Melissa Walton-Shirley, MD; John M. Mandrola, MD

Disclosures

March 24, 2017

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Melissa Walton-Shirley, MD: Hi. I am Melissa-Walton Shirley and this is my colleague, Dr John Mandrola. We are coming to you, for theheart.org on Medscape, from American College of Cardiology (ACC) 2017 in Washington, DC. We are going to kick around the FOURIER trial[1] a bit, John. Take it away with your thoughts.

John M. Mandrola, MD: Yes, this is an incredible trial. Secondary prevention in patients already on statin drugs—do the PCSK9 inhibitors improve cardiovascular outcomes? We have known that the PCSK9 inhibitors lower low-density lipoprotein cholesterol (LDL-C), but the big question is, would it improve outcomes?

Dr Walton-Shirley: My thought about that is that we should be finished with just LDL-C lowering. We have done it before; we have done it with niacin. Someone needs to talk about the cause and the effect and whether we are satisfied with events. Does it really translate into a mortality benefit? If it does not, then why not?

Dr Mandrola: This trial had 13,000 patients in each group, at more than 1000 centers in 49 countries. It turns out that the PCSK9 inhibitor versus placebo did improve outcomes. It reduced nonfatal infarction, but it did not improve cardiovascular death or all-cause mortality. The absolute risk reduction was statistically significant but it was pretty small. You are looking at number needed to treat of between 50 and 75 patients to prevent nonfatal events. What do you think about that?

Approved Without Outcomes Data

Dr Walton-Shirley: The question is, can you afford it? It is $14,000 to treat a patient for a year. Can we afford to spend that kind of money to get those kinds of statistics?

Dr Mandrola: I don't think so. I think what is going to have to happen is that there is going to have to be some kind of discussion, debate, fight between insurance companies and the Centers for Medicare & Medicaid Services (CMS) and pharmacy benefit managers. I just cannot imagine that the price of this drug is not going to have to come down.

Dr Walton-Shirley: There is also a backstory. How does a drug like this get to market with so little data about mortality, about 1.5-2 years ago? How does that happen?

Dr Mandrola: I wonder that too, but do you not think they were relying on the LDL hypothesis? If you lower LDL-C enough that you are going to improve outcomes because you did with statins. There have been other outliers, like the high-density lipoprotein (HDL) story, but I think they relied on the fact that lowering LDL was going to deliver improved outcomes—but it was a bit of a gamble, was it not?

Dr Walton-Shirley: Absolutely. Do you think we are not giving them enough credit because the lines are diverging, and maybe we just have not studied this drug long enough to produce a mortality benefit.

Dr Mandrola: That's an important point. One of the good stories from the FOURIER trial was that if you looked at the Kaplan-Meier curves on outcomes, there started to be separation, which makes perfect sense. LDL-C lowering is not going to help right away; it is going to take some time. The curves were separating and there may be a benefit. If you are preventing nonfatal myocardial infarctions, it may translate into reduced cardiovascular death or all-cause mortality, but it may take time.

The other thing we do not know is whether side effects might also accrue over time. One of the remarkable things about this trial was that 40% of the patients had LDL-C below 25 or 30 mg/dL (0.78 mmol/L). That is a remarkably low LDL-C, and I am trying to wrap my head around a 65-year-old living 10 years with that low of an LDL-C level. What do you think about that?

Dr Walton-Shirley: In the other naturally occurring lower-cholesterol trials, we see signals of increased risk for colon cancer.[2] My concern is that, after you put a 40-year-old or maybe a 20-year-old, with familial hypercholesterolemia (FH) on this—or maybe a teenager—what is going to happen with that patient if they live to be 70 years of age? We still do not know that. That is uncharted territory.

Dr Mandrola: I asked Dr Sabatine about this because they stopped the trial. FOURIER is a 2-year trial and it stopped. They are going to continue an observational arm of 6000 patients. I do not know that this is a 2-year story. We do not know what is going to happen with outcomes and we do not know what is going to happen with side effects. We are going to have to rely on observational data, and I think this is a problem. I understand why they stopped it, because they got the result and it cost Amgen a lot of money to do this trial, but it worries me a little.

Dr Walton-Shirley: I think the other issue is that if the price does come down, these results are going to be heavily extrapolated to people who are statin intolerant. That is not what this trial was about. This was about patients who had coronary disease who were on statins and could not get to goal. [Editor's note: Patients in FOURIER had established cardiovascular disease, including prior myocardial infarction, stroke, or symptomatic peripheral artery disease.] How does it work in those patients? I do not think anybody really knows the answer to that.

What Else Would You Do With the Money?

Dr Mandrola: Can I ask your feeling about this? There has been some talk on Twitter about the other things that we could do, in terms of cardiovascular prevention, with the money that we are going to spend on this 2% reduction in nonfatal events. I know you are big on this.

Dr Walton-Shirley: I will tell you, and it sounds kind of hateful, but I wonder if we would be having this talk about marginal benefit if the trial had an arm of the Mediterranean diet and 30 minutes of exercise 5 days per week. I don't think so. I think the results would be astounding in that cohort if they followed the Mediterranean diet and exercised. It would translate to a lot less money expended in the next 10-15 years on this molecule. We have to go back to education of our young kids in the elementary schools and teach them about disease prevention, detection, how to eat, how to exercise. That is where we should be spending the money in America and [because we're not,] that is probably why we are going broke.

Dr Mandrola: That's a really good point. It's hard to think that way at ACC; this is a pretty impressive place and that's not a common theme we hear here.

Dr Walton-Shirley: What would you do, though? What if your cholesterol was 375 mg/dL and your LDL was 290 mg/dL, would you take it?

Dr Mandrola: I don't know, but I would not know what my cholesterol is because I feel well, so I don't like to do tests on people who feel well. Although I will admit that I do like to know whether someone has familial hypercholesterolemia (FH). I think it is important. In the absence of that, not too much testing for me.

Dr Walton-Shirley: I agree with you that it is worth the gamble on the FH patients, because we know they are going to get sick, and we don't see harm coming from this thus far. I think that it is probably worth the gamble. I think that about everybody would agree with that notion. Anything else you want to say about it? This is your last chance.

Dr Mandrola: No. I am so happy that you made the comments about education, heart health, and the other things that we could do besides drugs.

Dr Walton-Shirley: Thank you for joining us here on theheart.org | Medscape Cardiology at ACC 2017, to hear our thoughts on the FOURIER trial. Thank you, John.

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