This is Ulf Landmesser from Charité University in Berlin. It's my great pleasure to discuss with you, in the next minutes, the challenge of choosing cardiovascular risk management therapies. My task is to highlight, for you, what are the choices. I think it's a very important topic, but because it's something that we really pushed forward over the last years, we want to offer our patients precision medicine in prevention of atherosclerotic cardiovascular disease. We will discuss the several options that we need to choose for our patients.

I have divided this here, for you, in segments of what we have to consider. What we really want, for our patients, is to reduce their vascular risk. By that, I mean largely the risk of having a myocardial infarction, having stroke. We want to also reduce their risk of developing heart failure. When we start with vascular risk here, atherogenic lipoproteins are really in the focus and are causal in the progression of disease. Therefore, this is a very important aspect that we need to choose the right treatment for the patient.

Just as an illustration, I brought you this figure here from a recent consensus statement of the European Atherosclerosis Society that we worked on together. You can really clearly see that atherogenic lipoproteins are in the center of atherosclerotic cardiovascular disease. What we have learned in the last years is, if we lower, in particular, the LDL particles further down than we used to do in the past, we can be much more effective in reducing the risk of progression of disease. We can, actually, in the majority of patients, achieve a reduction in the atherosclerotic plaques in the coronary arteries.

The guidelines are very clear. I would state here that, for most of the patients at very high cardiovascular risk, now the standard will be treatment with statin and ezetimibe in a combination. The question is which patients, in addition, will need a PCSK9 inhibitor therapy, and I will illustrate this to you in just a moment. This is the case for most patients with established atherosclerotic cardiovascular disease.

Here, you see what has happened over the past two decades. Two decades ago, we saw the 4S study, the first trial to really show that LDL lowering can reduce risk of myocardial infarction, can reduce the risk of stroke, and improve prognosis. Now, we have found several studies, the data, that combination treatment is more effective, and the most recent combination is PCSK9 inhibition here. We really need to evaluate and choose, in our clinical setting, the patients who do need these novel therapies. What is remarkable about LDL lowering that this treatment doesn't have relevant side effects, really. It's really a treatment that, as far as we know today, is very safe and, therefore, in the guidelines, it's also recommended to really bring LDL very far down in our patients with atherosclerotic cardiovascular disease.

What was fascinating, to me, was to see in the last year, two studies that really illustrate to us what is happening when we bring LDL far down in our patients. You see, here, the optical coherence tomography and the FCT, that is the fibrous cap thickness, which is the marker of plaque stability, was analyzed in two prospective randomized studies.

One is shown to you here, the HUYGENS OCT study. You see that the plaque cap thickness actually increases substantially on lowering of LDL cholesterol using a PCSK9 inhibitor in addition to statin therapy. This is for the first time, I think, that we can really see what is happening in our patient that we stabilize the plaque. One of the features is here that the plaque cap, that is the problem that it ruptures when you have an acute event, can be stabilized by further lowering LDL cholesterol. That is, I think, very instrumental to consider this in our patients and to choose the right combination of LDL lowering therapies depending on the level of LDL cholesterol and depending on the absolute risk of the patient.

This is our data here from Sweden from a national database, and this has been evaluated here how many patients will reach the guideline target when you use the combination of statin and ezetimibe. You see this in the middle bar here when you add ezetimibe in the whole database, in Sweden, after an acute coronary syndrome, you will approximately reach the target of the guidelines in about 50% of patients. That's why I said, for most of our patients, a combination of statin and ezetimibe treatment should be the standard of care in the future to really bring their LDL levels down so that we can reach the guideline target and have really also regression of atherosclerotic plaques in the coronary arteries. Now, when we want to have more patients to target, we will need to add PCSK9 inhibitors. In this, if you add this, you will reach the guideline target in close to 95%. Here we have, of course, to choose. I think, the first patients to choose PCSK9 inhibitors are patients with remaining high LDL levels and are patients who have a particular high absolute cardiovascular risk. This will be further discussed by Dr. Ray in the next talk.

Now, genetic data clearly have shown to us that LDL cholesterol is causal in the progression of atherosclerotic cardiovascular disease. This has been confirmed in clinical studies and, therefore, it's so important I think to deliver this opportunity to our patients.

There are also from genetic studies, new targets that are upcoming, and this is lipoprotein(a) from genetic studies, clearly a causal pathway for progression of atherosclerotic cardiovascular disease. We should measure this in our patients. This is also recommended in our present guidelines, at least, to recognize the risk associated with elevated lipoprotein(a).

There are treatments around the corner. In particular, here, the RNA-targeted therapies are far advanced now in the clinical development. You can achieve with these treatments really, for the first time, an effective lowering of lipoprotein(a); and that will be an important perspective for people who have this. You need to ask also for the family history in these patients because frequently it's a genetically determined risk factor. We have the HORIZON trial that already completed the recruitment of the patients, and we will get this data very soon. Hopefully, here, for patients who have this risk factor, we will offer a causal treatment in the future.

Now, another important area, where we need to choose treatment, is antithrombotic therapy. That really needs our clinical skills to really assess the ischemic risk in the patient and assess the bleeding risk. Of course, basic treatment will be aspirin or, if not tolerated, clopidogrel, an antiplatelet inhibitor in patients with atherosclerotic disease. If you have atrial fibrillation, you will likely use one of the non-vitamin K antagonists.

We have seen recent data that, by combination treatment, especially in patients after acute coronary syndrome or in patients with polyvascular disease, you can further reduce the ischemic risk. This is, certainly, an option that should be considered, but we need to also carefully evaluate the bleeding risk.

In a nice recent article here in the European Heart Journal, all these different options are discussed. We really need to choose, "Do we want to do a single antiplatelet therapy in our patients or do we want to do dual antithrombotic therapy?" We need to evaluate the ischemic risk of the patient and we need to evaluate the bleeding risk to make that decision.

Now, another interesting aspect, over the years, has been the immune modulation in atherosclerotic cardiovascular disease. What you can choose today is, whether you want to treat your patients with colchicine or not.

We have, now, data from the anti-inflammatory agent colchicine from more than 9,000 patients in two larger clinical trials, and what we can see is that the risk of progression of disease can be reduced by colchicine treatment, the risk of myocardial infarction, stroke, or cardiovascular death. We didn't see a reduction in all-cause mortality. That has not been shown. But for patients who, despite optimal risk factor management, have progression of disease, that is something that we can consider today, and we need to choose. We will get more data in the near future for colchicine, but that is from the anti-inflammatory therapies, the one that we can choose today in patients who have progressive disease.

Now, very importantly now we come also in the area where heart failure prevention is important that these patients who have metabolic risk factor such as type 2 diabetes. Here, we have new therapies, as you know, that not only reduce the dysglycemia, but also importantly reduce cardiovascular risk.

In our guidelines, now we have these strong recommendations in patients who have atherosclerotic cardiovascular disease to either treat with an SGLT2 inhibitor or a GLP-1 receptor agonist; and we have to make the choice between the two. They have both different impacts. SGLT2 inhibitor, as you know, is also a heart failure treatment. In a patient at risk for heart failure, it will be preferable. GLP-1 receptor agonists are also treatments that have a very strong impact on obesity or overweight. If weight reduction is an important topic, then these agents are likely chosen as a primary treatment; and that is one of the two should be chosen in patients who have atherosclerotic cardiovascular disease and diabetes. It is also strongly recommended now in our present guidelines.

In summary, I highlighted, for you, the aspects where we need to choose for vascular risk, we need to choose, in particular, whether patient need PCSK9 inhibitor or not. Statin and ezetimibe treatment should be, in many patients, now standard of care. Antithrombotic treatment is something where we need to choose. We need to evaluate the ischemic and the bleeding risk, and that is an option that we have in the management of the patient. For immune modulation, there are several trials available, but, clinically, we have only colchicine. In patients with progressive disease, you can consider this. Colchicine is very well known from pericarditis treatment where it's already standard, but we have now also the option to choose it for prevention of progression of atherosclerotic disease and, in particular, patients with metabolic risk factor such as diabetes which, we know, has more risk of progression of atherosclerosis as well as heart failure. We should choose one of the two agents that are shown not only to improve metabolic situation but also to improve prognosis in these patients and that is, in summary, what I would like to have discussed with you. I think it's also very important that we, as clinicians, can now make this choice for our patients. I hope, with this overview, I gave you some insights on that what we need to consider. By that, thank you very much for your kind attention.

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