Deepak L. Bhatt, MD, MPH: Let me turn now to Dr Navar to discuss what I think is an important part of the discussion. She’s done a lot of work on this. How do we actually estimate patients’ risk for cardiovascular events? Certainly, there’s something we can do, as Dr Cannon mentioned, on a community level that applies to everyone. But in terms of individualizing risk assessments, how do we figure out who’s at risk for cardiovascular disease?

Ann Marie Navar, MD, PhD: Thanks, Dr Bhatt. Thinking about the last question, asking about the payers, when we’re thinking about why risk assessment is so important, almost every single clinical trial that has looked at the efficacy of lipid-lowering therapies to prevent new cardiovascular disease or reduce recurrent events in those who have disease has found that there’s a benefit difference on the relative scale for any particular subgroup of patients.

Everybody gets the same proportional reduction in their cardiovascular risk from therapies like statins, PCSK9 [proprotein convertase subtilisin/kexin type 9]. The difference, though, is that the absolute benefit is going to be completely driven by what somebody’s absolute predicted risk of events is going to be. If we’re thinking about how to maximize the cost-effectiveness at a population level, we want to be targeting the expensive therapies to those who have the highest absolute risk at baseline because those are going to drive the highest absolute benefit.

The latest cholesterol guidelines did a nice job highlighting what ways we can identify the highest-risk group. In primary prevention, we’re very accustomed to using the pooled cohort equations to start our risk assessment in patients. For people who don’t have cardiovascular disease, very well evaluated equations can be used that use a combination of age, sex, race, blood pressure, diabetes status, smoking status, to generate a baseline risk.

But not every factor that increases a patient’s risk made it into that model for reasons that go beyond the context of this conversation. There are other really important high-risk groups that the new guidelines remind us to think about. Those include people with family history of early heart disease, chronic kidney disease, metabolic syndrome, women-specific conditions like preeclampsia in pregnancy or premature menopause, inflammatory diseases. So, psoriasis, rheumatoid arthritis, HIV, and certain ethnic groups like South Asian ancestry.

They also remind us to think about the duration of exposure to risk factors. People who have persistently elevated cholesterol levels or particularly high cholesterol levels are also at risk.

And then there are other biomarkers and other tests that we can use to help risk stratify. People with high lipoprotein (a) levels, high apoB [apolipoprotein B] levels, high-sensitivity CRP [C-reactive protein]. Also, the recent guidelines use scoring to identify people with preclinical or subclinical atherosclerosis. In the primary prevention space, that is how we think about identifying the highest-risk groups.

Now, in secondary prevention we used to paint everybody with the same brush and say, “If you have cardiovascular disease, you’re at high risk.” But we know that’s not the case, and that some patients with cardiovascular disease are at higher risk than others. This is particularly important, as the guideline authors mentioned, when we start thinking about who we are going to treat with therapies that potentially can be budget busters, like the PCSK9 inhibitors.

The guidelines encourage us to look for the highest-risk patients in secondary prevention as well. And those risk enhancers, or those very high-risk groups, are similar, with some notable acceptations. People with recent acute coronary syndrome. People who have had multiple events. And, those who have had vascular events in different territories. So, PAD [peripheral artery disease] and coronary disease, or PAD and cerebral vascular disease indicating more diffuse atherosclerotic burden. And then other high-risk conditions like familial hypercholesterolemia. Again, looking back to cumulative exposure to high LDL [low-density lipoprotein], and those with diabetes, hypertension, chronic kidney disease, history of smoking, or congestive heart failure. These are groups of patients that are at extremely high risk of recurrent events and are recommended for the most aggressive lipid-lowering therapies.

Deepak L. Bhatt, MD, MPH: That’s a great and comprehensive answer. I think times have changed in many respects. As you were saying about the value of risk scores, I was involved with the REACH Registry Risk Score, which was developed in part for secondary prevention. Great folks were involved, some of the folks involved in the Framingham Risk Score were involved. It was well thought out, but the initial journals we submitted it to; it had a hard time in editorial and peer review. The comment was, “Great score, nice statistics, wonderful, but who needs a risk score in secondary prevention? All of these patients are going to get the same stuff.” And I think the point you made is really good. When we are considering advanced therapies, therapies that might be expensive, therapies that might have [adverse] effects, it really does help to further risk stratify.

Also, it was good that you mentioned some of the novel things to think about, in terms of risk factors…and even risk factors that are sex or race/ethnicity-specific that we’ve learned a lot about in the past few years. That was a comprehensive type of review.