a very robust um hazard racial again at B. T. M. A. O. C. R. P L. P A Apple A one Appleby triglycerides. HDL everything you know and love you combine it with ceremonies so high central Cronin PM ceremonies, very robust risk predictor for mortality, cardiac mortality and myocardial infarction, not so much for stroke. And so I've been using this after reading these papers and after using it in over 200 people, I can tell you that people on Pcs cannot inhibitor. Staten Zetia cholesterol is in the dirt. You think that they're great. This is when I measure these two markers and I can't tell you how many people these are sky high and they predict plaque rupture. So we have ideas trials that show if you look with the knives and look for plaque ruptures and measure ceremonies, there's a really good tight correlation. Serra mites congregate in the block and they concentrate 50 fold and they lead to an unstable plot that ruptures and am I and cardiac death. So showing here the curve becomes geometric with ceremonies over five or six, four. Again, cardiovascular death. Or am I so powerful predictors better than most British Treasury years and discordant. And this is what is to me most helpful is that I can find people that I would pat on the back and say, you're beautiful. You're L. D. L. S minus 13. You're never going to die. And their ceremonies are 11. And it's like, oh my goodness, what would I miss? Or their troponin T. S. R. 30. And I sent him to Gonzales. We do a sita and we find, oh my goodness, we got triple vessel disease with no symptoms. So backing up to my conclusion, Cantos proved the pop the inflammatory prosthesis culture seen trials are probably closer to being used clinically and in perhaps that patient with residual inflammatory risk is having recurrent events Who we've got treated maximally. It has a role. It's a 32% drop in events and it's event reductions again, greater than pcs canine. Again, not that we shouldn't use them together. It may be exciting. Maybe additive using it with GOP one's and S. D. O. T. Two S. Could be additive needs studied. Uh there's some bench sites looking at using it with the EPA. Is anti inflammatory culture scene and EPA. Then you're going to offset the atrial fibrillation, possibly. So, again, there's a lot of, a lot of research to be done to really refine this no significant effective culture scene in a few corners syndrome, this cultures and uses for stable corner disease. Recent in my but not acute demise As far as we know until we have Further studies. Again, wait 73 days, we'll have twice some more information by then. They will have a different answer. methotrexate as to date, no proven benefit for preventing events. And again, new inflammatory markers such as ceremony means new Emmy markers, high centered troponin T which I showed earlier in my talk from the improvement trial from the timmy trials that those markers predict higher benefit from all the cholesterol lowering products. So biomarkers I think need to be out of their more sophisticated. They will make us able to make more aggressive choices and more appropriate treatment for the right patient and not for the wrong patient. So with that let me end and again. Thank you very much for your attention. All right well thank you dr Crippen we're two for two on staying on time doctor trip And that was that was great. Uh, I think really expanding our knowledge based on some of the newer biomarker, especially with inflammation crp, but also adding in uh, you know, the markers like the serra minds. I think that's going to really open up our toolbox. So thank you very much. I was great talk.
