Real-world evidence with PCSK9i mAb; implications and lessons for current clinical use

Hello, good morning. My name is Maciej Banach. I am professor of Preventative Cardiology, Epidemiology, and Lipidology from The Medical University of Lodz. This is my great pleasure to meet with you and with my great friend from São Paulo, Brazil, Professor Raul Santos, a great expert in the field, in order to discuss the issue of real-world data with PCSK9 inhibitors, what we have learned, and what kind of message we may have based on this data.

Raul, taking into account that ODYSSEY OUTCOMES was published few years ago, such as FOURIER trial, today at this time of this meeting we have FOURIER-OLE results presented. We have also a number of different data from the real life practice. There is at least few issues I guess we should try to discuss and try to use this experience in order to be more effective with our patients. First of all, please tell me what do you think about the fact that despite the fact we have such effective drugs, in many countries still there's so few percent of people being on the LDL cholesterol target. Especially we are talking about high-risk patients who are indicated for PCSK9 inhibitors.

It's a good pleasure to be with you, my friend. Unfortunately, despite all the knowledge that we have accrued over the decades, statins, ezetimibe, PCSK9 inhibitors, less than 20% of very high-risk people who really will get great benefit from cholesterol lowering, intensive cholesterol lowering, are on the recommended dose. Then when you talk about PCSK9 inhibitors, when you go to real-world evidence, I think less than 2% of these patients are really taking these drugs. This is something that's very worrisome because patients are not being benefitted from this therapy.

What do you think is the greatest obstacle in order to get this drug, because from my perspective as a person from Poland, in fact, I can say, okay, the greatest challenge is still to have extension availability to get this drug, taking into account the reimbursement criteria. Do you think it is the real reason and the most important reason that our patients do not have this drug? This is a great question. Of course, that depends on where you're from. For instance, in Brazil, these drugs are not reimbursed at all. Sincerely, I don't think this is the only issue. I see many barriers actually. Adequate prescription of them. First, okay, access is one thing. Second, many physicians are not convinced that you should reduce LDL intensively because they're not convinced of the benefits. Third, I think physicians and patients might be afraid, let's say, of very low LDL cholesterols. This is not the reality. We know that it's important and it's safe, and makes the difference for the patients.

Yes. Let's talk about what you have just mentioned because we are trying to educate, taking into account the data we have had from different, numerous trials, concerning the very low levels and the safety, not only efficacy. Efficacy is well known, with reduced cardiovascular outcomes due to the low levels of LDL cholesterol, reduced atheroma plaque volume and many other different things. What do you think about the safety, because at numerous meetings, taking into account that with PCSK9 inhibitors we may have even levels below 10 milligrams per dL. The patients and physicians are asking, "Don't you afraid of these very low levels of LDL cholesterol? I've heard that it is associated with one, two, three different adverse effects." As you can guess, the most important adverse effect, is hemorrhagic stroke, and many other different adverse effects. What do you think about it? Actually, when we go through this data from clinical trials and actual data from real world, we have actually millions of people already taking these drugs in different parts of the world. Actually, it's not true. We don't see a causal association of adverse events, and especially hemorrhagic stroke, that might have been seen in observational studies with people with low LDL cholesterol. Well, we don't see a causal association between reducing cholesterol with pharmacotherapies and increments in adverse events, and especially hemorrhagic strokes. I agree that people might be scared about this but this is not the reality. Actually, you might agree with me that when we're talking about very intensive LDL cholesterol reduction, we're talking about people who have very high risk of having an MI, a stroke, or even dying in the short term. Actually, let's say-- okay, 1 in 10,000 people might have an hemorrhagic stroke with very low LDL cholesterol levels, but the risks of these events, the atherothrombotic events, is much higher. Even if it were true, the benefits would be much greater than possible harm. Yes, I agree. That is why I believe one of the first messages we might have, don't be afraid of very low levels of LDL cholesterol. We have great data from different trials, subanalyses of ODYSSEY and subanalyses of FOURIER. We have just published also the greatest meta-analysis also showing that there is no link between the very low levels of LDL cholesterol and hemorrhagic stroke, and there's a significant reduction of ischemic stroke obviously.

There is another issue associated with low levels of LDL cholesterol. What to say to doctors, because in ODYSSEY APPRISE we've noticed that even 20%, so each fifth physician, that was included in this trial reduced the dose of alirocumab due to the fact of low level of LDL cholesterol. I remember the discussion about the 70-year-old man on evolocumab, on triple therapy with evolocumab, which obviously very high cardiovascular risk, with the level of LDL cholesterol 10. There was a question, what we should do with these patients. Whether we should continue this therapy, whether we should maybe reduce the dose, change evolocumab to alirocumab or something like that. Amazing, because we should say, "We are so happy having such a level of LDL cholesterol. Don't touch this guy," right? No, definitely. I think things have changed. We've learned a lot from these trials and real-world evidence in showing that low cholesterol is not bad. Look, having low cholesterol because you have cancer or if you have heart failure or liver failure is one thing, but reducing the cholesterol with pharmacotherapy, in people who really need that. It's another thing. It's safe and really can make the difference. Please, keep the drugs where they are. Don't change the drugs, please.

Another issue, obviously, is associated to the safety of PCSK9 inhibitors. Amazing that when we look at the data we have from real-life practices, it is amazing that the safety issues are observed less frequently in comparison to randomized control trials. It is another confirmation that we should use these drugs and we should not stop these drugs because they are not only very effective but there is in fact no safety concerns. How do you comment it? I fully agree with that. I think that cholesterol-lowering therapies are one of the safest we have in medicine. For instance, we're talking about aspirin, anti-coagulants, the risk of having adverse events is much greater than the ones that we deal with cholesterol. Actually, we've learned from the statins that actually most of these adverse events actually come from the heads of our patients, or ourselves, rather than the possible adverse events of these drugs. These drugs are safe. We must say that to the patients. Actually, first, we must be convinced about the safety, and second, we must speak with the patients, talk with our patients and tell them, "Look, the drugs are safe. Low cholesterol is good for your health. Please keep the therapies because we have amazing therapies." Adherence to therapies, I think, is one of the biggest challenges that we have. If people don't take the drugs, they won't benefit from the drugs. -That's how I see that.

-You've mentioned a critical issue. I believe this is adherence, right? In ODYSSEY APPRISE, and in fact, in the SAFEHEART study that was presented yesterday at the European Society of Cardiology, there was the same adherence to PCSK9 inhibitors, 97%, almost 97%. We may say, "We have finally drugs that are not only effective, safe, but there is a great adherence to this therapy." What may happen-- there is another observation for real-life practice that in Germany, in Italy, even 30 to 50% of patients discontinued PCSK9 inhibitors. What is going on? Why such an innovative and effective therapy might be discontinued? What do you think about it? That's very interesting. We really need to understand better why that is happening. In my opinion, might have to do with people who think that they're not at risk anymore, or they might not get the benefit, or maybe they think that something bad might happen to them. We have to better understand that. In my opinion,

this has much to do with people not understanding the risks of having an MI or stroke or dying off that in the short to medium term, and the possible benefits that these drugs may bring. It's important to emphasize that actually, we have secondary prevention patients that are at much higher risk than others. Actually, those who have the highest risk will get the greatest benefit. If you're diabetic, if you have PAD, if you have multiple arteries compromised, if you have the metabolic syndrome, you get a greater benefit from intensive LDL cholesterol lowering. I think this is important to tell our patients, especially those highest risk, because they should not stop taking these medications. I believe that you agree with me that in different guidelines now, we emphasize education - not only the physicians who are well-educated or not, and especially the patients, because if your patient understands that what kind of disease he has, why it is dangerous for him, taking to account the health and the perspective and the long-term perspective of his health, and why this therapy is effective and what is associated with, including also potential adverse effects, because the patients need to be well-informed. All those issues, I believe, might cause that we will not have only great therapy for which we might expect the adherence by even 100%, but the patients will be well-convinced in order to take this therapy. I believe that we should always have time for our patients in order to convince him, "It is for your health. It is for your good. It may prolong your life." I think to finish and summarize that, knowledge is power. -Knowledge is power.-Knowledge is power. Thank you so much, Raul. It was a great pleasure, my friend.