Initiating PCSK9 mAb after ACS: When and how to start?

-The topic of our dialogue is the acute coronary patient syndrome and when to start lipid-lowering therapy, especially also the powerful PCSK9 inhibitors.

They have shown the great value in great prospective randomized trial in which I was in the steering committee: ODYSSEY OUTCOMES. It's feasible, it helps, but that's of course something different than implying it in practice. You just wrote a beautiful paper and how to implement it in practice after an acute coronary syndrome. Could you explain how you do it, how you organize it?

-Thank you very much.

That was a paper that we published in a real-world setting in Italy with 800 patients. It's, at the moment,

the large real-world data set that we have from a single country. Of course, it's important because each country has its own rules for prescribing PCSK9. In our patient population, we observed that 20% out of the 800 patients were admitted to the therapy within the hospital stays. They were discharged with the PCSK9 on board at the time of discharge after—

-20%?

-20% of those.

-Who is then deciding it? Is it the interventional cardiologist that makes the decision or the cardiologist at the ward. Is the baseline LDL cholesterol taken into account by that person or is it just a system? You say, "Okay, I do this, I do that."

-Yes, we now are convinced that the timeframe of the hospital stay for the ACS patients is a golden time for optimizing therapy, and, usually, who decides is the cardiologist responsible for the ward of cardiology that takes the patient after revascularization and then discharges

the patient with the therapy. In Italy, we can do this because we are allowed to reimburse PCSK9 in patients with ACS, or recurrent events, or within 12 months from a previous ACS. It's feasible also for admin purposes.

-Do you then, first, optimize statin therapy or do you only do in patients that already are optimized on statin therapy and have a recurrent event or do you do it more or less regardless? You say, "Okay, this patient comes in, he or she has an acute coronary syndrome, so this patient should have the best LDL lowering that's available." That's the way, for instance,

we did it in the ODYSSEY OUTCOMES. They already were on optimized statin therapy and on top of that, you were given as soon as possible a PCSK9 inhibitor but, of course, for you, in clinical practice, it's more difficult to do it on the ward.

-The vast majority of patients that we treated with the immediate PCSK9 had onboard the statin therapy. -All of them?

-Not most but some of them also with ezetimibe. To do reimbursement in Italy, with the PCSK9, you have to get at least one measurement of LDL above 70 milligrams per deciliter, which is important. 70 milligrams per deciliter is the same cutoff that we used in the clinical trial, right?

-Yes.

-Now we can do this

in Italy and the patient

with statin, ezetimibe, single measurement

within 30 days, and then you can go

with PCSK9 if the LDL is above 70.

-Why do you think it's important to start that early? Of course, we had two acute trials. EVOPACS where we showed it was feasible and that we had a beautiful other study where we showed that we are probably influencing even on short notice the stability of the plaque. Perhaps, even inducing regression. Is that the reason that you started that early? Because in your opinion, you cannot start early enough, because plaque stabilization and regression is the most important thing you can do for the patient? You should not wait for 2 or 3 months in the outpatient clinic?

-Well, I think there are different reasons for getting the behavior for approaching the patient with very early intervention. First of all is a logistic opportunity, because we have a lot of patients that are-- Then after discharge, they are not followed properly in the territory, in the community, and therefore, to optimize therapy at discharge, it's a good opportunity for them.

-First time right?

-First of all. Then we have mechanistic evidence that this is good for the plaque and PACMAN-AMI and the HUYGENS study told us that this is good and the sooner you start, the earlier you get at the plaque level the changes that you want to see. The changes are the regression of plaque, the stabilization, reduction of macrophage, and all things that go in the direction of stabilizing the plaque and the patients, of course.

-What we actually, more or less, show that it's feasible

in prospective clinical randomized trials, you showed in practice that for the majority of people, it's also practice. Just do it. Just organize it.

-Absolutely.

-Okay.

-In Italy, many people do this. There are some algorithms that put, as a threshold, that baseline level of LDL. In the clinical practice, you do it very easy when the LDL is not at target, you have already on board the statins plus ezetimibe. In other patients, that are naive to therapy, you can calculate, of course, the target at the percent distance from the target and then go with the triple therapy from the beginning.

-Okay. Very clear. I think it's now clear that we cannot be hesitant, not for the reason for the patient that we should not delay treatment. We should not delay treatment for the plaque because if you want to improve prognosis, we should not wait. We do it as early as we can because, first of all, the patient has it on board, and second, we don't forget it. Otherwise, it perhaps would never happen.

-That's exactly the point. We have seen also data from, for instance, the FOURIER-OLE study that told us that even two years, the two years exposure of patient with the less, very much lower level of LDL as in the FOURIER trial, it counts, thereafter, when the patient after two years were brought to the same level of the interventional arm of the trial. Those two years provided a benefit in terms of biological changes at the plaque level that patient continues to see in the long follow-up.

-Now, we have even a paper. Just published in the European Heart Journal where we actually show if you push the patient to a very low LDL level, there's benefit, but it also is a prolonged benefit. Probably, it's a very good thing to just push it down as much as you can.

-As early as you can.

-As much as you can and as early as you can. That's, probably for majority of patients, I think, the best approach.

-Absolutely. Then we have also seen in our series in Italy that if you start, then the patient keeps going, keeps taking a PCSK9. Patients are very satisfied with this therapy. No side effects. Very good results in the LDL reduction. Very predictable results in the LDL reduction. We don't have much heterogeneity, which is, I think, quite important.

-That was going to be my last question, but you already answered it because starting some therapy, which we think is good, is very fine. Of course, patients should also tolerate it and have little side effects. Also, your experience with that is very positive, as I understand.

-Absolutely positive. The reaction of patients, the compliance of patients for this kind of therapy is very important. The only problem is that patients are so much satisfied with this therapy that maybe some of them try to give up the other background therapies, which is, of course, very important not to do, because in most cases, you need three drugs to get to the point where you want to get as far as the target is concerned.

-For ACS patients, more or less, the conclusion is you can safely and effectively reduce the cholesterol as much as you can and as early as you can.

-Go to target as early as you can.

-Thank you very much.

-Thank you very much.