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Editor's Note: From the American Heart Association 2016 Scientific Sessions in New Orleans, Dr Fuster and his panel zip through 10 trials. The five "stars" include the PRECISION trial on the cardiovascular (CV) safety of nonsteroidal anti-inflammatory drugs (NSAIDs); the PIONEER-AF-PCI trial comparing anticoagulation strategies in patients with atrial fibrillation who underwent percutaneous coronary intervention (PCI); the ART study of single vs double internal mammary artery (IMA) revascularization; the EUCLID trial comparing ticagrelor and clopidogrel in patients with peripheral artery disease (PAD); and the cognition substudy of HOPE-3, which looked at blood-pressure and cholesterol lowering in patients at CV risk. In quick succession, the panel reviews three lipid trials: GLAGOV, MILANO-PILOT, and AEGIS-1, ending with a brief overview of two heart-failure (HF) studies.
The Panel
Valentin Fuster, MD, PhD: I am Valentin Fuster from New York. I am here with four of my colleagues, and we are going to discuss something unique. Over the past 10 years that I have been involved with this show, I do not recall a time when we had more robust, important trials all at once.
We attend meetings of the European Society of Cardiology, the American Heart Association, and the American College of Cardiology. This meeting has been the most exciting over the years. Let us start.
On my left is Dr Jennifer Robinson, who is a professor in the departments of epidemiology and medicine at the University of Iowa. On her left is Dr Michelle O'Donoghue, who is investigator in the TIMI study and assistant professor of medicine at Harvard Medical School and an associate physician at the Brigham and Women's Hospital in Boston.
Dr Timothy Gardner, who is very well-known in this show, is professor in the department of surgery at Jefferson University School of Medicine in Philadelphia.
And Dr Clyde Yancy, who is the Magerstadt Professor of Medicine, professor of medical social sciences, and chief of the division of cardiology at Northwestern University.
Let me tell you what we have on the agenda and we will see how far we can go. We have five studies that we would call "stars." The first is about nonsteroidal NSAIDs, the whole story about Celebrex. Is this good, or is this bad? Watch. Second, for patients with atrial fibrillation and stenting, if you give three drugs including Coumadin, the patient may bleed. If you give two drugs, a platelet inhibitor and an anticoagulant, you might have thrombosis of the stent. What is the answer? Watch.
What about this idea that we should use arterial grafts for bypass surgery? Here is the story of one vs two. Surprises. Number 4—ticagrelor vs clopidogrel. These two drugs have been challenging each other forever. Let us see what happens in patients with peripheral vascular disease. Number 5—they say that cholesterol and hypertension may affect our heads and cause cognitive dysfunction by affecting the small vasculature of the brain. Is this true or false? Let us look at the HOPE-3 study. These are the five studies that we are going to pay attention to, but this is not the end of the story.
In case any of the people who work on lipids feel left out, they are not. We have three studies on lipids. In the GLAGOV study, the effect of [a proprotein convertase subtilisin kexin type 9] PCSK9 inhibitor on the progression of atherosclerotic disease by intravascular ultrasound. We have been always struggling with HDL. Let's inject it. I will tell you what happens in the [apolipoprotein A-1] apoA-1 MILANO PILOT study. I call it an apocalyptic trial. You will see why. Another injection of apoA-1, which is obtained from human plasma, [is evaluated in] the AEGIS-1 study. Very interesting.
Finally, heart failure. We will not forget that you are here [to Dr Yancy], but we left you to the end. We have left ventricular assist devices (LVADs). It appears that there is one now that does not thrombose. We will see it if this is true in the MOMENTUM 3 trial. Finally, these peptides, it seems that they are the defense mechanism. In heart failure, there is vasoconstriction—then the peptide comes out—everything vasodilates and diuresis takes place. Why do we not give these artificially? Is it not exciting?
After these 10 studies that I have mentioned, if you really are not excited, you need a consultation.
PRECISION: CV Outcomes With Celecoxib vs Naproxen or Ibuprofen
Let's begin with the study titled "Cardiovascular Safety of Celecoxib, Naproxen, or Ibuprofen for Arthritis."[1] Dr Steven Nissen from the Cleveland Clinic presented this paper, and he is the one who organized all the noise in 2004 when Vioxx was removed from the market because of cardiovascular side effects.
This is the PRECISION trial. Let's go into the background. If you recall, it was in 2004 when it came out that Vioxx [rofecoxib, Merck] was a problem. The US Food and Drug Administration (FDA) said "no more Vioxx." Pfizer's Celebrex was also a specific COX-2 inhibitor; the only one left. There were concerns with some minor studies that perhaps Celebrex was also a problem. Finally, it was accepted but approved only at a lower dose. The FDA said you should do a trial—we want to know about Celebrex. This is the trial that we are going to discuss today.
There were almost 25,000 patients with osteoarthritis or rheumatoid arthritis at moderate cardiovascular risk who were randomized to Celebrex, ibuprofen, or naproxen. The primary end point was a combination of nonfatal myocardial infarction (MI), nonfatal stroke, and cardiovascular death. On one hand was intention to treat; on the other hand was "let's see what goes on in those who were treated." This was very clever, and I will tell you why. From the start, 65% of the patients quit taking the medicines, which is very important when we analyze this study.
They also assessed gastrointestinal and renal effects. These are the results. The follow-up was about 20 months and in the intention-to-treat analysis, there was a small number of events—2.3% in one group, 2.5% in another group, and 2.7% in the last group. What about the issue of noninferiority? Noninferiority was met for all comparisons including the on-treatment analysis, with event rates of 1.7%, 1.8%, and 1.9%. The risk for gastrointestinal events was significantly lower with Celebrex than with the other two drugs.
This was published in the New England Journal of Medicine[1], and the summary states that at moderate doses (200 mg daily) Celebrex was found to be noninferior to ibuprofen or naproxen. The dose of these drugs was rather high with respect to cardiovascular safety. The question, and I am going to ask you first, Clyde, is the alarm over? Can we relax now? Can we use Celebrex?
Clyde W Yancy, MD, MSc: I don't know how we can go back to the COX-2 [inhibitors] without an ongoing concern. We know what happened with Vioxx and now we have these data. They are reasonably reassuring, but in addition to the 65% [of patients] who did not continue the drug, almost 30% were lost to follow-up. There are still some questions about the data set. We can bring the harm signal down a bit, but I do not think that we can reinvent the use of COX-2 inhibitors as analgesics.
Dr Fuster: Jennifer, do you use Celebrex?
Jennifer G Robinson, MD, MPH: I do not. I have some concerns about the trial. First, among the population who were going to take these drugs—largely women with arthritis—only 25% had cardiovascular disease. Did they even have enough risk to detect? The event rates were relatively low to detect a signal. I would have rather have seen the trial in people who had cardiovascular disease.
Dr Yancy: That is in a context of a study that went on for 10 years. You would have thought that you would have seen more events in people who started off with cardiovascular risk.
Dr Fuster: People with pain change drugs constantly. I think it is a valuable criticism. What do you think?
Michelle L O'Donoghue, MD, MPH: The loss to follow-up numbers were certainly of concern. I do like that they laid out both the on-treatment and intention-to-treat analysis populations. That is an important contribution. It provides some reassurance, but a relatively low dose of Celebrex was being evaluated. Some of the earlier concerns about the safety signal were only at higher doses. That question mark remains.
It might not just be a COX-2 story. We did not have a placebo arm to try to get at the question of whether naproxen and ibuprofen might have some risk as well and where that plays out.
Dr Fuster: Tim, you are a man of judgment. The FDA, in 2006 decided that the trial has to be done. They want to know whether this dose is going to work and put the people at peace. What is the answer? [Imagine] you are now the FDA.
Timothy J Gardner, MD: I am not sure I would do well at the FDA, but I will refer to what my former colleague Garret Fitzgerald said.[2] He called it the "imPRECISION trial" and raised some of the very same concerns and critiques mentioned here. I don't think [the trial] resolves a lot. The dose of Celebrex used may not be the therapeutic dose to treat arthritis symptoms anyway. I am not convinced by the results.
Dr Yancy: It raises yet another question. Inexplicably, the data for naproxen suggest that some really important questions have to be pursued. That is another whole set of investigations, but in terms of harm we have to be very thoughtful now.
Dr Fuster: About the renal and gastrointestinal effects.
Dr Yancy: And cardiovascular. The way that Elliot Amos summed it up made sense: use the lowest dose for the shortest period of time in the most carefully selected patient.
Dr Fuster: I use Celebrex only when everything else fails. The reason is because the event rate is so low. We talked about statistical issues when Vioxx came out and so forth—the huge number of patients, the P values, and certainly the impact. We are talking here about event rates of 1.7%, 1.5%. What I am saying is we should not be so alarmed, but this does not answer the question.
Dr Gardner: The only critique of what Elliot said (which was very good) is that these patients have chronic inflammatory conditions. They need relief. They need this medication long term.
Dr Fuster: That is the issue. It seems to me that we are all in agreement. This does not create much excitement.
Dr Yancy: I am not even sure the question needs to be pursued anymore.
PIONEER-AF-PCI: Two Rivaroxaban Doses vs Warfarin Plus Single or Dual Antiplatelet Therapy
Dr Fuster: The next study is very interesting. We all have been struggling with this one, the PIONEER AF-PCI study, which addresses an important issue. The title is "Prevention of Bleeding in Patients with Atrial Fibrillation Undergoing PCI."[3] Michael Gibson presented the paper. He is from the Beth Israel Deaconess Medical Center in Boston. Everybody has been waiting for this trial for the past 4 years or so.
Say you have a patient with atrial fibrillation. The patient has a stent. The patient needs anticoagulants for the atrial fibrillation and two antiplatelet agents for the stent, at least for the first year. The question is, do you give three agents? The data in the research show that the bleeding rate is pretty high. You decide, "No, I am going to use a platelet inhibitor and Coumadin. I am covering everything." The question is, what about the thrombotic phenomena? Maybe you are not covering enough.
This study addresses the issues with a drug other than Coumadin—rivaroxaban (Xarelto, Bayer/Janssen), which is a factor Xa inhibitor. It appears to be a little superior to Coumadin in terms of preventing thrombotic phenomena and at the same time, it causes fewer hemorrhagic strokes. It is a drug that, in comparison with Coumadin, looks positive. Let's see what the trial shows.
This was a study of more than 2000 patients with nonvalvular atrial fibrillation who had undergone PCI with stenting. They were divided into three groups. Usually, we use rivaroxaban 20 mg daily. They used 15 mg in one group and one platelet inhibitor (clopidogrel, prasugrel [Effient, Lilly/Daiichi-Sankyo], or ticagrelor [Brilinta/Brilique, AstraZeneca]). The second group received two platelet inhibitors, aspirin, and one of the others and a very low dose of rivaroxaban, 2.5 mg twice daily. The third group received the usual three drugs with Coumadin.
Who was the winner? They looked at safety first, because the problem of bleeding is, in our minds, more important than the possibility of thrombosis. The results were very significant. I won't go into how "significant bleeding" was defined, but it occurred at a rate of 16% in group 1. Remember, patients in group 1 were taking two drugs—15 mg of rivaroxaban and clopidogrel, prasugrel, or ticagrelor. With three drugs with a very small dose of rivaroxaban (2.5 mg twice daily), the bleeding rate was 18%. In the Coumadin group, the bleeding rate was 26%. Here, there were two real winners. Rates of death from cardiovascular causes, MI, and stroke were exactly the same in all groups.
The study was published in the New England Journal of Medicine.[3] However, another paper was published at the same time in Circulation[4] showing that in a post hoc analysis, the risk for all-cause mortality and recent hospitalizations was lower in the two rivaroxaban groups compared with the Coumadin group.
It seems that we are finding the answer to a very significant problem. Michelle, would you give us a thought about this. You are a TIMI-oriented person. You have been dealing with this issue constantly. What is your reaction to this paper?
Dr O'Donoghue: Everyone has been struggling with this question clinically for a long time. This trial is a very important contribution because it really starts the conversation. The question for all of us is, is it too soon to adopt this into clinical practice?
You mentioned the bleeding numbers. I was not surprised that there was a reduction in bleeding if you either reduce the dose of the antithrombotic or pull back an antiplatelet drug, but I was struck by how large of a reduction in bleeding there was. That part was quite profound and clearly demonstrated with both of the rivaroxaban regimens.
In terms of the safety from the thrombotic side, I am less concerned about the risk for stent thrombosis with either the reduced dose regimen or pulling back the antiplatelet drugs. Rivaroxaban does have some effects on stent thrombosis as well. You have the rivaroxaban effects as well as the effects of the antiplatelet drugs.
Where I am a little bit more nervous is about atrial fibrillation and cardioembolic risk.
Dr Fuster: Because of the dose of rivaroxaban?
Dr O'Donoghue: Exactly. We just do not know with any certainty, and you would have to do a trial of 20,000 people to really get to the bottom of it. I am not sure whether that trial is going to be done. Do we take this information and start making practice changes now? I would be interested in other thoughts from the group.
Dr Fuster: Thank you. Jennifer. Are you nervous about this? I am completely in agreement with Michelle. It is a relatively low dose. We give this to people who are elderly, of low body weight, and so forth.
Dr Robinson: I am not an interventional cardiologist. My comment would be to have more options available, considering the expense of all these fancy new drugs. I was concerned that stroke and rivaroxaban stent thrombosis were not measured, which was the whole point of both treatments.
Dr Fuster: We have concerns. Clyde?
Dr Yancy: I am more favorably inclined to accept these data. I see this problem much more frequently than I would have thought. Patients with reduced left ventricular function, atrial fibrillation, coronary disease, and, boom, we have to deal with this. It presents a conundrum. We forget that this is an important consideration for patients. They do not like to bleed. Having a regimen that reduces the bleeding that we believe has a null effect on the stroke risk, and I agree with you, we need to be certain about that. I would be more inclined to adopt this strategy sooner rather than later. This is an important clinical problem. From a patient viewpoint, this really is significant.
Dr Fuster: The only question is the follow-up, which was 12 months. It is worrisome because when we talk about stroke prevention, we would put these patients on a low dose for 5 or 10 years, it is an issue. We will see, but this is probably the most important question. What is your opinion?
Dr Gardner: I do not like warfarin even though I have to use it in a lot of my patients. With the momentum toward the [novel oral anticoagulants] NOACs, we are getting more reassuring data. I would say this is a positive for the NOACs and a way to perhaps escape warfarin in many patients.
ART: Single vs Bilateral IMA Grafting in CABG
Dr Fuster: We are solving one problem after the other. Let's get into another one.
This bypass graft study was somewhat surprising. This is the ART study,[5] a randomized trial of bilateral vs single internal thoracic artery grafts. David Taggart, the lead author, is from London.
Dr Gardner: He is professor of surgery at Oxford.
Dr Fuster: Yes, and he is very involved in this field. Let's go into the background.
The era of internal mammary artery (IMA) grafting has been quite exciting because the rate of graft occlusion is less than 10% over 15 years or so. Data began to evolve that with the bilateral approach (either with the right coronary or circumflex artery being involved) perhaps the occlusion rate would be even lower because you are substituting a saphenous vein graft with an arterial graft. The data began to show that two grafts, apparently, are more infectious in the sternum. This is the background. There were a lot of advocates for bilateral internal mammary artery (BIMA) grafts. Let's see what happened here.
The study included 3000 patients who were undergoing coronary artery bypass graft (CABG). They were randomized in 28 cardiac surgical centers across the world. In the single IMA group, a single artery was grafted—the left IMA (LIMA) to the left anterior descending coronary artery (LAD), and in the BIMA group, two arteries were grafted, either to the right coronary or the circumflex artery. One end point was the composite of death, MI, or stroke. The other end point was death alone.
Dr Gardner: Yes, survival.
Dr Fuster: This study will have 10-year follow up, but these are the 5-year data. We do not have the final data yet. Basically, the study showed exactly the same end points in both groups, with rates of death of 8.7% (bilateral group) and 8.4% (single group). The composite of death, MI, and stroke, was 12% in both groups. The difference was in the sternal-wound complication rate, which was 2.5% in the bilateral group and 1.9% in the single group.
Here we have, in summary, at least at 5 years of follow-up, which are not complete. It is not easy to justify doing two arteries instead of one. The saphenous vein grafts, Tim, occlude a little later. I am not sure that the 5-year data are strong enough to say that there is no need for two grafts.
Dr Gardner: That is what Prof Taggart said—we need the 10-year results. Many in the cardiovascular community ask, "Hasn't this blown a hole in our strong advocacy for multiple arterial grafts; in particular, bilateral mammaries?" I wrote an editorial a few years ago, "Two is better than one." I believed this was true for the right patient. We continue to believe that there is evidence based on late patency that multiple arterial grafts are better than one plus vein grafts. The operation has to be tailored to the patient. By the way, there was a 14% crossover—14% of the bilateral patients did not receive bilateral grafts.
The sternal-wound problem is a real one. We need to select patients appropriately. Obese patients, patients with chronic lung disease, or patients with diabetes are not candidates in most circumstances.
Dr Fuster: Why is the sternum so problematic?
Dr Gardner: Because of the microvasculature. We have learned in the past decade or so to take less of the soft tissue with the mammary artery. We call it "skeletonizing" the mammary artery. There is less necrosis in the sternum and adjacent tissues. Diabetics with small-vessel disease are more prone; also patients who have lots of stress on their sternal closure and so on. It is a randomized controlled trial. We were in fact surprised by the results. For a patient who is age 65 years or younger in whom we hope to see a 20-year survival, I would still do two grafts. We will see what the 10-year data show.
Dr Fuster: Michelle, any comments?
Dr O'Donoghue: I agree completely. I think that 5 years is probably a little bit too soon. The 10-year data are going to be important. That being said, my suspicion is that the double mammary approach might not end up modifying hard outcomes like all-cause mortality or long-term stroke risk. You alluded to the question of patency and perhaps repeat revascularization is where we could make a difference.
Dr Gardner: A paper[6] was presented today that compared single vs bilateral in terms of repeat revascularization with 12-year follow-up. The rate of repeat revascularization was higher in the single than the bilateral group.
Dr Fuster: You are in the prevention business. Let me tell you the problem. We did the FREEDOM trial.[7] We had 2000 patients all undergoing these procedures. Only 20% were taking the drugs appropriately. That is very interesting in all the discussions that we have in the academic circles. I went to the COURAGE trial.[8] It was the same thing. The BARI 2D[9] was also the same thing. All these discussions are fine, but we still are missing something. The patients continue to smoke, they are obese, or they are not taking their drugs for cholesterol or hypertension. What do you think?
Dr Robinson: I hope this trial was done in the background of optimal medical therapy, but what is that? Again, it goes back to the disease we really want to treat—atherosclerosis. We are waiting until way too late and only slightly modifying the course of the disease.
Dr Fuster: It is interesting, though. These people already know they have the disease. It seems to me that we do not change behavior. You feel well, you just go on. It is very striking.
Dr Gardner: This was a positive study in that respect. We are seeing secondary prevention, compliance, and better health in the coronary-bypass patient population. We are stressing it much more. The physicians are stressing it. The 5-year results—for the single group or both groups—were very good.
EUCLID: Ticagrelor vs Clopidogrel in PAD
Dr Fuster: This is boring—we are not getting into wars. We are in agreement on everything. Let's see if we find something here.
The next paper is about peripheral vascular disease. Dr William Hiatt from the University of Colorado presented the EUCLID study.[10] It was titled "Ticagrelor vs Clopidogrel in Symptomatic Peripheral Arterial Disease." This is what I recall. First of all, studies suggest that aspirin is good for peripheral vascular disease except a registry in Japan not too long ago. Clopidogrel is better than aspirin in peripheral vascular disease.
You are left with the finalists. What is clopidogrel going to do vs ticagrelor? This is what this study is all about. It was a large number—14,000 patients—with symptomatic PAD, with either previous revascularization or an ankle-brachial index of less than 0.8. The primary efficacy end point was the composite of death, MI, and ischemic stroke. They look at the safety of bleeding at 30 months of follow-up.
This is the story. The median age of the patients was 66 years, and 72% were men. The question was the primary efficacy end point, which was exactly the same between both groups (10.8% vs 10.6%). They looked at acute limb ischemia, and it was practically the same (1.7%). They looked at bleeding, which was 1.6%. This leads to you to think a lot about why these results are so similar. I just have a hypothesis and I want you to challenge it. The hypothesis is that peripheral vascular disease is a storm—the whole arterial system is affected by disease. There is not enough sensitivity for the drugs to do the job. This is my perception. A lot of studies have been done with imaging and the disease is very extensive when a patient begins to have claudication and so forth. What is your view? Why does this study show no difference? Do you think both drugs are the same?
Dr Yancy: We have to consider the context. For peripheral vascular disease, it is possible that clopidogrel may be better than what was previously presumed. For coronary disease, we know that there are some differences, but it could be that clopidogrel was actually quite reasonable. Yes, these are surprising findings, but I think we have to go back and rethink the whole hypothesis to begin with.
Dr Fuster: Any comments?
Dr Gardner: Peripheral vascular disease is extremely complex. It is not so much related to platelet aggregation and acute thrombosis. It is extensive disease. We see it start in the iliac arteries and go all the way to the feet. I would not have expected a lot of difference with this kind of agent—even with aspirin.
Dr Fuster: A question about aspirin?
Dr Gardner: The disease process overwhelms the drug that they are studying.
Dr Yancy: For the number of people with this condition, we really do have to discover effective medical therapies.
Dr Fuster: Yes, I agree. It is a huge problem. What do you think?
Dr Robinson: Again, we don't have an aspirin comparator; we don't have a placebo comparator. You could give either one, preferably the cheapest one, and side effects are the same. I do not know how it really changes the management.
Dr Fuster: I agree. It is so severe and extensive a disease that we are almost dealing with cosmetics. Let me see, what do you think, Michelle?
Dr O'Donoghue: PAD has just been a tough nut to crack, so to speak. They set the bar high for themselves by going up against clopidogrel as the comparator group because we are not even sure that clopidogrel necessarily works in the PAD state.
I do find it reassuring that although the trial results were overall neutral, when you look at people who did appear to have confirmed coronary artery disease in the subgroup analysis and prior coronary revascularization, there was at least a signal that there was more benefit for ticagrelor in those individuals. That is at least consistent with what we have seen in prior studies with ticagrelor. It gets back to the PAD question. It has just been tough for aspirin and clopidogrel, or any drug.
Dr Fuster: We really have to address this disease. What is interesting is that we are able to identify this disease with 3D ultrasound when it is beginning. The disease starts there in the bifurcation. There is so much we can do to prevent this from happening.
HOPE-3: Effect of Blood Pressure and LDL-C Lowering on Cognition
Dr Fuster: Let us go into the brain. This is an interesting study, which to me is misinterpreted, but you might say that I misinterpreted it. This is the HOPE-3 trial.[11] This subanalysis was presented by Dr Jackie Bosch from the McMaster University. As you know, the main papers were published not too long ago.[12,13,14]
When hypertension is not treated over a long period of time (the CARDIA study, for example) or hyperlipidemia, or diabetes, the small vasculature of the brain may be affected. It is not atherosclerotic disease; it is intimal thickening of the arteriole. You see lacunar lesions in the white matter of the brain. There are now data evolving that these small lesions in the white matter of the brain as a result of the obstructions may lead to cognitive dysfunction. In most of the people with degenerative brain disease—I am not talking about Alzheimer's now—one of the key factors that affect the large arteries have not been addressed over a long period of time.
This is the background. Let us see what happened. In the HOPE-3 study, about 1500 patients more than 70 years of age were evaluated over a period of about 5 years. Basically, what they did (and it was very well done) is measure cognitive dysfunction by the most sophisticated testing that I know—executive function, psychomotor speed, processing speed. These tests are well-standardized. These patients were followed for a period of 5 years.
The question was, what about those whose hypertension you treat vs those whose hypertension you don't treat, those whose hyperlipidemia you treat, and so forth? Here is the problem: a large number of these people did not have hypertension and did not have hyperlipidemia. The study was negative except for one thing. In those who had hypertension and those who had hyperlipidemia and were treated appropriately, there was almost a statistically significant difference in just 5 years in terms of cognitive function. This paper can be very misinterpreted.
I am very biased because I work in this field, but I want to know your opinion. I am not entirely sure it is the ideal study to assess cognitive function because of the number of people. What do you think, Jennifer?
Dr Robinson: They did study the right population because it was people aged 70 years and older who are the susceptible group. It tells us something very important about statins, which is that they don't hurt cognitive function, so that is very reassuring. We have actually seen that in the PROSPER[15] and Heart Protection[16] studies.
The patients probably were not quite old enough. They probably did not have high enough cholesterol to definitively say that lowering cholesterol prevents cognitive dysfunction. I still think it is an open question. There was a hint of benefit in the hypertension arm. It blunted the progression in those who were hypertensive (which is only one third of participants). We know from extensive epidemiologic data that midlife risk factors predict just about everything related to the heart and brain. That was the hypothesis tested in HOPE-3.
I think it is very reassuring. There is no harm, but benefit has yet to be determined in a properly done trial.
Dr Fuster: Any comments, Michelle?
Dr O'Donoghue: I agree completely with Jennifer. The baseline blood pressure for the patient population was not very elevated. If we were to look at those who had higher risk perhaps there would be benefit.
Dr Yancy: You remember that in the original report from HOPE[17] when the systolic blood pressure was greater than 144 mm Hg, there was a benefit in the treatment of hypertension. That helps us redefine our thresholds for intervention. It is pretty reassuring for the patients whom you would treat with today's understanding that you can probably delay some of the age-related cognitive decline.
Dr Fuster: We are doing a study between Europe and the United States to see how many people with degenerative brain disease (we do PET and MRI and so forth, including the large arteries) have risk factors that have not been addressed and how many people have disease of the large arteries or the tiny arteries of the brain.
There is another issue—the progression of Alzheimer's. It is pretty vascular-dependent, which is different from the etiology of Alzheimer's. What do you think, Tim?
Dr Gardner: The most reassuring thing to me is that statins do not seem to cause harm, which there has been a lot of buzz about, not in the scientific community but in the general community. That is good. The signal that treating active hypertension is a benefit is the other reassuring thing about this trial. It was somewhat disappointing that they could not be more definitive, but that is science for you.
GLAGOV: Effect of Evolocumab on Atherosclerosis Progression in Statin-Treated Patients
Dr Fuster: Let's get into what I would not call leftovers.
Let's get into lipids starting with the GLAGOV study,[18] a randomized clinical trial led by Dr Stephen Nicholls at the University of Adelaide. The study is titled "Effect of Evolocumab on Progression of Coronary Disease in Statin-Treated Patients." Basically, we know that when we lower low-density lipoprotein cholesterol (LDL-C) with a statin, two things happen. You prevent cardiovascular events, and if you do an intravascular ultrasound, you may see a slowing of progression or some degree of regression of plaque. It's not very significant, but certainly the data are suggestive.
What about the PCSK9 inhibitors? As you know, PCSK9 inactivates the LDL receptor. If you inhibit it, the LDL receptor does its job and the LDL-C goes into the liver and blood levels drop significantly.
Nearly 1000 patients in 197 academic centers across the world participated in this study. To participate, you had to have angiographic evidence of coronary artery disease. The patients actually all were receiving statins and they were then randomized into two groups. Half of them received subcutaneous injection of the PCSK9 inhibitor [evolocumab (Repatha, Amgen)] for 76 weeks and the other group received injected placebo. The question is, what happened with intravascular ultrasound? There were some differences. The differences were minute but statistically significant. The so-called [percent atheroma volume] PAV in the placebo group increased by 0.05%, and in the treated group with the PCSK9 inhibitor, PAV decreased by 0.95%. Interesting, in terms of side effects; the rates of myalgias, liver dysfunction, and diabetes were not different between the groups.
We will get into cholesterol levels; LDL-C levels of 36 mg/dL. This is always a question. I do not know if this affects the brain, but there is some evidence. We said before that these statins can't harm you, but here you drop the LDL-C to 36 mg/dL. You need lipid to think. These neurons, the membrane is made of lipid. What do you think?
Dr Robinson: I will comment first on the GLAGOV study and then maybe we can talk more about low LDL-C and PCSK9 inhibitors and cognitive function. What is interesting about GLAGOV are two really important findings. One is that we added something that just lowers LDL-C to background statin therapy and we still saw substantial regression in atherosclerosis. The [C-reactive protein] CRP levels were identical in both groups, so it seems to have been driven by very low LDL-C levels. In fact, this continued down to LDL-C levels as low as 20 mg/dL. There was more regression. The second thing is that they did a post hoc analysis and looked at baseline LDL-C levels less than 70 mg/dL. I am not an LDL-C "target person," and so I was so excited to see that there was actually more regression in those who started with an LDL-C level less than 70 mg/dL. In fact, as opposed to about 60% regression overall, over 80% had regression if they started with an LDL-C level less than 70 mg/dL and getting down to LDL-C levels of about 25 mg/dL.
We have a lot lower to go. I do not think we have established the lower limit of benefit.
Dr Fuster: You might regress the brain.
Dr Robinson: Benefit and harm. We have looked at this in the trials. I have reported the pooled experience from alirocumab [Praluent, Sanofi/Regeneron],[19] (the competitor) with LDL-C levels less than 25 mg/dL. About 1000 people were exposed for about a year and a half on average to LDL-C levels less than 25 mg/dL. We saw no signal for cognitive imbalance, but we did see a signal for cataracts, actually a slight increase. There may be something with the eye that is very cholesterol-rich, but I am less worried about cataracts than cognitive dysfunction.
That being said, in a pooled meta-analysis of all PCSK9 trials[20] (both evolocumab and alirocumab) there is a numeric excess of neurocognitive self-reported events in both studies using the highest doses. In a meta-analysis, the risk of neurocognitive events is about double.
Is there something about homeostasis? When we start treating poorly controlled diabetics and they go from a hemoglobin A1c of 12% to 8%, they are hypoglycemic. I think you might be right. We all need cholesterol in our myelin as we age and we are testing it in susceptible populations. In some people who are on the way to cognitive impairment, might we be tipping them over a little bit sooner, like statins do for diabetes, and are we are doing this for cataract?
Again, the outcome trials are ongoing. There are two, with 27,500, and 18,500 patients. They will be done within the next year and a half. These people will have very low LDL-C levels for about 2 or 3 years and we will have more data.
Dr Fuster: Are they testing cognitive function?
Dr Robinson: Yes, there is a substudy in FOURIER; not in the ODYSSEY Outcomes study, but they are doing a second trial that will be 4 years long to look at very strictly measured cognitive function. Unfortunately, the only trial that was measuring it was with bococizumab [Pfizer] (the SPIRE trials) but that development program was terminated.
Dr Fuster: The thing that might worry me is that we are born with LDL-C levels of 50 to 60 mg/dL. It seems to me that it goes against nature to start dropping LDL-C levels so much. I do not know. I know we could have a philosophical discussion. What do you think?
Dr O'Donoghue: Studies have shown that hunter-gatherer populations had lower LDL-C levels.[21] Other large animals have LDL-C levels in the 20–50 mg/dL range. That it is still physiologic. When it comes to the PCSK9 inhibitors, it seems that it is more dose-related (the reported neurocognitive effects) and not so much related to the achieved LDL-C level, necessarily. It might be something to do with fluctuations or rapid changes.
Dr Fuster: With the drug itself, and not necessarily the LDL-C level?
Dr O'Donoghue: I think at this point, it is all conjecture, to be honest. There are a lot of examples of people who live at low LDL-C concentrations who have not had any cognitive problems at all.
Dr Fuster: Would you like to have an LDL-C level of 25 mg/dL?
Dr Gardner: I am not so sure, especially as I get older. I think we are talking about two different populations. We really want to treat the cholesterol problem or the lipid problem in the younger patients to avoid premature cardiovascular disease, but we don't want to affect the elderly people who are already in a balance in terms of their cognitive function. This is pretty risky business, but we will see. We have to be very cautious, especially as we treat patients who are aging.
Dr Fuster: Clyde, you are a little younger than Tim, but I do not know how much.
Dr Yancy: Two or three years.
Dr Fuster: What about having an LDL-C level of 25 mg/dL? I would like to know your opinion.
Dr Yancy: I want my systolic blood pressure way below 144 mm Hg and I want my LDL-C level deep into the double digits. I will make my bed with that.
Dr Fuster: Double digits—you are not really answering the question.
Dr Yancy: I think less than 50 mg/dL; less than 40 mg/dL becomes more and more encouraging.
Dr Robinson: The science coming out of this is going to be very interesting because on the way to regression, you get massive plaque stabilization in the vast majority of people. That is not definitely proven, however.
We published a paper[22] suggesting that we should rethink perhaps the paradigm of what we are doing. You get 2 years of intensive plaque stabilization and induction therapy, stabilizing the plaque probably in 95% of the people. They can stop the PCSK9 inhibitor. They get all the benefit and none of the harm. You just simply maintain them long term on a statin or something (eg, ezetimibe) to keep their LDL-C levels below 100 mg/dL. They are not going to get new plaques. That is the legacy effect that we have seen in the statin trials.
You give pretty expensive drugs for 2 years, but if they do the posttrial follow-up in these trials and really document that separation over 10 years, it actually becomes extremely cost-effective to have a 10-year benefit with 2 years of treatment and also with the calculation of a very good safety profile. This is all speculative, but we are really encouraging them. Every time you talk to those companies, tell them to do it.
Dr Yancy: Along the lines of being able to speculate, when you think about a predominant theme that we have discussed at this meeting about precision medicine, we have five people sitting around this table who probably bear five very different profiles with respect to atherosclerotic cardiovascular disease.
On the question of what LDL-C levels to target, I would actually prefer to be informed of what LDL-C level I need to target based on the rest of my risk profile. If we can get to that point, then I think it would be helpful.
MILANO-PILOT: Infusion of an ApoA-1 HDL Mimetic and Regression of Atherosclerosis
Dr Fuster: Let's talk about HDL-C for a moment because it is fascinating. The same author, Dr Nicholls from Adelaide, did a very similar study[23] (MILANO), injecting the apoA-1 Milano, which has the pure HDL, and looked at intravascular ultrasound. I won't go into all the details. The results were quite negative, but what is interesting and it's why I call this study "apocalyptic." Apparently, they got so frustrated with this HDL-C–raising business that they say the findings support the decision to stop development of the drug. Then they say that unless one of these new agents demonstrates clinical benefits, the HDL story may soon come to an end. It was a short follow-up. It was intravascular ultrasound. I am not entirely sure I would be so disappointed, but certainly they are not proceeding with a big trial. This was a pilot study.
AEGIS-1: Safety of Infusible Human ApoA-1 Post AMI
On the other hand, we have another study[24] on HDL that is obtained from the plasma of humans; it is plasma-derived apoA-1. This is the AEGIS-1 study. It was presented by Michael Gibson. It has a similar concept. Here, what they are looking at is the effectiveness of injecting this material into what they call the efflux. Forget about the concentration of HDL-C; it does not mean anything. Whether the macrophages are able to deliver the cholesterol into the particles is what we are talking about.
They used two different doses of apoA-1 that were injected over a period of 4 weeks. They compared these with placebo in patients with MI. They found that the cholesterol efflux was affected very favorably, but the study was not powered for cardiovascular events. They are going to do a very large trial.
The question they are asking is important. They say that during MI, the efflux process to get the LDL out of the cell is impaired. Maybe we have to start thinking about the stage of the disease where we can be effective in counteracting the process by giving HDL. Do you have any comments?
Dr Robinson: The whole cholesterol-efflux hypothesis really remains to be proven. They have shown that with macrophages in a petri dish, you can take the cholesterol out of them. We have not even shown in humans that we can excrete cholesterol from the body by that mechanism. I am not holding stock in any companies investing in HDL drugs, but it has been very frustrating.
Dr Fuster: We were all excited about HDL-C drugs 5 years ago. Everybody had comments to make, but today, you stopped commenting already.
Dr Robinson: I will say, though, going back to the 2013 American College of Cardiology/American Heart Association guidelines,[25] we were heavily criticized for not considering the observational and epidemiologic data when we made our recommendations. We made recommendations for using drugs based only on evidence from drug trials. Over and over, we sit here listening to all these negative trials, all of these trials exploring epidemiologically generated hypotheses that have failed. Why wouldn't you want to wait to get drug trial information before using a drug? I would like some of my lipid colleagues to remember that.
Most of the cardiologists have such a massive wealth [of data]. For every question, a trial has been done. I am very used to thinking like that.
Dr Yancy: Not always with an answer.
Dr Robinson: You said, let's do a trial. That thinking has to disseminate throughout the field because if you are giving a drug, if you are using a device, you are doing something to people, and you have to prove not just that it works but that it is safe. These are recurring themes in our conversations
MOMENTUM-3: Magnetically Levitated Circulatory Pump For Advanced HF
Dr Fuster: We have a few minutes left and we have to give a chance to my friend here to discuss heart failure.
Dr Yancy: Yes.
Dr Fuster: There were two papers that I think were interesting. MOMENTUM-3 evaluates a new circulatory pump for left ventricular assistance,[26] which is a continuous-flow left ventricular assist system. They call this centrifugal continuous-flow. Basically, what they showed is that in patients undergoing LVAD, the need for reoperation and so forth is decreased because there is less thrombosis. Is this your feeling?
Dr Yancy: That is my feeling, but there are a couple of very important points here. About 50 years ago, there was an effort to identify and develop a mechanical alternative to a failing ventricle. We are looking 50 years later and we are getting closer and closer to that point.
This is a smaller device that can be implanted. The pump itself does not come in contact with the blood. Thrombosis was almost unmeasurable, and that has been the Achilles heel of the devices we use now, requiring reoperations with high morbidity to reestablish circulatory support.
If we are able to find a device that has even less morbidity, understanding that the efficacy has already been proven, we really can make the argument, even more emphatically now, that mechanical circulatory support ought to be a part of the treatment strategy for advanced heart failure. A cautionary note—this is niche medicine. Only a group of patients very carefully selected should go forward with this kind of therapy.
I am really excited about these data because we have been on a long pursuit to try to find the best platform to do this.
Dr Gardner: I agree completely. The third-generation devices, especially this one, are very promising. A lot of the issues that were so difficult for patients and for those of us taking care of them have been addressed. The promise of mechanical assistance that is reliable, durable, and patient-friendly is becoming more of a reality. There is a definite population of patients for whom this technology really is important and will extend meaningful life.
Dr Fuster: It is a significant advance. I won't talk about costs. It is not the discussion today, but it will come up.
Dr Gardner: The cost of doing this for a population of patients is an issue, but the cost of the device is not the issue.
TRUE AHF: Short- and Long-Term Effect of Immediate Vasodilator Therapy in Acute Decompensated HF
Dr Fuster: This last paper, which is interesting as a concept, is titled "Short- and Long-Term Effect of Immediate Vasodilator Therapy in Acute Decompensated Heart Failure: The TRUE-AHF Trial."[27] Milton Packer presented the TRUE-AHF trial.
Basically, the concept is that B-type natriuretic peptides (BNP) are released when there is a problem of congestion. They have a role (correct me if I am wrong) in sympathetic driving. In a way, these drugs do the opposite. Their release from the atrium does the opposite, and this vasodilation and diuresis help. It might not be sufficient in acute heart failure. What they say is that the dilation of the left ventricle may actually lead to some troponin release and damage.
The study uses a new approach in patients with acute decompensated heart failure. They use constant infusions over 48 hours of a peptide (ularitide). The results are negative in terms of mortality and so forth, but the results are very positive in terms of rehospitalization. The patients feel much better.
My question to you is not about the study in itself. In these people with such advanced disease, are we too obsessed with mortality, and shouldn't we be more obsessed about quality of life? This is a clear example of a negative study that I think is very positive because in terms of quality of life, the findings were very positive. What do you think?
Dr Yancy: I think it is an informative study without question, but the argument continues, because how can you presume or opine that a 48-hour exposure to anything would give you a survival advantage 6 months later?
That doesn't seem to be tenable. I think the important point is, in this setting of decompensated heart failure, what is the right target of therapy? Is it really trying to extend survival or is it preventing harm, not accelerating the process? I think the latter becomes very important.
Relief of symptoms is incredibly important. At the bedside, these are very uncomfortable people. Relieve the symptoms, do not engender harm, and use it as an opportunity to better treat the underlying condition—whatever is driving the heart failure.
The Panelists' Top Picks
Dr Fuster: Thank you. We have talked about the 10 trials so we achieved our goals, our end point. We talked about survival, not death. We did well.
Now comes the final question. You heard 10 trials and I am going to ask you which one you are most excited about. Each of you has to choose one of the 10.
Dr Gardner: Actually, I am surprised I say this—the PIONEER-AF study because of the issue of anticoagulation and bleeding risk.
The NOACs have gotten more momentum.
Dr Yancy: The MOMENTUM study—the LVAD study—not necessarily because it is showing that we have this very effective therapy for advanced heart disease, but what a brilliant story it is about the power of curiosity and investigation, test and retest, and technology. To see that we have come this far and we have something that should be able to make a difference, I just love the story that it tells.
Dr Robinson: The GLAGOV trial. Just the thought of having such an enormous impact on the atherosclerotic process and the tools at hand, perhaps, to have quite an important effect at studying perhaps even earlier in the disease state, I think it is an exciting time for lipidology.
Dr O'Donoghue: Mine is a two-part answer. I am most excited about the GLAGOV data in terms of what we might see in the future, but I think we still need to wait for the large outcomes trials. A lot of enthusiasm is being garnered there.
The PIONEER-AF study—in terms of what I face on a daily basis as a clinician, that is where a lot of thought and discussion will be going into whether it is too soon to start making some of those changes.
Dr Fuster: My choice is to combine everything you said because it was a great discussion, frankly. It was very nice. This is the most fruitful meeting that I recall over the past 10 years. You all chose different trials.'
I enjoyed very much this discussion. Thank you very much to the audience. I hope you enjoyed it too.
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Any views expressed above are the author's own and do not necessarily reflect the views of WebMD or Medscape.
Cite this: The Cardiology Show From AHA 2016 With Dr Valentin Fuster - Medscape - Nov 16, 2016.
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