Editor's Note: From the American College of Cardiology Scientific Sessions in Chicago, Dr Fuster and panel discuss new data on transcatheter aortic valves, the HOPE-3 trial on blood-pressure and cholesterol-lowering in moderate-risk adults, an analysis of the incidence of familial hypercholesterolemia in patients with high LDL-C levels, and a global trial using wearable technology to get people to move more and lose weight. Three negative trials also get a mention.
Valentin Fuster, MD, PhD: Good afternoon. I am Valentin Fuster from New York, and we are in Chicago. I called Dr Yancy, who's from Chicago, and he told me it's beautiful weather. I cannot tell you the temperature because it's so low. He feels quite optimistic.
Clyde Yancy, MD: Absolutely.
Dr Fuster: We are in Chicago for the national meeting for the American College of Cardiology, and as usual I have a few luminaries who will pull it all together. On my right, Dr Pamela Douglas, professor of research in cardiovascular disease at Duke University. To her right is Dr Sanjit Jolly, associate professor of the department of medicine at McMasters, and to the far left, Dr Pieter Kappetein, professor in the department of cardiothoracic surgery at the Erasmus University Medical Center in the Netherlands. What are you doing here?
A Pieter Kappetein, MD, PhD: A surgeon among all these cardiologists, I feel like a sheep among the wolves.
Dr Fuster: And here of course is Dr Clyde Yancy, vice dean of diversity and inclusion, professor of medicine, professor of medical social sciences, and chief of the division of cardiology at Northwestern University. On my immediate left is Prof Jennifer Robinson from the department of medicine, division of epidemiology, at the University of Iowa.
Well, we have a real task ahead of you. I would like to discuss 10 papers. Maybe that's wishful thinking? We'll see.
PARTNER 2: TAVR in Intermediate-Risk Patients
We will start with the paper that created positive noise, which is the TAVR paper. The title of this paper is "Transcatheter or surgical aortic valve replacement in intermediate-risk patients." It was presented in this meeting by Dr Clyde Smith from Columbia Presbyterian in New York. The paper came out in the New England Journal of Medicine, with Dr Marty Leon representing the PARTNER 2 investigators.
We have learned over the past few years that survival rates are similar with TAVR vs surgical aortic-valve replacement in high-risk patients with aortic stenosis. The question is, what about patients at intermediate risk? Basically there were 2000 so-called intermediate-risk patients with severe aortic stenosis at 57 centers randomized to TAVR or surgical aortic-valve replacement. The primary hypothesis was that TAVR would not be inferior to surgical replacement. Before randomization, however, patients were entered into two cohorts in terms of the TAVR access. For 76% of the patients the access was transfemoral and in 23% it was transthoracic (mostly transapical).
Before we go into the results I'd like to comment on some important details. First of all, these institutions already had a lot of experience in TAVR. Second, the device used, the balloon expandable Sapien-XT, is certainly an advance over previous ones. So from the technological point of view, this new device was expected to have better results, particularly in terms of aortic regurgitation, which has been a problem in the past.
The main end point was the rate of death from any cause or disabling stroke, and it was very similar in both groups. This is very interesting, because the rate of stroke was higher in previous studies. They did very well from that point of view in this particular study. At 2 years, the results were the same, and the number of events was 19.3% in the TAVR group and 21% in the surgical group. In the transfemoral-access cohort, TAVR resulted in a lower rate of death or disabling stroke than surgery—the results were very close to being statistically significant. And finally, TAVR resulted in large aortic-valve areas. In terms of kidney injury, bleeding, new onset of atrial fibrillation, the TAVR patients did better than the patients who underwent surgery. However, vascular complications were lower in the surgical arm, and the surgical patients also did a little bit better in terms of paravalvular aortic regurgitation.
The conclusion of this paper is that in intermediate-risk patients, TAVR was similar to surgical aortic-valve replacement with respect to the primary end point of death or disabling stroke. Pam, give me a general view of that. Are you excited about this?
Pamela S Douglas, MD, MACC: I am excited because this is a very different cohort from what was reported in the PARTNER 1 trials or in the pivotal CoreValve trial where the STS score was really off the charts. Those trials were in people that we're very reluctant to send to surgery except for that they have a fatal disease. The median STS scores were 4% to 6% in PARTNER 2, so that's still very high for what we would consider for CABG surgery but much, much lower [than prior studies]. It's phenomenal that we can extend that benefit.
Dr Fuster: You could call them intermediate-high risk.
Dr Douglas: Yes. If we can extend the benefit of TAVR from the prohibitively high-risk groups down into much more garden-variety people who had previously not been eligible for TAVR.
Dr Fuster: Pieter, the patients are getting away from you.
Dr Kappetein: That's true. But it's not only that TAVR takes patients away from surgery, it's also that there's a population expansion. What you see is more patients being referred for aortic-valve disease treatment than previously. There is slight decrease in surgical volume but not as much as the increase in TAVR treatment. So, we [surgeons] still have work to do.
Dr Fuster: Okay. Sanjit?
Sanjit S Jolly, MD, MSc: I think this is the start of a change. There are many centers around the world that are doing awake TAVR with locals and patients are being discharged very quickly. In 5 or 10 years this will be like angioplasty. There's been an evolution in technology, and the outcomes are very good. It's exciting to be at this stage where we're seeing things evolve.
Dr Fuster: It's interesting, isn't it? Jennifer, what do you think?
Jennifer Robinson, MD, MPH: Well, as you're going younger and younger and people are living longer and longer, I'd be interested in what the durability of the valves might be. I assume they're going to be following those original people out and the technology will continue to improve.
Dr Fuster: Clyde, your reaction?
Clyde Yancy, MD: There are some long-term data already,[3,4] and it looks like it is sustainable. I'm pleased to see that we're able to put in a large valve and get a better effective valve orifice, and I'm excited about the technology, particularly if it's a smaller point of entry so the vascular complications can be minimized. That would really make a big difference in terms of access.
Dr Fuster: There are several questions I have about this paper. I would like to ask you first, Pieter, about the incidence of bleeding; life-threatening or disabling bleeding was 40% [in the surgical arm].
Dr Kappetein: In the surgical cohort of course you have much more bleeding because the bleeding is adjudicated in the same way for both groups, and of course after surgery you will have blood loss.
Dr Fuster: So, it's the way they defined it. It's an unusual term, though.
Dr Kappetein: Exactly. It is defined according to VARC. We will change it in VARC-3. We will remove the term life-threatening bleeding as a name, because it's not really correct.
Valve Thrombosis and Imaging
Dr Fuster: Let's talk a little bit about the future. First of all, they didn't do imaging for thrombosis. People are beginning to talk about thrombosis of the aortic valve. What do you think, Sanjit, because this is an issue, although the stroke rate was very low?
Dr Jolly: It's a hot area. We don't know the answer yet, and we're going to need to follow these patients, and the question arose of whether these patients need some form of anticoagulation to reduce that stroke rate further. We'll only know that from future studies potentially, but it's a very interesting area.
Dr Fuster: Pam, I have a question. I just had a patient 45, 46 years of age and we were not talking about TAVR for lots of reasons, but let's assume that we are going into intermediate-risk patients and those younger and younger. What about duration of these valves? Do you think about it? If the valve gets calcified, do you think we can do a second procedure afterward?
Dr Douglas: Well, there are a couple of questions embedded in that. First is the long-term durability with transcatheter valves, and we just presented the 5-year data from PARTNER 1 and found no durability signal, no concerns there, no excess valvular, transvalvular regurgitation, or increase in gradient. At this meeting, we also presented as featured research the data from the TVT registry about the incidence of an increase in valve gradient at 30 days and 1 year, and it's about 2%. It's very low and didn't seem to be associated with events. We need to be really cautious about taking an imaging finding on CT and assuming that that translates into a clinically significant problem.
Dr Fuster: Absolutely. The other question I will ask you, since you work in the area of imaging, we have been a little concerned frankly about the brain. When you start doing MRI in these patients you begin to see little things which heaven knows what they mean, but it is concerning. What is your opinion about that, because there are not enough well-done studies on cognitive function with good follow-up?
Dr Douglas: We're going to come to that. The cognitive studies that have been done on CABG are actually a little concerning. There's even that term, pump head, right? The issue is which is worse [TAVR or surgery]. It happens with both procedures but is it significantly different?
Dr Fuster: Pieter, I have a question for you. What about aortic regurgitation?
Dr Kappetein: There are only a limited number of devices that you can use for pure aortic regurgitation (aortic insufficiency). In Europe, there's the Jena valve, which is not approved in the United States. That's a valve that you can use for pure aortic regurgitation. Otherwise, you need a little bit of calcium depending on which device you use.
Dr Fuster: To make it fix.
Dr Douglas: Yes, to anchor it.
Dr Fuster: Another question I have is about at least 25% of the patients that we see who would not be easy candidates for TAVR—for example, the bicuspid aortic-valve patients, the very hypertrophic ventricles with the low gradients and ejection fraction. These patients do not appear to be entered in any of these studies.
Dr Yancy: It will be a challenge.
Dr Fuster: 25% will go back to you, Pieter [joking].
Dr Yancy: I think Pamela commented on this as well. We're beginning to understand a lot more about the different phenotypes of aortic stenosis: small ventricles, low gradient, there are a number of things that we didn't appreciate fully; now that we have more therapeutic options we're studying these issues, and we're fascinated with this low gradient, small ventricle, and we ask, what is that and how do you deal with it?
Dr Fuster: Jennifer, you're an epidemiologist and you work in prevention. Is there a way to prevent surgery for aortic stenosis?
Dr Robinson: I can't see an easy angle for this one, but I'll think about it.
Sapien 3: Propensity-Matched Comparison of TAVR vs SAVR
Dr Fuster: Well it's exciting and very good news, but I'd like to touch on the second TAVR paper, which is the SAPIEN 3 observational study. It's on TAVR vs surgical valve replacement, also in intermediate-risk patients. Basically, they used Sapien 3, which is a new-generation device, and they tested it in a number of patients, and they found that these patients did very well, at least when they were followed for a month. Then they followed them for a year and they did very well. So, what they decided to do was to pull together the data of the surgical cohort from the PARTNER 2 trial that we just discussed and the data from SAPIEN 3 to see whether there was any difference. We are talking about over a thousand patients with intermediate risk over 50 sites and centers in the United States and Canada where they used both types of valves (Sapien-3 and Sapien-XT) and they did a prespecified propensity-score analysis. You match both groups because there's no randomization.
What they found is that the propensity-score analysis indicates statistical superiority for the composite outcome with TAVR compared with surgery, suggesting that TAVR might be the preferred treatment in intermediate-risk patients. Interesting, isn't it? What do you people think? Pam, give an opinion. Is this wishful thinking?
Dr Douglas: This is new. Right? Everything that has been done to this point with TAVR—the curves are superimposable virtually, and now they're saying superiority over surgery. As you get to lower- and lower-risk TAVR procedures with smaller [sheaths] with increasingly better procedural success, surgery is kind of staying the same. Everybody knows how to do the surgery, and the techniques have been refined for a decade, whereas TAVR continues to be refined; it's going to continue to drop because it's still a technology in evolution. It's new, but I don't know that it's entirely surprising. It's wonderful news, actually.
Dr Fuster: It's very interesting. However, when you start matching groups I don't know about that. What do you think, Clyde?
Dr Yancy: Well, it is interesting that for the transfemoral approach in PARTNER 2 there was almost a statistically significant advantage. So, it's not an inconceivable conclusion; I'm reticent to accept the observational analysis as definitive, but it certainly does go that direction.
Dr Fuster: Yes. We mentioned that the transfemoral-access cohort in the previous trial showed a trend toward superiority. Things are changing very rapidly, and I think this was a very good study.
HOPE-3: Blood-Pressure Lowering in Moderate-Risk Patients
Dr Fuster: Let's now go into the three HOPE studies from McMasters University. One relates to the lowering of blood pressure in intermediate-risk people without cardiovascular disease. The other is lipid-lowering medications in the same group. The third one is the combination of both. What is interesting is that these were not patients with high blood pressure or patients with high LDL cholesterol. People at intermediate risk could enter the study. It was across the population.
There are good data that antihypertensive therapy reduces the risk of cardiovascular events, but there has been a lot of discussion about the ideal level of blood pressure in the population that you are treating, which we will talk in a moment. In the SPRINT trial, lower is better, if you avoid talking about side effects, but let's leave this for later. In HOPE-3, they took this population and used a two-by-two factorial trial design—we will discuss the lipid aspect later. There were over 12,000 participants that they called intermediate risk. These patients were randomized to an antihypertensive regimen of low-dose hydrochlorothiazide 12.5 mg daily and candesartan at a dose of 16 mg daily vs placebo. They had two types of end points. The first was the composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. The second one shakes you up because they included resuscitated cardiac arrests in an intermediate-risk patient population. I don't know how they got that end point. It was included and also, heart failure and revascularization as well as CV death, MI, and stroke.
These two groups were followed for 5 years. First of all, they had a drop in blood pressure that was not very significant in the group treated with antihypertensive, basically 6 mm Hg [systolic blood pressure] SBP and 3 mm Hg [diastolic blood pressure] DBP. The result for the primary end point was 4.1% in the active-treatment group and 4.4% in the placebo group, so virtually the same, not significant. The second end point was practically the same. There was no significant difference. However, they used three prespecified subgroups or cohorts. One was the tertile with the highest baseline blood pressure, which was SBP >143.5 mm Hg. In this group, there were some significant results in terms of both composite end points vs the placebo group.
The paper's conclusion is that therapy with candesartan at the dose of 16 mg per day plus hydrochlorothiazide at the dose of 12.5 mg was not associated with a lower rate of major cardiovascular events than placebo among patients at intermediate risk who did not have cardiovascular disease. This was published together with the other two in the New England Journal of Medicine. We were joking before that if you have three papers in the New England Journal of Medicine on the same day, you really can close the shop. How they did that I don't know.
In a moment, we can discuss the SPRINT trial and how this compares with it, but I'd like your reaction first. Jennifer, what do you think when you read this?
Dr Robinson: I thought the blood-pressure arm was interesting because it took intermediate-risk people, and I want to be clear it's not the same as intermediate-risk TAVR patients. The projected 10-year [atherosclerotic cardiovascular disease] ASCVD risk for this group would be about 8% or 9%. We drew the line at 7.5% for the cholesterol guidelines, for example, to put it into perspective. It tells us two things. First of all, the only group that benefited was the top tertile with SBP over 143 mm Hg. There was actually a suggestion of harm in the lowest tertile that was treated. They were low risk, so I was relieved because it tells us we don't have to treat lower levels of blood pressure in low-risk people, we can probably wait. That's always the issue: when do you start treatment? How are you going to affect the progression of disease? To me, it says we can wait until they're a little higher risk, maybe a little farther along the atherosclerotic disease curve perhaps, a little older, and then start blood-pressure treatment over 140 mm Hg.
Dr Fuster: Clyde, the results to me were expected. If you drop the blood pressure 6 mm Hg in a low-risk population with relatively low blood pressure, do you expect you are going to achieve a miracle?
Dr Yancy: I hope not because it violates everything we think we understand about this.
Dr Fuster: It's a very low-risk population. Does the surgeon have something to say?
Dr Kappetein: It shows that medical treatment will become more powerful, and what we already see is a decline in coronary bypass surgery. We see that in lots of countries in Europe, and it points to the fact that preventive medicine is very important. So, another reason why we surgeons may be out of work in the future.
HOPE-3 BP and SPRINT in Context
Dr Fuster: Pam, let's go into SPRINT. In SPRINT they say the lower the better, but these were patients with hypertension to start with. Many were already taking antihypertensive medications. Although SPRINT says lower is better, when you reach a stage that the blood pressure is low there are side effects, and this was seen in SPRINT, although it was written in very small letters. I don't think this goes against SPRINT, do you?
Dr Douglas: No, I don't think so. That top tertile was hypertensive. We tell people to start thinking about treating patients with that kind of blood pressure. The suggestion of harm in the lowest tertile echoes the side effects that you see in SPRINT (the increased renal disease and so on). We really have to be concerned about hammering on blood pressure in some people. I think it may be too much.
Dr Fuster: Sanjit, we say lower blood pressure is better, but what we don't take into account are the side effects. We all have patients in whom either the agent makes the patient have side effects or drops the blood pressure too much. I don't think we should talk about a number. We should talk about the patient, because we can't treat beyond what the patient tolerates. I'd like to get this point across today, because there's an obsession with the number. Patients ask "What should my blood pressure be, because I read in the newspaper it should be below 120 mm Hg?" I tell them, well you should read again.
Dr Jolly: It's important to individualize patient therapy based on the side-effect profile. It's interesting that patients are becoming more informed. The come in with their blood-pressure diaries and they will tell you that they were symptomatic at this point. That's important because if they're very symptomatic and they have a syncopal episode driving a car, you've really reduced their quality of life.
Dr Fuster: What do you think, Jennifer, a single blood-pressure target or should we talk to the patient?
Dr Robinson: We have to talk to the patient. Going back to the cholesterol guidelines, for which I was the vice chair. We introduced that concept of net benefit. What's the absolute risk of the patient? How much are you going to reduce that risk with the added therapy to get a potential for benefit? Then you have to subtract the harms. Blood pressure is particularly remarkable in that stage. We need to really look at the potential net benefit for that patient.
Dr Fuster: I'm glad you brought that up.
Dr Robinson: Then the other thing that we introduced was this whole concept of shared decision making: Does the patient want to take another medication? Is that going to jeopardize what they're already on? Maybe they don't want to be on a diuretic and have to get up and go to the bathroom in the middle of the night. Shared decision making is critical.
Dr Fuster: Clyde, do you agree that we should not talk about the level of blood pressure but rather individualize it? Maybe personalized medicine is what we need to talk about.
Dr Yancy: What we should really talk about in hypertension is risk, and we haven't done a very good job of that. I really applaud the cholesterol guidelines for introducing that vernacular into the everyday discussion. SPRINT was so compelling to me because it really was about people with higher risk, probably 15% or greater by most risk calculators. That puts these data into a nice context, understanding that the risk of the HOPE-3 participants was at a least half of what it was in SPRINT. So, the benefit of treating hypertension was limited to just those who already had high blood pressure. It's especially important for us as practitioners to think about risk and not just look at a number and start treating.
Dr Fuster: Did you read this meta-analysis done in the Lancet? It was fantastic and included 123 studies on antihypertensive medication. What they showed is that the relative benefit is the same when you treat patients with antihypertensive medication, but obviously those at the higher risk have the greatest benefit because there are many more events, and I think that really helps. Usually we pay attention to the high-risk population.
Dr Yancy: That's right.
HOPE-3 Lipid Lowering
Dr Fuster: I think it's time that we move from this paper to the other one, also from the group of Salim Yusuf at McMaster. It was presented by Dr Jackie Bosch. I should note that Dr Eva Lonn gave a very good presentation of the first HOPE-3 paper.
This had basically the same methodology but with different types of medications. The same 12,000 participants were treated with rosuvastatin [Crestor, AstraZeneca] at a dose of 10 mg per day vs placebo. They used the same end points, but the results are very interesting. The drop in the LDL cholesterol was significant; it was about 30% (unlike the blood-pressure drop in the first study). According to the investigators they saw a huge benefit. The primary outcome occurred in 3.7% of the rosuvastatin group vs 4.8% in the placebo group. What has been transmitted to the press and everywhere is a 30% reduction, when in fact it's an absolute reduction of 1%. I really want to make this very clear. I think the study is fantastic, but we should be very careful with the way we portray the results.
For the secondary end point, the results were very similar. The difference was small but with so many patients the results were statistically significant. To summarize what the New England Journal of Medicine paper says: Treatment with rosuvastatin at the dose of 10 mg per day resulted in a significantly lower risk of cardiovascular events than placebo in this intermediate-risk, ethnically diverse population without cardiovascular disease.
What you think, Jennifer?
Dr Robinson: I think we're starting to define the lower limit of benefit for primary prevention for statins. An absolute risk reduction of 1% over 5 years is a number needed to treat of 91. The rule of thumb—and we could talk about whether it's right or not—is an NNT of about 50 for clinicians to consider something beneficial, and it's about 30 for patients if you ask them in a questionnaire. But that's a lot of people that you need to treat to prevent events. Now, there were a couple of issues. They were a lower-risk population—8% or 9% projected 10-year ASCVD risk, but they actually had a pretty modest LDL-C reduction. I think it was 34 mg/dL [at 3 years] so you'd actually only expect about a 20% reduction in events. Maybe if the LDL-C reduction had been more it would be more reasonable to do it.
We're defining the lower limit of when things are reasonable to do. Engage with our patients perhaps, as we recommended in the guidelines, to say here's the potential for benefit (fortunately there wasn't much harm with the statins), and there were some extra muscle aches. Then ask the patient how do you feel about it? Some patients want to reduce risk if they think they have any risk, and some are rather bland about wanting to do prevention. That's an important aspect here.
Dr Fuster: Per the AHA and ACC guidelines, these patients actually are on the borderline of low risk. But what does this mean in real life? Because it was said that this had a huge impact given the large number of patients that we have to treat with the statins, but I don't see this with the data available. Do you?
Dr Robinson: Our guidelines actually drew the line at a 10-year ASCVD risk of 7.5% and recommended a moderate-intensity statin. You'll get a 30% to 35% reduction with that, which is a little bit more than they got. Then it works out to be a pretty reasonable number needed to treat of about 45 to 50.
Dr Fuster: But would this increase the number of people treated from the usual guidelines?
Dr Robinson: Yes, this would. The inclusion criteria were men over 55 years, women over 65 years with one risk factor. It's moved away from measuring risk. I think there is still a role for risk prediction for the individual patient because if the average level is 8%, that means that half of these people were below that. It does suggest that we should be focusing on those higher-risk people and using statins on them.
Dr Fuster: Clyde, unlike with blood pressure, with LDL-C lower is better in a way because the side effects are not like the side effects that you have with antihypertensive medications. Is this not correct?
Dr Yancy: Well, it's debatable, because what Jennifer's getting at is that it's even more important to have the conversation. There are going to be those people that believe that this is a reasonable exposure to bring their rate of cardiovascular disease down by a small amount, and others may not think it's reasonable. Their lifestyle may not be benefited by being on a statin. This is when we have to sit down and really have a discussion.
Dr Fuster: Pam, when you read all of these, what was your reaction?
Dr Douglas: There are a couple of things. One is that the lipid situation, the statin situation is really different from the blood pressure.
The blood pressure is clearly a J curve. There's clearly a lower limit of benefit—and then it reverses. In the statin what we get is that the risk level in these patients gets so low that the benefit just dwindles away as opposed to actually actively causing harm. Conceptually it supports the idea of a risk assessment as the trigger for a statin as opposed to a particular LDL-C number. In that sense it's really the first trial to test the guidelines concept of moving away from targets and cut points, and that's a big contribution. As Jennifer said, we're also seeing the benefit get so small.
Dr Kappetein: Also in terms of cost, because that is an important issue if you need to treat 91 patients.
Dr Robinson: It still costs money, but it's about $15,000 per quality-adjusted life-year, down to about 5% or so. So, it would be cost-effective.
Dr Fuster: Let me tell you one thing here. Now you are going to see 100 patients that are intermediate risk, no cardiovascular disease, but one is obese and the other is not walking and has a sedentary lifestyle. The other has an HDL-C that is low. Are you going to give rosuvastatin 10 mg?
Dr Jolly: I think I'm going to have the conversation.
Dr Fuster: With yourself first [joking]?
Dr Jolly: Well, I'm not 55 years, but it was very interesting talking to colleagues. A number of the colleagues said they knew the results were going to be like this and that's why they took the statin. That was the immediate conversation.
Dr Fuster: Some of them have very normal LDL-C levels.
Dr Jolly: Yes, but the vast majority had an elevated waist-to-hip ratio, which is the interesting thing. You look around Chicago or much of North America, almost 80% of the population has an elevated waist-to-hip ratio.
Dr Fuster: For this study, it's a controversial issue because the data provided show that the benefit is very small.
Dr Yancy: But doesn't Sanjit get to the real root of this? If you think about population health you've got very simple treatments. You've got a fixed dose of hydrochlorothiazide, a fixed dose of an [angiotensin-receptor blocker] ARB, a small dose of a statin, administered to a lot of people at intermediate risk with some benefit. It is intriguing to think about.
HOPE-3: BP- and Lipid-Lowering Combined
Dr Fuster: Let's discuss the third paper of HOPE-3 because that's where the challenge is. For this third paper, they combined both, the antihypertensive and the lipid lowering. Basically the benefits were related by and large to the lipid lowering. This is the first test you could say of the concept of a polypill, but I will tell you, Clyde, the polypill is an issue that came out from the lack of adherence. In the FREEDOM trial only 20% of patients with diabetes and coronary disease were taking the right medications. If you used a polypill, could adherence be improved? HOPE-3 is not a polypill. Second, when you develop a polypill, the agents react with each other when they are together. Drugs that you can take separately with no reaction can react when you put them together in a single pill.
So, I think the question is, are the people going to take all of these pills? What I'm saying is you are correct. The population should be treated, but I'm not sure about giving so many pills, because they don't take them.
Dr Robinson: Well, I think it says you can give a polypill perhaps to men over 55, women over 65 with one risk factor and SBP over 140 mm Hg, and then it starts to look more like medical treatment vs a polypill approach where you're treating a whole population over age 50.
Dr Fuster: I may be wrong, but I'm quite skeptical about the polypill for primary prevention. Everybody's different, different blood pressures, LDL-C levels, and it's very difficult to pull it together.
Dr Douglas: Jennifer, there appeared to be less benefit in those patients with the higher LDL-C levels in the subgroup of HOPE-3.
Dr Robinson: I think that might have been nonadherence, because it was the on-treatment LDL-C. By the end of the trial about 25% were off the rosuvastatin. So, it could just be that those that weren't on the medication were in the top LDL-C tertile—of course, if you don't take the medication it doesn't work. We saw that in JUPITER also. When we look at the data as a whole from cholesterol trials, you get the same relative risk reduction across LDL-C level.
LDL-C, FH Mutation Status, and CAD Risk
Dr Fuster: Let's now move into a study of people with very high LDL cholesterol that assessed how many of these people have familial hypercholesterolemia, and if so, how many have mutations in one of the three genes involved. The paper's title is "Diagnostic yield of sequencing familial hypercholesterolemia genes in patients with severe hypercholesterolemia." It appeared in the Journal of the American College of Cardiology (JACC), and the three lead authors were Amit Khera from Mass General, Dr Hong-Hee Wan, and Dr Gina Peloso, the senior author being Dr Sekar Kathiresan.
In the introduction they say that almost 7% of US adults have severe hypercholesterolemia defined as ≥190 mg/dL. Such levels may be due to familial hypercholesterolemia, which is caused by mutations in three genes, although it's more complicated than that, but let's leave that aside for now. The hypothesis was that lifelong elevations of LDL cholesterol in patients with familial hypercholesterolemia might confer a risk for CAD that is much higher than LDL-C elevation without the genes being affected. They looked at a population of over 26,000 people. They looked at those with high LDL-C and followed them to look at events. What they basically found was that if you have an affected gene you have much higher risk.
How many of these people have the familiar hypercholesterolemia mutation? I was quite surprised. It's less than 2%.
Dr Robinson: Well, I think there are some issues with the population studied. We expect the prevalence of FH, defined by usual clinical criteria, to be about one in 200, one in 300 around the world in every continent. In this study, 7% of the whole population had LDL-C levels >190 mg/dL and only 2% of those had the mutation.
Dr Fuster: How do you explain that?
Dr Robinson: I think it's a result of the cohorts used. They picked middle-aged and elderly cohorts. Unfortunately, all the FH people were probably dead by then. That's really the point. When you have genetic hypercholesterolemia from birth, your risk is accelerated 20-fold, and that's what they found. Unfortunately, they didn't characterize family history, so that was the missing part, but if you look at people with a clinically defined family history, high cholesterol, their risk is 20-fold higher. There's nothing magic necessarily about having the gene. I would not want people to get the wrong impression that you only have high risk if you have the gene. If you have an LDL-C over 190 mg/dL and a family history of premature CAD, you've got FH. So treat them. Their risk is 20-fold. They should benefit.
Dr Fuster: We had a paper in JACC recently, by a Spanish group, a very large population of familial hypercholesterolemia. One of the things I was impressed with is how difficult it is to bring the LDL cholesterol down with conventional medications.
Dr Robinson: Really?
Dr Fuster: Let's assume, Clyde, that you have a patient with an LDL-C level of 200 mg/dL. If he has familial hypercholesterolemia, would you start with a PCSK-9 inhibitor?
Dr Yancy: I would certainly start with high-dose statins, but I would default very quickly to the PCSK9 inhibitors.
Dr Fuster: I think that's the message. What do you think?
Dr Douglas: The issue is, does the genetic information help in a treatment situation? Obviously it helps to define the epidemiology of the mutations and the disease, and we need to learn that, but in a treatment situation if you have somebody with an LDL-C over 190 mg/dL, family history of premature heart disease, do you really need the gene information? I don't need a lot more information. That person's going to get treated extremely aggressively.
Dr Fuster: True, but they saw a difference between those with familial hypercholesterolemia and those with no gene abnormalities. The point I'm trying to make is that at least this brings awareness, but I think we should not start doing studies for the sake of doing them.
Dr Robinson: In the guidelines, the second statin-benefit group is those with an LDL-C of 190 mg/dL or greater because it's too complicated for people to figure out if they have FH or not. An LDL-C of 190 mg/dL alone had an odds ratio of sixfold higher risk in this study. Since when do we not treat somebody with a sixfold higher risk? The message—and they showed some nice data later—is that the lifetime exposure is what's giving them the 20-fold higher risk, but anyone with an LDL-C of 190 mg/dL is a high-risk patient and should be treated. Now, if you have a person with an LDL-C of 260 mg/dL because they have an LDL-receptor defect, cutting that by 50% on a statin is still pretty high. I think those are the people who need a PCSK9 inhibitor.
Dr Fuster: That is what I'm driving at. If you have two patients, one with a mutation and one without, and both reach an LDL-C of 100 mg/dL, should you be much more aggressive in the one with FH? This is really my question. Having 20 times the risk is huge.
Dr Robinson: I would love to, but the problem is convincing insurers. We are encouraging the PCSK9 inhibitor manufacturers to do some imaging trials to ask if a person age 40 has a massive burden of atherosclerosis, can we regress that? We have to get their LDL-C below 100 mg/dL. We see regression on the [intravascular ultrasound] IVUS trials when LDL-C levels are down to 15 mg/dL. Wouldn't it be wonderful to clean out that person's arteries, reset them back to a 25-year-old, which is the promise of the PCSK9 inhibitors that we're so excited about?
Dr Fuster: Sometimes we cannot rely on a number. If you reach a number, I think this paper makes you reflect that maybe you have to go below that number. We still have four papers and five minutes.
Dr Douglas: We can do it.
Stepathlon CV Health Study: Global Mobile Health and Physical Activity
Dr Fuster: The next paper is called "International mobile health intervention and physical activity: The Stepathlon cardiovascular health study." The main author of this paper is Dr Anand Ganesan from Adelaide and Dr Derek Chew. They had work teams competing for over 100 days on how many steps you take, how many calories you burn, how much exercise you do, weight loss. There is a social aspect too, everybody connects with everybody else. It worked on weight reduction, increasing exercise, and so forth. The question is whether this is due to the competitiveness of people and whether after the 100 days you give up.
Sanjit, would you participate in that kind of thing?
Dr Jolly: I think I would. You see this, in popular culture, everybody has these wearable bands that count steps, or they use the iPhone or other devices. It's not only being cognizant of exercise but also the social nature. The whole concept is that everybody is going to see how many steps I did today, and so I'd better do my 10,000 steps. I think it's probably both and we're going to see this increasing. There are already a lot of apps.
Dr Fuster: I believe that there's a lot of peer pressure. We published a study recently in seven communities where we did group therapy and then the patients—actually they were not patients, they just had certain risk factors—were randomized in groups of 10. They helped each other in weight reduction and smoking cessation and so forth. The control groups were followed individually. The results were very significant. I think it's peer pressure because the participants work with each other. So maybe it means that as adults we need other adults to help us make changes.
Dr Robinson: Well, it's looking outside the medical model of doing a lot of this population-health stuff, right, to get people to have healthier lifestyle habits. Absolutely.
Dr Fuster: I think it's an interesting study. I hope they can have a follow-up longer than 100 days, maybe 10 years or 15 years, and see if they continue to compete with each other.
Dr Douglas: I just want to make a link with that and the HOPE trial. We're seeing diminishing returns from medical interventions and pharmacologic interventions. Isn't it wonderful that we're starting to develop more effective tools to do the lifestyle interventions where there is basically no downside?
Dr Kappetein: And it might be cheaper to reduce your blood pressure by 6 mm Hg by more exercise than giving you a pill.
Dr Robinson: I think they lost 3 pounds in 100 days. That's pretty good.
ACCELERATE: Evacetrapib in High-Risk Vascular Disease
Dr Fuster: Okay. We have three studies that actually the results were negative and at least in some of them, the results were expected to be positive.
The first one is the ACCELERATE trial. This was presented by Dr Steven Nicholls and they tested a cholesteryl ester transfer protein [CETP] inhibitor, evacetrapib, for reducing cardiovascular outcomes in 12,000 patients who were at high risk. The participants had acute coronary syndrome, peripheral arterial disease, diabetes with coronary disease, cerebrovascular disease.
The results—the lines in the Kaplan Meier curve were superimposable. That is unbelievable.
Dr Robinson: This is raising HDL-C 130% and lowering LDL-C?
Dr Fuster: I'll go into the details. They looked at how much the HDL-C increased and what happened with the LDL-C. The HDL-C increased from an average of 46 mg/dL to 104 mg/dL. The LDL-C actually went the other way from 84 mg/dL in the placebo group to 55 mg/dL. But it's astonishing that you don't see any kind of benefit; 1.5 years of follow-up is a short follow-up.
Dr Robinson: It was stopped early for futility.
Dr Fuster: I will read the final conclusion: "The findings continue to challenge the hope that CETP inhibition might successfully address residual CV risk." Maybe they are referring to a borderline reduction in all-cause mortality with a P value of 0.06, but we already have a number of trials on CETP inhibitors that have not provided a lot of hope.
Dr Robinson: There's one more still going on, the REVEAL study, which hasn't been stopped for futility yet.
Dr Yancy: But two studies[22,23] were stopped for futility and one of them had a negative signaling.
Dr Douglas: Suggesting harm.
Dr Yancy: So, I guess the question is, are we done yet?
Dr Douglas: The REVEAL study is still going on, but no hope here.
Dr Robinson: The mechanism matters. Lower might be better, but it matters how you get there and in whom, which we saw in HOPE-3. I think that's why the FDA has been hesitant to approve new mechanistic drugs for lowering LDL-C. The PCSK9 inhibitors lower LDL-C via the LDL receptor, which is how statins and ezetimibe lower LDL-C. Apparently the FDA felt more comfortable with that and approved PCSK9 inhibitors, but there are a whole bunch of other drugs in the pipeline, and each one is going to need to be proven.
INOVATE-HF: Vagal-Nerve Stimulation in HF Patients
Dr Fuster: The second negative trial I want to discuss is vagal stimulation for the treatment of heart failure, the INOVATE heart-failure trial. This is a study that was presented by Michael Gold from the University of South Carolina, and Douglas Mann was also involved. I have heard a lot about autonomic imbalance with excessive sympathetic activity contributing to cardiac failure. You might do sympathectomy or enhance the vagal tone. This was a large study in over 85 centers with more than 700 patients that were randomized over a period of 16 months into device therapy. One wire goes into the right ventricle and stimulates the right vagus nerve a few times a week. Is this correct?
Dr Yancy: Correct, with a small cuff around the neurovascular bundle.
Dr Fuster: When they looked at all of the parameters, it didn't work. Quality of life was a little bit better apparently, in terms of the 6-minute-walking distance, but in terms of hard outcomes there was no difference at all. The primary end point was the composite of death from any cause or first event for worsening heart failure. What do you think, Clyde?
Dr Yancy: Very quickly, I think Jennifer nailed it. It really does matter how you modulate neurohormonal activation. You can't just take any approach and assume that patients will be better off. That's the first thing. The second thing is that patients were not blinded. You have to take the more subjective end points in a very circumspect way. The third point is that patients were treated very well in this study, excellent investigators. Once again it shows you that when you have people on an appropriate evidence-based, guideline-directed therapy, they do reasonably well and it takes a lot for something to be superior to that. It's a negative study. It needed to be done. A lot of small studies were saying this might be a new direction.
Dr Fuster: People talk about sympathectomy too. What do you think?
Dr Yancy: This was a harmful procedure. In fact, when it was turned on patients requested it be turned off because they felt the stimulation. So, if you're going to put a patient through an experience like that with chronic discomfort, there really needs to be a very strong signal of benefit. I'm not in favor based on these data of continuing this line of research.
Early BAMI: Beta-blockers Before PCI
Dr Fuster: Okay. We have the last study, which was negative. I was a participant. That's why I wanted to have a short time for discussion.
It's an interesting study, actually. It was based on an earlier study (METOCARD-CNIC) we did with beta-blockers in the ambulance in acute myocardial infarction. The original study was an imaging study in about 300 patients with anterior myocardial infarction—that's critical—who had never taken beta-blockers. These patients were intervened with metoprolol vs placebo in the first 6 hours of myocardial infarction. We saw a difference in infarct size between 15% and 20%. We measured this using enzymes and MRI after 1 month. So we decided on a pilot study with a larger number of patients before doing a larger study measuring events.
We got together with a group in the Netherlands for Early BAMI It's still an imaging study—perhaps we were not strict enough. We doubled the number of patients and included all sorts of infarcts (not only anterior); 45% were nonanterior infarcts. We accepted patients who had been on beta-blockers, and the reality is that only 55% underwent MRI. I won't go into the details, but the intervention didn't work.
The imaging end points were the same. Now we are debating whether to go ahead with the larger study of 2000 patients looking at outcomes. Basically our data show that the earlier you go with a beta-blocker (within the first hour or two) the better the result. A large number of patients received beta-blockers after 6 hours. A little frustrating, but I will accept your opinion. Would you move forward with the larger study? Pam?
Dr Douglas: I don't think so. We have incredibly effective standard therapy, which is urgent primary PCI done very quickly. That's very effective. Beta-blockers within the first 12 hours if not sooner. I'm not sure the difference between beta-blockers at 6 hours and at 3 hours. That's a difference you're trying to slice. It's gets pretty hard to move the needle as you limbo under a lower and lower bar.
Dr Jolly: I agree with Pam. Animal models suggest that it works. That's really striking. If you tie off their LAD and you give them beta-blockers before the infarct, you reduce infarct size. I think if your surrogate outcome was large it would be worth putting in the effort. The challenge is when the difference is very small. It's a simple intervention, but I think it's going to be a challenge to show a difference.
Dr Fuster: Clyde?
Dr Yancy: This goes back to something that was presumed to be beneficial prior to contemporary therapies. I'm glad they did this because it allows us to rethink if it's still necessary. Maybe it's one way to fast-track to the lab and get to PCI more quickly by not taking that extra step. It made me take a deep breath because maybe something else we're doing is not as good as we thought it was.
Dr Robinson: I looked in there for the rate of statin utilization. I'm serious, because all the beta-blocker trials were done in the prestatin era, so it's actually hard to show any incremental benefit on top of contemporary medical therapy.
Dr Fuster: Any comments?
Dr Kappetein: You mentioned about the MRI issue, that is seen with studies of cerebroprotection devices, that it's very difficult to get people in the MRI. So, to use that as an end point creates a kind of bias.
Dr Fuster: It was not difficult in the original study. Almost everybody had an MRI at 1 month and then at 6 months. Well, I think we actually covered 10 studies. I think you guys should feel proud about it. I'd really like to give thanks to all of you for being here this afternoon, and I hope now that it's getting into the evening the sunshine will come out here in Chicago.