Real-World Experience With PCSK9 Inhibitors



Howard Weintraub, MD: One of the things we didn’t talk about is that in spite of an enormous amount of data, we know that getting LDL [low-density lipoprotein] down, not just into the 20s or below 55 mg/dL but even below 70 mg/dL, is not achieved in a large number of high-risk patients. Both the ACC/AHA [American College of Cardiology/American Heart Association Clinical Practice] Guidelines, and certainly the ESC [European Society of Cardiology Clinical Practice] Guidelines, call for much more aggressive utilization of lipid-lowering agents. The Europeans call for very early experience with PCSK9 modulation. It’s really sad that people are not motivated or feeling confident in using a PCSK9 inhibitor.

I’d love to know your experience. One of the things I’m going to ask you next is, how often do you have to switch people off PCSK9s? We have hundreds of patients on both of these drugs. Multiple times a week, I’m either renewing a prescription or writing a new one. I don’t think I’ve ever stopped a prescription for a PCSK9 because of a legitimate adverse effect. We had 1 patient that had a rash that was transient but not really allergic. She is still on the drug 2 years later. That’s an amazing thing. I can’t say that for aspirin. I can’t say that for many other drugs. There have also been great steps taken by the people who make or sell these drugs to reduce the price. They lowered the cost almost 60%, from a little over $14,000 to below $6000. It’s now close to $5600, putting the cost of these drugs in line with many other drugs that you and I prescribe on a day-to-day basis as antiplatelet drugs, diabetes drugs, or drugs for heart failure. This is important. Please tell me your experience. How often do you use a PCSK9 inhibitor in monotherapy, and how many of them do you use with ezetimibe? Do you use them most with statins?

Alan S. Brown, MD, FACC, FAHA, FNLA: Those are a lot of questions.

Howard Weintraub, MD: Sorry.

Alan S. Brown, MD, FACC, FAHA, FNLA: I’ll give you a synopsis of it. First, like you, I’ve had very few who have had to come off PCSK9 inhibitors. I’ve had 1 true allergic reaction in which the patient developed significant urticaria and had to come off. I’ve had a couple of patients who got absolutely no response, and we’re still analyzing what happened to them.

Howard Weintraub, MD: That’s a different story.

Alan S. Brown, MD, FACC, FAHA, FNLA: Because they got no response, their payer would not renew them, and I couldn’t argue with that. As far as the cost-effectiveness piece, the safety and tolerability has been great. You mentioned attributable adverse effects. I did have 1 patient who was fine until he saw that his LDL was 12 mg/dL. Then he had an anxiety attack and stopped taking it. But he was an anxious patient from the beginning, and that’s why he couldn’t tolerate anything else. We do have people who literally have tried every statin and can’t tolerate them. In those patients who have high-risk atherosclerosis and can’t tolerate any statins, for example, we’ve used monotherapy with PCSK9 inhibitors. We’ve published a small group of people who were unable to tolerate anything else and were only on PCSK9 inhibitors. The data were just what you would expect them to be. They got the same reduction in LDL as they would have if they had added the PCSK9 inhibitor to a statin, which was 55% to 60% LDL reduction. That said, many patients who have atherosclerosis and can’t tolerate any statins are on PCSK9 inhibitors alone. If their LDL isn’t adequately controlled, I frequently add ezetimibe to it, and that gives us another 20% LDL reduction. I do that with reckless abandon, and I’ve had good responses to that, as you pointed out.

The last thing is the cost. First, the retail price has little to do with what the patient pays, and we just have to be honest about that. It’s great for politics, but it has very little to do with reality, which is 1 of the problems with health care today. The price that is published as the actual market price for a drug is manipulated over multiple steps before it gets to the patient. All the patients care about is what they have to pay out of pocket, particularly with the retail price reductions that we were all so thrilled about in the PCSK9 inhibitor. As you said, it was a 60% reduction in price. That has brought the co-pays down very low, even for Medicare patients. That’s much better than it was before, which has made it easier to get patients to take it. Medicare was particularly a problem because their out-of-pocket costs are directly related to the retail price of the medication.

If you just assume that the cost is what’s published as the retail price, with that 60% price reduction—we published a paper at the NLA [National Lipid Association] on which Jennifer Robinson was the lead author. I participated in that to investigate whether they are cost-effective according to national standards. For example, most organizations that review cost-effectiveness would say that $50,000 for a quality-adjusted life year is cost-effective.

What we found was interesting. If your LDL is over 100 mg/dL despite maximum tolerated traditional therapy, it was actually highly cost-effective to give a PCSK9 inhibitor, by national standards of cost-effectiveness. You get unquestionable cost-effective benefit if the LDL remains above 100 mg/dL. If the LDL remains above 70 mg/dL, and you have a reasonable value, there is reasonable cost-effectiveness. It still falls into the reasonable range.

People should be quite confident that at the current retail price, knowing that it’s a bit of smoke and mirrors in terms of what patients and payers are actually spending on the drugs, they are cost-effective if your LDL is over 70 mg/dL on maximal therapy. You and I could find patients as you described. You described them beautifully. These are people continuing to have events who have very high LP(a), despite having relatively low LDLs, and who are progressing with their disease to having their second or third bypass operation. We know that they are at such high risk that, even if their LDL is below 70 mg/dL, they’re going to get benefit by adding a PCSK9 inhibitor. That’s always going to be a clinical judgment.

Based on what you and I do in the lipid field, we have the ability to assess risk in a complex patient and make that sort of a judgment. But for the average patient who the primary care doctor or family medicine specialist is treating, who has coronary disease plus some other risk like age or hypertension, whose LDL is still above 70 mg/dL, with the safety data that you described, they should not have any hesitation to consider using a PCSK9 inhibitor. Secondly, as you already described, even with very low LDLs, there’s no evidence of cognitive dysfunction based on a well-done subgroup analysis of FOURIER. That’s the EBBINGHAUS data. When someone says, “How low should your LDL be?” I always say, “You can’t be skinny enough, you can’t be rich enough, and your LDL can’t be low enough.” No one has proven me wrong. I’ve been saying that for 30 years and so far, no one has proven that wrong. The fear of using an injectable should go away. Most primary care physicians do it for diabetes and other things. If it’s appropriate, based on guidelines, this drug does not necessarily have to be given by a lipidologist, or even a cardiologist.

Transcript Edited for Clarity

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