Chapters Transcript Colchicine, is it finally time? Course: 4th Annual Cardiometabolic Risk in Inflammatory Conditions: Emerging Insights and Treatment of Inflammation in Cardiovascular Disease Colicine is it finally time after almost 15 years of research in this area, I am happy to say that yes, it is. Here are my disclosures. So let's start off with a case, a couple of cases. This is 76-year-old guy, has heart disease, prior stents from an outside hospital, also has a bunch of comorbidities, afib, chronic renal insufficiency, GFR is 50%, it's not terrible. EF is 45%, mild global hypokinesis, and he comes in with an NStemi or a non-ST segment elevation MI complicated by a stroke with a hemorrhagic conversion. This is his RCA, which is essentially a chronic total occlusion. And this is his left coronary artery, and you can see here there are uh osteo disease that both the involving the both the circumflex and the LED. So he was presented to the heart team. He was turned down for surgery given his recent stroke. He was recommended for optimization of medical therapy, started on dap, uh, with close neuro follow-up and had recurrent angina. Surgery was still not keen on taking him, so I took him to the lab. We did a transradial PCI um with two stents extending back into the left main. We left the residual disease, mild to moderate stuff distally. So on follow-up, he had no recurrent chest pain. His blood pressure and heart rate were well uh controlled on max doses of the ARB and beta blocker. His creatinine remained at baseline. He's a little overweight. B BMI was 28, but he had a normal A1C. His lipid panel was uh well controlled on high intensity statin, his LDL was 45, and his HSCRP was 3.1. So what would be the next treatment strategy here? Here's another case, 67 year old man, prior stents in a known distal cirtotal occlusion with mild LAD disease on a remote angiogram comes in with an exertional angina and his EF is normal, and we see this just diffuse disease in the LAD. Maybe nothing necessarily that sticks out as, as severe except for something further down distally which we would never treat, at least not uh mechanically. So I did a pressure wire and invasive physiology, um, showed that uh there was a nice step up right here between these two lesions. And so we were able to do a physiology guided PCI with one stent and show that invasive physiology, so anything with an RFR above 0.9, isn't considered technically significant, although ischemia is on a continuum. It, it was certainly improved with that one stent for, for now. But this patient really has just a lot of diffuse disease. And he had no recurrent chest pain, so we're glad we treated his angina. His heart rate and blood pressure were also under well controlled. His LDL was also 45, his HSCRP was 5.29. So how do we treat him? He's got tons of diffuse disease everywhere, but not necessarily a focal severe spot. So just to recap from everything that you've heard today, when you think about the pathophysiological role of inflammation and coronary artery disease and ACS we think about modifiable risk factors, we also think about non-modifiable risk factors, but we want to understand that a lot of this will come to atherosclerosis through some final common pathway mechanisms, including inflammation, as well as oxidative stress and insulin resistance. I'm gonna very briefly show you some pathophysiology to really just give you a sense as to what colchicine is targeting down the line. So the normal coronary endothelium is resistant to adhesion by circulating leukocytes. Inflamed or injured endothelium, such as an atherosclerosis or an acute plaque rupture, will attract neutrophils via selectin molecules. There are L-selectins on the neutrophils and there are E-selectins here on the endothelial cells. And then they adhere more tightly to the endothelium via integrin molecules, if you can just remember CD 18, anything with the CD. Uh, CD 18, CD11B in this case, and cellular adhesion molecules. They travel into the endothelium via chemokine gradient and once in the endothelium, they'll release inflammatory enzymes such as matrix metalloproteinase that makes the shoulders of plaque even more vulnerable to rupture, as well as production of IL1 beta, particularly from the NLRP3 inflammasome, which then leads to IL-6 production and subsequent CRP production. On the thrombotic side, neutrophils can also release serine proteases such as elastase, and we'll talk about that in a little bit, that inhibits tissue factor pathway inhibition. This allows thrombin to form, and thrombin is a very potent platelet activator. So you can see here how there is an interface between inflammation and thrombosis. And for us in the, in the interventional cardiology realm, platelet activators are a terrible thing. So leukocyte platelet aggregates as well as neutrophil platelet aggregates in particular, have been shown to be uh increased in the setting of acute coronary syndrome and uh and are considered a possible mediator of thrombo inflammation. So again, very briefly just to recap from today, inflammation and cardiovascular outcomes. We know there have been multiple studies that show that if you achieved both targets of LDL less than 70 and an HSCRP of less than 2 patients had improved outcomes and that's what's shown here on the red compared to one target alone in the middle or neither target in in blue up top. How about in um patients who are, are treated mechanically with PCI? Earlier studies showed elevated markers of CD 18 and CD11B. So remember these are the molecules that allow neutrophils to adhere tightly to the endothelial cells. They're much higher in patients who go on to develop re stenosis after a stent displaced in their coronary artery. More recently, we looked at the Paris registry. And showed that PAIPCI inflammation is a marker of adverse outcomes. Now you're going to say, Benita, of course, if you're, if a patient's white blood cell counts up, yes, I expect more events. I expect more cardiac death. But interestingly enough, there was also an increased risk associated with clinically indicated target lesion revascularization. So there was something about Um, whatever the background MU was to lead to uh adverse events related to the stent itself. From prospect, we know it's a three vessel intravascular ultrasound study in patients who were treated for acute coronary syndromes, and we know that the event rate, despite after PCI, is still 20% at 3 years, and only half of these are due to the culprit lesions or due to stent related issues. The other half are due to non-culprit uh lesion related events. So some of the therapeutic targets to improve outcomes after acute coronary syndromes and PCI include the lipid lowering therapies, platelet inhibition, anticoagulation, as well as advances in procedural technique and devices. But what can be some other targets here, and that could be the inflammatory cells and thrombo inflammation. So does lowering inflammation with targeted anti-inflammatory agents improve cardiovascular outcomes? We know from Canos that it does. Anti-IL1 um inhibitor canakinumab lowered events, uh, without, with a marked reduction in C reactive protein and no change in. LDL, so confirming the inflammatory hypothesis, and the secondary analysis showing that it was those who were treated and achieved uh treatment targets for HSCRPs less than 2 that actually derived the benefit. Those who were on treatment and did not lower their CRPs had event rates similar to placebo. What about um other anti-inflammatory agents? We have the CERT trial, um, Doctor Whitker led this one as well, patients with prior MI or or multi-vessel CAD and type 2 diabetes or metabolic syndrome, and they showed no difference between an event rates of non-fatal MI, stroke, or cardiovascular death between low dose methotrexate and placebo. However, there was also no difference in interleukin 1 beta, IL-6, or CRP. Remember, Canos looked at IL1 beta. So then the question is maybe blocking the adenosine mediated pathway via methotrexate does not work. Perhaps we should focus more on this particular pathway that we already know works with Cantos, um, IL1 beta, IL6 CRP pathways. So this is where colchicine can potentially play a role. Um, it's, as we heard earlier this morning, Doctor Pilinger said, you know, it, it's a natural product of this really beautiful autumn crocus plant, and, um, uh, we do, um, I do pull that out for any patient who says I don't want to take yet another medication, and yet they're taking all these herbal supplements, and I'll say, you know, this is from a plant. It's a botanical. Described use was first for rheumatism in 1500 BC, so I can very confidently say that it's been used for more than 2000 years. Um, it may actually be the mythical golden fleece that Jason was looking for, and I could give a whole talk on that. And it was brought over to North America by Benjamin Franklin. So what are the mechanisms that colchicine can, has been shown to target? Well, colchicine does have an impact on neutrophils. Our group, um, Doctor Konstein had shown uh uh decades ago that colchicine diminishes the expression of L-selectin on the surface of neutrophils. That's right here what I showed you that attracts the neutrophils to the endothelium in the first place, both in vitro and in healthy volunteers. We went on to take neutrophils isolated from patients who presented with acuteMI and treated them with various doses of colchicine and showed that the end of um interaction between these treated uh neutrophils to endothelial cells were a lot lower, so they were less sticky to endothelial cells as um colchicine was administered. colchicine has also been shown to decrease neutrophil chemotaxis and neutrophil activation, as well as potentially inhibit the inflammosome and thereby decrease IL1 beta production and subsequent IL-6 CRP production. We took uh isolated neutrophils from healthy volunteers and uh stimulated them with LPS and so those two markers up top are the neutrophils stimulated with LPS. Once they were administered with colchicine, you can see here the neutrophil metabolism, as measured by a seahorse assay was lower in those stimulated neutrophils treated with colchicine compared to stimulated neutrophils alone. Um, we looked at, uh, the benefits of colchicine in patients at high cardiovascular risk. Doctor Pillinger gave a great talk on gout this morning, and, uh, one of our earlier studies had shown that it was the consistent use of colchicine that led to the lowest CRP levels in these patients. And then Doctor Neidorf went on to do an early open label pilot study taking patients with stable CAD and seeing that colchicine had a benefit on CRP even on a background of aspirin and high intensity statins. So you can see here with colchicine and without colchicine CRP levels. What about its impact on platelets? We know that the microtubule disassembling actions can convert discoid platelets to rounded irregular forms. And however, in those we're seen with more higher doses with currently used clinically indicated doses that we use in gout nowadays, um, we can see these were given to healthy subjects. We can see that there is no difference in platelet to platelet aggregation. However, there was a difference in the extent of neutrophil platelet aggregation. So these were given colchicine, and you can see that although platelet to platelet aggregation did not decrease, neutrophil to platelet aggregation did. So it may not affect platelets alone. We've never seen an increase in bleeding events when it came to um patients on colchicine. But it may affect rather platelets at the site of inflammation. And this is very helpful to know because, uh, especially patients with coronary disease or prior MIs, they tend to be on more potent antiplatelet agents, and the last thing you want to do is add another agent that could potentially cause more bleeding. We saw these data earlier today, um, that treatment with colchicine led to an improvement in endothelial function in gout patients, as well as lowering the urate. And then there was a very nice study done down at Hopkins. They took 80 patients with acute coronary syndrome and randomized them to receive colchicine plus medical therapy or just medical therapy alone. And over time, um, on a mean follow up of about a little over a year, there was no change in LDL, but there was a greater reduction in low attenuation plaque volume as well as CRP, and this is low attenuation plaque volume. So this is a soft core in the plaque, and you can see that over time in the colchicine group that diminished more than in those who were not treated with colchicine. So it may play a role in plaque stabilization. What about colchicine and outcomes? Um, I'm gonna skip through incidence CAD. We had heard this morning that in a defined cohort of gout patients we saw that there were a lower incidence of new diagnoses of CAD in patients without kidney disease, and we could look at that because the interaction p value was quite strong here and that there's just leads us to question whether or not there's a benefit of colchicine on the development of CAD itself. How about its role in therapy of uh in PCI or in percutaneous coronary intervention in particular. So, uh, with my career development award, we had ran this double blind study, uh, randomizing patients who were coming to the cath lab requiring a coronary stent and ads administering an acute load of colchicine of 1 to 2 hours before the procedure to see if it reduced biomarker evidence of PCI related inflammation and myocardial injury when compared with placebo. Well, we saw no difference in myocardial injury, but interestingly enough, we did see that for the first time that colchicine dampens the inflammatory response to iatrogenic injury. So you can see here in the red is is placebo, and the blue is colchicine at 22 to 24 hours. The rise in IL-6, as well as the rise in CRP after PCI is much greater in the placebo group than in the colchicine group. So CO PCI went ahead and took that data and tested the use of colchicine earlier prior to PCI, and they did show a reduction in both minor and major periprocedural myocardial injury. But you're gonna tell me, well, OK, what, how am I gonna predict that a patient's going to have an MI? How am I gonna know to give them colchicine 6 to 24 hours before if you can't just give it right before the cath lab? And I'll agree with you, except there is one setting where you do know that you can predict. Uh, potential, uh, adverse event and that's after intermediate or high risk non-c cardiac surgery in a high risk patient population. So we're currently running, um, with federal funding a multi-center trial taking patients with established severe coronary artery disease, uh, who are undergoing intermediate or high risk non-cariac surgery and randomizing them to Colchicine periooperative Colchicine versus placebo to reduce negative events, hence the popcorn trial. And learning from our data from before, we are loading them a day before the surgery to see if we can reduce these negative events. So stay tuned. How about colchicine for re-stenosis? There was a small randomized trial. It's the only one that we have to date, but we don't have much, honestly, in the current era to reduce recurrent rest stenosis. So this is helpful. They took patients who are at high risk of re stenosis, diabetes treated with a bare metal stent. And they showed that treatment with colchicine versus placebo led to lower reststenosis rates, both defined on angiography as well as intravascular ultrasound on 6 month follow up. So in our resistant patients who keep coming back with IS instant reststenosis, this may be a potential, this is a good potential option. We also know that in patients who are at high risk of of uh of cardiovascular disease, these patients with gout, being on colchicine is associated with the lower risk of MI, and I'm bringing this up over and over again just to show you that it is consistent that you're gonna see over and over again that their colchicine uses is associated with the reduced risk of MI. Solomon's group at Brigham we um. Uh, we produced our data using their own EMR and showed that colchicine use was associated with reduced risk of MI stroke or TIA as well. In Lidoko too, uh, patients with more than 5000 patients with chronic coronary artery disease were randomized to low dose colchicine or placebo, and they looked at the primary endpoint of cardiovascular death and my stroke, and they included the soft endpoint of urgent revascularization and showed a benefit with colchicine. This was largely driven by again MI and ischemia driven revascularization, which again is a soft endpoint, but if you look at the secondary endpoint, which was all hard cardiovascular endpoints, there's no way to refute cardiovascular death, MI, or stroke, and you can see here that Colchicine reduced events, and again this was driven by a lower rate of MI. In the Colcot trial, patients within 30 days of an MI were randomized to low dose colchicine or placebo, and their primary endpoint of cardiovascular death, resuscitated cardiac arrest, MI, stroke, or urgent revask was lower with colchicine compared with placebo. It's interesting though that this was largely driven by a reduction in stroke, um, which we hadn't really seen before, uh, on its own and or such a dramatic difference, um, and urgent hospitalization for angina leading to revas, which I personally think is a soft cardiovascular endpoint and don't put too much effort into it. And there was not a reduction in MI so I actually think this is a little bit of an outlier and maybe, maybe a fluke compared to all the other data we have in the various populations. So there is the largest trial to date, clear trial, 7000 patients diagnosed with a large MI referred for primary PCI are being randomized to colchicine or sparolactone versus placebo. It's a 2x2 factorial design. Um, I have an RO1 to evaluate the biomarker substudy for the clear trial. So this hopefully the primary trial we have done with recruitment. 7000 patients were enrolled. Primary results will hopefully be presented in the fall, and the biomarker substudy thereafter, so stay tuned there, but that would be the largest acute MI trial that that we would have tested colchicine in. What about adverse events? Um, as noted earlier in the day, we have data on Colicine from gout patients, FMF patients, a whole host of other non-cardiovascular populations, and the event rates are really driven by diarrhea and gastrointestinal events. This is, um, pulled participants from randomized trials, more than 8000 patients, and you can see here in the green there's no difference in infectious rates here, um, or hematology or muscle or liver. Non-cardiovascular mortality, however, there has been shown to be a a signal. That's not looking so favorable for colchicine. That's largely driven by um cops and, and, uh, mostly by cops, and I'll and I'll go into what uh COPS and Ldokco 2 showed in terms of non-cardiovascular mortality. So these are just my thoughts. This is relatively new, seeing it in Lodoko and COPS, which was a very small trial. Um, it, you know, it's new and it has not been illustrated in in the other more than 8000 patients that were randomized for um for in other disease processes. There's also no clear biological root cause for the non-cardiovascular deaths. In COPs, um, the increased incidence of sepsis in the non-CV deaths would raise concern for a potential immunosuppressive effect, but again, there was never an increase in infection elsewhere, and the majority of the incidence of sepsis occurred after the medication was discontinued. So that's, that's important to note that this was after colchicine had already been discontinued for other reasons. And in Lodoko too, the non-cardiovascular deaths were unable to be attributed to any one specific cause, such as infection or cancer, so there wasn't really a trend to sort of root it down to. So given the low number of events, there really were overall low number of non-cardiovascular deaths, the wide confidence intervals, I think the observed differences in the non- CV mortality may be attributed to, um, you know, limited power or play by chance, but it's something that we do need to watch out for and we'll be very interested to see what Cle ends up showing in terms of the non-cardiovascular mortality. Consistently, however, across the board, CV mortality and MI has been lower with the use of colchicine. So in summary, inflammation plays an independent role in major adverse cardiovascular events after acute coronary syndrome. We think that targeting the specific pathway of IL1 beta, IL-6 CRP is probably the right path that we should be on and continue to investigate other uh targets in this area. Colchicine affects these pathways with a balance for safety and effect on clinical outcomes, particularly to reduce recurrent MI. The data for colchicine in the stable CAD setting is pretty strong, and then pending clear to determine how soon after an acuteMI it would be appropriate to start colchicine. Thank you very much. Published April 26, 2024 Created by Related Presenters Binita Shah, MD View full profile
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