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April 1, 2014
Recorded March 31, 2014

CoreValve, SYMPLICITY HTN-3, MADIT-CRT, STAMPEDE, and LAPLACE-2 are among the trials that piqued Dr Valentin Fuster's interest, but it will take more than surrogate end points and short-term data to determine the true winners. Recorded at ACC 2014 with panelists Drs Roger Blumenthal, Franz Messerli, Timothy Gardner, Mary "Minnow" Walsh, and Karol Watson

Valentin Fuster MD, PhD
Professor, Division of Cardiology,
Icahn School of Medicine, Mount Sinai Health System;
Director, Mount Sinai Heart;
Physician-in-Chief, Mount Sinai Hospital,
New York, New York

Valentin Fuster, MD, PhD, has disclosed no relevant financial relationships.

Roger S Blumenthal, MD
Kenneth Jay Pollin Professor of Cardiology,
Professor of Medicine and Epidemiology;
Director, Johns Hopkins Ciccarone Center for the Prevention of Heart Disease,
Johns Hopkins Hospital,
Baltimore, Maryland

Roger S Blumenthal, MD, has disclosed no relevant financial relationships.

Timothy J Gardner, MD
Professor of Surgery, Jefferson Medical College,
Thomas Jefferson University;
Adjunct Professor of Surgery, Perelman School of Medicine,
University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania;
Medical Director, Center for Heart and Vascular Health;
Executive Director, Value Institute,
Christiana Care Health System,
Newark, Delaware

Timothy J Gardner, MD, has disclosed the following relevant financial relationships:
Served as chair of steering committee for Mount Sinai School of Medicine with the Network for Cardiothoracic Surgical Investigations (National Heart, Lung, and Blood Institute)

Franz H Messerli, MD
Professor of Clinical Medicine,
Mount Sinai Health Medical Center,
Icahn School of Medicine at Mount Sinai;
Director, Hypertension Clinic,
Mount Sinai Roosevelt Hospital,
New York, New York

Franz H Messerli, MD, has disclosed the following relevant financial relationships:
Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for Daiichi Sankyo, Pfizer, Takeda Pharmaceuticals North America, Abbott Laboratories, Servier, Medtronic, Ipca Laboratories

Mary Norine Walsh, MD
Medical Director, Heart Failure and Cardiac Transplantation,
St Vincent Heart Center of Indiana,
Indianapolis, Indiana

Mary Norine Walsh, MD, has disclosed the following relevant financial relationships:
Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for United HealthCare Services, Eli Lilly, and Novartis Pharmaceuticals

Karol E Watson MD, PhD
Professor of Medicine, Department of Cardiology,
David Geffen School of Medicine;
Co-Director, University of California Los Angeles (UCLA)
Program in Preventive Cardiology,
UCLA Medical Center,
Los Angeles, California

Karol E Watson, MD, PhD, has disclosed the following relevant financial relationship:
Received income in an amount equal to or greater than $250 from Merck.


An Esteemed Panel of Cardiologists

Valentin Fuster, MD, PhD: This is Valentin Fuster from New York. We are in Washington, DC, at the 2014 Scientific Sessions of the American College of Cardiology (ACC). It is an honor to discuss the most important trials, in our view, that were presented at the meeting with colleagues of such high stature in their own specialties. On my left is Dr Minnow Walsh, medical director, heart failure and cardiac transplantation, at St Vincent's Heart Center of Indiana. Next is Roger Blumenthal, very well-known to the Cardiology Show, the Kenneth J Pollin Professor of Cardiology, professor of medicine and epidemiology, and director of the Johns Hopkins Ciccarone Center for the Prevention of Heart Disease. Dr Timothy Gardner (we always need a surgeon) is professor of surgery at Thomas Jefferson University and adjunct professor of surgery at the University of Pennsylvania School of Medicine. He is also medical director at the Center for Heart and Vascular Health, and executive director of the Valve Institute, Christiana Care Health System. On my right is Dr Karol Watson, professor of medicine, David Geffen School of Medicine, and codirector of the University of California at Los Angeles program in preventive cardiology. Finally, also on my right is Dr Franz Messerli; very well-known in the field of hypertension; he is director of the hypertension program at the health system of Mt Sinai and St Luke's.

We are going to have a good session today. We are going to be discussing five important aspects in the cardiovascular field; valvular heart disease, hypertension, heart failure, obesity, and cholesterol. We are not missing anything. It will be a pleasure to have this discussion with the five of you. We will begin with valvular heart disease.

CoreValve: Self-Expanding TAVR vs SAVR in High-Risk AS

The study[1] we are going to first discuss involves transcatheter aortic-valve replacement with a self-expanding prosthesis [CoreValve (Medtronic)]. This study was conducted in 45 clinical sites in the United States. It was presented by Dr David Adams from Mt Sinai in New York, and his coinvestigator is Dr Jeffrey Popma [Beth Israel Deaconess Medical Center, Boston, MA].

A little bit of background will help us understand this study. Aortic valvular stenosis in the elderly is becoming more frequent. Often, we don't know what to do. With more recent trials of percutaneous valve replacement, more patients have been accepted for surgery. The number of patients receiving intervention is increasing.

In the last three years we were able to review the PARTNER A trial[2], a trial that took place in the United States with balloon-expandable transcatheter aortic-valve replacement (TAVR). In fact, at one year of follow-up, the results were very attractive. The rates of mortality and symptomatology were not different from those in patients undergoing surgical aortic-valve replacement, and these were patients were at high risk.

The question is, what is next? Today, we are going to be discussing a different type of valve—a self-expandable device, which has also been used in patients with severe aortic stenosis. These patients were at significantly high risk, as in the PARTNER A study, and the results were just presented by Dr Adams. In fact, the risk assessment included the Society of Thoracic Surgeons Predicted Risk of Mortality (STS PROM) estimate, and other key risk factors were taken into account. Eligible patients were randomly assigned in a 1:1 ratio to TAVR with a self-expanding transcatheter valve or to surgical aortic-valve replacement. The total number of patients in the study was 795. The primary end point was the rate of death from any cause at one year and evaluated with the use of both noninferiority and superiority testing.

Now I am going to present the results, and some were surprising, at least to some of us. The rate of death from any cause at one year was significantly lower in the TAVR group than in the surgery group. The difference was close to 5% (14.2% vs 19.1%), with an absolute reduction of risk of 4.9%. The results were very significant for noninferiority but were also significant for superiority. We have to add that TAVR was noninferior with respect to echocardiographic indexes, valve stenosis, gradient, and functional status using patient quality of life. Some interesting analysis is evolving at the present time to suggest a reduction in the rate of measured cardiovascular and cerebrovascular events and no increase in the rate of stroke. These results are quite encouraging in terms of a population that is increasing—elderly people with significant aortic stenosis. Tim, as a surgeon, what do you think about this study? What is your first reaction to it?

Timothy J Gardner, MD: It's a very interesting study that demonstrates the effectiveness and safety of transcatheter valve replacement. It is another clear indication that this is a new technology that is here to stay and it should be applied to appropriate patients.

Dr Fuster: There are some differences between this study and the PARTNER A trial, particularly the difference in cerebrovascular events, which were significantly higher in the PARTNER A study (with TAVR) compared with the surgery group. Here, we see fewer such events with TAVR, so what do you think happened? Was this related to the risk of the patients, or was a more modern methodology used? What do you think was the reason for that difference?

Roger S Blumenthal, MD: In each of our academic centers, there has been a great partnership between the surgeons and the interventional cardiologists and a lot of the success of TAVR at our institution has been from the cardiac surgeons helping with many of the procedures, such as Dr John Conte at Hopkins. The key question, however, is what is the durability of TAVR? When people have their valves replaced and when we put in something like a St Jude valve, it's pretty much indestructible. We are still concerned about whether this (percutaneous device) will continue to function well for three years or five years. On the other hand, our patients certainly would prefer the percutaneous approach whenever they could and avoid that long hospital stay.

Dr Fuster: Minnow, when you look at the curves that were presented and actually published this week in the New England Journal of Medicine[1], the separation is very early, and then they go in parallel, which suggests that maybe the risk was lower in this population (I will ask Tim later), or maybe the instrumentation, the catheter that they used was much thicker—it was a 22-French in PARTNER, but in the CoreValve study it was 18-French. Does something happen early here that makes a difference?

Mary Norine Walsh, MD: You bring up the fact that the morbidity may have been less because of the instrumentation, but the other thing is that this was a more moderate-risk group of patients than had been treated before. They are still high risk, but that may be why the curves remain parallel later on.

Dr Fuster: Certainly, the hazard is very early. There was a significant discussion about the statistics, and I will tell you what the discussion was about. Some patients were lost in the follow-up and were not included in the final analysis. Obviously, the presenters were not the statisticians, but this was reviewed by a tremendous group of people, the US Food and Drug Administration, the New England Journal of Medicine, and so forth. Do you think that the exclusion of patients in a trial like this could have a significant implication?

Dr Karol E Watson: Absolutely, it can. When you don't have complete follow-up you are probably going to underestimate your events. You don't know what happened to the patients who are lost to follow-up. If you impute that they are survivors or that they aren't survivors, you will have altered the number of events and that is going to affect your statistics. It's hard to know. In that type of a clinical trial, follow-up should be pretty complete. You can get pretty robust data with very close follow-up. It isn't clear exactly what happened, but I'm sure that it somehow affected the results.

Dr Fuster: There were about five statisticians involved after the trial, so I have some trust in them.

Dr Walsh: But, I think 36 patients in the group who were randomized to surgery withdrew before the procedure, compared with none in the transcatheter group. What happened to those patients?

Franz H Messerli, MD: It doesn't take much—one or two patients—who die and have not been reported. The statistics were razor thin, so I'm not sure why so many patients were lost and we don't know exactly what happened.

CHOICE: Sapien vs CoreValve

Dr Gardner: In particular the superiority end point was "thin ice" statistically. The noninferiority was pretty solid, but the missing patients, the patients who did not go through with the surgery, and then the missing follow-up are issues here, and these will all be adjudicated. The comparisons between the CoreValve and the Edwards Sapien valve and the PARTNER trial will be worked through, but the main point of the trial is that we now have another option in terms of transcatheter valve insertion. The CoreValve is somewhat different, a smaller-delivery catheter with a higher incidence of requirement for pacemaker, but it is a solid option.

Dr Fuster: You are all saying the same thing in one way or another, that it's nice that we have this option today, but comparing different times, different methodologies, and so forth, perhaps we are not ready to do that. Another study that was presented at this meeting is the CHOICE study[3] from Germany with close to 300 patients, in which they looked at the comparison between both valves. They determined that the balloon-expandable valve was a little better than the other. Tim, are you familiar with this study?

Dr Gardner: I am, and the difference was the incidence of perivalvular leak, which was significantly higher with the self-expanding valve (the CoreValve), and there was also a marked discrepancy in the need for pacemaker placement. Those were the differences. There was no survival difference.

Dr Fuster: In the other study that we are discussing today, the degree of aortic regurgitation was significantly lower than in the PARTNER study.

Dr Gardner: In the German study they assessed perivalvular leak using both angiography and echo, and that may be a little more precise.

Dr Walsh: In the CHOICE study there was a significant difference in baseline characteristics, in that there were more women in one group, but that was the only difference. I don't know whether that plays a role in this disease or not.

Dr Messerli: You wouldn't think so, but I'm not surprised that you picked that up.

Dr Fuster: It seems that we can conclude that there is a lot of hope for this new approach, but I am a little cautious because people are beginning to talk about lower-risk populations and so forth. MRI is a particular interest of ours, and we look at the brain of many kinds of populations, and these lacunar lesions that appear in the brain after this procedure are worrisome. We don't know what that means, but certainly if we go into younger populations, we should be careful. What do you think, Karol?

Dr Watson: You are absolutely right, and others on this panel have said the same thing. We understand that there may be a short-term benefit, but we want to know what is going to happen in the long term, because the goal is not just to live longer, but also to live well. If we are giving up some long-term functionality, is that really what we want?

Dr Messerli: It is reassuring that the stroke risk is significantly lower in this study than it was in the PARTNER study, so that seems to be progress.

SYMPLICITY HTN-3: Renal Denervation vs Sham

Dr Fuster: We are now going to move to hypertension, so I hope your blood pressure is well-controlled. A very surprising study—the SYMPLICITY HTN-3 study[4]—was presented by Dr Deepak Bhatt from the Brigham and Women's Hospital in Boston. This study involved 88 sites in the United States. I have to make a comment about the background of these studies, because they have to be interpreted according to what we knew before the results were presented.

It appears that in the United States and probably across the world, resistant hypertension is quite common. Perhaps 10% of patients who have hypertension are resistant. They need three drugs and their blood pressures are still high (some define it as >140 mm Hg, and others define it as >160 mm Hg), but it is very common and associated with complications.

An interesting concept that goes back many years is the sympathetic cross talk between the kidneys and the brain. If you can control that, maybe blood pressure would drop. Over the last few years, several nonblinded studies (not properly randomized) all appeared to show (at least those that were published) that renal sympathectomy has a significant effect in reducing blood pressure in people with significant hypertension. I had 10 to 12 patients with very significant high blood pressure in whom the procedure was done, and I was very impressed by the results.

I will give a very brief description of the study that was presented. This is a prospective, single-blind, randomized, sham-controlled trial (and this was the uniqueness of this study) in 535 patients with severe resistant hypertension. They were randomly assigned in a 2:1 ratio to undergo renal denervation or the sham procedure. Before randomization, the patients were receiving a stable antihypertensive regimen involving maximum tolerated doses of at least three drugs including a diuretic. The primary efficacy end point was the change in office systolic blood pressure at six months, and a secondary efficacy end point was the change in mean 24-hour ambulatory systolic blood pressure. The primary safety end point was a composite of death and end-stage renal failure.

The results in these 535 patients were interesting. The mean reduction in systolic blood pressure at six months was 14 mm Hg in the denervation group and 11.7 mm Hg in the sham-procedure group. This was certainly a minimal reduction, with no significant difference between groups. The reduction in 24-hour ambulatory systolic blood pressure was 6.7 mm Hg in the denervation group, and 4.7 mm Hg in the sham-procedure group, and there were no significant differences in safety between the groups.

Franz, you are an expert in the field. Are you surprised? You wrote a good editorial[5], but tell us your gut feeling.

Dr Messerli: The two-year follow-up of the SYMPLICITY HTN-2 trial was just reported in the Lancet[6] a few weeks ago [Editor's Note: The three-year results of SYMPLICITY HTN-1 were published in the Lancet in February]. There was a fall in office blood pressure of 32/20 mm Hg, which is very impressive. Now here we are, and we see a reduction that was very similar for the first six months, about 10 mm Hg to 14 mm Hg, but with the sham control group, we see the same reduction. That is surprising, there is no question about it. This is the first sham-controlled trial. We didn't have a sham group before, and we stand to be corrected.

Dr Fuster: Do you know why this happened? You told us you are surprised, but do you have your own feeling?

Dr Messerli: There is a consideration there. Safety was absolutely superb, no question. Efficacy was not so good. There was no reduction in heart rate, whereas in all of the other studies, there was a slight reduction in heart rate—a beat or two. To my way of thinking, this could indicate that proper renal denervation—the real end point—was not achieved. That is a possibility to be considered. It is a very difficult study to recruit, and per site, about two procedures were done, so that is not a lot of experience. The real question is: Was renal denervation achieved in this trial?

Dr Fuster: Do you mean was it effective?

Dr Messerli: Was the renal denervation effective?

Dr Fuster: It was not measured.

Dr Messerli: Right, it was not measured by any standards.

Dr Fuster: This is one issue. The other issue—Roger, perhaps you can comment on this, is that in randomized trials everything is controlled, but the people in the street are different. Blood pressure is so labile. Our minds are labile, our emotions are labile, so once you start taking a very strict approach to something that is so labile, doesn't it raise some concerns?

Dr Blumenthal: It does. In this trial, a patient didn't know whether they had the procedure, but they also had very good follow-up, so the patient had to take their medicines. You wonder about many of these patients who have so-called resistant hypertension, who may not be taking their medicines all the time (even when they say that they do—we see that in practice quite a bit). I agree with Franz that when you have centers that are only doing an average of two procedures, you may not have the best operators doing this procedure. The technology will go forward, but it's going to be up to the true believers to design studies to show that perhaps the more experienced operators are getting better results.

Dr Fuster: Minnow, what is your take?

Dr Walsh: Unlike other hypertension trials, in which half of the patients are women, there were many more men (60%) in this trial. We see that a lot in trials when a device is used, that there are fewer women. So I was struck by the fact that although this is a hypertensive population (and in most hypertension trials we see about half and half) there were more men. I don't know whether women have any differences in denervation, but I wanted to bring that up.

Dr Fuster: Karol?

Dr Watson: You can look at this in one of two ways. You can either say that renal denervation was shockingly ineffective or that sham control was shockingly effective. This study was very well-designed, and I congratulate them on that. The management and follow-up of all patients was quite good. These were so-called resistant patients who were still on three drugs, but their blood pressures fell in the sham group by a respectable amount. I agree with everything that has been said, but it also goes to show that good attention to medications and blood-pressure control is very effective as well.

Dr Fuster: Tim, what do you think as a surgeon?

Dr Gardner: The biggest drawback to this study is that we do not know whether they achieved effective denervation. They think they did, but they may not have, and when a technique has not been done extensively and is done only a few times in each center, it is possible that the actual denervation mechanism did not work.

Global SYMPLICITY Registry

Dr Fuster: Another study was presented here—the Global SYMPLICITY study[7] involving 5000 people across the globe. The first 1000 were analyzed, and the results were quite significant. What do you have to say?

Dr Messerli: That is true. It is a registry, and as such, has drawbacks, because it's not blinded in any way. This is a registry from all of the countries where this procedure is approved—Korea, South Africa, Germany, Mexico, Canada, etc. It is a total of 5000 patients, and there was a significant reduction in blood pressure in all of these patients. When you look at those who had systolic blood pressures above 160 mm Hg, it is rather impressive. When you look at those whose blood pressures were 140 mm Hg or even lower, it's much less impressive. In fact, if baseline blood pressure was below 140 mm Hg, then there was an increase in blood pressure with the renal denervation. These patients all had to fulfill the criteria of having resistant hypertension, and then the blood pressure didn't matter that much, they were simply denervated. It is a registry; it looks impressive, but it's nowhere near comparable to a sham controlled trial.

Dr Fuster: I got a phone call on Friday from a patient with resistant hypertension. He called me and said my blood pressure today is 190 mm Hg. He checks his blood pressure constantly. What can I do? What is the answer?

Dr Messerli: The question is, what drugs is the patient taking? I'm practicing in Manhattan, and I'm scavenging quite a lot of severely hypertensive patients. It's rare that I cannot control their blood pressure.

Dr Fuster: So I will send the patient to you?

Dr Messerli: I would be happy to see the patient, yes.

Dr Fuster: Okay, that's the answer. But we are going to face the situation, we all see these patients, and the question is what to do. What do you do when you don't have options?

Dr Messerli: Renal denervation is a reasonable option, provided that it works, but now there is some doubt about whether it actually works on the basis of this trial. Having said that, however, Medtronic is committed to continuing to explore the issue. They will reboot, but they are committed to continuing. That is a positive aspect. They must feel that there is something to be gained from this procedure.

Dr Walsh: Patients are very interested in this therapy because they view it as the possibility of not having to take as many medicines. A chronic request is "what medicine can I stop taking?"

Dr Watson: I would point out that in all of the trials, all patients in the placebo group and the renal-denervation group are still are on three or more medicines, so they are not taking fewer medications. They may be on lower doses, but they are not taking fewer medications.

Dr Fuster: We can conclude by saying that these results were surprising, but we all have doubts. There is something there that we would like to understand in the future, and I'm very happy to hear that Medtronic is going to continue to pursue this study. Let's move into cardiac failure.


Dr Fuster: This is an interesting study, which also shows how important it is to have long-term follow-up on any trial. This is about survival with cardiac resynchronization therapy (CRT) in mild heart failure[8]. A regional study[9] was conducted by Dr Art Moss [University of Rochester, NY] in 2009, and this follow-up to that study was conducted by Dr Ilan Goldenberg [Sheba Medical Center and Tel Aviv University, Israel]. I am going to give a little background to how this evolved.

This is the MADIT CRT study using CRT with a defibrillator in patients with symptomatic or mildly symptomatic heart failure. In one group, CRT was performed, and in the other group, just the defibrillator was used. The study showed, when presented in 2009 (I think it was a one-year follow-up [median follow-up was 2.4 years]) that CRT was significantly better in terms of reduction in the risk for nonfatal heart-failure events or death. There was one issue, however. Mortality alone didn't reach statistical significance, but at least there was a reduction in hospitalization. They had the opportunity to follow these patients for over 2 more years. The question that they tried to answer was whether in patients who had mild cardiac failure in terms of symptomatology, but ejection fractions <30%, a defibrillator alone or defibrillator with synchronization makes a difference in mortality.

They evaluated the effect of CRT on long-term survival in the MADIT-CRT population. Posttrial follow-up over a median of 5.6 years was assessed among 1691 surviving patients. This was phase I. Subsequently, the trial stopped, and then they followed these extra 854 patients for a total of seven years of follow-up. The cumulative rate of death from any cause among patients with left bundle branch block (which was a characteristic of the group of patients who had success) was 18% in the group with CRT compared with 29% in those assigned to defibrillator therapy alone—a significant difference. Of interest, there was no difference when they looked at sex, cause of cardiomyopathy, or QRS duration, but I want to emphasize that only patients with left bundle branch block had significant results. The conclusion is that this study indicates that in patients with mild heart failure symptoms (left ventricular dysfunction, ejection fractions <30%) and left bundle branch block, early intervention with CRT is associated with significant long-term results. Minnow, are you surprised by this?

Dr Walsh: I am not surprised but very reassured and happy that the survival benefit follows the data that we already had on outcomes, which included patient symptoms. This is huge. With this trial, we have honed down who benefits. We know that patients with class 2 symptoms and higher, with a left bundle branch block, would benefit. This adds to the discussion that we have with patients that not only will you feel better, but we now have evidence that you will live longer.

Dr Fuster: Why left bundle branch block? What is the mechanism—how does the device work?

Dr Walsh: I am not sure that we know the mechanism, although we know that if the right ventricle alone is paced, we have long-term deleterious effects, and we also know that if the left ventricle alone is paced, we can see results similar to those with CRT. Long term, left bundle branch block or an induced left bundle branch block with right ventricular pacing is very deleterious as far as left ventricular remodeling. Honing down on which morphology benefits has been very important in this therapy. We used to think that everybody with long QRS would benefit, and we are better able to offer this to the select patient group.

Dr Fuster: Roger, how do you react to this study?

Dr Blumenthal: We may need to change the guidelines because before this, the guidelines said that if you had a large QRS with right bundle branch morphology, you would be eligible. This study strongly suggests that those people don't benefit. It is validation of Art Moss's fabulous work, and he is to be congratulated for starting so many of us in this field. It is a big step forward.

Dr Fuster: Karol?

Dr Watson: I absolutely agree, and the nice thing is that when you wait until someone is at end stage or late stage, you are never going to achieve such good outcomes as you will if you can catch them earlier. The fact that we have moved the bar earlier and can offer this potentially life-enhancing and life-prolonging therapy is huge.

Dr Fuster: Many patients who have hypertension have this problem.

Dr Messerli: It shouldn't make a difference here, but the interesting part is that QRS prolongation is no longer an indication. It is restricted to left bundle branch block. The guidelines need to be changed, as Roger said.

Dr Walsh: Vigilance is also needed for the asymptomatic patient, even with a normal ventricle, with a left bundle branch block.

Dr Watson: I agree.

Dr Walsh: That is another message, which is that a left bundle branch block is something to watch and to follow to make certain that the patient develops neither symptoms nor echocardiogram findings.

Dr Watson: We have always known that there is something cardiac going on if you have a left bundle branch block, but we haven't always thought that this was a predecessor to mortality (and other bad outcomes). We can now look at it and perhaps intervene. This could be a big game changer.

Dr Fuster: The early stages, that's what they are saying, although early stages here has to do with symptomatology, but not with ejection fraction. These patients had ejection fractions of less than 30%.

Dr Walsh: That is the next study.

Dr Fuster: We have to be sure what we are talking about.

Dr Watson: I am going to go out on a limb. I am going to make a prediction that it is probably going to hold in even earlier stages and people who don't necessarily have all the features of heart failure but have early features that you can detect with MR, for example. That left bundle branch block is going to lead to deleterious effects of left ventricular remodeling.

Dr Fuster: It is interesting. Can I ask you about the next study that you would like to see?

Dr Walsh: I would like to see the next study follow people who don't have the degree of left ventricular dysfunction that they had in this study and are maybe asymptomatic.

Dr Fuster: Has such a study been designed?

Dr Walsh: No, but we could do it. You're on.

Dr Fuster: What do you have to say to all of these cardiologists?

Dr Gardner: It is very important to have identified left bundle branch block as the substrate for benefit. There has been some confusion in the electrophysiology world about what to use and when. Obviously we have had a lot of pushback from the Centers for Medicare and Medicaid Services [CMS]. The guidelines need to be updated and promulgated. That is another important lesson from this.

Dr Fuster: The guidelines recommend it for significant symptomatic patients, is that correct?

Dr Watson: It was class 3 symptoms. We were somewhat befuddled, because this therapy would be implanted in people who had only prolonged QRS. Some people did phenomenally well—they were finally asymptomatic and doing great, and others had zero benefit and we couldn't tease it out. This really helps us.

Dr Walsh: This helps a lot with patient selection. In the past, in a patient with class 2 or class 3 symptoms and right bundle branch block, it was an indicated procedure and we had this discussion, but now we are better able to select the patient and be more definitive on how we think that patient will do.

Dr Fuster: It is interesting how the field has advanced in the last four or five years with defibrillators, the MADIT CRT trial, and synchronization. It is fascinating. It seems that we are doing something good. I am not sure about prevention, which will come in a moment. Certainly in treatment, things are exciting and interesting.

STAMPEDE: Bariatric Surgery vs Medical Therapy for Diabetes

This leads to the next article that we would like to discuss, which was just published in the New England Journal of Medicine[10]. It is a completely different subject—obesity in diabetes. It is very fascinating. It has a similar approach as the previous discussion. This study was presented by the group at the Cleveland Clinic with one-year follow-up study of bariatric surgery in patients with diabetes. Now we have the three-year follow-up to see what happened with these patients.

In the original report, the study is called STAMPEDE. It is a little complicated, but at one year after randomization, they found that gastric bypass or gastrectomy was superior to intensive medical therapy alone in achieving glycemic control and reducing cardiovascular risk factors. This was a year ago. Here we have the three-year follow up, which I am going to describe.

There were 150 obese patients with uncontrolled type 2 diabetes who originally received intensive medical therapy alone or intensive medical therapy plus gastric bypass or gastrectomy. The primary end point was a hemoglobin A1c level of 6% or less; this was the key. The mean age of the patients was 48 years, and 68% were women.

The hemoglobin A1c level was actually very high (9.3% on average), and the mean baseline body mass index was 36 kg/m2, so these were very obese people with very high hemoglobin A1c levels but let's see the results. At three years, the criteria for the primary end point, a hemoglobin A1c of 6% or less was met by 5% of the patients in the medical-therapy group compared with 38% of those in the gastric-bypass group, and 24% of those in the gastrectomy group; which was very significant. Many other things in this study are interesting. The use of glucose-lowering medications (including insulin) was lower, as was the use of hypertensive medications and lipid-lowering medications. Other things happened, which are quite important. The percentage weight reduction from baseline was 24% in the gastric-bypass group, 21% in the gastrectomy group, and 4.2% in the medical-therapy group. A drop in triglycerides as expected, and albuminuria also declined. Measures of physical and mental status were also improved. So it was a miracle—you solve all the problems. Maybe everyone should have that procedure. Roger, how did you react to this study?

Dr Blumenthal: It shows longer-term benefits in glycemic control, blood pressure, and lipids. All of us around this table have tried very hard to get our patients to lose weight, but only a minority of patients have sustained that improvement long term. It is a difficult decision when patients elect to go through bariatric surgery. They undergo elaborate physical and psychological screening, and they are told about all of the potential side effects and problems with surgery, but if they get through it, they can achieve much better metabolic control. With longer term follow-up and with more patients, hopefully we will be able to show that these improvements in glycemic control, blood pressure, and lipids translate into fewer revascularizations, heart attacks, strokes, and a lower death rate.

Dr Fuster: This is the challenge, a long follow-up. The only question is the number of patients, which is relatively small, so I'm not sure of the power of the study. Franz, how do you react to this presentation?

Dr Messerli: It is interesting. When you look at the previous study done by Schauer, also published in the New England Journal of Medicine[10], there is absolutely no question that after a year or two, blood pressure and blood sugar decline. After 10 years, blood sugar remains at bay, but then blood pressure creeps up ever so slowly, and at 10 years, it's almost back to baseline. This follow-up here of two to three years is not sufficient for blood pressure. I would anticipate that we will see an increase in blood pressure with time.

Dr Fuster: Karol?

Dr Watson: It's a very intriguing study. It is a single-center study, with a small number of patients and a modest follow-up. I would like to see a multicenter study with more patients and longer follow-up, but these are very impressive intermediate-term results in terms of cardiometabolic risk factors. I want to see the long-term follow-up. I predict that if all cardiometabolic risk factors are improving, we will have better outcomes as well. We would like to see that, but right now, this is looking fairly good. I don't want us to forget that lifestyle, diet, and exercise are the foundation of everything, so I don't want everybody running to the surgeon. I want to continue healthy lifestyles as well.

Dr Fuster: Tim, when I review all of the studies on obesity and this surgical intervention, I was struck by the complications of the intervention itself. The only thing is to give a word of caution. This is not like any intervention where everything is fine after. Many people have side effects and hypoglycemia. What is your feeling about it as a surgeon?

Dr Gardner: Gastric bypass is a more disruptive procedure. The gastrectomy/gastric banding is more appealing because it's less physiologically disruptive. In this report, there seems to be more effectiveness in the gastric-bypass patients, so that is another cautionary point. I am more inclined to recommend a band gastrectomy than the bypass.

Dr Fuster: Franz?

Dr Messerli: Karol made an excellent point. These are all surrogate end points, that look very nice, but we need real end points—heart attacks, stroke, and death. Then we can talk.

Dr Fuster: There are registries, but people look at registries positively and negatively. It will be very difficult to do a randomized study right with a large population. Roger, what do you think about looking at long follow-up in terms of events?

Dr Blumenthal: That is what we need for CMS and other groups to commit the resources for payment, but you are right, it's a challenging study to do and having had a lot of patients who have considered bariatric surgery, many change their minds after they hear about the potential downsides of the surgery.

LAPLACE-2 and GAUSS-2: Evolocumab PCSK9 Inhibitor

Dr Fuster: It's a nice study, with a small number of patients, but the results are quite attractive. Let's discuss the final study, on which I would like your views, the LAPLACE-2 trial[12]; a phase 3, double-blind, randomized, placebo-controlled, multicenter study to evaluate the safety, tolerability, and efficacy of evolocumab. This is the [proprotein convertase subtilisin-kexin type 9] PCSK9 monoclonal-antibody inhibitor that increases the ability of the liver to clear low-density-lipoprotein [LDL] cholesterol. There is a lot of enthusiasm about this possibility. This study was conducted in patients with primary hypercholesterolemia and mixed lipidemia.

Roger, would you start by talking about the controversy related to the guidelines to see where we are and where we should go? I know you like this subject. The 2013 ACC/American Heart Association cholesterol guidelines recommend a high-intensity statin for high-risk patients, and otherwise, a moderate-intensity statin is recommended. This is a view in this part of the world. Outside of the United States, the guidelines recommend an LDL-cholesterol level of <100 mg/dL or <70 mg/dL, depending on the level of risk. One looks at the cholesterol level, and the other looks at risk.

Let's go into the background of the study. It is correct that many patients who receive a statin, whether low- or high-dose, do not reach the levels of LDL-C that we want regardless of what kind of guidelines you follow. This drug, which is a human monoclonal antibody, is now being tested in a number of scenarios. We already have background data from the phase 2 trials, which showed significantly reduced LDL cholesterol, and the drug was very well tolerated. The design of this study is actually short; it is a 12-week study to evaluate the efficacy and safety of the drug administered biweekly, 140 mg subcutaneously, or monthly in combination with a statin.

This study has a complex design. Three groups of patients with hypercholesterolemia were studied. One group took any kind of statin with placebo, a second group took atorvastatin and ezetimibe [(Zetia, Merck/Schering-Plough], and the third group took any statin like the first group, but instead of a placebo, the statin was combined with evolocumab [Amgen, Thousand Oaks, CA], which is the drug that we are talking about. The problem that I have is that when you look at the different statins and different dosages (high-dose or low-dose), it is confusing. The evolocumab 140 mg biweekly or 120 mg monthly were equivalent clinically. The LDL-cholesterol level was achieved at less than 70 mg/dL in most of the patients on the drug: 86% and 94% in the statin group, and 93% and 95% in the high-intensity group. The combination with atorvastatin was very significant; it was less significant with ezetimibe. Another study is the GAUSS-2 study[13].

What I take from this particular presentation is that we have a drug that is at least hopeful. It is hopeful in patients who perhaps do not tolerate statins or the dose of a statin does not significantly lower the cholesterol level. This is a very interesting group. In familial hypercholesterolemia, this drug would be of interest. I would like to ask your opinion, Roger. We have had high hopes in the past with so many treatments for lowering LDL-C, and then somehow they fall later on (with the exception of statins). What do you think about this drug?

Dr Blumenthal: This is a very exciting class of medication. They had about seven studies using this medicine, which ranged from the short term (such as this) to 52-week follow-up. It looks as though the monoclonal antibody is a very clean compound. In individuals who had a lot of muscular side effects and who were statin-intolerant, when they were given this medication, there was only about a 10% incidence of muscle aches in the group who were prone to muscle aches. Our guidelines say to know your numbers and calculate your risk. In the United States, we don't necessarily have to reduce the LDL-cholesterol level to less than 70 mg/dL or a non-HDL cholesterol level of less than 100 mg/dL. Intuitively, though, most of us would like to. Our European colleagues and our Canadian colleagues still have a non-HDL target as a secondary target.

Karol and I were on the guidelines committee. Once we get the next study showing that an agent adds to a statin, the guideline committee will be happy to change the guidelines again with that new evidence. It is something that we are very excited about. Many people can't tolerate high-dose statins. Sometimes we do tricks, we give statin therapy twice a week or three times a week to get them on some therapy. This therapy could be a real game-changer, but we still have a long way to go.

Dr Fuster: Karol, what is your take?

Dr Watson: My take is very similar to Roger's. As a member of the guideline writing committee, I have to say that I agree. We need to treat risk, not just an arbitrary number, but the committee absolutely understands that many, if not most, clinicians will set their own bar for where they want the LDL-C level to be. We recommend intensive statin therapy for the highest-risk patients, but if you need additional LDL-C reduction after discussion with the patient, you could add on agents, and this could potentially be a very attractive one. I agree with you, though, we have seen many drugs that theoretically looked quite attractive—they raised HDL-C or lowered LDL-C, and yet when we do the randomized controlled clinical trial and try to see the benefit above statins, we haven't seen it. One of the reasons that I am more excited about this therapy than others is that it recapitulates the natural biologic processes that we all have that actually lower our LDL-C and hopefully lower risk. We have seen individuals who have inherently low PCSK9 levels and lifelong low LDL-C levels, and they have lifelong low cardiovascular risk. That makes me very hopeful that this therapy may well show benefit, but I'm not willing to commit, and neither are the guidelines at this time.

Dr Fuster: I was excited about Lp(a). It is beginning to be a molecule that we have to pay attention to. So far nothing works, we talk about niacin, we talk about many things, but the reality is how frustrating it is to reduce a cholesterol level of 300 mg/dL to a reasonable level.

Dr Watson: We think that it is a big risk factor.

Dr Fuster: Franz?

Dr Messerli: I have a question to Roger. You said that many patients do not tolerate statins, but there was a study in the Annals of Internal Medicine[14] recently in which patients were serving as their own controls and put on placebo, and many things that were perceived as side effects turned out to be not the case.

Dr Blumenthal: That's a great point, Franz. Many of these statin-intolerant patients are referred to us, so we see many of them. It would be nice if we had placebos to give to patients.

Dr Watson: Most patients can tolerate some dose of some statin. The problem is that when we take medications, most patients are used to not feeling anything, and sometimes they will feel something from a statin. Whether it is intolerable is an individual decision.

Dr Fuster: As a clinician, whenever you have a paper and you look at who did or did not tolerate the statin, they always say muscle pains and elevated creatinine phosphokinase, and so forth. Many patients are affected by the drug in ways that are subtle, such as sleeping, sexual activity, and fatigue. This is the reality. So if this new drug works, it will do much good for the kind of intolerance that we are talking about. Minnow, what about you?

Dr Walsh: I agree. Some patients cannot take statins, whether or not it is their perception. The lowering of LDL-C levels in this study is very impressive—a new class of drug. It remains a surrogate end point, however. I would like to see what it does with respect to cardiovascular risk events.

Dr Fuster: Can I ask you, Roger, there is the GAUSS 2 study in Amsterdam, in which 300 patients didn't tolerate statins. They had similar results, but ezetimibe didn't lower the LDL cholesterol as much as the monoclonal antibody. Is that correct?

Dr Blumenthal: Correct. In the studies with ezetimibe, it was a 15% to 20% lowering of the LDL level. I would look at GAUSS-2 and LAPLACE-2 as showing that no matter whether it is a low-dose statin, high-dose statin, or ezetimibe, there is an additional 55% to 65% lowering of LDL cholesterol. Right now, most of us think about ezetimibe or colesevelam [Welchol, Daiichi Sankyo] as alternatives for people who are truly statin intolerant and then we might add niacin or fenofibrate, but one of the beauties of this medicine, it seems very consistent somewhere in lowering the LDL-C about 55% to 65% even when you are on another agent.

Dr Fuster: You don't have to take the drug every day. It is subcutaneous, once a month, perhaps.

Dr Blumenthal: The once-monthly dose was equivalent in efficacy to the biweekly dose. If you took this monoclonal antibody orally, unfortunately, it would be broken down in the stomach and the intestine.

Dr Gardner: It is a promising drug, especially for patients with primary familial hypercholesterolemia. So I hope it pans out.

The Panelists Make Their Picks

Dr Fuster: We have talked about all the trials we mentioned at the beginning covering valvular heart disease, aortic stenosis, hypertension, cardiac failure, obesity, cholesterol. Quite exciting. I am going to ask you a final question. Of everything we discussed today, which are you most impressed about or want to take home? Which would you say is going to change practice? Minnow?

Dr Walsh: For my practice, the MADIT-CRT results will have the biggest impact on my discussions with patients going forward.

Dr Fuster: Roger?

Dr Blumenthal: I would agree with that in terms of patient applicability. I am most excited about the evolocumab data, and hopefully that will be a strategy that will work, because so many of the cholesteryl ester transfer protein (CETP) inhibitors have not.

Dr Fuster: And obesity is a secondary end point in your discussion?

Dr Blumenthal: Correct. I think that study it will add ammunition to convincing more patients to at least seriously consider it.

Dr Fuster: Tim?

Dr Gardner: Obviously from my perspective, the CoreValve trial was an important additional reassurance about transcatheter valve options.

Dr Fuster: Karol?

Dr Watson: I am most interested in seeing the follow-up of the renal-denervation and the PCSK9 trials. I am hopeful that we can find some way to target them to get better outcomes for patients.

Dr Fuster: Franz?

Dr Messerli: No question, the renal-denervation issue has the potential to change my practice, but now we need to reboot, reassess, and take it from there. We will see.

Dr Fuster: Thank you very much. We spent a wonderful hour together. We are in agreement about most of the messages that came from the studies. Thank you all, and to the audience until the next session of the ACC in 2015. Thank you.

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    11. Schauer PR, Bhatt DL, Kirwan JP, et al. Bariatric surgery versus intensive medical therapy for diabetes: 3-year outcomes. N Engl J Med 2014. Article

    12. Robinson J, Nedergaard BS, Rogers W, et al. The low-density lipoprotein cholesterol assessment with PCSK9 monoclonal antibody inhibition combined with statin therapy-2 trial: a phase 3, double-blind, randomized, placebo and ezetimibe controlled, multicenter study to evaluate safety, tolerability, and efficacy of evolocumab (AMG 145) in combination with statin therapy in subjects with primary hypercholesterolemia and mixed dyslipidemia. American College of Cardiology 2014 Scientific Sessions; Washington, DC; March 29-31, 2014. Session 402-10.

    13. Stroes ES, Colquhoun D, Sullivan D, et al. A phase III double-blind randomized study to assess the safety and efficacy of evolocumab (AMG-145) in hypercholesterolemic subjects unable to tolerate an effective dose of statin. American College of Cardiology 2014 Scientific Sessions; Washington, DC; March 29-31, 2014. Session 402-16.

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