Will ODYSSEY Clear Hurdles for PCSK9 Inhibitor Access?

Seth J. Baum, MD; Matthew J. Budoff, MD


March 22, 2018

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Seth J. Baum, MD : Hi. I'm Dr Seth Baum. I'm a preventive cardiologist and the president of the American Society for Preventive Cardiology (ASPC). I'm here with the esteemed Dr Matt Budoff, a professor of medicine at UCLA. Welcome.

Matthew J. Budoff, MD: Thank you. Great to be here.

Baum: Today we're going to be talking about the ODYSSEY Outcomes trial[1] which was just reported at this meeting, American College of Cardiology (ACC) 2018. We'll also discuss a little bit about two other trials that came before, FOURIER[2] and SPIRE.[3] We're going to have, hopefully, a robust conversation and even move on to access. I will start by asking you what your take was on these trials.

Budoff: I think ODYSSEY was a nice complement to the prior two studies. We have had two previous trials that were both positive and now we have a third. I think this one's a little bit different; it has a different population, different length of treatment. But it's a nice complement to what we already know.

Baum: Now that we have the three trials, is it safe to say that this class is excellent for reducing risk across several different populations of patients with atherosclerotic cardiovascular (CV) disease?

Budoff: Absolutely. I think that this trial adds another dimension: a little bit closer to [index] acute coronary syndrome, a little bit longer follow-up. But I think it does complement the other two quite nicely.

Baum: You and I were talking about the 100 mg/dL LDL-C cutpoint. We don't have the paper yet; we really can't get into the weeds, we can't discuss why certain things happen. There was clearly something that happened at an LDL of 100 mg/dL (2.6 mmol/L). I want to ask you: If you had a patient, post-ACS, on maximally tolerated statin therapy with an LDL-C of 99 mg/dL, what do you do with that patient?

Budoff: I don't think there's a magic number that's obvious. What this told me at least is that as we get higher LDL-C, there appeared to be bigger benefits and it was pretty robust—a 21% overall benefit. The CV death and the other endpoints looked quite robust as you get to the subgroup with higher baseline LDL-C. You alluded to the fact that there are some potential reasons for that, but I don't think it's completely unheard of for people with high LDL-C to benefit more from an LDL-lowering drug.

Baum: That's pretty much consistent with everything we know about this, correct?

Budoff: Sure.

Baum: The higher the LDL-C, the greater the risk, and therefore the greater the benefit of lowering the LDL, right? People are trying to spin this as something new. Maybe it's not really anything new; maybe it's simply that we need to aggressively treat our patients.

Access Issues

Baum: I'm also curious about your experience in prescribing PCSK9 inhibitors and your ability to access them for your patients. Are you having great success? Is it a hard process?

Budoff: It's easier than it used to be. I remember going into a doctor's office to have a meeting, and one of the nurse managers asked me, "What are you here for?" I said, "We're going to be talking about Praluent® [alirocumab]." And she said, "Oh—the tough one," referring to the process of getting it approved. Now that we have outcome data, and while CV death and all-cause mortality were hierarchically a little bit lower, it trends in the right direction.

The CV mortality trends are in the right direction, which is nice to see because we didn't see that in the other trials. I think, as expected, that when you lower LDL-C, you lower CV events, including CV death. That's going to be an important nuance that we're going to be able to talk more about. I think that's going to make more people comfortable with this class of agents.

Baum: More people, more clinicians, are comfortable in terms of prescribing drug?

Budoff: We didn't have the CV death reduction in FOURIER. Therefore, I think there was some question about what we're really doing here by lowering LDL-C with PCSK9 inhibitors. Now it's a pretty straightforward message.

Baum: In regard to the FOURIER trial, for me, lowering the risk for stroke and heart attack has significant benefit, obviously. Some people tried to minimize that. It was a very short trial and we never saw a mortality benefit. Compared with all of the lipid-lowering trials in the past decade, it was an outlier in that regard. My sense, and I'm wondering if you agree with this, is to look at this as a drug class affecting LDL-C. LDL-C is the bad guy and we need to lower it as best we can.

Dr Fuster said it very well in the panel discussion. His first question was, does this means we need to get LDL-C under 50 mg/dL (1.3 mmol/L)? The answer was yes. Would you agree with that?

Budoff: Absolutely. I'm not a huge fan of ezetimibe, but even the IMPROVE-IT trial[4] showed some benefit in getting LDL-C to 55 mg/dL. Now we have moved the needle further south: < 50 mg/dL; a mean LDL-C in the 40 mg/dL (1.0 mmol/L) range was very efficacious for our patients.

FH Patient Rejections a Thing of the Past?

Baum: I've seen a good number of familial hypercholesterolemia (FH) patients not get access to drug. As the secretary treasurer of the FH Foundation, I am very involved in that organization. We've been trying very hard to improve access for those patients; they're a very high-risk group. They have the very, very high LDL-C levels. The FH Foundation published a study in Circulation[5] showing that patients with FH and LDL-C over 190 mg/dL on maximally tolerated statin therapy (all on at least moderate-intensity statin therapy) were rejected over 60% of the time. Will that change?

Budoff: I hope so. Now that we have synergy with three studies across three PCSK9 inhibitor agents that all show event reduction, we can do the necessary analyses and hopefully see access changing for the better. I think you're right—a stroke or a heart attack is a terrible end. I think ODYSSEY was a little different; they withdrew therapy from 8% of people because their LDL-C fell below 15 mg/dL, which in retrospect may not have been the best thing to do. Despite that, there was still a significant event reduction. And again, as the baseline LDL-C went higher, the drug looked better and better, which I think fits those FH people you described, with LDL-C levels that are astronomically high. Imagine if ODYSSEY had a subgroup of LDL > 190 mg/dL—what that would have looked like for event reduction.

Baum: I can't even imagine; it would've been so immense. A little plug for something the ASPC just did: We released a mobile app to help doctors get access. There are many tools, many connections with other organizations, and I frankly would love everybody to download the ASPC app and use it to get access. A little plug for that.

Budoff: That's great. We all need help, and we need little tricks to help us navigate this increasingly challenging environment with insurance companies and restricted access to therapies that have an indication. Even if you're prescribing according to the indication, you're still getting denied.

Baum: I often say this: When we started practice—and I think you would probably agree with me—90% of what we prescribed was off label. We now cannot prescribe anything and get it on label. It's a crazy world in which the patient-doctor relationship or interaction has been undermined to some degree. I don't know if you're feeling the same thing I'm feeling.

Budoff: Absolutely. Often you're calling and giving this information, and then somebody says, "No, I'm sorry, you can't get the drug." I ask, "What kind of doctor are you?" and they say, "I'm a urologist." Well, if I had a PSA question, then I would give him a call; but I think that when it comes to deciding whether my cardiac patient needs a PCSK9 inhibitor, I could probably make a better independent decision.

Baum: Yes; a urologist is not the right guy to make that decision.

Budoff: It's frustrating, and every insurance company does it differently. The app or other tools, such as the National Lipid Association checklist of five things that you should do before you call, will help clinicians get these therapies in the people who fit the indication. That is going to be really important.

Baum: Hopefully everybody will download that ASPC app and use it. Do you have anything else to add?

Budoff: I would just remind people that the organizers of the ODYSSEY trial had about 2 weeks to go through the data. We don't have a lot of the data points that we're all interested in such as some of the subgroup analyses where they might have done better. We talked about the LDL-C ≥ 100 mg/dL, but there are probably some other high-risk subgroups that might have enhanced benefit. We now have treatment up to 4 years, so landmark analysis would be nice to see how the curves separate if the patients are on it for at least 3 or 4 years and what the event reduction really is.

The main presentation represents a mean follow-up of only about 2.8 years, but some people were on it for longer. I think that's going to be a really important analysis once that comes out. We can't fault the investigators; they did a tremendous job of putting together a great study and a great presentation, literally within 2 weeks.

Baum: I completely agree. They did a wonderful job and they deserve a lot of credit. We've had a great time having this conversation. I enjoyed being here. I thank Dr Matt Budoff, and we'll sign off from ACC 2018.

Budoff: Thank you again for having me.

Baum: Thank you.


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