Dr Philippe Gabriel Steg (00:06):

Hello. Welcome to this symposium called Lipid Lowering and Antiplatelet Strategies after ACS. It's a case based discussion. I'm Gabriel Steg from Paris, France. I'm delighted to moderate this symposium with my friends and colleagues, Professor Mehran from New York, and Professor Jukema from Leiden in the Netherlands. We're going to try to make this fun and interactive. It's very brief. It's only 45 minutes, and we're going to try to discuss clinical scenarios that are relevant to our everyday clinical practice.

So these are my titles. These are the titles of the faculty.

So, to start with, management of lipid lowering therapy in post ACS, clearly the ESC guidelines have identified various risk categories for cardiovascular prevention based on total cardiovascular risk estimation, identifying patients at low risk, moderate risk, high risk, and very high risk. And each of these categories has both clear definitions, defining the patient profiles, and these are well described in the guidelines, but also identifies a target LDL level for each of these categories. And as you know, the target LDL may vary from one point 16 mg per dL for patients at low risk, to as low as 55 mg per dL, or 1.4 millimole per liter for patients at very high risk. And there's even a provision that for patients who are at extremely high risk, who've had two events within the span of 24 months, there might even be a lower LDL target as we'll discuss later during our discussion.

Based on these recommendations for risk estimation and LDL targets, there's an algorithm that's put forward by the ESCs guidelines starting with high intensity statin therapy first, if goal is reached, everything is good. If the goal is not reached, sequentially consider adding a Ezetimibe. And if not at goal, consider adding a PCSK9 inhibitor to achieve the desired LDL target.

Now let's meet our patient. Our patient is a 64-year-old female patient with a history of hypertension treated with a sartan. The patient has been admitted for an inferior STEMI, admitted approximately 1.5 hours after symptom onset, and she has received successfully, two stents during a primary PCI of the right coronary artery.

The patient has had an uncomplicated hospital course, and was discharged at day three. Her discharge prescription includes, but is not limited to, a beta blocker, a sartan, and dual antiplatelet therapy. And now is the time for me to turn to Professor Mehran and ask her what she would consider and recommend as both the choice for dual antiplatelet therapy, as well as the duration of dual antiplatelet therapy.

Dr Dr Roxana Mehran (03:36):

Well, we have two major trials about the most potent, the potent P2Y12 inhibitors. Prasugrel with a TIMI 38, showing a reduction of death, MI, CVA, cardiovascular events reduced. Absolutely no question, these were patients who were undergoing PCI presenting with an acute coronary syndrome, showing a very, very good benefit in terms of not just death, MI and CVA, but also in reducing stent thrombosis. And the STEMI substudy of this study absolutely shows very similar things. And importantly, the Plato study with ticagrelor showing us exactly very similar reduction. And in fact, the reduction in mortality for the very first time with ticagrelor compared to clopidogrel.

And I think this is really important, both of these agents reducing ischemic events, but also associated with more bleeding. So something to think about, how do we choose for our patients? Because bleeding matters, and we know that that's an important thing. And in fact, the guidelines are supporting the use of these more potent agents for a duration of at least 12 months, except if there is a high bleeding risk and pretty much all of these over clopidogrel in acute coronary syndromes and in STEMI.

So for our patient, the preferred dual antiplatelet therapy would be aspirin ticagrelor, or aspirin prasugrel for at least 12 months. But there is a caveat, because not one size fits all, and we've got to be thinking about a patient. And going back to our patient, you have a patient who has hypertension. Who's a woman. She presents with an inferior STEMI. Has a PCI with two stents in the right coronary artery. So it's not a very complex lesion. And we're now moving towards shorter, even better, maybe. But right now, in a patient like this, 12 months is what we're asking for.

But I want to bring you back to the fact that not one size fits all. In every patient, we have to consider the risk of bleeding, and the risk of ischemic complications. And how do we then fit this into the categories of the duration of dual antiplatelet therapies, deescalation of some of these potent agents sooner rather than later, and maybe even ticagrelor, or we don't have that much data on prasugrel monotherapy, but P2Y12 monotherapy, even in some of these, when there is this overlapping risk of both bleeding, and ischemic complications. So think about these four quadrants and know that this is how we're going to be thinking about our patients in the future. And now we'll go to another issue.

Dr Philippe Gabriel Steg (06:52):

So let's turn our attention now to the lipid component of secondary prevention. That patient is statin naive and her LDL cholesterol measure at admission was 3.0 millimoles per liter, or one 16 mg per dL. So Professor Jukema, what would you recommend as initial lipid lowering therapy?

Dr J Wouter Jukema (07:09):

Well, for a double antiplatelet therapy, you just heard, you have to think a lot. For lipids, luckily, it's more easy because we have very straightforward guidelines from the European Society of Cardiology. It's also already depicted by the chairman, and I put next to it, the efficacy of separate statins. So this patient is by definition with the STEMI myocardial infarction, a very high patient. Then you only have to look at the graph and then you see that the goal where you should aim for, for your LDL cholesterol is around 1.4. Can we achieve this?

Because you just heard that this patient was coming from 3.0. So you need more than 50% LDL cholesterol lowering. And as you can see it on the graph on the right side, that's not easy to achieve. You can do that with high potency statin alone, but you need actually more than 50%, and that's difficult. So you will probably not get there with high potency statins like Atorva 80, or Roxifar 40 alone. So then the most easy step is, of course, and that says what the guideline said as Ezetimibe. And you can see, then you can easily cross this line if you add Atorva 40 plus Ezetimibe, you can come to 60%. Here you see what on top you could do after adding Ezetimibe, and that's of course, that's a PCSK9 inhibitor, because you need profound LDL lowering in this lady to get to the goal.

And we can do that. We have several trials, of course, with PCSK9 inhibition, the monoclonal antibodies I'm talking here specifically, where we have evolocumab from the FOURIER trial, and alirocumab from the Odyssey Outcomes trials, which we were involved in. And you'll see with the PCSK9 inhibitor on top of a statin, you can even reach 60% additional on top of the statin. So that's good. What are the results? From both trials, the FOURIER trial with stable coronary patients, and the Odyssey outcomes with an acute coronary syndrome population, both, they showed a 15 to 20% MACE risk reduction. So that's on top of what you already achieved with your statin. And then you say, well, can your cholesterol level then be not too low? Should be very worried about very low LDL levels? Let's say below 1.0 millimole per liter? And how do these novel type of agents compare with safety?

This is safety data for evolocumab. You see that there's almost no serious adverse events, nor clinical, non laboratory. This is the cardio for outcomes, obviously, outcomes where you see a reduction in MACE 15% non fatal events, even in all cause death, but in nominal P value because of the hierarchy of the endpoint. But this is impressive. You can reach this within a couple of years. So adding powerful lipid lower compound on top of your statin, because these patients were already on optimized statin therapy, is a reasonable, good option. And also, here in this trial, we saw actually no adverse events whatsoever. Apart from some reactions in the skin where you do the injections every two weeks. Now people say, okay, we shouldn't be worried if your LDL cholesterol is really, really low in, let's say below 1.0 or below 0.5 and what ischemic... Is stroke then, especially the hemorrhagic stroke a problem?

We looked at open Odyssey Outcomes. And actually what you see if you add a PCSK9 inhibitor, in this case, alirocumab on top of your statin, you see far less stroke. You see far less any stroke. You see far less ischemic stroke, and you do not have an excess of hemorrhagic stroke. Actually, if you saw something, it was even slightly less. So you shouldn't be afraid what was, in the old days, sometimes worrisome say, but very low LDL levels, should they, should it be cumbersome where you have a hemorrhagic stroke. That doesn't seem to be the case. Efficacy is there, and the side effects are minute, and safety is great, and you reduce not only myocardial infarctions, but you also reduce stroke.

Dr Philippe Gabriel Steg (11:24):

All right. So we've discussed the lipid lowering therapy and the strategy appears really straightforward. At least for LDL cholesterol. We've discussed the antiplatelet strategy that was a little more complex, but reasonably simple. Now we're going to make things much more complex, and I'm glad we have some time on our hand, because now we can change a little the scenario and have a patient who's on chronic oral anticoagulation therapy for a history of paroxysmal atrial fibrillation. So Roxana, how does this change bleeding risk? And how do we minimize bleeding? And how do we manage the anti thrombotic strategy in that scenario?

Dr Dr Roxana Mehran (12:03):

So the plot thickens, doesn't it? When you have to now combine oral anticoagulants with a dual antiplatelet therapy regimen. And what you're doing is you're really moving towards a target of too much bleeding. How do we avoid bleeding without exposing patient to ischemic risk? And that has been the subject of multiple clinical trials, especially now with the novel oral anticoagulants.

And if we go to the slides, I can go through it with you in a really good way. There have been now several novel oral anticoagulants tested in large scale clinical trials in patients who have an indication for an oral anticoagulation, who happen to present either within acute coronary syndrome, or require a PCI. And in that scenario, as you know, and in this particular patient who just presented with a STEMI, now has paroxysmal AF, has a CHADS VASC greater than two. We now are at a place where we need to make a choice. And the choice is that less is more for a patient like this. And that we need to think about, perhaps, the aspirin free strategies that I talked to you earlier, even further and faster than before here, in combination most likely with the novel oral anticoagulant.

And we now have meta-analysis from all of these trials that examined each and every one of the novel oral anticoagulants compared to warfarin, where there was a reduction with a novel oral anticoagulant combination and a single antiplatelet regimen with the aspirin dropping and keeping the P2Y12 inhibitor on board. Showing a major reduction in bleeding complications without change in ischemic events. And you might say, "Well, is that for everyone?" And that's not even for everyone, because you can't just stop aspirin in a complex PCI patient in whom you don't know if they're responding to clopidogrel immediately. The meta analyses seem to show that you're not going to have ischemic harm, but the devil is always in the details that we're seeing a little bit of more stent thrombosis, perhaps. And we need to think about this in, when do you transition?

I want to bring you back to the fact that the P2Y12 receptor is a very important one and it mediates platelet aggregation and the inflammatory processes and the thrombotic issues. And we already know that inhibition of this receptor will reduce stent thrombosis. So if it's a choice of which one of these we drop, it's probably going to be the aspirin than the P2Y12 inhibitor. And remember that these novel oral anticoagulants still have some anti thrombotic antiplatelet effects, because they inhibit thrombin.

So, that combination seems to be quite effective. The timing of transition though, is the one that you need to think about. The guidelines are telling us a default strategy for most of our patients, probably around the week where you could, about a week, you could drop the aspirin and go to a P2Y12 monotherapy with an oral anticoagulant, a novel oral anticoagulant, in favor of warfarin. But in some cases where you put in a bifurcation stent, and it's in the left main, you're going to go a little bit longer, up to a month, but no more than that, because these patients are at high bleeding risk, and we want to avoid that bleeding complication.

And in fact, if they're at a pretty high bleeding risk, we're even shortening the duration of that P2Y12 inhibitor and putting them on an oral anticoagulant alone. It used to be a combination with aspirin. After about six months to 12 months, we're really going to a oral anticoagulant alone, no longer indefinite aspirin in these patients in combination with an oral anticoagulant. So that timing of the transition is important. And between the North American consensus and the European guidelines, we're very much in line.

Dr Philippe Gabriel Steg (17:04):

Okay. So thank you. Let's now go back to lipids and make it a little more challenging for Wouter Jukema. Now, the patient is the same patient, but the patient has the same LDL cholesterol of 3.0, but now this patient was on chronic atorvastatin 10 mg, prior to her STEMI. So obviously, she has an elevated LDL cholesterol despite being on a statin. And even though it's a low dose of a statin, we know that most of the work for LDL cholesterol lowering is done with the first dose, due to the rule of six. You only gain six further percent reduction every time you double the dose. So, even low dose statin is not that ineffective, but here, it's clearly not sufficient.

Dr J Wouter Jukema (17:48):

I couldn't agree more. So now we are in real trouble with regard to LDL lowering. The first shot with a statin is the most important shot. And after that you get with each doubling of the dose, as just indicated, only 6%. So even if you double it two or three times, you will not get more than 18% max, 20% additional LDL lowering. Well, 3.0, and then you have to bring it down to 1.4, 20% LDL lowering is not enough. So this is what is depicted over here.

We are still with this very high risk patient. We still have the 1.4 millimole per liter goal. And you can see that the 10 mg does the majority of the trick, but with each doubling, you get a little bit further, but not too much. So, only doubling or tripling the dose of a statin will certainly not do the trick here. And then you go to the algorithm, which was shown already before, and then you add Ezetimibe. And then you could, of course, argue, why don't you do it just upfront, come on?

So you will see that you will never get there. Be a little bit handy and combine the statin right away with Ezetimibe. And I think that's a good suggestion. We have there a good reason for, because the IMPROVE-IT trial showed that Ezetimibe on top of statin theory is effective, and it's not only that you should add it later on, because always then you're a little bit punishing the patient and you say, "Okay, you're doing well, but you're not doing good enough. And I will give you something extra." Probably it's better to do it right away in one single shot. And then it's not, the efficacy is better, but even if you look at the same LDL efficacy in from this RACING, non-inferiority open label, randomized trial, where you actually see that the combination is just more handy. You see less discontinuation of the drug, and you see a better goal attainment.

So it's a little bit unhandy to just add, add, add, but if you already can predict that you will never get there, just do the combination right away. And then, of course, even then with Ezetimibe combination, you probably will not get there. So you need the injection of PCSK9 inhibitor every two weeks, or the monthly injection. And there is a sufficient data for acute myocardial infarctions, patients like this lady. And actually, there are two nice trials and I wanted to show you only one of them. This, the very recent PACMAN-AMI trial was presented at the last American College (of Cardiology conference), where you have patients with an acute myocardial infarction STEMI/non-STEMI, undergoing coronary angiography and successful PCI of the infarct vessel. And you also look at two non-infarct-related arteries with nonobstructive lesions.

And there they did some very intelligent work. They looked in three ways what was going to happen in this trial if you just give statin therapy, or you give statin therapy and a PCSK9 inhibitor, in this case, alirocumab. And they looked at it with IVUS to look at the total atheroma burden, they looked at the lipid component only with NIRS, and they looked at the fibrous cap thickness with OCT. So this is a lot of work and this is all acute infarct patients, STEMI and non-STEMI. So this is very interesting. So this is, I think, a very nice trial, which you can do acutely for your patient.

Did the medication do the job? Yes. Placebo lowered it with 50%. Of course, this is placebo with rosuvastatin. And on top of that, you see that alirocumab on top of rosuvastatin does far more. So the lipid was far more reduced in the alirocumab arm. And then what were you seeing in this type of acute myocardial infarction patients? How fast can we influence your atherosclerosis in your coronary arteries? Well, pretty fast. And you can see it here. Within months, you see the change in percent of atheroma volume. So with the statin-only you see, on the left panel, some regression of the disease, but it's more than double the regression if you have a profound LDL cholesterol lipid lowering. So the progression is now turned into a small amount of regression, and it's more than double with the statin only. Then you could look at the real, the true lipid component.

You do that with NIRS, I will not get with the technique, we don't have the time for it today, but also with this lipid comment, you see that the lipid component is almost two times as much reduced with the profound LDL lipid lowering by alirocumab. And then we looked on the other side. So we have less plaque with regard to lipids, but on the other hand you want to have a more stable cap. So it would be nice if the cap over the lipid component would be thicker, and it would not be prone to rupture. And actually, this is what you see. You see here the change in minimal fibrous cap thickness defined by optical coherence tomography. And you see this cap get thicker. So the total atheroma volume gets smaller, but it's better protected by a thicker cap. And you see this, already, this occurring in a couple of months.

So I would say this is pretty impressive what you can do for your acute coronary syndrome patients. So don't think doing a little bit is good enough, for this type of patients that have high risk, high LDL cholesterol leverage. You should be aggressive.

Dr Philippe Gabriel Steg (23:20):

So I won't let you off the hook that easily, Wouter. Now let's change again a little, the scenario. This patient actually had a prior ACS, 12 months ago. Now this is her second event. Does this change our goals and management?

Dr J Wouter Jukema (23:35):

Yeah. Also, now we're in trouble actually, because this patient is clearly a progressor under lipid lowering therapy. And then the goals become even more stringent, because then you really need to lower your LDL. So if your LDL is probably under one, it's very difficult to have progression. I say, you have to come from a good home to be a progressor if your LDL cholesterol is below one.

And that's what now the ESC guidelines say you have low risk, moderate at risk, and very high risk. And I told you the risk was for a very high 1.4. But if you have a recurrent event within a short time window, the goal is even lower. So it's 1.0. That's an advice, you don't have to do that, but that's an advice. And actually, this is what we see. This is again in the Odyssey Outcomes trials. This is patient with recent ACS and [inaudible 00:24:30] MI, without patients without [inaudible 00:24:32] MI. So it's patients that have another event after they just had an event. And then you see actually that the treatment is even more effective. So the gain is even better. So don't think, "Okay, this patient has a second event. Let it be. Season treatment. What can we do?" No it's wisdom to be even more aggressive here, and then strive to an LDL cholesterol like the ECS says of 1.0.

Dr Philippe Gabriel Steg (25:03):

So, I still have a question for you. This is all very nice. We agree on what should be done. And we have nice evidence to back it up. And we can decide at the time of hospital discharge what's going to be our strategy, both for anti thrombotics, and for lipid lowering. But we know that in reality, once the patient is out of the hospital, things become much more complicated, because the handoff from hospital care to outpatient care is sometimes very complicated. We're not going to see the patient ourselves. It might be a different physician, might not be a cardiologist. That physician may not agree with our strategy. That physician may have a more conservative approach in terms of choice of agents, duration of treatment, intensity of treatment, level of goals that we should be achieved. How do we ensure smooth handoff and agreement on goals, strategy, and adherence?

Dr J Wouter Jukema (25:53):

That's an excellent question, of course, because mainly, so we all know how we should do it. The problem is that we don't do it. And that comes from every survey that we do over and over again in the years, we do slightly better over the years, but it's far from ideal. And that has two reasons. First, I think we are not active enough. And second, we are not clear enough, because as we already indicated, so it's very often not the original doctor who's seeing the patient in the outpatient clinic. It can be the rehab doctor, or GP, or whatever. So what we mostly realize, and we had a European working group for that, a Europe path three group, and we had identified a couple of issues where we could do better, actually, what is very unclear, the prescription, there's inappropriate treatment on discharge.

So we are just not aggressive enough. We could have easily added the Ezetimibe on discharge if you see that the patient will never be on goal. That doesn't have to wait for four weeks later on the outpatient clinic. Very often the discharge letter doesn't even mention what the goal should be for this type of patient. So it's left to the discretion of the other doctor or the other person to do that. Sometimes this person doesn't actually know. So it's better to give the guidance say, in principle strive, sometimes you cannot do it, but in principle strive for this goal. There's inadequate lipid lowering therapy optimization. So do it straight away, do it upfront as possible. And sometimes the people just do not know. A lot of people have no idea that if you double the statin, that you will not have doubled the effect.

It's only 6% more, and mostly you will never get there without tripling the dose or adding Ezetimibe or PCSK9 inhibitor. And the patient concern? Sometimes you really have to talk to the patient as well because they read the news, and you know how it with the TV shows is, there are two opinions, one left, and one right. One is pro, one is con lipid lowering. The vast majority is on one side, and the single person is on one side, but still the lay press says it's one-to-one. But in principle it's mostly 999 against one. But then you say, "We have to opinions." Yeah, of course we have two opinions, but most of us know what is the right opinion. So we have proposed solutions for it. So standardize your discharge letter. Do the lipid lowering follow-up as soon as you can. Educate not only GPs, but also your fellow colleagues. And try to engage the patient.

Because if the patient finally, in the end, doesn't take the medication. It will not help. And the problem is now, even with an acute MI, you enter the hospital, you have chest pain. The people are very sick. After the PCI, they sometimes feel reborn, and they think the problem is over like that as we are some type of chimney sweepers. But the atherosclerotic problem is far from over, and the chimney will just get cluttered again, if you do not do the proper work with dual antiplatelet therapy and other therapies and proper anti atherosclerotic therapy. So this is, I think, true and practical guidance, how we could do better by being more active, and just do a better job.

Dr Dr Roxana Mehran (29:04):

This idea of handoff is even more complicated with dual antiplatelet therapies, and especially if there's an oral anticoagulant involved. These patients end up with procedures. Today, we saw the non-surgical, the non-cardiac surgery guidelines come out. It really is so important to keep informed. The handoffs are so important. When you have a STEMI patient, if you're an interventionalist, and then you see the patient back in the clinic, you've got to call the referring physician, explain what your plan is, what your intention is, and understanding that that plan could change in a second. As soon as that patient has another event, or has a bleeding event, whether it's ischemic or bleeding. And that their risk profile changes over time as well. So these are just such important intricacies that are very, very, sometimes often missed. We're great at cleaning this, the-

Dr J Wouter Jukema (30:08):

Cleaning the chimney.

Dr Dr Roxana Mehran (30:09):

... the chimney, but I think keeping it clean is absolutely important. So this whole idea of adherence, the handoff, communication across the healthcare professionals is tremendously important. And I also think that in a patient like this who presents with STEMI, we are very, very immediately thinking about the dual antiplatelet therapies and the anti thrombotic regimens, and often forget the other risk factor modifications. It's a diabetes, getting them on the best possible, reducing that hemoglobin A1C. If it's the lipids, as we just talked about, really pushing that forward. And if there is that patient at a high bleeding risk where you have to stop the dual antiplatelet therapies, it makes you feel more confident when you know that the other risk factors are being cared for. So this is really, really important to think about the entire patient and that handoff and everything else that goes along with it.

Dr Philippe Gabriel Steg (31:09):

Thank you. So now we have a little more than 10 minutes left for questions and answers. And questions start pouring in, and I encourage you to send more questions. We'll try to address as many as we can very quickly with quick questions, quick answer. Let me open the fire with a question for Professor Mehran. Should atrial fibrillation during an ACS, not preexisting, but during an ACS, be treated with oral anticoagulation lifelong, or is it not necessary and is dual antiplatelet therapy enough? That's a tough one.

Dr Dr Roxana Mehran (31:39):

Well, it's not that tough depending on what that risk of that patient is. If the CHADS VASC score is more than two in that patient, then you are moving towards a anticoagulation, I would believe, for lifelong. Especially if they're at low bleeding risk, because that stroke prevention, stroke is devastating, and the prevention of stroke is going to be incredibly important. And even if it's a paroxysmal afib, if that CHADS VASC score is high, it's often that you're not seeing the afib, it's happening off monitors, off the hospital, et cetera. And if they have a high CHADS VASC, I give them an oral anticoagulant for a lifetime. If I can.

Dr Philippe Gabriel Steg (32:25):

Professor Jukema, couple of questions. The first one is, will adding Ezetimibe to statin and provide meaningful mortality benefit or just make the numbers look nice?

Dr J Wouter Jukema (32:35):

No, yeah. Excellent question. No, it's not that the numbers just only look nicer. We have the IMPROVE IT, which was by the way, a long trial, because it took so long because we had drop-ins and dropouts over the time. But it's clearly, if you look at it over the line of how much LDL cholesterol we have with each compound, and then you always see for statins, for PCSK9 inhibitors and also for Ezetimibe the amount of LDL cholesterol lowering is predictive of the amount of clinical events lowering. So it's just not cosmetic surgery, it's just efficacy. But you should also realize the maximum effect of Ezetimibe LDL cholesterol is only 20%. It's a lot because it's three times doubling the statin. It's a lot, but it's by far no 50 or 60%, which you sometimes need.

Dr Philippe Gabriel Steg (33:29):

The ESC guidelines and the ESC recommended algorithm that you presented discusses statins, Ezetimibe, and PCSK9 inhibitors. Is there already a role for bempedoic acid, or should we wait for outcome results?

Dr J Wouter Jukema (33:43):

That's a good question. In theory, you would guess if you look at what a bempedoic acid does, it is in a more or less the same pathway as a statin, but somewhat lower. And it's supposed to have less side effects on muscle because the receptor is not in the muscle, but only in the liver. It should work. But I think that the CLEAR Outcomes trial is now coming to an end and it will be presented, I guess, the ASA is too early. So it will be the next ACC. So for the true results, we have to wait there. So nobody knows, the trial's not closed, but you could argue that why shouldn't it work? But that's no definite proof of course.

Dr Philippe Gabriel Steg (34:21):

A question for Roxana Mehran. What do you think about colchicine in that patient? Should we start implementing colchicine in secondary prevention routinely? Or do we need more evidence?

Dr Dr Roxana Mehran (34:30):

I think you need more evidence on the colchicine. I've used it in my patients, but it's not in everyone. And it's those patients that have a high inflammatory burden and there is so much other risk that I might consider, but definitely not routinely. How about you? Do you?

Dr J Wouter Jukema (34:54):

I don't use it routinely. I'm concerned with the increase that was seen in non-cardiovascular mortality, which I think is a signal that needs to be explored further to give us reassurance. We've noted that most of the benefit appears to be on non-fatal events. So I would love to see a more definitive evidence from further trials. And I know there are ongoing trials.

Dr Dr Roxana Mehran (35:15):

But on the lipid side, Gabriel, do you also go through the exact pathway in your own practice, or are you going to the PCSK9 faster? Because I'm just going to admit, I know that I try to give the statin some leeway, but getting that 50% in a high risk patient? I am really, really pushing forward to try to get that patient on a PCSK9 inhibitor.

Dr Philippe Gabriel Steg (35:45):

I certainly love the racing type strategy, which starts with Ezetimibe and statin upfront in most patients, unless they have a reasonably low LDL cholesterol to start with. Certainly in patients, who've had an event on a statin I will add Ezetimibe routinely. And then I try to keep an eye for those patients and bring them back to make sure that if they're not at goal, or if they're remote from goal, they really get a shot at having access to a PCSK9 inhibitor, if reimbursed by the third party payers, which can be a major issue, as we know in many countries. I also have a question for you, Roxana, regarding the conundrum of DAPT. Every month there's a trial coming out about DAPT, DAPT duration, DAPT intensity, escalation, deescalation, guided therapy, tailored therapy, genotype, platelet function test, whatever. I wonder, are we looking for a solution that you have already found? I think the Twilight trial was a great trial.

Dr Dr Roxana Mehran (36:45):

Thank you.

Dr Philippe Gabriel Steg (36:46):

And not only because it's you that did it, but it was confirmed by four other consistent randomized trials that showed the same thing. Dropping aspirin reasonably early has no downside, reduces bleeding by half, and keeps the efficacy. So why are we not using a Twilight type strategy in everybody and not worry about the rest?

Dr Dr Roxana Mehran (37:08):

I think because now that we're comfortable in dropping aspirin, we're going to need to do a trial in everybody and drop aspirin and see what happens. And I think that, to me, is what needs to happen going forward. Remember, global leaders tried to do that after a month. I even think you can stop earlier because we showed no difference in thrombogenicity, but it really needs to be done. The question is what's the comparator arm? And because the comparator arm could be different with multitudes of different comparators, it makes it difficult to do without studying 20, 30,000 patients.

I also think, why should we have aspirin indefinitely? Why not go to a P2Y12 monotherapy indefinitely? Because the data from post exam showed a great result. We have a lot of work to do still in that arena, but I still believe even despite all of the trials that we might have, that the way that we're going to solve the problem of DAPT is going to be through technology and probably some precision medicine and understanding, because the permutations are just way too many for a single clinical trial to answer all the questions.

Dr J Wouter Jukema (38:23):

May I ask a question on that?

Dr Dr Roxana Mehran (38:25):

Yes.

Dr J Wouter Jukema (38:26):

If you have, you say, okay, you go clopidogrel monotherapy sometimes, would you then advise genetic testing? Because we know that 20% of the patients is not fully responding to clopidogrel then.

Dr Dr Roxana Mehran (38:42):

I think the routine of... So there were a couple of things. In acute coronary syndrome patients, we saw that clopidogrel monotherapy from the stop DAPT ACS probably doesn't work because the non-inferiority was not met. And so it really behooves you to think about clopidogrel monotherapy, especially in a high risk patient with multiple stents, early discontinuation of aspirin, and going to clopidogrel might be detrimental in some of these patients with multitudes of stents and lots of ischemic risk. So I think that needs to be evaluated. So in those patients who come with afib, they're at high bleeding risk. I want to stop the aspirin early, but I just put in a bunch of stents? I am going to test to make sure that they're responding to clopidogrel before I pull it off. When I'm concerned, I leave them on it a little bit longer for about a month. And then after we stop.

Dr Philippe Gabriel Steg (39:42):

We have four minutes. So we're going to try to make the most of those four minutes, with really quick-

Dr Dr Roxana Mehran (39:46):

Fast questions, quick answers.... quick answers. We didn't discuss diet and physical activity. Can you say one word about diet and physical activity, Wouter? What do we know in secondary prevention, post ACS?

Dr J Wouter Jukema (39:59):

Good diet and physical activity is a very good plan, but you shouldn't expect miracles from it. So it doesn't come instead of good medication. So we should eat healthy. We should exercise, not to a ridiculous part. But do it, but don't expect that it will do the trick entirely.

Dr Philippe Gabriel Steg (40:18):

Okay. Is there an age or a frailty level that influences your choice of P2Y12 inhibitor in the DAPT strategy component of ACS treatment? Do you switch to clopidogrel instead of prasugrel/ticagrelor for older patients or for frail patients, or does it not impact your decision?

Dr Dr Roxana Mehran (40:42):

Age and frailty affects me a lot. It's that eye test. And so in those patients, I am concerned about bleeding, and I will deescalate sooner rather than later. But I'll make sure that I do a really good job in my PCI with using FFR, to make sure I'm not over stenting, and using IVUS to make sure that if I do stent, it's implanted beautifully.

Dr Philippe Gabriel Steg (41:11):

What about the results of ISAR-REACT-5, should we prefer prasugrel over ticagrelor?

Dr Dr Roxana Mehran (41:17):

Everybody loves that question from me. And I can't answer it like, wow, boom. Yeah. Well, the trial did show a surprising finding of reducing ischemic events without increasing bleeding events with prasugrel over ticagrelor. And I just don't understand that mechanism. So I would like to, I mean, it is a trial that needs to be repeated so that we could really understand is this real? Because if it is, that's a once a day drug, doesn't give you shortness of breath. It is irreversible. So it has some of its own issues, but certainly, I would love to be able to use it. I'm just not yet convinced.

Dr Philippe Gabriel Steg (42:04):

... What about Inclisiran for LDL lowering? Do we have enough evidence when it's available to switch from PCSK9 monoclonal antibodies to Inclisiran, or do we need outcome data from the ongoing clinical trials?

Dr J Wouter Jukema (42:16):

On one hand, we have enough data for Inclisiran. It's the LDL lowering part, it beautifully lowers your LDL on top of statin therapy for about 60%. And that with, on average, only two injections per year. Having said that, of course, the next step should always be, show me the data with regard to clinical event reduction. And those trials are now underway, actually, more than one. So I think we are eager to wait for those results. But for sure, in my opinion, it's very promising.

Dr Philippe Gabriel Steg (42:47):

Should we start statin therapy on day one of hospital admission? And if yes, is it because of practicality, because it's going to be done and the patient will adhere to it and will have time to assess the effect? Or is it because we expect acute benefits from intensive statin therapy on the "pleiotropic" pathways?

Dr J Wouter Jukema (43:07):

Both. We should start it right away. Otherwise, you may forget it. But it has been, there are several trials that the effect of statins are there to a certain extent within days or one or two weeks. So there's no reason, in my opinion, to wait.

Dr Philippe Gabriel Steg (43:23):

You discharged the patient with the perfect prescription. When do you check back again, the LDL cholesterol? One month, three months, a year?

Dr J Wouter Jukema (43:32):

Between one and three months.

Dr Philippe Gabriel Steg (43:33):

Between one and three months. In your expert opinion, Professor Mehran, how practicable is HBR-ARC score in daily routine for every patient after PCI to decide about the best plan for DAPT?

Dr Dr Roxana Mehran (43:47):

I think it's a no brainer. The HBR-ARC is very, very simple and we now have an app for it. So it's in the app store. But honestly, it's really truly a very, very simple score. We simplified it. You don't have to look at any levels or anything. You just need one major, two minor criteria. And you're in. Easy.

Dr Philippe Gabriel Steg (44:11):

Last final question, tough one, for Wouter. What about EPA? We've discussed LDL lowering. We haven't addressed triglycerides, fibrates, or EPA. In particular, EPA has trial results that go for it, but also some controversy about negative results from strengths and discussion about biomarkers, elevation with placebo. So what do we make of it?

Dr J Wouter Jukema (44:32):

Yeah. Well to reduce it shows pretty convincing results. Well, you are the main investigator so you know. So it just seems to work. The idea that we do not completely understand it, why it works, should not prohibit us from using it in the appropriate patients. That it perhaps is better than other fish oil-like things, that could be, well that's feasible, this a different product that does different things? So that we do not completely understand it, it should not prohibit us from using in the appropriate patients.

Dr Philippe Gabriel Steg (45:05):

4:16. We've completed the task. Addressed almost all of your questions. Thank you to both of our speakers.

Dr Dr Roxana Mehran (45:12):

Thank you. Thank you. Thank you all.