In the final installment of the AHA conference series, Parag Joshi, MD, explains the major changes of the 2018 cholesterol guidelines and how these cholesterol-lowering drugs can be used in practice for First Report Managed Care readers. He also discusses the cost-effectiveness of PCSK9 inhibitors.
My name's Parag Joshi. I'm a preventative cardiologist at UT Southwestern Medical Center in Dallas. My research interests and my clinical interests are in prevention of heart disease, that's heart attacks and strokes, especially things related to atherosclerosis or plaque build‑up in arteries.
The new guidelines that just came out in November of 2018 at the AHA Scientific Sessions have several major updates from the most recent, previous guidelines in 2013. One of the big shifts in recommendations in 2013 was that we moved away from an LBL cholesterol target.
Prior to 2013, there was a focus on estimating a patient's risk for a heart attack, which has remained in the guidelines. Then, based on that risk, targeting a certain LDL cholesterol level. In 2013, just to give you an example of what that means, if you were at high risk in the previous guidelines you would be targeted for more aggressive cholesterol levels. Your LDL target may be as low as 70 or 100 if you were at higher risk.
If you were estimated to have lower risk for heart attacks and strokes, then your target may be more lenient, like an LDL cholesterol of 130.
In 2013, that approach was reevaluated. We found that we didn't have the highest quality evidence to support that approach. There was no consensus on what the right target should be because none of our studies targeted a cholesterol level. Instead, in 2013, it became clear that the high intensity statin medications were outperforming any of our other cholesterol lowering medications at that time.
The 2013 guidelines shifted away from a cholesterol target and, instead, focused on a statin intensity or an intensity of therapy with statin medications. The goals of the guideline writers in 2013 was to maximize the use of statins when appropriate for high‑risk patients.
There was a lot of uncertainty about how that would be implemented into practice, but I think over the last five years that's shown in how providers are practicing in that statins are being prioritized as our primary way to address cholesterol related risk for heart attacks and strokes.
Of course, there's other things that go into the risk of a heart attack and stroke. There's blood pressure. There's diet. There's lifestyle. Both the 2013 guidelines and the current guidelines also emphasize diet, lifestyle, exercise as important ways to lower risk.
In 2018, though, we did see a re‑entrance of an LDL cholesterol target. In this case, for very high-risk patients. Those are patients who have had multiple heart attacks or strokes, or have had a heart attack or stroke, or needed bypass surgery, and also have another high-risk factor which we'll talk about.
In that group, it would be reasonable to target, also, an LDL cholesterol less than 70 with proven medications. The reason that the guideline writers have now changed back to a target, or at least incorporated that target, is that since 2013 we've had two big classes of medications that have had positive outcomes on events.
Prior to 2013, other than statins, there were no other therapies that had been proven to reduce heart attacks and strokes when added to statin therapy. Since 2013, there were three big trials that have been positive in terms of lowering cholesterol and lowering heart attacks and strokes when added to statins.
Those two classes of medications, one is ezetimibe, which in the IMPROVE‑IT study showed that a reduction in LDL cholesterol from about 70 to 50 led to an improvement in heart attacks, strokes, and revascularization procedures.
In 2015, we started to learn more about the PCSK9 inhibitors. This is a totally different way of lowering LDL cholesterol and a very effective way of lowering LDL cholesterol with reductions high as 50 or 60 percent on top of statin therapy.
In 2017 and this year, in 2018, we had reports in the outcomes trials of two of the PCSK9 inhibitors with evolocumab and alirocumab. Both of those studies showed dramatic reductions in LDL cholesterol on top of statin therapy. Accompanying that, showed dramatic reductions in risk for heart attacks and strokes.
With that new data, there was now enough evidence to say that with these other drugs on top of statins in a really high-risk population you can target an LDL less than 70. That was the major change that came up in the guidelines. That's targeting people who have already had heart attacks or strokes, what we call secondary prevention or the highest risk group for a repeat heart attack and stroke.
The other big group of risk that we think about, and maybe the larger population at risk, are the people who have not had a heart attack or stroke but are at risk for a first event. That's the group that we call primary prevention.
One of the big changes in our approach to primary prevention over the last five years is to better understand risk for a first event and what tests may help estimate that risk. In 2013, we had a new calculator to estimate a given patient's risk for a heart attack or stroke in the next 10 years. Since then, we've seen multiple studies that show areas where it may not be as accurate as we would hope.
In addition to that, we've seen studies showing how other tests can help with that estimate of risk and help our patients decide for themselves how aggressive they want to be with their treatment.
The big change to this guideline was that above all of these other tests that you can add onto the risk estimator, the test that's called a coronary artery calcium score, which is a CAT scan of the chest that looks for evidence of plaque buildup in the arteries. That test was prioritized over all others for two really important reasons.
One, the presence of coronary artery calcium varies across risk categories. There's a lot of heterogeneity between what your risk may be and whether or not you have coronary artery calcium. It's not just a test that when it's abnormal identifies who's at risk. Importantly, when it's normal, it can reclassify risk downwards.
The second important part about this test is that...When do we use it? It helps our patients decide for themselves whether they want to take a statin or be more aggressive with their therapies versus reassure them when they don't have any coronary artery calcium.
If a patient comes in and has an intermediate risk, which is now somewhere between 7 ½ to 20 percent estimated risk for a heart attack or stroke over the next 10 years, that intermediate risk group, we know that if they don't have coronary artery calcium on this test that their risk is really much lower than that. It can be cut in half, nearly.
If they have high burdens of coronary calcium, a score greater than 100, then it suggests that their risk is accurate or even higher than we're estimating. They really want to be aggressive with prevention.
The upgrade in that recommendation for that coronary artery calcium test as a tiebreaker when our patients are uncertain or when we, as physicians, are uncertain was a big change in the guidelines from 2013.
One of the big questions that's arisen over the last five years with new drugs such as PSCK9 inhibitors or ezetimibe is, how does that fit in with prescribing statins? A big emphasis that is really important to make is that the primary way to reduce risk related to cholesterol is with statins.
These other drugs should only be used either on top of statin therapy when risk is really high or in the small percentage of patients who can't tolerate statins. I would say, in my practice, 90 percent of my patients can tolerate statins, whether it's the first one we try or if we switch to a different one. There is a small percentage, somewhere around three to five percent, that we cannot get on enough statin medication to lower their risk.
In that group, that's where these other medications may play a role. Ezetimibe lowers cholesterol by about 20 percent and lowers risk over seven years by about 15 percent. The PCSK9 inhibitors lower cholesterol by about 50 percent and lower risk over just two to three years by 25 percent. You can imagine, over time, that risk reduction will be even greater.
The right patients for that, there are several groups of risk that we think about. One are the patients who have had a heart attack or stroke and still have a lot of high risk factors or have had multiple heart attacks and strokes whose LDL cholesterol is still above 70 despite being on as much statin as they can tolerate, preferably the highest dose of statin that they can take.
If they're still on a high intensity statin and they still have an LDL cholesterol above 70, those are the patients that we would recommend starting with adding ezetimibe, mostly because it's cheaper, and well tolerated, and well‑studied, to see if you can get below 70.
If you're still not able to get below that level, that's when we would add the PSK9 inhibitors. We really are talking about a tiered approach in that statins should be prioritized and then, if you need to get more aggressive targets, that's when you start adding these other medications on.
There's one other group that's really important here. That's the patients with what we think of as genetically high cholesterol, the familial hypercholesterolemia patient population, people whose LDL cholesterol is above 190. The risk for heart disease, in general, is made up of multiple risk pathways, a combination of cholesterol, smoking, lifestyle, diet, exercise, blood pressure. All of those things play a role.
People who have really high cholesterol, in this range where the LDL cholesterol is above 190, we know that that risk is really high despite any of their other risk factors. In that group, you really want to get the cholesterol related risk way down. That's the group where PCSK9 inhibitors, ezetimibe on top of statins definitely have a big role to play.
Another question that comes up in my patients is, what if you have a lot of coronary calcium? How aggressive should you be with non‑statin medications? That's more of a provider‑patient discussion. If we feel like there's still residual cholesterol related risk, that would be an area to target use of those medications in patients who haven't already had a heart attack or stroke but are at high risk for a future one.
The coronary calcium score identifies both patients who are at very low risk when it's absent, but when it's elevated in high amounts...It's a score that ranges from zero to several thousand. When it's above 100, we know that the risk is high for a heart attack or stroke.
When it's really high, above 400 or above 1,000, those might be patients that you worry about and get more aggressive above and beyond just a statin medication to try and get their cholesterol as low as you can get it.
What's really important in making these decisions, and helping our patients make these decisions, and identifying who's going to benefit the most from these medications in preventing events, you want to find the groups where the events are happening.
That's where the coronary calcium score makes a difference. It helps you find the people who are at risk for the events. With that in mind, the guideline writers were prioritizing the calcium score to help encourage payers to look at that as something that they would cover because it can have big implications in these decisions for lifelong medications.
There's a chance that if you have no coronary calcium that you don't need a statin for the next 5 to 10 years. Alternatively, the people who do have high burdens of coronary calcium are the ones who go on to have the highest risk for their first heart attack or stroke. They may be the right group to target the more aggressive preventive therapies in.
In general, patients with diabetes, which we know there's an epidemic of diabetes accompanying the obesity that we're seeing across the country and, really, across the world. In general, for that group, we already have known over the last 5 to 10 years or even longer that their risk for heart disease is higher than we generally would think.
The recommendations for that group has not changed dramatically. If you're age 40 to 75 and you have diabetes, the recommendation is that you should be on at least a moderate intensity statin if you have an LDL cholesterol above 70.
There is some risk estimation involved there. If you have really high risk based on a risk estimate where your 10‑year risk is greater than 20 percent, you may want to be even more aggressive with your statin therapy in those patients where you want to be on a high intensity statin.
Generally, for diabetes, we want to be aggressive with your risk reduction. That's a group where the recommendations have not changed dramatically. There have been small adjustments, but I'd say, for the broad population of diabetic patients, we want to be very aggressive with their cholesterol related risk and getting them on statins.
The elephant in the room with PCSK9 inhibitors is the cost of them. Certainly, we've seen the cost dropped by the two major companies that have a product on market recently. The question about cost effectiveness from a guideline perspective becomes more of a public health approach.
Does it make sense for a small benefit on a per dollar basis? Kind of a strange way to think of this, but a relatively smaller benefit if you were to end up prescribing this to everybody versus targeting this to the people that are going to benefit the most from it.
From a public health standpoint, that makes sense. From how we spend our health care dollars. On a patient‑provider standpoint, it becomes a little more murky.
If I tell a patient that there's a therapy that might help lower their risk, they don't necessarily care about the overall health care cost of that medication. They care about their co‑pay, how much it will cost them out of pocket. If it's not very much, then they're going to want that medication.
There is this challenge right now of, how do we target these medications best and make sure that people that benefit the most from it can get it? I think the guideline writers recognized that in identifying the highest risk group will be the ones that benefit the most from PCSK9 inhibitors.
That would be the group that we target the most. That is this group of familial hypercholesterolemia. They're genetically at risk for high cholesterol or they have LDL levels at that level. I don't know that you necessarily have to have the genetically proven familial hypercholesterolemia to warrant being treated aggressively with LDL reduction.
I think my patients who have an LDL above 190 are going to have high risk for heart disease going forward, whether it's a proven genetic mechanism or not for why their LDL's that high. Based on that, I think those patients should be on as much LDL lowering that they can tolerate and safely take, which it would include PCSK9 inhibitors.
Certainly, patients who have other high risk factors and whose LDL cholesterols are not getting as low as we would like are another group that we think would benefit from PCSK9 inhibitor. Identifying that group is what we're still working on. I think that's another role for calcium scoring.
If you do have a high coronary artery calcium score and a residual LDL cholesterol elevation despite a statin, that might be a group where you would say these are high risk folks. They would benefit from PCSK9 inhibition. We can figure out the cost effectiveness of that approach. That would be ideal.
How should you be using PCSK9 inhibitors in practice? Right now, I use it in my patients who have high risk or have had a heart attack or stroke and who can't tolerate a statin but still have an LDL that's elevated above 70.
In my patients, I use it in that group. I use it in my patients who have familial hypercholesterolemia, even if they can tolerate a statin. I want to drive their LDL down because that's a risk factor they've been exposed to for their whole life.
The other group is the patients that, even with a statin, they're at high risk. Their LDL is still above 70. They have evidence of coronary artery disease or coronary artery calcification.
Those are the groups that I targeted. Certainly, my patients who had multiple heart attacks or multiple events stand to benefit from more aggressive reduction if we haven't gotten them to where we think they should be.
One of the other factors that they changed in the guidelines for the primary prevention group, the group that we're trying to take an educated guess at who's at high risk and who's not at as high risk. They did endorse the use of some other risk enhancing factors that are known to be additive to our risk prediction.
Some of those factors include things like family history. If you have a family history of early heart disease we may be underestimating your true risk. If your cholesterol is above 160 and not just above 190, that's probably a higher risk group.
People with a metabolic syndrome, that's the obesity, high triglycerides, low HDL cholesterol, high blood pressure, insulin resistant kind of group. People who have had a history of preeclampsia, or women who've had a history of preeclampsia, or pregnancy related complications, or premature menopause.
We know that during reproductive years women have some protection from heart disease. If that's been truncated for whatever reason, then they may not have the same protection we would think.
People with chronic inflammatory disorders, rheumatoid arthritis, psoriasis. People with HIV are living much longer. They're actually suffering more from heart disease than from their HIV. That's because they are in this chronically inflamed condition.
South Asians were highlighted as a particularly high risk group that we may be underestimating the risk of. Then, there are some other tests that don't get the same recommendation that a calcium score does but do identify groups that are higher risk. Those tests are people with an apolipoprotein B greater than 130. That's a specific cholesterol related test that measures the burden of cholesterol in the body.
People with a high sensitivity C reactive protein greater than two. That's a measure of inflammation and has shown to be associated with higher risk. People with an ankle brachial index less than 0.9. That's a measure of blood flow to the legs compared to the arms and is a marker of peripheral artery disease.
People with a special test called lipoprotein a that's elevated. Lipoprotein a is a lipid test, a cholesterol particle that runs in families with heart disease, and is genetically controlled, and is a really strong marker of risk. About one in six families that have high burdens of heart disease, where multiple family members have heart disease, will have elevations in lipoprotein A.
These are factors that, when they're abnormal, can identify higher risk. The reason these don't get the same level of recommendation as a calcium score is because when they're normal it doesn't necessarily reclassify the risk downwards like a calcium score will. That's why the calcium score is really helpful in that decision making process with patients.
If you do happen to have these tested or you do have someone who's really concerned about their risk and these are present, then I think those are ways to help with decision making, as well, for how aggressive to be with prevention.