Advances in the Management of Hypercholesterolemia - Episode 10
Howard Weintraub, MD: There’s so much more that doctors need to know. As much as I’d love to think it’s not the case, many doctors are not fully aware of the data from the large outcome studies, mainly FOURIER and ODYSSEY. Can you give us what you feel are the important features of these trials and how these data, particularly some of the substudies, motivate your choices?
Alan S. Brown, MD, FACC, FAHA, FNLA: FOURIER was the study with evolocumab, and ODYSSEY OUTCOMES was a slightly different trial for patients with more acute coronary events but is very similar in its design. Both were outcome trials with the PCSK9 inhibitors. If you use the 140-mg dose of evolocumab vs the 150-mg dose of evolocumab, you get similar LDL [low-density lipoprotein] reductions of about 55%.
You already went through the fact that very low LDLs were achieved in those trials. One thing that’s been misrepresented about FOURIER is that when you look at the primary end point, which was 5-point MACE [major adverse cardiac events], there was about 15% relative risk reduction. The number needed to treat was about 50 people to save an event. Who were these people? These were people who had coronary disease and other risk factors—either a recent coronary event, hypertension, diabetes, or other risk factors to enhance their risk—on top of atherosclerosis. Carotid coronary peripheral vascular disease could get them in with other risk factors. They are who the ACC/AHA [American College of Cardiology/American Heart Association] multispecialty guidelines considered very high-risk patients.
Second, they were only followed for just under 3 years. When we look at the results of those trials, people may say they were a little disappointed that they didn’t see a bigger reduction with a 55% LDL reduction. They expected bigger event reduction, but we’re used to looking at 5- to 7-year trials, not 3-year trials. For 3 years, it was pretty robust risk reduction. It was highly statistically significant. Overall, cardiovascular outcomes including MI [myocardial infarction], stroke, risk of readmission to the hospital with unstable angina, and revascularization were all significantly reduced, which was very encouraging. We would expect the magnitude of reduction to get even greater over time.
Keeping in mind that these were shorter trials, they had a very satisfactory risk reduction. They looked at a lot of subgroup analyses, and what they found was an obvious rule of prevention. The highest-risk people always get the most benefit from anything that works, right? If you take someone who had a recent MI within the last 2 years, they’re going have a higher risk of a recurrent event, as opposed to someone who’s been stable and had an MI 10 years ago. That’s exactly what the study showed. Those with more recent MIs and more multivessel disease tended to have a higher benefit because they had a higher prevalence of disease. An analogy would be, if you had a drug that reduced the risk of breast cancer death, would you save more lives if you gave it to 1000 men or 1000 women? Obviously, the prevalence is so much higher in women. They have more events. The higher-risk individuals in all the subgroup analyses got benefit.
There were a couple of surprises. One was the peripheral arterial group. People who had symptomatic peripheral arterial disease, such as claudication, got a bigger reduction in cardiovascular events than virtually anyone else. I’m not 100% sure why that happened. I have my thoughts. When someone comes in with a recent MI, we always send them home on a statin. I’m not sure everyone thinks that way with someone who comes in with claudication. It may well be that those patients had not been as well treated prior to enrollment in the study, so maybe they were at higher risk. I’m not sure that’s true. Maybe their blood pressures were slightly different. It was a post hoc analysis, so we don’t know. But what was clear was that having symptomatic peripheral arterial disease identified a group that got the most benefit from being on a PCSK9 inhibitor. That comes from FOURIER data in particular. They are very encouraging.
Both groups also showed another interesting phenomenon. On average, LP(a) [lipoprotein (a)] dropped about 30% on the PCSK9 antibodies. That was interesting because we’re still debating how LP(a) is cleared. We’ve felt it might not be an LDL receptor mode of clearance. That was fascinating. Not every patient had a drop in their LP(a), but on average, it dropped about 30%. That was encouraging, and the question that everyone would have is, does that contribute to a reduction in cardiovascular events? It is not clear because there hasn’t been a prospective randomized trial to look at lowering LP(a) with PCSK9 inhibitors and outcomes. It was an observation. But Vera Bittner did a really interesting analysis of ODYSSEY outcomes. It was somewhat conjecture with statistical analysis, but it did suggest that those patients who got an LP(a) drop—in addition to a lowering of their LDL—had better outcomes. That’s very encouraging, especially in an era when we’re going to have some therapies that lower LP(a), in addition to what we saw with the PCSK9 antibodies.
That’s a long-winded answer, but there were a lot of interesting data from both outcome trials. The most important thing is that PCSK9 inhibitors showed definite, statistically significant reduction in events on top of maximally tolerated statin or statin plus ezetimibe.
Transcript Edited for Clarity