FOURIER/EBBINGHAUS: So Far, So Good. But Can We Afford It?

; Clyde W. Yancy, MD, MSc


March 23, 2017

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Robert A. Harrington, MD: Hello. I am Bob Harrington from Stanford University. Thank you for joining us here on Medscape Cardiology and I am here at the American College of Cardiology Meetings in Washington, DC. I have a chance to discuss one of the late-breaking clinical trials, which came out yesterday, with my good friend and colleague, Dr Clyde Yancy, who is a professor of medicine and the chief of the Division of Cardiology at Northwestern University.

Clyde W. Yancy, MD, MSc: Go 'Cats, man.

Dr Harrington: We are here to talk about one of the biggest pieces of news that has come out of the meeting thus far, and that is the FOURIER trial,[1] the first of the large outcome studies with the PCSK9 inhibitors. Put it into context, Clyde. Why was the room not just standing-room-only but the overflow rooms also had lines to try to get in?

Dr Yancy: Putting it in context is really a great question, Bob, because one context is the generation of science and evidence. Another context is, what does it mean to a clinician? A third context is, what does it mean to patients?

Dr Harrington: Maybe a fourth context is, who is going to pay for all of this?

Dr Yancy: Very quickly—I love the story of the PCSK9 inhibitor. It began from observational data, something you and I understand and know very well. It was an aha moment—why is this group not having the same incidence of coronary disease and why would their LDL be so low? You discover that there is just this collection of people who had a loss and gain functionality of the gene for PCSK9.

Dr Harrington: A brilliant piece of science.

Dr Yancy: Amazing, and then it goes through a rapid throughput, given how things have to progress in today's world, and now you have an inhibitor that is monoclonal antibody. We go through the derivation monoclonal antibody. It is a terrific story in science. To see it go from idea, to data, to bench, to clinical trial testing, to outcomes is absolutely brilliant.

Dr Harrington: When you think about that time horizon, not that long from observation, to clinical outcome data... Although for those of us who have been waiting for the data, it seems like a long time.

Dr Yancy: I will have you answer this part because it was an exceptionally well-done trial. What I loved about it was that not only do they address the potential benefits but they also very carefully incorporated assessments of potential issues in safety.

No Mortality Reduction Not Necessarily Disappointing

Dr Harrington: Let's dive right into that. Here is the question that we knew. We know from a lot of work that has been done, particularly with the statins, that lowering LDL-C in people who are at high risk for coronary events is associated with improvement of clinical outcomes. That is a truism.

Dr Yancy: That is the LDL hypothesis. It is true.

Dr Harrington: It is true. We know from work done by the cholesterol trial, as collaboration in others, that there seems to be this very predictable relationship between level of LDL, amount lowered, and clinical outcome.[2,3] I thought that a nice addition to that at the lower end was the ezetimibe story: highly predictable, very modest effect on LDL, very modest effect on clinical outcomes.[4] That line keeps going, from over 200 mg/dL (5.2 mmol/L) now to about 60 mg/dL (1.6 mmol/L). Then the question was, what if we lower even further to levels of 20-30 mg/dL (0.52-0.78 mmol/L)? Would the curve keep going like this or would it start to flatten out?

Dr Yancy: Think about what they did in FOURIER: 27,000 patients, randomized to placebo or evolocumab, either once a month or twice a month, based on patient preference. I cannot wait to see the regularity of that.

Dr Harrington: They did not show details on that, but this is the first presentation.

Dr Yancy: You look at the study and you begin to see some remarkable effects. There was a 59% lowering of LDL-C. What I really loved was that when you looked at the interquartile range of the magnitude of LDL lowering, the lower bounds was 19 mg/dL. Twenty-five percent of the patients in this study had an LDL less than 19 mg/dL (0.49 mmol/L). Bob, that is what I call a pause moment. We never have conceptualized the possibility of being able to get LDL to that threshold.

Dr Harrington: The only thing that we knew about that was, again, from the observational epidemiologic studies, that there are populations with exceedingly low LDLs. We know that when we are born we have exceedingly low LDLs. It is our lifestyle over time that in some ways increases the level of LDL-C. The question was, is that protective in a group of patients who did not start down there, against future coronary events, and is it safe to push people from an LDL-C of 90, 70, 60 mg/dL down to 20 mg/dL?

Dr Yancy: What was very interesting was that when you looked at the composite endpoint, 15% improvement that incorporated a number of very important clinical observations, if you will—hard outcomes like stroke, death, and MI, but also revascularization, admission for unstable angina—that was truism again. I was really struck that there was a 20% relative reduction in the secondary endpoints—death, MI, and stroke—the stuff that matters every day in clinical practice.

I would not quibble and say that 2% absolute is not much. That is a lot for the leading cause of death and disability in this country.

Dr Harrington: A 2% absolute reduction. For the primary endpoint it was 1% absolute reduction.

Dr Yancy: I would not quibble and say that 2% absolute is not much. That is a lot for the leading cause of death and disability in this country. When you look at the landmark analysis, this is when I felt that I have just seen something spectacular, because at 2 years going forward and at 3 years going forward, you are talking about 33% effect size at reduction on events, the curves diverging still. That is impressive, and this was a relatively short trial. Who knows where the plateau is.

Dr Harrington: You just brought up some of the key issues, the first of which is that this was a really well-done trial—the completeness of the data, the high quality. Kudos to Marc Sabatine and the TIMI Group.

Dr Yancy: Absolutely.

Dr Harrington: The choice of the primary endpoint versus the secondary is interesting. You heart failure guys have done this for years, where the primary endpoint is this expanded composite and then the secondary endpoint is what you really care about.

Dr Harrington: Traditionally, what happens is that you are way overpowered for the first and you lose for the second. You are hoping that you really hit it here [secondary endpoint], and you hit it here.

Dr Yancy: This study was actually powered for the secondary endpoint, which was great. If you continue this dynamic and look at the other side of the coin, they had the presence of mind to a priori assess for diabetes and cataracts—the things that worry the everyday patient who is exposed to these therapies. Other than some injection-site issues, it was pretty safe.

Dr Harrington: It appears very safe. We will get into the neurocognitive stuff in a minute. I want to tease through the components of the endpoint first. In some ways, they overthought the problem that the results were flat for unstable angina with hospitalization. That just became noise, and it did not actually help tease out the treatment effect. All of the treatment effect is in MI and stroke, and big effects in MI and stroke.

Dr Yancy: That makes us have to say something that is very important which was that we did not see an effect on death. There are some people who say that it is a disappointment, but statin therapy is very good therapy. These are benefits over and above what you get with statin therapy. I am not disappointed that we did not see a mortality benefit.

Dr Harrington: I am not quite there. I really thought that there would be a reduction in mortality. I am happy with an MI stroke diminution. You commented earlier about the landmark analysis—I'm concerned that we just did not follow these patients long enough; the median was 26 months. Statin trials followed people a lot longer, the ones that showed mortality benefits. I think the mortality question is still open.

Dr Yancy: As we follow it longer, we will see what happens there.

Dr Harrington: I am hoping that there is a message in the follow-up trials that are coming. I am involved with the ODYSSEY Outcomes trial and we as a study group will have tough conversations about whether to extend the follow-up; now that we have seen external data, should we go longer? I do not know the answer to that, but maybe.

Dr Yancy: This is a question, because we have already addressed two questions that we think are important. What about once a month versus twice a month? What about the longer-term issue on mortality? I also would like to see a little bit more granularity on the patient groups within the trial, understand more about women versus men; understand more about older, younger, white, non-white. Those data will come forward and will help us.

Dr Harrington: They did show that one forest plot. As you know, getting ready for this meeting, I am sure it was a last-minute preparation.

Costs and Clinical Practice Changes

Dr Yancy: Here is the real question on the table. Now that we have this information, we have talked about this brilliant history through science and this great clinical trial.

Dr Harrington: What are we going to do?

Dr Yancy: What are we going to do?

Dr Harrington: Here is where I think the careful work is going to have to be done, and that is the payer perspective. These drugs are really expensive right now. These drugs have really only been approved for familial hypercholesterolemiapatients, people with really high LDLs and we know we have to get their levels down.

Dr Yancy: It is almost an ethical thing.

Dr Harrington: Exactly, and now people are going to say, should we use them more broadly? I think that what is going to happen is the formal cost-effectiveness analyses have to be done, but I do not think they are going to support the current price point.

Dr Yancy: That is going to be hard.

Dr Harrington: The companies are going to have to rethink that price point. Given that data, I would like to use them in my patients, but I am not sure that, at that price point, the system can bear that.

Dr Yancy: There has to be some discounting. There is one other data point that might influence that decision. I would look to see what happens in lipoprotein(a) [Lp(a)] because there are a number of patients who are at risk particularly because of that, and these drugs do lower Lp(a).

Dr Harrington: Can we pick out a group that maybe gets preferential benefit? That is why your comment is so important, Clyde, about the subgroups. Let's just talk quickly about neurocognitive function, which had also been a concern. That looks to have been put to rest.

Dr Yancy: Can we just say that EBBINGHAUS[5] basically settled that question?

This is for secondary prevention; nothing that we are talking about applies to primary prevention. There are cost issues that remain.

Dr Harrington: It looks pretty good, does it not? Multiple measures of cognitive function. Patient-reported changes in cognitive function. All of it looks pretty flat, good sample size, nicely reported.

Dr Yancy: When you look at the cognitive study and at the methodology, those are some pretty smart people.

Dr Harrington: My own cognitive function was really put to the test while reading the methods of the paper. I do think, from an overall safety perspective, that the drug looks pretty good.

Dr Yancy: Why don't we wrap up and simply say, this is a new era because we can do more for atherosclerotic cardiovascular disease now than we could before. The target patient is the high-risk patient who has already been effectively treated with statin therapy but has not yet had a reduction in LDL to less than 70 mg/dL. This is for secondary prevention; nothing that we are talking about applies to primary prevention. There are cost issues that remain, but we should all be engaged and think about using this appropriately going forward.

Dr Harrington: Great summary. I am looking forward to seeing what the guideline writers do. In particular, I am interested in whether they will readdress the issue of LDL-C targets.

Dr Yancy: That will be very interesting.

Dr Harrington: It's going to be a good discussion. Do you want to close us out, Clyde?

Dr Yancy: Thank you. Thank you very much for watching Medscape,, as Bob Harrington and I have been reviewing this incredible set of data points. It really opens up a new arena in cardiovascular medicine. Thank you for your attention.


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