Never Too Late (or Too Early) for Lipid Lowering

This transcript has been edited for clarity. Michelle L. O’Donoghue, MD, MPH: Hi. This is Dr Michelle O’Donoghue, reporting for Medscape. I’m here at the European Society of Cardiology (ESC) Congress in Munich, Germany, and there have been many interesting studies looking at use of lipid-lowering therapy in addition to the prevalence of subclinical atherosclerosis. I thought we’d touch upon a couple of these topics today. Joining me today is an expert in this space, Dr Ann Marie Navar, who is a professor of medicine at UT Southwestern and a preventive cardiologist. Welcome. Ann Marie Navar, MD, PhD: Thanks, Michelle. It’s always fun to talk to you about this exciting science. Plugging the Statins in Older Adults Evidence Gap O’Donoghue: One area where we’ve had a relative paucity of data has been in understanding in a dedicated manner the safety and efficacy of lipid-lowering therapy in older adults. There has been some hesitation in some prior iterations of the guidelines to necessarily recommend more potent lipid-lowering therapy in older adults, yet at the same time, we know that they’re at higher risk for events. One of the interesting presentations from ESC Congress at this meeting has been STAREE. This was a primary prevention study that was conducted in Australia where they took all-comers above the age of 70, randomized them to either statin therapy with atorvastatin or to placebo, and followed them for 5-6 years.I was struck by the fact that this was a pragmatic trial looking at the real world, as it were — at a fairly unselected primary prevention population of older adults. I think it showed a really compelling benefit that accrues over time in terms of reducing risk for major adverse cardiovascular events.Navar: The context for this is when we looked at prior primary prevention studies, there were very few individuals over the age of 75 years. The US guidelines have generally restricted the recommendations in primary prevention to people up to age 75. We had said, “If you’re on a statin already and doing well, turning 75 doesn’t mean you need to stop.” But there was this evidence gap. People have many concerns about statins despite having hundreds of thousands of patients in clinical trials and large amounts of data showing their safety. There’s always a “But what about?” And one of those was, “But what about older adults?” The two key findings from STAREE are significant reductions major cardiovascular events and really no safety problems. This is very consistent with what we’ve seen in younger primary prevention studies: Statins prevent cardiovascular events, and statins are very safe. I think this is a really important trial as we think about iterations of guidelines, maybe not having that under-75-year restriction be so strict.O’Donoghue: It was a 30% reduction in cardiovascular death, myocardial infarction (MI), and stroke. I think that is really quite compelling. There were safety events on occasion, but overall, the efficacy of the atorvastatin therapy in this trial far outweighs any potential concerns, and the safety events were all relatively minor.Prior Statin Trials in Older Adults Navar: There are two trials we probably have to talk if we’re talking about older adults. We actually do have one primary prevention trial of lipid lowering: EWTOPIA 75. It’s ezetimibe vs placebo in adults over the age of 75, which showed statistically significant reductions in MI and stroke. STAREE is now not the first, but it adds to an existing evidence base that lipid lowering in older adults works. The PREVENTABLE trial is ongoing the United States. This is funded by the National Institutes of Health. There will be more to come in this space, and none of us are expecting that to show anything different than what we saw for STAREE. Your arteries don’t really care how many turns around sun they have had. Cholesterol continues to deposit in our artery walls, and statins prevent that from happening and help stabilize any plaque that’s there. Adults over the age of 75 are the highest risk, so I don’t think we can use age as an excuse to not have conversations about lipid lowering.Lifespan and Disability-Free Survival Unchanged O’Donoghue: I completely agree. It’s worth noting, though, that they did have a co-primary outcome of all-cause death and disability-free survival. That wasn’t modified with lipid-lowering therapy. What do you say in response to that critique?Navar: I’m fine not having a heart attack or stroke even if I don’t live longer. That finding is more of a reflection of how good we are at taking care of patients with heart attacks and strokes. I don’t think we need to have the bar set at mortality to be talking about medications. That’s something that we would have a conversation about with our patients. If my patient’s goal is, “I’m only going to take a medication if helps me live longer,” okay, fine. If they say, “ I don’t want to have a heart attack or stroke,” then a statin makes sense. I feel like people who criticize statin literature for lack of or unconvincing mortality data are probably not taking care of patients. My patients aren’t asking me if something’s going to help them live longer. They’re very happy to be on something that’s going to prevent a heart attack or a stroke. O’Donoghue: I think we have seen with many lipid-lowering therapies that it does take time for the mortality benefit to accrue. Very often, there is a late signal toward a mortality benefit. I suppose that’s part of what people might quibble about for older adults if their long-term trajectory isn’t expected to be that long. But who knows in this day and age, right? I mean, if we’re able to reduce the incidence of MI or stroke, that is a compelling outcome for many older adults.Navar: Cholesterol treatment trial meta-analyses show that statins prevent death. STAREE reminds us that there’s nothing different about older adults and their biology of atherosclerosis. Although that single trial didn’t show it, the totality of evidence does show that statins prevent mortality.Subclinical Atherosclerosis: The REACT Study O’Donoghue: Building further upon what we’re talking about right now, some interesting new data were also presented at ESC looking at the prevalence of subclinical atherosclerosis. Again, building on this concept of really dialing back the clock and thinking more about primary prevention rather than just waiting to get serious about lipid-lowering therapy after people have a first event.I think the data from REACT, which are now published in The New England Journal of Medicine, are interesting in that regard. An all-comer primary prevention population underwent assessments of their femorals, their carotids, and their coronaries through a coronary CT angiography at different ages to see the prevalence of subclinical atherosclerosis.We saw that nearly 9 of 10 older adults that were studied in this cohort had evidence of atherosclerosis. Even more striking, I think, was the prevalence of subclinical atherosclerosis in very young individuals where we’re not necessarily thinking about initiating lipid-lowering therapy.Navar: Well, it’s the other side of the coin to what we just talked about. STAREE tells that it’s never too late to think about lipid lowering, but REACT reminds us that it’s probably never too early. We’ve known this for decades. The autopsy studies from the Vietnam War show the beginnings of coronary atherosclerosis and fatty streaks in the late teenage years or early twenties. By the time someone shows up with an MI, an obstructive lesion, or even a significant amount of coronary calcium, those plaques have been years, if not decades, in the making. REACT is a nice reminder of that. REACT also fits in well with what we already knew from the PESA study, which is a longitudinal cohort study in Spain looking at prevalence of atherosclerosis also using ultrasound in the femorals and the carotids, What they showed was very similar to REACT. It looks like iliofemoral arteries are the first place we start getting atherosclerosis, they’re sort of the canary in the coalmine. As we get older, we start to get it in our carotids and then the coronaries. We’ve been thinking about using coronary calcium to find early coronary atherosclerosis. What REACT is making us question is, should we be looking even earlier? If we can find it in the femorals or the carotid, is it time at that point to start thinking about lowering low-density lipoprotein cholesterol (LDL-C)? It’s much easier to prevent lipids from getting into the artery first place than it is to regress plaque. To regress plaque, we have to get LDL-C into the 40s. To prevent atherosclerosis, the epidemiologic data suggest it’s probably less than 100 mg/dL, maybe less than 70 mg/dL if you have other high-risk features. We don’t need as much medication to prevent atherosclerosis than we do to treat it once it’s there.REACT may help us start to change our screening paradigm. We certainly have to do more work to figure out who needs to be screened and how do we screen them. Patients want to know, I think, about where they are in the disease state, and it’s much more motivating for our patients when they know they’ve got plaque already forming than a risk score. Imaging as Motivational Tool O’Donoghue: It’s an interesting concept, that idea of the imaging in and of itself being a powerful motivational tool. There are some who argue, because it hasn’t been strictly shown to impact outcomes, whether calcium score or any type of femoral-carotid imaging should be used to guide who should start lipid-lowering therapy. I think, it makes sense from the perspective of having patients feel motivated to improve their own health and as an additional incentive for thinking about lipid-lowering therapy in our higher-risk individuals.Navar: Well, our prevention paradigm for every other risk factor says if we know the risk factor causes disease and we have a safe way to treat it, we don’t wait to treat. If your blood pressure is 160 mm Hg, I don’t say, “You’re a young woman who is otherwise at low risk, and you don’t smoke, so I don’t have to treat you.” I treat it because the totality of the data suggests that prolonged exposure to hypertension causes disease. I wouldn’t say you can smoke if your LDL-C was 55 mg/dL and your blood pressure was controlled. For lipids, we should start to shift our paradigm as well. We know that elevated LDL-C is tightly associated with long-term risk for coronary and cardiovascular disease. We know now the presence of subclinical atherosclerosis in the femorals is a harbinger of subsequent coronary and then cardiac atherosclerosis. It’s not a huge biological stretch to say that, if you’re starting cholesterol buildup in your arteries now, whatever your LDL-C is, the level is too high. We should probably start to treat it. I think it would be doing our population an injustice to say we have to wait for an outcomes trial that would take decades and billions of dollars to do.O’Donoghue: Absolutely. It’s supported as well by data from trials like VESALIUS-CV that have demonstrated that just very intensive lipid-lowering therapy, in VESALIUS with a proprotein convertase subtilisin/kexin type 9 inhibitor, reduced not only major adverse cardiovascular events but also a nominal reduction in mortality.The Primary Prevention Sweet Spot for LDL-C Lowering Navar: The trials are starting to kind of converge around primary prevention is really the sweet spot for LDL-C lowering. The hazard ratio for benefit in clear outcomes was much stronger in the primary prevention arm than in the secondary prevention arm. It’s easier to prevent atherosclerosis than it is to treat it, and now we need to be figuring out who are the patients who are most at risk. I think imaging helping us develop a more personalized approach to that, and I’m excited to see where we’re going to go. The nice things about ultrasound are that there’s no radiation, it’s cheap, and there’s really little risk to looking in the femorals or carotids. O’Donoghue: Last thought before we wrap up was that one of the interesting things for the REACT findings as well was that it showed it on a sex-specific basis. They showed that in women, that there really was a steep rise in the prevalence of subclinical atherosclerosis, especially in midlife. I think it is a bit of a wake-up reminder to women that it’s not just a man’s disease. We really need to get serious about lipid-lowering therapy, which we know is underutilized in women. Irrespective of sex, the disease is there, so we need to get serious about lowering lipids.Navar: 100%. And we see that midlife bogeyman of menopause. Fortunately, we’re talking more about all of the things that happen at the time of menopause. One of the key things that happens is that there are many cardiometabolic perturbations that not only increase our risk but also increase atherosclerosis. We need to be having a conversation about cardiovascular prevention when we’re also talking about menopause and hormonal changes.O’Donoghue: Thanks again for discussing this with me. I think there are many important reminders there. Navar: Thanks, Michelle.O’Donoghue: Signing off for Medscape, this is Michelle O’Donoghue.Michelle O’Donoghue is a cardiologist at Brigham and Women’s Hospital and senior investigator with the TIMI Study Group. A strong believer in evidence-based medicine, she relishes discussions about the published literature. A native Canadian, Michelle loves spending time outdoors with her family but admits with shame that she’s never strapped on hockey skates.