Erin D. Michos, MD, MHS

: We have a second analysis, and the second analysis was to assess the consequences of the failure to achieve the LDL [low-density lipoprotein] guideline thresholds in patients at elevated risk, again using the same Family Heart database. But we are using it in a slightly different way. It’s the same 324 million individuals from 2012 to 2021. But in this data set, it’s a retrospective analysis looking at annual cardiovascular event rates. This is 56,000 individuals who met the following criteria: had to have 48 months or more of sufficient diagnostic, procedure, prescription, and lab data; [and] had to have more than 3 cholesterol levels—and this was something that eliminated a lot of people. It’s amazing how few people get regular cholesterol checking, even if they’re not at below threshold. Then we looked at those above or below thresholds for 70% of the time during the study period, including the baseline. We used the same guideline thresholds for high-risk primary and secondary prevention.

The patient histories were divided into contiguous episodes characterized by lipid-lowering therapies, whether it’s monotherapy, combination therapy, or, far too often, no therapy, prescriptions filled, and LDL levels, and we’ll look at the figure with that. We used an 18-month baseline period, and this was used to determine the covariates for the propensity score matching that we did. Individuals with a cardiac event during the baseline period were excluded. Following the baseline period, individuals were observed for 30 months or longer to determine that first cardiovascular event [and] the annual incidence rates. We also looked at second events too.

In total, there were 39,000 individuals who met the criteria for above threshold for greater than 70% of the time, and 17,000 who met the [criteria for] below threshold for 70% of the time. Then we one-to-one propensity score matched, giving us 14,755 individuals in each group. These patients were followed for a long period of time, 2091 days. What we found was not surprising but disturbing. Real-world data from the Family Heart database demonstrates that US residents in the above-threshold group had an annual incidence rate of first cardiovascular event [that was] 44% higher—this is a little over 4 years—than those below threshold. The event rates [were] 2.2% vs 1.5%, [respectively]. Total cardiovascular event—some people went on to a second event—in the above-threshold group was also 49% higher than those in the below-threshold group. This is a rather busy slide, but I’ll just say if you look at the individuals who are in the above-threshold group that’s represented by the top group of real-world evidence, you can see a lot of white, yellow—which is not on any drug—and pink and red—meaning on 1 or more medicines but still not at threshold. Below, where individuals were over 70% of the time below threshold, there's lots of green indicating below threshold on a single agent, or dark-green [indicating] below threshold on multiple agents. Our conclusion for this second analysis is that real-world evaluation of high-risk individuals achieving guideline recommended thresholds [showed] substantial reduction in the occurrence of a cardiovascular event. If you get to that below threshold [goal], you’re going to do better. So, a greater emphasis, as we’re all talking about today, on achieving LDL control will improve cardiovascular health at the population level.

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Mary McGowan, MD, FNLA, reviews real-world data from the Family Heart Database on the clinical consequences of failing to reach LDL-C thresholds.

Real-World Outcomes Data on Failure to Achieve LDL-C Thresholds

: Dr McGowan, I said you were going to show us some information, some real-world evidence of how [well] we’re doing or not doing in achieving LDL-C [low-density lipoprotein cholesterol] thresholds. What do you have?

: Thanks very much, Keith. I have some data from the Family Heart Foundation that I’d like to share with everybody. As a Family Heart Foundation, we have a large database. And what we did was 2 analyses. And I’m going to share those with all of you. And I thank you for indulging me for this. And I think this is not news to anybody, but there are extensive clinical trial data that demonstrate that lowering LDL, as we’ve all just been talking about, reduces heart attacks, strokes, and the need for cardiovascular interventions. And the 2018 multidisciplinary guideline on the management of blood cholesterol called for the initiation and intensification of lipid-lowering therapies if the LDL [level] exceeds the various thresholds that we’ve talked about. So we wanted to assess the achievement of below-threshold LDL levels in patients at elevated risk using a real-world database, the Family Heart Database. This database is huge. It comprises diagnostic, procedural, prescription, and laboratory data on over 324 million individuals in the US from 2012 to 2021. Now, everybody isn’t in the database for all that time. What we’re going to look at in analysis 1 is a data set that includes over 38 million patients who had sufficient diagnostic, procedure, medication, [and] lab data and had LDL [levels] above the thresholds we were talking about, an LDL [level] over 100 mg/dL in high-risk primary prevention or over 70 mg/dL in secondary prevention. We did not use the over 55-mg/dL [threshold] because, as you can see, we go through only 2021 in terms of the data.

Most patients at elevated risk, that is 72%, never achieved their LDL below their LDL threshold. For those—[and] this was really surprising—for those achieving periods below the [thresholds], the mean duration was very [short]. It was 159 days. One of the prime reasons is that most health care providers, that is 80% of those taking care of these individuals, never prescribed combination therapy, even though the guidelines, as we know, provide direction and a rationale for doing so. Analysis 1 gives you sort of an example of some of the things we saw. The ideal would be the top row, as you can see here. [Patient] comes to their provider, they’re above the threshold, but they’re not on any lipid-lowering therapy. The provider initially, as Erin pointed out, puts them on a single agent, likely a statin. And then that does not do the trick. In very short order, 12 weeks or so, [patient] comes back, gets rechecked, and then they get placed on multiple lipid-lowering agents or a second lipid-lowering agent to achieve their goal. But what we see is in the real world, things are actually quite messy. The reality is the last 3 rows as you can see. First of all, you can see the white data. That means we have insufficient data to even look at these individuals. But most people are either above threshold with a single lipid-lowering agent [or] above threshold on multiple lipid-lowering agents, which means that the primary care provider is trying to put people on more than 1 agent. Then most common, or very common, is about 40% of people above threshold [are] on no lipid-lowering therapy. Our conclusion from this first analysis [of] the Family Heart Database was despite effective and safe lipid-lowering therapies, the real world finds that most patients remain above guideline-recommended thresholds, and those who do achieve levels of LDL below thresholds are doing so for only a short period of time. In the United States, we know there’s insufficient prescribing of combination lipid-lowering therapies. And often patients themselves don’t understand the importance of adhering to these lipid-lowering therapies, [thus] putting them at increased risk for atherosclerosis.

Mary McGowan, MD, FNLA, discusses real-world data from the Family Heart Database on achieving LDL-C thresholds.

Real-World Data on Achieving LDL Thresholds

: Dr Michos, we now know there’s a 2022 expert consensus pathway that looks at nonstatin therapies. Can you give us a brief update on what some of the newer concepts are?

: I think this is a really important document because since the 2018 AHA/ACC [American Heart Association/American College of Cardiology] cholesterol guidelines, we have had 3 additional agents approved by the FDA for LDL [low-density lipoprotein] lowering. So the 2022 American College of Cardiology Expert Consensus Decision Pathway sort of updates some of those new data and new targets and brings us probably a little bit closer to the European guidelines. Essentially, it provides decision pathway support for different risk groups of patients for the role of adding nonstatins. For high-risk patients, there’s a first goal of reducing LDL by 50% or more with a maximally tolerated statin. And then if individuals remain above these risk-based thresholds, you can then initiate some of these nonstatin therapies, such as older nonstatin therapies like ezetimibe and newer agents that we have that we’re going to discuss. What are those thresholds? For secondary prevention, if someone has clinical atherosclerotic cardiovascular disease, or ASCVD, who’s also at very high risk—has had a recent acute coronary syndrome, MI [myocardial infarction], stroke, periarterial disease with other risk-enhancing factors—you want to get below an LDL level of 55 mg/dL. We’re trying to get lower than ever before. If you have secondary prevention ASCVD but are not at very high risk, perhaps a patient who may have gotten a coronary stent quite a while ago for stable angina but doesn’t have those high-risk features, that LDL threshold is less than 70 mg/dL. Now, for high-risk primary prevention, as in individuals with severe primary hypercholesterolemia, a group that’s enriched with patients with FH [familial hypercholesterolemia] who have LDL levels above 190 mg/dL in a primary prevention setting, we want to get below the LDL threshold of 100 mg/dL.

: Dr Ballantyne, I wanted to ask you about that high-risk primary prevention. What’s that new concept that’s in the consensus pathway?

: It’s great that we [as cardiologists] focus on the very high-risk patient, a very important group of individuals and people with documented disease, but you don’t want to wait until someone’s had an event to treat. In my family, for my dad’s first event, he had an MI. He was lucky. He had an episode of sudden death in the hospital but got resuscitated. My aunt was not so lucky. Her first symptoms were on the day she died. And my brother was not so lucky. The day of his first symptoms was the last day he lived. You don’t want to wait till someone has symptoms. And particularly, Mary, you mentioned FH. We’re missing so much. In addition to the over 190 mg/dL [LDL level] or FH, we have the pooled cohort equation. If it’s over 20%, now they’re suggesting you be more aggressive with that group, too, in terms of adding a second agent, if you need to. You want to drive their LDLs low. Let’s face it. We’ve got coronary calcium scores. It’s not a continuum. You don’t go from having no disease to an event. You had disease; you just didn’t know about it. We can detect that with the coronary calcium scores. So, using that, if you have a 0, that’s good. If you have any calcium, you have some increased risk. If you have a high percentile—a woman, for example, may have a low score, but it’s a very high percentile—be aggressive, knock that down. If it’s a really high CAC [coronary artery calcium] score, like over 1000—although some might argue over 300—you should be much more aggressive and get LDLs down, the same way we’re talking for secondary prevention. That’s in the guidelines. It’s an expert consensus pathway, but it’s about how do we use the CAC scores and treat more aggressively also in primary prevention. What we call primary prevention, as you and I both know and as the Bogalusa Heart Study showed us, doesn’t start when you’re 45 or 50 years old, Keith.

: Yeah, Bogalusa, Louisiana, as you know as the Berenson Chair. Gerry showed this a long time ago. It starts early in life.

: Dr McGowan, I’m going to ask you to show us [how] we’re doing in terms of real-world evidence with LDL-C [cholesterol] lowering. But before I do that, this whole concept of primary vs secondary prevention and the sliding scale of how it’s really an amorphous definition. How do you approach that, Dr Kohli?

: I think Dr Ballantyne made an excellent point, which is that we need to be smarter. And the 2022 Expert Consensus Decision Pathway has told us we need to personalize risk assessment for every individual so we’re not using the same shotgun approach, waiting for their event and then being reactive. We need to be proactive. And that means really using every tool in our toolbox. The calcium scores, of course, being a good one, but also other risk modifiers, as well, such as elevated lipoprotein a, elevated high-sensitivity CRP [C-reactive protein], family history, and things that the pooled cohort equation may not capture. Ethnicity, for example, is a big one. For me as a South Asian individual, that’s an amorphous sort of a thing that most risk calculators don’t capture. We also need to sort of start thinking about lifetime risk based on what we talked about earlier with cholesterol years of exposure, rather than just the 10-year risk when we’re deciding whether to reduce somebody’s LDL. So I think it’s really been an advancement in how we think about personalizing care. How we think about taking the No. 1 killer of men and women and proactively getting ahead of it rather than waiting for the disease to get ahead of us and then reacting.

: I really like that concept. Primary, secondary kind of slides. It’s amorphous. And now we know for many people, the first time they know they have heart disease, they’re unfortunately having a fatal event.

A panel of cardiologists discuss the key updates from the 2022 ACC Expert Consensus Decision Pathway on the role of nonstatin therapies for LDL-C lowering in the management of atherosclerotic cardiovascular disease risk.

New Guidance in Lowering LDL-C

 entitled, “New Guidance, New Data, and New Targets for the Management of Hyperlipidemia.” I’m Dr Keith C. Ferdinand, the Gerald S. Berenson Endowed Chair in Preventive Cardiology and professor of medicine at the Tulane University School of Medicine in New Orleans, Louisiana. Joining me today in this discussion are 4 of my favorite colleagues, very diverse, from all parts of the country. Will each of you introduce yourselves? Dr Christie Ballantyne, Dr Mary McGowan, Dr Payal Kohli, and Dr Erin Michos. Christie.…

: I’m Dr Christie Ballantyne from Houston, Texas, and chief of the Section of Cardiovascular Research. Keith, great to be here with you.

: I’m Dr Mary McGowan. I’m at Dartmouth Medical School, and I am the chief medical officer of the Family Heart Foundation.

: I’m Dr Payal Kohli. I’m a noninvasive and preventive cardiologist. I’m an associate clinical professor of medicine at the University of Colorado. It’s a pleasure to be here today.

: Hi, I’m Dr Erin Michos. I’m the associate director of preventive cardiology and the director of women’s cardiovascular health research at Johns Hopkins University. I’m also really honored to be part of this program today.

: This program is in partnership with the Family Hearts Foundation, a nonprofit organization dedicated to supporting research, advocacy, and education for individuals with the 2 most common inherited lipid disorders, familial hypercholesterolemia, or FH, and elevated lipoprotein(a), or LP(a). This 

will focus more broadly on strategies to improve control of LDL cholesterol [LDL-C ] in high-risk individuals. We will discuss real-world data on reaching LDL-C thresholds and emerging therapies for lipid lowering. We will also review strategies to help implement lipid-lowering therapies into your clinical practice. Welcome, everyone. Let’s get started. Dr Kohli, what is the role of LDL risk? We have various data (eg, experimental, observational, clinical trials).

: It’s one of those agents that I feel like we have such a compelling body of evidence about. Mendelian randomization, Dr Ferdinand, I would say, is one of the strongest types of evidence that we have. This essentially means if you’re born with a genetic mutation where you have a loss of function in your LDL receptor, meaning your LDL-C levels are super high, you get premature atherosclerosis. And the opposite is also true. If your LDL levels are low genetically, you have a much-reduced risk of having heart disease. This really establishes a causal relationship of LDL-C being what I like to call an endotoxin, which is a poison to the blood vessels. We really need to start thinking about LDL-C almost like we think about smoking—the cholesterol years of exposure. It’s not just the level, but it’s how long it’s been at that level that really confers the risk; the area under the curve, so to speak. The idea here is to try to lower cholesterol aggressively and to lower it early enough that you can really start to modify that area under the curve. Now, the Cholesterol Treatment Trialists’ Collaboration does tell us that the slope of how much bang for your buck you get when you reduce your cholesterol depends on your underlying risk. But in general, every 39 mg/dL that you drop your LDL-C, you’ll get about a 22% reduction in major adverse cardiovascular events.

: Wow. That’s a lot of evidence coming from different components of science. Erin, do you see anything else that you’d like to add related to LDL-C as an enhancer, or is it a risk factor?

: No, I think there’s overwhelming evidence that LDL-C is causally related to atherosclerotic cardiovascular disease. You heard some of these lines of evidence. We have evidence from genetic studies, from animal studies, from observational data, and also from interventional studies from randomized clinical trials. So this is very consistent. Although statins remain our first line of therapy in both primary and secondary prevention, we see that it is really all about the LDL lowering, not necessarily something magical about statins. Because if we achieve similar LDL reduction per millimole of liter per cholesterol lowering with nonstatin agents, we also see a similar reduction in major adverse cardiovascular events. So that is good news for our patients who either cannot tolerate the right amount of statin to get to their LDL goal, or they’re on the maximally tolerated statin, and because of genetic elevation, they start out so high that they need additional nonstatin therapy to get to our desired thresholds.

: You guys have given me a lot of information, and it indicates that LDL-C is causal for ASCVD [atherosclerotic cardiovascular disease]. But Christie, I remember they used to say the LDL hypothesis. What happened to that concept?

: Well, let me take it back to LDL as an atherogenic lipoprotein vs LDL-C. We measure LDL-C as a surrogate for those particles with it. All these particles that contain apo B [apolipoprotein B], so that’s LDL particles, VLDL [very low-density lipoprotein] remnants, IDL [intermediate-density lipoprotein], and LP(a). I don’t want to get too technical, but basically, all of that could be non-HDL [high-density lipoprotein] cholesterol. LP(a) is also important. So we focus on LDL-C as a surrogate for the bad particles, but there are other tests like apo B and LP(a) that could also be important or non-HDL cholesterol. I do think it’s the lipoproteins in our circulation. There are a lot of bad ones. When you see a high triglyceride level, very frequently that person has a problem, too, even though the LDL-C might appear to be somewhat borderline.

: Mary, I guess you’re going to have to agree. Our colleagues have given us so much information on the importance of LDL-C.

: No, I absolutely agree. The thing that I’d like to drive home is the difference between, as Dr Kohli pointed out, being born with a protective mutation. Say, for example, a loss-of-function mutation in 

 (proprotein convertase subtilisin/kexin type 9). You set yourself up for a lifetime of lower cholesterol vs getting on a statin later in life. It really gives us the message that the earlier we start to reduce LDL-C, the better. So often we don’t initiate therapy until after somebody has already had a cardiac event.

Expert cardiologists discuss the various lines of evidence that have shown a causative effect of LDL-C in the development of atherosclerosis.

Erin D. Michos, MD, MHS

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